[Ibandronate in the treatment of postmenopausal osteoporosis].

PubMed

Lakatos, Péter

2008-10-01

Postmenopausal osteoporosis affects 7-10% of the population of developed countries. During the past decade, a number of new therapeutical modalities have been made available. Among these, bisphosphonates mean the mainstay of medical treatment. Ibandronate belongs to the amino-bisphosphonate group of these drugs. Amino-bisphosphonates act via the mevalonate metabolic pathway, thus, inhibiting protein prenylation. Several clinical studies have shown a significant reduction in the fracture risk of osteoporotic patients treated with ibandronate. This compound can be administered orally once a month or intravenously once in every 3 months. Longer dosing intervals stimulate patient compliance, and consequently increase efficacy and cost effectiveness.

Comparison of concurrent treatment with vitamin K2 and risedronate compared with treatment with risedronate alone in patients with osteoporosis: Japanese Osteoporosis Intervention Trial-03.

PubMed

Tanaka, Shiro; Miyazaki, Teruhiko; Uemura, Yukari; Miyakawa, Nobuaki; Gorai, Itsuo; Nakamura, Toshitaka; Fukunaga, Masao; Ohashi, Yasuo; Ohta, Hiroaki; Mori, Satoshi; Hagino, Hiroshi; Hosoi, Takayuki; Sugimoto, Toshitsugu; Itoi, Eiji; Orimo, Hajime; Shiraki, Masataka

2017-07-01

The aim of this study was to investigate the efficacy of concurrent treatment with vitamin K 2 and risedronate compared with treatment with risedronate alone in patients with osteoporosis and to explore subsets of patients for which concurrent treatment is particularly efficacious. Women with osteoporosis aged 65 years or older were recruited from 123 institutes in Japan and allocated to take either vitamin K 2 (45 mg/day) and risedronate (2.5 mg/day or 17.5 mg/week) or risedronate (2.5 mg/day or 17.5 mg/week) alone. The primary end point was the incidence of any fracture (vertebral and nonvertebral). The secondary end points were bone mineral density, height, undercarboxylated osteocalcin concentration, quality of life, and safety. Over a 2-year follow-up, vertebral or nonvertebral fractures occurred in 117 or 22 sites respectively among 931 patients in the risedronate and vitamin K 2 group and in 104 or 26 sites respectively among 943 patients in the risedronate alone group. The rates of any incident fracture were similar between the two groups (incidence rate ratio 1.074, 95 % confidence interval 0.811-1.422, p = 0.62), implying that the primary end point was not met. There were no differences in the degree of increase in bone mineral density between the two groups. Undercarboxylated osteocalcin concentration decreased from 5.81 ± 3.93 ng/mL to 2.59 ± 1.52 ng/mL at 6 months in the risedronate and vitamin K 2 group, whereas the change in the risedronate alone group was minimal (from 5.96 ± 4.36 ng/mL to 4.05 ± 3.40 ng/mL at 6 months) (p < 0.01). The treatment discontinuation rate was higher in the risedronate and vitamin K 2 group than in the risedronate alone group (10.0 % vs 6.7 %). No unknown adverse drug reactions were reported. In conclusion, concurrent treatment with vitamin K 2 and risedronate was not efficacious compared with monotherapy with risedronate in terms of fracture prevention.

Differences in In Vitro Disintegration Time among Canadian Brand and Generic Bisphosphonates

PubMed Central

Olszynski, Wojciech P.; Adachi, Jonathan D.; Davison, K. Shawn

2014-01-01

The objective of this study was to compare the disintegration times among Canadian-marketed brand (alendronate 70 mg, alendronate 70 mg plus vitamin D 5600 IU, and risedronate 35 mg) and generic (Novo-alendronate 70 mg and Apo-alendronate 70 mg) once-weekly dosed bisphosphonates. All disintegration tests were performed with a Vanderkamp Disintegration Tester. Disintegration was deemed to have occurred when no residue of the tablet, except fragments of insoluble coating or capsule shell, was visible. Eighteen to 20 samples were tested for each bisphosphonate group. The mean (±standard deviation) disintegration times were significantly (P < 0.05) faster for Apo-alendronate (26 ± 5.6 seconds) and Novo-alendronate (13 ± 1.1 seconds) as compared to brand alendronate (147 ± 50.5 seconds), brand alendronate plus vitamin D (378 ± 60.5 seconds), or brand risedronate (101 ± 20.6 seconds). The significantly faster disintegration of the generic tablets as compared to the brand bisphosphonates may have concerning safety and effectiveness implications for patients administering these therapies. PMID:25349772

Differences in In Vitro Disintegration Time among Canadian Brand and Generic Bisphosphonates.

PubMed

Olszynski, Wojciech P; Adachi, Jonathan D; Davison, K Shawn

2014-01-01

The objective of this study was to compare the disintegration times among Canadian-marketed brand (alendronate 70 mg, alendronate 70 mg plus vitamin D 5600 IU, and risedronate 35 mg) and generic (Novo-alendronate 70 mg and Apo-alendronate 70 mg) once-weekly dosed bisphosphonates. All disintegration tests were performed with a Vanderkamp Disintegration Tester. Disintegration was deemed to have occurred when no residue of the tablet, except fragments of insoluble coating or capsule shell, was visible. Eighteen to 20 samples were tested for each bisphosphonate group. The mean (±standard deviation) disintegration times were significantly (P < 0.05) faster for Apo-alendronate (26 ± 5.6 seconds) and Novo-alendronate (13 ± 1.1 seconds) as compared to brand alendronate (147 ± 50.5 seconds), brand alendronate plus vitamin D (378 ± 60.5 seconds), or brand risedronate (101 ± 20.6 seconds). The significantly faster disintegration of the generic tablets as compared to the brand bisphosphonates may have concerning safety and effectiveness implications for patients administering these therapies.

The effect of dosing regimen on the pharmacokinetics of risedronate

PubMed Central

Mitchell, David Y; Heise, Mark A; Pallone, Karen A; Clay, Marian E; Nesbitt, John D; Russell, Darrell A; Melson, Chad W

1999-01-01

Aims To examine the effect of timing of a risedronate dose relative to food intake on the rate and extent of risedronate absorption following single-dose, oral administration to healthy male and female volunteers. Methods A single-dose, randomized, parallel study design was conducted with volunteers assigned to four treatment groups (31 or 32 subjects per group, 127 subjects total). Each subject was orally administered 30 mg risedronate. Group 1 was fasted for 10 h prior to and 4 h after dosing (fasted group); Groups 2 and 3 were fasted for 10 h and were dosed 1 and 0.5 h, respectively, before a high-fat breakfast; and Group 4 was dosed 2 h after a standard dinner. Blood and urine samples were collected for 168 h after dosing. Pharmacokinetic parameters were estimated by simultaneous analysis of risedronate serum concentration and urinary excretion rate-time data. Results Extent of risedronate absorption (AUC and Ae) was comparable (P = 0.4) in subjects dosed 2 h after dinner and 0.5 h before breakfast; however, a significantly greater extent of absorption occurred when risedronate was given 1 or 4 h prior to a meal (1.4- to 2.3-fold greater). Administration 0.5, 1, or 4 h prior to a meal resulted in a significantly greater rate of absorption (Cmax 2.8-, 3.5-, and 4.1-fold greater, respectively) when compared with 2 h after dinner. Conclusions The comparable extent of risedronate absorption when administered either 0.5–1 h before breakfast or 2 h after an evening meal support previous clinical studies where risedronate was found to have similar effectiveness using these dosing regimens. This flexibility in the timing of risedronate administration may provide patients an alternative means to achieve the desired efficacy while maintaining their normal daily routine. PMID:10583024

Ibandronate promotes osteogenic differentiation of periodontal ligament stem cells by regulating the expression of microRNAs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Qiang; Zhao, Zhi-Ning; Cheng, Jing-Tao

2011-01-07

Research highlights: {yields} Ibandronate significantly promote the proliferation of PDLSC cells. {yields} Ibandronate enhanced the expression of ALP, COL-1, OPG, OCN, Runx2. {yields} The expression of a class of miRNAs, e.g., miR-18a, miR-133a, miR-141 and miR-19a, was significantly modified in PDLSC cells cultured with ibandronate. {yields} Ibandronate regulates the expression of diverse bone formation-related genes via miRNAs in PDLSCs. {yields} Ibandronate can suppress the activity of osteoclast while promoting the proliferation of osteoblast by regulating the expression of microRNAs. -- Abstract: Bisphosphonates (BPs) have a profound effect on bone resorption and are widely used to treat osteoclast-mediated bone diseases. Theymore » suppress bone resorption by inhibiting the activity of mature osteoclasts and/or the formation of new osteoclasts. Osteoblasts may be an alternative target for BPs. Periodontal ligament stem cells (PDLSCs) exhibit osteoblast-like features and are capable of differentiating into osteoblasts or cementoblasts. This study aimed to determine the effects of ibandronate, a nitrogen-containing BP, on the proliferation and the differentiation of PDLSCs and to identify the microRNAs (miRNAs) that mediate these effects. The PDLSCs were treated with ibandronate, and cell proliferation was measured using the MTT (3-dimethylthiazol-2,5-diphenyltetrazolium bromide) assay. The expression of genes and miRNAs involved in osteoblastic differentiation was assayed using quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR). Ibandronate promoted the proliferation of PDLSCs and enhanced the expression of alkaline phosphatase (ALP), type I collagen (COL-1), osteoprotegerin (OPG), osteocalcin (OCN), and Runx2. The expression of miRNAs, including miR-18a, miR-133a, miR-141 and miR-19a, was significantly altered in the PDLSCs cultured with ibandronate. In PDLSCs, ibandronate regulates the expression of diverse bone formation

Comparison of orally administered bisphosphonate drugs in reducing the risk of hip fracture in older adults: a population-based cohort study.

PubMed

Cadarette, Suzanne M; Lévesque, Linda; Mamdani, Muhammad; Perreault, Sylvie; Juurlink, David N; Paterson, J Michael; Carney, Greg; Gunraj, Nadia; Hawker, Gillian A; Tadrous, Mina; Wong, Lindsay; Dormuth, Colin R

2013-09-01

Orally administered bisphosphonate drugs (i.e., alendronate, etidronate, risedronate) can reduce the risk of vertebral fracture. However, only alendronate and risedronate have proven efficacy in reducing the risk of hip fracture. We sought to examine the comparative effectiveness of orally administered bisphosphonate drugs in reducing hip fractures among older adults. We identified new users of orally administered bisphosphonate drugs in British Columbia and Ontario between 2001 and 2008. We used province- and sex-specific propensity score-matching strategies to maximize comparability between exposure groups. We used Cox proportional hazards models to compare time-to-hip fracture within 1 year of treatment between exposures by sex in each province. Our secondary analyses considered hip fracture rates within 2 and 3 years' follow-up. We used alendronate as the reference for all comparisons and pooled provincial estimates using random effects variance-weighted meta-analysis. We identified 321 755 patients who were eligible for inclusion in the study. We found little difference in fracture rates between men (pooled hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.74-1.14) or women (pooled HR 1.15, 95% CI 0.73-1.56) taking risedronate and those taking alendronate. We similarly identified little difference in fracture rates between women taking etidronate and those taking alendronate (pooled HR 1.00, 95% CI 0.82-1.18). However, we identified lower rates of hip fracture among men taking etidronate relative to alendronate (pooled HR 0.77, 95% CI 0.60-0.94). Results extended to 2 and 3 years' follow-up were similar. However, with 3 years' follow-up, rates of hip fracture were lower among women in British Columbia who had taken alendronate. We identified little overall difference between alendronate and risedronate in reducing the risk of hip fracture in men or women. Our finding that etidronate is associated with lower fracture risk among men is likely due to

Interaction between Bisphosphonates and Mineral Water: Study of Oral Risedronate Absorption in Rats.

PubMed

Itoh, Akihisa; Akagi, Yuuki; Shimomura, Hitoshi; Aoyama, Takao

2016-01-01

Bisphosphonates are antiosteoporotic agents prescribed for patients with osteoporosis. Drug package inserts for bisphosphonate supplements indicate that their bioavailability is reduced by high levels of metal cations (Ca(2+), Mg(2+), etc.). However, standards for these cations in water used for taking risedronate have not been defined. Here, we examined the effect of calcium and magnesium in mineral waters on the bioavailability of the third-generation bisphosphonate, risedronate, following oral administration in rats. As risedronate is unchanged and eliminated renally, risedronate absorption was estimated from the amount excreted in the urine. Risedronate was dissolved in mineral water samples and administered orally at 0.35 mg/kg. Urine samples were collected for 24 h after dosing. Risedronate was extracted from urine using ion-pair solid-phase cartridges and quantified by HPLC with UV detection (262 nm). Cumulative recovery of risedronate was calculated from the amount excreted in the urine. The 24-h recovery of risedronate from evian® (0.32±0.02% [mean±standard deviation (S.D.)], n=4) and Contrex(®) (0.22±0.05%) mineral waters was significantly lower than that from tap water (0.47±0.04%, p<0.01). Absorption of risedronate in calcium chloride and magnesium chloride aqueous solutions of the same hardness (822 mg/L) was 54% (0.27±0.04%) and 12% (0.51±0.08%) lower, respectively, compared with ultrapure water; suggesting that absorption of risedronate declines as the calcium concentration of mineral waters increases. Consumption of mineral waters containing high levels of calcium (80 mg/L or above), such as evian® and Contrex(®), is therefore not recommended when taking risedronate.

Effect of risedronate on bone in renal transplant recipients.

PubMed

Coco, Maria; Pullman, James; Cohen, Hillel W; Lee, Sally; Shapiro, Craig; Solorzano, Clemencia; Greenstein, Stuart; Glicklich, Daniel

2012-08-01

Bisphosphonates may prevent or treat the bone loss promoted by the immunosuppressive regimens used in renal transplantation. Risedronate is a commonly used third-generation amino-bisphosphonate, but little is known about its effects on the bone health of renal transplant recipients. We randomly assigned 42 new living-donor kidney recipients to either 35 mg of risedronate weekly or placebo for 12 months. We obtained bone biopsies at the time of renal transplant and after 12 months of protocol treatment. Treatment with risedronate did not affect bone mineral density (BMD) in the overall cohort. In subgroup analyses, it tended to preserve BMD in female participants but did not significantly affect the BMD of male participants. Risedronate did associate with increased osteoid volume and trabecular thickness in male participants, however. There was no evidence for the development of adynamic bone disease. In summary, further study is needed before the use of prophylactic bisphosphonates to attenuate bone loss can be recommended in renal transplant recipients.

Effect of oral monthly ibandronate on bone microarchitecture in women with osteopenia-a randomized placebo-controlled trial.

PubMed

Chapurlat, R D; Laroche, M; Thomas, T; Rouanet, S; Delmas, P D; de Vernejoul, M-C

2013-01-01

We have examined the effect of oral monthly ibandronate on distal radius and tibia microarchitecture with high-resolution peripheral quantitative tomography compared with placebo, in women with osteopenia, and found that ibandronate did not significantly affect trabecular bone but improved cortical density and thickness at the tibia. We have examined the effect of ibandronate on bone microarchitecture with peripheral high-resolution quantitative computed tomography (HR-pQCT) in a randomized placebo-controlled trial among 148 women with osteopenia. Patients received either oral 150 mg monthly ibandronate or placebo over 24 months. Bone microarchitecture was assessed at baseline, 6, 12, and 24 months, using HR-pQCT at the distal radius and tibia; areal bone mineral density (aBMD) was measured with DXA at the spine, hip, and radius. At 12 months, there was no significant difference in trabecular bone volume at the radius (the primary end point) between women on ibandronate (10.8 ± 2.5%) and placebo (10.5 ± 2.9%), p = 0.25. There was no significant difference in other radius trabecular and cortical microarchitecture parameters at 12 and 24 months. In contrast, at the tibia, cortical vBMD in the ibandronate group was significantly greater than in the placebo group at 6, 12, and 24 months, with better cortical thickness at 6, 12, and 24 months. With ibandronate, aBMD was significantly increased at the hip and spine at 12 and 24 months but at the radius was significantly superior to placebo only at 24 months. Most of the adverse events related to ibandronate were expected with bisphosphonate use, and none of them were serious. We conclude that 12 months of treatment with ibandronate in women with osteopenia did not affect trabecular bone microarchitecture, but improved cortical vBMD at the tibia at 12 and 24 months, and preserved cortical thickness at the tibia.

Risedronate and ergocalciferol prevent hip fracture in elderly men with Parkinson disease.

PubMed

Sato, Yoshihiro; Honda, Yoshiaki; Iwamoto, Jun

2007-03-20

There is a high incidence of hip fractures in patients with Parkinson disease (PD). Bone mineral density (BMD) is decreased in patients with PD, correlating with the immobilization-induced bone resorption and hypovitaminosis D with compensatory hyperparathyroidism. To evaluate the effectiveness of risedronate, an inhibitor of bone resorption, on osteoporosis and the risk of hip fractures in elderly men with PD. This was a 2-year, randomized, double-blind, placebo-controlled trial. In a prospective study of patients with PD, 121 patients received a daily dose of 2.5 mg risedronate and vitamin D2 1,000 IU for 2 years, and the remaining 121 received placebo and vitamin D2 1,000 IU. Incidence of hip fractures was compared between the two groups. Nine patients sustained hip fractures in the placebo group, and three hip fractures occurred in the risedronate group. The relative risk of a hip fracture in the risedronate group vs the placebo group was 0.33 (95% CI, 0.09 to 1.20). BMD increased by 2.2% in the risedronate group and decreased by 2.9% in the placebo group (p < 0.0001). Urinary deoxypyridinoline, a bone resorption marker, decreased by 46.7% in the risedronate group and by 33.0% in the placebo group. Treatment with risedronate and vitamin D2 increases bone mineral density in elderly men with Parkinson disease and reduces the risk of hip fractures.

A 1-year randomized, double-blind, placebo-controlled study of intravenous ibandronate on bone loss following renal transplantation.

PubMed

Smerud, K T; Dolgos, S; Olsen, I C; Åsberg, A; Sagedal, S; Reisæter, A V; Midtvedt, K; Pfeffer, P; Ueland, T; Godang, K; Bollerslev, J; Hartmann, A

2012-12-01

The clinical profile of ibandronate as add-on to calcitriol and calcium was studied in this double-blind, placebo-controlled trial of 129 renal transplant recipients with early stable renal function (≤ 28 days posttransplantation, GFR ≥ 30 mL/min). Patients were randomized to receive i.v. ibandronate 3 mg or i.v. placebo every 3 months for 12 months on top of oral calcitriol 0.25 mcg/day and calcium 500 mg b.i.d. At baseline, 10 weeks and 12 months bone mineral density (BMD) and biochemical markers of bone turnover were measured. The primary endpoint, relative change in BMD for the lumbar spine from baseline to 12 months was not different, +1.5% for ibandronate versus +0.5% for placebo (p = 0.28). Ibandronate demonstrated a significant improvement of BMD in total femur, +1.3% versus -0.5% (p = 0.01) and in the ultradistal radius, +0.6% versus -1.9% (p = 0.039). Bone formation markers were reduced by ibandronate, whereas the bone resorption marker, NTX, was reduced in both groups. Calcium and calcitriol supplementation alone showed an excellent efficacy and safety profile, virtually maintaining BMD without any loss over 12 months after renal transplantation, whereas adding ibandronate significantly improved BMD in total femur and ultradistal radius, and also suppressed biomarkers of bone turnover. Ibandronate was also well tolerated. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

Efficacy of anti-osteoporotic medications in patients with type 1 and 2 diabetes mellitus: a systematic review.

PubMed

Anagnostis, Panagiotis; Paschou, Stavroula A; Gkekas, Nifon N; Artzouchaltzi, Aikaterini-Maria; Christou, Konstantinos; Stogiannou, Dimitrios; Vryonidou, Andromachi; Potoupnis, Michael; Goulis, Dimitrios G

2018-06-01

Both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) have been associated with bone fragility and increased fracture risk. However, little is known regarding the effect of anti-osteoporotic treatment on bone mineral density (BMD) and/or fracture risk in these patients. We aimed to systematically investigate the efficacy of anti-osteoporotic medications in patients with diabetes in comparison with non-diabetic subjects. MEDLINE and Scopus databases were searched (up to 31st October 2017). Nine studies fulfilled the pre-defined inclusion criteria [patients with T2DM (n = 8) or either T1DM or T2DM (n = 1)]. Regarding fracture risk, five studies were identified. Alendronate demonstrated comparable vertebral anti-fracture efficacy in patients with and without diabetes (n = 2), whereas non-vertebral fracture risk was either the same (n = 1) or higher in diabetic patients (n = 1). Raloxifene also demonstrated comparable vertebral anti-fracture efficacy in both groups (n = 2), without any effect on non-vertebral fractures in either group. In one study, diabetic patients exposed to raloxifene demonstrated the same vertebral and non-vertebral fracture risk with non-diabetic patients. Teriparatide (n = 1) demonstrated the same non-vertebral fracture rates in both patients with and without T2DM. Regarding BMD, equal increases in spine BMD were observed with alendronate (n = 4), risedronate (n = 1), and teriparatide (n = 1). With respect to hip BMD, similar increases were observed with teriparatide (n = 1), whereas data regarding alendronate were controversial (n = 3). No eligible study was found for zoledronic acid, ibandronate, strontium ranelate, denosumab, or bazedoxifene. The presence of diabetes does not alter anti-osteoporotic treatment response, regarding BMD increase and vertebral fracture risk reduction.

[Effect of pamidronate and ibandronate on orthodontic root resorption in rats].

PubMed

Zhao, Shu-ya; Wang, Xu-xia; Liu, Wan-xin; Dong, Rui; Li, Jing; Zhang, Jun

2013-09-01

To compare the effects of pamidronate and ibandronate on orthodontic root resorption. Seventy-two 6-week-old female specific pathogen free (SPF) Wistar rats were selected to establish models for orthodontic tooth movement. The rats were randomly divided into three groups: the control group (C group), pamidronate group (Pm group) and ibandronate group (Ib group). 0.9% normal saline,0.5 mmol/L pamidronate and 0.5 mmol/L ibandronate were injected every 3 days. The rats were executed in batch on the 3rd, 7th and 14th day to make tissue sections. All statistical analysis was performed using the PASW Statistics 18 software package. On the 7th and 14th day, the amount of cementoclast, the expression of osteoclast differentiation factor (ODF) and root resorption index were significantly lower in Pm group [the 7th day: (2.675 ± 0.002), (0.1683 ± 0.0007), (0.103 ± 0.003); the 14th day: (3.886 ± 0.048), (0.1873 ± 0.0014), (0.283 ± 0.001)] and Ib groups[the 7th day: (2.601 ± 0.001), (0.1634 ± 0.0010), (0.099 ± 0.002); the 14th day: (3.754 ± 0.019), (0.1818 ± 0.0016), (0.281 ± 0.001)] than in C group[the 7th day: (2.810 ± 0.001), (0.1792 ± 0.0008), (0.120 ± 0.001); the 14th day: (4.800 ± 0.001), (0.2060 ± 0.0007), (0.401 ± 0.001)] (P < 0.05). However, no significant difference was found between Pm and Ib groups on the 3rd, 7th and 14th day (P > 0.05). Both pamidronate and ibandronate could inhibit orthodontic root resorption.

Biochemical Bone Turnover Markers and Osteoporosis in Older Men: Where Are We?

PubMed Central

Szulc, Pawel

2011-01-01

In men aged less than 60, the association of serum and urinary levels of biochemical bone turnover markers (BTMs) and bone mineral density (BMD) is weak or not significant. After this age, higher BTM levels are correlated weakly, but significantly, with lower BMD and faster bone loss. Limited data from the cohort studies suggest that BTM measurement does not improve the prediction of fragility fractures in older men in comparison with age, BMD, history of falls and fragility fractures. Testosterone replacement therapy (TRT) decreases bone resorption. During TRT, bone formation markers slightly increase (direct effect on osteoblasts), then decrease (slowdown of bone turnover). Bisphosphonates (alendronate, risedronate, ibandronate, zoledronate) induce a rapid decrease in bone resorption followed by a milder decrease in bone formation. In men receiving antiresorptive therapy for prostate cancer, zoledronate, denosumab and toremifene decrease significantly levels of bone resorption and bone formation markers. Teriparatide induced a rapid increase in serum concentrations of bone formation markers followed by an increase in bone resorption. We need more studies on the utility of BTM measurement for the improvement of the persistence and adherence to the anti-osteoporotic treatment in men. PMID:22220284

Nephrotoxicity of ibandronate and zoledronate in Wistar rats with normal renal function and after unilateral nephrectomy.

PubMed

Bergner, R; Siegrist, B; Gretz, N; Pohlmeyer-Esch, G; Kränzlin, B

2015-09-01

A previous animal study compared the nephrotoxic effect of ibandronate (IBN) and zoledronate (ZOL), but interpretation of these study results was limited because of the model of minimal nephrotoxic dosage with a dosage ratio of 1:3. The present study investigated the nephrotoxicity of ibandronate and zoledronate in a 1.5:1 dose ratio, as used in clinical practice and compared the nephrotoxicity in rats with normal and with mildly to moderately impaired renal function. We compared rats with normal renal function (SHAM) and with impaired renal function after unilateral nephrectomy (UNX), treated either with ibandronate 1.5mg/kg, zoledronate 1mg/kg or placebo once (1×) or nine (9×) times. Renal function and markers of tubular toxicity were measured over a 27 week period. After last bisphosphonate treatment the rats were sacrificed and kidneys examined histologically. All bisphosphonate treated animals showed a significant tubular toxicity, which was temporary except in the ZOL-UNX-9×-group. Also the renal function was only transiently reduced except in the ZOL-UNX-9×-group. Histologically, bisphosphonate treatment led to cortical tubuloepithelial degeneration/necrosis and medullary tubuloepithelial swelling which were slightly more pronounced in ibandronate treated animals, when compared to zoledronate treated animals, especially with impaired renal function. In contrast to the previous study we found a similar nephrotoxicity of ibandronate and zoledronate in rats with normal renal function. In rats with impaired renal function the peak of toxicity had not even been fully reached until end of experiment in the zoledronate treated animals. The peak of toxicity seems to be more severe and delayed in rats with impaired renal function compared with rats with normal renal function. Copyright © 2015 Elsevier Ltd. All rights reserved.

Comparative gastrointestinal safety of weekly oral bisphosphonates

PubMed Central

Katz, J. N.; Brookhart, M. A.; Stürmer, T.; Stedman, M. R.; Levin, R.; Solomon, D. H.

2012-01-01

Summary Weekly bisphosphonates are the primary agents used to treat osteoporosis. Although these agents are generally well tolerated, serious gastrointestinal adverse events, including hospitalization for gastrointestinal bleed, may arise. We compared the gastrointestinal safety between weekly alendronate and weekly risedronate and found no important difference between new users of these agents. Introduction Weekly bisphosphonates are the primary agents prescribed for osteoporosis. We examined the comparative gastrointestinal safety between weekly bisphosphonates. Methods We studied new users of weekly alendronate and weekly risedronate from June 2002 to August 2005 among enrollees in a state-wide pharmaceutical benefit program for seniors. Our primary outcome was hospitalization for upper gastrointestinal bleed. Secondary outcomes included outpatient diagnoses for upper gastrointestinal disease, symptoms, endoscopic procedures, use of gastroprotective agents, and switching between therapies. We used Cox proportional hazard models to compare outcomes between agents within 120 days of treatment initiation, adjusting for propensity score quintiles. We also examined composite safety outcomes and stratified results by age and prior gastrointestinal history. Results A total of 10,420 new users were studied, mean age=79 years (SD, 6.9), and 95% women. We observed 31 hospitalizations for upper gastrointestinal bleed (0.91 per 100 person-years) within 120 days of treatment initiation. Adjusting for covariates, there was no difference in hospitalization for upper gastrointestinal bleed among those treated with risedronate compared with alendronate (HR, 1.12; 95%CI, 0.55 to 2.28). Risedronate switching rates were lower; otherwise, no differences were observed for secondary or composite outcomes. Conclusions We found no important difference in gastrointestinal safety between weekly oral bisphosphonates. PMID:19266138

In vivo microfocal computed tomography and micro-magnetic resonance imaging evaluation of antiresorptive and antiinflammatory drugs as preventive treatments of osteoarthritis in the rat.

PubMed

Jones, Michael D; Tran, Charles W; Li, Guang; Maksymowych, Walter P; Zernicke, Ronald F; Doschak, Michael R

2010-09-01

To determine whether treatment with an antiresorptive drug in combination with an antiinflammatory drug reduces periarticular bone and soft tissue adaptations associated with the progression of posttraumatic secondary osteoarthritis (OA). We used in vivo microfocal computed tomography (micro-CT) to map bony adaptations and in vivo micro-magnetic resonance imaging (micro-MRI) to examine joint inflammation in a rat model of surgically induced OA secondary to knee triad injury. We examined the arthroprotective effects of the bisphosphonates alendronate and risedronate and the nonsteroidal antiinflammatory drug (NSAID) meloxicam. Micro-CT revealed reduced levels of periarticular trabecular bone loss in animals with knee triad injury treated with the bisphosphonate drugs alendronate or risedronate, or the NSAID meloxicam, compared with untreated animals. Alendronate treatment reduced bony osteophyte development. While risedronate as a monotherapy did not positively impact osteophytogenesis, combination therapy with risedronate and meloxicam reduced osteophyte severity somewhat. Micro-MRI revealed an increased, diffuse water signal in the epiphyses of untreated rats with knee triad injury 8 weeks after surgery, suggestive of a bone marrow lesion-like stimulus. In contrast, meloxicam-treated rats showed a significant reduction in fluid signal compared with both bisphosphonate-treated groups 8 weeks after surgery. Histologic analysis qualitatively confirmed the chondroprotective effect of both bisphosphonate treatments, showing fewer degradative changes compared with untreated rats with knee triad injury. Our findings indicate that select combinations of bisphosphonate and NSAID drug therapy in the early stages of secondary OA preserve trabecular bone mass and reduce the impact of osteophytic bony adaptations and bone marrow lesion-like stimulus. Bisphosphonate and NSAID therapy may be an effective disease-modifying drug regimen if administered early after the initial

German adjuvant intergroup node-positive study: a phase III trial to compare oral ibandronate versus observation in patients with high-risk early breast cancer.

PubMed

von Minckwitz, Gunter; Möbus, Volker; Schneeweiss, Andreas; Huober, Jens; Thomssen, Christoph; Untch, Michael; Jackisch, Christian; Diel, Ingo J; Elling, Dirk; Conrad, Bettina; Kreienberg, Rolf; Müller, Volkmar; Lück, Hans-Joachim; Bauerfeind, Ingo; Clemens, Michael; Schmidt, Marcus; Noeding, Stefanie; Forstbauer, Helmut; Barinoff, Jana; Belau, Antje; Nekljudova, Valentina; Harbeck, Nadia; Loibl, Sibylle

2013-10-01

Bisphosphonates prevent skeletal-related events in patients with metastatic breast cancer. Their effect in early breast cancer is controversial. Ibandronate is an orally and intravenously available amino-bisphosphonate with a favorable toxicity profile. It therefore qualifies as potential agent for adjuvant use. The GAIN (German Adjuvant Intergroup Node-Positive) study was an open-label, randomized, controlled phase III trial with a 2 × 2 factorial design. Patients with node-positive early breast cancer were randomly assigned 1:1 to two different dose-dense chemotherapy regimens and 2:1 to ibandronate 50 mg per day orally for 2 years or observation. In all, 2,640 patients and 728 events were estimated to be required to demonstrate an increase in disease-free survival (DFS) by ibandronate from 75% to 79.5% by using a two-sided α = .05 and 1-β of 80%. We report here the efficacy analysis for ibandronate, which was released by the independent data monitoring committee because the futility boundary was not crossed after 50% of the required DFS events were observed. Between June 2004 and August 2008, 2,015 patients were randomly assigned to ibandronate and 1,008 to observation. Patients randomly assigned to ibandronate showed no superior DFS or overall survival (OS) compared with patients randomly assigned to observation (DFS: hazard ratio, 0.945; 95% CI, 0.768 to 1.161; P = .589; OS: HR, 1.040; 95% CI, 0.763 to 1.419; P = .803). DFS was numerically longer if ibandronate was used in patients younger than 40 years or older than 60 years compared with patients age 40 to 59 years (test for interaction P = .093). Adjuvant treatment with oral ibandronate did not improve outcome of patients with high-risk early breast cancer who received dose-dense chemotherapy.

Impact of oral ibandronate 150 mg once monthly on bone structure and density in post-menopausal osteoporosis or osteopenia derived from in vivo μCT.

PubMed

Bock, Oliver; Börst, Hendrikje; Beller, Gisela; Armbrecht, Gabriele; Degner, Corina; Martus, Peter; Roth, Heinz-Jürgen; Felsenberg, Dieter

2012-01-01

The effect of ibandronate 150 mg/once monthly in the treatment of post-menopausal osteopenia and osteoporosis on bone micro-structure at the distal tibia and radius has not been considered to date. Seventy post-menopausal women with osteoporosis or osteopenia were recruited. All subjects received calcium and vitamin D supplementation and were randomized to either a group which took 150 mg ibandronate oral monthly or a placebo group over a 12-month period. μCT measures of the distal tibia and radius were conducted every three months, with DXA lumbar spine and hip measurements conducted only pre and post and serum markers of bone formation and resorption measured every 6 months. After 12-months no significant impact of ibandronate on the primary outcome measures bone-volume to tissue-volume and trabecular separation at the distal tibia (p≥0.15) was found. Further multiple regression analyses of the primary end-points indicated a significant effect favoring the ibandronate intervention (p=0.045). Analysis of secondary end-points showed greater increases in distal tibia cortical thickness, cortical density and total density (p≤0.043) with ibandronate and no significant effects at the distal radius, but greater increases of hip DXA-BMD and lumbar spine DXA-BMD (p≤0.017). Ibandronate use resulted in a marked reduction in bone turnover (p<0.001). While ibandronate resulted in greater mineralization of bone, this effect differed from one body region to another. There was some impact of ibandronate on bone structure (cortical thickness) at the distal tibia, but not on bone-volume to tissue-volume or trabecular separation. Copyright © 2011 Elsevier Inc. All rights reserved.

Generic alendronate use among Medicare beneficiaries: are Part D data complete?

PubMed

Yun, Huifeng; Curtis, Jeffrey R; Saag, Kenneth; Kilgore, Meredith; Muntner, Paul; Smith, Wilson; Matthews, Robert; Wright, Nicole; Morrisey, Michael A; Delzell, Elizabeth

2013-01-01

Generic alendronate was approved in the United States on February 6, 2008. Medicare beneficiaries might pay for generic alendronate out-of-pocket without having claims submitted, resulting in misclassification of generic alendronate use in Medicare data. To estimate the completeness of generic alendronate use in 2008 Medicare Part D data; to identify factors associated with staying on branded alendronate versus switching to a generic product. We identified Medicare beneficiaries highly adherent (medication possession ratio ≥80%) with branded alendronate during 1/1/06-2/6/07 ("2007 cohort") and during 1/1/07-2/6/08 ("2008 cohort"). The outcome was medication status at the end of follow-up (12/31/2007 or 12/31/2008), classified as continued branded alendronate, switched to generic alendronate, switched to another bisphosphonate or presumed discontinued bisphosphonate therapy. Cox regression estimated the hazard ratio (HR) for discontinuation in 2008 compared to 2007. Multinomial logistic regression identified factors associated with medication status for the 2008 cohort. Among 15,310 subjects using branded alendronate in the 2008 cohort, 81% switched to generic alendronate. The proportion presumably discontinuing bisphosphonate therapy was 8.9% in 2008 compared to 7.7% in the 2007 cohort (adjusted HR, 1.15; 95% confidence interval, 1.05, 1.26). Factors associated with staying on branded alendronate in 2008 were higher income, eligibility for a low income subsidy and use of Fosamax® plus vitamin D. Evaluation of Medicare prescription drug data suggests that the amount of missing claims for generic alendronate in 2008 was not substantial, and misclassification of exposure in studies examining alendronate use post-generic product availability should be minimal. Copyright © 2012 John Wiley & Sons, Ltd.

Aromatase Inhibitors and Bone Loss

PubMed Central

PEREZ, EDITH A.; M., Serene; Durling, Frances C.; WEILBAECHER, KATHERINE

2009-01-01

The aromatase inhibitors (AIs) anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are significantly more effective than the selective estrogen-receptor modulator (SERM) tamoxifen in preventing recurrence in estrogen receptor–positive early breast cancer. Aromatase inhibitors are likely to replace SERMs as first-line adjuvant therapy for many patients. However, AIs are associated with significantly more osteoporotic fractures and greater bone mineral loss. As antiresorptive agents, oral and intravenous bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), pamidronate (Aredia), and zoledronic acid (Zometa) have efficacy in preventing postmenopausal osteoporosis, cancer treatment–related bone loss, or skeletal complications of metastatic disease. Clinical practice guidelines recommend baseline and annual follow-up bone density monitoring for all patients initiating AI therapy. Bisphosphonate therapy should be prescribed for patients with osteoporosis (T score < −2.5) and considered on an individual basis for those with osteopenia (T score < −1). Modifiable lifestyle behaviors including adequate calcium and vitamin D intake, weight-bearing exercise, and smoking cessation should be addressed. Adverse events associated with bisphosphonates include gastrointestinal toxicity, renal toxicity, and osteonecrosis of the jaw. These safety concerns should be balanced with the potential of bisphosphonates to minimize or prevent the debilitating effects of AI-associated bone loss in patients with early, hormone receptor–positive breast cancer. PMID:16986348

Impact of bone marker feedback on adherence to once monthly ibandronate for osteoporosis among Asian postmenopausal women.

PubMed

Kung, Annie Wai-Chee; Rachman, Ichramsjah A; Adam, John M F; Roeshadi, Djoko; Torralba, Tito; Navarra, Sandra; Gamilla, Zayda; Cañete, Arthur; de la Rosa, Miles; Tsai, KehSung; Lin, Hsiao-Yi; Soong, Yung Kuei; Lan, Joung-Liang; Hsu, Horng-Chaung; Tu, Shih-Te; Lin, Ruey-Mo; Yuktanandana, Pongsak; Songpatanasilp, Thawee; Ngarmukos, Srihatach; Soontrapa, Sugree; Soontrapa, Suppasin; Rojanasthien, Sattaya; Luevitoonvechkij, Sirichai; Leerapan, Taninnit; Albert, Adelin; Vanbelle, Sophie

2009-09-01

This study assesses the impact of serum carboxy-terminal collagen crosslinks (CTX) bone marker feedback (BMF) on adherence to ibandronate treatment in Asian postmenopausal women with osteoporosis. This was a 12-month (6-monthly phased), randomized, prospective, open-label, multi-center study conducted in 596 (of 628 enrolled) postmenopausal women with osteoporosis (< or = 85 years old) who were naïve, lapsed, or current bisphosphonate users. Patients were randomized into two arms: serum CTX BMF at 3 months versus no-BMF. Once-monthly 150 mg ibandronate tablet was administered for 12 months and adherence to therapy was assessed at 6 and 12 months. In addition, patient satisfaction and safety of ibandronate treatment were also assessed. Serum CTX BMF at 3 months showed no impact on adherence. The proportions of adherent patients were comparable in the BMF versus no-BMF arms (92.6%vs. 96.0%, P = 0.16); overall, serum CTX levels were similar for adherent and non-adherent patients. However, BMF patients felt more informed about their osteoporosis (P < 0.001) and more satisfied (P < 0.01) than no-BMF patients. The Asian postmenopausal osteoporosis patients in this study had a high adherence rate to once-monthly ibandronate therapy. Use of serum CTX BMF had no further impact on increasing adherence, but increased treatment satisfaction.

Local application of an ibandronate/collagen sponge improves femoral fracture healing in ovariectomized rats

PubMed Central

Liu, Yansong; Hou, Zhiyong; Chen, Wei; Jin, Lin; Tian, Ye; Ju, Linlin; Liu, Bo; Dong, Tianhua; Zhang, Fei

2017-01-01

Non-union is a major clinical problem in the healing of fractures, especially in patients with osteoporosis. The systemic administration of drugs is time consuming and large doses are demanding and act slowly, whereas local release acts rapidly, increases the quality and quantity of the bone tissue. We hypothesize that local delivery demonstrates better therapeutic effects on an osteoporotic fracture. The aim of this paper is to investigate the effect of the local application of ibandronate loaded with a collagen sponge on regulating bone formation and remodeling in an osteoporotic rat model of fracture healing. We found that the local delivery of ibandronate exhibited excellent effects on improving the bone microarchitecture and suppressed effects on bone remodeling. At 4 weeks, more callus formation and improvement of mechanical character and microstructure were observed in a local delivery via μCT, mechanical test, histological research and serum analysis. The suppression of bone remodeling was compared with a systemic treatment at 12 weeks, and the structural mechanical properties and microarchitecture were also improved with local delivery. This research identifies an earlier, safer and integrated approach for local delivery of ibandronate with collagen and provides a better strategy for the treatment of osteoporotic fracture in rats. PMID:29108027

Developments in the pharmacotherapeutic management of osteoporosis.

PubMed

Close, Pierre; Neuprez, Audrey; Reginster, Jean-Yves

2006-08-01

During the last two decades, several medications have been granted a marketing authorisation for the management of osteoporosis. Bisphosphonates are the most widely prescribed drugs in this area, worldwide. Alendronate and risedronate are given daily or weekly and have demonstrated their ability to reduce fracture rates at the spine and hip. Ibandronate has demonstrated spine antifracture efficacy with intervals between dosings greater than weekly. New developments in this class include intravenous administration of ibandronate or zoledronate, once every three months or once yearly. Raloxifene, a selective estrogen-receptor modulator, reduces spine fractures and, in post-hoc analyses, non-spine fractures in high-risk subjects. New selective estrogen-receptor modulators, including lasofoxifene, bazedoxifene and arzoxifene, are expected to demonstrate antifracture efficacy at the hip level, whilst retaining the extra-skeletal benefits (such as in the breast) that are obtained with raloxifene. The peptides from the parathyroid hormone family are potent stimulators of bone formation. Teriparatide (1 - 34 amino acid fragment of the parathyroid hormone) reduces spine and non-spine fractures, an effect that is sustained for up to 30 months after the withdrawal of treatment. The intact hormone (1 - 84 amino acids) showed similar results on spine fractures, and more data are requested to evaluate its effect on non-spine or hip fractures. Strontium ranelate is suggested to be the first medication to uncouple bone formation from bone resorption. It has shown antifracture efficacy at all sites in a large number of postmenopausal women. New developments include: denosumab, an antibody against receptor activator of NF-kappaB ligand (RANKL); a cytokine that is responsible for osteoclastogenesis; and inhibitors of cathepsin K, a cysteine protease that is involved in the cleavage of collagen.

Adverse events, bone mineral density and discontinuation associated with generic alendronate among postmenopausal women previously tolerant of brand alendronate: a retrospective cohort study

PubMed Central

2010-01-01

Background A rise in gastrointestinal (GI) adverse events (AEs) and a decline in bone mineral density (BMD) was observed in patients previously tolerant to brand alendronate shortly after generic versions were introduced in July 2005 to the Canadian market. The objective of our study was to quantify changes in AE rates and BMD scores, as well as associated alendronate discontinuation among patients before and after switch from brand to generic alendronate. Methods A chart review of postmenopausal women 50 years of age and older between 2003 and 2007 was conducted in two specialized tertiary care referral centers. Patients on alendronate both before and after July 2005 were included. The change in the number of AEs, changes in BMD and associated alendronate discontinuation was compared before and after the switch from brand to generic alendronate. Results 301 women with an average age of 67.6 years (standard deviation (SD) = 9.5) had a total of 47 AEs between July 2003 and December 2007 that resulted in discontinuation of the medication. There was a significant increase in the rate of AEs per patient-months-at-risk from 0.0001 before to 0.0044 after October 2005 (p < 0.001). The most common AEs were GI in nature (stomach pain, GI upset, nausea, and reflux). In addition, 23 patients discontinued alendronate due to BMD reduction after January 2006. In these patients, BMD scores were significantly reduced from their prior BMD measures (change of -0.0534, p < 0.001 for spine BMD and change of -0.0338, p = 0.01 for femur BMD). Among patients who discontinued due to BMD reduction, BMD was stable in the period prior to January 2006 (change of -0.0066, p = 0.5 for spine BMD and change of 0.0011, p = 0.9 for femur BMD); however, testing for reduction after January 2006 in BMD measures (one-sided T-test) revealed there was a significant reduction in BMD scores for both anatomic sites (change of -0.0321, p = .005 for spine, change of -0.0205, p = 0.05 for femur). Conclusions

Bisphosphonates for prevention of postmenopausal osteoporosis.

PubMed

Ravn, Pernille

2002-02-01

Our studies showed that 5 mg alendronate per day was the lowest, most effective dose that persistently prevented bone loss in recently postmenopausal women with normal bone mass. The effect on bone mass and biochemical markers was found comparable to that of commonly recommended regimens of postmenopausal HRT, and 5 mg alendronate per day is suggested as a new option for prevention of postmenopausal osteoporosis. HRT must, however, still be considered the first choice for this indication because of additional beneficial effects on other organ systems. The effect of alendronate was unaffected by bone or fat mass status, but increased with increasing postmenopausal age. The implications were that alendronate stabilized bone mass to a comparable extent in women at particular risk of osteoporosis because of thin body habitus or low bone mass and in healthy postmenopausal women with normal bone mass. Calcium supplementation was insufficient to prevent bone loss and did not add an effect on bone metabolism when combined with alendronate treatment in recently postmenopausal women. The gastrointestinal risk and adverse event profile of 5 mg alendronate per day was comparable to that of placebo, and this dose of alendronate appeared safe for long-term use. Bone loss resumed at a normal postmenopausal rate promptly after withdrawal of alendronate in early postmenopausal women consistent with a substantial underlying natural bone loss during early menopause. Oral ibandronate increased bone mass at all skeletal regions in elderly postmenopausal women with low bone mass, and 2.5 mg ibandronate per day was the lowest dose with this effect. The results are indicative of ibandronate as an option for secondary prevention of postmenopausal osteoporosis, but longer-term phase III trials should be performed before ibandronate can be recommended for this indication. The study showed that 2.5 mg ibandronate per day was efficient for prevention of bone loss and increment in bone mass in

[Influence of mineral water on absorption of oral alendronate in rats].

PubMed

Akagi, Yuuki; Sakaue, Tomoyuki; Yoneyama, Eiji; Aoyama, Takao

2011-01-01

Alendronate, an oral bisphosphonate (e.g., Fosamax(®)), is effective in the treatment of osteoporosis, and the Fosamax(®) package insert advises that the bioavailability is reduced when taken with mineral water containing high levels of metal cations (Ca(2+), Mg(2+), etc.). However, standards regarding the water used when taking alendronate are unclear. In this study, the influence of mineral water on the absorption of oral alendronate was investigated based on urinary excretion of its unchanged form in rats. Alendronate was diluted in each water sample and administered orally (0.7 mg/kg) to male Wistar rats after 24-hour fast. Urine samples were collected until 24 h after dosing. Urine samples were alkalinized, and alendronate in urine was precipitated as a calcium salt, followed by loading on an anion exchange cartridge. Eluted alendronate was derivatized with 9-fluorenylmethoxycarbonyl (Fmoc) chloride and determined by HPLC with fluorescent detection. Cumulative urinary excretion recoveries of alendronate were calculated from the amounts of urinary excretion. Alendronate was rapidly excreted in the first 6 h, and similar elimination rate constants were seen (from 0.28 to 0.45 h(-1/2)) among the water samples. Cumulative urinary excretion recoveries with tap water, evian(®) and 100% deep ocean water were 0.98±0.17%, 0.80±0.18% and 1.01±0.16% (mean±S.E., n=4). Those with Contrex(®) (0.33±0.07%) were significantly lower when compared with ultrapure water (1.56±0.35%, p<0.01). These findings suggest that the absorption of alendronate decreases based on the calcium concentration of mineral water. In conclusion, mineral water containing high levels of calcium is not recommended when alendronate is taken.

[Esophagus-enteric anastomosis ulceration caused by alendronate].

PubMed

Duques, P; Araújo, R S; de Amorim, W P

2001-01-01

Alendronate sodium is an aminobisphosphonate indicated for the treatment of osteoporosis in post-menopausal women and has been associated with esophagitis in many reports. Esophageal stenosis, gastrointestinal symptoms as dyspepsia, nausea, vomiting and abdominal pain could be present. Report a case of a patient who underwent total gastrectomy with Y-en-Roux anastomosis for a gastric carcinoid tumor and developed an esophagus-enteric anastomosis ulceration after the use of alendronate. A 63-year-old woman started medical therapy with alendronate in a dose of 10 mg daily. After a period of one month of medical treatment with this drug she began to complain of dysphagic symptoms and abdominal pain. She was submitted to endoscopic examination that showed an esophageal ulceration, an enteric ulceration of the anastomosis and an esophageal stenosis. Medical treatment with alendronate was discontinued and the symptom of abdominal pain disappeared. The intensity of dysphagia has decreased. The ulcerated lesion remitted although esophageal stenosis did not. The patient was subsequently treated with esophagus-enteric anastomosis dilation. She improved in her general state and nowadays she is free of symptoms. Alendronate sodium could cause lesions of the inferior esophageal portion or in distal segments of the gastrointestinal tube, in patients with a fast gastrointestinal transit. Special attention must be given to gastrectomized patients that use this drug because of the possibility to develop mucosal lesions in the enteric anastomosed part and its fearful complications as stenosis.

ESWT and alendronate sodium demonstrate equal protective effects in osteoarthritis of the knee

NASA Astrophysics Data System (ADS)

Wang, Ching-Jen; Chou, Wen-Yi; Hsu, Shan-Ling; Huang, Chien-Yiu; Cheng, Jai-Hong

2016-01-01

This study compared the effects of extracorporeal shock wave therapy (ESWT) and alendronate sodium (alendronate) in osteoarthritis (OA) of rat knees. The control group was subjected to a sham surgery and did not receive either ESWT or alendronate treatment. The OA group underwent anterior cruciate ligament transection (ACLT) and medial meniscectomy (MM) surgery and did not receive either ESWT or alendronate. The ESWT group underwent ACLT and MM surgery and received ESWT after the surgery. The alendronate group received alendronate after ACLT and MM surgery. The evaluations included radiograph, bone mineral density (BMD), serum C-telopeptide collagen II (CTX-II), cartilage oligomeric protein (COMP), alkaline phosphatase and osteocalcin, histopathological examination and immunohistochemical analysis. Radiographs at 12 weeks showed pronounced OA changes in the OA group. The BMD values, CTX-II, COMP, alkaline phosphatase and osteocalcin showed no significant difference between ESWT and alendronate groups. In histopathology, the Mankin and Safranin O scores significantly increased in the OA, ESWT and alendronate groups, but without any significant difference between the ESWT and alendronate groups. In immunohistochemical analysis, the von Willebrand factor (vWF), vascular endothelial factor (VEGF), soluble vascular cell adhesion molecule (sVCAM), proliferating cell nuclear antigen (PCNA), bone morphogenetic protein 2 (BMP-2), and osteocalcin expressions in articular cartilage and subchondral bone showed a significant decrease in the OA group, but no difference was noted between the ESWT and alendronate groups. In conclusion, ESWT and alendronate sodium demonstrate equal protective effects from developing osteoarthritis of the knee in rats.

Update on long-term treatment with bisphosphonates for postmenopausal osteoporosis: a systematic review.

PubMed

Eriksen, Erik F; Díez-Pérez, Adolfo; Boonen, Steven

2014-01-01

Osteoporosis is a progressive skeletal disorder that requires long-term treatment. However, there is little guidance regarding optimal treatment duration and what the treatment discontinuation and retreatment criteria should be. Given that bisphosphonates are the most commonly prescribed class of agent for the treatment of osteoporosis, we reviewed the long-term data relating to these therapies and discussed the considerations for using bisphosphonates in postmenopausal women with osteoporosis. A PubMed search, using the search terms 'bisphosphonate', 'postmenopausal osteoporosis' and 'long term' and/or 'extension' was conducted in January 2013. Results from nine controlled studies that prospectively assessed alendronate, risedronate, ibandronate or zoledronic acid in women with postmenopausal osteoporosis were reviewed. Clinical studies in postmenopausal women with osteoporosis showed that long-term use of bisphosphonates resulted in persistent antifracture and bone mineral density (BMD) increasing effects beyond 3 years of treatment. No unexpected adverse events were identified in these studies and the long-term tolerability profiles of bisphosphonates remain favorable. Data from the withdrawal extension studies of alendronate and zoledronic acid also showed that residual fracture benefits were seen in patients who discontinued treatment for 3 to 5 years after an initial 3- to 5-year treatment period. BMD monitoring and fracture risk assessments should be conducted regularly to determine whether treatment could be stopped or should be reinitiated. Patients exhibiting T-scores<-2.5 or who have suffered a new fracture while on treatment should continue treatment, while patients with T-scores>-2.5 could be considered for discontinuation of active treatment while undergoing continued monitoring of their bone health. The duration and potential discontinuation of treatment should be personalized for individual patients based on their response to treatment, fracture

The association between automatic generic substitution and treatment persistence with oral bisphosphonates.

PubMed

Ström, O; Landfeldt, E

2012-08-01

Automatic generic substitution of alendronate products, used to reduce drug costs, and medication persistence was studied retrospectively between 2006 and 2009. During this period the number of, and the rate of substitution between, alendronate products increased while persistence decreased. Patient preferences should be considered when designing and evaluating generic policies. Automatic generic substitution (AGS) was implemented in Sweden in 2002. The objective of this study was to investigate the association between AGS and persistence with alendronate treatment of primary osteoporosis in Sweden. An open historical cohort of women and men (n = 36,433) was identified in the Swedish Prescribed Drug Register through filled prescriptions for alendronate or risedronate between 2005 and 2009. Co-morbidity data was extracted from the National Patient Register. The association between AGS and medication persistence was investigated using non-parametric and parametric survival analysis. Between 2006 and 2009, the number of alendronate products increased from 15 to 25, the proportion of prescriptions constituting a substitution increased from 10.8% to 45.2%, and the proportion of patients persisting with alendronate treatment for 12 months fell from 66.9% to 51.7%. Patients starting alendronate treatment in 2006 had lower risk of stopping treatment compared with those starting in 2007 (HR 1.34, 95% CI 1.29-1.39), 2008 (HR 1.49, 95% CI 1.43-1.55), and 2009 (HR 1.50, 95% CI 1.40-1.60). No difference was observed in persistence with proprietary risedronate during the same period. Individuals who had their alendronate product substituted at the first prescription refill had significantly higher probability of discontinuation (HR 1.25, 95% CI 1.20-1.30). AGS causes increased product substitution which appears to be associated with reduced treatment persistence. Poor health outcomes and associated costs due to forgone drug exposure should be taken into account in the

Inhibitory effects of a bisphosphonate (risedronate) on experimental periodontitis in rats.

PubMed

Shoji, K; Horiuchi, H; Shinoda, H

1995-07-01

The present study was designed to examine whether systemic administration of a bisphosphonate, risedronate, could prevent alveolar bone resorption in rats with experimental periodontitis. On Day 1, an elastic ring was placed around the neck of the right mandibular 1st molar to induce inflammatory periodontitis. The animals were given daily injections of either 0.9% NaCl (control group), or 0.8, 1.6 or 3.2 mumoles/kg (s.c.) of risedronate (experimental groups) from Days 1 to 7, and were killed on Day 8. Histological examinations and determination of bone mineral density in the interdental area between the 1st and 2nd molars with an image analyzer revealed that the presence of the elastic ring induced a loss of attachment and bone resorption in the control group. Vigorous bone resorption, with appearance of a large number of osteoclasts, was observed in the interdental and bifurcation areas. In the experimental groups, however, the resorption of alveolar bone and the loss of bone mineral content in these areas were prevented in a dose-dependent fashion, especially at doses of 1.6 and 3.2 mumoles/kg. Many osteoclasts were detached from the surface of the alveolar bone and had degenerated appearances, such as rounded shapes, loss of polarity and pyknosis. These results suggest that administration of risedronate is effective in preventing bone resorption in periodontitis.

Management of osteoporosis: the Indian perspective.

PubMed

Handa, Rohini

2004-09-01

Osteoporosis is a common but neglected problem in India. The major challenges to management are lack of awareness and resource constraints. The management is also hampered by the non-availability of normative data for bone mineral density in Indians. Subclinical vitamin D deficiency is widespread. The drugs available in the country include calcium, vitamin D, hormone replacement therapy, raloxifene, alendronate, risedronate, calcitonin and teriparatide. Bisphosphonates (alendronate) constitute the mainstay of treatment in India. There is a need for evidence based, context specific and resource sensitive guidelines.

Osteoporosis: strategies for prevention and management.

PubMed

Keen, Richard

2007-02-01

Osteoporosis is a serious public health issue, affecting up to 1 in 2 women and 1 in 5 men over the age of 50 years. The common osteoporotic fractures occur at the spine, wrist and hip. For the patient affected by osteoporosis, these fractures are associated with significant morbidity and, in the case of hip and spine fractures, an excess mortality. The treatment of osteoporotic fractures is also associated with a significant healthcare cost for society. Currently, measurement of bone mineral density using dual energy X-ray absorptiometry is the gold standard for the diagnosis of osteoporosis. In the future, however, assessment of fracture risk will be based on algorithms incorporating clinical risk factors and bone density measurements, where appropriate. The goal of treatment is to reduce the risk of future fracture. Patients at high risk for fracture should be assessed and screened to exclude secondary causes for osteoporosis. Bisphosphonates (alendronate, etidronate, ibandronate, risedronate) are the first-line therapy for the majority of patients and these treatments can be given either orally or intravenously. Alternative treatment options include strontium ranelate and raloxifene. Anabolic therapy with parathyroid hormone can be considered for patients with severe disease. These patients will often require referral for specialist assessment and monitoring. All patients at risk of developing osteoporosis should be given lifestyle advice regarding dietary intake of calcium and vitamin D and regular weight-bearing exercise.

Biocompatibility evaluation of alendronate paste in rat's subcutaneous tissue.

PubMed

Mori, Graziela Garrido; de Moraes, Ivaldo Gomes; Nunes, Daniele Clapes; Castilho, Lithiene Ribeiro; Poi, Wilson Roberto; Capaldi, Maria Luciana P Manzoli

2009-04-01

Alendronate is a known inhibitor of root resorption and the development of alendronate paste would enhance its utilization as intracanal medication. Therefore, this study aimed to investigate the biocompatibility of experimental alendronate paste in subcutaneous tissue of rats, for utilization in teeth susceptible to root resorption. The study was conducted on 15 male rats, weighing approximately 180-200 grams. The rats' dorsal regions were submitted to one incision on the median region and, laterally to the incision, the subcutaneous tissue was raised and gently dissected for introduction of two tubes, in each rat. The tubes were sealed at one end with gutta-percha and taken as control. The tubes were filled with experimental alendronate paste. The animals were killed at 7, 15 and 45 days after surgery and the specimens were processed in laboratory. The histological sections were stained with hematoxylin-eosin and analyzed by light microscopy. Scores were assigned to the inflammatory process and statistically compared by the Tukey test (P < 0.05). Alendronate paste promoted severe inflammation process at 7 days, with statistically significant difference compared to the control (P < 0.05%). However, at 15 days, there was a regression of inflammation and the presence of connective tissue with collagen fibers, fibroblasts and blood vessels was observed. After 45 days, it was observed the presence of well-organized connective tissue, with collagen fibers and fibroblasts, and few inflammatory cells. No statistical difference was observed between the control and experimental paste at 15 and 45 days. The experimental alendronate paste was considered biocompatible with subcutaneous tissue of rat.

Long-term effects of local pretreatment with alendronate on healing of replanted rat teeth.

PubMed

Komatsu, K; Shimada, A; Shibata, T; Shimoda, S; Oida, S; Kawasaki, K; Nifuji, A

2008-04-01

Our previous study showed that topical alendronate, an inhibitor of bone resorption, reduces root resorption and ankylosis for 21 d after replantation of rat teeth. The aim of the present study was to evaluate the long-term inhibitory effects of topical alendronate in the replanted teeth. The rat maxillary first molars were extracted, placed in saline containing 1 mm alendronate (alendronate group) or saline (saline group) for 5 min and then replanted. The maxillae were dissected at 60 and 120 d. Microcomputed tomography horizontal sections at three root levels were analyzed for root and bone resorption, ankylosis and pulp mineralization. In the alendronate group at 60 and 120 d, the frequencies of resorption of roots and bone were lower than those in the saline group. The p values show statistical significances of lower frequencies in the alendronate group than in the saline group by chi-square test (see Table 1). Ankylosis and pulp mineralization occurred in the alendronate and saline groups. Bone marrow spaces were narrowed in conjunction with bone tissue expansion around the replanted teeth in the alendronate group. The inhibitory effects of topical alendronate were retained on root and bone resorption, but not on ankylosis and pulp mineralization, in the replanted teeth for 4 mo. Alendronate might also stimulate bone formation around the rat replanted teeth.

Pharmacological management of severe postmenopausal osteoporosis.

PubMed

Gaudio, Agostino; Morabito, Nancy

2005-01-01

The most devastating consequence of osteoporosis is bone fracture, particularly at the vertebral or femoral level. As defined by the WHO, patients with osteoporosis who have had one or more fragility fractures have severe osteoporosis. Those who sustain a vertebral fracture represent a particularly vulnerable group whose risk of another vertebral fracture within the following year is increased by a factor of 3-5. In addition, the presence of a vertebral fracture is associated with an increased risk of hip fracture. In light of these data, treatment of established osteoporosis is extremely important to prevent other fragility fractures. This review examines the therapies approved by the US FDA for the treatment of osteoporosis that have been shown to reduce the incidence of new fractures in patients with established osteoporosis. We evaluated the mechanisms of action, available formulations, efficacy in preventing fractures and increasing bone mineral density (BMD), duration of treatment, adverse effects and contraindications to use of alendronic acid (alendronate), risedronic acid (risedronate), calcitonin, raloxifene and teriparatide. All these drugs are able to prevent new vertebral fractures in patients with established osteoporosis. Only alendronic acid and risedronic acid have also been shown to reduce the risk of fracture at the femoral level, but they are contraindicated in patients with upper gastrointestinal diseases. Calcitonin is a good option in subjects with back pain because of its analgesic effect. Raloxifene is useful when patients have high plasma lipid levels or a family history of breast cancer. Teriparatide is indicated in subjects with very low BMD and multiple vertebral fractures. Patient characteristics should determine selection of therapy but the decision is always difficult and fraught with uncertainty.

Fracture healing with alendronate treatment in the Brtl/+ mouse model of osteogenesis imperfecta

PubMed Central

Meganck, J.A.; Begun, D.L.; McElderry, J.D.; Swick, A.; Kozloff, K.M.; Goldstein, S.A.; Morris, M.D.; Marini, J.C.; Caird, M.S.

2014-01-01

Osteogenesis imperfecta (OI) is a heritable bone dysplasia characterized by increased skeletal fragility. Patients are often treated with bisphosphonates to attempt to reduce fracture risk. However, bisphosphonates reside in the skeleton for many years and long-term administration may impact bone material quality. Acutely, there is concern about risk of non-union of fractures that occur near the time of bisphosphonate administration. This study investigated the effect of alendronate, a potent aminobisphosphonate, on fracture healing. Using the Brtl/+ murine model of type IV OI, tibial fractures were generated in 8-week-old mice that were untreated, treated with alendronate before fracture, or treated before and after fracture. After 2, 3, or 5 weeks of healing, tibiae were assessed using microcomputed tomography (μCT), torsion testing, quantitative histomorphometry, and Raman microspectroscopy. There were no morphologic, biomechanical or histomorphometric differences in callus between untreated mice and mice that received alendronate before fracture. Alendronate treatment before fracture did not cause a significant increase in cartilage retention in fracture callus. Both Brtl/+ and WT mice that received alendronate before and after fracture had increases in the callus volume, bone volume fraction and torque at failure after 5 weeks of healing. Raman microspectroscopy results did not show any effects of alendronate in wild-type mice, but calluses from Brtl/+ mice treated with alendronate during healing had a decreased mineral-to-matrix ratio, decreased crystallinity and an increased carbonate-to-phosphate ratio. Treatment with alendronate altered the dynamics of healing by preventing callus volume decreases later in the healing process. Fracture healing in Brtl/+ untreated animals was not significantly different from animals in which alendronate was halted at the time of fracture. PMID:23774443

Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure.

PubMed Central

Sato, M; Grasser, W; Endo, N; Akins, R; Simmons, H; Thompson, D D; Golub, E; Rodan, G A

1991-01-01

Studies of the mode of action of the bisphosphonate alendronate showed that 1 d after the injection of 0.4 mg/kg [3H]alendronate to newborn rats, 72% of the osteoclastic surface, 2% of the bone forming, and 13% of all other surfaces were densely labeled. Silver grains were seen above the osteoclasts and no other cells. 6 d later the label was 600-1,000 microns away from the epiphyseal plate and buried inside the bone, indicating normal growth and matrix deposition on top of alendronate-containing bone. Osteoclasts from adult animals, infused with parathyroid hormone-related peptide (1-34) and treated with 0.4 mg/kg alendronate subcutaneously for 2 d, all lacked ruffled border but not clear zone. In vitro alendronate bound to bone particles with a Kd of approximately 1 mM and a capacity of 100 nmol/mg at pH 7. At pH 3.5 binding was reduced by 50%. Alendronate inhibited bone resorption by isolated chicken or rat osteoclasts when the amount on the bone surface was around 1.3 x 10(-3) fmol/microns 2, which would produce a concentration of 0.1-1 mM in the resorption space if 50% were released. At these concentrations membrane leakiness to calcium was observed. These findings suggest that alendronate binds to resorption surfaces, is locally released during acidification, the rise in concentration stops resorption and membrane ruffling, without destroying the osteoclasts. Images PMID:1661297

Association Between Alendronate Use and Hip Fracture Risk in Older Patients Using Oral Prednisolone

PubMed Central

Axelsson, Kristian F.; Nilsson, Anna G.; Wedel, Hans; Lundh, Dan

2017-01-01

Importance Oral glucocorticoid treatment increases fracture risk, and evidence is lacking regarding the efficacy of alendronate to protect against hip fracture in older patients using glucocorticoids. Objective To investigate whether alendronate treatment in older patients using oral prednisolone is associated with decreased hip fracture risk and adverse effects. Design, Setting, and Participants Retrospective cohort study using a national database (N = 433 195) of patients aged 65 years or older undergoing a health evaluation (baseline) at Swedish health care facilities; 1802 patients who were prescribed alendronate after at least 3 months of oral prednisolone treatment (≥5 mg/d) were identified. Propensity score matching was used to select 1802 patients without alendronate use from 6076 patients taking prednisolone with the same dose and treatment time criteria. Follow-up occurred between January 2008 and December 2014. Exposures Alendronate vs no alendronate use; no patients had previously taken alendronate at the time of prednisolone initiation. Main Outcomes and Measures The primary outcome was incident hip fracture. Results Of the 3604 included patients, the mean age was 79.9 (SD, 7.5) years, and 2524 (70%) were women. After a median follow-up of 1.32 years (interquartile range, 0.57-2.34 years), there were 27 hip fractures in the alendronate group and 73 in the no-alendronate group, corresponding to incidence rates of 9.5 (95% CI, 6.5-13.9) and 27.2 (95% CI, 21.6-34.2) fractures per 1000 person-years, with an absolute rate difference of −17.6 (95% CI, −24.8 to −10.4). The use of alendronate was associated with a lower risk of hip fracture in a multivariable-adjusted Cox model (hazard ratio, 0.35; 95% CI, 0.22-0.54). Alendronate treatment was not associated with increased risk of mild upper gastrointestinal tract symptoms (alendronate vs no alendronate, 15.6 [95% CI, 11.6-21.0] vs 12.9 [95% CI, 9.3-18.0] per 1000 person-years; P = .40) or

The prevention of hip fracture with risedronate and ergocalciferol plus calcium supplementation in elderly women with Alzheimer disease: a randomized controlled trial.

PubMed

Sato, Yoshihiro; Kanoko, Tomohiro; Satoh, Kei; Iwamoto, Jun

A high incidence of fractures, particularly of the hip, represents an important problem in patients with Alzheimer disease (AD), who are prone to falls and have osteoporosis. We previously found that deficiency of 25-hydroxyvitamin D and compensatory hyperparathyroidism cause reduced bone mineral density in female patients with AD. We address the possibility that treatment with risedronate sodium and ergocalciferol plus calcium supplementation may reduce the incidence of nonvertebral fractures in elderly women with AD. A total of 500 elderly women with AD were randomly assigned to daily treatment with 2.5 mg of risedronate sodium or a placebo, combined with 1000 IU of ergocalciferol and 1200 mg of elementary calcium, and followed up for 18 months. At baseline, patients of both groups showed 25-hydroxyvitamin D deficiency with compensatory hyperparathyroidism. During the study period, bone mineral density in the risedronate group increased by 4.1% and decreased by 0.9% in the control group. Vertebral fractures occurred in 29 patients (24 hip fractures) in the control group and 8 patients (5 hip fractures) in the risedronate group. The relative risk in the risedronate group compared with the control group was 0.28 (95% confidence interval, 0.13-0.59). Elderly patients with AD hypovitaminosis D are at increased risk for hip fracture. Treatment with risedronate and ergocalciferol may be safe and effective in reducing the risk of a fracture in elderly patients with AD.

Hip fracture risk and safety with alendronate treatment in the oldest-old.

PubMed

Axelsson, K F; Wallander, M; Johansson, H; Lundh, D; Lorentzon, M

2017-12-01

There is high evidence for secondary prevention of fractures, including hip fracture, with alendronate treatment, but alendronate's efficacy to prevent hip fractures in the oldest-old (≥80 years old), the population with the highest fracture risk, has not been studied. To investigate whether alendronate treatment amongst the oldest-old with prior fracture was related to decreased hip fracture rate and sustained safety. Using a national database of men and women undergoing a fall risk assessment at a Swedish healthcare facility, we identified 90 795 patients who were 80 years or older and had a prior fracture. Propensity score matching (four to one) was then used to identify 7844 controls to 1961 alendronate-treated patients. The risk of incident hip fracture was investigated with Cox models and the interaction between age and treatment was investigated using an interaction term. The case and control groups were well balanced in regard to age, sex, anthropometrics and comorbidity. Alendronate treatment was associated with a decreased risk of hip fracture in crude (hazard ratio (HR) 0.62 (0.49-0.79), P < 0.001) and multivariable models (HR 0.66 (0.51-0.86), P < 0.01). Alendronate was related to reduced mortality risk (HR 0.88 (0.82-0.95) but increased risk of mild upper gastrointestinal symptoms (UGI) (HR 1.58 (1.12-2.24). The alendronate association did not change with age for hip fractures or mild UGI. In old patients with prior fracture, alendronate treatment reduces the risk of hip fracture with sustained safety, indicating that this treatment should be considered in these high-risk patients. © 2017 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.

Risedronate therapy for the prevention of steroid-induced osteoporosis in patients with minimal-change nephrotic syndrome.

PubMed

Takei, Takashi; Itabashi, Mitsuyo; Tsukada, Misao; Sugiura, Hidekazu; Moriyama, Takahito; Kojima, Chiari; Shiohira, Shunji; Shimizu, Ari; Karasawa, Kazunori; Amemiya, Nobuyuki; Kawanishi, Kunio; Ogawa, Tetsuya; Uchida, Keiko; Tsuchiya, Ken; Nitta, Kosaku

2010-01-01

Minimal-change nephrotic syndrome (MCNS) is treated by the administration of prednisolone (PSL) at high doses. Steroid-induced osteoporosis is a serious adverse effect of this drug. Patients with MCNS were randomly assigned to two groups, the risedronate (2.5 mg/day) + alfacalcidol (0.25 µg/day) group (n=20) and the alfacalcidol (0.25 µg/day)-alone group (n=20). All the patients had received PSL and the clinical characteristics were compared between the two groups at baseline and at 12 months. A significant decrease of the mean bone mineral density (BMD) of the lumbar spine from 0.710±0.162 (g/cm(2)) to 0.588±0.125 was observed in the alfacalcidol-alone group (p=0.02), while no such decrease of the bone mineral density was found in the risedronate + alfacalcidol group (0.663±0.169 at baseline and 0.626±0.129 at 12 months). No significant differences in the results of other biochemical tests performed at the baseline and at 12 months were observed between the two groups. The likelihood of development of steroid-induced osteoporosis was influenced by the cumulative dose of PSL, the mean BMD at the baseline, occurrence of disease relapse, and risedronate therapy. Risedronate appears to be effective in preventing steroid-induced osteoporosis. It is necessary to use bisphosphonates to maintain the BMD in patients with MCNS receiving prolonged steroid therapy.

Cost-effectiveness of oral ibandronate compared with intravenous (i.v.) zoledronic acid or i.v. generic pamidronate in breast cancer patients with metastatic bone disease undergoing i.v. chemotherapy.

PubMed

De Cock, E; Hutton, J; Canney, P; Body, J J; Barrett-Lee, P; Neary, M P; Lewis, G

2005-12-01

Ibandronate is the first third-generation bisphosphonate to have both oral and intravenous (i.v.) efficacy. An incremental cost-effectiveness model compared oral ibandronate with i.v. zoledronic acid and i.v. generic pamidronate in female breast cancer patients with metastatic bone disease, undergoing i.v. chemotherapy. A global economic model was adapted to the UK National Health Service (NHS), with primary outcomes of direct healthcare costs and quality-adjusted life years (QALYs). Efficacy, measured as relative risk reduction of skeletal-related events (SREs), was obtained from clinical trials. Resource use data for i.v. bisphosphonates and the cost of managing SREs were obtained from published studies. Hospital management and SRE treatment costs were taken from unit cost databases. Monthly drug acquisition costs were obtained from the British National Formulary. Utility scores were applied to time with/without an SRE to adjust survival for quality of life. Model design and inputs were validated through expert UK clinician review. Total cost, including drug acquisition, was pound 386 less per patient with oral ibandronate vs. i.v. zoledronic acid and pound 224 less vs. i.v. generic pamidronate. Oral ibandronate gained 0.019 and 0.02 QALYs vs. i.v. zoledronic acid and i.v. pamidronate, respectively, making it the economically dominant option. At a threshold of pound 30,000 per QALY, oral ibandronate was cost-effective vs. zoledronic acid in 85% of simulations and vs. pamidronate in 79%. Oral ibandronate is a cost-effective treatment for metastatic bone disease from breast cancer due to reduced SREs, bone pain, and cost savings from avoidance of resource use commonly associated with bisphosphonate infusions.

Effects of glucosamine and risedronate alone or in combination in an experimental rabbit model of osteoarthritis

PubMed Central

2014-01-01

Background The osteoarthritis (OA) treatment in humans and in animals is a major orthopaedic challenge because there is not an ideal drug for preserving the joint structure and function. The aim of this study was to assess the effects of the treatment with oral glucosamine and risedronate alone or in combination on articular cartilage, synovial membrane and subchondral bone in an experimental rabbit model of OA. Osteoarthritis was surgically induced on one knee of 32 New Zealand White rabbits using the contralateral as healthy controls. Three weeks later treatments were started and lasted 8 weeks. Animal were divided in four groups of oral treatment: the first group received only saline, the second 21.5 mg/kg/day of glucosamine sulfate, the third 0.07 mg/kg/day of risedronate; and the fourth group both drugs simultaneously at the same dosages. Following sacrifice femurs were removed and osteochondral cylinders and synovial membrane were obtained for its histological and micro-CT evaluation. Results Sample analysis revealed that the model induced osteoarthritic changes in operated knees. OA placebo group showed a significant increase in cartilage thickness respect to the control and inflammatory changes in synovial membrane; whereas subchondral bone structure and volumetric bone mineral density remained unchanged. All the treated animals showed an improvement of the cartilage swelling independent of the drug used. Treatment with glucosamine alone seemed to have no effect in the progression of cartilage pathology while risedronate treatment had better results in superficial fibrillation and in resolving the inflammatory changes of the tissues, as well as modifying the orientation of trabecular lattice. The combination of both compounds seemed to have additive effects showing better results than those treated with only one drug. Conclusions The results of this animal study suggested that glucosamine sulfate and risedronate treatment alone or in combination may be

Use of Oral Bisphosphonates by Older Adults with Fractures and Impaired Renal Function

PubMed Central

Sadowski, Cheryl A; Spencer, Tara; Yuksel, Nese

2011-01-01

Background: The manufacturers of oral bisphosphonates (alendronate, risedronate) recommend avoiding use of these drugs in patients with renal impairment. However, many patients who have osteoporosis or who are at risk of fracture are elderly and may have renal impairment. This situation poses a quandary for clinicians in deciding how best to manage osteoporosis in this high-risk population. Objective: To synthesize published evidence regarding the use and safety of oral bisphosphonates for patients with impaired renal function. Methods: The following databases were searched up to October 2010: PubMed, MEDLINE, Embase, the Cochrane Library, and International Pharmaceutical Abstracts. The following key words and terms were used for the searches: bisphosphonates, alendronate, risedronate, Fosamax, Actonel, “renal failure”, “renal insufficiency”, “chronic kidney disease”, and “end-stage renal disease”. The manufacturers of Fosamax and Actonel were asked to provide information about use of their products in patients with renal impairment, including unpublished pharmacokinetic studies or reports of adverse drug events. Results: The search yielded 2 post hoc analyses of safety data, 1 case–control study, 1 case series, 4 retrospective chart analyses, and 2 prospective studies. According to these publications, numerous patients with decreased renal function have received bisphosphonates and have experienced improvement in bone mineral density and/or reduction in risk of fractures, with no increase in adverse effects. Increased renal damage occurred in some individuals with underlying renal disorders, as described in case reports. Conclusions: Although the literature is limited, there is evidence that alendronate and risedronate are well tolerated and effective when used by individuals with renal impairment. Further research is required to confirm the benefits and risks of using these medications in patients with renal impairment. PMID:22479027

Fractures in women treated with raloxifene or alendronate: a retrospective database analysis

PubMed Central

2013-01-01

Background Raloxifene and alendronate are anti-resorptive therapies approved for the prevention and treatment of postmenopausal osteoporosis. Raloxifene is also indicated to reduce the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk of invasive breast cancer. A definitive study comparing the fracture effectiveness and rate of breast cancer for raloxifene and alendronate has not been published. The purpose of this retrospective cohort study was to evaluate fracture and breast cancer rates among patients treated with raloxifene or alendronate. Methods Females ≥45 years who initiated raloxifene or alendronate in 1998–2006 Truven Health Analytics MarketScan® Databases, had continuous enrollment 12 months prior to and at least 12 months after the index date, and had a treatment medication possession ratio ≥80% were included in this study. Rates of vertebral and nonvertebral fractures and breast cancer during 1, 3, 5, 6, 7, and 8 years of treatment with raloxifene or alendronate were evaluated. Fracture rates were adjusted for potential treatment bias using inverse probability of treatment weights. Multivariate hazard ratios were estimated for vertebral and nonvertebral fractures. Results Raloxifene patients had statistically significantly lower rates of vertebral fractures in 1, 3, 5, and 7 years and for nonvertebral fractures in 1 and 5 years. There were no statistically significant differences in the adjusted fracture rates between raloxifene and alendronate cohorts, except in the 3-year nonvertebral fracture rates where raloxifene was higher. Multivariate hazard ratios of raloxifene versus alendronate cohorts were not significantly different for vertebral and nonvertebral fracture in 1, 3, 5, 6, 7, and 8 years. Unweighted and weighted breast cancer rates were lower among raloxifene recipients. Conclusions Patients treated with alendronate and raloxifene had similar adjusted

Ibandronate and cementless total hip arthroplasty: densitometric measurement of periprosthetic bone mass and new therapeutic approach to the prevention of aseptic loosening

PubMed Central

Muratore, Maurizio; Quarta, Eugenio; Quarta, Laura; Calcagnile, Fabio; Grimaldi, Antonella; Orgiani, M. Antonio; Marsilio, Antonio; Rollo, Giuseppe

2012-01-01

Summary Studies of the mechanisms of periprosthetic bone loss have led to the development of pharmacologic strategies intended to enhance bone mass recovery after surgery and consequently prevent aseptic loosening and prolong the implant survival. Bisphosphonates, potent anti-resorptive drugs widely used in the treatment of osteoporosis and other disorders of bone metabolism, were shown to be particularly effective in reducing periprosthetic bone resorption in the first year after hip and knee arthroplasty, both cemented and cementless. Based on these results, we investigated the inhibitory effects of ibandronate on periprosthetic bone loss in a 2-year study of postmenopausal women that underwent cementless total hip arthroplasty. In the first 6 months both groups (A, treated with ibandronate 3 mg i.v. within five days after surgery and then with oral ibandronate 150 mg/month, plus calcium and vitamin D supplementation; and B, treated with calcium and vitamin D supplementation only) experienced bone loss, though to a lesser extent in group A. After 12 months, group A showed a remarkable BMD recovery, that was statistically significant versus baseline values (about +1, 74% of global BMD) and most evident in region R1 (+3, 81%) and R2 (+4, 12%); in group B, on the contrary, BMD values were unchanged compared with those at 6 months post-surgery. Quality of life scores also showed a greater improvement in group A, both at 6 and 12 months after surgery, likely because of the pain-reducing effects of ibandronate treatment. PMID:22783337

Controlled release of alendronate from nitrogen-doped mesoporous carbon

DOE PAGES

Saha, Dipendu; Spurri, Amanda; Chen, Jihua; ...

2016-04-13

With this study, we have synthesized a nitrogen doped mesoporous carbon with the BET surface area of 1066 m 2/g, total pore volume 0.6 cm 3/g and nitrogen content of 0.5%. Total alendronate adsorption in this carbon was ~5%. The release experiments were designed in four different media with sequential pH values of 1.2, 4.5, 6.8 and 7.4 for 3, 1, 3 and 5 h, respectively and at 37 °C to imitate the physiological conditions of stomach, duodenum, small intestine and colon, respectively. Release of the drug demonstrated a controlled fashion; only 20% of the drug was released in themore » media with pH = 1.2, whereas 64% of the drug was released in pH = 7.4. This is in contrary to pure alendronate that was completely dissolved within 30 min in the first release media (pH = 1.2) only. The relatively larger uptake of alendronate in this carbon and its sustained fashion of release can be attributed to the hydrogen bonding between the drug and the nitrogen functionalities on carbon surface. Based on this result, it can be inferred that this formulation may lower the side effects of oral delivery of alendronate.« less

Effect of alendronate on early bone loss of renal transplant recipients.

PubMed

Abediazar, S; Nakhjavani, M R

2011-03-01

Renal transplant recipients (RTRs) are at risk of developing osteoporosis and osteopenia due to underlying renal osteodystrophy, hypophosphatemia, and immunosuppression. This process occurs more frequently in the first year after renal transplantation (RTX), resulting in eventual bone loss and fractures. The purpose of this study was to evaluate the effect of low-dose alendronate to prevent early bone loss after RTX. We prospectively studied 43 successful RTR including 22 men and 21-women with a mean overall age of 39.16±11.73 years, mean body mass index of 23.6±3.73, and mean dialysis duration of 25.73±17.67 months. We matched them based on age and sex: the alendronate-treated group received vitamin D (Vit D) during the study plus 30 mg alendronate weekly from 1 month after RTX. The control group only received Vit D. We measured serum calcium, phosphate, alkaline phosphatase, blood urea, creatinine, and intact parathyroid hormone (iPTH) at the pretransplant baseline and monthly thereafter as well as BMD of the lumbar spine, femur, and radius pretransplant baseline versus 3 and 6 months after RTX. At 6 month after RTX, the lumbar BMD in the alendronate group increased significantly from 0.819±0.11 to 0.863±0.14 (P<.01), while it decreased in the control group from 0.897±0.17 to 0.817±0.16 (P<.001). There was also a significant increase in radius BMD (P<.001) and a nonsignificant increase in femoral BMD in the alendronate versus a significant decrease of femoral and radius BMD (P<.001) in the control group at 6 months. Upon multivariate analysis, there was a significant correlation between alendronate and spine BMD (r=.45, P<.001) but no linear regression between age, sex, BMI, dialysis duration of or iPTH with femoral, spine, or radius BMD changes at month 6. Low-dose alendronate was significantly useful to mitigate fast bone loss and increase BMD immediately after RTX. Copyright © 2011. Published by Elsevier Inc.

Phase III Randomized, Placebo-Controlled, Double-Blind Trial of Risedronate for the Prevention of Bone Loss in Premenopausal Women Undergoing Chemotherapy for Primary Breast Cancer

PubMed Central

Hines, Stephanie L.; Mincey, Betty Anne; Sloan, Jeff A.; Thomas, Sachdev P.; Chottiner, Elaine; Loprinzi, Charles L.; Carlson, Mark D.; Atherton, Pamela J.; Salim, Muhammad; Perez, Edith A.

2009-01-01

Purpose Risedronate prevents bone loss in postmenopausal women. The purpose of this study was to determine whether risedronate prevents bone loss in premenopausal women undergoing chemotherapy for breast cancer. Patients and Methods Premenopausal women undergoing chemotherapy for breast cancer were treated with oral calcium 600 mg and vitamin D 400 U daily and randomly assigned to receive oral risedronate 35 mg weekly or placebo, with all these therapies beginning within a month of the start of chemotherapy. Most chemotherapy regimens included anthracyclines, taxanes, or cyclophosphamide. Bone mineral density (BMD) was measured at baseline and 1 year. The primary end point was the change in lumbar spine (LS) BMD from baseline to 1 year. Results A total of 216 women enrolled; 170 women provided BMD data at 1 year. There was no difference in the mean change or percent change in LS BMD between groups, with a loss of 4.3% in the risedronate arm and 5.4% for placebo at 1 year (P = .18). Loss of BMD at the femoral neck and total hip were also similar between treatment groups. Risedronate was well tolerated, with no significant differences in adverse events compared with placebo, except that arthralgias and chest pain were worse in those receiving the placebos. Conclusion Risedronate did not prevent bone loss in premenopausal women undergoing adjuvant chemotherapy for breast cancer. PMID:19075260

In vitro disintegration studies of weekly generic and branded risedronate sodium formulations available in Canada.

PubMed

Walker, A D; Adachi, J D

2011-09-01

The aim of this study was to evaluate the in vitro disintegration of the five newly available Canadian generic risedronate 35 mg tablets compared to the innovator (branded) product, ACTONEL * *ACTONEL is a registered trade name of Warner Chilcott Company, LLC. (risedronate sodium) 35 mg. Tablets were inspected for colour and appearance. Disintegration times were determined using United States Pharmacopeia 33 (USP33-NF 28) methods. Disintegration onset time was also evaluated. The mean disintegration onset time values for the generic risedronate 35 mg tablets ranged from 2 to 29 seconds, and the mean disintegration completion times ranged from 81 to 260 seconds. The mean disintegration onset and completion time values for the ACTONEL 35 mg tablets were 23 and 43 seconds respectively. Four out of the five generic tablets tested had shorter disintegration onset times than the branded product; two of the generic tablet products had very fast disintegration onset times i.e. 2-3 seconds. Disintegration completion time for all five generic products tested was longer than that observed for the branded product; two generic products had disintegration completion time values five to six times longer than the branded product. Differences in the in vitro disintegration times were observed between the generic risedronate 35 mg tablets commercially available in Canada and the branded product, ACTONEL. The rapid disintegration onset times of two generic products may be important as this could increase the possibility of drug exposure in both the mouth and the esophagus during swallowing, resulting in unwanted localized irritation. However, it should be noted that an in vitro/in vivo correlation has not been established. Until such studies are completed it may be important to be aware of such in vitro disintegration differences when evaluating patients with newly presenting upper gastrointestinal complaints upon being switched from the branded product to generic formulations.

Cytotoxicity evaluation of sodium alendronate on cultured human periodontal ligament fibroblasts.

PubMed

Correia, Vera de Fátima Padrão; Caldeira, Celso L; Marques, Márcia Martins

2006-12-01

External root resorption processes are usually associated with dental trauma, mainly avulsion and intrusion. In such cases endodontic therapy aims to prevent this process by using medications that can inhibit osteoclastic activity, such as bisphosphonates. However, these drugs must be biocompatible to the periapical tissues. The aim of this study was to analyze the cytotoxicity of a bisphosphonate (sodium alendronate) on human periodontal ligament fibroblasts (PDL cells). Cells were plated in a density of 1 x 10(3) cells per dish. The experimental groups were GI (control) no sodium alendronate, and GII, GIII, and GIV with sodium alendronate at the concentrations of 10(-5), 10(-6), and 10(-7) M, respectively. The experimental times were 1, 6, 12, and 24 h (short-term) for viability and 2, 4, 6, and 8 days (long-term) for cell survival. Data in triplicate were statistically analyzed. Cultures treated with the highest alendronate concentration (GII) showed cell viability percentages significantly lower (P < 0.01) than those of the other groups (GI, GIII, and GIV), at 12 and 24 h. Cell growth on GII and GIII groups was similar. GII presented smaller growth than the other groups (P < 0.05). We concluded that sodium alendronate, on direct contact with human periodontal ligament fibroblasts, is cytotoxic in concentrations higher than of 10(-6) M.

A rapid and sustained improvement of calcification propensity score (serum T50 ) after successful kidney transplantation: Reanalysis of a randomized controlled trial of ibandronate.

PubMed

Smerud, Knut T; Åsberg, Anders; Kile, Håkon; Pasch, Andreas; Dahle, Dag O; Bollerslev, Jens; Godang, Kristin; Hartmann, Anders

2017-12-01

A serum test called T 50 assesses the overall propensity for calcification of the blood and is associated with cardiovascular outcomes. We aimed to examine T 50 over time in kidney transplant recipients and also address any effects of ibandronate. Serum samples taken from kidney transplant patients included in a prospective, randomized placebo controlled study of ibandronate were analyzed in retrospect. Adequate analyses were performed at baseline (approximately 3 weeks after transplantation) in 129 patients, at 10 weeks in 127 patients and at 1 year in 123 patients. There were no statistical differences between ibandronate and placebo treatment in terms of T 50 at 10 weeks (P = .094) or at 1 year (P = .116). Baseline T 50 was a significant covariate (P < .0001) for T 50 scores at 10 weeks and 1 year. In the total cohort, there was a highly significant (P < .0001) increase in T 50 of 26.6% after 10 weeks and T 50 remained stable after 1 year. T 50 change was inversely correlated to phosphate of -0.515 (P < .0001) and to change in serum albumin (P < .03). We found that T 50 increased from baseline to 10 weeks after transplantation with no further change after 1 year. Ibandronate had no effect on T 50 . © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Efficacy of osteoporosis pharmacotherapies in preventing fracture among oral glucocorticoid users: a network meta-analysis.

PubMed

Amiche, M A; Albaum, J M; Tadrous, M; Pechlivanoglou, P; Lévesque, L E; Adachi, J D; Cadarette, S M

2016-06-01

Efficacy of osteoporosis medication is not well-established among patients taking oral glucocorticoids. We assessed the efficacy of approved osteoporosis pharmacotherapies in preventing fracture by combining data from randomized controlled trials. Teriparatide, risedronate, and etidronate were associated with decreased vertebral fracture risk. Several osteoporosis drugs are approved for the prevention and treatment of glucocorticoid (GC)-induced osteoporosis. However, the efficacy of these treatments among oral GC users is still limited. We aimed to examine the comparative efficacy of osteoporosis treatments among oral GC users. We updated a systematic review through to March 2015 to identify all double-blinded randomized controlled trials (RCTs) that examined osteoporosis treatment among oral GC users. We used a network meta-analysis with informative priors to derive comparative risk ratios (RRs) and 95 % credible intervals (95 % CrI) for vertebral and non-vertebral fracture and mean differences in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD). Treatment ranking was estimated using the surface under the cumulative ranking curve (SUCRA) statistic. A meta-regression was completed to assess a subgroup effect between patients with prior GC exposures and GC initiators. We identified 27 eligible RCTs examining nine active comparators. Etidronate (RR, 0.41; 95%CrI = 0.17-0.90), risedronate (RR = 0.30, 95%CrI = 0.14-0.61), and teriparatide (RR = 0.07, 95%CrI = 0.001-0.48) showed greater efficacy than placebo in preventing vertebral fractures; yet, no treatment effects were statistically significant in reducing non-vertebral fractures. Alendronate, risedronate, and etidronate increased LS BMD while alendronate and raloxifene increased FN BMD. In preventing vertebral fractures, teriparatide was ranked as the best treatment (SUCRA: 77 %), followed by risedronate (77 %) and zoledronic acid (76 %). For non-vertebral fractures

A fast and simple spectrofluorometric method for the determination of alendronate sodium in pharmaceuticals

PubMed Central

Ezzati Nazhad Dolatabadi, Jafar; Hamishehkar, Hamed; de la Guardia, Miguel; Valizadeh, Hadi

2014-01-01

Introduction: Alendronate sodium enhances bone formation and increases osteoblast proliferation and maturation and leads to the inhibition of osteoblast apoptosis. Therefore, a rapid and simple spectrofluorometric method has been developed and validated for the quantitative determination of it. Methods: The procedure is based on the reaction of primary amino group of alendronate with o-phthalaldehyde (OPA) in sodium hydroxide solution. Results: The calibration graph was linear over the concentration range of 0.0-2.4 μM and limit of detection and limit of quantification of the method was 8.89 and 29 nanomolar, respectively. The enthalpy and entropy of the reaction between alendronate sodium and OPA showed that the reaction is endothermic and entropy favored (ΔH = 154.08 kJ/mol; ΔS = 567.36 J/mol K) which indicates that OPA interaction with alendronate is increased at elevated temperature. Conclusion: This simple method can be used as a practical technique for the analysis of alendronate in various samples. PMID:24790897

Diagnostic PET Imaging of Mammary Microcalcifications Using 64Cu-DOTA-Alendronate in a Rat Model of Breast Cancer

PubMed Central

Ahrens, Bradley J.; Li, Lin; Ciminera, Alexandra K.; Chea, Junie; Poku, Erasmus; Bading, James R.; Weist, Michael R.; Miller, Marcia M.; Colcher, David M.

2017-01-01

The development of improved breast cancer screening methods is hindered by a lack of cancer-specific imaging agents and effective small-animal models to test them. The purpose of this study was to evaluate 64Cu-DOTA-alendronate as a mammary microcalcification-targeting PET imaging agent, using an ideal rat model. Our long-term goal is to develop 64Cu-DOTA-alendronate for the detection and noninvasive differentiation of malignant versus benign breast tumors with PET. Methods: DOTA-alendronate was synthesized, radiolabeled with 64Cu, and administered to normal or tumor-bearing aged, female, retired breeder Sprague–Dawley rats for PET imaging. Mammary tissues were subsequently labeled and imaged with light, confocal, and electron microscopy to verify microcalcification targeting specificity of DOTA-alendronate and elucidate the histologic and ultrastructural characteristics of the microcalcifications in different mammary tumor types. Tumor uptake, biodistribution, and dosimetry studies were performed to evaluate the efficacy and safety of 64Cu-DOTA-alendronate. Results: 64Cu-DOTA-alendronate was radiolabeled with a 98% yield. PET imaging using aged, female, retired breeder rats showed specific binding of 64Cu-DOTA-alendronate in mammary glands and mammary tumors. The highest uptake of 64Cu-DOTA-alendronate was in malignant tumors and the lowest uptake in benign tumors and normal mammary tissue. Confocal analysis with carboxyfluorescein-alendronate confirmed the microcalcification binding specificity of alendronate derivatives. Biodistribution studies revealed tissue alendronate concentrations peaking within the first hour, then decreasing over the next 48 h. Our dosimetric analysis demonstrated a 64Cu effective dose within the acceptable range for clinical PET imaging agents and the potential for translation into human patients. Conclusion: 64Cu-DOTA-alendronate is a promising PET imaging agent for the sensitive and specific detection of mammary tumors as well as

Improvement in bone properties by using risedronate adsorbed hydroxyapatite novel nanoparticle based formulation in a rat model of osteoporosis.

PubMed

Sahana, H; Khajuria, Deepak Kumar; Razdan, Rema; Mahapatra, D Roy; Bhat, M R; Suresh, Sarasija; Rao, R Ramachandra; Mariappan, L

2013-02-01

A superior drug formulation capable of achieving efficient osteogenesis is in imperative demand for the treatment of osteoporosis. In the present study we investigated the potential of using novel risedronate-hydroxyapatite (HA) nanoparticle based formulation in an animal model of established osteoporosis. Nanoparticles of HA loaded with risedronate (NHLR) of various sizes (80-130 nm) were generated for bone targeted drug delivery. Three months after ovariectomy, 36 ovariectomized (OVX) rats were divided into 6 equal groups and treated with various doses of NHLR (500, 350 and 250 microg/kg intravenous single dose) and sodium risedronate (500 microg/kg, intravenous single dose). Untreated OVX and sham OVX served as controls. One month after drug administration, the left tibia and femur were tested for bone mechanical properties and histology, respectively. In the right femur, bone density was measured by method based on Archimedes principle and bone porosity analyses were performed using X-ray imaging. NHLR (250 microg/kg) showed a significant increase in bone density and reduced bone porosity when compared with OVX control. Moreover, NHLR (250 microg/kg) significantly increased bone mechanical properties and bone quality when compared with OVX control. The results strongly suggest that the NHLR, which is a novel nanoparticle based formulation, has a therapeutic advantage over risedronate sodium monotherapy for the treatment of osteoporosis in a rat model of postmenopausal osteoporosis.

Risedronate Prevents Early Radiation-Induced Osteoporosis in Mice at Multiple Skeletal Locations

PubMed Central

Willey, Jeffrey S.; Livingston, Eric W.; Robbins, Michael E.; Bourland, J. Daniel; Tirado-Lee, Leidamarie; Smith-Sielicki, Hope; Bateman, Ted A.

2009-01-01

Introduction Irradiation of normal, non-malignant bone during cancer therapy can lead to atrophy and increased risk of fracture at several skeletal sites, particularly the hip. This bone loss has been largely attributed to damaged osteoblasts. Little attention has been given to increased bone resorption as a contributor to radiation-induced osteoporosis. Our aims were to identify if radiation increases bone resorption resulting in acute bone loss, and if bone loss could be prevented by administering risedronate. Methods Twenty-week old female C57BL/6 mice were either: not irradiated and treated with placebo (NR+PL); whole-body irradiated with 2 Gy X-rays and treated with placebo (IR+PL); or irradiated and treated with risedronate (IR+RIS; 30μg/kg every other day). Calcein injections were administered 7 and 2 days before sacrifice. Bones were collected 1, 2, and 3 weeks after exposure. MicroCT analysis was performed at 3 sites: proximal tibial metaphysis; distal femoral metaphysis; and the body of the 5th lumbar vertebra (L5). Osteoclasts were identified from TRAP-stained histological sections. Dynamic histomorphometry of cortical and trabecular bone was performed. Circulating TRAP5b and osteocalcin concentrations were quantified. Results In animals receiving IR+PL, significant (P < 0.05) reduction in trabecular volume fraction relative to non-irradiated controls was observed at all three skeletal sites and time points. Likewise, radiation-induced loss of connectivity and trabecular number relative to NR+PL were observed at all skeletal sites throughout the study. Bone loss primarily occurred during the first week post-exposure. Trabecular and endocortical bone formation was not reduced until Week 2. Loss of bone volume was absent in animals receiving IR+RIS. Histology indicated greater osteoclast numbers at Week 1 within IR+PL mice. Serum TRAP5b concentration was increased in IR+PL mice only at Week 1 compared to NR+PL (P = 0.05). Risedronate treatment prevented

Effects of alendronate on restoration of biomechanical properties of periodontium in replanted rat molars.

PubMed

Shibata, T; Komatsu, K; Shimada, A; Shimoda, S; Oida, S; Kawasaki, K; Chiba, M

2004-12-01

We examined the effect of the pretreatment of roots with alendronate on the restoration of the support function of the healing periodontal ligament in replanted rat molars. The left maxillary first molars were extracted, placed in 0.9% NaCl containing 1 mm alendronate (alendronate group) or 0.9% NaCl (control group) for 5 min, and were replanted into their sockets. Groups of animals were killed at 7, 14, and 21 days after replantation. Normal control rats were also killed on the same days. The force required to extract the replanted or normal tooth from its socket was measured, and a load-deformation curve was developed and analyzed. Micro-computed tomography and histologic analyses were also made. The mechanical properties of the healing periodontal ligament in the alendronate group were gradually restored from 7 to 21 days. However, fractures of the roots and bones during mechanical testing occurred in most of the replanted teeth in the control group at 21 days. The rates of restoration of the mechanical strength, extensibility, stiffness, and toughness for the alendronate group at 21 days were 67, 98, 74, and 68% of the normal controls, respectively. Micro-computed tomography and histologic observations revealed that bone-like structures within the pulp and ankylosis between the roots and socket bones occurred commonly in the control group, but were uncommon in the alendronate group. Our findings suggest that the pretreatment with alendronate inhibits the formation of abnormal mineralized tissues and results in better restoration of the support function of the healing periodontal ligament in replanted teeth. (c)Blackwell Munksgaard 2004

Extemporaneous procedures for dissolving risedronate tablets for oral administration and for feeding tubes.

PubMed

Dansereau, Richard J; Crail, Debbie J

2005-01-01

Risedronate (Actonel, Procter & Gamble Pharmaceuticals) is commercially available only as film-coated tablets. Extemporaneous procedures for dissolving tablets for feeding tubes and for preparation of an oral liquid have not previously been evaluated. To evaluate procedures for dissolving risedronate sodium tablets for administration in liquid form and drug recovery following dissolution in cups and following passage through different types of feeding tubes. Tablets (5 and 35 mg) were individually dispersed in 2 oz of water. After 2 minutes, the solution was stirred for 30 seconds, dispensed, and rinsed with an additional 4 oz of water. The sample was filtered and analyzed by HPLC. Ten replicates were performed using the various cups. Gastrostomy and nasoenteric tubes were flushed with 1 oz of water. Individual tablets were dispersed in 2 oz of water; after 2 minutes, the solution was stirred for 30 seconds and poured through the tube and flushed with 1 oz of water. Samples were filtered and analyzed by HPLC. Ten replicates were performed for each type of feeding tube. For cups, the mean amount of drug recovered ranged from 95.7% to 100.5% of the label claim, with a relative standard deviation (RSD) range of 1.1-6.3%. For gastrostomy and nasoenteric tubes, the mean amount of drug recovered ranged from 98.3% to 101.9% of label claim, with an RSD range of 0.9-3.3%. A simple and accurate procedure was developed for dissolving risedronate tablets in water to prepare a liquid formulation for administration orally or through feeding tubes.

The utility of changes in serum levels of C-terminal telopeptide of type I collagen in predicting patient response to oral monthly ibandronate therapy.

PubMed

Hochberg, Marc C; Silverman, Stuart L; Barr, Charles E; Miller, Paul D

2010-01-01

Bone turnover markers may provide a more rapid indication of patient response to osteoporosis treatment than bone mineral density (BMD) measurements. This post hoc analysis of data from the MOBILE (Monthly Oral iBandronate In LadiEs) study assessed the relationship between increases in BMD at 12 mo from baseline after starting ibandronate treatment and changes in bone resorption marker serum C-terminal telopeptide of type I collagen (sCTX) from baseline at 3 and 6 mo. MOBILE enrolled postmenopausal women aged 55-80 yr with mean lumbar spine (LS) BMD T-score of -2.5 to -5.0. This analysis included women who received 150-mg monthly oral ibandronate (n=323). A high proportion of women were classified as BMD responders after 1 yr (BMD increase was >/=0%, i.e., 74-91% depending on skeletal site; BMD increase was >/=3%, i.e., 34-67%). Women with larger decreases in sCTX were more likely to be BMD responders. The percent increase in LS BMD at 12 mo was significantly associated with the percent decrease in sCTX at 3 mo from baseline (Pearson correlation coefficient: -0.19, p=0.0016). In linear regression models, percent decrease in sCTX at 3 mo from baseline was a significant predictor of 1-yr LS BMD response (R(2)=0.61, p=0.0007). These data suggest that 3-mo changes in sCTX levels are associated with 1-yr LS BMD increases in postmenopausal women treated with once-monthly oral ibandronate. The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.

Pharmacokinetic characteristics of formulated alendronate transdermal delivery systems in rats and humans.

PubMed

Choi, Ahyoung; Gang, Hyesil; Whang, Jiae; Gwak, Hyesun

2010-05-01

The objective of this study was to examine the absorption of alendronate from formulated transdermal delivery systems in rats and humans. When alendronate was applied to rats by transdermal delivery systems (7.2 mg) and oral administration (30 mg/kg), a statistically significant difference was found in the amount remaining to be excreted at time t (Ae(t)) and the amount remaining to be excreted at time 0 (Ae(infinity)) (p < 0.01). The highest Ae(infinity) (1267.7+/-65.2 ng) was found in the formulation containing 6% caprylic acid in propylene glycol (PG), which was 5.4- and 2.0-times higher than the PG only formulation and oral administration, respectively. Compared to oral administration, significantly delayed half-life values were obtained from all the formulated transdermal delivery systems. There was a linear relationship (r(2) = 0.9854) between the drug loading dose and Ae(infinity). The Ae(infinity) values from the transdermal delivery system containing 6% caprylic acid (53.8 mg as alendronate) and an oral product (Fosamax), 70 mg as alendronate) in humans were 127.0 +/- 34.2 microg and 237.2 +/- 56.3 microg, respectively. The dose-adjusted relative Ae(infinity) ratio of the transdermal delivery system to oral product was calculated to be 69.7%. The long half-life of alendronate in the transdermal delivery system (50.6 +/- 6.4 h), compared to that of the oral product (3.5 +/- 1.1 h) could allow less-frequent dosing. In conclusion, this study showed that a transdermal delivery system containing 6% caprylic acid in PG could be a favorable alternative for alendronate administration.

Diagnostic PET Imaging of Mammary Microcalcifications Using 64Cu-DOTA-Alendronate in a Rat Model of Breast Cancer.

PubMed

Ahrens, Bradley J; Li, Lin; Ciminera, Alexandra K; Chea, Junie; Poku, Erasmus; Bading, James R; Weist, Michael R; Miller, Marcia M; Colcher, David M; Shively, John E

2017-09-01

The development of improved breast cancer screening methods is hindered by a lack of cancer-specific imaging agents and effective small-animal models to test them. The purpose of this study was to evaluate 64 Cu-DOTA-alendronate as a mammary microcalcification-targeting PET imaging agent, using an ideal rat model. Our long-term goal is to develop 64 Cu-DOTA-alendronate for the detection and noninvasive differentiation of malignant versus benign breast tumors with PET. Methods: DOTA-alendronate was synthesized, radiolabeled with 64 Cu, and administered to normal or tumor-bearing aged, female, retired breeder Sprague-Dawley rats for PET imaging. Mammary tissues were subsequently labeled and imaged with light, confocal, and electron microscopy to verify microcalcification targeting specificity of DOTA-alendronate and elucidate the histologic and ultrastructural characteristics of the microcalcifications in different mammary tumor types. Tumor uptake, biodistribution, and dosimetry studies were performed to evaluate the efficacy and safety of 64 Cu-DOTA-alendronate. Results: 64 Cu-DOTA-alendronate was radiolabeled with a 98% yield. PET imaging using aged, female, retired breeder rats showed specific binding of 64 Cu-DOTA-alendronate in mammary glands and mammary tumors. The highest uptake of 64 Cu-DOTA-alendronate was in malignant tumors and the lowest uptake in benign tumors and normal mammary tissue. Confocal analysis with carboxyfluorescein-alendronate confirmed the microcalcification binding specificity of alendronate derivatives. Biodistribution studies revealed tissue alendronate concentrations peaking within the first hour, then decreasing over the next 48 h. Our dosimetric analysis demonstrated a 64 Cu effective dose within the acceptable range for clinical PET imaging agents and the potential for translation into human patients. Conclusion: 64 Cu-DOTA-alendronate is a promising PET imaging agent for the sensitive and specific detection of mammary tumors as

Alendronate prevents glucocorticoid-induced osteoporosis in patients with rheumatic diseases

PubMed Central

Kan, Shun-Li; Yuan, Zhi-Fang; Li, Yan; Ai, Jie; Xu, Hong; Sun, Jing-Cheng; Feng, Shi-Qing

2016-01-01

Abstract Glucocorticoid-induced osteoporosis (GIOP) is a serious problem for patients with rheumatic diseases requiring long-term glucocorticoid treatment. Alendronate, a bisphosphonate, has been recommended in the prevention of GIOP. However, the efficacy and safety of alendronate in preventing GIOP remains controversial. We performed a meta-analysis to investigate the efficacy and safety of alendronate in preventing GIOP in patients with rheumatic diseases. We retrieved randomized controlled trials from PubMed, EMBASE, and the Cochrane Library. Two reviewers extracted the data and evaluated the risk of bias and quality of the evidence. We calculated the risk ratio (RR) with a 95% confidence interval (CI) for dichotomous outcomes, and the mean difference (MD) with a 95% CI for continuous outcomes using Review Manager, version 5.3. A total of 339 studies were found, and 9 studies (1134 patients) were included. Alendronate was not able to reduce the incidence of vertebral fractures (RR = 0.63, 95% CI: 0.10–4.04, P = 0.62) and nonvertebral fractures (RR = 0.40, 95% CI: 0.15–1.12, P = 0.08). Alendronate significantly increased the percent change in bone mineral density (BMD) at the lumbar spine (MD = 3.66, 95% CI: 2.58–4.74, P < 0.05), total hip (MD = 2.08, 95% CI: 0.41–3.74, P < 0.05), and trochanter (MD = 1.68, 95% CI: 0.75–2.61, P < 0.05). Significant differences were not observed in the percent change in BMD at the femoral neck (MD = −0.33, 95% CI: −2.79 to 2.13, P = 0.79) and total body (MD = 0.64, 95% CI: −0.06 to 1.34, P = 0.07). No significant differences in the adverse events were observed in patients treated with alendronate versus the controls (RR = 1.00, 95% CI: 0.94–1.07, P = 0.89). The odds of gastrointestinal adverse events were significantly reduced (RR = 0.77, 95% CI: 0.62–0.97, P < 0.05). Our analysis suggests that alendronate can increase the percent change in BMD at the

Microarchitectural Deterioration of Cortical and Trabecular Bone: Differing Effects of Denosumab and Alendronate

PubMed Central

Seeman, Ego; Delmas, Pierre D; Hanley, David A; Sellmeyer, Deborah; Cheung, Angela M; Shane, Elizabeth; Kearns, Ann; Thomas, Thierry; Boyd, Steven K; Boutroy, Stephanie; Bogado, Cesar; Majumdar, Sharmila; Fan, Michelle; Libanati, Cesar; Zanchetta, Jose

2015-01-01

The intensity of bone remodeling is a critical determinant of the decay of cortical and trabecular microstructure after menopause. Denosumab suppresses remodeling more than alendronate, leading to greater gains in areal bone mineral density (aBMD). These greater gains may reflect differing effects of each drug on bone microarchitecture and strength. In a phase 2 double-blind pilot study, 247 postmenopausal women were randomized to denosumab (60mg subcutaneous 6 monthly), alendronate (70mg oral weekly), or placebo for 12 months. All received daily calcium and vitamin D. Morphologic changes were assessed using high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius and distal tibia and QCT at the distal radius. Denosumab decreased serum C-telopeptide more rapidly and markedly than alendronate. In the placebo arm, total, cortical, and trabecular BMD and cortical thickness decreased (−2.1% to −0.8%) at the distal radius after 12 months. Alendronate prevented the decline (−0.6% to 2.4%, p = .051 to < .001 versus placebo), whereas denosumab prevented the decline or improved these variables (0.3% to 3.4%, p < .001 versus placebo). Changes in total and cortical BMD were greater with denosumab than with alendronate (p ≤ .024). Similar changes in these parameters were observed at the tibia. The polar moment of inertia also increased more in the denosumab than alendronate or placebo groups (p < .001). Adverse events did not differ by group. These data suggest that structural decay owing to bone remodeling and progression of bone fragility may be prevented more effectively with denosumab. PMID:20222106

Whole body vibration exercise improves body balance and walking velocity in postmenopausal osteoporotic women treated with alendronate: Galileo and Alendronate Intervention Trail (GAIT).

PubMed

Iwamoto, J; Sato, Y; Takeda, T; Matsumoto, H

2012-09-01

A randomized controlled trial was conducted to determine the effect of 6 months of whole body vibration (WBV) exercise on physical function in postmenopausal osteoporotic women treated with alendronate. Fifty-two ambulatory postmenopausal women with osteoporosis (mean age: 74.2 years, range: 51-91 years) were randomly divided into two groups: an exercise group and a control group. A four-minute WBV exercise was performed two days per week only in the exercise group. No exercise was performed in the control group. All the women were treated with alendronate. After 6 months of the WBV exercise, the indices for flexibility, body balance, and walking velocity were significantly improved in the exercise group compared with the control group. The exercise was safe and well tolerated. The reductions in serum alkaline phosphatase and urinary cross-linked N-terminal telopeptides of type I collagen during the 6-month period were comparable between the two groups. The present study showed the benefit and safety of WBV exercise for improving physical function in postmenopausal osteoporotic women treated with alendronate.

Assessment of OPG, RANKL, bone turnover markers serum levels and BMD after treatment with strontium ranelate and ibandronate in patients with postmenopausal osteoporosis.

PubMed

Stuss, Michał; Sewerynek, Ewa; Król, Iwona; Stępień-Kłos, Wioletta; Jędrzejczyk, Sławomir

2016-01-01

The aim of this study was to evaluate quantitative changes in OPG and RANKL proteins after treatment with strontium ranelate (SR) and ibandronate in patients with postmenopausal osteoporosis. A total of 89 women with postmenopausal osteoporosis (PO), aged 51-85 years, patients of the Outpatient Clinic of Osteoporosis of the Military Teaching Hospital in Lodz, were enrolled in the study. The patients were randomly assigned to different therapies: ibandronate and (SR). Patients of the control group received only calcium and vitamin D3 supplements. The patients' visits were repeated after three and six months. Measurements of beta-CTX (C-terminal Telopeptide of type 1 collagen), osteocalcin, RANKL, osteoprotegerin (OPG), alkaline phosphatase concentrations in serum, as well as of total 24-hour calcium and phosphate levels in serum and urine, were carried out in material collected at baseline and after three and six months of therapy. Left hip and lumbar spine densitometry was done twice (at baseline visit and after six months). In all three groups there were no significant differences noted in the concentrations of OPG and RANKL serum protein levels during the study period. Both negative and positive correlations or tendencies of correlations were found between OPG serum concentrations and BMD changes in the SR group. Both ibandronate and SR do not seem to cause any significant changes in OPG and RANKL protein serum levels during the first six months of treatment. OPG may play a role in osteoclast activity suppression in the course of treatment with ibandronate in patients with PO. OPG may play an important role in the mechanism of SR therapy and may be viewed as a potentially valuable parameter for monitoring and predicting the course of treatment with SR in PO.

Effect of heparin and alendronate coating on titanium surfaces on inhibition of osteoclast and enhancement of osteoblast function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moon, Ho-Jin; Yun, Young-Pil; Han, Choong-Wan

2011-09-23

Highlights: {yields} We examine bone metabolism of engineered alendronate attached to Ti surfaces. {yields} Alendronate-immobilized Ti enhances activation of osteoblast differentiation. {yields} Alendronate-immobilized Ti inhibits osteoclast differentiation. {yields} Alendronate-immobilized Ti may be a bioactive implant with dual functions. -- Abstract: The failure of orthopedic and dental implants has been attributed mainly to loosening of the implant from host bone, which may be due to weak bonding of the implant material to bone tissue. Titanium (Ti) is used in the field of orthopedic and dental implants because of its excellent biocompatibility and outstanding mechanical properties. Therefore, in the field of materialsmore » science and tissue engineering, there has been extensive research to immobilize bioactive molecules on the surface of implant materials in order to provide the implants with improved adhesion to the host bone tissue. In this study, chemically active functional groups were introduced on the surface of Ti by a grafting reaction with heparin and then the Ti was functionalized by immobilizing alendronate onto the heparin-grafted surface. In the MC3T3-E1 cell osteogenic differentiation study, the alendronate-immobilized Ti substrates significantly enhanced alkaline phosphatase activity (ALP) and calcium content. Additionally, nuclear factor kappa B ligand (RANKL)-induced osteoclast differentiation of RAW264.7 cells was inhibited with the alendronate-immobilized Ti as confirmed by TRAP analysis. Real time PCR analysis showed that mRNA expressions of osteocalcin and osteopontin, which are markers for osteogenesis, were upregulated in MC3T3-E1 cells cultured on alendronate-immobilized Ti. The mRNA expressions of TRAP and Cathepsin K, markers for osteoclastogenesis, in RAW264.7 cells cultured on alendronate-immobilized Ti were down-regulated. Our study suggests that alendronate-immobilized Ti may be a bioactive implant with dual functions to

Favorable therapeutic response of osteoporosis patients to treatment with intravenous zoledronate compared with oral alendronate

PubMed Central

Al-Bogami, Mohammed M.; Alkhorayef, Mohammed A.; Bystrom, Jonas; Akanle, Olufunso A.; Al-Adhoubi, Nasra K.; Jawad, Ali S.; Mageed, Rizgar A.

2015-01-01

Objectives: To evaluate the efficacy of orally-administered alendronate compared with intravenously-administered zoledronate. Methods: This prospective study was carried out at Barts Health HNS Trust between April 2010 and March 2012. This study compares changes in bone mineral density (BMD) in 234 patients treated with 2 bisphosphonates: alendronate taken orally, and zoledronate administered intravenously. One hundred and eighteen patients received alendronate at 70 mg/week, while 116 patients received zoledronate once annually. Dual energy x-ray absorptiometry was used to measure BMD of the left hip and anterior-posterior spine (lumbar L1-L4) skeletal sites at baseline, and at one-, and 2-years post-treatment. Results: This study provides evidence that lumbar spine BMD increased by 3.6% in patients receiving alendronate, and 5.7% in patients receiving zoledronate after 2 years compared with baseline values (p=0.0001 for both). Total hip BMD decreased in patients treated with alendronate by 0.4% but increased in patients receiving zoledronate by 0.8% (p=0.0001). Conclusion: This study provides evidence that zoledronate is more effective than alendronate in treating patients with osteoporosis and with no gastrointestinal (GI) serious side effects. Furthermore, zoledronate appears to have the added advantage of a better safety profile in patients suffering from GI intolerance of oral bisphosphonates. PMID:26593163

Alendronate for the Treatment of Osteoporosis in Men: A Meta-Analysis of Randomized Controlled Trials.

PubMed

Xu, Zhiguo

Alendronate has been widely used in the treatment of osteoporosis. However, the effect of alendronate in the male osteoporosis remains controversial. We conducted a meta-analysis to assess the efficacy of alendronate in the treatment of men with osteoporosis. PubMed, Embase, and Web of Science were searched from their inception to October 25, 2015. Eligible studies were randomized controlled trials that evaluated the effect of alendronate in the male osteoporosis. The outcomes included mean percentage changes in bone mineral density (BMD) of lumbar spine, femoral neck, total hip, trochanter, and total body, and the incidence of new vertebral fractures. Results were expressed with weighted mean difference (WMD), and risk ratio with 95% CIs. A fixed-effects model or random-effects model was used for the meta-analysis according to heterogeneity. Eight studies involving 988 patients met the inclusion criteria. Alendronate significantly increased the mean percentage BMD at the lumbar spine (WMD = 4.95, 95% CI, 2.40-7.49; P < 0.001), femoral neck (WMD = 2.59, 95% CI, 1.52-3.66; P < 0.001), and total hip (WMD = 2.39, 95% CI, 1.05-3.27; P < 0.001), but not at the trochanter (WMD = 1.76, 95% CI, -0.69 to 4.21; P = 0.158) and total body (WMD = 3.29, 95% CI, -0.04 to 6.62; P = 0.053). Moreover, alendronate was also decreased the incidence of vertebral fractures (risk ratio = 0.46, 95% CI, 0.28-0.77; P = 0.003). Subgroup analysis showed that among the male osteoporosis, greater increase in the lumbar spine BMD (WMD = 5.99, 95% CI, 3.42-8.56; P < 0.001) and femoral neck BMD (WMD = 3.66, 95% CI, 2.57-4.76; P = 0.023) was observed when the alendronate was administrated with a dose of 10 mg. Based on current evidence, alendronate shows beneficial effect on the lumbar spine, femoral neck, and total hip BMD, and the incidence of new vertebral fractures.

Patterns of osteoporosis treatment change and treatment discontinuation among commercial and Medicare Advantage Prescription Drug members in a national health plan.

PubMed

Xu, Yihua; Viswanathan, Hema N; Ward, Melea A; Clay, Brad; Adams, John L; Stolshek, Bradley S; Kallich, Joel D; Fine, Shari; Saag, Kenneth G

2013-02-01

Multiple treatments are available for osteoporosis; however, little is known about treatment change patterns and associated factors. Osteoporosis treatment change patterns, discontinuation and factors associated with treatment change in members of a large national health plan were examined. A retrospective cohort study was conducted in 7315 commercial and 34 146 Medicare Advantage Prescription Drug (MAPD) members newly initiated on an osteoporosis medication between 2006 and 2008. Osteoporosis treatment change, discontinuation and re-initiation patterns were assessed. Multivariate logistic regression was used to examine factors associated with treatment change. Commercial and MAPD members were assessed separately because of differences in demographics and insurance benefits. Approximately 12% of members had a change in index therapy within 12 months. Almost 60% of members discontinued the index medication at least once, based on a 90-day refill gap. Over 40% of members discontinued all osteoporosis medications by the end of 12 months post-index. Among MAPD and commercial members, women and those with risedronate, ibandronate or calcitonin at index, index therapy in 2008 and an osteoporosis diagnosis were more likely to have a treatment change while members with health plans other than health maintenance organizations and generic alendronate at index were less likely to have a treatment change. Osteoporosis treatment change occurred in approximately 12% of members, while a greater proportion of members discontinued treatment completely within 12 months. Member characteristics may be used to predict therapy change for evaluation and quality initiatives within a health plan. © 2011 Blackwell Publishing Ltd.

Computational Insights into Binding of Bisphosphates to Farnesyl Pyrophosphate Synthase

PubMed Central

Ohno, K; Mori, K; Orita, M; Takeuchi, M

2011-01-01

Bisphosphonates (BPs) are the most widely used and effective treatment for osteoporosis and Paget's disease. Non-nitrogen containing BPs (non-N-BPs), namely etidronate, clodronate, tiludronate, as well as nitrogen-containing BPs (N-BPs), namely pamidronate, alendronate, ibandronate, risedronate, zoledronate and minodronate have been launched on the market to date. N-BPs act by inhibiting the enzyme farnesyl pyrophosphate synthase (FPPS), and several crystal structures of complexes between FPPS and N-BPs have been revealed. Understanding the physical basis of the binding between protein and small molecules is an important goal in both medicinal chemistry and structural biology. In this review, we analyze in detail the energetic basis of molecular recognition between FPPS and N-BPs. First, we summarize the interactions between ligands and proteins observed in N-BPs-FPPS complexes in the Protein Data Bank (PDB). Second, we present an interaction energy analysis on the basis of full quantum mechanical calculation of FPPS and N-BP complexes using the fragment molecular orbital (FMO) method. The FMO result revealed that not only hydrogen bond and electrostatic interaction but also CH-O and π-π interaction with FPPS are important for N-BP’s potency. Third, we describe a binding site analysis of FPPS on the basis of the inhomogeneous solvation theory which, by clustering the results from an explicit solvent molecular dynamics simulation (MD), is capable of describing the entropic and enthalpic contributions to the free energies of individual hydration sites. Finally, we also discuss the structure-activity relationship (SAR) of the series of minodronate derivatives. PMID:21110804

Effects of Bisphosphonates and Calcium plus Vitamin-D Supplements on Cognitive Function in Postmenopausal Osteoporosis§.

PubMed

Safer, Umut; Safer, Vildan Binay; Demir, Sibel Ozbudak; Yanikoglu, Inci

2016-01-01

Postmenopausal osteoporosis has been linked to accelerated cognitive decline; however, little is known about the effects of medical treatment on cognitive functions. In this prospective study, we evaluated the effects of bisphosphonate treatment and calcium plus vitamin D supplementation on cognitive functions in 45 women with postmenopausal osteoporosis who were started on medical treatment. The medications included alendronate, zoledronic acid, risedronate, or ibandronic acid along with a low or high dose of calcium plus vitamin D supplements. The cognitive function was assessed by the mini-mental state examination (MMSE) test. All subjects underwent bone mineral density (BMD) measurement via dual-energy X-ray absorptiometry at baseline and at study completion. The mean T-score improved significantly at 1 year, except for neck of the femur area. The mean MMSE score did not change significantly at 12 months (26.40 ± 2.07 vs. 26.48 ± 2.07; p = 0.513), with no difference among bisphosphonates combined with calcium plus vitamin D. Higher dose (1200 mg/800 U/day) of calcium plus vitamin D supplementation tended to have a greater improvement as compared with lower dose (600 mg/400 U/day) (Δ MMSE: 0.11 ± 0.72 vs. -0.14 ± 0.69). Cognitive functions in the women remained unaltered, whereas bone BMD T-scores were significantly improved at the 12(th) month after the administration of bisphosphonates and calcium plus vitamin D supplements. Higher doses of calcium plus vitamin D supplements were likely to have better cognitive effects as compared with lower doses.

Highly sensitive determination of alendronate in human plasma and dialysate using metal-free HPLC-MS/MS.

PubMed

Yamada, Miho; Lee, Xiao-Pen; Fujishiro, Masaya; Iseri, Ken; Watanabe, Makoto; Sakamaki, Hiroshi; Uchida, Naoki; Matsuyama, Takaaki; Kumazawa, Takeshi; Takahashi, Haruo; Ishii, Akira; Sato, Keizo

2018-01-01

A highly sensitive method was developed for the analysis of alendronate in human plasma and dialysate using MonoSpin™ SAX ® extraction and metal-free high-performance liquid chromatography (HPLC)-tandem mass spectrometry (MS/MS) following methylation with trimethylsilyldiazomethane. The chromatographic separation of the derivatives for alendronate and alendronate-d 6 was achieved on an L-column2 ODS metal-free column (50 mm  ×  2 mm i.d., particle size 3 µm) with a linear gradient elution system composed of 10 mM ammonium acetate (pH 6.8) and acetonitrile at a flow rate of 0.3 ml/min. Quantification was performed by multiple reaction monitoring (MRM) with positive-ion electrospray ionization (ESI). Distinct peaks were observed for alendronate and for the internal standard on each channel within 1 min. The regression equations showed good linearity within the ranges of 2.0-100 ng/0.5 ml for the plasma and 1.0-100 ng/0.5 ml for the dialysate, with the limits of detection at 1.0 ng/0.5 ml for the plasma and 0.5 ng/0.5 ml for the dialysate. Extraction efficiencies for alendronate for the plasma and dialysate were 41.1-51.2% and 63.6-73.4%, respectively. The coefficient of variation (CV) was ≤8.5%. The method was successfully applied to the analyses of real plasma and dialysate samples derived after intravenous administration of alendronate. Copyright © 2017 Elsevier B.V. All rights reserved.

Differences in otosclerotic and normal human stapedial osteoblast properties are normalized by alendronate in vitro.

PubMed

Gronowicz, Gloria; Richardson, Yvonne L; Flynn, John; Kveton, John; Eisen, Marc; Leonard, Gerald; Aronow, Michael; Rodner, Craig; Parham, Kourosh

2014-10-01

Identify and compare phenotypic properties of osteoblasts from patients with otosclerosis (OSO), normal bones (HOB), and normal stapes (NSO) to determine a possible cause for OSO hypermineralization and assess any effects of the bisphosphonate, alendronate. OSO (n = 11), NSO (n = 4), and HOB (n = 13) cultures were assayed for proliferation, adhesion, mineralization, and gene expression with and without 10(-10)M-10(-8)M alendronate. Academic hospital. Cultures were matched for age, sex, and passage number. Cell attachment and proliferation + alendronate were determined by Coulter counting cells and assaying tritiated thymidine uptake, respectively. At 7, 14, and 21 days of culture + alendronate, calcium content and gene expression by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were determined. OSO had significantly more cells adhere but less proliferation than NSO or HOB. Calcification was significantly increased in OSO compared to HOB and NSO. NSO and HOB had similar cell adhesion and proliferation rates. A dose-dependent effect of alendronate on OSO adhesion, proliferation, and mineralization was found, resulting in levels equal to NSO and HOB. All cultures expressed osteoblast-specific genes such as RUNX2, alkaline phosphatase, type I collagen, and osteocalcin. However, osteopontin was dramatically reduced, 9.4-fold at 14 days, in OSO compared to NSO. Receptor activator of nuclear factor κB ligand/osteoprotegerin (RANKL/OPG), important in bone resorption, was elevated in OSO with decreased levels of OPG levels. Alendronate had little effect on gene expression in HOB but in OSO increased osteopontin levels and decreased RANKL/OPG. OSO cultures displayed properties of hypermineralization due to decreased osteopontin (OPN) and also had increased RANKL/OPG, which were normalized by alendronate. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014.

Alendronate as an Effective Countermeasure to Disuse Induced Bone loss

NASA Technical Reports Server (NTRS)

LeBlanc, Adrian D.; Driscol, Theda B.; Shackelford, Linda C.; Evans, Harlan J.; Rianon, Nahid J.; Smith, Scott M.; Lai, Dejian

2002-01-01

Microgravity, similar to diuse immobilization on earth, causes rapid bone loss. This loss is believed to be an adaptive response to the reduced musculoskelatal forces in space and occurs gradually enough that changes occurring during short duration space flight are not a concern. Bone loss, however, will be a major impediment for long duration missions if effective countermeasures are not developed and implemented. Bed rest is used to simulate the reduced mechanical forces in humans and was used to test the hypothesis that oral alendronate would reduce the effects of long duration (17 weeks) inactivity on bone. Eight male subjects were given daily oral doses of alendronate during 17 weeks of horizontal bed rest and compared with 13 male control subjects not given the drug. Efficacy was evaluated based on measurements of bone markers, calcium balance and bone density performed before, during and after the bed rest. The results show that oral alendronate attenuates most of the characteristic changes associated with long duration bed rest and presumably space flight.

Human Disorientation as a Factor in Spacecraft Centrifuge Design

DTIC Science & Technology

2002-09-01

medications and cannot be administered with food or caffeine. It also increases the risk of GI problems if any Non - Steroidal Anti - inflammatory Drugs ...are several other drugs on the market that are used to treat Osteporosis. Risedronate (Actonel), like Alendronate Sodium, alters the remodeling...marketed drugs , only calcitonin would be useful to astronauts. Raloxifene is intended for women who choose not to take estrogen or other medications.16

Inhibition of particulate debris-induced osteolysis by alendronate in a rat model.

PubMed

Thadani, Peter J; Waxman, Bryan; Sladek, Eduard; Barmada, Riad; Gonzalez, Mark H

2002-01-01

A rat model was used to study the efficacy of alendronate therapy in inhibition of particle-induced periprosthetic osteolysis. A prosthesis was simulated by inserting a cylindrical polymethylmethacrylate plug into the distal femur of 24 rats allowing the plug to communicate with the joint space. Intra-articular injections of irregularly-shaped ultra-high molecular weight polyethylene particles of 20-200 pm in diameter were administered at 2-week intervals. The rats were randomized into two groups (n=12 each). Group A rats received twice weekly subcutaneous injections of alendronate sodium while group B rats received injections of saline vehicle only. At 10 weeks all rats were sacrificed. The distal femurs were harvested and axial sections were prepared for histologic analysis. Each section was graded on a scale of 1-4, quantifying the degree of osteolysis surrounding the polymethylmethacrylate plug. Microscopic examination showed a significant (P<.0001) difference in the amount of periprosthetic bone. Femurs from group A treated with alendronate demonstrated mostly normal or near-normal periprosthetic trabeculations, whereas femurs from group B treated with saline showed extensive bone resorption. There was no qualitative difference in the inflammatory cellular response between the groups. This study established the ability of alendronate to inhibit the osteoclastic-mediated osteolysis around joint implants.

Effects of teriparatide versus alendronate for treatment of postmenopausal osteoporosis: A meta-analysis of randomized controlled trials.

PubMed

Wang, Ya-Kang; Qin, Si-Qing; Ma, Tao; Song, Wei; Jiang, Ren-Qi; Guo, Jian-Bin; Li, Kun; Zhang, Yu-Min

2017-05-01

Osteoporosis remains a clinical challenge. Teriparatide is an anabolic drug and alendronate is an antiresorptive agent; both are used in the treatment of osteoporosis. Comprehensive reviews investigating the comparative safety and efficacy of teriparatide versus alendronate are scarce. Therefore, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the safety and efficacy of teriparatide versus alendronate for the treatment of postmenopausal osteoporosis. We conducted a comprehensive literature review of the PubMed, EMBASE, Cochrane Controlled Trials Registry, and the China Academic Journal Network Publishing databases for relevant RCTs of teriparatide versus alendronate in postmenopausal osteoporosis patients. Outcome measures were percentage change in lumbar spine and femoral neck bone mineral density (BMD) and incidence of vertebral and nonvertebral fractures. Effect size was reported as weighted mean differences (WMDs) for continuous outcomes and odds ratios (OR) for dichotomous outcomes, with associated 95% confidence intervals (CIs). Six trials involving 618 patients were included. The meta-analysis demonstrated a significant increase in lumbar spine BMD (WMD: 3.46, 95% CI: 2.15-4.77, P < .00001), but not femoral neck BMD (WMD = 1.50, 95% CI: 0.04-2.95, P = .04), in postmenopausal osteoporosis patients treated with teriparatide compared with alendronate for 6 to 18 months. These beneficial effects were apparent in the lumbar spine at 12 months of treatment (WMD: 4.49, 95% CI: 2.57-6.40, P < .01). Teriparatide was not superior to alendronate in reducing fracture risk (OR: -0.03, 95% CI: -0.12 to 0.07; P = .52). Teriparatide may be superior to alendronate for increasing lumbar spine BMD in postmenopausal osteoporosis. The efficacy and safety of long-term teriparatide and alendronate treatment in postmenopausal osteoporosis should be further investigated in clinical trials.

Evidence for Using Alendronate to Treat Adult Avascular Necrosis of the Femoral Head: A Systematic Review

PubMed Central

Luo, Ru-Bin; Lin, Tiao; Zhong, Hui-Ming; Yan, Shi-Gui; Wang, Jian-An

2014-01-01

Osteonecrosis or avascular osteonecrosis (AVN) of the femoral head is a devastating multifactorial disease that affects 20 000 persons each year in the United States. The purpose of this systematic review was to determine the efficacy and safety of alendronate for adult AVN during short- and long-term follow-up. Electronic databases were searched for randomized or nonrandomized clinical trials, cohort, case-control studies, and series of cases in which alendronate was used for treatment of adult AVN of the femoral head. Relevant articles with adequate data on reduction of pain, improvement of articular function, slowing of bone collapse progression, or need for total hip arthroplasty (THA) were included after applying inclusion and exclusion criteria. Eight articles involving 788 hips with evidence level 1b to 3b were included in this systematic review. Most studies suggested a positive short-term efficacy of alendronate treatment in reducing pain, improving articular function, slowing of bone collapse progression, and delaying the need for THA for adult AVN patients. The favorable long-term results were also presented in those treated patients after 10-year follow-up. In addition, there were no severe adverse effects associated with alendronate treatment observed during short- and long-term follow-up, and most of the included studies suggested use of alendronate in early AVN with small necrotic lesion to achieve better outcomes. The findings support consideration of alendronate use for adult AVN, particularly with early stage and small necrotic size. The lack of large-scale, randomized, and double-blind studies justifies new studies to demonstrate the detailed indication and the optimized strategy of alendronate treatment. Level of evidence: Level 3a. PMID:25424061

Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial.

PubMed

Kendler, David L; Marin, Fernando; Zerbini, Cristiano A F; Russo, Luis A; Greenspan, Susan L; Zikan, Vit; Bagur, Alicia; Malouf-Sierra, Jorge; Lakatos, Péter; Fahrleitner-Pammer, Astrid; Lespessailles, Eric; Minisola, Salvatore; Body, Jean Jacques; Geusens, Piet; Möricke, Rüdiger; López-Romero, Pedro

2017-11-09

No clinical trials have compared osteoporosis drugs with incident fractures as the primary outcome. We compared the anti-fracture efficacy of teriparatide with risedronate in patients with severe osteoporosis. In this double-blind, double-dummy trial, we enrolled post-menopausal women with at least two moderate or one severe vertebral fracture and a bone mineral density T score of less than or equal to -1·50. Participants were randomly assigned to receive 20 μg of teriparatide once daily plus oral weekly placebo or 35 mg of oral risedronate once weekly plus daily injections of placebo for 24 months. The primary outcome was new radiographic vertebral fractures. Secondary, gated outcomes included new and worsened radiographic vertebral fractures, clinical fractures (a composite of non-vertebral and symptomatic vertebral), and non-vertebral fractures. This study is registered with ClinicalTrials.gov (NCT01709110) and EudraCT (2012-000123-41). We enrolled 680 patients in each group. At 24 months, new vertebral fractures occurred in 28 (5·4%) of 680 patients in the teriparatide group and 64 (12·0%) of 680 patients in the risedronate group (risk ratio 0·44, 95% CI 0·29-0·68; p<0·0001). Clinical fractures occurred in 30 (4·8%) of 680 patients in the teriparatide group compared with 61 (9·8%) of 680 in the risedronate group (hazard ratio 0·48, 95% CI 0·32-0·74; p=0·0009). Non-vertebral fragility fractures occurred in 25 (4·0%) patients in the teriparatide group and 38 (6·1%) in the risedronate group (hazard ratio 0·66; 95% CI 0·39-1·10; p=0·10). Among post-menopausal women with severe osteoporosis, the risk of new vertebral and clinical fractures is significantly lower in patients receiving teriparatide than in those receiving risedronate. Lilly. Copyright © 2017 Elsevier Ltd. All rights reserved.

Treatment of bone loss in osteopenic patients with Crohn's disease: a double-blind, randomised trial of oral risedronate 35 mg once weekly or placebo, concomitant with calcium and vitamin D supplementation.

PubMed

van Bodegraven, Ad A; Bravenboer, Nathalie; Witte, Birgit I; Dijkstra, Gerard; van der Woude, C Janneke; Stokkers, Pieter C M; Russel, Maurice G; Oldenburg, Bas; Pierik, Marieke; Roos, Jan C; van Hogezand, Ruud A; Dik, Vincent K; Oostlander, Angela E; Netelenbos, J Coen; van de Langerijt, Lex; Hommes, Daniel W; Lips, Paul

2014-09-01

Osteoporosis and fractures are frequently encountered in patients with Crohn's disease. In order to prevent fractures, treatment with bone protecting drugs appears warranted early in the course of bone disease when bone loss is not yet prominent. We therefore aimed to demonstrate a beneficial effect on bone density of the bisphosphonate risedronate in osteopenic Crohn's disease patients. This double-blind, placebo-controlled randomised trial of risedronate with calcium and vitamin D supplementation was performed in osteopenic Crohn's disease patients. Patients were treated for 2 years with follow-up after 3 and after every 6 months. Disease characteristics and activity and bone turnover markers were assessed at all visits; dual x-ray absorptiometry was performed at baseline, 12 and 24 months; radiographs of the spine at baseline and 24 months. Of 132 consenting patients, 131 were randomised (67 placebo and 64 risedronate). Patient characteristics were similar in both groups, although the risedronate group was slightly heavier (body mass index 24.3 vs 23.0 kg/m(2)). Bone mineral density at lumbar spine increased 0.04 g/cm(2) on average in the risedronate group versus 0.01 g/cm(2) in the placebo group (p=0.007). The mean increase in total hip bone mineral density was 0.03 versus 0.01 g/cm(2), respectively (p=0.071). Fracture prevalence and incidence were similar. Change of T-scores and concentrations of bone turnover markers were consistent with a beneficial effect of risedronate when compared with placebo. The effect of risedronate was primarily demonstrated in the first 12 months of treatment. No serious unexpected suspected adverse events were observed. A 24-month treatment course with risedronate 35 mg once weekly, concomitant with calcium and vitamin D supplementation, in osteopenic Crohn's disease patients improved bone density at lumbar spine. NTR 163 Dutch Trial Register. Published by the BMJ Publishing Group Limited. For permission to use

[Clinical application of alendronate for osteoporosis/osteopenia secondary to hyperthyroidism].

PubMed

Yang, Li-Juan; Shen, Fei-Xia; Zheng, Jing-Chen; Zhang, Hai-Ling

2012-02-01

To evaluate the efficacy and safety of alendronate for the treatment of osteoporosis/osteopenia secondary to hyperthyroidism. From April 2008 to November 2009, 27 patients with hyperthyroidism with osteoporosis/ osteopenia measured by dual energy X-ray absorptiometry (DXA) were included in this study, and then they were randomly divided into two groups (group A and group B) by simple random sampling. Group A consisted of 14 patients treated with antithyroid drug and caltrate D, the antithyroid drug change with thyroid function, and caltrate D 600 mg per day. Group B consisted of 13 patients treated with antithyroid drug, caltrate D and alendronate, antithyroid drug and caltrate D the same as group A, and alendronate 70 mg weekly. Meanwhile, 21 healthy voluntary adults were chosen as control group. And compared with the control group which was treated with nothing. Followed-up for one year, the bone mineral density (including T-score, Z-score, BMD) in lumbar spine (LS), femoral neck (FN) and distal radius (DR) and general information, were compared before and after treatment. BMD at FN and DR were significantly higher at 12 months after treatment than at the baseline in group A (P = 0.000); T-score, Z-score, and BMD at the LS, FN and DR were all significantly higher at 12 months after treatment than at the baseline in group B (P < 0.05), but these data could not arrive to normal level. In group A, the percentage increased in BMD at the LS, FN, and DR were (4.34 +/- 10.5)%, (3.21 +/- 1.38)%, (1.95 +/- 0.44)%, respectively, at 12 months after treatment. In group B, the percentage increased in BMD at the LS, FN, and DR were (6.10 +/- 8.12)%, (4.10 +/- 5.64)%, (3.10 +/- 3.23)%, respectively, at 12 months after treatment. There was significant difference in the rate of increase between two groups (P < 0.05). AKP decreased, weight, BMI increased, and thyroid function decreased, after treatment than those before in both of the two groups. (P < 0.05). Alendronate can

The efficacy and safety of weekly 35-mg risedronate dosing regimen for Chinese postmenopausal women with osteoporosis or osteopenia: 1-year data.

PubMed

Gu, Jie-mei; Wang, Li; Lin, Hua; Chen, De-cai; Tang, Hai; Jin, Xiao-lan; Xia, Wei-bo; Hu, Yun-qiu; Fu, Wen-zhen; He, Jin-wei; Zhang, Hao; Wang, Chun; Yue, Hua; Hu, Wei-wei; Liu, Yu-juan; Zhang, Zhen-lin

2015-07-01

Oral risedronate is effective in the treatment of postmenopausal osteoporosis when administered daily, weekly, or monthly. In this 1-year, randomized, double-blind, multicenter study we compared the weekly 35-mg and daily 5-mg risedronate dosing regimens in the treatment of Chinese postmenopausal women with osteoporosis or osteopenia. Postmenopausal women with primary osteoporosis or osteopenia were randomly assigned to the weekly group or daily group (n=145 for each) that received oral risedronate 35 mg once a week or 5 mg daily, respectively, for 1 year. The subjects' bone mineral densities (BMDs), bone turnover markers (P1NP and β-CTX), new vertebral fractures, and adverse events were assessed at baseline and during the treatments. All subjects in the weekly group and 144 subjects in the daily group completed the study. The primary efficacy endpoint after 1 year, ie the mean percent changes in the lumbar spine BMD (95% CI) were 4.87% (3.92% to 5.81%) for the weekly group and 4.35% (3.31% to 5.39%) for the daily group. The incidences of clinical adverse events were 48.3% in the weekly group and 54.2% in the daily group. The weekly 35-mg and daily 5-mg risedronate dosing regimens during 1 year of follow-up show similar efficacy in improving BMDs and biochemical markers of bone turnover in Chinese postmenopausal women with osteoporosis or osteopenia. Moreover, the two dosing regimens exhibit similar safety and tolerability.

Determination of pKa values of alendronate sodium in aqueous solution by piecewise linear regression based on acid-base potentiometric titration.

PubMed

Ke, Jing; Dou, Hanfei; Zhang, Ximin; Uhagaze, Dushimabararezi Serge; Ding, Xiali; Dong, Yuming

2016-12-01

As a mono-sodium salt form of alendronic acid, alendronate sodium presents multi-level ionization for the dissociation of its four hydroxyl groups. The dissociation constants of alendronate sodium were determined in this work by studying the piecewise linear relationship between volume of titrant and pH value based on acid-base potentiometric titration reaction. The distribution curves of alendronate sodium were drawn according to the determined pKa values. There were 4 dissociation constants (pKa 1 =2.43, pKa 2 =7.55, pKa 3 =10.80, pKa 4 =11.99, respectively) of alendronate sodium, and 12 existing forms, of which 4 could be ignored, existing in different pH environments.

Treatment of immobilization hypercalciuria using weekly alendronate in two quadriplegic patients.

PubMed

Atalay, Ayce; Turhan, Nur

2008-01-01

Metabolic and urinary problems encountered in spinal cord injury patients are multifaced. We report two patients with high-level spinal cord injuries who have developed hypercalciuria after admission to the rehabilitation unit. To establish a clean intermittent self-catheterization programme, the hypercalciuria was treated successfully with alendronate. Twenty-four-hour urinary calcium excretion decreased significantly after medical treatment for hypercalciuria. Since high-level quadriplegic patients may not be mobilized in the acute phase of the rehabilitation, use of alendronate for preventing hypercalciuria and maintaining a successful clean intermittent self-catheterization programme can be considered as a supportive/complementary measure.

Impregnation of bone chips with alendronate and cefazolin, combined with demineralized bone matrix: a bone chamber study in goats

PubMed Central

2012-01-01

Background Bone grafts from bone banks might be mixed with bisphosphonates to inhibit the osteoclastic response. This inhibition prevents the osteoclasts to resorb the allograft bone before new bone has been formed by the osteoblasts, which might prevent instability. Since bisphosphonates may not only inhibit osteoclasts, but also osteoblasts and thus bone formation, we studied different bisphosphonate concentrations combined with allograft bone. We investigated whether locally applied alendronate has an optimum dose with respect to bone resorption and formation. Further, we questioned whether the addition of demineralized bone matrix (DBM), would stimulate bone formation. Finally, we studied the effect of high levels of antibiotics on bone allograft healing, since mixing allograft bone with antibiotics might reduce the infection risk. Methods 25 goats received eight bone conduction chambers in the cortical bone of the proximal medial tibia. Five concentrations of alendronate (0, 0.5 mg/mL, 1 mg/mL, 2 mg/mL, and 10 mg/mL) were tested in combination with allograft bone and supplemented with cefazolin (200 μg/mL). Allograft not supplemented with alendronate and cefazolin served as control. In addition, allograft mixed with demineralized bone matrix, with and without alendronate, was tested. After 12 weeks, graft bone area and new bone area were determined with manual point counting. Results Graft resorption decreased significantly (p < 0.001) with increasing alendronate concentration. The area of new bone in the 1 mg/mL alendronate group was significantly (p = 0.002) higher when compared to the 10 mg/mL group. No differences could be observed between the group without alendronate, but with demineralized bone, and the control groups. Conclusions A dose-response relationship for local application of alendronate has been shown in this study. Most new bone was present at 1 mg/mL alendronate. Local application of cefazolin had no effect on bone remodelling. PMID:22443362

Influence of Alendronate and Endplate Degeneration to Single Level Posterior Lumbar Spinal Interbody Fusion

PubMed Central

Rhee, Wootack; Ha, Seongil; Lim, Jae Hyeon; Jang, Il Tae

2014-01-01

Objective Using alendronate after spinal fusion is a controversial issue due to the inhibition of osteoclast mediated bone resorption. In addition, there are an increasing number of reports that the endplate degeneration influences the lumbar spinal fusion. The object of this retrospective controlled study was to evaluate how the endplate degeneration and the bisphosphonate medication influence the spinal fusion through radiographic evaluation. Methods In this study, 44 patients who underwent single-level posterior lumbar interbody fusion (PLIF) using cage were examined from April 2007 to March 2009. All patients had been diagnosed as osteoporosis and would be recommended for alendronate medication. Endplate degeneration is categorized by the Modic changes. The solid fusion is defined if there was bridging bone between the vertebral bodies, either within or external to the cage on the plain X-ray and if there is less than 5° of angular difference in dynamic X-ray. Results In alendronate group, fusion was achieved in 66.7% compared to 73.9% in control group (no medication). Alendronate did not influence the fusion rate of PLIF. However, there was the statistical difference of fusion rate between the endplate degeneration group and the group without endplate degeneration. A total of 52.4% of fusion rate was seen in the endplate degeneration group compared to 91.3% in the group without endplate degeneration. The endplate degeneration suppresses the fusion process of PLIF. Conclusion Alendronate does not influence the fusion process in osteoporotic patients. The endplate degeneration decreases the fusion rate. PMID:25620981

Treatment dynamics of newly marketed drugs and implications for comparative effectiveness research.

PubMed

Gagne, Joshua J; Bykov, Katsiaryna; Willke, Richard J; Kahler, Kristijan H; Subedi, Prasun; Schneeweiss, Sebastian

2013-01-01

Clinicians and payers require rapid comparative effectiveness (CE) evidence generation to inform decisions for new drugs. We empirically assessed treatment dynamics of newly marked drugs and their implications for conducting CE research. We used claims data to evaluate five drug-outcome pairs: 1) raloxifene (vs. alendronate) and fracture; 2) risedronate (vs. alendronate) and fracture; 3) simvastatin plus ezetimibe fixed-dose combination (simvastatin + ezetimibe) (vs. simvastatin alone) and cardiovascular events; 4) rofecoxib (vs. nonselective nonsteroidal anti-inflammatory drugs [ns-NSAIDs]) and myocardial infarction; and 5) rofecoxib (vs. ns-NSAIDS) and gastrointestinal bleed. We examined utilization dynamics in the early marketing period, including evolving utilization patterns, outcome risk among those treated with new versus established drugs, and prior treatment patterns that may indicate treatment resistance or intolerance. We addressed these challenges by replicating active CE monitoring with sequential matched cohort analysis. Patients initiating new drugs were more likely to have used other drugs for the same indication in the past, but the majority of patients in all new drug cohorts were treatment naive (82.0% overall). Patients initiating rofecoxib had higher predicted baseline risk of gastrointestinal bleed than did patients initiating ns-NSAIDs. Patients initiating risedronate and alendronate had similar predicted baseline risks of fracture, while those initiating raloxifene and simvastatin + ezetimibe had lower risks of outcomes of interest relative to their comparators. Prospective monitoring yielded results consistent with expectation for each example. Many challenges to assessing the CE of new drugs are borne out in empirical data. Attention to these challenges can yield valid CE results. Copyright © 2013, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc.

The Effect of Alendronate on Various Graft Materials Used in Maxillary Sinus Augmentation: A Rabbit Study.

PubMed

Ayranci, Ferhat; Gungormus, Metin; Omezli, Mehmet Melih; Gundogdu, Betul

2015-12-01

Increasing sinus pneumatization and the accompanying alveolar bone resorption complicate dental implant placement. This problem can be overcome today by raising the maxillary sinus floor with graft materials. Bisphosphonates are commonly used to accelerate the recovery of the graft materials and to prevent resorption. The purpose of this study is to investigate whether systemic administration of a bisphosphonate (alendronate) would improve new bone formation and reduce fibrous tissue formation over a 6-week follow-up in rabbits treated with two different grafting materials for maxillary sinus floor augmentation. This experimental animal study was conducted at the Experimental Medical Application and Research Center at Erzurum/ Turkey. Twelve New Zealand rabbits, each weighing between 2.7 and 3.3 kg, were used. Twenty-four maxillary sinus floor elevation operations were performed, two on each animal (n = 24). Each elevation was repaired with either deproteinized bovine bone (xenograft) or autogenous bone graft obtained from the iliac crest. Both groups were divided into 2 subgroups: saline-treated and alendronate-treated. All groups underwent the same surgical procedures and evaluation, and were sacrificed at the 6th postoperative week. Sinuses augmented with deproteinized bovine bone (xenograft) and autogenous bone graft were examined histopathologically and histomorphometrically. At 6 weeks, the bone area was significantly larger in the Xenograft-Alendronate group (33.0% ± 5.0%) than in the Xenograft-Saline group (20.8% ± 4.9%) and the bone area was significantly larger in the Autogenous-Alendronate group (43.3% ± 3.8%) than in the Autogenous-Saline group (37.5% ± 6.6%) (P = 0.001). The histomorphometric and histopathological results consistently showed that alendronate stimulated bone formation and reduced fibrous tissue formation in maxillary sinus augmentation grafts, especially in the deproteinized bovine bone group (xenograft). Alendronate may be

The Effect of Alendronate on Various Graft Materials Used in Maxillary Sinus Augmentation: A Rabbit Study

PubMed Central

Ayranci, Ferhat; Gungormus, Metin; Omezli, Mehmet Melih; Gundogdu, Betul

2015-01-01

Background: Increasing sinus pneumatization and the accompanying alveolar bone resorption complicate dental implant placement. This problem can be overcome today by raising the maxillary sinus floor with graft materials. Bisphosphonates are commonly used to accelerate the recovery of the graft materials and to prevent resorption. Objectives: The purpose of this study is to investigate whether systemic administration of a bisphosphonate (alendronate) would improve new bone formation and reduce fibrous tissue formation over a 6-week follow-up in rabbits treated with two different grafting materials for maxillary sinus floor augmentation. Materials and Methods: This experimental animal study was conducted at the Experimental Medical Application and Research Center at Erzurum/ Turkey. Twelve New Zealand rabbits, each weighing between 2.7 and 3.3 kg, were used. Twenty-four maxillary sinus floor elevation operations were performed, two on each animal (n = 24). Each elevation was repaired with either deproteinized bovine bone (xenograft) or autogenous bone graft obtained from the iliac crest. Both groups were divided into 2 subgroups: saline-treated and alendronate-treated. All groups underwent the same surgical procedures and evaluation, and were sacrificed at the 6th postoperative week. Sinuses augmented with deproteinized bovine bone (xenograft) and autogenous bone graft were examined histopathologically and histomorphometrically. Results: At 6 weeks, the bone area was significantly larger in the Xenograft-Alendronate group (33.0% ± 5.0%) than in the Xenograft-Saline group (20.8% ± 4.9%) and the bone area was significantly larger in the Autogenous-Alendronate group (43.3% ± 3.8%) than in the Autogenous-Saline group (37.5% ± 6.6%) (P = 0.001). The histomorphometric and histopathological results consistently showed that alendronate stimulated bone formation and reduced fibrous tissue formation in maxillary sinus augmentation grafts, especially in the deproteinized

Alendronate-coated long-circulating liposomes containing 99mtechnetium-ceftizoxime used to identify osteomyelitis

PubMed Central

Ferreira, Diego dos Santos; Boratto, Fernanda Alves; Cardoso, Valbert Nascimento; Serakides, Rogéria; Fernandes, Simone Odília; Ferreira, Lucas Antônio Miranda; Oliveira, Mônica Cristina

2015-01-01

Osteomyelitis is a progressive destruction of bones caused by microorganisms. Inadequate or absent treatment increases the risk of bone growth inhibition, fractures, and sepsis. Among the diagnostic techniques, functional images are the most sensitive in detecting osteomyelitis in its early stages. However, these techniques do not have adequate specificity. By contrast, radiolabeled antibiotics could improve selectivity, since they are specifically recognized by the bacteria. The incorporation of these radiopharmaceuticals in drug-delivery systems with high affinity for bones could improve the overall uptake. In this work, long-circulating and alendronate-coated liposomes containing 99mtechnetium-radiolabeled ceftizoxime were prepared and their ability to identify infectious foci (osteomyelitis) in animal models was evaluated. The effect of the presence of PEGylated lipids and surface-attached alendronate was evaluated. The bone-targeted long-circulating liposomal 99mtechnetium–ceftizoxime showed higher uptake in regions of septic inflammation than did the non-long-circulating and/or alendronate-non-coated liposomes, showing that both the presence of PEGylated lipids and alendronate coating are important to optimize the bone targeting. Scintigraphic images of septic or aseptic inflammation-bearing Wistar rats, as well as healthy rats, were acquired at different time intervals after the intravenous administration of these liposomes. The target-to-non-target ratio proved to be significantly higher in the osteomyelitis-bearing animals for all investigated time intervals. Biodistribution studies were also performed after the intravenous administration of the formulation in osteomyelitis-bearing animals. A significant amount of liposomes were taken up by the organs of the mononuclear phagocyte system (liver and spleen). Intense renal excretion was also observed during the entire experiment period. Moreover, the liposome uptake by the infectious focus was significantly

Alendronate increases skeletal mass of growing rats during unloading by inhibiting resorption of calcified cartilage

NASA Technical Reports Server (NTRS)

Bikle, D. D.; Morey-Holton, E. R.; Doty, S. B.; Currier, P. A.; Tanner, S. J.; Halloran, B. P.

1994-01-01

Loss of bone mass during periods of skeletal unloading remains an important clinical problem. To determine the extent to which resorption contributes to the relative loss of bone during skeletal unloading of the growing rat and to explore potential means of preventing such bone loss, 0.1 mg P/kg alendronate was administered to rats before unloading of the hindquarters. Skeletal unloading markedly reduced the normal increase in tibial mass and calcium content during the 9 day period of observation, primarily by decreasing bone formation, although bone resorption was also modestly stimulated. Alendronate not only prevented the relative loss of skeletal mass during unloading but led to a dramatic increase in calcified tissue in the proximal tibia compared with the vehicle-treated unloaded or normally loaded controls. Bone formation, however, assessed both by tetracycline labeling and by [3H]proline and 45Ca incorporation, was suppressed by alendronate treatment and further decreased by skeletal unloading. Total osteoclast number increased in alendronate-treated animals, but values were similar to those in controls when corrected for the increased bone area. However, the osteoclasts had poorly developed brush borders and appeared not to engage the bone surface when examined at the ultrastructural level. We conclude that alendronate prevents the relative loss of mineralized tissue in growing rats subjected to skeletal unloading, but it does so primarily by inhibiting the resorption of the primary and secondary spongiosa, leading to altered bone modeling in the metaphysis.

Effect of topical alendronate on root resorption of dried replanted dog teeth.

PubMed

Levin, L; Bryson, E C; Caplan, D; Trope, M

2001-06-01

Alendronate (ALN) is a third generation bisphosphonate with demonstrated osteoclast inhibitory activity that may slow down the resorptive process after severe traumatic injuries. Eighty-two premolar roots of five mongrel dogs were endodontically treated and restored, extracted and treated as follows: 70 roots were bench dried for either 40 or 60 min. Thirty-eight of these roots were then soaked for 5 min in a 1 mM solution of ALN in Hanks' Balanced Salt Solution (HBSS) and replanted. Thirty-two roots were soaked for 5 min in HBSS and replanted. In the remaining 12 roots which were not exposed to the bench drying procedure, a 0.5 mM deep lingual mid-root cemental defect was made. Six of these roots were soaked in a 1 mM solution of ALN in HBSS for 5 min and replanted. The other six roots were soaked for 5 min in HBSS and replanted. Historical negative and positive controls were used from similarly treated teeth in our previous studies. After 4 months the dogs were killed and the roots prepared for histological evaluation. Five-microm-thick cross-sections of the root and surrounding tissue taken every 70 microm were evaluated for healing according to the criteria of Andreasen. In the 12 roots with cemental defects, healing with cementum of the damaged root surface was evaluated. In addition, residual root mass was also measured to determine the extent of root structure loss for each soaking method. Cemental healing took place in all 12 artificially damaged roots, indicating that these soaking media did not inhibit cementogenesis. The alendronate-soaked roots had statistically significantly more healing than the roots soaked in HBSS without alendronate. This improvement in healing was seen in all dogs except one and in all teeth except the first premolar. Soaking in alendronate also resulted in significantly less loss in root mass due to resorption compared to those teeth soaked in HBSS without alendronate.

In vitro disintegration studies of weekly generic alendronate sodium tablets (70 mg) available in the US.

PubMed

Dansereau, Richard J; Crail, Debbie J; Perkins, Alan C

2009-02-01

Bisphosphonates as a class have the potential to cause upper gastrointestinal irritation. Although the generic alendronate sodium tablets are bioequivalent to the branded product, a potential concern is that the pharmaceutical attributes of the various generic formulations my affect the potential for local irritation and tolerability. The in vitro disintegration times were determined using the method described in the US Pharmacopeia 30 (USP 30). The disintegration of three generic alendronate sodium tablets 70 mg available in the United States was compared to that of the branded product. The mean disintegration times of the generic alendronate sodium tablets ranged from 9 to 10 s for the Barr lots to 108 s for the Watson lot. The disintegration time of the branded product (Fosamax) was 53 s. The three Barr lots and one Teva lot had rapid disintegration times which were similar to the disintegration standards (< 30 s) for orally disintegrating tablets. Since there is no established disintegration time for alendronate sodium tablets there can be no assurance that the generic tablets are equivalent to the branded product in terms of esophageal exposure. However, the in vitro disintegration times have not been correlated with in vivo disintegration performance. Copies of generic alendronate sodium tablets are approved based on the results of single-dose bioavailability studies in healthy subjects and this is not considered adequate to establish similar disintegration characteristics.

Alendronate-associated osteonecrosis of the jaws: A review of the main topics

PubMed Central

Paiva-Fonseca, Felipe; Santos-Silva, Alan R.; Della-Coletta, Ricardo; Vargas, Pablo A.

2014-01-01

Bisphosphonates is a group of inorganic pyrophosphates analogues that suppress bone resorption by inducing osteoclast inactivation, being frequently used for management of diseases affecting bone metabolism, bone metastases and bone tumors. However, since 2003 many cases describing the presence of necrotic bone exposures in the jaws have been described in patients receiving these drugs, what represent a significant complication of bisphosphonates treatment. The overall incidence of bisphosphonate-related osteonecrosis of the jaws is low, ranging from 0.7% to 12%, mainly observed in those patients receiving intravenously treatment. Osteonecrosis of the jaws associated to oral bisphosphonate, particularly alendronate, has also been reported by a number of authors. Considering that alendronate is one of the most used drugs worldwide, specially for treatment of osteoporosis, a better understanding of osteonecrosis of the jaws related to its use and how to manage these patients is extremely important. Therefore, in the current manuscript the authors aim to review the most important topics related to this pathological presentation. Key words:Bisphosphonates, alendronate, bisphosphonate-related osteonecrosis of the jaws, osteonecrosis. PMID:23986020

Use of bone alkaline phosphatase to monitor alendronate therapy in individual postmenopausal osteoporotic women.

PubMed

Kress, B C; Mizrahi, I A; Armour, K W; Marcus, R; Emkey, R D; Santora, A C

1999-07-01

Biochemical bone markers are sensitive to the changes in bone turnover that result from treatment of postmenopausal osteoporotic women with antiresorptive therapies. Although information is available on the use of bone markers in monitoring therapy in groups of subjects, less is known regarding how these markers perform in individual patients. Serum bone alkaline phosphatase (bone ALP) concentrations, measured with the Tandem(R) Ostase(R) assay, were used to monitor the biochemical response of bone in postmenopausal women with osteoporosis receiving either 10 mg/day alendronate therapy (n = 74) or calcium supplementation (n = 148) for 24 months. Bone ALP decreased significantly from baseline at 3 months (P alendronate therapy. The magnitude of the bone ALP decrease in the treated osteoporotic population was consistent with normalization to premenopausal concentrations. Of the 74 alendronate-treated subjects, 63 (85.1%) demonstrated a decrease from baseline in bone ALP by 6 months that exceeded the least significant change of 25%. The bone ALP decrease from baseline exceeded 25% in 72 (97%) by the end of the study. The bone ALP assay is a sensitive and reliable tool that may be used to monitor the reduction in bone turnover after alendronate therapy in individual postmenopausal osteoporotic women.

Alendronate promotes osteoblast differentiation and bone formation in ovariectomy-induced osteoporosis through interferon-β/signal transducer and activator of transcription 1 pathway

PubMed Central

Ma, Xiaoqing; Xu, Zhongyang; Ding, Shaofeng; Yi, Guangkun; Wang, Qian

2018-01-01

Alendronate is commonly used for the treatment of postmenopausal osteoporosis; however, the underlying pathological molecular mechanisms of its action remain unclear. In the present study, the alendronate-treated signaling pathway in bone metabolism in rats with ovariectomy induced by osteoporosis was investigated. Rats with osteoporosis were orally administered alendronate or phosphate-buffered saline (control). In addition, the interferon-β (IFN-β)/signal transducer and activator of transcription 1 (STAT1) signaling pathway was investigated in osteoblasts following treatment with alendronate in vitro and in vivo. During the differentiation period, IFN-β (100 ng/ml) was used to treat the osteoblast cells, and the activity, viability and bone metabolism-associated gene expression levels (STAT1, p-STAT1, Fra1, TRAF6 and SOCS1) were analyzed in osteoblast cells. Histopathological changes were used to evaluate osteoblasts, osteoclasts, inflammatory phase of bone healing and osteonecrotic areas. The results demonstrated that alendronate significantly inhibited the activity of osteoporotic osteoclasts by stimulating expression of IFN-β, as well as markedly improved the viability and activity of osteoblasts compared with the control group. In addition, alendronate increased the expression and phosphorylation levels of STAT1 in osteoclasts, enhanced osteoblast differentiation, upregulated the expression levels of alkaline phosphatase and osteocalcin, and increased the expression of osteoblast differentiation-associated genes (osteocalcin, osterix and Runx2). Inhibition of IFN-β expression canceled the benefits of alendronate-mediated osteoblast differentiation. Notably, alendronate enhanced bone formation in rats with osteoporosis induced by ovariectomy. In conclusion, these findings suggest that alendronate can regulate osteoblast differentiation and bone formation in rats with osteoporosis induced by ovariectomy through upregulation of IFN-β/STAT1 signaling

Randomized, Double-Blinded, Placebo-Controlled, Trial of Risedronate for the Prevention of Bone Mineral Density Loss in Nonmetastatic Prostate Cancer Patients Receiving Radiation Therapy Plus Androgen Deprivation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choo, Richard; Lukka, Himu; Cheung, Patrick

Purpose: Androgen deprivation therapy (ADT) has been used as an adjuvant treatment to radiation therapy (RT) for the management of locally advanced prostate carcinoma. Long-term ADT decreases bone mineral density (BMD) and increases the risk of osteoporosis. The objective of this clinical trial was to evaluate the efficacy of risedronate for the prevention of BMD loss in nonmetastatic prostate cancer patients undergoing RT plus 2 to 3 years of ADT. Methods and Materials: A double-blinded, placebo-controlled, randomized trial was conducted for nonmetastatic prostate cancer patients receiving RT plus 2 to 3 years of ADT. All had T scores > −2.5more » on dual energy x-ray absorptiometry at baseline. Patients were randomized 1:1 between risedronate and placebo for 2 years. The primary endpoints were the percent changes in the BMD of the lumbar spine at 1 and 2 years from baseline, measured by dual energy x-ray absorptiometry. Analyses of the changes in BMD and bone turnover biomarkers were carried out by comparing mean values of the intrapatient changes between the 2 arms, using standard t tests. Results: One hundred four patients were accrued between 2004 and 2007, with 52 in each arm. Mean age was 66.8 and 67.5 years for the placebo and risedronate, respectively. At 1 and 2 years, mean (±SE) BMD of the lumbar spine decreased by 5.77% ± 4.66% and 13.55% ± 6.33%, respectively, in the placebo, compared with 0.12% ± 1.29% at 1 year (P=.2485) and 0.85% ± 1.56% (P=.0583) at 2 years in the risedronate. The placebo had a significant increase in serum bone turnover biomarkers compared with the risedronate. Conclusions: Weekly oral risedronate prevented BMD loss at 2 years and resulted in significant suppression of bone turnover biomarkers for 24 months for patients receiving RT plus 2 to 3 years of ADT.« less

Skeletal Health After Continuation, Withdrawal, or Delay of Alendronate in Men With Prostate Cancer Undergoing Androgen-Deprivation Therapy

PubMed Central

Greenspan, Susan L.; Nelson, Joel B.; Trump, Donald L.; Wagner, Julie M.; Miller, Megan E.; Perera, Subashan; Resnick, Neil M.

2008-01-01

Purpose Androgen-deprivation therapy (ADT) for prostate cancer is associated with bone loss and osteoporotic fractures. Our objective was to examine changes in bone density and turnover with sustained, discontinued, or delayed oral bisphosphonate therapy in men receiving ADT. Patients and Methods A total of 112 men with nonmetastatic prostate cancer receiving ADT were randomly assigned to alendronate 70 mg once weekly or placebo in a double-blind, partial-crossover trial with a second random assignment at year 2 for those who initially received active therapy. Outcomes included bone mineral density and bone turnover markers. Results Men initially randomly assigned to alendronate and randomly reassigned at year 2 to continue had additional bone density gains at the spine (mean, 2.3% ± 0.7) and hip (mean, 1.3% ± 0.5%; both P < .01); those randomly assigned to placebo in year 2 maintained density at the spine and hip but lost (mean, −1.9% ± 0.6%; P < .01) at the forearm. Patients randomly assigned to begin alendronate in year 2 experienced improvements in bone mass at the spine and hip, but experienced less of an increase compared with those who initiated alendronate at baseline. Men receiving alendronate for 2 years experienced a mean 6.7% (± 1.2%) increase at the spine and a 3.2% (± 1.5%) at the hip (both P < .05). Bone turnover remained suppressed. Conclusion Among men with nonmetastatic prostate cancer receiving ADT, once-weekly alendronate improves bone density and decreases turnover. A second year of alendronate provides additional skeletal benefit, whereas discontinuation results in bone loss and increased bone turnover. Delay in bisphosphonate therapy appears detrimental to bone health. PMID:18802155

Alendronate inhalation ameliorates elastase-induced pulmonary emphysema in mice by induction of apoptosis of alveolar macrophages.

PubMed

Ueno, Manabu; Maeno, Toshitaka; Nishimura, Satoshi; Ogata, Fusa; Masubuchi, Hiroaki; Hara, Kenichiro; Yamaguchi, Kouichi; Aoki, Fumiaki; Suga, Tatsuo; Nagai, Ryozo; Kurabayashi, Masahiko

2015-03-10

Alveolar macrophages play a crucial role in the pathogenesis of emphysema, for which there is currently no effective treatment. Bisphosphonates are widely used to treat osteoclast-mediated bone diseases. Here we show that delivery of the nitrogen-containing bisphosphonate alendronate via aerosol inhalation ameliorates elastase-induced emphysema in mice. Inhaled, but not orally ingested, alendronate inhibits airspace enlargement after elastase instillation, and induces apoptosis of macrophages in bronchoalveolar fluid via caspase-3- and mevalonate-dependent pathways. Cytometric analysis indicates that the F4/80(+)CD11b(high)CD11c(mild) population characterizing inflammatory macrophages, and the F4/80(+)CD11b(mild)CD11c(high) population defining resident alveolar macrophages take up substantial amounts of the bisphosphonate imaging agent OsteoSense680 after aerosol inhalation. We further show that alendronate inhibits macrophage migratory and phagocytotic activities and blunts the inflammatory response of alveolar macrophages by inhibiting nuclear factor-κB signalling. Given that the alendronate inhalation effectively induces apoptosis in both recruited and resident alveolar macrophages, we suggest this strategy may have therapeutic potential for the treatment of emphysema.

Prevention of aromatase inhibitor-induced bone loss with alendronate in postmenopausal women: The BATMAN Trial.

PubMed

Lomax, Anna J; Yee Yap, Saw; White, Karen; Beith, Jane; Abdi, Ehtesham; Broad, Adam; Sewak, Sanjeev; Lee, Chooi; Sambrook, Philip; Pocock, Nicholas; Henry, Margaret J; Yeow, Elaine G; Bell, Richard

2013-12-01

Postmenopausal women on aromatase inhibitors (AI) are at risk of aromatase inhibitor-associated bone loss (AIBL) and fractures. In 2005 Osteoporosis Australia proposed an algorithm for bisphosphonate intervention. Three hundred and three postmenopausal women with early breast cancer (EBC) were enrolled (osteoporotic, n=25; osteopaenic, n=146; normal bone mineral density (BMD), n=126). Weekly alendronate (70 mg) treatment efficacy as triggered by the algorithm in preventing bone loss was evaluated. All patients received anastrozole (1 mg daily), calcium and vitamin D. All osteoporotic patients received alendronate at baseline. Eleven out of the 146 (7.5%) osteopaenic patients commenced alendronate within 18 months of participation and eleven commenced after. One hundred and twenty four out of the 146 (84.9%) osteopaenic patients and all 126 with normal baseline BMD did not trigger the algorithm. At three years, lumbar spine mean BMD increased (15.6%, p<0.01) in the osteoporotic group. BMD in the osteopaenic group with early intervention significantly increased at three years (6.3%, p=0.02). No significant change was seen in the late intervention group. No change was observed in those with osteopaenia without alendronate. There was a significant drop in lumbar spine (-5.4%) and hip (-4.5%) mean BMD, in the normal BMD group, none of whom received alendronate. Fracture data will be presented. In postmenopausal women with endocrine-responsive EBC, BMD improved over time when a bisphosphonate is administered with anastrozole in osteoporotic patients using an osteoporosis schedule. Subjects with normal baseline BMD experienced the greatest BMD loss, although none became osteoporotic.

Alendronate Sodium as Enteric Coated Solid Lipid Nanoparticles; Preparation, Optimization, and In Vivo Evaluation to Enhance Its Oral Bioavailability

PubMed Central

Hosny, Khaled Mohamed

2016-01-01

Treatment of osteoporosis with alendronate sodium has several challenges. The first challenge is the low bioavailability. The second main challenge is side effects, which include oesophageal ulceration. The aim of this research was to reformulate alendronate sodium as enteric coated solid lipid nanoparticles in order to enhance its bioavailability, and preventing the free alendronate sodium from coming into direct contact with the gastrointestinal mucosa, and thereby reducing the possibility of side effects. Enteric coated solid lipid nanoparticles were prepared according to the Box-Behnken design employing Design expert® software, and characterized for size, morphology, and entrapment efficiency. The optimized formula was coated with an Eudragit S100 and evaluated for drug release in acidic and basic media, stability studies and pharmacokinetic evaluations on rabbits. The results indicated that, using Derringer's desirability functional tool for optimization, the highest entrapment efficiency value of 74.3% and the smallest size value of 98 nm were predicted under optimum conditions with a desirability value of 0.917. The optimized nanoparticles released alendronate sodium only at an alkaline pH. The pharmacokinetic evaluation revealed that alendronate sodium bioavailability was enhanced by more than 7.4-fold in rabbits. In conclusion, enteric coated solid lipid nanoparticles is a promising formula for the delivery of alendronate sodium, eliminating its oesophageal side effects and enhancing its bioavailability. PMID:27148747

Alendronate Sodium as Enteric Coated Solid Lipid Nanoparticles; Preparation, Optimization, and In Vivo Evaluation to Enhance Its Oral Bioavailability.

PubMed

Hosny, Khaled Mohamed

2016-01-01

Treatment of osteoporosis with alendronate sodium has several challenges. The first challenge is the low bioavailability. The second main challenge is side effects, which include oesophageal ulceration. The aim of this research was to reformulate alendronate sodium as enteric coated solid lipid nanoparticles in order to enhance its bioavailability, and preventing the free alendronate sodium from coming into direct contact with the gastrointestinal mucosa, and thereby reducing the possibility of side effects. Enteric coated solid lipid nanoparticles were prepared according to the Box-Behnken design employing Design expert® software, and characterized for size, morphology, and entrapment efficiency. The optimized formula was coated with an Eudragit S100 and evaluated for drug release in acidic and basic media, stability studies and pharmacokinetic evaluations on rabbits. The results indicated that, using Derringer's desirability functional tool for optimization, the highest entrapment efficiency value of 74.3% and the smallest size value of 98 nm were predicted under optimum conditions with a desirability value of 0.917. The optimized nanoparticles released alendronate sodium only at an alkaline pH. The pharmacokinetic evaluation revealed that alendronate sodium bioavailability was enhanced by more than 7.4-fold in rabbits. In conclusion, enteric coated solid lipid nanoparticles is a promising formula for the delivery of alendronate sodium, eliminating its oesophageal side effects and enhancing its bioavailability.

Alendronate decreases orthotopic PC-3 prostate tumor growth and metastasis to prostate-draining lymph nodes in nude mice

PubMed Central

Tuomela, Johanna M; Valta, Maija P; Väänänen, Kalervo; Härkönen, Pirkko L

2008-01-01

Background Metastatic prostate cancer is associated with a high morbidity and mortality but the spreading mechanisms are still poorly understood. The aminobisphosphonate alendronate, used to reduce bone loss, has also been shown to inhibit the invasion and migration of prostate cancer cells in vitro. We used a modified orthotopic PC-3 nude mouse tumor model of human prostate cancer to study whether alendronate affects prostate tumor growth and metastasis. Methods PC-3 cells (5 × 105) were implanted in the prostates of nude mice and the mice were treated with alendronate (0.5 mg/kg/day in PBS, s.c.) or vehicle for 4 weeks. After sacrifice, the sizes of tumor-bearing prostates were measured and the tumors and prostate-draining regional iliac and sacral lymph nodes were excised for studies on markers of proliferation, apoptosis, angiogenesis and lymphangiogenesis, using histomorphometry and immunohistochemistry. Results Tumor occurrence in the prostate was 73% in the alendronate-treated group and 81% in the control group. Mean tumor size (218 mm3, range: 96–485 mm3, n = 11) in the alendronate-treated mice was 41% of that in the control mice (513 mm3, range: 209–1350 mm3, n = 13) (p < 0.05). In the iliac and sacral lymph nodes of alendronate-treated mice, the proportion of metastatic area was only about 10% of that in control mice (p < 0.001). Immunohistochemical staining of tumor sections showed that alendronate treatment caused a marked decrease in the number of CD34-positive endothelial cells in tumors (p < 0.001) and an increase in that of ISEL positive apoptotic cells in tumors as well as in lymph node metastases (p < 0.05) compared with those in the vehicle-treated mice. The density of m-LYVE-1-stained lymphatic capillaries was not changed. Conclusion Our results demonstrate that alendronate treatment opposes growth of orthotopic PC-3 tumors and decreases tumor metastasis to prostate-draining lymph nodes. This effect could be at least partly explained by

Atypical Fracture of the Sternum After Long-Term Alendronate Plus Cholecalciferol Treatment: A Case Report.

PubMed

Martín Arias, Luis H; García Ortega, Pilar; Sáinz Gil, María; Navarro García, Ester; Treceño Lobato, Carlos; Delgado Armas, Virginia

2017-12-01

A 55-year-old woman developed an atraumatic sternum fracture during treatment with alendronate for osteoporosis. The woman received alendronate 70 mg in combination with cholecalciferol 5600 IU once weekly, as well as nonsteroidal anti-inflammatory drugs. After 4 years of treatment, following a dorsal flexion with no direct thoracic trauma, the patient suffered a fracture of the sternum, with an X-ray revealing sternal body fracture. This fracture was seen to be transverse, noncomminuted and without displacement. Magnetic resonance imaging was carried out to rule out the presence of either a pathological fracture or a fracture resulting from osteoporotic fragility, and showed a triple sternal fracture involving the body, as well as the upper and lower manubrium of the sternum. This fracture presented the features of an atypical femur fracture, except for the location. The alendronate and cholecalciferol combination was discontinued and denosumab was prescribed. After the withdrawal of alendronate, the patient showed clinical improvement, with a decrease in pain, and is currently having routine checkups. The causality algorithm of the Spanish Pharmacovigilance System shows a score of 5, indicating a possible relationship between the patient's sternum fracture and her use of the suspect drug (Naranjo scale 6 = probable).

Cost-minimization study comparing annual infusion of zoledronic acid or weekly oral alendronate in women with low bone mineral density.

PubMed

Chávez-Valencia, Venice; Arce-Salinas, César Alejandro; Espinosa-Ortega, Fabricio

2014-01-01

Cost-minimization study to assess the annual direct costs of 2 antiresorptive strategies in postmenopausal women with low bone mineral densities (BMDs). Patients were randomly assigned to receive 70 mg of oral weekly alendronate or a 1-time 5mg of intravenous zoledronic acid. All medical and nonmedical direct costs were recorded for 1 yr. Student's t-test or the Chi-squared test was used. A total of 101 postmenopausal women were enrolled with a mean age of 58.3 ± 7.6 yr and a postmenopausal period of 13.5 ± 8.3 yr. A total of 50 patients completed 1 yr of alendronate and 51 patients received zoledronic acid. At baseline, no differences were seen between the 2 groups in anthropometric measures, comorbidities, and bone mineral density. The costs for medical attention for low bone mass were $81,532 (US Dollars) for the alendronate group and $69,251 for the zoledronic acid group; the cost per patient was $1631 in the alendronate group vs $1358 in the zoledronic acid group (p<0.0001). Therefore, zoledronic acid treatment provided an annual savings of 15% of the direct costs compared with oral alendronate treatment. Moreover, there was a significant increase in lumbar spine T-scores in the zoledronic acid group when compared with the alendronate group. Annual zoledronic acid infusion as an antiresorptive treatment in women with low BMD provides significant monetary savings when compared with weekly alendronate therapy for 1 yr. Zoledronic acid infusion is also linked to higher increase in BMD and compliance. Copyright © 2014 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.

Synthesis and evaluation of alendronate-modified gelatin biopolymer as a novel osteotropic nanocarrier for gene therapy.

PubMed

Mekhail, George M; Kamel, Amany O; Awad, Gehanne As; Mortada, Nahed D; Rodrigo, Rowena L; Spagnuolo, Paul A; Wettig, Shawn D

2016-09-01

To synthesize an osteotropic alendronate functionalized gelatin (ALN-gelatin) biopolymer for nanoparticle preparation and targeted delivery of DNA to osteoblasts for gene therapy applications. Alendronate coupling to gelatin was confirmed using Fourier transform IR, (31)PNMR, x-ray diffraction (XRD) and differential scanning calorimetry. ALN-gelatin biopolymers prepared at various alendronate/gelatin ratios were utilized to prepare nanoparticles and were optimized in combination with DNA and gemini surfactant for transfecting both HEK-293 and MG-63 cell lines. Gelatin functionalization was confirmed using the above methods. Uniform nanoparticles were obtained from a nanoprecipitation technique. ALN-gelatin/gemini/DNA complexes exhibited higher transfection efficiency in MG-63 osteosarcoma cell line compared with the positive control. ALN-gelatin is a promising biopolymer for bone targeting of either small molecules or gene therapy applications.

Parathyroid hormone plus alendronate in osteoporosis: a meta-analysis of randomized controlled trials.

PubMed

Zhang, Qinggang; Qian, Jing; Zhu, Yuchang

2015-01-01

Parathyroid hormone (PTH) increases both bone formation (BMD) and bone resorption, whereas alendronate reduces bone resorption. It is possible that the combination therapy of PTH with alendronate will enhance their effects on BMD. Therefore, we conducted this meta-analysis to evaluate the efficacy of the combination therapy of PTH with alendronate in the treatment of patients with osteoporosis. A comprehensive literature search of PubMed, Embase, and Web of Science was conducted to identify relative studies. Eligible studies were randomized controlled trials (RCT), which assessed the efficacy of combination therapy in patients with osteoporosis. The outcomes included the mean percent increases in BMD of lumbar spine, femoral neck, total hip, and distal radius. Weighted mean difference (WMD) with 95% confidence intervals (CIs) were calculated using of random-effects or fixed-effects model, depending on the heterogeneity between the included studies. Six RCTs with a total number of 833 patients were included in this meta-analysis. The pooled estimates showed that, the combination therapy of PTH with alendronate resulted in a higher mean percent change of increased BMD in distal radius (WMD = 2.45, 95% CI: 1.58, 3.31; P = 0.000), but not in lumbar spine (WMD = -0.83, 95% CI: -3.48, 1.81; P = 0.538), femoral neck (WMD = -0.99, 95% CI: -2.04, 0.07; P = 0.068), and total hip (WMD = -0.06, 95% CI: -0.93, 0.81; P = 0.892). The subgroup analysis based on the dosage and schedule of PTH, study duration, gender of patients, and anabolic agents, were conducted. And results revealed that among the patients in the combination therapy group, greater increases in the spine BMD were observed when the PTH was administered with a dosage of 20 μg (WMD = 2.33, 95% CI: 1.24, 3.43; P = 0.000), or the treatment duration lasted more than 12 months (WMD = 2.23, 95% CI: 1.00, 3.47; P = 0.000), or the combination therapy was used in osteoporosis women (WMD = 1.58, 95% CI: 0.63, 2.53; P = 0

Alendronate and raloxifene affect the osteoprotegerin/RANKL system in human osteoblast primary cultures from patients with osteoporosis and osteoarthritis.

PubMed

Giner, Mercè; Rios, Ma José; Montoya, Ma José; Vázquez, Ma Angeles; Miranda, Cristina; Pérez-Cano, Ramón

2011-01-15

The osteoprotegerin/RANKL system modulates bone remodelling. Alendronate and raloxifene are anti-resorptive drugs effective in osteoporotic disease. They reduce fracture risk, the activity of bone remodelling and increase bone mineral density. It is not known if they can exert a direct effect in osteoblasts via the osteoprotegerin/RANKL system. Our objective was to assess the effects of alendronate and raloxifene among osteoprotegerin production (ELISA), as well as osteoprotegerin and RANKL expression (RT-PCR), in primary cultures of human osteoblasts (hOB). We compared 17 osteoporotic patients with 16 patients affected by osteoarthritis in basal conditions and after incubation with alendronate (10(-6) M), raloxifene (10(-7) M) or 17-β estradiol (10(-7) M) for 24 h. The statistical analysis was determined by ANOVA. Osteoprotegerin protein secretion in hOB cultures was higher in patients with osteoporosis than osteoarthritis. Osteoprotegerin secretion levels remained unchanged after each treatment. The osteoporotic group was more sensitive to treatment. Both raloxifene (34%) and estradiol (37%) increased osteoprotegerin mRNA expression, and alendronate (118%) and raloxifene (61%) increased the mRNA expression of RANKL. The RANKL/osteoprotegerin mRNA ratio was higher in osteoporotic than osteoarthritic patients. In the osteoporotic group, the RANKL/osteoprotegerin mRNA ratio was significantly increased after treatment with alendronate (112%) and after treatment with raloxifene (60%). These results indicate a direct action of alendronate and raloxifene on hOB cultures from osteoporotic patients, and the cited drugs are able to modulate the osteoprotegerin/RANKL system. Copyright © 2010 Elsevier B.V. All rights reserved.

Short term sodium alendronate administration improves the peri-implant bone quality in osteoporotic animals

PubMed Central

de OLIVEIRA, Danila; HASSUMI, Jaqueline Suemi; GOMES-FERREIRA, Pedro Henrique da Silva; POLO, Tárik Ocon Braga; FERREIRA, Gabriel Ramalho; FAVERANI, Leonardo Perez; OKAMOTO, Roberta

2017-01-01

Abstract Sodium alendronate is a bisphosphonate drug that exerts antiresorptive action and is used to treat osteoporosis. Objective The aim of this study was to evaluate the bone repair process at the bone/implant interface of osteoporotic rats treated with sodium alendronate through the analysis of microtomography, real time polymerase chain reactions and immunohistochemistry (RUNX2 protein, bone sialoprotein (BSP), alkaline phosphatase, osteopontin and osteocalcin). Material and Methods A total of 42 rats were used and divided in to the following experimental groups: CTL: control group (rats submitted to fictitious surgery and fed with a balanced diet), OST: osteoporosis group (rats submitted to a bilateral ovariectomy and fed with a low calcium diet) and ALE: alendronate group (rats submitted to a bilateral ovariectomy, fed with a low calcium diet and treated with sodium alendronate). A surface treated implant was installed in both tibial metaphyses of each rat. Euthanasia of the animals was conducted at 14 (immunhostochemistry) and 42 days (immunohistochemistry, micro CT and PCR). Data were subjected to statistical analysis with a 5% significance level. Results Bone volume (BV) and total pore volume were higher for ALE group (P<0.05). Molecular data for RUNX2 and BSP proteins were significantly expressed in the ALE group (P<0.05), in comparison with the other groups. ALP expression was higher in the CTL group (P<0.05). The immunostaining for RUNX2 and osteopontin was positive in the osteoblastic lineage cells of neoformed bone for the CTL and ALE groups in both periods (14 and 42 days). Alkaline phosphatase presented a lower staining area in the OST group compared to the CTL in both periods and the ALE at 42 days. Conclusion There was a decrease of osteocalcin precipitation at 42 days for the ALE and OST groups. Therefore, treatment with short-term sodium alendronate improved bone repair around the implants installed in the tibia of osteoporotic rats. PMID

Process analytical technology to understand the disintegration behavior of alendronate sodium tablets.

PubMed

Xu, Xiaoming; Gupta, Abhay; Sayeed, Vilayat A; Khan, Mansoor A

2013-05-01

Various adverse events including esophagus irritations have been reported with the use of alendronate tablets, likely attributed to the rapid tablet disintegration in the mouth or esophagus. Accordingly, the disintegration of six alendronate tablet drug products was studied using a newly developed testing device equipped with in-line sensors, in addition to the official compendial procedure for measuring the disintegration time. The in-line sensors were used to monitor the particle count and solution pH change to assess the onset and duration of disintegration. A relatively large variation was observed in the disintegration time of the tested drug products using the compendial method. The data collected using the in-line sensors suggested that all tested drug products exhibited almost instantaneous onset of disintegration, under 2 s, and a sharp drop in solution pH. The drop in pH was slower for tablets with slower disintegration. The in-house prepared alendronate test tablets also showed similar trends suggesting rapid solubilization of the drug contributed to the fast tablet disintegration. This research highlights the usefulness of the newly developed in-line analytical method in combination with the compendial method in providing a better understanding of the disintegration and the accompanying drug solubilization processes for fast disintegrating tablet drug products. Copyright © 2013 Wiley Periodicals, Inc.

Comparing Tolerability and Efficacy of Generic versus Brand Alendronate: A Randomized Clinical Study in Postmenopausal Women with a Recent Fracture

PubMed Central

van den Bergh, Joop P. W.; Bouts, Marian E.; van der Veer, Eveline; van der Velde, Robert Y.; Janssen, Marcel J. W.; Geusens, Piet P.; Winkens, Bjorn; Oldenhof, Nico J. J.; van Geel, Tineke A. C. M.

2013-01-01

Introduction An increasing number of generic alendronate formulations have become available. Although expected to have the same tolerability and efficacy, head-to head comparison of generic and brand alendronate was never performed. Therefore, we compared the tolerability and efficacy of generic and brand alendronate. Methods In a randomized double-blinded single centre cross-over study in 37 postmenopausal women (mean age 65.4±6.4 years) with osteoporosis were treated with generic and branded alendronate during 24 (2x12) weeks. Tolerance was evaluated by the Gastro intestinal Symptom Rating Scale (GSRS) and self-reported side effects. Efficacy was assessed by serum bone turnover markers, carboxy terminal telopeptide (CTX) and procollagen type I N-terminal propeptide (PINP). No wash out period was allowed (ethical reasons). Because of possible carry over effect only data of the first 12 weeks were analyzed using linear mixed models. Results There were no significant differences in overall tolerance (GSRS) between treatment groups. However, for subscale abdominal pain, patients using generic had a significantly higher mean GSRS score at week 4 (estimated mean difference (B): 0.40; 95%CI: 0.05 to 0.74, p = 0.024). The level of bone turnover markers significantly decreased over 12 weeks of follow-up for generic and branded alendronate (p < 0.001). Mean level of CTX was significantly lower with branded at week 4 (B: 121.3; 95%CI: 52.0 to 190.5), but not at week 12 (B: 53.6; 95%CI:-3.7 to 110.9). No significant differences were found for PINP at week 4 or 12. Conclusions Bone turnover markers were significantly reduced with branded and generic alendronate. With branded, CTX was significantly lower at 4 weeks. Generic caused significantly higher abdominal pain scores in the first 4 weeks of treatment. Therefore, generic alendronate may not have the same tolerability and efficacy as branded alendronate in the first weeks after starting treatment in patients with a recent

Prevention and treatment of glucocorticoid-induced osteoporosis: a comparison of calcitriol, vitamin D plus calcium, and alendronate plus calcium.

PubMed

Sambrook, Philip N; Kotowicz, Mark; Nash, Peter; Styles, Colin B; Naganathan, Vasi; Henderson-Briffa, Kathy N; Eisman, John A; Nicholson, Geoff C

2003-05-01

High-dose corticosteroids, used for many medical conditions, are associated with rapid bone loss from sites such as the vertebrae, and compression fractures can be observed within months. Recent trials suggest treatment with bisphosphonates or active vitamin D analogs can reduce bone loss and the risk of fracture associated with glucocorticoids, but few studies have directly compared such agents. We conducted a randomized, multicenter, open-label trial to compare the efficacy of alendronate, calcitriol, and simple vitamin D in prevention and treatment of glucocorticoid-induced bone loss. A total of 195 subjects (134 females and 61 males) commencing or already taking glucocorticoids were randomized to one of three groups: calcitriol, 0.5 to 0.75 microg/day; simple vitamin D (ergocalciferol, 30,000 IU weekly) plus calcium carbonate (600 mg daily); or alendronate, 10 mg/day plus calcium carbonate (600 mg daily). Over 2 years, mean lumbar bone mineral density change was +5.9% with alendronate, -0.5% with ergocalciferol, and -0.7% with calcitriol (p < 0.001). At the femoral neck, there was no significant difference in bone mineral density change between the treatments over 2 years: alendronate (+0.9%), ergocalciferol (-3.2%), and calcitriol (-2.2%). Lumbar bone loss varied according to whether patients were starting or receiving chronic glucocorticoids, and there was a significant treatment x prior glucocorticoid use interaction effect. Six of 66 calcitriol subjects, 1 of 61 ergocalciferol subjects, and 0 of 64 alendronate subjects sustained new vertebral fractures. These data do not suggest any difference between simple vitamin D and calcitriol but do show that alendronate was superior to either treatment for glucocorticoid induced bone loss.

Comparative Effects of Teriparatide and Risedronate in Glucocorticoid-Induced Osteoporosis in Men: 18-Month Results of the EuroGIOPs Trial

PubMed Central

Glüer, Claus-C; Marin, Fernando; Ringe, Johann D; Hawkins, Federico; Möricke, Rüdiger; Papaioannu, Nikolaos; Farahmand, Parvis; Minisola, Salvatore; Martínez, Guillermo; Nolla, Joan M; Niedhart, Christopher; Guañabens, Nuria; Nuti, Ranuccio; Martín-Mola, Emilio; Thomasius, Friederike; Kapetanos, Georgios; Peña, Jaime; Graeff, Christian; Petto, Helmut; Sanz, Beatriz; Reisinger, Andreas; Zysset, Philippe K

2013-01-01

Data on treatment of glucocorticoid-induced osteoporosis (GIO) in men are scarce. We performed a randomized, open-label trial in men who have taken glucocorticoids (GC) for ≥3 months, and had an areal bone mineral density (aBMD) T-score ≤ –1.5 standard deviations. Subjects received 20 μg/d teriparatide (n = 45) or 35 mg/week risedronate (n = 47) for 18 months. Primary objective was to compare lumbar spine (L1–L3) BMD measured by quantitative computed tomography (QCT). Secondary outcomes included BMD and microstructure measured by high-resolution QCT (HRQCT) at the 12th thoracic vertebra, biomechanical effects for axial compression, anterior bending, and axial torsion evaluated by finite element (FE) analysis from HRQCT data, aBMD by dual X-ray absorptiometry, biochemical markers, and safety. Computed tomography scans were performed at 0, 6, and 18 months. A mixed model repeated measures analysis was performed to compare changes from baseline between groups. Mean age was 56.3 years. Median GC dose and duration were 8.8 mg/d and 6.4 years, respectively; 39.1% of subjects had a prevalent fracture, and 32.6% received prior bisphosphonate treatment. At 18 months, trabecular BMD had significantly increased for both treatments, with significantly greater increases with teriparatide (16.3% versus 3.8%; p = 0.004). HRQCT trabecular and cortical variables significantly increased for both treatments with significantly larger improvements for teriparatide for integral and trabecular BMD and bone surface to volume ratio (BS/BV) as a microstructural measure. Vertebral strength increases at 18 months were significant in both groups (teriparatide: 26.0% to 34.0%; risedronate: 4.2% to 6.7%), with significantly higher increases in the teriparatide group for all loading modes (0.005 < p < 0.015). Adverse events were similar between groups. None of the patients on teriparatide but five (10.6%) on risedronate developed new clinical fractures (p = 0.056). In conclusion, in this

Effect of two forms of alendronate administration upon bone mass after two years of treatment.

PubMed

Sosa, M; Hernández, D; Segarra, M C; Gómez, A; de la Peña, E; Betancor, P

2002-01-01

The efficacy of alendronate in slowing the loss of bone mass, or even in increasing it, in osteoporotic patients and thus reducing the risk of new fractures has been described. Nevertheless, the way of taking this drug, together with its side effects, sometimes produces withdrawals. In this study, we analyzed if an alternative way of taking the alendronate improves the follow-up of the treatment and if it had the same effect on bone mineral metabolism than the traditional way of prescription. An open, intention-to-treat study, with follow-up of 2 yr was conducted. Eighty women suffering from postmenopausal osteoporosis were included in the study. They were classified in a random manner into two groups, each one of them received 10 mg/d alendronate, together with 1.2 g of calcium and 800 IU of Vitamin D3. Group I received the drug fasting, before breakfast, as usually prescribed and group II received the alendronate fasting, at noon, before lunch. Biochemical markers of bone remodeling were determined. Total alkaline phosphatase, osteocalcin, tartrate-resistant acid phosphatase, urine calcium/creatinine ratio, crosslinked N-telopeptides of type I collagen/creatinine ratio, serum calcium, and parathyroid hormone were also determined, and a lateral dorsolumbar radiography of the spine was performed. Bone mineral density was determined in the lumbar spine by dual-energy X-ray absorptiometry and quantitative computed tomography and by dual-energy X-ray absorptiometry in the proximal femur. Both groups showed an increase in bone mineral density in the lumbar spine and in the proximal femur, which was statistically significant after 1 yr of treatment in the range between 1.5% and 4.3%, depending on the anatomical localization where bone mineral density was measured. There was also an important decrease in the biochemical markers of bone remodeling, between 5.6% and 42.5%, depending on the biochemical marker; the decrease of amino-terminal telopetide during the first year

Modulation of adhesion-dependent cAMP signaling by echistatin and alendronate

NASA Technical Reports Server (NTRS)

Fong, J. H.; Ingber, D. E.

1996-01-01

We measured intracellular cAMP levels in cells during attachment and spreading on different extracellular matrix (ECM) proteins. Increases in cAMP were observed within minutes when cells attached to fibronectin, vitronectin, and a synthetic RGD-containing fibronectin peptide (Petite 2000), but not when they adhered to another integrin alpha nu beta 3 ligand, echistatin. Because echistatin also inhibits bone resorption, we measured the effects of adding another osteoporosis inhibitor, alendronate, in this system. Alendronate inhibited the cAMP increase induced by ligands that primarily utilize integrin alpha nu beta 3 (vitronectin, Peptite 2000), but not by fibronectin which can also use integrin alpha 5 beta 1. These results show that cell adhesion to ECM can increase intracellular cAPM levels and raise the possibility that inhibitors of osteoporosis may act, in part, by preventing activation of this pathway by integrins.

Effects of risedronate 5 mg/d on bone mineral density and bone turnover markers in late-postmenopausal women with osteopenia: a multinational, 24-month, randomized, double-blind, placebo-controlled, parallel-group, phase III trial.

PubMed

Välimäki, Matti J; Farrerons-Minguella, Jordi; Halse, Johan; Kröger, Heikki; Maroni, Marilyn; Mulder, Henk; Muñoz-Torres, Manuel; Sääf, Maria; Snorre Øfjord, Erik

2007-09-01

Randomized clinical trials have shown that risedronate reduces the risk for both ver- tebral and nonvertebral fractures in postmenopausal women with osteoporosis (bone mineral density [BMD] T-score, <-2.5). If left untreated, osteopenia (T-score, between -1 and -2.5) may progress to osteo- porosis. Risedronate sodium, a pyridinyl bisphospho- nate, is an antiresorptive drug approved by the US Food and Drug Administration for the prevention and treatment of osteoporosis in postmenopausal women. Although the effects of risedronate in preventing frac- tures has been established, its effects in maintaining or increasing BMD in osteopenia have not. In this clinical trial, the efficacy and tol- erability of risedronate in improving and maintaining BMD levels in late-postmenopausal women with os- teopenia were assessed. This 24-month, randomized, double- blind, placebo-controlled, parallel-group, Phase III trial was conducted at 14 study centers across Finland, The Netherlands, Norway, Spain, and Sweden. Late- postmenopausal (> or =5 years from menopause) women with lumbar spine (LS) BMD T-score between -1 and -2.5 and the presence of > or =1 additional risk factor for osteo- porosis or proximal femur (Fern) BMD T-score < or = -1 were randomized to receive risedronate 5 mg (n = 114) or placebo (n = 57) PO QD for 24 months. The primary efficacy end point was the percentage change from baseline in LS BMD at study end point (24 months or last observation carried forward). Secondary efficacy end points were the percentage changes from base- line in total proximal Fern BMD and 2 bone turnover markers-urinary type I collagen cross-linked N-telopeptide (uNTx) and serum bone-specific alkaline phosphatase (sBAP)-at 12 months and study end point. Tolerability was assessed using reported adverse events (AEs), laboratory analysis, and physical exami- nation including vital-sign measurements. A total of 171 women were included (mean [SD] age, 65.9 [6.8] years; mean [SD] LS BMD T

Alendronate augments interleukin-1{beta} release from macrophages infected with periodontal pathogenic bacteria through activation of caspase-1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deng Xue; Tamai, Riyoko; Endo, Yasuo

2009-02-15

Nitrogen-containing bisphosphonates (NBPs) are anti-bone-resorptive drugs with inflammatory side effects that include osteomyelitis and osteonecrosis of the jaw. Oral bacteria have been considered to be a trigger for these NBP-associated jaw bone diseases. The present study examined the effects of alendronate (a typical NBP) and clodronate (a non-NBP) on the production of proinflammatory cytokines by macrophages infected with Porphyromonas gingivalis and Tannerella forsythia, which are important pathogens of periodontal diseases. Pretreatment with alendronate augmented IL-1{beta}, but not TNF{alpha}, production by macrophages infected with P. gingivalis or T. forsythia. This augmentation of IL-1{beta} production was inhibited by clodronate. Furthermore, caspase-1, amore » promoter of IL-1{beta} production, was activated by treatment with alendronate, and caspase-1 inhibitor reduced the production of IL-1{beta} induced by alendronate and P. gingivalis. These results suggest that NBPs augment periodontal pathogenic bacteria-induced IL-1{beta} release via caspase-1 activation, and this phenomenon may contribute to the development of NBP-associated inflammatory side effects including jaw osteomyelitis. Co-treatment with clodronate may prevent and/or reduce these inflammatory effects induced by NBPs.« less

Efficacy and Safety of Risedronate in Osteoporosis Subjects with Comorbid Diabetes, Hypertension, and/or Dyslipidemia: A Post Hoc Analysis of Phase III Trials Conducted in Japan.

PubMed

Inoue, Daisuke; Muraoka, Ryoichi; Okazaki, Ryo; Nishizawa, Yoshiki; Sugimoto, Toshitsugu

2016-02-01

Many osteoporotics have comorbid diabetes mellitus (DM), hypertension (HT), and dyslipidemia (DL). However, whether such comorbidities alter response to anti-osteoporotic treatment is unknown. We did post hoc analyses of combined data from three risedronate Japanese phase III trials to determine whether the presence of DM, HT, or DL affects its efficacy and safety. Data from 885 subjects who received 48-week treatment with risedronate were collected and combined from the three phase III trials. They were divided into two groups by the presence or absence of comorbidities: DM (n = 53) versus non-DM (n = 832); HT (n = 278) versus non-HT (n = 607); and DL (n = 292) versus non-DL (n = 593). Bone mineral density (BMD), urinary type 1 collagen N-telopeptide (uNTX), and serum bone-specific alkaline phosphatase (BAP) were measured at baseline and sequentially until 48 weeks. BMD or bone markers were not different between any of the two groups. Overall, BMD was increased by 5.52%, and uNTX and BAP were decreased by 35.4 and 33.8%, respectively. Some bone markers were slightly lower in DM and DL subjects, but the responses to risedronate were not significantly different. Statin users had lower uNTX and BAP, but showed no difference in the treatment response. All the other medications had no apparent effect. Adverse event incidence was marginally higher in DL compared with non-DL (Relative risk 1.06; 95% confidence interval 1.01-1.11), but was not related to increase in any specific events. Risedronate shows consistent safety and efficacy in suppressing bone turnover and increasing BMD in osteoporosis patients with comorbid DM, HT, and/or DL.

Cytotoxicity analysis of alendronate on cultured endothelial cells and subcutaneous tissue. a pilot study.

PubMed

Moreira, Maria Stella; Katayama, Emilio; Bombana, Antonio Carlos; Marques, Márcia Martins

2005-12-01

The use of alendronate, a bisphosphonate which is able to inhibit bone resorption, in order to prevent dental root resorption after tooth replantation would be of clinical relevance. However, this drug must be biocompatible to the periapical tissues. The aim of this study was to analyze the effect of an alendronate paste in polyethyleneglycol (2 g ml(-1)) on endothelial cells in culture (in vitro) and on rat subcutaneous tissue (in vivo). For the in vitro study the paste was applied on round glass coverslips that were immersed into confluent cell cultures (clone Cips). The cell viability percentages of these cultures were obtained 0, 6 and 12 h after contact with the substance. As control, cultures that received plain coverslips were used. This analysis was carried out in triplicate using the Trypan blue dye exclusion assay. For the in vivo study the paste was introduced into polyethylene tubes that were placed into the rat subcutaneous tissue. The rats were killed 7 and 14 days later; then, the tissue sections stained with hematoxylin-eosin were analyzed. In vitro, the alendronate caused a significant decrease in the cell viability in 6 h (P < 0.05) and 12 h (P < 0.01), when compared with the control cultures. In vivo the tissue response was exuberant and similar at the two experimental times. There was a necrosis in a comprehensive area in contact with the open end of the tube. Presence of micro-abscesses and intense inflammatory infiltrate in the hypoderm permeating the muscle fibers and fat lobules were observed. In conclusion, the alendronate paste in polyethylene glycol as used showed to be highly cytotoxic in vitro as well as in vivo.

Zoledronic acid and alendronate sodium and the implications in orthodontic movement.

PubMed

Franzoni, J S; Soares, F M P; Zaniboni, E; Vedovello Filho, M; Santamaria, M P; Dos Santos, G M T; Esquisatto, M A M; Felonato, M; Mendonca, F A S; Franzini, C M; Santamaria, M

2017-08-01

To evaluate orthodontic tooth movement (OTM) in rats treated with two types of bisphosphonates (BPs), alendronate sodium (A) and zoledronic acid (Z). In all, 15 male Wistar rats were randomly divided into three groups. Group OTM+A: orthodontic tooth movement and subcutaneous administration of alendronate sodium (2.5 mg/kg); Group OTM+Z: orthodontic tooth movement and subcutaneous administration of zoledronic acid (0.02 mg/kg), and Group OTM: orthodontic tooth movement and subcutaneous injection of saline. The BPs were administered once a day during 25 days before OTM started and during 10 days of OTM. The left upper first molar was moved with a stainless-steel closed coil spring which delivered an initial force of 0.4N. OTM was measured with a digital caliper comparing the moved and the contralateral side. The histomorphometric analysis counted the number of osteoclasts, inflammatory cells, blood vessels and fibroblasts (n/10 4  m 2 ) in periodontal ligament (PDL) of the distobuccal root. A reduction of 58.3% of OTM was found in Group OTM+A and 99.6% in Group OTM+Z, when compared with Group OTM. There was a significant decrease of osteoclasts and inflammatory cells in BP-treated groups. Blood vessels and fibroblastic cells decreased mainly in Group OTM+Z. Alendronate sodium and zoledronic acid have similar effects on the periodontal tissue during orthodontic treatment in rats. Especially, zoledronic acid can affect orthodontic tooth movement. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Mutual augmentation of the induction of the histamine-forming enzyme, histidine decarboxylase, between alendronate and immuno-stimulants (IL-1, TNF, and LPS), and its prevention by clodronate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deng Xue; Department of Oral Diagnosis, Graduate School of Dentistry, Tohoku University, Seiryo-machi, Aoba-ku, Sendai 980-8575; Yu Zhiqian

2006-05-15

Nitrogen-containing bisphosphonates (N-BPs), powerful anti-bone-resorptive drugs, have inflammatory side effects, while histamine is not only an inflammatory mediator, but also an immuno-modifier. In murine models, a single intraperitoneal injection of an N-BP induces various inflammatory reactions, including the induction of the histamine-forming enzyme histidine decarboxylase (HDC) in tissues important in immune responses (such as liver, lungs, spleen, and bone marrow). Lipopolysaccharide (LPS) and the proinflammatory cytokines IL-1 and TNF are also capable of inducing HDC. We reported previously that in mice (i) the inflammatory actions of N-BPs depend on IL-1 (ii) N-BP pretreatment augments both LPS-stimulated IL-1 production and HDCmore » induction, and (iii) the co-administration of clodronate (a non-N-BP) with an N-BP inhibits the latter's inflammatory actions (including HDC induction). Here, we add the new findings that (a) pretreatment with alendronate (a typical N-BP) augments both IL-1- and TNF-induced HDC elevations, (b) LPS pretreatment augments the alendronate-induced HDC elevation, (c) co-administration of clodronate with alendronate abolishes these augmentations, (d) alendronate does not induce HDC in IL-1-deficient mice even if they are pretreated with LPS, and (e) alendronate increases IL-1{beta} in all tissues tested, but not in the serum. These results suggest that (1) there are mutual augmentations between alendronate and immuno-stimulants (IL-1, TNF, and LPS) in HDC induction, (2) tissue IL-1{beta} is important in alendronate-stimulated HDC induction, and (3) combination use of clodronate may have the potential to reduce the inflammatory effects of alendronate (we previously found that clodronate, conveniently, does not inhibit the anti-bone-resorptive activity of alendronate)« less

Hydroxyapatite nanocrystals functionalized with alendronate as bioactive components for bone implant coatings to decrease osteoclastic activity

NASA Astrophysics Data System (ADS)

Bosco, Ruggero; Iafisco, Michele; Tampieri, Anna; Jansen, John A.; Leeuwenburgh, Sander C. G.; van den Beucken, Jeroen J. J. P.

2015-02-01

The integration of bone implants within native bone tissue depends on periprosthetic bone quality, which is severely decreased in osteoporotic patients. In this work, we have synthesized bone-like hydroxyapatite nanocrystals (nHA) using an acid-base neutralization reaction and analysed their physicochemical properties. Subsequently, we have functionalized the nHA with alendronate (nHAALE), a well-known bisphosphonate drug used for the treatment of osteoporosis. An in vitro osteoclastogenesis test was carried out to evaluate the effect of nHAALE on the formation of osteoclast-like cells from monocytic precursor cells (i.e. RAW264.7 cell line) showing that nHAALE significantly promoted apoptosis of osteoclast-like cells. Subsequently, nHA and nHAALE were deposited on titanium disks using electrospray deposition (ESD), for which characterisation of the deposited coatings confirmed the presence of alendronate in nHAALE coatings with nanoscale thickness of about 700 nm. These results indicate that alendronate linked to hydroxyapatite nanocrystals has therapeutic potential and nHAALE can be considered as an appealing coating constituent material for orthopaedic and oral implants for application in osteoporotic patients.

Effect of insulin-like growth factor-1 (IGF-1) plus alendronate on bone density during puberty in IGF-1-deficient MIDI mice.

PubMed

Stabnov, L; Kasukawa, Y; Guo, R; Amaar, Y; Wergedal, J E; Baylink, D J; Mohan, S

2002-06-01

Insulin-like growth factor-1 (IGF-1) increases both bone formation and bone resorption processes. To test the hypothesis that treatment with an antiresorber along with IGF-1, during the pubertal growth phase, would be more effective than IGF-1 alone to increase peak bone mass, we used an IGF-1 MIDI mouse model, which exhibits a >60% reduction in circulating IGF-1 levels. We first determined an optimal IGF-1 delivery by evaluating IGF-1 administration (2 mg/kg body weight/day) by either a single daily injection, three daily injections, or by continuous delivery via a minipump during puberty. Of the three regimens, the three daily IGF-1 injections and IGF-1 through a minipump produced a significant increase in total body bone mineral density (BMD) (6.0% and 4.4%, respectively) and in femoral BMD (4.3% and 6.2%, respectively) compared with the control group. Single subcutaneous (s.c.) administration did not increase BMD. We chose IGF-1 administration three times daily for testing the combined effects of IGF-1 and alendronate (100 microg/kg per day). The treatment of IGF-1 + alendronate for a period of 2 weeks increased total body BMD at 1 week and 3 weeks after treatment (21.1% and 20.5%, respectively) and femoral BMD by 29% at 3 weeks after treatment. These increases were significantly greater than those produced by IGF-1 alone. IGF-1, but not alendronate, increased bone length. IGF-1 and/or alendronate increased both periosteal and endosteal circumference. Combined treatment caused a greater increase in the total body bone mineral content (BMC) and periosteal circumference compared with individual treatment with IGF-1 or alendronate. Our data demonstrate that: (1) inhibition of bone turnover during puberty increases net bone density; and (2) combined treatment with IGF-1 and alendronate is more effective than IGF-1 or alendronate alone in increasing peak bone mass in an IGF-1-deficient MIDI mouse model.

The prevention of hip fracture with menatetrenone and risedronate plus calcium supplementation in elderly patients with Alzheimer disease: a randomized controlled trial.

PubMed

Sato, Yoshihiro; Honda, Yoshiaki; Umeno, Kazuo; Hayashida, Norimasa; Iwamoto, Jun; Takeda, Tsuyoshi; Matsumoto, Hideo

2011-01-01

A high incidence of fractures, particularly of the hip, represents an important problem in patients with Alzheimer disease (AD), who are prone to falls and have osteoporosis. We previously found that vitamin K deficiency and low 25-hydroxyvitamin D (25-OHD) with compensatory hyperparathyroidism cause reduced bone mineral density (BMD) in female patients with AD. This may modifiable by intervention with menatetrenone (vitamin K2) and risedronate sodium; we address the possibility that treatment with menatetrenone, risedronate and calcium may reduce the incidence of nonvertebral fractures in elderly patients with AD. A total of 231 elderly patients with AD were randomly assigned to daily treatment with 45 mg of menatetrenone or a placebo combined with once weekly risedronate sodium, and followed up for 12 months. At baseline, patients of both groups showed high undercarboxylated osteocalcin (ucOC) and low 25-OHD insufficiency with compensatory hyperparathyroidism. During the study period, BMD in the treatment group increased by 5.7% and increased by 2.1% in the control group. Nonvertebral fractures occurred in 15 patients (10 hip fractures) in the control group and 5 patients (2 hip fractures) in the treatment group. The relative risk in the treatment group compared with the control group was 0.31 (95% confidence interval, 0.12-0.81). Elderly AD patients with hypovitaminosis K and D are at increased risk for hip fracture. The study medications were well tolerated with relatively few adverse events and effective in reducing the risk of a fracture in elderly patients with AD.

Zoledronate, ibandronate and clodronate enhance osteoblast differentiation in a dose dependent manner--a quantitative in vitro gene expression analysis of Dlx5, Runx2, OCN, MSX1 and MSX2.

PubMed

Koch, Felix Peter; Merkel, Christina; Al-Nawas, Bilal; Smeets, Ralf; Ziebart, Thomas; Walter, Christian; Wagner, Wilfried

2011-12-01

Bisphosphonates are widely used in the clinical treatment of bone diseases with increased bone resorption. In terms of side effects, they are known to be associated with osteonecrosis of the jaw (BONJ). There are two groups of bisphosphonates: the nitrogen-containing bisphosphonates, e.g. zoledronate and ibandronate, and the non-nitrogen-containing bisphosphonates, e.g. clodronate. Their impact on bone metabolism seems to differ. The objective of this study was to compare the osteogenic differentiation potency of these two pharmacologic groups. Human osteoblasts were stimulated with zoledronate and ibandronate at concentrations of 5×10(-5) M, 5×10(-6) M and 5×10(-7) M over the experimental periods of 1, 2, 5, 10 and 14 days. Clodronate was applied with concentrations of 5×10(-3), 5×10(-5) M and 5×10(-6) M. At each time point, the cells were dissolved, the mRNA extracted, and the gene expression level of the osteoblast specific differentiation markers of the homeobox transcription factors MSX1 and MSX2, the distal-less homeobox 5 (Dlx5), the Runt-related transcription factor 2 (Runx2/CBF1a) and osteocalcin (OCN) were quantified by Real-Time PCR. The gene expression was compared to an unstimulated osteoblast cell culture as control. The results showed a significant difference between the nitrogen-containing and the non-nitrogen-containing bisphosphonates. Zoledronate and ibandronate at concentrations of 5×10(-5) M enhanced the gene expression of all differentiation markers by several hundred folds compared to unstimulated control after 10 days, whereas clodronate had less influence on gene expression, even at higher concentrations of 5×10(-3) M. Lower concentrations of zoledronate and ibandronate, however, led to a decreased gene expression. These data confirm the results of other studies which have shown the osteogenic stimulus on osteoblasts in a dose dependent manner. The nitrogen-containing bisphosphonates appear to enhance bone density by stimulation of

Alendronate for fracture prevention in postmenopause.

PubMed

Holder, Kathryn K; Kerley, Sara Shelton

2008-09-01

Osteoporosis is an abnormal reduction in bone mass and bone deterioration leading to increased fracture risk. Alendronate (Fosamax) belongs to the bisphosphonate class of drugs, which act to inhibit bone resorption by interfering with the activity of osteoclasts. To assess the effectiveness of alendronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women. The authors searched Central, Medline, and EMBASE for relevant randomized controlled trials published from 1966 to 2007. The authors undertook study selection and data abstraction in duplicate. The authors performed meta-analysis of fracture outcomes using relative risks, and a relative change greater than 15 percent was considered clinically important. The authors assessed study quality through reporting of allocation concealment, blinding, and withdrawals. Eleven trials representing 12,068 women were included in the review. Relative and absolute risk reductions for the 10-mg dose were as follows. For vertebral fractures, a 45 percent relative risk reduction was found (relative risk [RR] = 0.55; 95% confidence interval [CI], 0.45 to 0.67). This was significant for primary prevention, with a 45 percent relative risk reduction (RR = 0.55; 95% CI, 0.38 to 0.80) and 2 percent absolute risk reduction; and for secondary prevention, with 45 percent relative risk reduction (RR = 0.55; 95% CI, 0.43 to 0.69) and 6 percent absolute risk reduction. For nonvertebral fractures, a 16 percent relative risk reduction was found (RR = 0.84; 95% CI, 0.74 to 0.94). This was significant for secondary prevention, with a 23 percent relative risk reduction (RR = 0.77; 95% CI, 0.64 to 0.92) and a 2 percent absolute risk reduction, but not for primary prevention (RR = 0.89; 95% CI, 0.76 to 1.04). There was a 40 percent relative risk reduction in hip fractures (RR = 0.60; 95% CI, 0.40 to 0.92), but only secondary prevention was significant, with a 53 percent relative risk reduction (RR = 0.47; 95% CI

Strategy for prevention of hip fractures in patients with Parkinson's disease.

PubMed

Iwamoto, Jun; Sato, Yoshihiro; Takeda, Tsuyoshi; Matsumoto, Hideo

2012-09-18

Hypovitaminosis D and K due to malnutrition or sunlight deprivation, increased bone resorption due to immobilization, low bone mineral density (BMD) and an increased risk of falls may contribute to an increased risk of hip fractures in patients with Parkinson's disease. The purpose of the present study was to clarify the efficacy of interventions intended to prevent hip fractures in elderly patients with Parkinson's disease. PubMed was used to search the literature for randomized controlled trials (RCTs) regarding Parkinson's disease and hip fractures. The inclusion criteria were 50 or more subjects per group and a study period of 1 year or longer. Five RCTs were identified and the relative risk and 95% confidence interval were calculated for individual RCTs. Sunlight exposure increased serum hydroxyvitamin D [25(OH)D] concentration, improved motor function, decreased bone resorption and increased BMD. Alendronate or risedronate with vitamin D supplementation increased serum 25(OH)D concentration, strongly decreased bone resorption and increased BMD. Menatetrenone (vitamin K(2)) decreased serum undercarboxylated osteocalcin concentration, decreased bone resorption and increased BMD. Sunlight exposure (men and women), menatetrenone (women), alendronate and risedronate with vitamin D supplementation (women) significantly reduced the incidence of hip fractures. The respective RRs (95% confidence intervals) according to the intention-to-treat analysis were 0.27 (0.08, 0.96), 0.13 (0.02, 0.97), 0.29 (0.10, 0.85) and 0.20 (0.06, 0.68). Interventions, including sunlight exposure, menatetrenone and oral bisphosphonates with vitamin D supplementation, have a protective effect against hip fractures elderly patients with Parkinson's disease.

Formulation, characterization and cytotoxicity studies of alendronate sodium-loaded solid lipid nanoparticles.

PubMed

Ezzati Nazhad Dolatabadi, Jafar; Hamishehkar, Hamed; Eskandani, Morteza; Valizadeh, Hadi

2014-05-01

Solid lipid nanoparticles (SLNs) are novel drug delivery system for drug targeting in various routs of administration such as parenteral, oral, ophthalmic and topical. These carriers have some advantages such as high drug payload, increased drug stability, the possibility of incorporation of lipophilic and hydrophilic drugs, and low biotoxicity. In this study, alendronate sodium was used as a hydrophilic model drug and was incorporated into SLNs. Hot homogenization method was used for preparation of alendronate sodium-loaded SLN formulations and the encapsulation efficiency of drug in SLNs was determined by ultrafiltration method using centrifugal devices. Scanning electron microscopy (SEM) was carried out to study the morphological behaviors of prepared SLNs like sphericity. Several cytotoxicity studies including MTT, DAPI staining and DNA fragmentation assays were used for biocompatibility assays. High drug encapsulation efficiency (70-85%) was achieved by drug determination through derivatization with o-phthalaldehyde. The physical stability of drug-loaded SLNs in aqueous dispersions was assessed in terms of size and drug leakage during two weeks. Scanning electron microscopy images showed spherical particles in the nanometer range confirming the obtained data from size analyzer. Several cytotoxicity studies including MTT, DAPI staining and DNA fragmentation assays as well as flow cytometry analysis confirmed the low toxicity of alendronate-loaded SLNs. The cost-efficient procedure, the avoidance of organic solvents application, acceptable reproducibility, ease of manufacturing under mild preparation conditions, high level of drug encapsulation, desirable physical stability and biocompatibility are the advantages of the proposed SLN formulations. Copyright © 2014 Elsevier B.V. All rights reserved.

Cost effectiveness of denosumab compared with oral bisphosphonates in the treatment of post-menopausal osteoporotic women in Belgium.

PubMed

Hiligsmann, Mickaël; Reginster, Jean-Yves

2011-10-01

Denosumab has recently been shown to be well tolerated, to increase bone mineral density (BMD) and to significantly reduce the risk of hip, vertebral and non-vertebral fractures in the FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months) trial. It is becoming increasingly important to evaluate not only the therapeutic value of a new drug but also the cost effectiveness compared with the most relevant treatment alternatives. The objective of this study was to estimate the cost effectiveness of denosumab compared with oral bisphosphonates (branded and generic drugs) in the treatment of post-menopausal osteoporotic women in Belgium. Cost effectiveness of 3 years of treatment with denosumab was compared with branded risedronate and branded and generic alendronate using an updated version of a previously validated Markov microsimulation model. The model was populated with relevant cost, adherence and epidemiological data for Belgium from a payer perspective and the results were presented as costs per QALY gained (&U20AC;, year 2009 values). Analyses were performed in populations (aged ≥60 years) in which osteoporosis medications are currently reimbursed in many European countries, i.e. those with BMD T-score of -2.5 or less or prevalent vertebral fracture. Patients receiving denosumab were assumed to have a 46% lower risk of discontinuation than those receiving oral bisphosphonates, and the effect of denosumab after treatment cessation was assumed to decline linearly to zero over a maximum of 1 year. Denosumab was cost effective compared with all other therapies, assuming a willingness to pay of &U20AC;40 000 per QALY gained. In particular, denosumab was found to be cost effective compared with branded alendronate and risedronate at a threshold value of &U20AC;30 000 per QALY and denosumab was dominant (i.e. lower cost and greater effectiveness) compared with risedronate from the age of 70 years in women with a T-score of -2.5 or

The efficiency of risedronate in reducing bone resorption after total hip arthroplasty: a meta-analysis of randomized control trials at a minimum of 6 months' follow-up.

PubMed

Yang, Liqing

2018-04-17

Recently risedronate is suggested to be effective for the prevention and treatment of for osteoporosis in total hip arthroplasty. This meta-analysis aimes to evaluate the efficacy of risedronate in reducing femoral periprosthetic bone mineral density loss in patients undergoing primary total hip arthroplasty. A systematic search was performed in Medline (1966-31 October 2017), PubMed (1966-31 October 2017), Embase (1980-31 October 2017), ScienceDirect (1985-31 October 2017) and the Cochrane Library. Only randomized controlled trial (RCT) were included. Fixed/random effect model was used according to the heterogeneity tested by I2 statistic. Meta-analysis was performed using Stata 11.0 software. The outcome measures included periprosthetic bone mineral density, length of stay and adverse effects. Four RCTs including 198 patients met the inclusion criteria. The present meta-analysis showed that there were significant differences between treatment groups in terms of periprosthetic bone mineral density in Gruen zones 1 (standard mean difference (SMD) = 0.758, 95% CI 0.469 to 1.047, P = 0.000), 2 (SMD = 0.814, 95% CI 0.523 to 1.106, P = 0.000), 3 (SMD = 0.340, 95% CI 0.059 to 0.622, P = 0.018), 6 (SMD = 2.400, 95% CI 2.029 to 2.771, P = 0.000), and 7 (SMD = 2.400, 95% CI 2.029 to 2.771, P = 0.000). Oral risedronate could significantly reduce periprosthetic bone resorption around an uncemented femoral stem (Gruen zones 1, 2, 3, 6, and 7) up to 6 months after THA. In addition, no severe adverse events were identified. Future trials of risedronate treatment after THA should focus on clinically relevant end points such as the risks of fracture and revision arthroplasty.

Antiresorption implant coatings based on calcium alendronate and octacalcium phosphate deposited by matrix assisted pulsed laser evaporation.

PubMed

Boanini, Elisa; Torricelli, Paola; Forte, Lucia; Pagani, Stefania; Mihailescu, Natalia; Ristoscu, Carmen; Mihailescu, Ion N; Bigi, Adriana

2015-12-01

The integration of an implant material with bone tissue depends on the chemistry and physics of the implant surface. In this study we applied matrix assisted pulsed laser evaporation (MAPLE) in order to synthesize calcium alendronate monohydrate (a bisphosphonate obtained by calcium sequestration from octacalcium phosphate by alendronate) and calcium alendronate monohydrate/octacalcium phosphate composite thin films on titanium substrates. Octacalcium phosphate coatings were prepared as reference material. The powders, which were synthesized in aqueous medium, were suspended in deionised water, frozen at liquid nitrogen temperature and used as targets for MAPLE experiments. The transfer was conducted with a KrF* excimer laser source (λ = 248 nm, τFWHM ≤ 25 ns) in mild conditions of temperature and pressure. XRD, FTIR and SEM analyses confirmed that the coatings contain the same crystalline phases as the as-prepared powder samples. Osteoblast derived from stem cells and osteoclast derived from monocytes of osteoporotic subjects were co-cultured on the coatings up to 14 days. Osteoclast displayed significantly reduced proliferation and differentiation in the presence of calcium alendronate monohydrate, pointing to a clear role of the coatings containing this bisphosphonate on inhibiting excessive bone resorption. At variance, osteoblast production of alkaline phosphatase and type I pro-collagen were promoted by the presence of bisphosphonate, which also decreased the production of interleukin 6. The positive influence towards osteoblast differentiation was even more enhanced in the composite coatings, thanks to the presence of octacalcium phosphate. Copyright © 2015 Elsevier B.V. All rights reserved.

Self-assembled monolayers of alendronate on Ti6Al4V alloy surfaces enhance osteogenesis in mesenchymal stem cells

NASA Astrophysics Data System (ADS)

Rojo, Luis; Gharibi, Borzo; McLister, Robert; Meenan, Brian J.; Deb, Sanjukta

2016-07-01

Phosphonates have emerged as an alternative for functionalization of titanium surfaces by the formation of homogeneous self-assembled monolayers (SAMs) via Ti-O-P linkages. This study presents results from an investigation of the modification of Ti6Al4V alloy by chemisorption of osseoinductive alendronate using a simple, effective and clean methodology. The modified surfaces showed a tailored topography and surface chemistry as determined by SEM microscopy and RAMAN spectroscopy. X-ray photoelectron spectroscopy revealed that an effective mode of bonding is created between the metal oxide surface and the phosphate residue of alendronate, leading to formation of homogenous drug distribution along the surface. In-vitro studies showed that alendronate SAMs induce differentiation of hMSC to a bone cell phenotype and promote bone formation on modified surfaces. Here we show that this novel method for the preparation of functional coatings on titanium-based medical devices provides osseoinductive bioactive molecules to promote enhanced integration at the site of implantation.

Self-assembled monolayers of alendronate on Ti6Al4V alloy surfaces enhance osteogenesis in mesenchymal stem cells

PubMed Central

Rojo, Luis; Gharibi, Borzo; McLister, Robert; Meenan, Brian J.; Deb, Sanjukta

2016-01-01

Phosphonates have emerged as an alternative for functionalization of titanium surfaces by the formation of homogeneous self-assembled monolayers (SAMs) via Ti-O-P linkages. This study presents results from an investigation of the modification of Ti6Al4V alloy by chemisorption of osseoinductive alendronate using a simple, effective and clean methodology. The modified surfaces showed a tailored topography and surface chemistry as determined by SEM microscopy and RAMAN spectroscopy. X-ray photoelectron spectroscopy revealed that an effective mode of bonding is created between the metal oxide surface and the phosphate residue of alendronate, leading to formation of homogenous drug distribution along the surface. In-vitro studies showed that alendronate SAMs induce differentiation of hMSC to a bone cell phenotype and promote bone formation on modified surfaces. Here we show that this novel method for the preparation of functional coatings on titanium-based medical devices provides osseoinductive bioactive molecules to promote enhanced integration at the site of implantation. PMID:27468811

EFFECTS OF LONG-TERM ALENDRONATE TREATMENT ON A LARGE SAMPLE OF PEDIATRIC PATIENTS WITH OSTEOGENESIS IMPERFECTA.

PubMed

Lv, Fang; Liu, Yi; Xu, Xiaojie; Wang, Jianyi; Ma, Doudou; Jiang, Yan; Wang, Ou; Xia, Weibo; Xing, Xiaoping; Yu, Wei; Li, Mei

2016-12-01

Osteogenesis imperfecta (OI) is a group of inherited diseases characterized by reduced bone mass, recurrent bone fractures, and progressive bone deformities. Here, we evaluate the efficacy and safety of long-term treatment with alendronate in a large sample of Chinese children and adolescents with OI. In this prospective study, a total of 91 children and adolescents with OI were included. The patients received 3 years' treatment with 70 mg alendronate weekly and 500 mg calcium daily. During the treatment, fracture incidence, bone mineral density (BMD), and serum levels of the bone turnover biomarkers (alkaline phosphatase [ALP] and cross-linked C-telopeptide of type I collagen [β-CTX]) were evaluated. Linear growth speed and parameters of safety were also measured. After 3 years of treatment, the mean annual fracture incidence decreased from 1.2 ± 0.8 to 0.2 ± 0.3 (P<.01). BMD at the lumbar spine and femoral neck significantly increased by 74.6% and 39.5%, with their BMD Z-score increasing from -3.0 to 0.1 and from -4.2 to -1.3, respectively (both P<.01 vs. baseline). In addition, serum ALP and β-CTX levels decreased by 35.6% and 44.3%, respectively (both P<.05 vs. baseline). Height significantly increased, but without an obvious increase in its Z-score. Patient tolerance of alendronate was good. Three years' treatment with alendronate was demonstrated for the first time to significantly reduce fracture incidence, increase lumbar spine and femoral neck BMD, and decrease bone turnover biomarkers in Chinese children and adolescents with OI. ALP = alkaline phosphatase β-CTX = cross-linked C-telopeptide of type I collagen BMD = bone mineral density BP = bisphosphonate DXA = dual-energy X-ray absorptiometry 25OHD = 25-hydroxyvitamin D OI = osteogenesis imperfecta PTH = parathyroid hormone.

Prospective evaluation of free radicals and antioxidant activity following 6-month risedronate treatment in patients with postmenopausal osteoporosis.

PubMed

Zinnuroglu, Murat; Dincel, Aylin Sepici; Kosova, Funda; Sepici, Vesile; Karatas, Gulcin Kaymak

2012-04-01

In addition to the well-described implications of estrogen deficiency in postmenopausal osteoporosis (PMO), free radicals are also effective on bone metabolism. The antioxidant vitamins C and E play an important role in the production of collagen, mesenchymal cell differentiation into osteoblasts, and bone mineralization. Therefore, the incidence of osteoporosis and the risk of fractures were decreased with vitamin C and E. It was proposed that free oxygen radicals are responsible for biological aging, atherosclerosis, carcinogenesis, and osteoclastic activity via their negative effects on the cell and DNA. In this study, we aimed to investigate and compare the levels of free radicals and serum antioxidant activity in patients with PMO and healthy subjects before and after six-month treatment with risedronate, which is an inhibitor of bone resorption. Twenty-three postmenopausal patients aged between 52-83 (mean [± standard deviation] 67.6 ± 8.17) with T scores below -2.5 in femur neck or L1-L4, and 23 postmenopausal healthy subjects were enrolled into the study. Patients who had received any medications within the last 6 months that could alter bone metabolism were excluded. Serum malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) levels were analyzed in both groups. The patients with PMO were commenced on 5 mg of risedronate, 1,200 mg of calcium, and 800 IU of vitamin D daily. The patients were reevaluated at the end of the sixth month. MDA and SOD levels were similar in patients with PMO when compared to the healthy group before the treatment, while the GPx levels were lower in patients with PMO (P = 0.014). GPx (P = 0.028) and MDA (P = 0.04) levels were increased in patients with PMO after the treatment. In contrast, SOD levels were decreased when compared to the initial levels (P = 0.006). There may be an insufficiency in different steps of the enzymatic antioxidant systems in patients with PMO without treatment. We observed

The influence of alendronate on the healing of extraction sockets of ovariectomized rats assessed by in vivo micro-computed tomography.

PubMed

Jee, Jeong-Hyun; Lee, Wan; Lee, Byung Do

2010-08-01

Many dental patients take bisphosphonates to reduce the risk of hip and vertebral fractures. In vivo micro-computed tomography (micro-CT) was used to examine the longitudinal inhibitory effect of alendronate on the healing of extraction sockets in ovariectomized rats. Twenty 5-week-old Sprague-Dawley rats were assigned randomly to 1 of 3 groups: sham-operated (n = 5), and 2 ovariectomized (OVX) groups: saline treated (0.1 mL/100 g/d, n = 7) and alendronate treated (1 mg/kg/d, n = 8). Before micro-CT scanning, the left maxillary first molars of the rats were extracted. In vivo micro-CT (spatial resolution 50 x 50 mum) of the jaw was performed at baseline and at 2-week intervals for 6 weeks. Alveolar-bone radiographic densities and dimensions were analyzed with repeated measures analysis of variance. The bony healing patterns of the extraction sockets were also evaluated in each group. The radiographic socket densities of the sham-treated and OVX-alendronate groups significantly increased during the first 4 weeks after extraction (P < .05). At 2 weeks, the radiographic densities of the sockets in the OVX-saline group increased, but the increase was significantly lower than for the other groups at 4 weeks (P < .05). Newly formed bone was identified in the extraction sockets in all groups 2 to 6 weeks after extraction. There was a significant loss of alveolar ridge height at the second week postextraction compared with baseline, and at the fourth week compared with the second week (P < .05) except in the alendronate group. Alendronate appears to promote the healing of extraction sockets in estrogen-deficient rats and helps resist the loss of alveolar bone adjacent to extraction sockets. Copyright 2010 Mosby, Inc. All rights reserved.

Morphometric and microscopic evaluation of the effect of a solution of alendronate as an intracanal therapeutic agent in rat teeth submitted to late reimplantation.

PubMed

Mori, Graziela Garrido; Garcia, Roberto Brandão; Gomes de Moraes, Ivaldo; Bramante, Clóvis Monteiro; Bernardineli, Norberti

2007-08-01

The use of substances that inhibit root resorption may be an alternative for cases of unsuccessful reimplants. Hence, the purpose of this study was to test a solution of alendronate, a resorption inhibitor, as an intracanal therapeutic agent for teeth submitted to late reimplantation. Thirty rat maxillary right central incisors were avulsed and kept dry for 30 min. The teeth were instrumented, and the root surfaces treated with 1% hypochlorite solution followed by application of 2% sodium fluoride. Thereafter, the teeth were divided in two groups according to the intracanal dressing: (i) group I, solution of alendronate and (ii) group II, calcium hydroxide paste. Teeth were then reimplanted in their respective sockets. The animals were killed at 15, 30 and 60 days after reimplantation and the samples processed for morphometric and microscopic analysis. The results demonstrated that the solution of alendronate and the calcium hydroxide paste limited the root resorption, yet did not impair its occurrence. It may be concluded that alendronate and calcium hydroxide paste demonstrated similar behavior.

The Effect of Local Delivery Doxycycline and Alendronate on Bone Repair.

PubMed

Limirio, Pedro Henrique Justino Oliveira; Rocha, Flaviana Soares; Batista, Jonas Dantas; Guimarães-Henriques, João César; de Melo, Geraldo Batista; Dechichi, Paula

2016-08-01

The aim of the present study was to investigate the local effect of 10% doxycycline and 1% alendronate combined with poly(lactic-co-glycolic acid) (PLGA) on bone repair. Thirty rats were divided into three groups, as follows: control group (CG), drug group (DG), and vehicle-PLGA group (VG). Bone defect was created in the right femur and filled with the following: blood clot (CG); PLGA gel, 10% doxycycline and 1% alendronate (DG); or vehicle-PLGA (VG). The animals were euthanized 7 or 15 days after surgery. Bone density, bone matrix and number of osteoclasts were quantified. At 7 days, the findings showed increased density in DG (177.75 ± 76.5) compared with CG (80.37 ± 27.4), but no difference compared with VG (147.1 ± 41.5); no statistical difference in bone neoformation CG (25.6 ± 4.8), VG (27.8 ± 4), and DG (18.9 ± 7.8); and decrease osteoclasts in DG (4.6 ± 1.9) compared with CG (26.7 ± 7.4) and VG (17.3 ± 2.7). At 15 days, DG (405.1 ± 63.1) presented higher density than CG (213.2 ± 60.9) and VG (283.4 ± 85.8); there was a significant increase in percentage of bone neoformation in DG (31.5 ± 4.2) compared with CG (23 ± 4), but no difference compared with VG (25.1 ± 2.9). There was a decreased number of osteoclasts in DG (20.7 ± 4.7) and VG (29.5 ± 5.4) compared with CG (40 ± 9.4). The results suggest that the association of 10% doxycycline and 1% alendronate with PLGA-accelerated bone repair.

The inhibitory effect of alendronate, a nitrogen-containing bisphosphonate on the PI3K-Akt-NFkappaB pathway in osteosarcoma cells.

PubMed

Inoue, Ryosuke; Matsuki, Nori-aki; Jing, Gao; Kanematsu, Takashi; Abe, Kihachiro; Hirata, Masato

2005-11-01

1 Bisphosphonates are inhibitors of tumor cell growth as well as of bone resorption by inducing cell apoptosis. However, little is known regarding the mechanisms by which the drug induces cell apoptosis. The aim of the present study was to determine the effect of alendronate, one of the nitrogen-containing bisphosphonates on the phoshoinositide 3-kinase (PI3K)-Akt-NFkappaB pathway, the major cell survival pathway. 2 The PI3K-Akt-NFkappaB pathway was activated in the osteosarcoma cell line MG-63 treated with tumor necrosis factor-alpha or insulin. Saos-2 was also used in some experiments. This was assessed by the production of phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)), increased PI3K activity, phosphorylation of Akt at serine 473 and threonine 308, increase in activity of the inhibitor of nuclear factor kappaB (IkappaB) kinase (IKK) and finally phosphorylation of IkappaB and its subsequent degradation. 3 Pretreatment with alendronate at 100 microM for 24 h prior to the stimulation with tumor necrosis factor-alpha or insulin partially inhibited the IkappaB phosphorylation and degradation. These events were more clearly observed in the presence of inhibitors of proteasomes, which are responsible for the degradation of IkappaB. The drug also partially inhibited the activity of IKK, but almost fully inhibited the phosphorylation of Akt and the production of PtdIns(3,4,5)P(3). 4 The inhibitory effect of alendronate on IkappaB phosphorylation and degradation was not attenuated by the exogenous addition of geranylgeraniol to replenish the cytosolic isoprenyl lipid substrate. 5 The present findings demonstrate that alendronate inhibited the PI3K-Akt-NFkappaB cell survival pathway at the point of PI3K activation, thus indicating the presence of new targets of alendronate.

Glucocorticoid Steroid and Alendronate Treatment Alleviates Dystrophic Phenotype with Enhanced Functional Glycosylation of α-Dystroglycan in Mouse Model of Limb-Girdle Muscular Dystrophy with FKRPP448L Mutation.

PubMed

Wu, Bo; Shah, Sapana N; Lu, Peijuan; Richardson, Stephanie M; Bollinger, Lauren E; Blaeser, Anthony; Madden, Kyle L; Sun, Yubo; Luckie, Taylor M; Cox, Michael D; Sparks, Susan; Harper, Amy D; Lu, Qi Long

2016-06-01

Fukutin-related protein-muscular dystrophy is characterized by defects in glycosylation of α-dystroglycan with variable clinical phenotypes, most commonly as limb-girdle muscular dystrophy 2I. There is no effective therapy available. Glucocorticoid steroids have become the standard treatment for Duchenne and other muscular dystrophies with serious adverse effects, including excessive weight gain, immune suppression, and bone loss. Bisphosphonates have been used to treat Duchenne muscular dystrophy for prevention of osteoporosis. Herein, we evaluated prednisolone and alendronate for their therapeutic potential in the FKRPP448L-mutant mouse representing moderate limb-girdle muscular dystrophy 2I. Mice were treated with prednisolone, alendronate, and both in combination for up to 6 months. Prednisolone improved muscle pathology with significant reduction in muscle degeneration, but had no effect on serum creatine kinase levels and muscle strength. Alendronate treatment did not ameliorate muscle degeneration, but demonstrated a limited enhancement on muscle function test. Combined treatment of prednisolone and alendronate provided best improvement in muscle pathology with normalized fiber size distribution and significantly reduced serum creatine kinase levels, but had limited effect on muscle force generation. The use of alendronate significantly mitigated the bone loss. Prednisolone alone and in combination with alendronate enhance functionally glycosylated α-dystroglycan. These results, for the first time, demonstrate the efficacy and feasibility of this alliance treatment of the two drugs for fukutin-related protein-muscular dystrophy. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Estimating the Time to Benefit for Preventive Drugs with the Statistical Process Control Method: An Example with Alendronate.

PubMed

van de Glind, Esther M M; Willems, Hanna C; Eslami, Saeid; Abu-Hanna, Ameen; Lems, Willem F; Hooft, Lotty; de Rooij, Sophia E; Black, Dennis M; van Munster, Barbara C

2016-05-01

For physicians dealing with patients with a limited life expectancy, knowing the time to benefit (TTB) of preventive medication is essential to support treatment decisions. The aim of this study was to investigate the usefulness of statistical process control (SPC) for determining the TTB in relation to fracture risk with alendronate versus placebo in postmenopausal women. We performed a post hoc analysis of the Fracture Intervention Trial (FIT), a randomized, controlled trial that investigated the effect of alendronate versus placebo on fracture risk in postmenopausal women. We used SPC, a statistical method used for monitoring processes for quality control, to determine if and when the intervention group benefited significantly more than the control group. SPC discriminated between the normal variations over time in the numbers of fractures in both groups and the variations that were attributable to alendronate. The TTB was defined as the time point from which the cumulative difference in the number of clinical fractures remained greater than the upper control limit on the SPC chart. For the total group, the TTB was defined as 11 months. For patients aged ≥70 years, the TTB was 8 months [absolute risk reduction (ARR) = 1.4%]; for patients aged <70 years, it was 19 months (ARR = 0.7%). SPC is a clear and understandable graphical method to determine the TTB. Its main advantage is that there is no need to define a prespecified time point, as is the case in traditional survival analyses. Prescribing alendronate to patients who are aged ≥70 years is useful because the TTB shows that they will benefit after 8 months. Investigators should report the TTB to simplify clinical decision making.

Ibandronate metal complexes: solution behavior and antiparasitic activity.

PubMed

Demoro, Bruno; Rostán, Santiago; Moncada, Mauricio; Li, Zhu-Hong; Docampo, Roberto; Olea Azar, Claudio; Maya, Juan Diego; Torres, Julia; Gambino, Dinorah; Otero, Lucía

2018-03-01

To face the high costs of developing new drugs, researchers in both industry and academy are looking for ways to repurpose old drugs for new uses. In this sense, bisphosphonates that are clinically used for bone diseases have been studied as agents against Trypanosoma cruzi, causative parasite of Chagas disease. In this work, the development of first row transition metal complexes (M = Co 2+ , Mn 2+ , Ni 2+ ) with the bisphosphonate ibandronate (iba, H 4 iba representing the neutral form) is presented. The in-solution behavior of the systems containing iba and the selected 3d metal ions was studied by potentiometry. Mononuclear complexes [M(H x iba)] (2-x)- (x = 0-3) and [M(Hiba) 2 ] 4- together with the formation of the neutral polynuclear species [M 2 iba] and [M 3 (Hiba) 2 ] were detected for all studied systems. In the solid state, complexes of the formula [M 3 (Hiba) 2 (H 2 O) 4 ]·6H 2 O were obtained and characterized. All obtained complexes, forming [M(Hiba)] - species under the conditions of the biological studies, were more active against the amastigote form of T. cruzi than the free iba, showing no toxicity in mammalian Vero cells. In addition, the same complexes were selective inhibitors of the parasitic farnesyl diphosphate synthase (FPPS) enzyme showing poor inhibition of the human one. However, the increase of the anti-T. cruzi activity upon coordination could not be explained neither through the inhibition of TcFPPS nor through the inhibition of TcSPPS (T. cruzi solanesyl-diphosphate synthase). The ability of the obtained metal complexes of catalyzing the generation of free radical species in the parasite could explain the observed anti-T. cruzi activity.

Disintegration/dissolution profiles of copies of Fosamax (alendronate).

PubMed

Epstein, S; Cryer, B; Ragi, S; Zanchetta, J R; Walliser, J; Chow, J; Johnson, M A; Leyes, A E

2003-01-01

Poor quality has been reported for some generics and other copies of original products. We performed a pilot study to compare the disintegration/dissolution profiles of FOSAMAX (alendronate) 70 mg tablets with those of copies of FOSAMAX that were manufactured outside the United States. We used the standard United States Pharmacopeia (USP) disintegration method to evaluate FOSAMAX 70 mg tablets and 13 copies. At least 12 (n = 12) dosage units were tested for each product (except Fosmin, n = 10). The dissolution profiles of FOSAMAX and one representative copy were also compared. Nine copies (Osteomax, Defixal, Fosmin, Endronax, Osteomix, Genalmen, Fixopan, Osteoplus, and Fosval) disintegrated two- to ten-fold faster than FOSAMAX. Three other copies (Neobon, Regenesis, and Ostenan) disintegrated at least five-fold slower than FOSAMAX. Neobon is a softgel capsule, so special consideration was given to this different dosage form. One copy (Arendal) did not fall into either category but exhibited potentially large inter- and intra-lot variability. Dissolution of alendronate from Regenesis lagged behind that from FOSAMAX. Slower disintegration may reduce efficacy because bisphosphonates must be taken in the fasting state and contact with food or even certain beverages severely reduces bioavailability. Faster disintegration (or the use of gel-caps or other alterations to the drug formulation) could increase the risk of esophagitis, an adverse event associated with prolonged contact of the esophagus with bisphosphonates. These disintegration and dissolution results suggest that important differences may exist between FOSAMAX and its copies with regard to bioavailability, pharmacokinetics, and clinical efficacy and safety profiles. Additional testing is warranted to evaluate the pharmacokinetics and clinical safety of these copies.

The Effects of Partial Mechanical Loading and Ibandronate on Skeletal Tissues in the Adult Rat Hindquarter Suspension Model for Microgravity

NASA Technical Reports Server (NTRS)

Schultheis, Lester W.

1999-01-01

We report initial data from a suspended rat model that quantitatively relates chronic partial weightbearing to bone loss. Chronic partial weightbearing is our simulation of the effect of limited artificial gravity aboard spacecraft or reduced planetary gravity. Preliminary analysis of bone by PQCT, histomorphometry, mechanical testing and biochemistry suggest that chronic exposure to half of Earth gravity is insufficient to prevent severe bone loss. The effect of episodic full weightbearing activity (Earth Gravity) on rats otherwise at 50% weightbearing was also explored. This has similarity to treatment by an Earth G-rated centrifuge on a spacecraft that normally maintained artificial gravity at half of Earth G. Our preliminary evidence, using the above techniques to analyze bone, indicate that 2 hours daily of full weightbearing was insufficient to prevent the bone loss observed in 50% weightbearing animals. The effectiveness of partial weightbearing and episodic full weightbearing as potential countermeasures to bone loss in spaceflight was compared with treatment by ibandronate. Ibandronate, a long-acting potent bisphosphonate proved more effective in preventing bone loss and associated functionality based upon structure than our first efforts at mechanical countermeasures. The effectiveness of ibandronate was notable by each of the testing methods we used to study bone from gross structure and strength to tissue and biochemistry. These results appear to be independent of generalized systemic stress imposed by the suspension paradigm. Preliminary evidence does not suggest that blood levels of vitamin D were affected by our countermeasures. Despite the modest theraputic benefit of mechanical countermeasures of partial weightbearing and episodic full weightbearing, we know that some appropriate mechanical signal maintains bone mass in Earth gravity. Moreover, the only mechanism that correctly assigns bone mass and strength to oppose regionally specific force

Hydrophobically Modified Glycol Chitosan Nanoparticles for Targeting Breast Cancer Microcalcification Using Alendronate Probes

NASA Astrophysics Data System (ADS)

Vishnu, Kamalakannan

In 2016, invasive breast cancer was diagnosed in about 246,660 women and 2,600 men. An additional 61,000 new cases of in situ breast cancer was diagnosed in women. Microcalcifications are most common abnormalities detected by mammography for breast cancer, present in about 30% of all malignant breast lesions. Tumor specific biomarkers are used for targeting these abnormalities. Nanoparticles with multimodal and combinatorial therapies and conjunction of bio-ligands for specific molecular targeting using surface modifications effectually deliver a variety of drugs and are simultaneously used to image tumor progression. Alendronate, a germinal bisphosphonate conjugation as a targeting ligand would improve the nanoparticle's direct binding to hydroxyapatite (HA) mimicking calcified spots in breast cancer lesions. In this study, the hydrophobically modified glycol chitosan (HGC) micelle was modified with alendronate surface functionalization using a biotin-avidin interaction to improve the nanomicelle's calcification targeting ability. Biotinylated, avidinlyated hydrophobically modified iv glycol chitosan particles were linked to biotinylated alendronate via a strong biotin-avidin linkage. Cyanine 3, a red fluorescent dye was conjugated to the amine groups on HGC for visualization of micelles. The size of the nanoparticles measured was 254.0 +/- 0.43 nm and 209.7 +/- 1.0 nm for Cy3- BHGCA and Cy3-BHGCA-BALN nanoparticles respectively. The average surface charge was measured to be +26.9 +/- 0.19 mV and +27.68 +/- 0.20 mV for Cy3-BHGCA and Cy3-BHGCA- BALN nanoparticles respectively. Binding affinity using hydroxyapatite (HA) revealed that both Cy3 BHGCA BALN and Cy3 BHGCA nanoparticles displayed 95% binding in 24 hours. However, the biotin quenched nanoparticle Cy3 BHGCAB displayed 68% binding in 24 hours. The synthesis and binding chemistry was verified using Fourier transform infrared spectroscopy (FTIR).

Role of Prostaglandin Pathway and Alendronate-Based Carriers to Enhance Statin-induced Bone

PubMed Central

Lee, Yeonju; Liu, Xinming; Nawshad, Ali; Marx, David B.; Wang, Dong; Reinhardt, Richard A.

2011-01-01

Objective This study investigated the role of the prostaglandin (PG) pathway in locally-applied, simvastatin-induced oral bone growth. The possibility of enhancing long-term bone augmentation with an alendronate-based carrier was initiated. Methods Mandibles of 44 mature female rats were treated bilaterally with the following combinations: 2 mg simvastatin in ethanol (SIM-EtOH), EtOH, 2 mg simvastatin acid complexed with alendronate-beta-cyclodextrin conjugate (SIM/ALN-CD), ALN-CD, or ALN. Bone wash technology (injection of PBS and recollection by suction) was used to sample injection sites at baseline (day 0), and 3, 7, 14 and 21 days post-treatment. After 21-24 or 48 days, histomorphometric analysis was done. The amount of PGE2 in bone wash fluid was measured by ELISA, normalized by total protein, and compared between high and low bone growth groups (ANOVA) and correlated with subsequent bone histology at 21 days (Spearman). SIM-stimulated PGE2 synthase and EP4 receptor mRNA in murine osteoblast and fibroblast cell lines were evaluated with real-time PCR. Results Single injections of 2 mg SIM-EtOH induced significantly more new bone than control side after 21 days. PGE2/protein ratios peaked at day 7 and were correlated with the subsequent 21-day new bone width. The correlations at day 14 between PGE2 and new bone width changed to a negative relationship in the test group. SIM-stimulated osteoblasts expressed increased mRNA levels of PGE receptor EP4, while SIM activated PGE synthesis in fibroblasts. SIM/ALN-CD tended to preserve bone long-term. Conclusion Findings suggest that PGE pathway activation and higher levels of PGE2 during the first week following SIM-induced bone growth are desirable, and alendronate-beta-cyclodextrin conjugates not only act as tissue-specific carriers, but preserve new bone. PMID:21438610

Are the results of multiple drilling and alendronate for osteonecrosis of the femoral head better than those of multiple drilling? A pilot study.

PubMed

Kang, Pengde; Pei, Fuxing; Shen, Bin; Zhou, Zongke; Yang, Jing

2012-01-01

The treatment of osteonecrosis of the femoral head (ONFH) remains controversial. A recently proposed treatment is multiple drilling core decompression combined with systemic alendronate as a femoral head-preserving procedure for ONFH. However, it is not known whether alendronate enhances the risk of collapse. We wondered whether the combined procedure could delay or prevent progression of ONFH compared to multiple drilling alone. Patients with early-stage ONFH were randomly assigned to be treated with either multiple drilling combined with alendronate (47 patients, 67 hips) or multiple drilling alone (46 patients, 60 hips). We defined failure as the need for THA or a Harris score less than 70. The minimum follow-up was 48 months for the 77 patients completing the protocol. After a minimum 4-year follow-up, 91% (40/44) of patients with Stage II disease and 62% (8/13) of patients with Stage III disease had not required THA in alendronate group, compared to 79% (31/39) of patients with Stage II disease and 46% (6/13) of patients with Stage III disease had not required THA in control group (P=0.12, P=0.047, respectively). Small or medium and central lesions had a better successful rate in both groups. Risk factors did not seem to affect the clinical successful rate of this procedure. Multiple small-diameter drilling core decompression combined with systemic alendronate administration can reduce pain and delay progression of early-stage ONFH. Even in Ficat IIA and III hips, some benefit was obtained from this approach at least delay in the need for THA. Copyright © 2011. Published by Elsevier SAS.

Iontophoresis significantly increases the trans-dentinal delivery of osteoprotegerin, alendronate, and calcitonin.

PubMed

Kitchens, James A; Schwartz, Scott A; Schindler, William G; Hargreaves, Kenneth M

2007-10-01

The purpose of this study was to evaluate the delivery of alendronate, calcitonin, and osteoprotegerin (OPG) through human dentin by both diffusion and iontophoresis for the potential treatment of invasive cervical resorption. Radiolabeled alendronate, calcitonin, and OPG were added to the top of a split chamber device that contained 1-mm thick dentin disks devoid of a smear layer. Transdentinal movement of medicaments by either random diffusion or application of an iontophoretic current was measured by analysis of gamma emission of effluent fractions. In addition, calcitonin delivery was evaluated at differing magnitudes of current (0-4 mA) by using the aforementioned chamber. Diffusion of all 3 medicaments was minimal. In contrast, the application of a 3-mA iontophoretic gradient significantly increased delivery for all 3 compounds at 10-, 20-, and 30-minute intervals. In addition, a linear increase in permeability was seen for calcitonin as milliamperes were increased from 0 to 4 (r = 0.947), with more than a 100-fold increase in delivery observed with iontophoresis. Delivery of the tested medicaments by using iontophoresis might prove to be a useful technique for treatment of invasive cervical resorption.

Is cortical bone hip? What determines cortical bone properties?

PubMed

Epstein, Sol

2007-07-01

Increased bone turnover may produce a disturbance in bone structure which may result in fracture. In cortical bone, both reduction in turnover and increase in hip bone mineral density (BMD) may be necessary to decrease hip fracture risk and may require relatively greater proportionate changes than for trabecular bone. It should also be noted that increased porosity produces disproportionate reduction in bone strength, and studies have shown that increased cortical porosity and decreased cortical thickness are associated with hip fracture. Continued studies for determining the causes of bone strength and deterioration show distinct promise. Osteocyte viability has been observed to be an indicator of bone strength, with viability as the result of maintaining physiological levels of loading and osteocyte apoptosis as the result of a decrease in loading. Osteocyte apoptosis and decrease are major factors in the bone loss and fracture associated with aging. Both the osteocyte and periosteal cell layer are assuming greater importance in the process of maintaining skeletal integrity as our knowledge of these cells expand, as well being a target for pharmacological agents to reduce fracture especially in cortical bone. The bisphosphonate alendronate has been seen to have a positive effect on cortical bone by allowing customary periosteal growth, while reducing the rate of endocortical bone remodeling and slowing bone loss from the endocortical surface. Risedronate treatment effects were attributed to decrease in bone resorption and thus a decrease in fracture risk. Ibandronate has been seen to increase BMD as the spine and femur as well as a reduced incidence of new vertebral fractures and non vertebral on subset post hoc analysis. And treatment with the anabolic agent PTH(1-34) documented modeling and remodelling of quiescent and active bone surfaces. Receptor activator of nuclear factor kappa B ligand (RANKL) plays a key role in bone destruction, and the human monoclonal

Treatment of primary osteoporosis in men

PubMed Central

Giusti, Andrea; Bianchi, Gerolamo

2015-01-01

With the aging of the population worldwide, osteoporosis and osteoporotic fractures are becoming a serious health care issue in the Western world. Although less frequent than in women, osteoporosis in men is a relatively common problem. Hip and vertebral fractures are particularly relevant, being associated with significant mortality and disability. Since bone loss and fragility fractures in men have been recognized as serious medical conditions, several randomized controlled trials (RCTs) have been undertaken in males with osteoporosis to investigate the anti-fracture efficacy of the pharmacological agents commonly used to treat postmenopausal osteoporosis. Overall, treatments for osteoporosis in men are less defined than in women, mainly due to the fact that there are fewer RCTs performed in male populations, to the relatively smaller sample sizes, and to the lack of long-term extension studies. However, the key question is whether men are expected to respond differently to osteoporosis therapies than women. The pharmacological properties of bisphosphonates, teriparatide, denosumab, and strontium ranelate make such differentiation unlikely, and available clinical data support their efficacy in men with primary osteoporosis as well as in women. In a series of well-designed RCTs, alendronate, risedronate, zoledronic acid, and teriparatide were demonstrated to reduce the risk of new vertebral fractures in men presenting with primary osteoporosis (including osteoporosis associated with low testosterone levels) and to improve the bone mineral density (BMD). In preliminary studies, ibandronate, denosumab, and strontium ranelate also showed their beneficial effects on surrogate outcomes (BMD and markers of bone turnover) in men with osteoporosis. Although direct evidence about their non-vertebral anti-fracture efficacy are lacking, the effects of bisphosphonates, denosumab, teriparatide, and strontium ranelate on surrogate outcomes (BMD and markers of bone turnover

Pharmacokinetics of coadministration of levothyroxine sodium and alendronate sodium new effervescent formulation.

PubMed

Bone, H G; Walter, M A; Hurley, M E; Epstein, S

2017-05-01

No clinically important pharmacokinetic interference of alendronate occurred between a new effervescent formulation of alendronate and levothyroxine when coadministered. The combination does not materially affect levothyroxine absorption. Concurrent treatment of osteoporosis with alendronate (Aln) and hypothyroidism with levothyroxine (LT4) may be problematic because both drugs are to be taken separately after fasting overnight. The primary objective was to assess pharmacokinetic interactions between a new effervescent formulation of Aln (Aln-NEF) and LT4. A randomized, open-label, 3-way crossover study was conducted in 30 healthy adults (15 women). Subjects were dosed 3 times, separated by 35 days, after overnight fasts, with Aln-NEF alone (70 mg), LT4 alone (600 μg), or Aln-NEF and LT4 concurrently. Samples were analyzed for plasma Aln and serum LT4. Pharmacokinetic drug-drug interaction was assessed using 90% confidence intervals (CIs) for the test/reference ratio of the geometric means for area under the concentration-time curve from time zero to last measureable time point (AUC 0-t ) and maximum concentration (C max ). Results were compared to the default no-effect boundaries of 80 to 125% for the ratio Aln-NEF and LT4 concurrently/Aln-NEF alone and the ratio Aln-NEF and LT4 concurrently/LT4 alone. Geometric mean ratios (Aln-NEF with LT4/Aln-NEF alone) were 0.927 (90% CI 0.795-1.081) for AUC 0-8 and 0.912 (90% CI 0.773-1.077) for C max , demonstrating LT4 does not appreciably affect the pharmacokinetics of Aln. Geometric mean ratios (LT4 with Aln-NEF/LT4 alone) were 1.049 (90% CI 0.983-1.119) for AUC 0-48 and 1.075 (90% CI 1.006-1.148) for C max , demonstrating LT4 is bioequivalent between the 2 treatments. Coadministration of Aln-NEF and LT4 was well tolerated. There was no clinically important pharmacokinetic interference between the Aln-NEF formulation and LT4. Aln-NEF does not materially affect LT4 absorption.

OPG, RANKL, and RANK gene polymorphisms and the bone mineral density response to alendronate therapy in postmenopausal Chinese women with osteoporosis or osteopenia.

PubMed

Zheng, Hui; Wang, Chun; He, Jin-Wei; Fu, Wen-Zhen; Zhang, Zhen-Lin

2016-01-01

The aim of the study was to explore the association between OPG, RANKL, and RANK gene variations and the bone mineral density (BMD) response to alendronate therapy in postmenopausal Chinese women with osteoporosis or osteopenia. In the present study, 40 single-nucleotide polymorphisms (SNPs) in the OPG, RANKL, and RANK genes were genotyped in 501 postmenopausal Chinese women with osteoporosis or osteopenia who were given alendronate (70 mg weekly) orally for 1 year. The BMD at the lumbar spine 1-4 (L1-L4), femoral neck, and total hip was measured. A total of 442 patients completed 1 year of alendronate therapy. The rs7239261 SNP of the RANK gene was significantly associated with baseline L1-L4 BMD (P=0.0004) after correction for age and BMI. Participants with the SNP A allele (C/A and A/A) had a higher BMD than those with the C/C genotype (C/A vs. C/C, P=0.001; A/A vs. C/C, P=0.025). Haplotypes AG of rs7239261-rs12969154, GG of rs3826619-rs11877530, and CACG of rs1805034-rs8083511-rs17069895-rs7231887 in the RANK gene were genetic protective factors toward a higher baseline L1-L4 BMD. No association was observed between any SNP or haplotype of the OPG, RANKL, and RANK genes and the response of BMD to alendronate therapy. The RANK gene might contribute to genetic variability in L1-L4 BMD in postmenopausal Chinese women with osteoporosis or osteopenia. No evidence of an association between any SNP or haplotype of the OPG, RANKL, and RANK genes and the response of BMD to alendronate therapy was found in postmenopausal Chinese women with osteoporosis or osteopenia.

Patterns of use for brand-name versus generic oral bisphosphonate drugs in Ontario over a 13-year period: a descriptive study.

PubMed

Fraser, Lisa-Ann; Albaum, Jordan M; Tadrous, Mina; Burden, Andrea M; Shariff, Salimah Z; Cadarette, Suzanne M

2015-01-01

Bisphosphonates are the first-line therapy for the treatment of osteoporosis. In the province of Ontario, the Ontario Drug Benefit Program funds medications for patients aged 65 years and older. The Ontario Drug Benefit Program has a generic substitution policy that requires lower-cost generic drugs to be dispensed when they are available. However, there is controversy surrounding the efficacy and tolerability of generic bisphosphonates. The objective of this study was to describe patterns in the use of brand-name versus generic formulations when dispensing oral bisphosphonate over a 13-year period. We identified all osteoporotic preparations for alendronate and risedronate that were dispensed through the Ontario Drug Benefit Program from 2001 to 2014. We stratified our sample into community-dwelling residents and residents in long-term care facilities. The number of prescriptions dispensed per month were plotted to illustrate trends over time. We found a rapid switch from brand-name to generic bisphosphonate equivalents immediately after the generic became available on the Ontario Drug Benefit formulary, with generics accounting for > 88% of dispensed drug within 2 months. We also observed a reduction in the number of generic drugs dispensed each time a new brand-name alternative (e.g., monthly risedronate, weekly alendronate plus vitamin D) was introduced to the formulary. The dispensing trends were similar in the community and long-term care settings. The Ontario Drug Benefit Program generic substitution policy resulted in rapid uptake of generic oral bisphosphonates among seniors in Ontario. However, there was a switch away from generic medications to new brand-name alternatives whenever they were introduced to the formulary. Therefore, some patients continued to use brand-name bisphosphonate despite the availability of generic options.

[Role of bones in the physiopathology of idiopathic hypercalciuria: effect of amino-bisphosphonate alendronate].

PubMed

Weisinger, J R; Alonzo, E; Machado, C; Carlini, R; Martinis, R; Paz-Martínez, V; Bellorín-Font, E

1997-01-01

Previous studies from our laboratory demonstrated that bone mineral content is affected in patients with idiopathic hypercalciuria and that there is a correlation between bone mineral loss and in-vitro cytokine production. At the same time we found that short term treatment with alendronate decreased urinary calcium in these subjects. In the present study we have examined the long-term effects of alendronate treatment (10 mg/day for one year) on urinary calcium, urinary hydroxyproline and bone mineral content in 18 idiopathic hypercalciuric and 8 normocalciuric stone formers. Clinical characteristics, as well as gender and age distribution were similar in both groups. Urinary calcium and hydroxyproline, were measured monthly. Calcium excretion decreased significantly at the end of the first month, and remained lower thereafter (277 +/- 28, before vs. 202 +/- 26 mg/g creatinine, after 12 months on alendronate, p < 0.01). Urinary hydroxyproline decreased significantly during the study (125.5 +/- 32.1 vs. 39.66 +/- 17.5 mg/g creatinine, p < 0.05). Serum calcium, glomerular filtration rate, and urinary sodium, did not change during the study. Lumbar spine bone density (trabecular bone) obtained with X ray absorptiometry revealed a significant increase from 1.162 +/- 0.231 to 1.197 +/- 0.248 g/cm2 (p < 0.01). These changes were associated with a significant decrease in IL-1 alpha mRNA transcription by unstimulated and lipopolysaccharide stimulated blood mononuclear cells, as tested by the reverse transcriptase polymerase chain reaction. No changes were observed in bone cortical sites (femoral neck). Normocalciuric subjects showed no significant changes in urinary calcium. In summary, the changes observed in urinary calcium excretion and different bone metabolic parameters, suggest a role of bone in the pathophysiology of idiopathic hypercalciuria.

Mouse macrophages primed with alendronate down-regulate monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha) production in response to Toll-like receptor (TLR) 2 and TLR4 agonist via Smad3 activation.

PubMed

Masuda, Takahiro; Deng, Xue; Tamai, Riyoko

2009-08-01

Alendronate is one of the nitrogen-containing bisphosphonates (NBPs) used as anti-bone resorptive drugs. However, NBPs have inflammatory side effects including osteomyelitis and osteonecrosis of the jaw. In the present study, we examined the effects of alendronate on chemokine production by the macrophage-like cell line, J774.1, when incubated with Pam(3)CSK(4) (a Toll-like receptor (TLR) 2 agonist) and Lipid A (a TLR4 agonist). Pretreatment of J774.1 cells with alendronate decreased the production of TLR ligand-induced monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha) but did not influence nuclear factor-kappaB (NF-kappaB) activation. While this agent induced caspase-8 activation, a caspase-8 inhibitor did not affect the decrease in MCP-1 production by alendronate and TLR ligands. Thus, the alendronate-mediated decrease in chemokine production was independent of NF-kappaB and caspase-8 activation. Although transforming growth factor-beta1 (TGF-beta1) is known to inhibit chemokine production by various cell types via Smad3 activation, pretreatment with alendronate did not increase TGF-beta1 production by J774.1 cells incubated in the presence or absence of TLR ligands. However, alendronate directly activated Smad3. These results suggest that by down-regulating MCP-1 and MIP-1alpha production via Smad3, long-term use of alendronate might inhibit normal activation and migration of osteoclasts and cause osteonecrosis.

Effectiveness of alendronate as an adjunct to scaling and root planing in the treatment of periodontitis: a meta-analysis of randomized controlled clinical trials

PubMed Central

2016-01-01

Purpose Alendronate has been proposed as a local and systemic drug treatment used as an adjunct to scaling and root planing (SRP) for the treatment of periodontitis. However, its effectiveness has yet to be conclusively established. The purpose of the present meta-analysis was to assess the effectiveness of SRP with alendronate on periodontitis compared to SRP alone. Methods Five electronic databases were used by 2 independent reviewers to identify relevant articles from the earliest records up to September 2016. Randomized controlled trials (RCTs) comparing SRP with alendronate to SRP with placebo in the treatment of periodontitis were included. The outcome measures were changes in bone defect fill, probing depth (PD), and clinical attachment level (CAL) from baseline to 6 months. A fixed-effect or random-effect model was used to pool the extracted data, as appropriate. Mean differences (MDs) with 95% confidence intervals (CIs) were calculated. Heterogeneity was assessed using the Cochrane χ2 and I2 tests. Results After the selection process, 8 articles were included in the meta-analysis. Compared with SRP alone, the adjunctive mean benefits of locally delivered alendronate were 38.25% for bone defect fill increase (95% CI=33.05–43.45; P<0.001; I2=94.0%), 2.29 mm for PD reduction (95% CI=2.07–2.52 mm; P<0.001; I2=0.0%) and 1.92 mm for CAL gain (95% CI=1.55–2.30 mm; P<0.001; I2=66.0%). In addition, systemically administered alendronate with SRP significantly reduced PD by 0.36 mm (95% CI=0.18–0.55 mm; P<0.001; I2=0.0%) and increased CAL by 0.39 mm (95% CI=0.11–0.68 mm; P=0.006; I2=6.0%). Conclusions The collective evidence regarding the adjunctive use of alendronate locally and systemically with SRP indicates that the combined treatment can improve the efficacy of non-surgical periodontal therapy on increasing CAL and bone defect fill and reducing PD. However, precautions must be exercised in interpreting these results, and multicenter studies evaluating

Development and validation of a reversed-phase ion-pair high-performance liquid chromatographic method for the determination of risedronate in pharmaceutical preparations.

PubMed

Kyriakides, Demetra; Panderi, Irene

2007-02-12

A stability indicating, reversed-phase ion-pair high-performance liquid chromatographic method was developed and validated for the determination of risedronate in pharmaceutical dosage forms. The determination was performed on a BDS C(18) analytical column (250 mm x 4.6 mm i.d., 5 microm particle size); the mobile phase consisted of 0.005 M tetrabutylammonium hydroxide and 0.005 M pyrophosphate sodium (pH 7.0) mixed with acetonitrile in a ratio (78:22, v/v) and pumped at a flow rate 1.00 mL min(-1). The ultraviolet (UV) detector was operated at 262 nm. The retention times of magnesium ascorbyl phosphate, which was used as internal standard and risedronate were 4.94 and 5.95 min, respectively. The calibration graph was ranged from 2.50 to 20.00 microg mL(-1), while detection and quantitation limits were found to be 0.48 and 1.61 microg mL(-1), respectively. The intra- and inter-day percentage relative standard deviations, %R.S.D., were less than 5.9%, while the relative percentage error, %E(r), was less than 0.4%. The method was applied to the quality control of commercial tablets and content uniformity test and proved to be suitable for rapid and reliable quality control.

Two-way crossover bioequivalence study of alendronate sodium tablets in healthy, non-smoking male volunteers under fasted conditions.

PubMed

Thudi, Nageshwar Rao; Gagnon, Stéphanie; Hussain, Saleh; Abolfathi, Zohreh; Singla, Ajay; Pai, Raveendra; Kumar, Sudershan; Monif, Tausif

2009-01-01

This study was conducted in order to assess the bioequivalence of two different formulations containing 70 mg alendronate sodium (CAS 121268-17-5) under fasted conditions. One hundred twenty-two healthy male volunteers were enrolled in an open label, randomized, crossover design with a wash-out period of 20 days in one study center. Urine samples were collected up to 36 h post-dose, and the concentrations of alendronic acid were determined using a high performance liquid chromatographic method with pre-derivatization and fluorescence detection (HPLC/FL) method. The mean Ae(0-t) were 604.24 +/- 348.73 microg and 627.36 +/- 327.99 microg, while the mean R(max) were 193.87 +/- 114.68 microg/h and 202.00 +/- 107.83 microg/h for the test and reference formulations, respectively. The T(max) of the test and reference tablets were 1.26 +/- 0.58 h and 1.26 +/- 0.51 h, respectively. No significant differences of pharmacokinetic parameters between the two studied formulations were found. The 90% confidence intervals for the primary target parameters, intra-individual ratios for Ae(0-t) and R(max) of alendronic acid, were between 0.86-1.00 and 0.85-1.01, respectively, and thus within the acceptance range for bioequivalence criteria. In the light of the present study it can be concluded that the test formulation is bioequivalent to the reference formulation.

Effect of alendronate on bone mineral density in adult patients with Laron syndrome (primary growth hormone insensitivity).

PubMed

Eshed, Varda; Benbassat, Carlos A; Laron, Zvi

2006-04-01

Severe short stature resulting from a deficiency in insulin-like growth factor-I (IGF-I) is a prominent feature of Laron syndrome (LS). Whether patients with LS are osteopenic or not, and whether they need treatment with bisphosphonates, remains uncertain. The aim of this study was to investigate the action of alendronate on the IGF-I-deficient bones of adult patients with LS and osteoporosis, as determined by dual X-ray absorptiometry . Seven patients (5 women and 2 men) of mean age 40.8+/-7.6 years and mean bone mass density (BMD) 0.843+/-0.06 g/cm2 (T score -2.9+/-0.5) at the lumbar spine and 0.734+/-0.11 g/cm2 (T score -2.2+/-0.9) at the femoral neck were treated with alendronate 70 mg once/weekly over a 12-month period. Treatment led to an increase of 5.3% in BMD (p=0.038) at the femoral neck. There was a similar trend at the lumbar spine, but the difference was not statistically significant (2.3%, p=0.34). Mean total alkaline phosphatase decreased by 14% from normal range at baseline (p=0.007). Urinary deoxypyridinoline levels, which were elevated at baseline (10+/-2.3 nM/mMcre), showed a nonsignificant change during treatment. Our study suggests that treatment with alendronate may have positive effects in patients with LS and low BMD on dual X-ray absorptiometry.

Synergistic antiosteoporotic effect of Lepidium sativum and alendronate in glucocorticoid-induced osteoporosis in Wistar rats.

PubMed

Elshal, Mohamed F; Almalki, Abdulrahman L; Hussein, Hussein K; Khan, Jalal A

2013-01-01

Alendronate belongs to a class of drugs called bisphosphonates. Bisphosphonates (BP) therapy is a vital option to reduce the risk of bone fracture in people who suffer from osteoporosis. Yet, bisphosphonate have displayed several side effects. Lepidium sativum (LS) seeds have been used in traditional folk medicine to heal fractured bones. However, there is a dearth of information on the impact of LS on bone metabolism especially in cases of glucocorticoids induced osteoporosis. Therefore, the aim of the study was to compare the biochemical bone markers and histological responses of LS alone (6 g of LS seeds in diet daily, n=8), ALD (alendronate, 70 mg/kg s.c.; n=8) alone, or LS and ALD combined in a rat model of glucocorticoid-induced osteoporosis (GIO) by injecting rats with methylprednisolone 3.5 mg/kg per day for 4 weeks. Serum calcium (Ca), albumin, phosphorus (P), bone-specific alkaline phosphatase (b-ALP), and tartrate-resistant acid phosphatase (TRAP) were measured 4 weeks after induction of GIO. GIO-group showed significantly increased serum TRAP and decreased b-ALP. GIO-group also showed significantly decreased serum P and unaltered Ca concentrations. Histological examination of GIO-group tibia bones indicated an osteoporotic change and a concomitant decrease in percentage of trabecular area or bone marrow area (PTB) in the proximal femoral epiphysis. Treatment with either LS and/or ALD ameliorated the above mentioned changes with variable degrees, with a net results of enhanced serum calcium, bone architecture, PTB, b-ALP and decreased TRAP in LS and LS+ALD groups compared to that of animals treated with alendronate alone. In conclusion, our findings present evidence supporting the potential benefits of LS in reducing the burden of GCs on bone health.

The role of counselling and other factors in compliance of postmenopausal osteoporotic patients to alendronate 70 therapy

PubMed Central

Horst-Sikorska, Hanna; Stępień-Kłos, Wioletta; Antkowiak, Agnieszka; Janik, Małgorzata; Cieślak, Karol; Marcinkowska, Michalina; Cegłowska, Agnieszka; Stuss, Michał

2013-01-01

Introduction The aim of the study was to assess the role of patient counselling, nurse assistance and effects of biochemical examinations in adherence of women with postmenopausal osteoporosis to alendronate 70 administration over 12 months of therapy. Material and methods Compliance and persistence to alendronate 70 therapy were assessed in a prospective study of 123 postmenopausal women, followed up for one year. The patients were divided into 4 groups (controls, counselled group, biochemical group and nurse assisted group) with monitoring every 6 months; in the nurse assisted group, additional phone contacts were made after 3 and 9 months of treatment. After 12 months, compliance and persistence were analysed. The medication possession ratio (MPR) was regarded as optimal when its value exceeded 80%. Results The compliance to alendronate 70 therapy was 54.03% in the control group and the mean persistence with medication was 197 days. The MPR above 80% was observed in 37.5%, and, after 1 year, 43.75% of patients were found persistent with the therapy. In the remaining groups, both compliance and persistence were higher but not statistically significantly, compared to the control group. Neither patient's age, education, diet, nor physical activity influenced the compliance with prescribed therapy. The most common reason to discontinue therapy was either its side effects or smoking. Conclusions The obtained results suggest that better adherence with medical recommendations is observed in patients who receive additional attention, e.g. counselling, biochemical tests or nursing care. The critical elements for therapy discontinuation were side effects and smoking. PMID:23671440

Effect of low-magnitude whole-body vibration combined with alendronate in ovariectomized rats: a random controlled osteoporosis prevention study.

PubMed

Chen, Guo-Xian; Zheng, Shuai; Qin, Shuai; Zhong, Zhao-Ming; Wu, Xiu-Hua; Huang, Zhi-Ping; Li, Wei; Ding, Ruo-Ting; Yu, Hui; Chen, Jian-Ting

2014-01-01

Alendronate (ALE) is a conventional drug used to treat osteoporosis. Low-magnitude whole-body vibration (WBV) exercise has been developed as a potential treatment for osteoporosis. The aim of this study was to investigate whether low-magnitude WBV could enhance the protective effect of ALE on bone properties in ovariectomized rats. A total of 128 Sprague-Dawley rats were randomly divided into five groups (SHAM, OVX+VEH, OVX+WBV, OVX + ALE, OVX+WBV+ALE). The level of WBV applied was 0.3 g at 45-55 Hz for 20 min/day, 5 day/week and for 3 months. ALE was administered in dose of 1 mg/Kg once a week. Every four weeks eight rats from each group were sacrificed and their blood and both tibiae were harvested. The expression of osteocalcin and CTX in serum was measured by enzyme-linked immunosorbent assay (ELISA) and the tibiae were subjected to metaphyseal three-point bending and μCT analysis. Osteocalcin rose after ovariectomy and was not appreciably changed by either alendronate or WBV alone or in combination. Alendronate treatment significantly prevented an increase in CTX. WBV alone treatment did not alter this effect. Compared with the OVX+WBV group, nearly all tested indices such as the BV/TV, TV apparent, Tb.N, Tb.Th, and Conn.D were higher in the OVX+ALE group at week 12.Compared with the OVX+WBV group, certain tested indices such as BV/TV, TV apparent, Tb.N, and Con.D, were higher in the OVX+WBV+ALE group at week 12. At week 12, tibiae treated with WBV+ALE exhibited a significantly higher Fmax compared to the OVX+VEH group, and a significant difference was also found in energy absorption between the OVX+WBV+ALE and OVX+VEH groups. Compared with the WBV, ALE was more effective at preventing bone loss and improved the trabecular architecture. However, WBV enhanced the effect of alendronate in ovariectomized rats by inducing further improvements in trabecular architecture.

Effect of Low-Magnitude Whole-Body Vibration Combined with Alendronate in Ovariectomized Rats: A Random Controlled Osteoporosis Prevention Study

PubMed Central

Zhong, Zhao-Ming; Wu, Xiu-Hua; Huang, Zhi-Ping; Li, Wei; Ding, Ruo-Ting; Yu, Hui; Chen, Jian-Ting

2014-01-01

Background Alendronate (ALE) is a conventional drug used to treat osteoporosis. Low-magnitude whole-body vibration (WBV) exercise has been developed as a potential treatment for osteoporosis. The aim of this study was to investigate whether low-magnitude WBV could enhance the protective effect of ALE on bone properties in ovariectomized rats. Methods A total of 128 Sprague-Dawley rats were randomly divided into five groups (SHAM, OVX+VEH, OVX+WBV, OVX + ALE, OVX+WBV+ALE). The level of WBV applied was 0.3 g at 45–55 Hz for 20 min/day, 5 day/week and for 3 months. ALE was administered in dose of 1 mg/Kg once a week. Every four weeks eight rats from each group were sacrificed and their blood and both tibiae were harvested. The expression of osteocalcin and CTX in serum was measured by enzyme-linked immunosorbent assay (ELISA) and the tibiae were subjected to metaphyseal three-point bending and μCT analysis. Results Osteocalcin rose after ovariectomy and was not appreciably changed by either alendronate or WBV alone or in combination. Alendronate treatment significantly prevented an increase in CTX. WBV alone treatment did not alter this effect. Compared with the OVX+WBV group, nearly all tested indices such as the BV/TV, TV apparent, Tb.N, Tb.Th, and Conn.D were higher in the OVX+ALE group at week 12.Compared with the OVX+WBV group, certain tested indices such as BV/TV, TV apparent, Tb.N, and Con.D, were higher in the OVX+WBV+ALE group at week 12. At week 12, tibiae treated with WBV+ALE exhibited a significantly higher Fmax compared to the OVX+VEH group, and a significant difference was also found in energy absorption between the OVX+WBV+ALE and OVX+VEH groups. Conclusions Compared with the WBV, ALE was more effective at preventing bone loss and improved the trabecular architecture. However, WBV enhanced the effect of alendronate in ovariectomized rats by inducing further improvements in trabecular architecture. PMID:24796785

Cost-effectiveness of alendronate in the treatment of postmenopausal women in 9 European countries--an economic evaluation based on the fracture intervention trial.

PubMed

Ström, O; Borgström, F; Sen, S S; Boonen, S; Haentjens, P; Johnell, O; Kanis, J A

2007-08-01

Treatment with alendronate (Fosamax) has been shown to significantly reduce the risk of fragility fractures. Cost-effectiveness of treatment was assessed in nine European countries in a Markov model and was generally found to be cost effective in women with a previous spine fracture. Treatment with alendronate (Fosamax) reduces the risk of osteoporotic fractures at the spine, hip and wrist in women with and without prevalent vertebral fracture. Cost-effectiveness estimates in one country may not be applicable elsewhere due to differences in fracture risks, costs and drug prices. The aim of this study was to assess the cost-effectiveness of treating postmenopausal women with alendronate in nine European countries, comprising Belgium, Denmark, France, Germany, Italy, Norway, Spain, Sweden, and the UK. A Markov model was populated with data for the nine European populations. Effect of treatment was taken from the Fracture Intervention Trial, which recruited women with low BMD alone or with a prior vertebral fracture. The cost per QALY gained of treating postmenopausal women with prior vertebral fractures ranged in the base case from "cost saving" in the Scandinavian countries to 15,000 in Italy. Corresponding estimates for women without prior vertebral fractures ranged from "cost saving" to 40,000. In relation to thresholds generally used, the analysis suggests that alendronate is very cost effective in the treatment of women with previous vertebral fracture, and in women without previous vertebral fracture, cost-effectiveness depends on the country setting, discount rates, and chosen monetary thresholds.

Prolonged use of alendronate alters the biology of cranial repair in estrogen-deficient rats' associated simultaneous immunohistochemical expression of TGF-β1+, α-ER+, and BMPR1B.

PubMed

Giovanini, Allan Fernando; de Sousa Passoni, Giuliene Nunes; Göhringer, Isabella; Deliberador, Tatiana Miranda; Zielak, João Cesar; Storrer, Carmem Lucia Muller; Costa-Casagrande, Thais Andrade; Scariot, Rafaela

2018-06-01

TGF-β1 is a cytokine that may induce both osteoneogenesis through Runx-2 or fibrosis via the transcription of α-smooth muscle actin (α-SMA). Because it has been previously known that alendronate increases the level of TGF-β1 and that under the usual condition of bone metabolism the estrogen may prevent the fibrotic effect of TGF-β1, the aim of this study was to evaluate if alendronate alters the cellular differentiation process post calvarial surgery in estrogen-deficient specimens. A transosseous defect that was 5 mm in diameter was created on the calvarium of each of 32 female rats with previous ovarian-salpingo-oophorectomy. All defects were treated with autografts, and 16 rats received the administration of 1 mg/kg of alendronate three times a week until euthanasia on the 15th and 60th day post surgery. Histomorphometric and immunohistochemical analyses of the expression of TGF-β1, estrogen receptor alpha nuclear (α-ER), α-SMA, BMPR1B, and Runx-2 were performed, and ELISA was used to measure the level of estrogen. All animals demonstrated low levels of estrogen post ovarian-salpingo-oophorectomy. The histological results demonstrated larger bone matrix deposition in specimens treated with alendronate on the 15th day post surgery. The result was associated with a higher co-expression of TGF-β1, BMPR1B, and Runx-2 when compared with the control group. In addition, on the 60th day post surgery, the increase of bone matrix deposition from 15th to 60th day was discrete in specimens treated with alendronate compared with the control group. This result coincided with the intense simultaneous expression of TGF-β1, α-ER, and α-SMA, whereas the expression of BMPR1B and Runx-2 decreased. The prolonged administration of alendronate altered the cranial repair in ovarian-salpingo-oophorectomized specimens due to the simultaneous occurrence of low estrogen and the presence of TGF-β1+/α-ER+ inducing the presence of α-SMA + , whereas BMPR1B and Runx-2 were

Alveolar bone dynamics in osteoporotic rats treated with raloxifene or alendronate: confocal microscopy analysis

NASA Astrophysics Data System (ADS)

Ramalho-Ferreira, Gabriel; Faverani, Leonardo Perez; Grossi-Oliveira, Gustavo Augusto; Okamoto, Tetuo; Okamoto, Roberta

2015-03-01

In this study, the characteristics of the alveolar bone of rats with induced osteoporosis were examined. Thirty-two rats were divided into four groups according to the induction of osteoporosis and drugs administered: OG, osteoporotic rats without treatment (negative control); SG, rats which underwent sham surgery ovariectomy (SHAM); alendronate (AG), osteoporotic rats treated with alendronate; and RG, osteoporotic rats treated with raloxifene (RG). On the 8th day after ovariectomy and SHAM surgeries, drug therapy was started with AG or RG. On the 52nd day, 20 mg/kg calcein was administered to all of the rats, and on the 80th day, 20 mg/kg alizarin red was administered. Euthanasia was performed on the 98th day. The bone area marked by fluorochromes was calculated and data were subjected to two-way ANOVA test and Tukey's post-hoc test (p<0.05). The comparison of the induced osteoporosis groups showed no statistically significant differences in bone turnover only between RG and SG (p=0.074) and AG and OG (p=0.138). All other comparisons showed significant differences (p<0.001). The largest bone turnover was observed in RG and SG groups. RG was the medication that improved the dynamics of the alveolar bone of rats with induced osteoporosis, resembling that of healthy rats.

Skeletal Structural Consequences of Reduced Gravity Environments

NASA Technical Reports Server (NTRS)

Ruff, Christropher B.

1999-01-01

The overall goal of this project is to provide structurally meaningful data on bone loss after exposure to reduced gravity environments so that more precise estimates of fracture risk and the effectiveness of countermeasures in reducing fracture risk can be developed. The project has three major components: (1) measure structural changes in the limb bones of rats subjected to complete and partial nonweightbearing, with and without treatment with ibandronate and periodic full weightbearing; (2) measure structural changes in the limb bones of human bedrest subjects, with and without treatment with alendronate and resistive exercise, and Russian cosmonauts flying on the Mir Space Station; and (3) validate and extend the 2-dimensional structural analyses currently possible in the second project component (bedrest and Mir subjects) using 3-dimensional finite element modeling techniques, and determine actual fracture-producing loads on earth and in space.

Vitamin K to prevent fractures in older women: systematic review and economic evaluation.

PubMed

Stevenson, M; Lloyd-Jones, M; Papaioannou, D

2009-09-01

difference between treatment groups in non-vertebral fracture incidence. In the ECKO trial, phylloquinone was not associated with an increase in adverse events. In the menatetrenone trials, adverse event reporting was generally poor; however, in the OF study, menatetrenone was associated with a significantly higher incidence of skin and skin appendage lesions. No published economic evaluations of vitamin K were found and a mathematical model was thus constructed to estimate the cost-effectiveness of vitamin K1. Comparators were alendronate, risedronate and strontium ranelate. Vitamin K1 and alendronate were markedly more cost-effective than either risedronate or strontium ranelate. The base-case results favoured vitamin K1, but this relied on many assumptions, particularly on the efficacy of preventing hip and vertebral fractures. Calculation of the expected value of sampled information was conducted assuming a randomised controlled trial of 5 years' duration comparing alendronate with vitamin K1. The costs incurred in obtaining updated efficacy data from a trial with 2000 women per arm were estimated to be a cost-effective use of resources. There is currently large uncertainty over whether vitamin K1 is more cost-effective than alendronate; further research is required. It is unlikely that the present prescribing policy (i.e. alendronate as first-line treatment) would be altered.

Experience with alendronate treatment for 7 years among Japanese men with osteoporosis or osteopenia and clinical risk factors for fractures.

PubMed

Iwamoto, Jun; Uzawa, Mitsuyoshi

2016-01-01

A retrospective study was performed to evaluate the outcome of alendronate treatment for 7 years among Japanese men with osteoporosis or osteopenia and clinical risk factors for fractures. Thirty-five Japanese men with osteoporosis or osteopenia and clinical risk factors for fractures (mean age at baseline 58.2 years) who had been treated with alendronate for over 7 years in our outpatient clinic were analyzed. The lumbar spine or total hip bone mineral density (BMD) was measured using dual energy X-ray absorptiometry; the urinary levels of cross-linked N-terminal telopeptides of type I collagen (NTX) and the serum levels of alkaline phosphatase (ALP) were monitored; the incidence of fractures during the 7-year treatment period was then assessed. The urinary NTX and serum ALP levels decreased (-46.1% at 3 months and -21.1% at 7 years, respectively) and the lumbar spine and total hip BMD increased (+14.2 and +10.1% at 7 years, respectively), compared with the baseline values. Four patients (11.4%) experienced vertebral fractures, and one patient (2.9%) experienced a nonvertebral fracture. No serious adverse events were observed, including osteonecrosis of the jaw or atypical femoral fractures. These results suggested that alendronate suppressed bone turnover and increased the lumbar spine and total hip BMD from the baseline values over the course of the 7-year treatment period without causing any severe adverse events in Japanese men with osteoporosis or osteopenia and clinical risk factors for fractures.

Acute bilateral uveitis and right macular edema induced by a single infusion of zoledronic acid for the treatment of postmenopausal osteoporosis as a substitution for oral alendronate: a case report.

PubMed

Tian, Yiming; Wang, Rui; Liu, Lianyuan; Ma, Chunming; Lu, Qiang; Yin, Fuzai

2016-02-11

Zoledronic acid-induced uveitis (ZAIU) is rare but severe, and has been recently considered part of an acute phase reaction. Only 15 cases have been reported since 2005. Here we describe a case with macular edema, which is the first reported case observed after long-term alendronate tolerance. A 63-year-old Asian woman received her first intravenous zoledronic acid treatment for the management of postmenopausal osteoporosis as a more convenient substitute for oral alendronate. Twenty-four hours later, bilateral eye irritations, periorbital swelling, blurred vision, and diplopia presented. The complete blood count and transaminase levels were normal, but the erythrocytic sedimentation, C-reactive protein, and serum C4 levels were elevated. On detailed ophthalmological examination, a diagnosis of bilateral acute uveitis and macular edema in the right eye was made. The ocular symptoms were not improved until administration of topical and oral steroids. Complete resolution was achieved. There was no rechallenge of bisphosphonates, and no recurrence at 6 months follow-up. Based on an extensive review, abnormal fundus is rarely reported, especially in cases of macular edema. Rechallenge with zoledronic acid in five cases induced no additional uveitis, and changing the medication to pamidronate in another patient was also tolerated. Interestingly, our patient suffered from uveitis soon after intravenous zoledronate exposure after a two-year tolerance to oral alendronate. This is the first report of zoledronic acid induced uveitis with macular edema after long-term alendronate tolerance. Prior oral alendronate may not entirely prevent ZAIU. Steroids are usually necessary in the treatment of ZAIU. Bisphosphonate rechallenge is not fully contraindicated, and prior steroid administration may be a more reasonable treatment choice according to the available evidence.

Minodronate for the treatment of osteoporosis.

PubMed

Ohishi, Tsuyoshi; Matsuyama, Yukihiro

2018-01-01

Minodronate is a third-generation bisphosphonate that was developed and approved for clinical use in osteoporosis therapy in Japan. The mechanism of action for suppressing bone resorption is the inhibition of farnesyl pyrophosphate synthase, a key enzyme in the mevalonic acid metabolic pathway of osteoclasts, to induce apoptosis of the cells. Minodronate is the strongest inhibitor of bone resorption among the currently available oral bisphosphonates. Large randomized, placebo-controlled, double-blind clinical trials have revealed an increase in bone mineral density of both the lumbar spine and femoral neck over 3 years of daily minodronate therapy and risk reduction in vertebral fractures over 2 years of therapy. The increase in bone mass and the prevention of vertebral fractures are similar to those with alendronate or risedronate. The incidence of adverse events, especially gastrointestinal disturbance, is the same as or less than that with weekly or daily alendronate or risedronate. The unique mechanism of action of minodronate via the inhibition of the P2X(2/3) receptor compared with other bisphosphonates may be an advantage in reducing low back pain in patients with osteoporosis. The monthly regimen of minodronate, introduced in 2011, is expected to have better patient adherence and longer persistence. In experimental animal models, minodronate preserved, or even ameliorated, bone microarchitectures, including microcracks and perforation of the trabeculae in the short term. The lowest incidence of bisphosphonate-related osteonecrosis of the jaw among all bisphosphonates and the lack of atypical femoral fractures attributed to its use to date, however, are partly because only a smaller population used minodronate than those using other bisphosphonates. To date, minodronate is available only in Japan. Hip fracture risk reduction has not been verified yet. More clinical studies on minodronate and its use in osteoporosis treatment, with a large number of subjects

Disuse bone loss in hindquarter suspended rats: partial weightbearing, exercise and ibandronate treatment as countermeasures

NASA Technical Reports Server (NTRS)

Schultheis, L.; Ruff, C. B.; Rastogi, S.; Bloomfield, S.; Hogan, H. A.; Fedarko, N.; Thierry-Palmer, M.; Ruiz, J.; Bauss, F.; Shapiro, J. R.

2000-01-01

The purpose of this study was to evaluate potential countermeasures for bone loss during long-term space missions in the hindquarter suspended rat, including partial weight bearing (surrogate for artificial gravity) episodic full weight bearing (2 hour/day full weight bearing) and treatment with the third generation bisphosphonate ibandronate (Roche). Graded mechanical loading was studied by housing the animals on a novel servo controlled force plate system which permitted the titration of mechanical force at varying frequency and amplitude and different levels of weight bearing. The force plate, which forms the cage floor, is a glass platform supported by an 18" diameter speaker cone filled with expanding polyurethane foam. An infrared optical sensor attached to the speaker cone yields a voltage linearly related to vertical displacement of the glass platform. The dynamic force on the paw was computed as a product of the apparent mass of the animal on the platform at rest and the acceleration of the platform determined from the second derivative of the optical sensor output. The mass of the animal on the platform was varied by adjusting tension on the tether suspending the animal. Mechanical impact loading was titrated with the force plate resonating at different frequencies, including 3 Hz and 16 Hz.

Effects of the bisphosphonate alendronate on molars of young rats after lateral luxation.

PubMed

Rothbarth, Cláudia Pires; Bradaschia-Correa, Vivian; Ferreira, Lorraine Braga; Arana-Chavez, Victor Elias

2014-12-01

The bisphosphonate alendronate (ALN) was employed with the aim of investigating its effects on dental and periodontal tissues after lateral luxation of developing molars. Twenty-one-day-old Wistar rats had their second upper molars laterally luxated. Daily 2.5 mg kg(-1) ALN injections started at the day of the luxation; controls received sterile saline solution. The teeth were analyzed 7, 14, and 21 days after the procedure. On the days cited, the maxillae were fixed, decalcified, and embedded in paraffin or Spurr resin. The paraffin sections were stained with H&E, incubated for TRAP histochemistry or immunolabeled for osteopontin (OPN). Spurr ultrathin sections were examined in a transmission electron microscope. After 21 days, the root apex of luxated molars without ALN was wide open and disorganized and also covered by an irregular layer of cellular cementum, which was not observed in ALN-treated animals. Ankylosis sites were observed in ALN rats in both luxated and non-luxated teeth. The TRAP-positive osteoclasts were more numerous in ALN group, despite their latent ultrastructural appearance without the presence of resorption apparatus compared to controls. OPN immunolabeling revealed a thick immunopositive line in the dentin that must be resultant from the moment of the luxation, while ALN-treated specimens did not present alterations in dentin. The present findings indicate that alendronate inhibits some alterations in dentin and cementum formation induced by dental trauma. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Duration-dependent effects of clinically relevant oral alendronate doses on cortical bone toughness in beagle dogs

PubMed Central

Burr, David B.; Liu, Ziyue; Allen, Matthew R.

2014-01-01

Bisphosphonates (BPs) have been shown to significantly reduce bone toughness in vertebrae within one year when given at clinical doses to dogs. Although BPs also reduce toughness in cortical bone when given at high doses, their effect on cortical bone material properties when given at clinical doses is less clear. In part, this may be due to the use of small sample sizes that were powered to demonstrate differences in bone mineral density rather than bone’s material properties. Our lab has conducted several studies in which dogs were treated with alendronate at a clinically relevant dose. The goal of this study was to examine these published and unpublished data collectively to determine whether there is a significant time-dependent effect of alendronate on toughness of cortical bone. This analysis seemed particularly relevant given the recent occurrence of atypical femoral fractures in humans. Differences in the toughness of ribs taken from dogs derived from five separate experiments were measured. The dogs were orally administered saline (CON, 1 ml/kg/day) or alendronate (ALN) at a clinical dose (0.2 mg/kg/day). Treatment duration ranged from 3 months to 3 years. Groups were compared using ANOVA, and time trends analyzed with linear regression analysis. Linear regressions of the percent difference in toughness between CON and ALN at each time point revealed a significant reduction in toughness with longer exposure to ALN. The downward trend was primarily driven by a downward trend in post-yield toughness, whereas toughness in the pre-yield region was not changed relative to CON. These data suggest that a longer duration of treatment with clinical doses of ALN results in deterioration of cortical bone toughness in a time-dependent manner. As the duration of treatment is lengthened, the cortical bone exhibits increasingly brittle behavior. This may be important in assessing the role that long-term BP treatments play in the risk of atypical fractures of femoral

Impact of medication adherence on health care utilization and productivity: self-reported data from a cohort of postmenopausal women on osteoporosis therapy.

PubMed

Wade, Sally W; Satram-Hoang, Sacha; Nadkar, Aalok; Macarios, David; Tosteson, Anna N A

2011-12-01

Many pharmacologic agents are approved for the prevention and treatment of osteoporosis, which is common among postmenopausal women. Evidence exists relating treatment persistence to fracture risk. Less is known about treatment persistence and the use of health care service and individual productivity. This study was undertaken to describe health care use and productivity loss relative to osteoporosis medication persistence using women's self-reported data from the Prospective Observational Scientific Study Investigating Bone Loss Experience (POSSIBLE US™), a large, longitudinal (October 2004-December 2009) osteoporosis cohort study of postmenopausal women. Analyses included women on pharmacologic osteoporosis therapy (alendronate, risedronate, ibandronate, calcitonin, raloxifene, or teriparatide) who provided health care use/productivity data collected using semiannual questionnaires over 1 year of follow-up. Participant characteristics, use, and productivity metrics were summarized. Logistic regression models and generalized linear models were used to examine use, time missed from usual activities, number of days spent in bed, and lost work time relative to treatment persistence, adjusting for potential confounders. At entry, of the 2528 women studied (91% white, 3.1% Hispanic/Latino, 2.3% African American/black, 1.1% Asian, and 2.1% American Indian/Native Alaskan, Native Hawaiian/Pacific Islander, or other; mean age, 64.6 [range, 37-97] years), 43.1% had osteoporosis and 23.4% had a previous fracture. After adjustment, subjects who switched therapies during follow-up were more likely to have had any kind of diagnostic testing (95.2% of switchers vs 91.2% of persistent subjects and 88.9% of discontinuers, P < 0.05). Discontinuers were less likely than persistent subjects to visit their primary care physicians (92.0% vs 94.4%, P = 0.0337). Variations in the number of days spent in bed, time missed from usual activities, and work loss (n = 852 employed subjects

Efficacy of alendronate, a bisphosphonate, in the treatment of AVN of the hip. A prospective open-label study.

PubMed

Agarwala, S; Jain, D; Joshi, V R; Sule, A

2005-03-01

To study the efficacy of alendronate, in the treatment of avascular necrosis (AVN) of the hip. Sixty patients with AVN of the hip (100 hips with AVN) were studied. The follow-up period ranged from 3 months to 5 yr. The most common cause of AVN was steroids. Parameters studied were walking time, standing time, pain and disability on a visual analogue scale (VAS), range of motion of the hip, X-ray and MRI of the hip. All patients were treated with alendronate 10 mg/day (or 70 mg/week) along with 500-1000 mg of daily calcium and vitamin D supplements, and were advised to avoid weight-bearing. NSAIDs and analgesics were permitted as needed and were recorded. Forty-one patients (71 AVN hips) with AVN have been followed up for a minimum of 1 yr, 24 patients (42 AVN hips) for 2 yr and 21 patients (37 AVN hips) for more than 2 yr (average 37 month). Fourteen patients have been followed up for less than 1 yr (3-9 months). Significant reduction in pain and disability scores (P < 0.001) and significant increase in standing and walking time (P < 0.001) were observed. All hip movements improved at 1 yr (P value 0.000-0.009) with an insignificant decline after that (P > 0.001). Radiologically, the hips either stabilized in the same grade or progressed by one grade. MRI showed a decrease in marrow oedema in most cases at the 1-yr follow-up. Six patients (10 hips) required surgery and there were two (three hips) dropouts. The drug was well tolerated and there was a reduction in NSAID requirement. Alendronate reduces pain, improves function and retards AVN progression. Early surgical intervention can be avoided in most patients.

Efficacy and Safety of Different Bisphosphonates for Bone Loss Prevention in Kidney Transplant Recipients: A Network Meta-Analysis of Randomized Controlled Trials

PubMed Central

Yang, Yan; Qiu, Shi; Tang, Xi; Li, Xin-Rui; Deng, Ling-Hui; Wei, Qiang; Fu, Ping

2018-01-01

Background: Mineral and bone disorder is one of the severe complications in kidney transplant recipients (KTRs). Previous studies showed that bisphosphonates had favorable effects on bone mineral density (BMD). We sought to compare different bisphosphonate regimens and rank their strategies. Methods: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) up to April 01, 2017, for randomized controlled trials (RCTs) comparing bisphosphonate treatments in adult KTRs. The primary outcome was BMD change. We executed the tool recommended by the Cochrane Collaboration to evaluate the risk of bias. We performed pairwise meta-analyses using random effects models and network meta-analysis (NMA) using Bayesian models and assessed the quality of evidence. Results: A total of 21 RCTs (1332 participants) comparing 6 bisphosphonate regimens were included. All bisphosphonates showed a significantly increased percentage change in BMD at the lumbar spine compared to calcium except clodronate. Pamidronate with calcium and Vitamin D analogs showed improved BMD in comparison to clodronate with calcium (mean difference [MD], 9.84; 95% credibility interval [CrI], 1.06–19.70). The combination of calcium and Vitamin D analogs had a significantly lower influence than adding either pamidronate or alendronate (MD, 6.34; 95% CrI, 2.59–11.01 and MD, 6.16; 95% CrI, 0.54–13.24, respectively). In terms of percentage BMD change at the femoral neck, both pamidronate and ibandronate combined with calcium demonstrated a remarkable gain compared with calcium (MD, 7.02; 95% CrI, 0.30–13.29 and MD, 7.30; 95% CrI, 0.32–14.22, respectively). The combination of ibandronate with calcium displayed a significant increase in absolute BMD compared to any other treatments and was ranked best. Conclusions: Our NMA suggested that new-generation bisphosphonates such as ibandronate were more favorable in KTRs to improve BMD. However, the conclusion should be treated

Evaluation of the topical effect of alendronate on the root surface of extracted and replanted teeth. Microscopic analysis on rats' teeth.

PubMed

Lustosa-Pereira, Adriana; Garcia, Roberto Brandão; de Moraes, Ivaldo Gomes; Bernardineli, Norberti; Bramante, Clovis Monteiro; Bortoluzzi, Eduardo Antunes

2006-02-01

The treatment of choice for tooth avulsion is replantation. The ideal replantation should be realized as quickly as possible, or at least, the avulsed tooth should be kept in an adequate solution to preserve the periodontal ligament attached to the root. If that is not possible, treatment of the radicular surface should be done in order to prevent radicular resorption. The purpose of this study was to test sodium alendronate as a substance for topical treatment of the radicular surface of avulsed teeth in an attempt to prevent the occurrence of dental resorptions. Fifty-four rat maxillary right central incisors were extracted and replanted. Group I--extra-alveolar dry period of 15 min, intracanal dressing with calcium hydroxide (CALEN, S.S. White, Artigos Dentários LTDA, Rio de Janeiro, Brazil) and replantation; Groups II and III - extra-alveolar dry periods of 30 and 60 min, respectively, immersion in 1% sodium hypochlorite for 30 min for removal of the periodontal ligament, washing in saline solution for 5 min, and treatment of the radicular surface with 3.2 mg/l sodium alendronate solution for 10 min. Intracanal dressing with calcium hydroxide and replantation followed. At 15, 60, and 90 days post-reimplantation, the animals were killed and the samples obtained and processed for microscopic analysis. The results indicated that sodium alendronate was able to reduce the incidence of radicular resorption, but not of dental ankylosis. No significant differences were observed regarding variations in the extra-alveolar periods among the groups.

Effect of an estrogen-deficient state and alendronate therapy on bone loss resulting from experimental periapical lesions in rats.

PubMed

Xiong, Haofei; Peng, Bin; Wei, Lili; Zhang, Xiaolei; Wang, Li

2007-11-01

The aim of the research was to evaluate the impact of an estrogen-deficient state and alendronate (ALD) therapy on bone loss resulting from experimental periapical lesions in rats. Periapical lesions were induced on ovariectomized (OVX) and sham-ovariectomized (Sham) rats. After sample preparation, histologic and radiographic examination for periapical bone loss area and an enzyme histochemical test for tartrate-resistant acid phosphatase (TRAP) were performed. The results showed that OVX significantly increased bone loss resulting from periradicular lesions. After daily subcutaneous injection of ALD, the bone loss area and the number of TRAP-positive cells (osteoclasts) were reduced. These findings suggested that alendronate may protect against increased bone loss from experimental periapical lesions in estrogen-deficient rats. Given recent recognition of adverse effects of bisphosphonates, including an increased risk for osteonecrosis, the findings from this study should not be interpreted as a new indication for ALD treatment. However, they may offer insight into understanding and predicting outcomes in female postmenopausal patients already on ALD therapy for medical indications.

Development and characterization of a gastroretentive dosage form composed of chitosan and hydroxyethyl cellulose for alendronate

PubMed Central

Chen, Ying-Chen; Ho, Hsiu-O; Chiu, Chiao-Chi; Sheu, Ming-Thau

2014-01-01

In this study, alendronate, the most commonly used biphosphonate for treating osteoporosis, was formulated as gastroretentive dosage form (GRDF) tablets to enhance its oral bioavailability. GRDF tablets were characterized with the effects of different molecular weights (MWs) of chitosan (CS) and hydroxyethyl cellulose (HEC) at various ratios on swelling, floating, and physical integrity. The CS component was formed using various acids: acetic, lactic, malic, succinic, and citric, and a high viscosity grade of HEC was selected. The results demonstrated that the swelling ratios of the formulations comprising high MW CS were lower than those of low or medium MW CS when salts were formed with any countering acids except for acetic acid. The decreasing ranking of the swelling rates was: CS-citrate > CS-malate > CS-lactate > CS-succinate > CS-acetate. A negative correlation was found between the pKa of the respective countering acid and the swelling rate. The swelling rate was promoted if an acidic salt of CS with a lower water content was incorporated, while it became slower when tablet hardness was higher or the compression force to form tablets was increased. Although HEC did not contribute to swelling or floating, it played a role in maintaining structural integrity. A prolonged dissolution profile of alendronate GRDF tablets developed in this study was observed. PMID:24403821

Efficacy on the risk of vertebral fracture with administration of once-weekly 17.5 mg risedronate in Japanese patients of established osteoporosis with prevalent vertebral fractures: a 156-week longitudinal observational study in daily practice.

PubMed

Soen, Satoshi; Umemura, Takashi; Ando, Tsuyoshi; Kamisaki, Toshiaki; Nishikawa, Masahiko; Muraoka, Ryoichi; Ikeda, Yoshinori; Takeda, Kyoko; Osawa, Mitsuharu; Nakamura, Toshitaka

2017-07-01

Currently, the only available evidence for the efficacy of once-weekly 17.5 mg risedronate in preventing vertebral fractures was obtained in a 48-week study in Japan. We performed a 156-week prospective, longitudinal, observational study to determine the efficacy of the 17.5 mg risedronate in preventing vertebral fractures. We included Japanese patients with established osteoporosis who were older than 50 years and had radiographically confirmed vertebral fractures. The primary endpoint was the incidence of vertebral fractures every 24 weeks, with the final interval spanning 36 weeks. We also calculated the change in bone mineral density of the lumbar spine (L 2-4 BMD) and urinary N-telopeptide of type I collagen (u-NTX), and assessed the incidence of adverse drug reactions and the drug adherence rate. Data from 241 patients were available for analysis of vertebral fracture prevention. The incidence rate of vertebral fractures decreased in a time-dependent manner (P = 0.0006; Poisson regression analysis). The risk ratio (fracture incidence per 100 person-years in the final 36 weeks versus that in the first 24 weeks) was 0.21 (95 % confidence interval 0.08-0.55). Compared to baseline values, L 2-4 BMD increased by 6.41 % at 156 weeks, while u-NTX decreased by 36 % at 24 weeks and was maintained thereafter (P < 0.0001). The incidence rate of adverse drug reactions was 9.18 %. Drug adherence rates assessed every 4 weeks were over 90 %. Our results indicate that 156 weeks of treatment with once-weekly 17.5 mg risedronate effectively reduced the risk of vertebral fracture in Japanese patients with established osteoporosis older than 50 years.

Histological comparison of alendronate, calcium hydroxide and formocresol in amputated rat molar.

PubMed

Cengiz, S Burcak; Batirbaygil, Yildiz; Onur, Mehmet Ali; Atilla, Pergin; Asan, Esin; Altay, Nil; Cehreli, Zafer C

2005-10-01

The purpose of this study was to evaluate the potential of alendronate sodium (ALN), a biphosohonate to stimulate hard tissue formation in pulpotomized (amputated) rat molars. Two commonly used pulpotomy materials, calcium hydroxide (CH) and formocresol (FC) were utilized for comparisons. Histological evaluations were performed by observers blinded to treatment allocation on days 7, 15, 30 and 60, followed by statistical analysis of selected histological criteria. In all evaluation periods, hard tissue deposition was evident along the radicular dentin in ALN and CH groups. In days 30 and 60, the latter two groups showed no differences in inflammatory cell response and hard tissue deposition scores (P > 0.05). ALN appears to be capable of maintaining pulpal vitality, while promoting hard tissue formation, similar to CH.

Treatment of low bone density in young people with cystic fibrosis: a multicentre, prospective, open-label observational study of calcium and calcifediol followed by a randomised placebo-controlled trial of alendronate.

PubMed

Bianchi, Maria Luisa; Colombo, Carla; Assael, Baroukh M; Dubini, Antonella; Lombardo, Mariangela; Quattrucci, Serena; Bella, Sergio; Collura, Mirella; Messore, Barbara; Raia, Valeria; Poli, Furio; Bini, Rita; Albanese, Carlina V; De Rose, Virginia; Costantini, Diana; Romano, Giovanna; Pustorino, Elena; Magazzù, Giuseppe; Bertasi, Serenella; Lucidi, Vincenzina; Traverso, Gabriella; Coruzzo, Anna; Grzejdziak, Amelia D

2013-07-01

Long-term complications of cystic fibrosis include osteoporosis and fragility fractures, but few data are available about effective treatment strategies, especially in young patients. We investigated treatment of low bone mineral density in children, adolescents, and young adults with cystic fibrosis. We did a multicentre trial in two phases. We enrolled patients aged 5-30 years with cystic fibrosis and low bone mineral density, from ten cystic fibrosis regional centres in Italy. The first phase was an open-label, 12-month observational study of the effect of adequate calcium intake plus calcifediol. The second phase was a 12-month, double-blind, randomised, placebo-controlled, parallel group study of the efficacy and safety of oral alendronate in patients whose bone mineral apparent density had not increased by 5% or more by the end of the observational phase. Patients were randomly assigned to either alendronate or placebo. Both patients and investigators were masked to treatment assignment. We used dual x-ray absorptiometry at baseline and every 6 months thereafter, corrected for body size, to assess lumbar spine bone mineral apparent density. We assessed bone turnover markers and other laboratory parameters every 3-6 months. The primary endpoint was mean increase of lumbar spine bone mineral apparent density, assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01812551. We screened 540 patients and enrolled 171 (mean age 13·8 years, SD 5·9, range 5-30). In the observational phase, treatment with calcium and calcifediol increased bone mineral apparent density by 5% or more in 43 patients (25%). 128 patients entered the randomised phase. Bone mineral apparent density increased by 16·3% in the alendronate group (n=65) versus 3·1% in the placebo group (n=63; p=0·0010). 19 of 57 young people (33·3%) receiving alendronate attained a normal-for-age bone mineral apparent density Z score. In the observational

Low concentrations of alendronate increase the local invasive potential of osteoblastic sarcoma cell lines via connexin 43 activation.

PubMed

Yoshitani, Kazuhiro; Kido, Akira; Honoki, Kanya; Akahane, Manabu; Fujii, Hiromasa; Tanaka, Yasuhito

2011-07-15

Bisphosphonates (BPs) are agents used for treating disorders of excessive bone resorption. In addition, due to their cell-killing activity, BPs were potent candidates for adjuvant cancer therapy. On the other hand, low-concentrations of BPs have been reported to increase cellular viability in several types of tumor cells. Therefore, we focused on the effect of BPs on cellular aggressiveness of malignant bone tumors at low concentrations. MTS assay was performed using osteosarcoma cell lines MG63 and HOS, fibrosarcoma cell line HT1080, and prostate cancer cell line PC3. All the cell lines showed toxicity at high concentrations. On the other hand, at lower concentrations, the cellular viabilities of HOS and MG63 were rather higher than those of untreated controls. Since this tendency was most evident, HOS was used for further assays, including cellular motility, bone resorption activity, and cathepsin K activity. The low-concentration of alendronate enhanced cellular viability and motility, which correlated with the expression of connexin 43 at the mRNA and protein levels. Interestingly, oleamide, a potent connexin 43 inhibitor, had an inhibitory effect on the enhanced proliferation. Our data suggest that alendronate may enhance the proliferation of osteoblastic cell line through connexin 43 activation. Copyright © 2011 Elsevier GmbH. All rights reserved.

Magnetic resonance imaging of osteosarcoma using a bis(alendronate)-based bone-targeted contrast agent.

PubMed

Ge, Pingju; Sheng, Fugeng; Jin, Yiguang; Tong, Li; Du, Lina; Zhang, Lei; Tian, Ning; Li, Gongjie

2016-12-01

Magnetic resonance (MR) is currently used for diagnosis of osteosarcoma but not well even though contrast agents are administered. Here, we report a novel bone-targeted MR imaging contrast agent, Gd 2 -diethylenetriaminepentaacetate-bis(alendronate) (Gd 2 -DTPA-BA) for the diagnosis of osteosarcoma. It is the conjugate of a bone cell-seeking molecule (i.e., alendronate) and an MR imaging contrast agent (i.e., Gd-DTPA). Its physicochemical parameters were measured, including pK a , complex constant, and T 1 relaxivity. Its bone cell-seeking ability was evaluated by measuring its adsorption on hydroxyapatite. Hemolysis was investigated. MR imaging and biodistribution of Gd 2 -DTPA-BA and Gd-DTPA were studied on healthy and osteosarcoma-bearing nude mice. Gd 2 -DTPA-BA showed high adsorption on hydroxyapatite, the high MR relaxivity (r 1 ) of 7.613mM -1 s -1 (2.6 folds of Gd-DTPA), and no hemolysis. The MR contrast effect of Gd 2 -DTPA-BA was much higher than that of Gd-DTPA after intravenous injection to the mice. More importantly, the MR imaging of osteosarcoma was significantly improved by Gd 2 -DTPA-BA. The signal intensity of Gd 2 -DTPA-BA reached 120.3% at 50min, equal to three folds of Gd-DTPA. The bone targeting index (bone/blood) of Gd 2 -DTPA-BA in the osteosarcoma-bearing mice was very high to 130 at 180min. Furthermore, the contrast enhancement could also be found in the lung due to metastasis of osteosarcoma. Gd 2 -DTPA-BA plays a promising role in the diagnoses of osteosacomas, including the primary bone tumors and metastases. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Alendronate-Eluting Biphasic Calcium Phosphate (BCP) Scaffolds Stimulate Osteogenic Differentiation

PubMed Central

Kim, Sung Eun; Lee, Deok-Won; Kang, Eun Young; Jeong, Won Jae; Lee, Boram; Jeong, Myeong Seon; Kim, Hak Jun; Park, Kyeongsoon; Song, Hae-Ryong

2015-01-01

Biphasic calcium phosphate (BCP) scaffolds have been widely used in orthopedic and dental fields as osteoconductive bone substitutes. However, BCP scaffolds are not satisfactory for the stimulation of osteogenic differentiation and maturation. To enhance osteogenic differentiation, we prepared alendronate- (ALN-) eluting BCP scaffolds. The coating of ALN on BCP scaffolds was confirmed by scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy (EDS), and attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR). An in vitro release study showed that release of ALN from ALN-eluting BCP scaffolds was sustained for up to 28 days. In vitro results revealed that MG-63 cells grown on ALN-eluting BCP scaffolds exhibited increased ALP activity and calcium deposition and upregulated gene expression of Runx2, ALP, OCN, and OPN compared with the BCP scaffold alone. Therefore, this study suggests that ALN-eluting BCP scaffolds have the potential to effectively stimulate osteogenic differentiation. PMID:26221587

[Incidence of hip fractures due to osteoporosis in relation to the prescription of drugs for their prevention and treatment in Galicia, Spain].

PubMed

Guerra-García, María Mercedes; Rodríguez-Fernández, José Benito; Puga-Sarmiento, Elías; Charle-Crespo, María Ángeles; Gomes-Carvalho, Claudia Sofía; Prejigueiro-Santás, Ana

2011-02-01

To analyse the evolution in the incidence of hip fractures in our autonomous community in relationship to the trend in the prescription of medicines for the prevention and/or treatment of osteoporotic hip fracture. Descriptive observational ecological study. Public health network in the whole autonomous community over five years, from 1st January 2004 to 31st December 2008. Patients over 44 years old admitted with osteoporotic hip fracture. Medicines dispensed at a pharmacy which are indicated for the prevention of osteoporotic hip fractures (alendronate, risedronate and strontium ranelate). Exclusion: Open fractures, hospital or private or prescriptions. Incidence (number of new cases of hip fractures occurring in a year), Incidence rate (incidence per 100,000 inhabitants), Dispersion rate (number of packets dispensed per year per 100,000 inhabitants) and Hazard ratio (HR, ratio between the rate of last year and first). Annual rates were calculated standardised by the direct method. We identified 12,137 hospital admissions for fractured hip (2,792 men and 9,345 women). Sub-capital fractures: Mean Incidence Rate (MIR)=86.14,95%CI[61.85-110.42]; HR=1.22, 95%CI[0.82-1.63] (men) and MIR=180.88,95%CI[124.74-237.02]; HR=1.08,95%CI[0.73-1.43] (women). Trochanteric fractures: MIR=56.30,95%CI[39.18-73.42], HR=1.04,95%CI[0.75-1.34] (men) and MIR=136.51,95%CI[90.23-182.78]; HR=1.12,95%CI[0.89-1.35] (women). Subtrochanteric fractures: MIR=8.92,95%CI[6.52-11.32]; HR=1.26,95%CI[0.05-2.46] (men) and MIR=22.91,95%CI[15.24-30.58]; HR=1.08,95%CI[0.57-1.58] (women). Total HR fractures=1.07, 95%CI[0.92-1.23] (men) and 0.99,95%CI[0.83-1.17] (women). Drug dispensing (2008-2004): HR alendronate=1.30; HR risedronate=1.92; HR strontium ranelate=10.38. Over five years the dispensing of drugs by the public health service has multiplied for the prevention and treatment of hip fractures while the incidence has remained unaltered. Copyright © 2010 Elsevier España, S.L. All rights reserved.

Effects of long-term alendronate treatment on postmenopausal osteoporosis bone material properties.

PubMed

Hassler, N; Gamsjaeger, S; Hofstetter, B; Brozek, W; Klaushofer, K; Paschalis, E P

2015-01-01

Raman microspectroscopic analysis of iliac crest from patients that were treated with alendronate (ALN) for 10 years revealed minimal, transient alterations in bone material properties confined to actively forming bone surfaces compared to patients that were on ALN for 5 years. These changes were not encountered in the bulk tissue. Alendronate (ALN) and other bisphosphonates (BPs) are the most widely prescribed therapy for postmenopausal osteoporosis. Despite their overall excellent safety record and efficacy in reducing fractures, questions have been raised regarding potential detrimental effects that may be related to prolonged bone turnover reduction, although no definite cause-effect relationship has been established to date. The purpose of the present study was to evaluate bone material properties in patients that were receiving ALN for 5 or 10 years. Raman microspectroscopic analysis was used to analyze iliac crest biopsies from postmenopausal women with osteoporosis who had been treated with ALN for 5 years and were then re-randomized to placebo (PBO, N = 14), 5 mg/day ALN (N = 10), or 10 mg/day ALN (N = 6) for another 5 years. The parameters monitored and expressed as a function of tissue age were (i) the mineral/matrix ratio (MM), (ii) the relative proteoglycan content (PG), (iii) the relative lipid content (LPD), (iv) the mineral maturity/crystallinity (MMC), and (v) the relative pyridinoline content (PYD). The obtained data indicate that 10-year ALN use results in minimal, transient bone tissue composition changes compared to use for 5 years, confined to actively forming trabecular surfaces, implying potential differences in bone matrix maturation that nevertheless did not result in differences of these values in bulk tissue. The data suggest that prolonged reduction in bone turnover during 10 years of therapy with ALN by itself is unlikely to be associated with adverse effects on bone material properties.

Systematic review and meta-analysis of the efficacy and safety of alendronate and zoledronate for the treatment of postmenopausal osteoporosis.

PubMed

Serrano, Ana Julissa; Begoña, Leire; Anitua, Eduardo; Cobos, Raquel; Orive, Gorka

2013-12-01

The aim of this meta-analysis was to evaluate the efficacy and safety of two bisphosphonates (alendronate and zoledronate) in the treatment of postmenopausal osteoporosis. The incidence of fractures was considered as primary endpoint. Only randomized trials with a follow-up period of 1 year or more were included in this systematic review and meta-analysis. We excluded studies that included patients with secondary osteoporosis especially in relation to therapy with corticosteroids or other drugs or diseases known to affect bone mineral density. Studies published as subgroup analysis, extension studies, economic evaluations, and comparisons with active control were excluded. The methodological quality of controlled clinical trials that met these inclusion criteria was evaluated. No studies were excluded from analysis due to lack of quality. The risk ratio of hip, vertebral and wrist fractures for alendronate were 0.61 [95% confidence interval (CI) 0.40-0.93], 0.54 (95% CI 0.44-0.66) and 0.65 (95% CI 0.33-1.25), respectively. Zoledronate risk ratio was 0.62 (95% CI 0.46-0.82) and 0.38 (95% CI 0.22-0.67) for hip and vertebral fractures, respectively.

Comparative permeability studies with radioactive and nonradioactive risedronate sodium from self-microemulsifying drug delivery system and solution.

PubMed

Ilem-Ozdemir, Derya; Gundogdu, Evren; Ekinci, Meliha; Ozgenc, Emre; Asikoglu, Makbule

2015-01-01

The purpose of this work is to prepare a self-microemulsifying drug delivery system (SMEDDS) for risedronate sodium (RSD) and to compare the permeability with RSD solution. The solubility of RSD was determined in different vehicles. Phase diagrams were constructed to determine the optimum concentration of oil, surfactant, and cosurfactant. RSD SMEDDS was prepared by using a mixture of soybean oil, cremophor EL, span 80, and transcutol (2.02:7.72:23.27:61.74, w/w, respectively). The prepared RSD SMEDDS was characterized by droplet size value. In vitro Caco-2 cell permeability studies were performed for SMEDDS and solution of radioactive ((99 m)Tc-labeled RSD) and nonradioactive RSD. The experimental results indicated that RSD SMEDDS has good stability and its droplet size is between 216.68 ± 3.79 and 225.26 ± 7.65 during stability time. In addition, RSD SMEDDS has higher permeability value than the RSD solution for both radioactive and nonradioactive experiments. The results illustrated the potential use of SMEDDS for delivery of poorly absorbed RSD.

Oral bisphosphonate-related osteonecrosis of the jaws: Clinical characteristics of a series of 20 cases in Spain

PubMed Central

López-Cedrún, José L.; Fernández-Sanromán, Jacinto; García-García, Abel; Fernández-Feijoo, Javier; Diz-Dios, Pedro

2012-01-01

Objective: The objective of this study was to define the clinical characteristics of osteonecrosis of the jaws (ONJ) induced by oral bisphosphonates in a series of patients from a circumscribed area in northwest Spain. Study Design:A retrospective multicentre study was undertaken in 3 hospitals in an area with a radius less than 100 km in the Autonomous Community of Galicia (Spain). The medical records were reviewed and an oral examination was performed of patients diagnosed with oral bisphosphonate-related ONJ in the previous 3 years. Results: We detected 20 cases of ONJ (24 lesions) related to oral bisphosphonates (alendronate [16 patients] and ibandronate [4 patients]), which were mainly administered as treatment for osteoporosis (17 patients). The mean interval between initiation of treatment and confirmation of a diagnosis of ONJ was 66±43 months (range, 6-132 months); in 7 patients (35%) the interval was less than 36 months. The past history revealed hypertension in 13 cases (65%) and diabetes in 4 (20%); 7 patients (35%) were on corticosteroid treatment. Oral surgery had been previously performed in 13 patients (65%) and the remaining 7 patients (35%) had removable dental prostheses. The lesions most frequently affected the posterior mandible (62.5%). The majority of the lesions (75%) were classified as stage 2, although lesions were identified in all established clinical stages (including 2 stage 0 lesions). Conclusion: In conclusion, in the present series, ONJ induced by oral bisphosphonates typically develops in women around 70 years of age, taking alendronate, that underwent oral surgery. Most lesions are located in the posterior mandible and are classified as stage 2 at diagnosis. Some patients presented no known risk factors, suggesting that there may be risk factors still to be identified. There are well-defined patterns of clinical presentation that can facilitate early diagnosis of ONJ. Key words:Oral bisphosphonates, osteonecrosis of the jaws

Confounder summary scores when comparing the effects of multiple drug exposures.

PubMed

Cadarette, Suzanne M; Gagne, Joshua J; Solomon, Daniel H; Katz, Jeffrey N; Stürmer, Til

2010-01-01

Little information is available comparing methods to adjust for confounding when considering multiple drug exposures. We compared three analytic strategies to control for confounding based on measured variables: conventional multivariable, exposure propensity score (EPS), and disease risk score (DRS). Each method was applied to a dataset (2000-2006) recently used to examine the comparative effectiveness of four drugs. The relative effectiveness of risedronate, nasal calcitonin, and raloxifene in preventing non-vertebral fracture, were each compared to alendronate. EPSs were derived both by using multinomial logistic regression (single model EPS) and by three separate logistic regression models (separate model EPS). DRSs were derived and event rates compared using Cox proportional hazard models. DRSs derived among the entire cohort (full cohort DRS) was compared to DRSs derived only among the referent alendronate (unexposed cohort DRS). Less than 8% deviation from the base estimate (conventional multivariable) was observed applying single model EPS, separate model EPS or full cohort DRS. Applying the unexposed cohort DRS when background risk for fracture differed between comparison drug exposure cohorts resulted in -7 to + 13% deviation from our base estimate. With sufficient numbers of exposed and outcomes, either conventional multivariable, EPS or full cohort DRS may be used to adjust for confounding to compare the effects of multiple drug exposures. However, our data also suggest that unexposed cohort DRS may be problematic when background risks differ between referent and exposed groups. Further empirical and simulation studies will help to clarify the generalizability of our findings.

A urine midmolecule osteocalcin assay shows higher discriminatory power than a serum midmolecule osteocalcin assay during short-term alendronate treatment of osteoporotic patients.

PubMed

Srivastava, A K; Mohan, S; Singer, F R; Baylink, D J

2002-07-01

We isolated and characterized a peptide fragment corresponding to amino acid sequence 14-28 of human osteocalcin in urine from Paget's disease, and developed a polyclonal antibody reactive to this peptide in urine. We used this antibody to measure urinary fragments of osteocalcin and compared to efficacy of the urinary osteocalcin assay with a serum osteocalcin (sOC) assay (ELISA-Osteo, Cis-Bio International) to monitor the short-term changes in bone turnover in response to alendronate treatment. The synthetic peptide-based urinary osteocalcin (uOC) radioimmunoassay (RIA) showed an analytical sensitivity of 6.25 ng/mL, standard curve range of 3.12-400 ng/mL, and mean intra- (n = 20) and interassay (n = 30) coefficient of variation (CV) of <15%. Urine osteocalcin concentrations in postmenopausal osteoporotic patients were approximately 90% higher than in normal premenopausal controls. Series of 24 h urine and matched serum samples were collected at baseline, 30 days, and 90 days after treatment of postmenopausal osteoporotic patients with daily dose of 10 mg alendronate. We measured urinary osteocalcin (uOc) levels and urinary N-telopeptide (uNTx, Ostex) in urine samples and serum N-telopeptide (sNTx), C-telopeptide (sCTx, Osteometer), serum osteocalcin (sOC) as well as bone-specific alkaline phosphatase (sALP) (Alkphose-B, Metra Biosystems) in serum samples. The percent change data obtained between baseline and 30 days (n = 18) posttreatment suggested a rapid decline in uOC concentration (-27%, p < 0.01) in response to alendronate treatment, as compared with a marginal and nonsignificant decrease in sOC (-7.2%, p = 0.417) or sALP (-3.4%, p = 0.689), two specific markers of bone formation. As expected, due to the coupling of bone formation and bone resorption, the concentration of all markers showed a 30%-45% decline compared with baseline values after 90 days (n = 16) of treatment. Correlation of markers after a 30 day treatment with alendronate revealed a higher

Improvement of cancellous bone microstructure in patients on teriparatide following alendronate pretreatment.

PubMed

Fahrleitner-Pammer, Astrid; Burr, David; Dobnig, Harald; Stepan, Jan J; Petto, Helmut; Li, Jiliang; Krege, John H; Pavo, Imre

2016-08-01

An increase in procollagen type I amino-terminal propeptide (PINP) early after teriparatide initiation was shown to correlate with increased lumbar spine areal BMD and is a good predictor of the anabolic response to teriparatide. Few data exist correlating PINP and bone microstructure, and no data exist in patients on teriparatide following prior potent antiresorptive treatment. This exploratory analysis aimed to investigate the effects of teriparatide on cancellous bone microstructure and correlations of bone markers with microstructure in alendronate-pretreated patients. This was a post hoc analysis of changes in bone markers and three-dimensional indices of bone microstructure in paired iliac crest biopsies from a prospective teriparatide treatment study in postmenopausal women with osteoporosis who were either treatment-naïve (TN, n=16) or alendronate-pretreated (ALN, n=29) at teriparatide initiation. Teriparatide (20μg/day) was given for 24months; biopsies were taken at baseline and endpoint, and serum concentrations of PINP and type 1 collagen cross-linked C-telopeptide (βCTX) were measured at intervals up to 24months. In the TN and ALN groups, respectively, mean (SD) increases in three-dimensional bone volume/tissue volume were 105 (356)% (P=0.039) and 55 (139)% (P<0.005) and trabecular thickness 30.4 (30)% (P<0.001) and 30.8 (53)% (P<0.001). No significant changes were observed in trabecular number or separation. In the ALN patients, 3-month change of neither PINP nor βCTX correlated with indices of cancellous bone microstructure. However, 12-month changes in biochemical bone markers correlated significantly with improvements in bone volume/tissue volume, r=0.502 (P<0.01) and r=0.378 (P<0.05), trabecular number, r=0.559 (P<0.01) and r=0.515 (P<0.01), and reduction of trabecular separation, r=-0.432 (P<0.05) and r=-0.530 (P<0.01), for PINP and βCTX, respectively. We conclude that cancellous bone microstructure improved with teriparatide therapy

Effects of odanacatib on BMD and safety in the treatment of osteoporosis in postmenopausal women previously treated with alendronate: a randomized placebo-controlled trial.

PubMed

Bonnick, Sydney; De Villiers, Tobias; Odio, Alberto; Palacios, Santiago; Chapurlat, Roland; DaSilva, Carolyn; Scott, Boyd B; Le Bailly De Tilleghem, Celine; Leung, Albert T; Gurner, Deborah

2013-12-01

Odanacatib (ODN) is a selective cathepsin K inhibitor being developed to treat osteoporosis. The effects of ODN were evaluated on bone mineral density (BMD), biochemical markers of bone turnover, and safety in patients previously treated with alendronate. This was a randomized, double-blind, placebo-controlled, 24-month study. The study was conducted at private or institutional practices. Postmenopausal women (n = 243) ≥ 60 years of age with low BMD at the total hip, femoral neck, or trochanter (T-score ≤-2.5 but >-3.5 without prior fracture or ≤-1.5 but >-3.5 with prior fracture) on alendronate for ≥ 3 years. The intervention included ODN 50 mg or placebo weekly. The primary end point was percentage change from baseline of femoral neck BMD at month 24. BMD was assessed by dual-energy x-ray absorptiometry at baseline and 6, 12, and 24 months. Biochemical markers of bone turnover (serum C-telopeptides of type 1 collagen, urinary N-telopeptides of type 1 collagen, serum bone specific alkaline phosphatase, and serum N-terminal propeptide of type 1 collagen) were measured at baseline and 3, 6, 12, 18, and 24 months. In the ODN group, BMD changes from baseline at the femoral neck, trochanter, total hip, and lumbar spine at 24 months (1.7%, 1.8%, 0.8%, and 2.3%, respectively) were significantly different from the placebo group. ODN significantly decreased urinary N-telopeptides of type 1 collagen to creatinine ratio and significantly increased serum N-terminal propeptide of type 1 collagen compared with placebo. Serum C-telopeptides of type 1 collagen was unexpectedly increased with ODN treatment. The safety profile appeared similar between groups. ODN provided incremental BMD gains in osteoporotic women after alendronate treatment.

Validated spectrophotometric methods for determination of Alendronate sodium in tablets through nucleophilic aromatic substitution reactions

PubMed Central

2012-01-01

Background Alendronate (ALD) is a member of the bisphosphonate family which is used for the treatment of osteoporosis, bone metastasis, Paget's disease, hypocalcaemia associated with malignancy and other conditions that feature bone fragility. ALD is a non-chromophoric compound so its determination by conventional spectrophotometric methods is not possible. So two derivatization reactions were proposed for determination of ALD through the reaction with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) and 2,4-dinitrofluorobenzene (DNFB) as chromogenic derivatizing reagents. Results Three simple and sensitive spectrophotometric methods are described for the determination of ALD. Method I is based on the reaction of ALD with NBD-Cl. Method II involved heat-catalyzed derivatization of ALD with DNFB, while, Method III is based on micellar-catalyzed reaction of the studied drug with DNFB at room temperature. The reactions products were measured at 472, 378 and 374 nm, for methods I, II and III, respectively. Beer's law was obeyed over the concentration ranges of 1.0-20.0, 4.0-40.0 and 1.5-30.0 μg/mL with lower limits of detection of 0.09, 1.06 and 0.06 μg/mL for Methods I, II and III, respectively. The proposed methods were applied for quantitation of the studied drug in its pure form with mean percentage recoveries of 100.47 ± 1.12, 100.17 ± 1.21 and 99.23 ± 1.26 for Methods I, II and III, respectively. Moreover the proposed methods were successfully applied for determination of ALD in different tablets. Proposals of the reactions pathways have been postulated. Conclusion The proposed spectrophotometric methods provided sensitive, specific and inexpensive analytical procedures for determination of the non-chromophoric drug alendronate either per se or in its tablet dosage forms without interference from common excipients. Graphical abstract PMID:22472190

Validated spectrophotometric methods for determination of Alendronate sodium in tablets through nucleophilic aromatic substitution reactions.

PubMed

Walash, Mohamed I; Metwally, Mohamed E-S; Eid, Manal; El-Shaheny, Rania N

2012-04-02

Alendronate (ALD) is a member of the bisphosphonate family which is used for the treatment of osteoporosis, bone metastasis, Paget's disease, hypocalcaemia associated with malignancy and other conditions that feature bone fragility. ALD is a non-chromophoric compound so its determination by conventional spectrophotometric methods is not possible. So two derivatization reactions were proposed for determination of ALD through the reaction with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) and 2,4-dinitrofluorobenzene (DNFB) as chromogenic derivatizing reagents. Three simple and sensitive spectrophotometric methods are described for the determination of ALD. Method I is based on the reaction of ALD with NBD-Cl. Method II involved heat-catalyzed derivatization of ALD with DNFB, while, Method III is based on micellar-catalyzed reaction of the studied drug with DNFB at room temperature. The reactions products were measured at 472, 378 and 374 nm, for methods I, II and III, respectively. Beer's law was obeyed over the concentration ranges of 1.0-20.0, 4.0-40.0 and 1.5-30.0 μg/mL with lower limits of detection of 0.09, 1.06 and 0.06 μg/mL for Methods I, II and III, respectively. The proposed methods were applied for quantitation of the studied drug in its pure form with mean percentage recoveries of 100.47 ± 1.12, 100.17 ± 1.21 and 99.23 ± 1.26 for Methods I, II and III, respectively. Moreover the proposed methods were successfully applied for determination of ALD in different tablets. Proposals of the reactions pathways have been postulated. The proposed spectrophotometric methods provided sensitive, specific and inexpensive analytical procedures for determination of the non-chromophoric drug alendronate either per se or in its tablet dosage forms without interference from common excipients. GRAPHICAL

Protocol for a randomized controlled trial to compare bone-loading exercises with risedronate for preventing bone loss in osteopenic postmenopausal women.

PubMed

Bilek, Laura D; Waltman, Nancy L; Lappe, Joan M; Kupzyk, Kevin A; Mack, Lynn R; Cullen, Diane M; Berg, Kris; Langel, Meghan; Meisinger, Melissa; Portelli-Trinidad, Ashlee; Lang, Molly

2016-08-30

In the United States, over 34 million American post-menopausal women have low bone mass (osteopenia) which increases their risk of osteoporosis and fractures. Calcium, vitamin D and exercise are recommended for prevention of osteoporosis, and bisphosphonates (BPs) are prescribed in women with osteoporosis. BPs may also be prescribed for women with low bone mass, but are more controversial due to the potential for adverse effects with long-term use. A bone loading exercise program (high-impact weight bearing and resistance training) promotes bone strength by preserving bone mineral density (BMD), improving bone structure, and by promoting bone formation at sites of mechanical stress. The sample for this study will be 309 women with low bone mass who are within 5 years post-menopause. Subjects are stratified by exercise history (≥2 high intensity exercise sessions per week; < 2 sessions per week) and randomized to a control or one of two treatment groups: 1) calcium + vitamin D (CaD) alone (Control); 2) a BP plus CaD (Risedronate); or 3) a bone loading exercise program plus CaD (Exercise). After 12 months of treatment, changes in bone structure, BMD, and bone turnover will be compared in the 3 groups. Primary outcomes for the study are bone structure measures (Bone Strength Index [BSI] at the tibia and Hip Structural Analysis [HSA] scores). Secondary outcomes are BMD at the hip and spine and serum biomarkers of bone formation (alkaline phosphase, AlkphaseB) and resorption (Serum N-terminal telopeptide, NTx). Our central hypothesis is that improvements in bone strength will be greater in subjects randomized to the Exercise group compared to subjects in either Control or Risedronate groups. Our research aims to decrease the risk of osteoporotic fractures by improving bone strength in women with low bone mass (pre-osteoporotic) during their first 5 years' post-menopause, a time of rapid and significant bone loss. Results of this study could be used in

Cost-utility and budget impact analysis of primary prevention with alendronate of osteoporotic hip fractures in Catalonia.

PubMed

Pueyo, María J; Larrosa, Marta; Surís, Xavier; Garcia-Ruiz, Antonio J

2012-01-01

To determine whether primary drug prevention of osteoporotic hip fracture is a useful measure in Catalonia and what would be their budgetary impact. We performed a cost-utility social perspective study with a time horizon of 10 to 20 years. Univariate sensitivity analysis was performed. Doing nothing is compared with an intervention that includes screening for osteoporosis in women> 64 years and in those diagnosed and who received treatment with generic alendronate for 10 years. Decision trees are developed for groups of 65-69, 70-74 and 75-79. HF data is from 2009 hospital discharges .Costs are derived from fees paid by public insurance. In 2009 there were 9262 HF. The direct cost was € 55 million (€ 5,943.4/patient). The total cost was € 227 million for 10 years. The intervention dominates in all age groups in a 20 year perspective. In any horizon and age group, the different scenario puts the value per QALY below or within the proposed values for Spain. The budgetary impact is estimated at € 8.9 million which increased by 31% the actual direct cost, and 0.5% of the public pharmacy budget. Considering the total costs and the prospect of 20 years, annual savings of 7.4 million € were seen. The prevention of HF with alendronate in osteoporotic women>64 years is cost-useful in the long term (20 years) with a low budgetary impact in the 75-79 year group. Copyright © 2011 Elsevier España, S.L. All rights reserved.

Collagenase-3 (MMP-13) and its activators in rheumatoid arthritis: localization in the pannus-hard tissue junction and inhibition by alendronate.

PubMed

Konttinen, Y T; Salo, T; Hanemaaijer, R; Valleala, H; Sorsa, T; Sutinen, M; Ceponis, A; Xu, J W; Santavirta, S; Teronen, O; López-Otín, C

1999-08-01

The hypothesis of the present work was that the pannus tissue overlying the articular hard tissues has an aggressive phenotype and contains the newly discovered collagenase-3 and its endogenous inducers and activators. We therefore analyzed the eventual presence of collagenase-3 and its regulation at the pannus-cartilage junction. Collagenase-3 mRNA (in situ hybridization) and enzyme protein (ABC and immunofluorescence staining) were found in the pannocytes in the pannus-hard tissue junction. Inflammatory round cells associated with the critical interface contained TNF-alpha and IL-1beta. These cytokines induced collagenase-3 secretion in cultured rheumatoid synovial fibroblasts. Procollagenase-3 activators, stromelysin-1, 72 kDa type IV collagenase/gelatinase and membrane-type 1-MMP, were also found in the pannus-hard tissue junction. Active collagenase-3 was inhibited with alendronate (IC50 = 500-750 microM). Collagenase-3, due to its substrate profile and local synthesis in a milieu favoring its activation, might play a major role in the degradation of cartilage type II and bone type I collagens. Alendronate, at concentrations attainable in vivo, is able to inhibit collagenase-3. This might offer an option to control collagenase-3-mediated tissue destruction in rheumatoid arthritis.

Preparation and Biological Study of (68)Ga-DOTA-alendronate.

PubMed

Fakhari, Ashraf; Jalilian, Amir R; Johari-Daha, Fariba; Shafiee-Ardestani, Mehdi; Khalaj, Ali

2016-01-01

In line with previous research on the development of conjugated bisphosphonate ligands as new bone-avid agents, in this study, DOTA-conjugated alendronate (DOTA-ALN) was synthesized and evaluated after labeling with gallium-68 ((68)Ga). DOTA-ALN was synthesized and characterized, followed by (68)Ga-DOTA-ALN preparation, using DOTA-ALN and (68)GaCl3 (pH: 4-5) at 92-95° C for 10 min. Stability tests, hydroxyapatite assay, partition coefficient calculation, biodistribution studies, and imaging were performed on the developed agent in normal rats. The complex was prepared with high radiochemical purity (>99% as depicted by radio thin-layer chromatography; specific activity: 310-320 GBq/mmol) after solid phase purification and was stabilized for up to 90 min with a log P value of -2.91. Maximum ligand binding (65%) was observed in the presence of 50 mg of hydroxyapatite; a major portion of the activity was excreted through the kidneys. With the exception of excretory organs, gastrointestinal tract organs, including the liver, intestine, and colon, showed significant uptake; however, the bone uptake was low (<1%) at 30 min after the injection. The data were also confirmed by sequential imaging at 30-90 min following the intravenous injection. The high solubility and anionic properties of the complex led to major renal excretion and low hydroxyapatite uptake; therefore, the complex failed to demonstrate bone imaging behaviors.

Medication-taking behaviour in Bulgarian women with postmenopausal osteoporosis treated with denosumab or monthly oral bisphosphonates.

PubMed

Petranova, T; Boyanov, M; Shinkov, A; Petkova, R; Intorcia, M; Psachoulia, E

2017-12-21

Persistence with osteoporosis therapy is critical for fracture risk reduction. This observational study evaluated medication-taking behaviour of women with postmenopausal osteoporosis receiving denosumab or oral ibandronate in real-world clinical practice in Bulgaria. Compared with ibandronate, densoumab was associated with a lower discontinuation rate and greater increases in bone mineral density. Persistence with osteoporosis therapy is critical for fracture risk reduction and the effectiveness of such treatments may be reduced by low persistence. Alternative therapies such as denosumab may improve persistence. This study aimed to describe medication-taking behaviour in women with osteoporosis, prescribed denosumab or oral ibandronate, in Bulgarian clinical practice. This retrospective, observational, multicentre chart review (with up to 24 months follow-up) enrolled postmenopausal women initiating 6-monthly denosumab injection or monthly oral ibandronate treatment for osteoporosis between 1 October 2011 and 30 September 2012. Overall, 441 women were enrolled (224 had initiated denosumab, 217 had initiated ibandronate). At baseline, more women in the denosumab group than in the ibandronate group had a previous fracture (25.5 vs 17.5%; p = 0.043) and past exposure to osteoporosis therapy (19.6 vs 12.0%; p = 0.028). At 24 months, 4.5% of women receiving denosumab had discontinued therapy compared with 56.2% of women receiving ibandronate. Median time to discontinuation was longer in the denosumab group (729 days; interquartile range (IQR), 728.3-729.0) than in the ibandronate group (367 days; IQR, 354.0-484.8; p < 0.001). At 24 months, there were significantly greater changes in BMD T-scores at the lumbar spine (p < 0.001) and femoral neck (p < 0.001) in patients receiving denosumab than in those receiving ibandronate. At 24 months, persistence with denosumab was 98.7%. This real-world study demonstrates there is a low discontinuation rate and

Osteoporosis medication dispensing for older Australian women from 2002 to 2010: influences of publications, guidelines, marketing activities and policy.

PubMed

Peeters, Geeske; Tett, Susan E; Duncan, Emma L; Mishra, Gita D; Dobson, Annette J

2014-12-01

Developments in anti-osteoporosis medications (AOMs) have led to changes in guidelines and policy, which, along with media and marketing strategies, have had an impact upon the prescribing of AOM. The aim was to examine patterns of AOM dispensing in older women (aged 76-81 years at baseline) from 2002 to 2010. Administrative claims data were used to describe AOM dispensing in 4649 participants (born in 1921-1926 and still alive in 2011) in the Australian Longitudinal Study on Women's Health. The patterns were interpreted in the context of changes in guidelines, indications for subsidy, publications (scholarly and general media), and marketing activities. Total use of AOM increased from 134 DDD/1000/day in 2002 to 216 DDD/1000/day in 2007 but then decreased to 184 DDD/1000/day in 2010. Alendronate was the most commonly dispensed AOM but decreased from 2007, while use of risedronate (2002 onward), strontium ranelate (2007 onward) and zoledronic acid (2008 onward) increased. Etidronate and hormone replacement therapy (HRT) prescriptions gradually decreased over time. The decline in alendronate dispensing coincided with increases of other bisphosphonates and publicity about potential adverse effects of bisphosphonates, despite relaxing indications for bone density testing and subsidy for AOM. Overall dispense of AOM from 2002 reached a peak in 2007 and thereafter declined despite increases in therapeutic options and improved subsidised access. The recent decline in overall AOM dispensing seems to be explained largely by negative publicity rather than specific changes in guidelines and policy. Copyright © 2014 John Wiley & Sons, Ltd.

Effect of bisphosphonate use on risk of postmenopausal breast cancer: results from the randomized clinical trials of alendronate and zoledronic acid.

PubMed

Hue, Trisha F; Cummings, Steven R; Cauley, Jane A; Bauer, Douglas C; Ensrud, Kristine E; Barrett-Connor, Elizabeth; Black, Dennis M

2014-10-01

Studies have shown that bisphosphonates may have antitumor and antimetastatic properties. Recently, observational studies have suggested a possible protective effect of bisphosphonates on breast cancer, but the effect of bisphosphonate use on risk of breast cancer has not been tested in randomized trials. To assess the relationship of postmenopausal breast cancer incidence and bisphosphonate use using data from 2 randomized (1:1), double-blind, placebo-controlled trials. The Fracture Intervention Trial (FIT) randomly assigned 6459 women aged 55 to 81 years to alendronate or placebo for a mean follow-up of 3.8 years. The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) randomly assigned 7765 women aged 65 to 89 years to annual intravenous zoledronic acid or placebo for a mean follow-up of 2.8 years. Data were collected at clinical centers in the United States (FIT and HORIZON-PFT) and in Asia and the Pacific, Europe, North America, and South America (HORIZON-PFT). Women, in either study, with recurrent breast cancer or who reported a history of breast cancer were excluded from analyses. In each trial, a blinded review was conducted of each cancer adverse event report to verify incident invasive breast cancer cases. The primary analysis compared events in the active vs placebo group using a log-rank test. Alendronate vs placebo (FIT) or zoledronic acid vs placebo (HORIZON-PFT). Hazard ratio for incident breast cancer in the bisphosphonate treatment group compared to the placebo group. There was no significant difference in the rate of breast cancer in FIT: 1.5% (n = 46) in the placebo group and 1.8% (n = 57) in the alendronate group (hazard ratio [HR], 1.24 [95% CI, 0.84-1.83]). In HORIZON-PFT, there was also no significant difference: 0.8% (n = 29) in the placebo group and 0.9% (n = 33) in the zoledronic acid group (HR, 1.15 [95% CI, 0.70-1.89]). There was also no significant difference when

Preparation and Biological Study of 68Ga-DOTA-alendronate

PubMed Central

Fakhari, Ashraf; Jalilian, Amir R.; Johari-Daha, Fariba; Shafiee-Ardestani, Mehdi; Khalaj, Ali

2016-01-01

Objective(s): In line with previous research on the development of conjugated bisphosphonate ligands as new bone-avid agents, in this study, DOTA-conjugated alendronate (DOTA-ALN) was synthesized and evaluated after labeling with gallium-68 (68Ga). Methods: DOTA-ALN was synthesized and characterized, followed by 68Ga-DOTA-ALN preparation, using DOTA-ALN and 68GaCl3 (pH: 4-5) at 92-95° C for 10 min. Stability tests, hydroxyapatite assay, partition coefficient calculation, biodistribution studies, and imaging were performed on the developed agent in normal rats. Results: The complex was prepared with high radiochemical purity (>99% as depicted by radio thin-layer chromatography; specific activity: 310-320 GBq/mmol) after solid phase purification and was stabilized for up to 90 min with a log P value of -2.91. Maximum ligand binding (65%) was observed in the presence of 50 mg of hydroxyapatite; a major portion of the activity was excreted through the kidneys. With the exception of excretory organs, gastrointestinal tract organs, including the liver, intestine, and colon, showed significant uptake; however, the bone uptake was low (<1%) at 30 min after the injection. The data were also confirmed by sequential imaging at 30-90 min following the intravenous injection. Conclusion: The high solubility and anionic properties of the complex led to major renal excretion and low hydroxyapatite uptake; therefore, the complex failed to demonstrate bone imaging behaviors. PMID:27408898

Star-shaped poly(oligoethylene glycol) copolymer-based gels: Thermo-responsive behaviour and bioapplicability for risedronate intranasal delivery.

PubMed

Soliman, Mahmoud E; Elmowafy, Enas; Casettari, Luca; Alexander, Cameron

2018-05-30

The aim of this work was to obtain an intranasal delivery system with improved mechanical and mucoadhesive properties that could provide prolonged retention time for the delivery of risedronate (RS). For this, novel in situ forming gels comprising thermo-responsive star-shaped polymers, utilizing either polyethylene glycol methyl ether (PEGMA-ME 188, Mn 188) or polyethylene glycol ethyl ether (PEGMA-EE 246, Mn 246), with polyethylene glycol methyl ether (PEGMA-ME 475, Mn 475), were synthesized and characterized. RS was trapped in the selected gel-forming solutions at a concentration of 0.2% w/v. The pH, rheological properties, in vitro drug release, ex vivo permeation as well as mucoadhesion were also examined. MTT assays were conducted to verify nasal tolerability of the developed formulations. Initial in vivo studies were carried out to evaluate anti-osteoporotic activity in a glucocorticoid induced osteoporosis model in rats. The results showed successful development of thermo-sensitive formulations with favorable mechanical properties at 37 °C, which formed non-irritant, mucoadhesive porous networks, facilitating nasal RS delivery. Moreover, sustained release of RS, augmented permeability and marked anti-osteoporotic efficacy as compared to intranasal (IN) and intravenous (IV) RS solutions were realized. The combined results show that the in situ gels should have promising application as nasal drug delivery systems. Copyright © 2018 Elsevier B.V. All rights reserved.

Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy.

PubMed

Madan, Babita; McDonald, Mitchell J; Foxa, Gabrielle E; Diegel, Cassandra R; Williams, Bart O; Virshup, David M

2018-01-01

Dysregulated Wnt signaling is associated with the pathogenesis of cancers, fibrosis, and vascular diseases. Inhibition of Wnt signaling has shown efficacy in various pre-clinical models of these disorders. One of the key challenges in developing targeted anti-cancer drugs is to balance efficacy with on-target toxicity. Given the crucial role Wnts play in the differentiation of osteoblasts and osteoclasts, acute inhibition of Wnt signaling is likely to affect bone homeostasis. In this study, we evaluated the skeletal effect of small molecule inhibitor of an o-acyl transferase porcupine (PORCN) that prevents Wnt signaling by blocking the secretion of all Wnts. Micro-computed tomography and histomorphometric evaluation revealed that the bones of mice treated with two structurally distinct PORCN inhibitors LGK974 and ETC-1922159 (ETC-159) had loss-of-bone volume and density within 4 weeks of exposure. This decreased bone mass was associated with a significant increase in adipocytes within the bone marrow. Notably, simultaneous administration of a clinically approved anti-resorptive, alendronate, a member of the bisphosphonate family, mitigated loss-of-bone mass seen upon ETC-159 treatment by regulating activity of osteoclasts and blocking accumulation of bone marrow adipocytes. Our results support the addition of bone protective agents when treating patients with PORCN inhibitors. Mitigation of bone toxicity can extend the therapeutic utility of Wnt pathway inhibitors.

Effect of a sequential treatment combining abaloparatide and alendronate for the management of postmenopausal osteoporosis.

PubMed

Reginster, J Y; Al Daghri, Nasser; Kaufman, Jean-Marc; Bruyère, Olivier

2018-02-01

The recently published results of the sequential treatment of postmenopausal osteoporotic women with subcutaneous abaloparatide (80 µg/day) (ABL) for 18 months followed by 6 months of oral alendronate (70 mg/week) (ALN) support the administration of an anti-resorptive agent after completion of a treatment course with an osteoanabolic agent. The ABL/ALN sequence resulted in greater bone mineral density gains at all skeletal sites and in a reduction of vertebral, non-vertebral, major and clinical fractures compared to what is observed after 18 months of placebo followed by 6 months of ALN. Whereas questions remained unanswered about the ideal anti-resorptive agent to be used after ABL, the optimal duration of the administration of the anti-resorptive drug or the potential interest of re-initiating a course of ABL after a limited administration of ALN, these results support the use of the ABL/ALN sequence in the management of postmenopausal osteoporosis.

Low Doses of Simvastatin Potentiate the Effect of Sodium Alendronate in Inhibiting Bone Resorption and Restore Microstructural and Mechanical Bone Properties in Glucocorticoid-Induced Osteoporosis.

PubMed

Sequetto, Priscila L; Gonçalves, Reggiani V; Pinto, Aloísio S; Oliveira, Maria G A; Maldonado, Izabel R S C; Oliveira, Tânia T; Novaes, Rômulo D

2017-10-01

By using an experimental model of dexamethasone-induced osteoporosis we investigated the effects of different therapeutic schemes combining sodium alendronate (SA) and simvastatin on bone mineral and protein composition, microstructural and mechanical remodeling. Wistar rats were randomized into eight groups: G1: non-osteoporotic; G2: osteoporotic; G3, G4, and G5: osteoporotic+SA (0.2, 0.4, and 0.8 mg/kg, respectively); G6, G7, and G8: osteoporotic+SA (0.2, 0.4, and 0.8 mg/kg, respectively)+simvastatin (0.4, 0.6, and 1 mg/kg, respectively). Osteoporosis was induced by dexamethasone (7 mg/kg, i.m.) once a week for 5 weeks. All treatments were administered for 8 weeks. Dexamethasone increased serum levels of alkaline phosphatase, calcium, phosphorus, and urea, especially in non-treated animals, which showed severe osteoporosis. Dexamethasone also induced bone microstructural fragility and reduced mechanical resistance, which were associated with a marked depletion in mineral mass, collagenous and non-collagenous protein levels in cortical and cancellous bone. Although SA has attenuated osteoporosis severity, the effectiveness of drug therapy was enhanced combining alendronate and simvastatin. The restoration in serum parameters, organic and inorganic bone mass, and mechanical behavior showed a dose-dependent effect that was potentially related to the complementary mechanisms by which each drug acts to induce bone anabolism, accelerating tissue repair.

Efficacy and safety of medical therapy for low bone mineral density in patients with Crohn disease

PubMed Central

Zhao, Xiaojing; Zhou, Changcheng; Chen, Han; Ma, Jingjing; Zhu, Yunjuan; Wang, Peixue; Zhang, Yi; Ma, Haiqin; Zhang, Hongjie

2017-01-01

Abstract Background: Low bone mineral density (BMD) is a frequent complication of inflammatory bowel disease (IBD), particularly in patients with Crohn disease (CD). The aim of our study is to determine the efficacy and safety of different drugs used to treat low BMD in patients with CD. Methods: PUBMED/MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were searched for eligible studies. A random-effects model within a Bayesian framework was applied to compare treatment effects as standardized mean difference (SMD) with their corresponding 95% credible interval (CrI), while odds ratio (OR) was applied to compare adverse events with 95% CrI. The surface under the cumulative ranking area (SUCRA) was calculated to make the ranking of the treatments for outcomes. Results: Twelve randomized controlled trials (RCTs) were eligible. Compared with placebo, zoledronate (SMDs 2.74, 95% CrI 1.36–4.11) and sodium-fluoride (SMDs 1.23, 95% CrI 0.19–2.26) revealed statistical significance in increasing lumbar spine BMD (LSBMD). According to SUCRA ranking, zoledronate (SUCRA = 2.5%) might have the highest probability to be the best treatment for increasing LSBMD in CD patients among all agents, followed by sodium-fluoride (27%). For safety assessment, the incidence of adverse events (AEs) demonstrated no statistical difference between agents and placebo. The corresponding SUCRA values indicated that risedronate (SUCRA = 77%) might be the most safe medicine for low BMD in CD patients and alendronate ranked the worst (SUCRA = 16%). Conclusions: Zoledronate might have the highest probability to be the best therapeutic strategy for increasing LSBMD. For the safety assessment, risedronate showed the greatest trend to decrease the risk of AEs. In the future, more RCTs with higher qualities are needed to make head-to-head comparison between 2 or more treatments. PMID:28296781

The efficacy of bisphosphonates in preventing aromatase inhibitor induced bone loss for postmenopausal women with early breast cancer: a systematic review and meta-analysis.

PubMed

Anagha, Pooleriveetil Padikkal; Sen, Suchandra

2014-01-01

Objectives. We aim to determine the efficacy of bisphosphonates in preventing aromatase inhibitor induced bone loss (AIBL) in postmenopausal women with early breast cancer. The secondary objective was to determine the safety of bisphosphonates. Materials and Methods. We searched electronic databases in a time period of 1995 January to 2013 June. Random effects meta-analytical models were used; between study heterogeneity and publication bias was assessed. Results. A total of six eligible studies reported the BMD T score of LS at 12 months and from that 3 trials of Zoledronic acid compared the change in BMD in immediate ZOL versus delayed ZOL done with subgroups like patients with normal BMD at baseline (OR = 5.402, 95% CI = 1.329-21.959, P value = 0.018) and osteopenic BMD at baseline (OR = 4.008, 95% CI = 2.249-7.143, P value = 0.0002). Both had a significant decrease in BMD that favoured the delayed ZOL; 3 trials of risedronate and ibandronate also had a significant decrease in BMD in AIs alone group. Immediate ZOL versus delayed ZOL also showed increased risk of getting an ADR in immediate group. Conclusion. Third generation bisphosphonates has an effect on BMD of patients who are on treatment of AIs in breast cancer. Furthermore, the patients treated with immediate ZOL had a significantly high risk of musculoskeletal ADR's than patients with delayed ZOL.

Formulation and evaluation of Alendronate Sodium gel for the treatment of bone resorptive lesions in Periodontitis.

PubMed

Reddy, G Thirumal; Kumar, T M Pramod; Veena

2005-01-01

Alendronate sodium is formulated into gels and evaluated for the treatment of bone resorptive lesions in periodontitis. Carbopol 934P was used for the preparation of gels in three different concentrations. The prepared gel was evaluated for various properties such as preformulation, content uniformity, viscosity, compatibility, sterility, in vitro diffusion, and in vivo studies. The drug and the polymer were found to be compatible and confirmed by Fourier transform infrared spectroscopy. Viscosity of the gels increased with the increase in the polymer concentration. The formulations were found to be sterile. In vitro release study revealed that drug released from the gel follows non-Fickian diffusion followed by first-order release. In vivo studies were carried out for 6 months in patients. The results revealed a significant improvement in the clinical parameters such as gingival index, probing pocket depth, clinical attachment level, and potent inhibitory effect on bone resorption by inhibition of osteoclasts. In addition, there was increase in the new bone formation.

Ibandronate

MedlinePlus

... or other problems with your stomach or esophagus (tube that connects the throat to the stomach); cancer; any type of infection, especially in your mouth; problems with your mouth, teeth, or gums; any condition that stops your blood ...

Bioequivalence of generic alendronate sodium tablets (70 mg) to Fosamax® tablets (70 mg) in fasting, healthy volunteers: a randomized, open-label, three-way, reference-replicated crossover study

PubMed Central

Zhang, Yifan; Chen, Xiaoyan; Tang, Yunbiao; Lu, Youming; Guo, Lixia; Zhong, Dafang

2017-01-01

Purpose The aim of this study was to evaluate the bioequivalence of a generic product 70 mg alendronate sodium tablets with the reference product Fosamax® 70 mg tablet. Materials and methods A single-center, open-label, randomized, three-period, three-sequence, reference-replicated crossover study was performed in 36 healthy Chinese male volunteers under fasting conditions. In each study period, the volunteers received a single oral dose of the generic or reference product (70 mg). Blood samples were collected at pre-dose and up to 8 h after administration. The bioequivalence of the generic product to the reference product was assessed using the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) reference-scaled average bioequivalence (RSABE) methods. Results The average maximum concentrations (Cmax) of alendronic acid were 64.78±43.76, 56.62±31.95, and 60.15±37.12 ng/mL after the single dose of the generic product and the first and second doses of the reference product, respectively. The areas under the plasma concentration–time curves from time 0 to the last timepoint (AUC0–t) were 150.36±82.90, 148.15±85.97, and 167.11±110.87 h⋅ng/mL, respectively. Reference scaling was used because the within-subject standard deviations of the reference product (sWR) for Cmax and AUC0–t were all higher than the cutoff value of 0.294. The 95% upper confidence bounds were −0.16 and −0.17 for Cmax and AUC0–t, respectively, and the point estimates for the generic/reference product ratio were 1.08 and 1.00, which satisfied the RSABE acceptance criteria of the FDA. The 90% CIs for Cmax and AUC0–t were 90.35%–129.04% and 85.31%–117.15%, respectively, which were within the limits of the EMA for the bioequivalence of 69.84%–143.19% and 80.00%–125.00%. Conclusion The generic product was bioequivalent to the reference product in terms of the rate and extent of alendronate absorption after a single 70 mg oral dose under fasting

The prevention of fragility fractures in patients with non-metastatic prostate cancer: a position statement by the international osteoporosis foundation

PubMed Central

Cianferotti, Luisella; Bertoldo, Francesco; Carini, Marco; Kanis, John A.; Lapini, Alberto; Longo, Nicola; Martorana, Giuseppe; Mirone, Vincenzo; Reginster, Jean-Yves; Rizzoli, Rene; Brandi, Maria Luisa

2017-01-01

Androgen deprivation therapy is commonly employed for the treatment of non-metastatic prostate cancer as primary or adjuvant treatment. The skeleton is greatly compromised in men with prostate cancer during androgen deprivation therapy because of the lack of androgens and estrogens, which are trophic factors for bone. Men receiving androgen deprivation therapy sustain variable degrees of bone loss with an increased risk of fragility fractures. Several bone antiresorptive agents have been tested in randomized controlled trials in these patients. Oral bisphosphonates, such as alendronate and risedronate, and intravenous bisphosphonates, such as pamidronate and zoledronic acid, have been shown to increase bone density and decrease the risk of fractures in men receiving androgen deprivation therapy. Denosumab, a fully monoclonal antibody that inhibits osteoclastic-mediated bone resorption, is also effective in increasing bone mineral density and reducing fracture rates in these patients. The assessment of fracture risk, T-score and/or the evaluation of prevalent fragility fractures are mandatory for the selection of patients who will benefit from antiresorptive therapy. In the future, new agents modulating bone turnover and skeletal muscle metabolism will be available for testing in these subjects. PMID:29088899

The prevention of fragility fractures in patients with non-metastatic prostate cancer: a position statement by the international osteoporosis foundation.

PubMed

Cianferotti, Luisella; Bertoldo, Francesco; Carini, Marco; Kanis, John A; Lapini, Alberto; Longo, Nicola; Martorana, Giuseppe; Mirone, Vincenzo; Reginster, Jean-Yves; Rizzoli, Rene; Brandi, Maria Luisa

2017-09-26

Androgen deprivation therapy is commonly employed for the treatment of non-metastatic prostate cancer as primary or adjuvant treatment. The skeleton is greatly compromised in men with prostate cancer during androgen deprivation therapy because of the lack of androgens and estrogens, which are trophic factors for bone. Men receiving androgen deprivation therapy sustain variable degrees of bone loss with an increased risk of fragility fractures. Several bone antiresorptive agents have been tested in randomized controlled trials in these patients. Oral bisphosphonates, such as alendronate and risedronate, and intravenous bisphosphonates, such as pamidronate and zoledronic acid, have been shown to increase bone density and decrease the risk of fractures in men receiving androgen deprivation therapy. Denosumab, a fully monoclonal antibody that inhibits osteoclastic-mediated bone resorption, is also effective in increasing bone mineral density and reducing fracture rates in these patients. The assessment of fracture risk, T-score and/or the evaluation of prevalent fragility fractures are mandatory for the selection of patients who will benefit from antiresorptive therapy. In the future, new agents modulating bone turnover and skeletal muscle metabolism will be available for testing in these subjects.

Oral bisphosphonate-associated osteonecrosis of maxillary bone: A review of 18 cases

PubMed Central

Mardenlli, Fabiana; Paz, Marisa

2014-01-01

Biphosphonate-associated maxillary bone osteonecrosis (BPMO) is a complication related to nitrogen-containing biphosphonate therapy. This adverse effect occasionally appears in patients who are administered biphosphonates through intravenous infusion for the treatment of cancer involving bone metastases. It can also present, in a lesser degree, in patients who take these drugs orally for the treatment of osteoporosis. Lately, there has been an increase in the number of cases of osteopenia and osteoporosis due to the increasing life expectancy of the world’s population. In our country, a risk group composed mainly of older women who have been diagnosed with osteopenia or osteoporosis, and submitted to the continuous action of oral biphosphonates, is emerging. In this paper we present 18 cases of BPMO associated to the use of oral biphosphonates, diagnosed and treated in the Department of Stomatology of the School or Dentistry at Universidad Nacional de Rosario, Argentina. A protocol was designed in which the following information was recorded: age and sex of the patients, the original disease which led to therapy with oral biphosphonates, the drugs used and the period in which those drugs were administered, the clinical features and location of the lesions, together with triggering factors. Key words:Maxillary osteonecrosis, mandibular osteonecrosis, oral biphosphonates, alendronate, ibandronate. PMID:25674321

Photonic monitoring of chitosan nanostructured alginate microcapsules for drug release

NASA Astrophysics Data System (ADS)

Khajuria, Deepak Kumar; Konnur, Manish C.; Vasireddi, Ramakrishna; Roy Mahapatra, D.

2015-02-01

By using a novel microfluidic set-up for drug screening applications, this study examines delivery of a novel risedronate based drug formulation for treatment of osteoporosis that was developed to overcome the usual shortcomings of risedronate, such as its low bioavailability and adverse gastric effects. Risedronate nanoparticles were prepared using muco-adhesive polymers such as chitosan as matrix for improving the intestinal cellular absorption of risedronate and also using a gastric-resistant polymer such as sodium alginate for reducing the gastric inflammation of risedronate. The in-vitro characteristics of the alginate encapsulated chitosan nanoparticles are investigated, including their stability, muco-adhesiveness, and Caco-2 cell permeability. Fluorescent markers are tagged with the polymers and their morphology within the microcapsules is imaged at various stages of drug release.

High payload nanostructured lipid carriers fabricated with alendronate/polyethyleneimine ion complexes.

PubMed

Abd El-Hamid, Basma N; Swarnakar, Nitin K; Soliman, Ghareb M; Attia, Mohamed A; Pauletti, Giovanni M

2018-01-15

Oral bioavailability of the anti-osteoporotic drug alendronate (AL) is limited to ≤ 1% due to unfavorable physicochemical properties. To augment absorption across the gastrointestinal mucosa, an ion pair complex between AL and polyethyleneimine (PEI) was formed and incorporated into nanostructured lipid carriers (NLCs) using a modified solvent injection method. When compared to free AL, ion pairing with PEI increased drug encapsulation efficiency in NLCs from 10% to 87%. Drug release from NLCs measured in vitro using fasted state simulated intestinal fluid, pH 6.5 (FaSSIF-V2) was significantly delayed after PEI complexation. Stability of AL/PEI was pH-dependent resulting in 10-fold faster dissociation of AL in FaSSIF-V2 than measured at pH 7.4. Intestinal permeation properties estimated in vitro across Caco-2 cell monolayers revealed a 3-fold greater flux of AL encapsulated as hydrophobic ion complex in NLCs when compared to AL solution (P app  = 8.43 ± 0.14 × 10 -6 cm/s and vs. 2.76 ± 0.42 × 10 -6 cm/s). Cellular safety of AL/PEI-containing NLCs was demonstrated up to an equivalent AL concentration of 2.5 mM. These results suggest that encapsulation of AL/PEI in NLCs appears a viable drug delivery strategy for augmenting oral bioavailability of this clinically relevant bisphosphonate drug and, simultaneously, increase gastrointestinal safety. Copyright © 2017 Elsevier B.V. All rights reserved.

Role of gastric mucosal and gastric juice cytokine concentrations in development of bisphosphonate damage to gastric mucosa.

PubMed

Thomson, A B R; Appleman, S; Keelan, M; Wallace, J L

2003-02-01

Previous studies have shown that the bisphosphonates (BP) vary in their damaging effect on the gastric mucosa, and endoscopy scores (erosions or erosions plus ulcers) after 1 and 2 weeks use of BP were significantly lower in H. pylori-positive versus -negative subjects. The mechanism of this damaging effect of BP and the interaction with H. pylori is unknown. As part of a separately reported study of the incidence of gastric damage after 2 weeks of treatment of healthy female postmenopausal volunteers with risedronate (5 mg/day) or alendronate (10 mg/day), gastric aspirates were taken at the time of the baseline esophagogastroduodenoscopy (EGD), and again at 1 and 2 weeks after daily intake of a BP At the time of the third EGD, when the volunteers had been on risedronate or alendronate for 2 weeks, antral biopsies were taken from normal-appearing mucosa. Gastric juice and antral biopsies were assessed for their concentration of the cytokines interleukin-la (IL-1alpha), IL-8, IL-13, and epidermal growth factor (EGF). H. pylori, the use of BP, and development of gastric mucosal lesions had no effect on gastric mucosal concentrations of IL-1alpha, IL-13, or EGF. In contrast, the concentration of IL-8 in antral mucosal biopsies of volunteers given BP for 2 weeks was higher in the presence than in the absence of an H. pylori infection and was increased further in those who develop lesions associated with the use of BP. There was no correlation between gastric mucosal and gastric juice concentrations of IL-8. Gastric juice concentrations of IL-8 and EGF were not affected by H. pylori status, the use of BP, or the development of lesions. However, gastric juice concentrations of IL-1alpha were numerically lower in those who were negative for H. pylori with no mucosal lesions (Hp-L-), intermediate in those who were H. pylori-negative with lesions (Hp-L+), and highest in those who were positive for H. pylori and had lesions (Hp+L+). The gastric juice concentration of IL-13

Massive Bone Loss Due to Orchidectomy and Localized Disuse: Preventive Effects of a Biosphonsphonate

NASA Astrophysics Data System (ADS)

Libouban, H.; Moreau, M. F.; Chappard, D.

2008-06-01

Orchidectomy (ORX) and hindlimb paralysis induced by botulinum neurotoxin (BTX) were combined to see if their effects were cumulative and if bone loss could be prevented by an antiresorptive agent (risedronate) or testosterone. Four groups of mature rats were studied for 1 month: SHAM operated; ORX and right hindlimb immobilization (BTX); ORX+BTX+risedronate or testosterone. Bone loss and microarchitecture deterioration were maximized on the immobilized bone. Risedronate but not testosterone prevented trabecular bone loss but was less effective on cortical bone loss. ORX and BTX had additive effects on bone loss which can be prevented by risedronate but not testosterone.

The absorption of (99m)Tc-alendronate given by rectal route in rabbits.

PubMed

Asikoğlu, Makbule; Ozguney, Isik; Ozcan, Ipek; Orumlu, Oya; Guneri, Tamer; Koseoğlu, Kamil; Ozkilic, Hayal

2008-01-01

Alendronate sodium (ALD) is a bisphosphonate medication used in the treatment and prevention of osteoporosis. Absorption of ALD as oral formulation is very poor (0.5%-1%). Its bioavailability can decrease with food effect. It has some gastrointestinal adverse effects such as gastritis, gastric ulcer, and esophagitis. The aim of this study was to develop a rectal formulation of ALD as an alternative to oral route and to investigate the absorption of it by using gamma scintigraphy. For this reason, ALD was labeled with Technetium-99m ((99m)Tc) by direct method. The radiochemical characterization of the (99m)Tc-ALD was carried out by paper chromatography, thin layer chromatography, and electrophoresis methods. The labeling efficiency of (99m)Tc-ALD was found 99% without significant changes until 6 h postlabeling at room temperature. The rectal suppositories containing (99m)Tc-ALD were prepared by fusion method using polyethylene glycol (PEG) 1500. The (99m)Tc-labeled ALD suppositories were administrated to rabbits by rectal route. Serial scintigrams over all bodies of the rabbits were obtained at different time intervals using a gamma camera. We found that the rectal absorption of (99m)Tc-ALD from suppository formulation was possible. According to our results, this formulation of ALD can be suggested for the therapy of osteoporosis as an alternative route.

Application of Certain π-Acceptors for the Spectrophotometric Determination of Alendronate Sodium in Pharmaceutical Bulk and Dosage Forms.

PubMed

Raza, Asad; Zia-Ul-Haq, Muhammad

2011-01-01

Two simple, fast, and accurate spectrophotometric methods for the determination of alendronate sodium are described. The methods are based on charge-transfer complex formation of the drug with two π-electron acceptors 7,7,7,8-tetracyanoquinodimethane (TCNQ) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in acetonitrile and methanol medium. The methods are followed spectrophotometrically by measuring the maximum absorbance at 840 nm and 465 nm, respectively. Under the optimized experimental conditions, the calibration curves showed a linear relationship over the concentration ranges of 2-10 μg mL(-1) and 2-12 μg mL(-1), respectively. The optimal reactions conditions values such as the reagent concentration, heating time, and stability of reaction product were determined. No significant difference was obtained between the results of newly proposed methods and the B.P. Titrimetric procedures. The charge transfer approach using TCNQ and DDQ procedures described in this paper is simple, fast, accurate, precise, and extraction-free.

3D printed alendronate-releasing poly(caprolactone) porous scaffolds enhance osteogenic differentiation and bone formation in rat tibial defects.

PubMed

Kim, Sung Eun; Yun, Young-Pil; Shim, Kyu-Sik; Kim, Hak-Jun; Park, Kyeongsoon; Song, Hae-Ryong

2016-09-29

The aim of this study was to evaluate the in vitro osteogenic effects and in vivo new bone formation of three-dimensional (3D) printed alendronate (Aln)-releasing poly(caprolactone) (PCL) (Aln/PCL) scaffolds in rat tibial defect models. 3D printed Aln/PCL scaffolds were fabricated via layer-by-layer deposition. The fabricated Aln/PCL scaffolds had high porosity and an interconnected pore structure and showed sustained Aln release. In vitro studies showed that MG-63 cells seeded on the Aln/PCL scaffolds displayed increased alkaline phosphatase (ALP) activity and calcium content in a dose-dependent manner when compared with cell cultures in PCL scaffolds. In addition, in vivo animal studies and histologic evaluation showed that Aln/PCL scaffolds implanted in a rat tibial defect model markedly increased new bone formation and mineralized bone tissues in a dose-dependent manner compared to PCL-only scaffolds. Our results show that 3D printed Aln/PCL scaffolds are promising templates for bone tissue engineering applications.

Preparation and characterisation of alendronate-loaded chitosan microparticles obtained through the spray drying technique.

PubMed

Ochiuz, Lacramioara; Peris, José-Esteban

2009-03-01

Microparticles of chitosan (CHT) containing alendronate sodium (AL) were prepared in four drug:polymer ratios (1:1, 1:2, 1:4, 1:6) using the spray drying technique. The efficiency of the method was evaluated by determining production yield (about 70 %) and microencapsulation efficiency, which was almost 100 % in the case of all four of the formulations studied. Particles had a mean size of between 3.6 and 4.6 microm, and a near-spherical shape. The formulations with the highest content of AL (drug:polymer ratio 1:1 and 1:2) showed an asymmetrical distribution of particles, which were larger in size, and had a higher proportion of irregular particles than the other formulations. FT-IR analysis revealed an ionic interaction between AL and CHT. Differential scanning calorimetry and thermogravimetric analysis confirmed the microencapsulation of AL and the increased thermal stability of encapsulated AL. The dissolution profiles of AL from CHT microspheres, at pH values of 1.2 and 6.8, showed a delayed release of AL from microspheres, and the dissolution rate was dependent on the pH and the drug:polymer ratio. It can be concluded that spray drying is a suitable technique for preparing AL-loaded CHT microspheres, and that the drug:polymer ratio can be used to control the rate of AL release from microspheres.

Osteoporosis in the aging male: Treatment options

PubMed Central

Tuck, Stephen P; Datta, Harish K

2007-01-01

In elderly women, loss in bone mass and micro-architectural changes are generally attributed to the onset of menopause. Men do not experience menopause, they do, however, experience age-related acceleration in bone loss and micro-architecture deterioration. The incidence of osteoporotic fractures in elderly men, just as in aged women, increases exponentially with age; the rise in men, however, is some 5–10 years later than in women. Up to 50% of male osteoporotics have no identifiable etiology; however elderly males have much higher likelihood of having an identifiable secondary cause than younger men. Therefore, clinical and laboratory evaluation of aged male osteoporotics must be thorough and should be aimed at identifying lifestyle or conditions contributing to bone loss and fragility. It is essential to identify and treat secondary causes and ensure adequate vitamin D and calcium intake before embarking upon treatment with pharmacological agents. The evidence from a limited number of trials suggests that bisphosphonates, especially alendronate and risedronate, are effective in improving BMD, and seem to be the treatments of choice in aged men with osteoporosis. In cases where bisphosphonates are contra-indicated or ineffective, teriparatide or alternatives such as strontium should be considered. PMID:18225452

Bisphosphonate-related osteonecrosis of the jaw: historical, ethical, and legal issues associated with prescribing.

PubMed

Faiman, Beth; Pillai, Aiswarya Lekshmi Pillai Chandran; Benghiac, Ana Gabriela

2013-01-01

The long-term effects of many drugs are unknown. Established risks are communicated to patients who participate in clinical trials during the informed consent process. However, unknown and unanticipated side effects of medications may occur years after treatment. Patients with metastatic bone cancer experience an imbalance between tumor cells and the bone marrow microenvironment. Increased cytokine release, osteoclastic activity, and uncoupled osteoblastic activity lead to weakened bone structure and osteolytic lesions. The bisphosphonates are a class of drugs available in IV and oral formulations to treat and prevent bone loss and decrease the risk of skeletal-related events. Intravenous bisphosphonates such as zoledronic acid and pamidronate disodium are approved by the US Food and Drug Administration for the treatment of bone pain and hypercalcemia of malignancy and the prevention of painful bone fractures in patients with metastatic bone cancer. Oral bisphosphonates such as alendronate, risedronate, and etidronate are used to reduce the risk of skeletal fractures in patients with osteoporosis and in breast cancer. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare but painful complication of treatment characterized by infection, exposed bone, and poor wound healing. In this article, we discuss BRONJ and identify past, present, and future ethical and legal issues surrounding bisphosphonate administration.

Application of Certain π-Acceptors for the Spectrophotometric Determination of Alendronate Sodium in Pharmaceutical Bulk and Dosage Forms

PubMed Central

Raza, Asad; Zia-ul-Haq, Muhammad

2011-01-01

Two simple, fast, and accurate spectrophotometric methods for the determination of alendronate sodium are described. The methods are based on charge-transfer complex formation of the drug with two π-electron acceptors 7,7,7,8-tetracyanoquinodimethane (TCNQ) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in acetonitrile and methanol medium. The methods are followed spectrophotometrically by measuring the maximum absorbance at 840 nm and 465 nm, respectively. Under the optimized experimental conditions, the calibration curves showed a linear relationship over the concentration ranges of 2–10 μg mL−1 and 2–12 μg mL−1, respectively. The optimal reactions conditions values such as the reagent concentration, heating time, and stability of reaction product were determined. No significant difference was obtained between the results of newly proposed methods and the B.P. Titrimetric procedures. The charge transfer approach using TCNQ and DDQ procedures described in this paper is simple, fast, accurate, precise, and extraction-free. PMID:21760789

Fabrication and physicochemical characterization of porous composite microgranules with selenium oxyanions and risedronate sodium for potential applications in bone tumors.

PubMed

Kolmas, Joanna; Pajor, Kamil; Pajchel, Lukasz; Przekora, Agata; Ginalska, Grażyna; Oledzka, Ewa; Sobczak, Marcin

2017-01-01

Nanocrystalline hydroxyapatite containing selenite ions (SeHA; 9.6 wt.% of selenium) was synthesized using wet method and subject to careful physicochemical analysis by powder X-ray diffraction, Fourier transform infrared spectroscopy, transmission electron microscopy, solid-state nuclear magnetic resonance, wavelength dispersive X-ray fluorescence, and inductively coupled plasma optical emission spectrometry. SeHA was then used to develop the selenium-containing hydroxyapatite/alginate (SeHA/ALG) composite granules. Risedronate sodium (RIS) was introduced to the obtained spherical microgranules of a size of about 1.1-1.5 mm in 2 ways: during the granules' preparation (RIS solution added to a suspension of ALG and SeHA), and as a result of SeHA/ALG granules soaking in aqueous RIS solution. The analysis made using 13 C and 31 P cross-polarization magic angle spinning nuclear magnetic resonance confirmed the presence of RIS and its interaction with calcium ions. Then, the release of selenium (inductively coupled plasma optical emission spectrometry) and RIS (high-performance liquid chromatography) from microgranules was examined. Moreover, cytotoxicity of fabricated granules was assessed by MTT test. Selenium release was biphasic: the first stage was short and ascribed to a "burst release" probably from a hydrated surface layer of SeHA crystals, while the next stage was significantly longer and ascribed to a sustained release of selenium from the crystals' interior. The study showed that the method of obtaining microgranules containing RIS significantly affects its release profile. Performed cytotoxicity test revealed that fabricated granules had high antitumor activity against osteosarcoma cells. However, because of the "burst release" of selenium during the first 10 h, the granules significantly reduced viability of normal osteoblasts as well.

Fabrication and physicochemical characterization of porous composite microgranules with selenium oxyanions and risedronate sodium for potential applications in bone tumors

PubMed Central

Kolmas, Joanna; Pajor, Kamil; Pajchel, Lukasz; Przekora, Agata; Ginalska, Grażyna; Oledzka, Ewa; Sobczak, Marcin

2017-01-01

Nanocrystalline hydroxyapatite containing selenite ions (SeHA; 9.6 wt.% of selenium) was synthesized using wet method and subject to careful physicochemical analysis by powder X-ray diffraction, Fourier transform infrared spectroscopy, transmission electron microscopy, solid-state nuclear magnetic resonance, wavelength dispersive X-ray fluorescence, and inductively coupled plasma optical emission spectrometry. SeHA was then used to develop the selenium-containing hydroxyapatite/alginate (SeHA/ALG) composite granules. Risedronate sodium (RIS) was introduced to the obtained spherical microgranules of a size of about 1.1–1.5 mm in 2 ways: during the granules’ preparation (RIS solution added to a suspension of ALG and SeHA), and as a result of SeHA/ALG granules soaking in aqueous RIS solution. The analysis made using 13C and 31P cross-polarization magic angle spinning nuclear magnetic resonance confirmed the presence of RIS and its interaction with calcium ions. Then, the release of selenium (inductively coupled plasma optical emission spectrometry) and RIS (high-performance liquid chromatography) from microgranules was examined. Moreover, cytotoxicity of fabricated granules was assessed by MTT test. Selenium release was biphasic: the first stage was short and ascribed to a “burst release” probably from a hydrated surface layer of SeHA crystals, while the next stage was significantly longer and ascribed to a sustained release of selenium from the crystals’ interior. The study showed that the method of obtaining microgranules containing RIS significantly affects its release profile. Performed cytotoxicity test revealed that fabricated granules had high antitumor activity against osteosarcoma cells. However, because of the “burst release” of selenium during the first 10 h, the granules significantly reduced viability of normal osteoblasts as well. PMID:28848343

DFT computational study on the phosphate functionalized SWCNTs as efficient drug delivery systems for anti-osteoporosis zolendronate and risedronate drugs

NASA Astrophysics Data System (ADS)

Nikfar, Zahra; Shariatinia, Zahra

2017-07-01

The pristine (4,4)-armchair SWCNT as well as its three phosphate functionalized (CNT-nH2PO4, n=1-3) forms were studied as novel drug delivery systems for the two commercially famous anti-osteoporosis drugs including risedronate (RIS) and zolendronate (ZOL) using the density functional theory (DFT) computations at both B3LYP and B3PW91 levels. Results revealed that the binding energy was increased by increasing number of H2PO4 moieties attached on the CNT with the most negative binding energy was measured for the CNT-3H2PO4 carrier. The dipole moments of all phosphate containing CNTs were much greater ( 1.5-4.5 D) than that of pristine CNT ( 0 D). The contour maps verified that when the CNT was functionalized by H2PO4 groups, the symmetric distribution of electric charge was vanished so that the highest and the lowest asymmetric charge distributions were achieved for the CNT-2H2PO4 and CNT-3H2PO4, respectively, leading to the greatest and the smallest dipole moments for the CNT-2H2PO4 (4.177 D) and the CNT-3H2PO4 (1.614 D). The compounds RIS-CNT-3H2PO4 and ZOL-CNT-3H2PO4 displayed the greatest electronegativity and electrophilicity index which were appropriate for the binding of drugs onto the bone surface (having partial positive charge due to the presence of Ca2+) and therefore effectively inhibiting the osteoporosis. Consequently, it was proposed that the drug-CNT-3H2PO4 was the most appropriate drug-carrier system for both of the RIS and ZOL drugs which could be employed as the most efficient vehicle.

Assessment and clinical management of bone disease in adults with eating disorders: a review.

PubMed

Drabkin, Anne; Rothman, Micol S; Wassenaar, Elizabeth; Mascolo, Margherita; Mehler, Philip S

2017-01-01

To review current medical literature regarding the causes and clinical management options for low bone mineral density (BMD) in adult patients with eating disorders. Low bone mineral density is a common complication of eating disorders with potentially lifelong debilitating consequences. Definitive, rigorous guidelines for screening, prevention and management are lacking. This article intends to provide a review of the literature to date and current options for prevention and treatment. Current, peer-reviewed literature was reviewed, interpreted and summarized. Any patient with lower than average BMD should weight restore and in premenopausal females, spontaneous menses should resume. Adequate vitamin D and calcium supplementation is important. Weight-bearing exercise should be avoided unless cautiously monitored by a treatment team in the setting of weight restoration. If a patient has a Z-score less than expected for age with a high fracture risk or likelihood of ongoing BMD loss, physiologic transdermal estrogen plus oral progesterone, bisphosphonates (alendronate or risedronate) or teriparatide could be considered. Other agents, such as denosumab and testosterone in men, have not been tested in eating-disordered populations and should only be trialed on an empiric basis if there is a high clinical concern for fractures or worsening bone mineral density. A rigorous peer-based approach to establish guidelines for evaluation and management of low bone mineral density is needed in this neglected subspecialty of eating disorders.

A novel alendronate functionalized nanoprobe for simple colorimetric detection of cancer-associated hypercalcemia.

PubMed

Sahu, Abhishek; Hwang, Youngmin; Vilos, Cristian; Lim, Jong-Min; Kim, Sunghyun; Choi, Won Il; Tae, Giyoong

2018-05-22

The calcium (Ca2+) ion concentration in the blood serum is tightly regulated, and any abnormalities in the level of serum calcium ions are associated with many potentially dangerous diseases. Thus, monitoring of the Ca2+ ion concentration in the blood serum is of fundamental importance. Gold nanoparticle (GNP)-based colorimetric biosensors have enormous potential in clinical diagnostic applications due to their simplicity, versatility, and unique optical properties. In this study, we have developed an alendronate functionalized gold nanoparticle (GNP-ALD) system for the measurement of Ca2+ ion concentration in biological samples. The GNP-ALD system showed higher sensitivity towards the Ca2+ ion compared to adenosine diphosphate (ADP) or adenosine triphosphate (ATP). The strong interaction between the Ca2+ ion and ALD at the GNP/solution interface resulted in significant aggregation of the ALD conjugated GNPs, and induced a color change of the solution from red to blue, which could be visually observed with the naked eye. The interaction between the Ca2+ ion and GNP-ALD was characterized by UV-visible spectroscopy, transmission electron microscopy (TEM) imaging, and dynamic light scattering (DLS) analysis. Under the optimized conditions, the lower limit of Ca2+ ion detection using this method was found to be 25 μM and a linear response range from 25 μM to 300 μM Ca2+ ions was obtained with excellent discrimination against other metal ions. The GNP-ALD nanoprobe could successfully determine the ionized Ca2+ concentration in various serum samples and the results were validated using a commercial calcium assay kit. Moreover, as a practical application, we demonstrated the utility of this nanoprobe for the detection of cancer-associated hypercalcemia in a mouse model.

Alendronate treatment alters bone tissues at multiple structural levels in healthy canine cortical bone.

PubMed

Acevedo, Claire; Bale, Hrishikesh; Gludovatz, Bernd; Wat, Amy; Tang, Simon Y; Wang, Mingyue; Busse, Björn; Zimmermann, Elizabeth A; Schaible, Eric; Allen, Matthew R; Burr, David B; Ritchie, Robert O

2015-12-01

Bisphosphonates are widely used to treat osteoporosis, but have been associated with atypical femoral fractures (AFFs) in the long term, which raises a critical health problem for the aging population. Several clinical studies have suggested that the occurrence of AFFs may be related to the bisphosphonate-induced changes of bone turnover, but large discrepancies in the results of these studies indicate that the salient mechanisms responsible for any loss in fracture resistance are still unclear. Here the role of bisphosphonates is examined in terms of the potential deterioration in fracture resistance resulting from both intrinsic (plasticity) and extrinsic (shielding) toughening mechanisms, which operate over a wide range of length-scales. Specifically, we compare the mechanical properties of two groups of humeri from healthy beagles, one control group comprising eight females (oral doses of saline vehicle, 1 mL/kg/day, 3 years) and one treated group comprising nine females (oral doses of alendronate used to treat osteoporosis, 0.2mg/kg/day, 3 years). Our data demonstrate treatment-specific reorganization of bone tissue identified at multiple length-scales mainly through advanced synchrotron x-ray experiments. We confirm that bisphosphonate treatments can increase non-enzymatic collagen cross-linking at molecular scales, which critically restricts plasticity associated with fibrillar sliding, and hence intrinsic toughening, at nanoscales. We also observe changes in the intracortical architecture of treated bone at microscales, with partial filling of the Haversian canals and reduction of osteon number. We hypothesize that the reduced plasticity associated with BP treatments may induce an increase in microcrack accumulation and growth under cyclic daily loadings, and potentially increase the susceptibility of cortical bone to atypical (fatigue-like) fractures. Published by Elsevier Inc.

Effects of Prostaglandin E2 and Risedronate Administration on Cancellous Bone in Older Female Rats

NASA Technical Reports Server (NTRS)

Lin, B. Y.; Jee, W. S. S.; Ma, Y. F.; Ke, H. Z.; Kimmel, D. B.; Li, X. J.

1994-01-01

The effects of Prostaglandin E2 (PGE2) and Risedronate (Ris) both separately and in combination (PGE2 + Ris) were studied on the intact aged female rat skeleton to determine whether the combination of PGE2 with an antiresorptive agent is more effective anabolically than PGE2 alone. Nine month-old Sprague-Dawley rats were injected subcutaneously either with vehicle, 6 mg PGE2/kg per day, 1 or 5 microgram Ris/kg twice a week, or 6 mg PGE2/kg per day plus 1 or 5 microgram Ris/kg twice a week (PGE2 + 1 Ris or PGE2 + 5 Ris) for 60 days. After the treatment, we determined the longitudinal bone growth rate, the qualitative appearance of the primary spongiosa (PS), and the static and dynamic bone histomorphometry of the secondary spongiosa (SS) of the proximal tibial metaphysis (PTM) by examining undecalcified longitudinal sections after double fluorescent labeling. The relative effects of these treatments on longitudinal bone growth were ranked as follows: PGE2 + 5 Ris greater than PGE2 + 1 Ris = basal greater than PGE2 greater than 1 microgram Ris = 5 microgram Ris = aging. The density of the PS was ranked as follows: PGE2 + 5 Ris greater than PGE2 + 1 Ris = PGE2 = 5 microgram Ris = 1 microgram Ris greater than basal = aging. The increase in density of the PS was the result of stimulated longitudinal growth and the action of bisphosphonate. Bone mass in the SS was ranked as follows: PGE2 + 5 Ris = PGE2 + 1 Ris = PGE2 greater than 5 microgram Ris = 1 microgram Ris = aging = basal. However, PGE2 alone and its cotreatment with Ris accumulated bone by different tissue mechanisms. PGE2 alone created new bone by increasing activation frequency 8.3-fold and the formation to resorption ratio 1.3-fold from the controls. The combination of PGE2 and Ris depressed activation frequency (-54% to -74%), and bone formation rate (tissue-based -31%, and bone-based -42%) and eroded surface (-79% to -81%), so as to increase the formation to resorption ratio (three- to four-fold) over PGE2

The Electroporation as a Tool for Studying the Role of Plasma Membrane in the Mechanism of Cytotoxicity of Bisphosphonates and Menadione.

PubMed

Šilkūnas, Mantas; Saulė, Rita; Batiuškaitė, Danutė; Saulis, Gintautas

2016-10-01

In this study, the role of the cell plasma membrane as a barrier in the mechanism of the cytotoxicity of nitrogen-containing bisphosphonates and menadione was studied, and the possibility of increasing the efficiency of bisphosphonates and menadione (vitamin K 3 ) as chemotherapeutic agents by permeabilizing the cell plasma membrane has been investigated in vitro. The plasma membrane barrier was reduced by electropermeabilization with the pulse of strong electric field. Two membrane-impermeant bisphosphonates with different hydrophilicities were chosen as study objects: ibandronate and pamidronate. For the comparison, an amphiphilic vitamin K 3 , which is able to cross the cell membrane, was studied as well. The impact of nitrogen-containing bisphosphonates and vitamin K 3 on MH-22A cells viability was evaluated for the case of long (9 days) and short (20 min) exposure. When cells were cultured in the medium with vitamin K 3 for 9-10 days, it exhibited toxicity of 50 % over the control at 6.2 µM for mouse hepatoma MH-22A cells. Ibandronate and pamidronate were capable of reducing drastically the cell viability only in the case of long 9-days incubation and at high concentrations (~20 µM for pamidronate and over 100 µM for ibandronate). Single, square-wave electric pulse with the duration of 100 µs and the field strength of 2 kV/cm was used to electroporate mouse hepatoma MH-22A cells in vitro. The results obtained here showed that the combination of the exposure of cells to membrane-impermeable bisphosphonates pamidronate and ibandronate with electropermeabilization of the cell plasma membrane did not increase their cytotoxicity. In the case of membrane-permeable vitamin K 3 , cell electropermeabilization did increase vitamin K 3 killing efficiency. However, this increase was not substantial, within the range of 20-30 % depending on the duration of the exposure. Electropermeabilization improved cytotoxic effect of vitamin K 3 but not of pamidronate

Alendronate promotes bone formation by inhibiting protein prenylation in osteoblasts in rat tooth replantation model.

PubMed

Komatsu, Koichiro; Shimada, Akemi; Shibata, Tatsuya; Wada, Satoshi; Ideno, Hisashi; Nakashima, Kazuhisa; Amizuka, Norio; Noda, Masaki; Nifuji, Akira

2013-11-01

Bisphosphonates (BPs) are a major class of antiresorptive drug, and their molecular mechanisms of antiresorptive action have been extensively studied. Recent studies have suggested that BPs target bone-forming cells as well as bone-resorbing cells. We previously demonstrated that local application of a nitrogen-containing BP (N-BP), alendronate (ALN), for a short period of time increased bone tissue in a rat tooth replantation model. Here, we investigated cellular mechanisms of bone formation by ALN. Bone histomorphometry confirmed that bone formation was increased by local application of ALN. ALN increased proliferation of bone-forming cells residing on the bone surface, whereas it suppressed the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts in vivo. Moreover, ALN treatment induced more alkaline phosphatase-positive and osteocalcin-positive cells on the bone surface than PBS treatment. In vitro studies revealed that pulse treatment with ALN promoted osteocalcin expression. To track the target cells of N-BPs, we applied fluorescence-labeled ALN (F-ALN) in vivo and in vitro. F-ALN was taken into bone-forming cells both in vivo and in vitro. This intracellular uptake was inhibited by endocytosis inhibitors. Furthermore, the endocytosis inhibitor dansylcadaverine (DC) suppressed ALN-stimulated osteoblastic differentiation in vitro and it suppressed the increase in alkaline phosphatase-positive bone-forming cells and subsequent bone formation in vivo. DC also blocked the inhibition of Rap1A prenylation by ALN in the osteoblastic cells. These data suggest that local application of ALN promotes bone formation by stimulating proliferation and differentiation of bone-forming cells as well as inhibiting osteoclast function. These effects may occur through endocytic incorporation of ALN and subsequent inhibition of protein prenylation.

Inhibited osteoclastic bone resorption through alendronate treatment in rats reduces severe osteoarthritis progression.

PubMed

Siebelt, M; Waarsing, J H; Groen, H C; Müller, C; Koelewijn, S J; de Blois, E; Verhaar, J A N; de Jong, M; Weinans, H

2014-09-01

Osteoarthritis (OA) is a non-rheumatoid joint disease characterized by progressive degeneration of extra-cellular cartilage matrix (ECM), enhanced subchondral bone remodeling, osteophyte formation and synovial thickening. Alendronate (ALN) is a potent inhibitor of osteoclastic bone resorption and results in reduced bone remodeling. This study investigated the effects of pre-emptive use of ALN on OA related osteoclastic subchondral bone resorption in an in vivo rat model for severe OA. Using multi-modality imaging we measured effects of ALN treatment within cartilage and synovium. Severe osteoarthritis was induced in left rat knees using papain injections in combination with a moderate running protocol. Twenty rats were treated with subcutaneous ALN injections and compared to twenty untreated controls. Animals were longitudinally monitored for 12weeks with in vivo μCT to measure subchondral bone changes and SPECT/CT to determine synovial macrophage activation using a folate-based radiotracer. Articular cartilage was analyzed at 6 and 12weeks with ex vivo contrast enhanced μCT and histology to measure sulfated-glycosaminoglycan (sGAG) content and cartilage thickness. ALN treatment successfully inhibited subchondral bone remodeling. As a result we found less subchondral plate porosity and reduced osteophytosis. ALN treatment did not reduce subchondral sclerosis. However, after the OA induction phase, ALN treatment protected cartilage ECM from degradation and reduced synovial macrophage activation. Surprisingly, ALN treatment also improved sGAG content of tibia cartilage in healthy joints. Our data was consistent with the hypothesis that osteoclastic bone resorption might play an important role in OA and may be a driving force for progression of the disease. However, our study suggest that this effect might not solely be effects on osteoclastic activity, since ALN treatment also influenced macrophage functioning. Additionally, ALN treatment and physical activity

The association of adherence to osteoporosis therapies with fracture, all-cause medical costs, and all-cause hospitalizations: a retrospective claims analysis of female health plan enrollees with osteoporosis.

PubMed

Halpern, Rachel; Becker, Laura; Iqbal, Sheikh Usman; Kazis, Lewis E; Macarios, David; Badamgarav, Enkhjargal

2011-01-01

Osteoporosis affects approximately 10 million people in the United States and is associated with increased fracture risk and fracture-related costs. Poor adherence to osteoporosis medications is associated with higher general burden of illness compared with optimal adherence. To examine the associations of adherence to osteoporosis therapies with (a) occurrence of closed fracture, (b) all-cause medical costs, and (c) all-cause hospitalizations. This retrospective analysis of administrative claims data examined women with osteoporosis initiating therapy with alendronate, risedronate, ibandronate, or raloxifene from July 1, 2002, to March 10, 2006. Data were from a large, geographically diverse U.S. health plan that covered about 12.6 million females during the identification period. Commercially insured and Medicare Advantage plan enrollees were observed for 1 year before (baseline period) and 540 days after therapy initiation (follow-up period). Outcomes included closed fractures, all-cause medical costs, and all-cause hospitalizations; all outcomes were measured starting 180 days after therapy initiation through follow-up. All subjects had at least 2 pharmacy claims for any of the targeted osteoporosis medications. Adherence was measured with a medication possession ratio (MPR) and accounted for all osteoporosis treatment. High adherence was MPR of at least 0.80; low adherence was MPR less than 0.50. Covariates included baseline fracture, "early" fracture (in the first 180 days of follow-up), baseline corticosteroid or thyroid hormone use, health status indicators, and demographic characteristics. Outcome fractures were modeled with Cox survival regression with time-dependent cumulative MPR. All-cause medical costs and all-cause hospitalizations were modeled, respectively, with generalized linear model regression (gamma distribution, log link) and negative binomial regression. The sample comprised 21,655 patients--16,295 (75.2%) commercial and 5,360 (24

Bisphosphonates Improve Trabecular Bone Mass and Normalize Cortical Thickness in Ovariectomized, Osteoblast Connexin43 Deficient Mice

PubMed Central

Watkins, Marcus P.; Norris, Jin Yi; Grimston, Susan K.; Zhang, Xiaowen; Phipps, Roger J.; Ebetino, Frank H.; Civitelli, Roberto

2012-01-01

The gap junction protein, connexin43 (Cx43) controls both bone formation and osteoclastogenesis via osteoblasts and/or osteocytes. Cx43 has also been proposed to mediate an anti-apoptotic effect of bisphosphonates, potent inhibitors of bone resorption. We studied whether bisphosphonates are effective in protecting mice with a conditional Cx43 gene deletion in osteoblasts and osteocytes (cKO) from the consequences of ovariectomy on bone mass and strength. Ovariectomy resulted in rapid loss of trabecular bone followed by a slight recovery in wild type (WT) mice, and a similar degree of trabecular bone loss, albeit slightly delayed, occurred in cKO mice. Treatment with either risedronate (20µg/kg) or alendronate (40µg/kg) prevented ovariectomy-induced bone loss in both genotypes. In basal conditions, bones of cKO mice have larger marrow area, higher endocortical osteoclast number, and lower cortical thickness and strength relative to WT. Ovariectomy increased endocortical osteoclast number in WT but not in cKO mice. Both bisphosphonates prevented these increases in WT mice, and normalized endocortical osteoclast number, cortical thickness and bone strength in cKO mice. Thus, lack of osteoblast/osteocyte Cx43 does not alter bisphosphonate action on bone mass and strength in estrogen deficiency. These results support the notion that one of the main functions of Cx43 in cortical bone is to restrain osteoblast and/or osteocytes from inducing osteoclastogenesis at the endocortical surface. PMID:22750450

Gateways to Clinical Trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2002-09-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Adalimumab, aeroDose insulin inhaler, agomelatine, alendronic acid sodium salt, aliskiren fumarate, alteplase, amlodipine, aspirin, atazanavir; Bacillus Calmette-Guérin, basiliximab, BQ-788, bupropion hydrochloride; Cabergoline, caffeine citrate, carbamazepine, carvedilol, celecoxib, cyclosporine, clopidogrel hydrogensulfate, colestyramine; Dexamethasone, diclofenac sodium, digoxin, dipyridamole, docetaxel, dutasteride; Eletriptan, enfuvirtidie, eplerenone, ergotamine tartrate, esomeprazole magnesium, estramustine phosphate sodium; Finasteride, fluticasone propionate, fosinopril sodium; Ganciclovir, GBE-761-ONC, glatiramer acetate, gliclazide, granulocyte-CSF; Heparin sodium, human isophane insulin (pyr), Hydrochlorothiazide; Ibuprofen, inhaled insulin, interferon alfa, interferon beta-1a; Laminvudine, lansoprazole, lisinopril, lonafarnib, losartan potassium, lumiracoxib; MAb G250, meloxicam methotrexate, methylprednisolone aceponate, mitomycin, mycophenolate mofetil; Naproxen sodium, natalizumab, nelfinavir mesilate, nemifitide ditriflutate, nimesulide; Omalizumab, omapatrilat, omeprazole, oxybutynin chloride; Pantoprazole sodium, paracetamol, paroxetine, pentoxifylline, pergolide mesylate, permixon, phVEGF-A165, pramipexole hydrochloride, prasterone, prednisone, probucol, propiverine hydrochloride; Rabeprazole sodium, resiniferatoxin, risedronate sodium, risperidone, rofecoxib rosiglitazone maleate, ruboxistaurin mesilate hydrate; Selegiline transdermal system, sertraline, sildenafil citrate, streptokinase; Tadalafil, tamsulosin hydrochloride, technosphere/Insulin, tegaserod maleate, tenofovir disoproxil

Tc-99m Radiolabeled Alendronate Sodium Microemulsion: Characterization and Permeability Studies Across Caco-2 Cells.

PubMed

Elitez, Yetkin; Ekinci, Meliha; Ilem-Ozdemir, Derya; Gundogdu, Evren; Asikoglu, Makbule

2018-01-01

Alendronate sodium (ALD) is used orally but it is poorly absorbed from the gastrointestinal (GI) tract. For this reason, microemulsion system was chosen to evaluate ALD from the GI tract after oral delivery. This study was aimed to prepare water-in-oil (w/o) microemulsion formulation of ALD and evaluate the permeability of ALD microemulsion from Caco-2 cell lines with radioactive and nonradioactive studies. The ALD microemulsion was developed by using pseudo-ternary phase diagram and composed of Soybean oil, Colliphor EL, Tween 80, Transcutol and distilled water. The prepared ALD microemulsion was characterized by physical appearance, droplet size, viscosity, pH, electrical conductivity and refractive index. The stability of the formulation was investigated for 6 months at 25±2°C/60±5% of relative humidity (RH) as well as at 40±2°C/75±5% RH. After that 1 mg of ALD was radiolabeled with 99mTc and added to microemulsion. The permeability studies were performed with both 99mTc-ALD microemulsion and ALD microemulsion. The experimental results suggested that ALD microemulsion presented adequate stability with droplet size varying from 37.8±0.9 to 39.9±1.2 nm during incubation time. In addition, ALD microemulsion was radiolabeled with high labeling efficiency (>95%). In a non-radioactive study, ALD permeability was found to be 45 µg.mL-1 and microemulsion has high permeability percentage when compared to another study. The novel w/o microemulsion formulation has been developed for oral delivery of ALD. Based on the results, permeability of ALD could be significantly improved by the microemulsion formulation. In addition, 99mTc-ALD microemulsion in capsule can be used for bone disease treatment and diagnosis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Effects of adding alendronate to ongoing hormone therapy on bone mineral density in postmenopausal Korean women: a randomized, double-blind, placebo-controlled clinical trial.

PubMed

Min, Yong-Ki; Lee, Dong-Yun; Choi, Suk-Joo; Kim, Joo Han; Choi, DooSeok; Yoon, Byung-Koo

2013-07-01

This study was conducted to evaluate the effects of adding the bisphosphonate alendronate (ALEN) to ongoing hormone therapy (HT) on bone mineral density (BMD) in postmenopausal Korean women. This randomized, double-blind, placebo-controlled clinical trial at a university hospital included a total of 139 postmenopausal women who had low BMD after HT lasting at least 1 year. Women received either ALEN (10 mg/d) or placebo in combination with HT for 1 year. Changes in BMD and biochemical markers of bone turnover were evaluated. Lumbar spine and total hip BMDs increased significantly in both treatment groups after 1 year. The addition of ALEN, when compared with HT alone, did not produce a significant change in BMD at the lumbar spine (3.7% vs 4.3%) and total hip (2.2% vs 3.2%) after adjusting for controllable variables. Serum osteocalcin showed a similar change, but urinary deoxypyridinoline response differed between treatment groups. Compared with HT alone, the addition of ALEN to ongoing HT for 1 year does not make a difference in BMD among postmenopausal Korean women with low BMD.

Role of 1% alendronate gel as adjunct to mechanical therapy in the treatment of chronic periodontitis among smokers.

PubMed

Sharma, Anuj; Raman, Achala; Pradeep, Avani Raju

2017-01-01

Alendronate (ALN) inhibits osteoclastic bone resorption and triggers osteostimulative properties both in vivo and in vitro, as shown by increase in matrix formation. This study aimed to explore the efficacy of 1% ALN gel as local drug delivery (LDD) in adjunct to scaling and root planing (SRP) for the treatment of chronic periodontitis among smokers. 75 intrabony defects were treated in 46 male smokers either with 1% ALN gel or placebo gel. ALN gel was prepared by adding ALN into carbopol-distilled water mixture. Clinical parameters [modified sulcus bleeding index, plaque index, probing depth (PD), and periodontal attachment level (PAL)] were recorded at baseline, at 2 months, and at 6 months, while radiographic parameters were recorded at baseline and at 6 months. Defect fill at baseline and at 6 months was calculated on standardized radiographs by using the image analysis software. Mean PD reduction and mean PAL gain were found to be greater in the ALN group than in the placebo group, both at 2 and 6 months. Furthermore, a significantly greater mean percentage of bone fill was found in the ALN group (41.05±11.40%) compared to the placebo group (2.5±0.93%). The results of this study showed 1% ALN stimulated a significant increase in PD reduction, PAL gain, and an improved bone fill compared to placebo gel in chronic periodontitis among smokers. Thus, 1% ALN, along with SRP, is effective in the treatment of chronic periodontitis in smokers.

In Vitro and In Vivo Evaluation of Commercially Available Fibrin Gel as a Carrier of Alendronate for Bone Tissue Engineering.

PubMed

Kim, Beom Su; Shkembi, Feride; Lee, Jun

2017-01-01

Alendronate (ALN) is a bisphosphonate drug that is widely used for the treatment of osteoporosis. Furthermore, local delivery of ALN has the potential to improve the bone regeneration. This study was designed to investigate an ALN-containing fibrin (fibrin/ALN) gel and evaluate the effect of this gel on both in vitro cellular behavior using human mesenchymal stem cells (hMSCs) and in vivo bone regenerative capacity. Fibrin hydrogels were fabricated using various ALN concentrations (10 -7 -10 -4  M) with fibrin glue and the morphology, mechanical properties, and ALN release kinetics were characterized. Proliferation and osteogenic differentiation of and cytotoxicity in fibrin/ALN gel-embedded hMSCs were examined. In vivo bone formation was evaluated using a rabbit calvarial defect model. The fabricated fibrin/ALN gel was transparent with Young's modulus of ~13 kPa, and these properties were not affected by ALN concentration. The in vitro studies showed sustained release of ALN from the fibrin gel and revealed that hMSCs cultured in fibrin/ALN gel showed significantly increased proliferation and osteogenic differentiation. In addition, microcomputed tomography and histological analysis revealed that the newly formed bone was significantly enhanced by implantation of fibrin/ALN gel in a calvarial defect model. These results suggest that fibrin/ALN has the potential to improve bone regeneration.

In Vitro and In Vivo Evaluation of Commercially Available Fibrin Gel as a Carrier of Alendronate for Bone Tissue Engineering

PubMed Central

Kim, Beom Su; Shkembi, Feride

2017-01-01

Alendronate (ALN) is a bisphosphonate drug that is widely used for the treatment of osteoporosis. Furthermore, local delivery of ALN has the potential to improve the bone regeneration. This study was designed to investigate an ALN-containing fibrin (fibrin/ALN) gel and evaluate the effect of this gel on both in vitro cellular behavior using human mesenchymal stem cells (hMSCs) and in vivo bone regenerative capacity. Fibrin hydrogels were fabricated using various ALN concentrations (10−7–10−4 M) with fibrin glue and the morphology, mechanical properties, and ALN release kinetics were characterized. Proliferation and osteogenic differentiation of and cytotoxicity in fibrin/ALN gel-embedded hMSCs were examined. In vivo bone formation was evaluated using a rabbit calvarial defect model. The fabricated fibrin/ALN gel was transparent with Young's modulus of ~13 kPa, and these properties were not affected by ALN concentration. The in vitro studies showed sustained release of ALN from the fibrin gel and revealed that hMSCs cultured in fibrin/ALN gel showed significantly increased proliferation and osteogenic differentiation. In addition, microcomputed tomography and histological analysis revealed that the newly formed bone was significantly enhanced by implantation of fibrin/ALN gel in a calvarial defect model. These results suggest that fibrin/ALN has the potential to improve bone regeneration. PMID:28210623

The hydrogen sulfide donor, Lawesson's reagent, prevents alendronate-induced gastric damage in rats

PubMed Central

Nicolau, L.A.D.; Silva, R.O.; Damasceno, S.R.B.; Carvalho, N.S.; Costa, N.R.D.; Aragão, K.S.; Barbosa, A.L.R.; Soares, P.M.G.; Souza, M.H.L.P.; Medeiros, J.V.R.

2013-01-01

Our objective was to investigate the protective effect of Lawesson's reagent, an H2S donor, against alendronate (ALD)-induced gastric damage in rats. Rats were pretreated with saline or Lawesson's reagent (3, 9, or 27 µmol/kg, po) once daily for 4 days. After 30 min, gastric damage was induced by ALD (30 mg/kg) administration by gavage. On the last day of treatment, the animals were killed 4 h after ALD administration. Gastric lesions were measured using a computer planimetry program, and gastric corpus pieces were assayed for malondialdehyde (MDA), glutathione (GSH), proinflammatory cytokines [tumor necrosis factor (TNF)-α and interleukin (IL)-1β], and myeloperoxidase (MPO). Other groups were pretreated with glibenclamide (5 mg/kg, ip) or with glibenclamide (5 mg/kg, ip)+diazoxide (3 mg/kg, ip). After 1 h, 27 µmol/kg Lawesson's reagent was administered. After 30 min, 30 mg/kg ALD was administered. ALD caused gastric damage (63.35±9.8 mm2); increased levels of TNF-α, IL-1β, and MDA (2311±302.3 pg/mL, 901.9±106.2 pg/mL, 121.1±4.3 nmol/g, respectively); increased MPO activity (26.1±3.8 U/mg); and reduced GSH levels (180.3±21.9 µg/g). ALD also increased cystathionine-γ-lyase immunoreactivity in the gastric mucosa. Pretreatment with Lawesson's reagent (27 µmol/kg) attenuated ALD-mediated gastric damage (15.77±5.3 mm2); reduced TNF-α, IL-1β, and MDA formation (1502±150.2 pg/mL, 632.3±43.4 pg/mL, 78.4±7.6 nmol/g, respectively); lowered MPO activity (11.7±2.8 U/mg); and increased the level of GSH in the gastric tissue (397.9±40.2 µg/g). Glibenclamide alone reversed the gastric protective effect of Lawesson's reagent. However, glibenclamide plus diazoxide did not alter the effects of Lawesson's reagent. Our results suggest that Lawesson's reagent plays a protective role against ALD-induced gastric damage through mechanisms that depend at least in part on activation of ATP-sensitive potassium (KATP) channels. PMID:23969974

Do estrogen and alendronate improve metaphyseal fracture healing when applied as osteoporosis prophylaxis?

PubMed

Kolios, Leila; Hoerster, Ann Kristin; Sehmisch, Stephan; Malcherek, Marie Christin; Rack, Thomas; Tezval, Mohammed; Seidlova-Wuttke, Dana; Wuttke, Wolfgang; Stuermer, Klaus Michael; Stuermer, Ewa Klara

2010-01-01

Osteoporosis is accompanied by predominantly metaphyseal fractures with a delayed and qualitatively reduced healing process. This study addressed the question of whether fracture healing in the context of osteoporosis prophylaxis is improved with estrogen (E) or alendronate (ALN). Thirty-six ovariectomized and 12 sham-operated 12-week-old rats received soy-free (osteoporotic C, sham), E-, or ALN- supplemented diets. After 10 weeks, a metaphyseal tibia osteotomy and standardized T-plate fixation were performed. After a 5-week healing process, the fracture callus was evaluated qualitatively by biomechanical bending test and quantitatively in microradiographic sections. The time course of callus formation was examined using fluorochrome-labeled histological sections. Administration of E improved the biomechanical properties of callus (stiffness [N/mm]: sham: 110.2 + or - 76.07, C: 41.28 + or - 33.70, E: 85.72 + or - 47.24, ALN: 72.07 + or - 34.68). The resistance to microfracturing seen in E-treated animals was significantly enhanced and even superior to sham (yield load [N] sham: 27.44 + or - 9.72, C: 21.04 + or - 12.47, E: 42.85 + or - 13.74(Delta), ALN: 25.28 + or - 6.4(.)) (* P < 0.05 vs. sham group, (Delta) P < 0.05 vs. C group, (*) P < 0.05 vs. E group). Trabecular bone in particular was improved, indicating the presence of physiological endosteal bridging (Tr.Dn [%] sham: 10.53 + or - 18.9, C: 1.01 + or - 0.14, E: 24.13 + or - 34.09(Delta), ALN: 3.99 + or - 8.3(.)). ALN did not help bone healing, as shown by mechanical tests. Compared to the C group, statistically, ALN did not show worse properties. The induction of callus formation under ALN treatment was slightly delayed (Tt.Cl [mm(2)] sham: 3.68 + or - 0.66, C: 3.44 + or - 0.42, E: 3.69 + or - 0.58, ALN: 3.06 + or - 0.56). Osteoporotic metaphyseal fracture healing was qualitatively and quantitatively improved by E prophylaxis. The process of fracture healing occurred nearly physiologically (shamlike

Effect of 1% sodium alendronate in the non-surgical treatment of periodontal intraosseous defects: a 6-month clinical trial

PubMed Central

DUTRA, Bernardo Carvalho; OLIVEIRA, Alcione Maria Soares Dutra; OLIVEIRA, Peterson Antônio Dutra; MANZI, Flavio Ricardo; CORTELLI, Sheila Cavalca; COTA, Luís Otávio de Miranda; COSTA, Fernando Oliveira

2017-01-01

Abstract Background and objectives Few studies have evaluated the effect of the topical application of sodium alendronate (ALN) on the treatment of intrabuccal bone defects, especially those caused by periodontitis. This 6-month randomized placebo controlled clinical trial aimed at evaluating the effect of non-surgical periodontal treatment associated with the use of 1% ALN, through clinical evaluations and cone-beam computed tomography (CBCT). Material and Methods Twenty individuals with chronic periodontitis underwent periodontal examination at the baseline as well as 3 and 6 months after periodontal treatment, registering clinical attachment level (CAL), periodontal probing depth (PPD), and bleeding on probing (BOP) as the clinical outcomes. After manual scaling and root planing, 40 bilateral sites with interproximal vertical bone defects were randomly treated with either 1% ALN gel or a placebo. Bone defects were evaluated through CBCT at the baseline and 6 months post-treatment. The clinical and CBCT parameters were compared using the Wilcoxon and Friedman tests (p<0.05). Results Although ALN produced a greater CAL gain when compared to the placebo at 6 months post-treatment (p=0.021), both treatments produced similar effects on the PPD, BOP, and bone height. Significant differences in bone fill were observed only in patients of the ALN group (4.5 to 3.8 mm; p=0.003) at 6 months post-treatment. Conclusions Topical application of 1% ALN might be a beneficial adjuvant to non-surgical periodontal therapy. PMID:28678950

Role of 1% alendronate gel as adjunct to mechanical therapy in the treatment of chronic periodontitis among smokers

PubMed Central

SHARMA, Anuj; RAMAN, Achala; PRADEEP, Avani Raju

2017-01-01

Abstract Objective Alendronate (ALN) inhibits osteoclastic bone resorption and triggers osteostimulative properties both in vivo and in vitro, as shown by increase in matrix formation. This study aimed to explore the efficacy of 1% ALN gel as local drug delivery (LDD) in adjunct to scaling and root planing (SRP) for the treatment of chronic periodontitis among smokers. Material and Methods 75 intrabony defects were treated in 46 male smokers either with 1% ALN gel or placebo gel. ALN gel was prepared by adding ALN into carbopol-distilled water mixture. Clinical parameters [modified sulcus bleeding index, plaque index, probing depth (PD), and periodontal attachment level (PAL)] were recorded at baseline, at 2 months, and at 6 months, while radiographic parameters were recorded at baseline and at 6 months. Defect fill at baseline and at 6 months was calculated on standardized radiographs by using the image analysis software. Results Mean PD reduction and mean PAL gain were found to be greater in the ALN group than in the placebo group, both at 2 and 6 months. Furthermore, a significantly greater mean percentage of bone fill was found in the ALN group (41.05±11.40%) compared to the placebo group (2.5±0.93%). Conclusions The results of this study showed 1% ALN stimulated a significant increase in PD reduction, PAL gain, and an improved bone fill compared to placebo gel in chronic periodontitis among smokers. Thus, 1% ALN, along with SRP, is effective in the treatment of chronic periodontitis in smokers. PMID:28678942

Alendronate and Resistive Exercise Countermeasures Against Bed Rest-Induced Bone Loss: Biochemical Markers of Bone and Calcium Metabolism

NASA Technical Reports Server (NTRS)

Smith, Scott M.; Nillen, Jeannie L.; Davis-Street, Janis E.; DeKerlegand, Diane E.; LeBlanc, Adrian; Shackelford, Linda C.

2001-01-01

Weightlessness-induced bone loss must be counteracted to ensure crew health during extendedduration space missions. Studies were conducted to assess two bone loss countermeasures in a ground-based model: horizontal bed rest. Following a 3-wk ambulatory adaptation period, male and female subjects (aged 21-56 y) completed a 17-wk bed rest protocol. Subjects were assigned to one of three treatments: alendronate (ALEN; 10 mg/d, n=6), resistive exercise (RE; 1.5 h/d, 6 d/wk, n=8), or control (CN; no countermeasure, n=8). Dietary intake was adjusted to maintain body weight. Endocrine and biochemical indices were measured in blood and urine using standard laboratory methods. All data reported are expressed as percent change from individual pre-bedrest data. Serum calcium changed little during bed rest, and tended to decrease (4-8%) in ALEN subjects. In RE subjects, bone alkaline phosphatase and osteocalcin were increased >65 and >30%, respectively, during bed rest, while these were unchanged or decreased in ALEN and CN subjects. Urinary calcium was increased 50% in CN subjects, but was unchanged or decreased in both ALEN and RE groups. Urinary n-telopeptide excretion was increased 40-50% in CN and RE subjects, but decreased 20% in ALEN subjects. Pyridinium crosslink and deoxypyridinoline excretion were increased 20-50% during bed rest. These data suggest that RE countermeasures are effective at increasing markers of bone formation in an analog of weightlessness, while ALEN reduces markers of bone resorption. Counteracting the bone loss of space flight may require both pharmacologic and exercise countermeasures.

Novel Methods of Determining Urinary Calculi Composition: Petrographic Thin Sectioning of Calculi and Nanoscale Flow Cytometry Urinalysis

PubMed Central

Gavin, Carson T; Ali, Sohrab N; Tailly, Thomas; Olvera-Posada, Daniel; Alenezi, Husain; Power, Nicholas E; Hou, Jinqiang; St. Amant, Andre H; Luyt, Leonard G; Wood, Stephen; Wu, Charles; Razvi, Hassan; Leong, Hon S

2016-01-01

Accurate determination of urinary stone composition has significant bearing on understanding pathophysiology, choosing treatment modalities and preventing recurrence. A need exists for improved methods to determine stone composition. Urine of 31 patients with known renal calculi was examined with nanoscale flow cytometry and the calculi collected during surgery subsequently underwent petrographic thin sectioning with polarized and fluorescent microscopy. Fluorescently labeled bisphosphonate probes (Alendronate-fluorescein/Alendronate-Cy5) were developed for nanoscale flow cytometry to enumerate nanocrystals that bound the fluorescent probes. Petrographic sections of stones were also imaged by fluorescent and polarized light microscopy with composition analysis correlated to alendronate +ve nanocrystal counts in corresponding urine samples. Urine samples from patients with Ca2+ and Mg2+ based calculi exhibited the highest alendronate +ve nanocrystal counts, ranging from 100–1000 nm in diameter. This novel urine based assay was in agreement with composition determined by petrographic thin sections with Alendronate probes. In some cases, high alendronate +ve nanocrystal counts indicated a Ca2+ or Mg2+ composition, as confirmed by petrographic analysis, overturning initial spectrophotometric diagnosis of stone composition. The combination of nanoscale flow cytometry and petrographic thin sections offer an alternative means for determining stone composition. Nanoscale flow cytometry of alendronate +ve nanocrystals alone may provide a high-throughput means of evaluating stone burden. PMID:26771074

The resistance of cortical bone tissue to failure under cyclic loading is reduced with alendronate.

PubMed

Bajaj, Devendra; Geissler, Joseph R; Allen, Matthew R; Burr, David B; Fritton, J C

2014-07-01

Bisphosphonates are the most prescribed preventative treatment for osteoporosis. However, their long-term use has recently been associated with atypical fractures of cortical bone in patients who present with low-energy induced breaks of unclear pathophysiology. The effects of bisphosphonates on the mechanical properties of cortical bone have been exclusively studied under simple, monotonic, quasi-static loading. This study examined the cyclic fatigue properties of bisphosphonate-treated cortical bone at a level in which tissue damage initiates and is accumulated prior to frank fracture in low-energy situations. Physiologically relevant, dynamic, 4-point bending applied to beams (1.5 mm × 0.5 mm × 10 mm) machined from dog rib (n=12/group) demonstrated mechanical failure and micro-architectural features that were dependent on drug dose (3 groups: 0, 0.2, 1.0mg/kg/day; alendronate [ALN] for 3 years) with cortical bone tissue elastic modulus (initial cycles of loading) reduced by 21% (p<0.001) and fatigue life (number of cycles to failure) reduced in a stress-life approach by greater than 3-fold with ALN1.0 (p<0.05). While not affecting the number of osteons, ALN treatment reduced other features associated with bone remodeling, such as the size of osteons (-14%; ALN1.0: 10.5±1.8, VEH: 12.2±1.6, ×10(3) μm2; p<0.01) and the density of osteocyte lacunae (-20%; ALN1.0: 11.4±3.3, VEH: 14.3±3.6, ×10(2) #/mm2; p<0.05). Furthermore, the osteocyte lacunar density was directly proportional to initial elastic modulus when the groups were pooled (R=0.54, p<0.01). These findings suggest that the structural components normally contributing to healthy cortical bone tissue are altered by high-dose ALN treatment and contribute to reduced mechanical properties under cyclic loading conditions. Copyright © 2014 Elsevier Inc. All rights reserved.

Heel Ultrasound Can Assess Maintenance of Bone Mass in Women with Breast Cancer

PubMed Central

Langmann, Gabrielle A.; Vujevich, Karen T.; Medich, Donna; Miller, Megan E.; Perera, Subashan; Greenspan, Susan L.

2016-01-01

Postmenopausal women with early-stage breast cancer are at increased risk for bone loss and fractures. Bisphosphonates can prevent bone loss, but little data are available on changes in bone mass assessed by heel quantitative ultrasound (QUS). Our objectives were to determine if (1) heel QUS would provide a reliable and accessible method for evaluation of changes in bone mass in women with breast cancer as compared to the current standard of bone mass measurement, dual-energy x-ray absorptiometry (DXA), and (2) oral risedronate could affect these changes. Eighty-six newly postmenopausal (up to 8 years) women with nonmetastatic breast cancer were randomized to risedronate, 35 mg once weekly or placebo. Outcomes were changes in heel QUS bone mass measurements and conventional dual-energy x-ray absorptiometry (DXA) derived bone mineral density (BMD). Over 2 years, bone mass assessed by heel QUS remained stable in women on risedronate, while women on placebo had a 5.2% decrease (p ≤ 0.05) in heel QUS bone mass. Both total hip BMD and femoral neck BMD assessed by DXA decreased by 1.6% (p ≤ 0.05) in the placebo group and remained stable with risedronate. Spine BMD remained stable in both groups. Heel QUS was moderately associated with BMD measured by DXA at the total hip (r = 0.50), femoral neck (r = 0.40), and spine (r = 0.46) at baseline (all p ≤ 0.001). In conclusion, risedronate helps to maintain skeletal integrity as assessed by heel QUS for women with early-stage breast cancer. Heel QUS is associated with DXA-derived BMD at other major axial sites and may be used to follow skeletal health and bone mass changes in these women. PMID:22425507

Enhanced anti-tumor activity and safety profile of targeted nano-scaled HPMA copolymer-alendronate-TNP-470 conjugate in the treatment of bone malignances

PubMed Central

Segal, Ehud; Pan, Huaizhong; Benayoun, Liat; Kopečková, Pavla; Shaked, Yuval; Kopeček, Jindčrich; Satchi-Fainaro, Ronit

2015-01-01

Bone neoplasms, such as osteosarcoma, exhibit a propensity for systemic metastases resulting in adverse clinical outcome. Traditional treatment consisting of aggressive chemotherapy combined with surgical resection, has been the mainstay of these malignances. Therefore, bone-targeted non-toxic therapies are required. We previously conjugated the aminobisphosphonate alendronate (ALN), and the potent anti-angiogenic agent TNP-470 with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. HPMA copolymer-ALN-TNP-470 conjugate exhibited improved anti-angiogenic and anti-tumor activity compared with the combination of free ALN and TNP-470 when evaluated in a xenogeneic model of human osteosarcoma. The immune system has major effect on toxicology studies and on tumor progression. Therefore, in this manuscript we examined the safety and efficacy profiles of the conjugate using murine osteosarcoma syngeneic model. Toxicity and efficacy evaluation revealed superior anti-tumor activity and decreased organ-related toxicities of the conjugate compared with the combination of free ALN plus TNP-470. Finally, comparative anti-angiogenic activity and specificity studies, using surrogate biomarkers of circulating endothelial cells (CEC), highlighted the advantage of the conjugate over the free agents. The therapeutic platform described here may have clinical translational relevance for the treatment of bone-related angiogenesis-dependent malignances. PMID:21429572

Oral bisphosphonates do not increase the risk of severe upper gastrointestinal complications: a nested case–control study

PubMed Central

2014-01-01

Background Data on the effect of oral bisphosphonates (BPs) on risk of upper gastrointestinal complications (UGIC) are conflicting. We conducted a large population-based study from a network of Italian healthcare utilization databases aimed to assess the UGIC risk associated with use of BPs in the setting of secondary prevention of osteoporotic fractures. Methods A nested case–control study was carried out within a cohort of 68,970 patients aged 45 years or older, who have been hospitalized for osteoporotic fracture from 2003 until 2005. Cases were the 804 patients who experienced hospitalization for UGIC until 2007. Up to 20 controls were randomly selected for each case. Conditional logistic regression model was used to estimate odds ratio (OR) associated with current and past use of BPs (i.e. for drug dispensation within 30 days and over 31 days prior the outcome onset, respectively) after adjusting for several covariates. Results Compared with patients who did not use BPs, current and past users had OR (and 95% confidence interval) of 0.86 (0.60 to 1.22) and 1.07 (0.80 to 1.44) respectively. There was no difference in the ORs estimated according with BPs type (alendronate or risedronate) and regimen (daily or weekly), nor with co-therapies and comorbidities. Conclusions Further evidence that BPs dispensed for secondary prevention of osteoporotic fractures are not associated with increased risk of severe gastrointestinal complications is supplied from this study. Further research is required to clarify the role BPs and other drugs of co-medication in inducing UGIC. PMID:24397769

Peri-implant and systemic effects of high-/low-affinity bisphosphonate-hydroxyapatite composite coatings in a rabbit model with peri-implant high bone turnover

PubMed Central

2012-01-01

Background Hydroxyapatite (HA) coatings composed with bisphosphonates (BPs) which have high mineral-binding affinities have been confirmed to successfully enhance implant stability. However, few previous studies focused on HA coatings composed with low-affinity BPs or on systemic effects of locally released BPs. Methods In this long-term study, we developed two kinds of BP-HA composite coatings using either high-affinity BP (alendronate, ALN) or low-affinity BP (risedronate, RIS). Thirty-six rabbits were divided into three groups according to different coating applications (group I: HA, group II: ALN-HA, and group III: RIS-HA). Implants were inserted into the proximal region of the medullary cavity of the left tibiay. At insertion, 2 × 108 wear particles were injected around implants to induce a peri-implant high bone turnover environment. Both local (left tibias) and systemic (right tibias and lumbar vertebrae) inhibitory effect on bone resorption were compared, including bone-implant integration, bone architecture, bone mineral density (BMD), implant stability, and serum levels of bone turnover markers. Results The results indicated that ALN-HA composite coating, which could induce higher bone-implant contact (BIC) ratio, bone mass augmentation, BMD, and implant stability in the peri-implant region, was more potent on peri-implant bone, while RIS-HA composite coating, which had significant systemic effect, was more potent on non-peri-implant bone, especially lumbar vertebrae. Conclusions It is instructive and meaningful to further clinical studies that we could choose different BP-HA composite coatings according to the patient’s condition. PMID:22686414

Exercise and pharmacological countermeasures for bone loss during long-duration space flight.

PubMed

Cavanagh, Peter R; Licata, Angelo A; Rice, Andrea J

2005-06-01

Bone loss in the lower extremities and lumbar spine is an established consequence of long-duration human space flight. Astronauts typically lose as much bone mass in the proximal femur in 1 month as postmenopausal women on Earth lose in 1 year. Pharmacological interventions have not been routinely used in space, and countermeasure programs have depended solely upon exercise. However, it is clear that the osteogenic stimulus from exercise has been inadequate to maintain bone mass, due to insufficient load or duration. Attention has therefore been focused on several pharmacological interventions that have been successful in preventing or attenuating osteoporosis on Earth. Anti-resorptives are the class of drugs most commonly used to treat osteoporosis in postmenopausal women, notably alendronate sodium, risedronate sodium, zoledronic acid, and selective estrogen receptor modulators, such as raloxifene. There has also been considerable recent interest in anabolic agents such as parathyroid hormone (PTH) and teriparatide (rhPTH [1-34]). Vitamin D and calcium supplementation have also been used. Recent studies of kindreds with abnormally high bone mineral density have provided insight into the genetic regulation of bone mass. This has led to potential therapeutic interventions based on the LRP5, Wnt and BMP2 pathways. Another target is the RANK-L/osteoprotegerin signaling pathway, which influences bone turnover by regulating osteoclast formation and maturation. Trials using such therapies in space are being planned. Among the factors to be considered are dose-response relationships, bone quality, post-use recovery, and combination therapies--all of which may have unique characteristics when the drugs are used in space.

New approaches to pharmacological treatment of osteoporosis.

PubMed Central

Akesson, Kristina

2003-01-01

Osteoporosis has been recognized as a major public health problem for less than two decades. The increasing incidence of fragility fractures, such as vertebral, hip, and wrist fractures, first became apparent from epidemiological studies in the early and mid-1980s, when effective treatment was virtually unavailable. Pharmacological therapies that effectively reduce the number of fractures by improving bone mass are now available widely in countries around the world. Most current agents inhibit bone loss by reducing bone resorption, but emerging therapies may increase bone mass by directly promoting bone formation--as is the case with parathyroid hormone. Current treatment alternatives include bisphosphonates, calcitonin, and selective estrogen receptor modulators, but sufficient calcium and vitamin D are a prerequisite. The availability of evidence-based data that show reductions in the incidence of fractures of 30-50% during treatment has been a major step forward in the pharmacological prevention of fractures. With all agents, fracture reduction is most pronounced for vertebral fracture in high-risk individuals; alendronate and risedronate also may protect against hip fracture in the elderly. New approaches to pharmacological treatment will include further development of existing drugs, especially with regard to tolerance and frequency of dosing. New avenues for targeting the condition will emerge as our knowledge of the regulatory mechanisms of bone remodelling increases, although issues of tissue specificity may be difficult to solve. In the long term, information gained through knowledge of bone genetics may be used to adapt pharmacological treatments more precisely to each individual. PMID:14710507

Exercise and pharmacological countermeasures for bone loss during long-duration space flight

NASA Technical Reports Server (NTRS)

Cavanagh, Peter R.; Licata, Angelo A.; Rice, Andrea J.

2005-01-01

Bone loss in the lower extremities and lumbar spine is an established consequence of long-duration human space flight. Astronauts typically lose as much bone mass in the proximal femur in 1 month as postmenopausal women on Earth lose in 1 year. Pharmacological interventions have not been routinely used in space, and countermeasure programs have depended solely upon exercise. However, it is clear that the osteogenic stimulus from exercise has been inadequate to maintain bone mass, due to insufficient load or duration. Attention has therefore been focused on several pharmacological interventions that have been successful in preventing or attenuating osteoporosis on Earth. Anti-resorptives are the class of drugs most commonly used to treat osteoporosis in postmenopausal women, notably alendronate sodium, risedronate sodium, zoledronic acid, and selective estrogen receptor modulators, such as raloxifene. There has also been considerable recent interest in anabolic agents such as parathyroid hormone (PTH) and teriparatide (rhPTH [1-34]). Vitamin D and calcium supplementation have also been used. Recent studies of kindreds with abnormally high bone mineral density have provided insight into the genetic regulation of bone mass. This has led to potential therapeutic interventions based on the LRP5, Wnt and BMP2 pathways. Another target is the RANK-L/osteoprotegerin signaling pathway, which influences bone turnover by regulating osteoclast formation and maturation. Trials using such therapies in space are being planned. Among the factors to be considered are dose-response relationships, bone quality, post-use recovery, and combination therapies--all of which may have unique characteristics when the drugs are used in space.

Effects of combined elcatonin and alendronate treatment on the architecture and strength of bone in ovariectomized rats.

PubMed

Ogawa, Koko; Hori, Masayuki; Takao, Ryoko; Sakurada, Toyozo

2005-01-01

We examined the combined effects of elcatonin (ECT) and alendronate (ALN) on bone mass, architecture, and strength in ovariectomized (OVX) rats. Fifty female Sprague Dawley rats, aged 13 weeks, were divided into Sham, OVX, OVX+ECT, OVX+ALN, and OVX+ECT+ALN groups (n = 10). Immediately after ovariectomy, ECT was administered at a dose of 15 units (U)/kg three times a week, and ALN was administered daily at a dose of 2.0 microg/kg, subcutaneously for 12 weeks. The three-dimensional architecture of the bone in the distal femoral metaphysis was analyzed using a microfocus X-ray computed tomography system (microCT), and bone strength was measured using a material-testing machine. Trabecular bone volume (BV/TV) and number (Tb.N) were significantly greater in the OVX+ECT and OVX+ALN groups than in the OVX group. In the OVX+ECT+ALN group, BV/TV and Tb.N were significantly greater when compared with those in the OVX+ECT and OVX+ALN groups. Trabecular thickness (Tb.Th) was significantly greater in the OVX+ECT+ALN group than in the OVX+ALN group. With regard to bone strength, the compression strength in the femoral metaphysis was significantly lower in the OVX group than in the Sham group. The reduction of compression strength was slightly lower in the OVX+ECT and OVX+ALN groups. In the OVX+ECT+ALN group, the compression strength in the femoral metaphysis significantly increased when compared with the OVX and OVX+ECT groups. These results suggest that the combined treatment of ECT and ALN does not alter the individual effects of each drug and that it exerts an additive effect on trabecular architecture and bone strength in OVX rats.

Cost-effectiveness analysis of once-yearly injection of zoledronic acid for the treatment of osteoporosis in Japan.

PubMed

Moriwaki, K; Mouri, M; Hagino, H

2017-06-01

Model-based economic evaluation was performed to assess the cost-effectiveness of zoledronic acid. Although zoledronic acid was dominated by alendronate, the incremental quality-adjusted life year (QALY) was quite small in extent. Considering the advantage of once-yearly injection of zoledronic acid in persistence, zoledronic acid might be a cost-effective treatment option compared to once-weekly oral alendronate. The purpose of this study was to estimate the cost-effectiveness of once-yearly injection of zoledronic acid for the treatment of osteoporosis in Japan. A patient-level state-transition model was developed to predict the outcome of patients with osteoporosis who have experienced a previous vertebral fracture. The efficacy of zoledronic acid was derived from a published network meta-analysis. Lifetime cost and QALYs were estimated for patients who had received zoledronic acid, alendronate, or basic treatment alone. The incremental cost-effectiveness ratio (ICER) of zoledronic acid was estimated. For patients 70 years of age, zoledronic acid was dominated by alendronate with incremental QALY of -0.004 to -0.000 and incremental cost of 430 USD to 493 USD. Deterministic sensitivity analysis indicated that the relative risk of hip fracture and drug cost strongly affected the cost-effectiveness of zoledronic acid compared to alendronate. Scenario analysis considering treatment persistence showed that the ICER of zoledronic acid compared to alendronate was estimated to be 47,435 USD, 27,018 USD, and 10,749 USD per QALY gained for patients with a T-score of -2.0, -2.5, or -3.0, respectively. Although zoledronic acid is dominated by alendronate, the incremental QALY is quite small in extent. Considering the advantage of annual zoledronic acid treatment in compliance and persistence, zoledronic acid may be a cost-effective treatment option compared to alendronate.

Time-of-flight secondary ion mass spectrometry study on the distribution of alendronate sodium in drug-loaded ultra-high molecular weight polyethylene.

PubMed

Liu, Xiaomin; Qu, Shuxin; Lu, Xiong; Ge, Xiang; Leng, Yang

2009-12-01

The aim of this study was to investigate the drug distribution in ultra-high molecular weight polyethylene (UHMWPE) loaded with alendronate sodium (ALN), which was developed to treat particle-induced osteolysis after artificial joint replacements, since the drug distribution in UHMWPE could play a key role in controlling drug release. A mixture of UHMWPE powder and ALN was dried and hot pressed to prepare UHMWPE loaded with ALN (UHMWPE-ALN). Fourier transform infrared spectroscopy analysis demonstrated that the hot press had no effect on the functional groups of ALN in UHMWPE-ALN. X-ray diffraction indicated that there was no phase change of the UHMWPE after hot pressing. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) spectra revealed the existence of characteristic elements and functional groups from ALN in UHMWPE-ALN, such as Na+, C3H8N+, PO3(-) and PO3H(-). In addition, SIMS images suggested that ALN did not agglomerate in UHMWPE-ALN. A small punch test and hardness test were carried out and the results indicated that ALN did not affect the mechanical properties at the present content level. The present study demonstrated that it was feasible to fabricate the un-agglomerated distributed drug in UHMWPE with good mechanical properties. This ALN loaded UHMWPE would have potential application in clinics.

Clinical and radiographic evaluation of effect of risedronate 5 mg as an adjunct to treatment of chronic periodontitis in postmenopausal women (12-month study).

PubMed

Bhavsar, N V; Trivedi, S R; Dulani, K; Brahmbhatt, N; Shah, S; Chaudhri, D

2016-08-01

Bisphosphonates are beneficial to women, after menopause, in treatment of gum diseases. In this study, significant improvement in the disease condition was found and that no further progress was noted, and no side effects were reported. Bisphosphonates can be safely and successfully be used to support oral health procedures. The purpose of this study was to evaluate host modulating effect of bisphosphonate adjunct with the treatment of chronic periodontitis in osteopenic and osteoporotic postmenopausal women. Twenty-two osteopenic and osteoporotic postmenopausal women with moderate to severe chronic periodontitis were selected for the study. On intraoral examination, periodontal parameters like probing depth (PD), clinical attachment level (CAL), Plaque Index (PI) and Gingival Index (GI) were recorded. Scaling and root planing were done. Intraoral periapical X-rays were taken, and alveolar bone density (ABD) was measured with cone beam computed tomography (CBCT), and then, medications (risedronate 5 mg once daily (OD), calcium citrate 250 mg OD, vitamin D 400 IU OD) were given. Patients were recalled for follow-up at 3, 6 and 12 months. Intraoral periapical (IOPA) X-rays were taken at 6 and 12 months and ABD was measured at baseline and 12 months. There was a significant improvement in all the parameters. There was an increase of 0.02 ± 0.001 cm on CT scan and 0.38 ± 0.005 mm on IOPA in bone height over 12 months from baseline. Bone density increased by 118.56 ± 3.251 Hounsfield units (HU). There was no progress in the disease, and further bone loss was not noticed. This is in correlation with clinical parameters which showed highly significant gain in CAL (3.57 ± 0.234 mm) and reduction in PD (2.20 ± 0.229 mm) Bisphosphonate therapy as an adjunct to scaling and root planing may have significant beneficial clinical effects on the periodontium of postmenopausal women with moderate to severe chronic periodontitis.

Effect of alendronate on post-traumatic osteoarthritis induced by anterior cruciate ligament rupture in mice.

PubMed

Khorasani, Mohammad S; Diko, Sindi; Hsia, Allison W; Anderson, Matthew J; Genetos, Damian C; Haudenschild, Dominik R; Christiansen, Blaine A

2015-02-16

Previous studies in animal models of osteoarthritis suggest that alendronate (ALN) has antiresorptive and chondroprotective effects, and can reduce osteophyte formation. However, these studies used non-physiologic injury methods, and did not investigate early time points during which bone is rapidly remodeled prior to cartilage degeneration. The current study utilized a non-invasive model of knee injury in mice to investigate the effect of ALN treatment on subchondral bone changes, articular cartilage degeneration, and osteophyte formation following injury. Non-invasive knee injury via tibial compression overload or sham injury was performed on a total of 90 mice. Mice were treated with twice weekly subcutaneous injections of low-dose ALN (40 μg/kg/dose), high-dose ALN (1,000 μg/kg/dose), or vehicle, starting immediately after injury until sacrifice at 7, 14 or 56 days. Trabecular bone of the femoral epiphysis, subchondral cortical bone, and osteophyte volume were quantified using micro-computed tomography (μCT). Whole-joint histology was performed at all time points to analyze articular cartilage and joint degeneration. Blood was collected at sacrifice, and serum was analyzed for biomarkers of bone formation and resorption. μCT analysis revealed significant loss of trabecular bone from the femoral epiphysis 7 and 14 days post-injury, which was effectively prevented by high-dose ALN treatment. High-dose ALN treatment was also able to reduce subchondral bone thickening 56 days post-injury, and was able to partially preserve articular cartilage 14 days post-injury. However, ALN treatment was not able to reduce osteophyte formation at 56 days post-injury, nor was it able to prevent articular cartilage and joint degeneration at this time point. Analysis of serum biomarkers revealed an increase in bone resorption at 7 and 14 days post-injury, with no change in bone formation at any time points. High-dose ALN treatment was able to prevent early trabecular

Maintaining Restored Bone with Bisphoshonate in the Ovariectomized Rat Skeleton: Dynamic Histomorphometry of Changes in Bone Mass

NASA Technical Reports Server (NTRS)

Jee, W. S. S.; Tang, L.; Ke, H. Z.; Setterberg, R. B.; Kimmel, D. B.

1993-01-01

This experiment contains the crucial data for the Lose, Restore and Maintain (LRM) concept, a practical approach for reversing existing osteoporosis. The LRM concept uses ovariectomy (ox) to lose bone, an anabolic agent to restore bone mass and then switches to an anti-resorptive agent to maintain bone mass. We ox'd or sham-ox'd rats for 150 days (Loss Phase), treated them with 6 mg PGE2/kg/d for 75 days to restore lost cancellous bone mass (Restore Phase) and then stopped PGE2 treatment and began treatment with 1 or 5 micro-g/kg Risedronate, a bisphosphonate twice a week for 60 days (Maintain Phase). During the Loss Phase, cancellous bone volumes of the proximal tibial metaphysis (PTM) in the ox'd rat fell to 19% of initial controls. During the Restore Phase, the PTM bone volume in ox'd rats doubled. However, when PGE2 treatment was stopped, the PGE2-induced cancellous bone disappeared. In contrast, 5 micro-g of Risedronate inhibited the bone loss and maintained it at the PGE2 treatment level. The key dynamic histomorphometry value for the restore (R) and maintenance (M) phases was the ratio of bone formation to resorption rates. The ratio was elevated to 5.8 in the R phase and depressed to 0.4 for no and 1 micro-g Risedronate treated M phase and to a ratio of near unity of 1.1 for the 5 micro-g Risedronate treatment. These findings indicate that we were successful in maintaining the new PTM bone induced by PGE2 after discontinuing PGE2 by administering enough Risedronate, a resorption inhibitor. We concluded that the LRM concept is correct and such an approach should be considered when employing anabolic agents or growth factors in the treatment of osteoporosis. Continued use of an anabolic agent may not be appropriate because of cost, potential adverse side effects and a loss of efficacy.

Maintaining Restored Bone with Bisphosphonate in the Ovariectomized Rat Skeleton: Dynamic Histomorphometry of Changes in Bone Mass

NASA Technical Reports Server (NTRS)

Jee, W. S. S.; Tang, L.; Ke, H. Z.; Setterberg, R. B.; Kimmel, D. B.

1993-01-01

This experiment contains the crucial data for the Lose, Restore and Maintain (LRM) concept, a practical approach for reversing existing osteoporosis. The LRM concept uses ovariectomy (ox) to lose bone, an anabolic agent to restore bone mass and then switches to an antiresorptive agent to maintain bone mass. We ox'd or sham-ox'd rats for 150 days (Loss Phase), treated them with 6 mg PGE(sub 2)kg/d for 75 days to restore lost cancellous bone mass (Restore Phase) and then stopped PGE(sub 2) treatment and began treatment with 1 or 5 micrograms/kg Risedronate, a bisphosphonate twice a week for 60 days (Maintain Phase). During the Loss Phase, cancellous bone volumes of the Proximal Tibial Metaphysis (PTM) in the ox'd rat fell to 19% of initial controls. During the Restore Phase, the PTM bone volume in ox'd rats doubled. However, when PGE(sub 2) treatment was stopped, the PGE(sub 2)-induced cancellous bone disappeared. In contrast, 5 miligrams of Risedronate inhibited the bone loss and maintained it at the PGE(sub 2) treatment level. The key dynamic histomorphometry value for the Restore (R) and Maintenance (M) phases was the ratio of bone formation to resorption rates. The ratio was elevated to 5.8 in the R phase and depressed to 0.4 for no and 1 miligram Risedronate treated M phase and to a ratio of near unity of 1.1 for the 5miligrams Risedronate treatment. These findings indicate that we were successful in maintaining the new PTM bone induced by PGE(sub 2) after discontinuing PGE(sub 2) by administering enough Risedronate, a resorption inhibitor. We concluded that the LRM concept is correct and such an approach should be considered when employing anabolic agents or growth factors in the treatment of osteoporosis. Continued use of an anabolic agent may not be appropriate because of cost, potential adverse side effects and a loss of efficacy.

The effects of bone remodeling inhibition by alendronate on three-dimensional microarchitecture of subchondral bone tissues in guinea pig primary osteoarthrosis.

PubMed

Ding, Ming; Danielsen, Carl Christian; Hvid, Ivan

2008-01-01

We assessed whether increase of subchondral bone density enhances cartilage stress during impact loading, leading to progressive cartilage degeneration and accelerated osteoarthrosis (OA) progression. Sixty-six male guinea pigs were randomly divided into six groups. During a 9-week treatment period, four groups received twice-weekly subcutaneous injections of alendronate (ALN) in two doses: two groups received 10 microg/kg and two groups received 50 microg/kg. The two control groups received vehicle. After 9 weeks, one 10 microg/kg ALN group, one 50 microg/kg ALN group, and one control group were killed. The remaining three groups (17-week groups) were left for an additional 8 weeks, receiving the same treatment regimen before death. The left proximal tibiae were scanned by micro-computed tomography to quantify the microarchitecture of subchondral bone, followed by mechanical testing and determination of collagen and mineral. The control groups had typical OA-related cartilage degeneration at 9 and 17 weeks, whereas the 50 microg/kg ALN group had even worse degeneration in the medial condyle. It is unclear whether there is a direct or a secondary effect of ALN on the cartilage. The 9-week ALN group had significantly greater subchondral plate thickness. The 9- and 17-week groups had similar changes of cancellous bone microarchitecture, with greater volume fraction and connectivity and an extremely plate-like structure. The 9-week ALN group had greater bone mineral concentration, and the 17-week ALN group had reduced collagen concentration and greater mineral concentration. Treatment with ALN did not significantly change the mechanical properties of the cancellous bone.

A novel alginate-encapsulated system to study biological response to critical-sized wear particles of UHMWPE loaded with alendronate sodium.

PubMed

Liu, Yumei; Shi, Feng; Bo, Lin; Zhi, Wei; Weng, Jie; Qu, Shuxin

2017-10-01

The aim of this study was to develop a novel alginate-encapsulated system (Alg beads) to investigate the cell response to critical-sized wear particles of ultra-high molecular weight polyethylene loaded with alendronate sodium (UHMWPE-ALN), one of the most effective drugs to treat bone resorption in clinic. The extrusion method was used to prepare Alg beads encapsulating rat calvarial osteoblasts (RCOs) and critical-sized UHMWPE-ALN wear particles with spherical morphology and uniform size. The morphology, permeability and stability of Alg beads were characterized. The proliferation, ALP activity, cell apoptosis and distribution of live/dead RCOs co-cultured with wear particles in Alg beads were evaluated. RCOs and critical-sized UHMWPE-ALN wear particles distributed evenly and contacted efficiently in Alg beads. Alg beads were both permeable to trypsin and BSA, while the smaller the molecular was, the larger the diffuse was. The proliferation of RCOs in Alg beads increased with time, which indicated that Alg beads provided suitable conditions for cell culture. The long-term stability of Alg beads indicated the possibility for the longer time of co-cultured cells with wear particles. Critical-sized UHMWPE-ALN and UHMWPE wear particles both inhibited the proliferation and differentiation of RCOs, and induced the apoptosis of RCOs encapsulated in Alg beads. However, these effects could be significantly alleviated by the ALN released from the critical-sized UHMWPE-ALN wear particles. The present results suggested that this novel-developed co-culture system was feasible to evaluate the cell response to critical-sized UHMWPE-ALN wear particles for a longer time. Copyright © 2017 Elsevier B.V. All rights reserved.

[Progress in the treatment of osteoporosis].

PubMed

Sugimoto, Toshitsugu

2008-10-01

The purpose of the treatment of osteoporosis is to reduce fracture risk and maintain/improve quality of life (QOL). The criteria for initiating pharmacotherapy to prevent fragility fractures should be provided separately from the criteria for diagnosis of osteoporosis. In Japan, low bone mineral density (BMD), prevalent fracture, and age are established as fracture risk factors from available data. A meta-analysis conducted by the WHO assured that excessive drinking (2 units a day or more), current smoking, and a family history of hip fracture are fracture risk factors. Moreover, in WHO technical report 921, high levels of CTX, a bone resorption marker as well as uncarboxylated osteocalcin were cited as risk factors of hip fracture, which can be measured in medical practice in Japan. Pharmacotherapy should be initiated with the consideration of the above risk factors. Recent large scale of randomized control trial(RCT), followed by meta-analysis demonstrated that bisphosphonates such as alendronate and risedronate as well as raloxifene (selective estrogen receptor modulator) are top grade of drugs which prevent fragility fracture in osteoporotic patients. Now, it is possible to perform evidence-based medicine in daily medical practice. As for secondary osteoporosis, along with treatment of underlying diseases, treatment aimed at preventing bone loss is necessary in many cases. Accumulating evidence is available about increased fracture threshold in glucocorticoid- and diabetes mellitus-induced osteoporosis. Therefore, early treatment should be appropriate in these cases. In osteoporotic patients, atherosclerotic vascular calcification as well as abnormal lipid metabolism often coexists. Multiple vertebral fractures followed by kyphosis often causes functional disorders of the digestive and respiratory systems.

Alendronate is more effective than elcatonin in improving pain and quality of life in postmenopausal women with osteoporosis.

PubMed

Iwamoto, J; Makita, K; Sato, Y; Takeda, T; Matsumoto, H

2011-10-01

A randomized controlled trial was performed to compare the short-term effects of alendronate (ALN) and ECT on pain and quality of life (QOL) in postmenopausal women with osteoporosis. Back pain and QOL [Short-Form Health Survey (SF-8)] significantly improved at 1, 3, and 6 months in both groups, with greater improvements in the ALN group than in the ECT group. These results suggested that ALN reduced back pain and improved QOL more markedly than ECT in postmenopausal osteoporotic women with back pain. Intramuscular ECT is known to reduce pain via the central nervous system. A multicenter randomized controlled trial was performed to compare the short-term effects of ALN and ECT on pain and QOL in postmenopausal women with osteoporosis. One hundred and 94 postmenopausal osteoporotic women with back pain (mean age 79.8 years, range 60-96 years) were randomly divided into two groups: the ALN group (35 mg weekly) and the ECT group (intramuscular 20 units a week). The duration of the study was 6 months. The trial was completed in 97 (100%) women of the ALN group and 96 (99.0%) women of the ECT group. Urinary levels of cross-linked N-terminal telopeptide of type I collagen (NTX), serum alkaline phosphatase (ALP), face scale score (FSS, back pain), and SF-8 (QOL) were monitored. Urinary NTX levels significantly decreased at 3 months in the ALN group, but not in the ECT group. Serum ALP levels significantly decreased at 6 months in the both groups, with a greater reduction in the ALN group. The FSS and SF-8 significantly improved at 1, 3, and 6 months in both groups, with greater improvements in the ALN group than in the ECT group. ALN suppressed bone turnover, reduced back pain, and improved QOL more markedly than ECT in postmenopausal osteoporotic women with back pain.

Bone Density, Balance and Quality of Life of Postmenopausal Women Taking Alendronate Participating in Different Physical Activity Programs

PubMed Central

Borba-Pinheiro, Cláudio Joaquim; de Alencar Carvalho, Mauro César Gurgel; da Silva, Nádia Souza Lima; Drigo, Alexandre Janotta; Bezerra, Jani Cléria Pereira; Dantas, Estélio Henrique Martin

2010-01-01

Background: The objective of this study was to determine the effects of different physical activity (PA) programs on bone density, balance and quality of Life of postmenopausaL women taking concomitant aLendronate. A quasi-experimental study was conducted with 35 volunteers divided into four groups: practitioners of resistance training (RTG, n = 9, 49.8±4.2 years), judo (JUG, n= 11, 52.2 ±5.3 years), water aerobics (WAG, n = 8, 57.1 ±7.4 years) and the control group (CG, n = 7, 53.8±4.4 years). Methods: The following assessment tools were used: bone mineral density (BMD) measured by dual X-ray absorptiometry of the spine and proximal femur, the ‘Osteoporosis Assessment Questionnaire’ (OPAQ) and the ‘Static Balance Test with Visual Control’. The physical activities were planned for 12 months in cycles with different intensities. A two-way analysis of variance (ANOVA) was used for analysis between groups, and a Scheffe post-hoc test was used for multiple comparisons. Results: The multiple comparisons results showed that the RTG and JUG groups were significantly more efficient in the variables studied, including: Lumbar BMD (Δ% = 6.8%, p = 0.001), balance (Δ% = 21.4%, p = 0.01), OPAQ (Δ% = 9.1%, p = 0.005) and Lumbar BMD (Δ% = 6.4%, p = 0.003), balance (Δ% = U%, p = 0.02) and OPAQ (Δ% = 16.8%, p =0.000) compared with the CG. Furthermore, the RTG (Δ% = 4.8%, p =0.02) was significantly better than the WAG for the neck of femur BMD, and the JUG (Δ% = 16.8, p = 0.0003) also demonstrated superiority to the WAG in the OPAQ. Conclusions: The physical activities studied appear to improve BMD, balance and quality of Life of postmenopausaL women taking a bisphosphonate. In this small sample, the RTG and the JUG groups were superior to the other groups. PMID:22870446

Glucocorticoid-induced bone loss can be reversed by the actions of PTH and Risedronate on different pathways for bone formation and mineralization

PubMed Central

Yao, Wei; Cheng, Zhiqiang; Pham, Aaron; Busse, Cheryl; Zimmermann, Elizabeth A.; Ritchie, Robert O.; Lane, Nancy E.

2008-01-01

Glucocorticoid (GC) excess decreases bone mineralization and microarchitecture and lead to reduced bone strength. Both anabolic (PTH) and anti-resorptive agents are used to prevent and treat GC-induced bone loss, yet these bone active agents alter bone turnover by very different mechanisms. Our study objective was to determine how PTH and risedronate (Ris) alter bone quality following GC excess. Five-month-old Swiss-Webster male mice were treated with the glucocorticoid (GC) prednisolone (5 mg/kg 60-day slow-release pellet) or placebo (PL)]. At day 28−56, two groups of GC-treated animals had either PTH (5μg/kg, 5x/wk) or Ris (5μg/kg, 5x/wk) intervention. Bone quality and quantity measurements include x-ray tomography microscopy (XTM) for the degree of bone mineralization (DBM), microCT for bone microarchitecture, compression testing for trabecular bone strength, biochemistry and histomorphometry for bone turnover. In addition, real-time PCR and immunohistochemistry were performed to monitor the expression of several key genes regulating Wnt signaling (bone formation) and mineralization. Results Compared to the placebo treated mice, GC treatment decreased trabecular bone volume (BV/TV) and serum osteocalcin, but increased serum CTX and osteoclast surface with a peak at day 28. GC+PTH increased and GC+Ris restored BV/TV to the PL levels after a 28 day treatment period. Average DBM was lowered after GC treatment (−27%), and it was restored to PL level with GC+Ris and GC+PTH. At day 56, RT-PCR revealed that continuous exposure to GC and GC+PTH increased, while GC+Ris decreased the expression of genes that inhibit bone mineralization (Dmp1 and Phex), compared to the PL group. Wnt signaling antagonists Dkk1, Sost and Wif1 were up-regulated by GC treatment but were down-regulated after GC+PTH treatment. Immunohistochemistry of bone sections found GC increased N terminal dmp-1 while PTH treatment increased both N and C terminal dmp-1 staining around osteocytes

A novel automated hydrophilic interaction liquid chromatography method using diode-array detector/electrospray ionization tandem mass spectrometry for analysis of sodium risedronate and related degradation products in pharmaceuticals.

PubMed

Bertolini, Tiziana; Vicentini, Lorenza; Boschetti, Silvia; Andreatta, Paolo; Gatti, Rita

2014-10-24

A simple, sensitive and fast hydrophilic interaction liquid chromatography (HILIC) method using ultraviolet diode-array detector (UV-DAD)/electrospray ionization tandem mass spectrometry was developed for the automated high performance liquid chromatography (HPLC) determination of sodium risedronate (SR) and its degradation products in new pharmaceuticals. The chromatographic separations were performed on Ascentis Express HILIC 2.7μm (150mm×2.1mm, i.d.) stainless steel column (fused core). The mobile phase consisted of formate buffer solution (pH 3.4; 0.03M)/acetonitrile 42:58 and 45:55 (v/v) for granules for oral solution and effervescent tablet analysis, respectively, at a flow-rate of 0.2mL/min, setting the wavelength at 262nm. Stability characteristics of SR were evaluated by performing stress test studies. The main degradation product formed under oxidation conditions corresponding to sodium hydrogen (1-hydroxy-2-(1-oxidopyridin-3-yl)-1-phosphonoethyl)phosphonate was characterized by high performance liquid chromatography-electrospray ionization-mass tandem mass spectrometry (HPLC-ESI-MS/MS). The validation parameters such as linearity, sensitivity, accuracy, precision and selectivity were found to be highly satisfactory. Linear responses were observed in standard and in fortified placebo solutions. Intra-day precision (relative standard deviation, RSD) was ≤1.1% for peak area and ≤0.2% for retention times (tR) without significant differences between intra- and inter-day data. Recovery studies showed good results for all the examined compounds (from 98.7 to 101.0%) with RSD ranging from 0.6 to 0.7%. The limits of detection (LOD) and quantitation (LOQ) were 1 and 3ng/mL, respectively. The high stability of standard and sample solutions at room temperature means an undoubted advantage of the method allowing the simultaneous preparation of many samples and consecutive chromatographic analyses by using an autosampler. The developed stability indicating

Evaluation of the effects of pulsed wave LLLT on tibial diaphysis in two rat models of experimental osteoporosis, as examined by stereological and real-time PCR gene expression analyses.

PubMed

Mohsenifar, Zhaleh; Fridoni, Mohammadjavad; Ghatrehsamani, Mahdi; Abdollahifar, Mohammad-amin; Abbaszadeh, Hojjatallah; Mostafavinia, Atarodalsadat; Fallahnezhad, Somaye; Asghari, Mohammadali; Bayat, Saba; Bayat, Mohammad

2016-05-01

Osteoporosis (OP) and osteoporotic fracture are major public health issues for society; the burden for the affected individual is also high. Previous studies have shown that pulsed wave low-level laser therapy (PW LLLT) has osteogenic effects. This study intended to evaluate the impacts of PW LLLT on the cortical bone of osteoporotic rats' tibias in two experimental models, ovariectomized and dexamethasone-treated. We divided the rats into four ovariectomized induced OP (OVX-d) and four dexamethasone-treated (glucocorticoid-induced OP, GIOP) groups. A healthy (H) group of rats was considered for baseline evaluations. At 14 weeks following ovariectomy, we subdivided the OVX-d rats into the following groups: (i) control which had OP, (ii) OVX-d rats treated with alendronate (1 mg/kg), (iii) OVX-d rats treated with LLLT, and (iv) OVX-d rats treated with alendronate and PW LLLT. The remaining rats received dexamethasone over a 5-week period and were also subdivided into four groups: (i) control rats treated with intramuscular (i.m.) injections of distilled water (vehicle), (ii) rats treated with subcutaneous alendronate injections (1 mg/kg), (iii) laser-treated rats, and (iv) rats simultaneously treated with laser and alendronate. The rats received alendronate for 30 days and underwent PW LLLT (890 nm, 80 Hz, 0.972 J/cm(2)) three times per week during 8 weeks. Then, the right tibias were extracted and underwent a stereological analysis of histological parameters and real-time polymerase chain reaction (RT-PCR). A significant increase in cortical bone volume (mm(3)) existed in all study groups compared to the healthy rats. There were significant decreases in trabecular bone volume (mm(3)) in all study groups compared to the group of healthy rats. The control rats with OP and rats from the vehicle group showed significantly increased osteoclast numbers compared to most other groups. Alendronate significantly decreased osteoclast numbers in osteoporotic rats. Concurrent

Bone Histology of Two Cases with Osteomalacia Related to Low-dose Adefovir.

PubMed

Hiramatsu, Rikako; Ubara, Yoshifumi; Sawa, Naoki; Hasegawa, Eiko; Kawada, Masahiro; Imafuku, Aya; Sumida, Keiichi; Hoshino, Junichi; Takaichi, Kenmei

We performed a bone histomorphometric analysis in two patients demonstrating Fanconi syndrome with hypophosphatemia, adefovir-related bone disease and chronic hepatitis B infection. Both patients had osteomalacia, but showed two different histological patterns. The osteoid volume of the patient without risedronate increased with [(osteoid volume/ bone volume)×100=18.6%]. However, the osteoid volume of the patient receiving risedronate without vitamin D analogue showed a greater increase of 53.8%. In both patients bone pain and hypophosphatemia subsided soon after the discontinuation of adefovir and the administration of phosphate derivative. These findings show that bisphosphonate may worsen this disease when this drug is administered without a vitamin D analogue.

Design and development of novel hyaluronate-modified nanoparticles for combo-delivery of curcumin and alendronate: Fabrication, characterization, and cellular and molecular evidence of enhanced bone regeneration.

PubMed

Dong, Jinlei; Thu, Hnin Ei; Abourehab, Mohammed A S; Hussain, Zahid

2018-05-18

Osteoporosis is a medical condition of fragile bones with an increased susceptibility to bone fracture. Despite having availability of a wide range of pharmacological agents, prevalence of this metabolic disorder is continuously escalating. Owing to excellent biomedical achievements of nanomedicines in the last few decades, we aimed combo delivery of bone anti-resorptive agent, alendronate (ALN), and bone density enhancing drug, curcumin (CUR), in the form of polymeric nanoparticles. To further optimize the therapeutic efficacy, the prepared ALN/CUR nanoparticles were decorated with hyaluronic acid which is a well-documented biomacromolecule having exceptional bone regenerating potential. The optimized nanoformulation was evaluated for bone regeneration efficacy by assessing the time-mannered modulation in the proliferation, differentiation, and mineralization of MC3T3-E1 cells, a pre-osteoblast model. Moreover, the time-mannered expressions of various bone-forming protein biomarkers including bone morphogenetic protein, runt related transcription factor 2, and osteocalcin were assessed in the cell lysates. Results revealed that HA-ALN/CUR NPs provoke remarkable increase in proliferation, differentiation, and mineralization in the ECM of MC3T3-E1 cells which ultimately leads to enhanced bone formation. This new strategy employing simultaneous delivery of anti-resorptive and bone forming agents would open new horizons for the scientists as an efficient alternative pharmacotherapy for the management of osteoporosis. Copyright © 2017. Published by Elsevier B.V.

Combination therapy with ONO-KK1-300-01, a cathepsin K inhibitor, and parathyroid hormone results in additive beneficial effect on bone mineral density in ovariectomized rats.

PubMed

Ochi, Yasuo; Yamada, Hiroyuki; Mori, Hiroshi; Kawada, Naoki; Tanaka, Makoto; Imagawa, Akira; Ohmoto, Kazuyuki; Kawabata, Kazuhito

2016-01-01

This study examined the effects of a novel cathepsin K inhibitor, ONO-KK1-300-01 (KK1-300), used concurrently with parathyroid hormone (PTH) in ovariectomized (OVX) rats. KK1-300 (3 mg/kg, twice daily), alendronate (1 mg/kg, once daily) or vehicle were orally administered to OVX rats for 56 days, starting the day after ovariectomy, followed by combination treatment with or without PTH (3 μg/kg, subcutaneously three times a week) for another 28 days. OVX control animals exhibited a significant increase in both bone resorption (urinary deoxypyridinoline; DPD) and formation markers (serum osteocalcin) as well as microstructural changes associated with decreased bone mineral density (BMD). Combination treatment with KK1-300 and PTH significantly decreased urinary DPD and increased serum osteocalcin, indicating a sustained beneficial effect compared to the effect of each mono-therapy. On the other hand, combination therapy with alendronate and PTH weakened the PTH-induced increase in osteocalcin. In proximal tibia, combination treatment with KK1-300 and PTH increased BMD to a level significantly higher than that achieved following single treatment with KK1-300 or PTH alone. On the other hand, combination treatment with alendronate and PTH failed to produce any significant additive effect on BMD following single treatment with alendronate or PTH alone. Microstructural analysis revealed that the PTH-induced increase in bone formation (MS/BS and BFR/BS) was fully maintained following combination treatment with KK1-300 and PTH, but not following combination treatment with alendronate and PTH. These findings indicate that KK1-300, unlike alendronate, has an additive effect on the preventive action of PTH on bone loss in OVX rats.

Severe hypocalcemia following bisphosphonate treatment in a patient with Paget's disease of bone.

PubMed

Whitson, Heather E; Lobaugh, Bruce; Lyles, Kenneth W

2006-10-01

Bisphosphonate therapy is a common and effective treatment for Paget's disease of bone, osteoporosis, hypercalcemia of malignancy and cancer metastatic to bone. Clinically significant hypocalcemia has not been reported in patients with Paget's disease of bone and normal parathyroid function treated with an aminobisphosphonate. We treated a 52-year-old woman with polyostotic Paget's disease of bone (serum alkaline phosphatase level-1971 IU/L [normal 31-110 IU/L]), who had not previously received bisphosphonates, with daily oral 30 mg risedronate, oral 1000 mg elemental calcium and oral 400 IU cholecalciferol. After 10 days of treatment, she developed severe hypocalcemia (5.4 mg/dL [normal 8.7-10.2 mg/dL]), requiring hospitalization and support with 5 days of intravenous calcium gluconate. On the day risedronate treatment began, her PTH was low normal at 14 pg/mL (normal 12-72 pg/mL), consistent with a relatively suppressed PTH axis due to high bone turnover. Her vitamin D level was within normal limits (serum 25(OH)D 19 ng/mL [normal 8-38 ng/mL]), although possibly not optimally repleted. We hypothesize that this case represents an example of hungry bone syndrome in a patient with extensive Paget's disease of bone who received risedronate, causing acute suppression of bone resorption while elevated bone formation rates continued. In the year following her recovery, the patient was successfully treated with slowly titrated anti-resorptive therapy (subcutaneous calcitonin followed by titrated doses of risedronate), and is now clinically well. Physicians should be aware of the potential for hypocalcemia when patients with polyostotic Paget's disease and markedly elevated indicators of bone remodeling are initiated on powerful anti-resorptive therapy.

Exploring methods for comparing the real-world effectiveness of treatments for osteoporosis: adjusted direct comparisons versus using patients as their own control.

PubMed

Karlsson, Linda; Mesterton, Johan; Tepie, Maurille Feudjo; Intorcia, Michele; Overbeek, Jetty; Ström, Oskar

2017-09-21

Using Swedish and Dutch registry data for women initiating bisphosphonates, we evaluated two methods of comparing the real-world effectiveness of osteoporosis treatments that attempt to adjust for differences in patient baseline characteristics. Each method has advantages and disadvantages; both are potential complements to clinical trial analyses. We evaluated methods of comparing the real-world effectiveness of osteoporosis treatments that attempt to adjust for both observed and unobserved confounding. Swedish and Dutch registry data for women initiating zoledronate or oral bisphosphonates (OBPs; alendronate/risedronate) were used; the primary outcome was fracture. In adjusted direct comparisons (ADCs), regression and matching techniques were used to account for baseline differences in known risk factors for fracture (e.g., age, previous fracture, comorbidities). In an own-control analysis (OCA), for each treatment, fracture incidence in the first 90 days following treatment initiation (the baseline risk period) was compared with fracture incidence in the 1-year period starting 91 days after treatment initiation (the treatment exposure period). In total, 1196 and 149 women initiating zoledronate and 14,764 and 25,058 initiating OBPs were eligible in the Swedish and Dutch registries, respectively. Owing to the small Dutch zoledronate sample, only the Swedish data were used to compare fracture incidences between treatment groups. ADCs showed a numerically higher fracture incidence in the zoledronate than in the OBPs group (hazard ratio 1.09-1.21; not statistically significant, p > 0.05). For both treatment groups, OCA showed a higher fracture incidence in the baseline risk period than in the treatment exposure period, indicating a treatment effect. OCA showed a similar or greater effect in the zoledronate group compared with the OBPs group. ADC and OCA each possesses advantages and disadvantages. Combining both methods may provide an estimate of real

Comparison of raloxifene and bisphosphonates based on adherence and treatment satisfaction in postmenopausal Asian women.

PubMed

Pasion, Ellewellyn G; Sivananthan, Shanmugam K; Kung, Annie Wai-Chee; Chen, Sung-Hsiung; Chen, Yen-Jen; Mirasol, Roberto; Tay, Boon Keng; Shah, Ghazanfar Ali; Khan, Mansoor Ali; Tam, Frances; Hall, Belinda J; Thiebaud, Daniel

2007-01-01

We evaluated adherence with raloxifene therapy compared with daily bisphosphonate in Asian postmenopausal women at increased risk of osteoporotic fractures. In this 12-month observational study conducted in Asia (Hong Kong, Malaysia, Pakistan, Philippines, Singapore, Taiwan), 984 postmenopausal women (aged 55 years or older) were treated with raloxifene 60 mg/day (n = 707; 72%) or daily bisphosphonate (alendronate 10 mg/day; n = 206; 21%, or risedronate 5 mg/day; n = 71; 7%) during their normal course of care. Patients were assessed at baseline, 6, and 12 months. Baseline characteristics (including age, race, education, menopausal status, and baseline fractures) were comparable between the raloxifene and bisphosphonate groups. More women on raloxifene completed the study compared with those on bisphosphonate (50.2% versus 37.5%; P < 0.001). Patients also took raloxifene for a longer period than bisphosphonate (median, 356 versus 348 days; P = 0.011). Compared with those taking bisphosphonate, significantly fewer patients taking raloxifene discontinued the study because of stopping treatment (5.7% versus 10.1%, P = 0.017) or changing treatment (2.8% versus 9.7%, P < 0.001). Inconvenient dosing was reported as a primary reason for discontinuation due to stopping or changing treatment in 19 (6.9%) bisphosphonate patients compared with 0 raloxifene patients. The percentage of patients who had consumed 80% or more of their study medication was similar for raloxifene patients (48-56 weeks; 95.2%) and bisphosphonate patients (48-56 weeks; 93.3%). More raloxifene patients responded that they were satisfied with their medication than bisphosphonate patients at 48-56 weeks (P = 0.002). We concluded that Asian postmenopausal women at increased risk of osteoporotic fractures showed a greater propensity to remain on raloxifene compared with bisphosphonate. The women on raloxifene exhibited lower discontinuation rates and higher treatment satisfaction.

Location of fractures and the characteristics of patients with atypical femoral fractures: analyses of 38 Japanese cases.

PubMed

Hyodo, Kojiro; Nishino, Tomofumi; Kamada, Hiroshi; Nozawa, Daisuke; Mishima, Hajime; Yamazaki, Masashi

2017-03-01

The purpose of this study was to determine fracture location and the characteristics of patients with atypical femoral fractures (AFFs). We studied 38 AFFs in 34 patients admitted to our institution between November 2007 and July 2013. The diagnostic criteria for the AFFs were based on 2014 American Society of Bone and Mineral Research guidelines. We classified the fracture location as proximal, middle, or distal to trisect the femoral diaphysis from just distal to the lesser trochanter to just proximal to the supracondylar flare. Bowing was defined as a line through the inside of the tip of the great trochanter and a condylar center that was outside the medullary cavity. We investigated the fracture's location, existence of coronal bowing, and bisphosphonates (BPs), glucocorticoids (GCs), and proton pump inhibitors therapy. We analyzed associations between fracture location and demographic and clinical factors. Twelve fractures were proximal, 25 were middle, and one was distal. Nineteen limbs showed femoral bowing. Thirty-one patients received BP treatment-20 patients received alendronic acid, eight risedronic acid, and three minodronic acid. Fourteen patients received a GC, and 16 received a proton pump inhibitor. There was a significant association between coronal bowing and middle fracture locations, GC therapy and proximal fracture locations, and older age and middle fracture locations. Tall height and heavy weight had an association with proximal fracture location, and short height and light weight had an association with middle fracture location. In conclusion, we provide evidence supporting a causal relationship between BP-related severely suppressed bone turnover and AFFs. We also provide evidence supporting additional influences from altered distribution of mechanical stress with femoral bowing and various factors, such as GC therapy, age, body weight, and height, which might negatively affect bone intensity and quality and result in fracture.

Bone Histology of Two Cases with Osteomalacia Related to Low-dose Adefovir

PubMed Central

Hiramatsu, Rikako; Ubara, Yoshifumi; Sawa, Naoki; Hasegawa, Eiko; Kawada, Masahiro; Imafuku, Aya; Sumida, Keiichi; Hoshino, Junichi; Takaichi, Kenmei

2016-01-01

We performed a bone histomorphometric analysis in two patients demonstrating Fanconi syndrome with hypophosphatemia, adefovir-related bone disease and chronic hepatitis B infection. Both patients had osteomalacia, but showed two different histological patterns. The osteoid volume of the patient without risedronate increased with [(osteoid volume/ bone volume)×100=18.6%]. However, the osteoid volume of the patient receiving risedronate without vitamin D analogue showed a greater increase of 53.8%. In both patients bone pain and hypophosphatemia subsided soon after the discontinuation of adefovir and the administration of phosphate derivative. These findings show that bisphosphonate may worsen this disease when this drug is administered without a vitamin D analogue. PMID:27746441

Bisphosphonate-modified gold nanoparticles: a useful vehicle to study the treatment of osteonecrosis of the femoral head

NASA Astrophysics Data System (ADS)

Fanord, Fedena; Fairbairn, Korie; Kim, Harry; Garces, Amanda; Bhethanabotla, Venkat; Gupta, Vinay K.

2011-01-01

Legg-Calvé-Perthes disease (LCPD) is a juvenile form of osteonecrosis of the femoral head that presents in children aged 2-14 years. To date, there is no effective medical therapy for treating LCPD largely due to an inability to modulate the repair process, including the predominance of bone resorption. This investigation aims to evaluate the feasibility of using gold nanoparticles (GNPs) that are surface modified with a bisphosphonate compound for the treatment of osteonecrosis at the cellular level. Studies have found osteoclast-mediated resorption to be a process that contributes significantly to the pathogenesis of femoral head deformities arising from Perthes disease. Our in vitro model was designed to elucidate the effect of alendronate-(a bisphosphonate) modified GNPs, on osteoclastogenesis and osteoclast function. RAW 264.7 macrophage cells were cultured with recombinant mouse receptor activator of NF-κB ligand (RANKL), which stimulates osteoclastogenesis, and were then treated with alendronate-modified GNPs for 24, 48, and 72 h. Cell proliferation, osteoclast function, and osteoclast morphology were evaluated by trypan blue dye exclusion assay, tartrate-resistant acid phosphatase (TRAP) staining, and transmission electron microscopy (TEM) imaging. Comparative studies were performed with GNPs that were only stabilized with citrate ions and with alendronate alone. Neither osteoclastogenesis nor osteoclast function were adversely affected by the presence of the citrate-GNP. Alendronate-modified GNPs had an enhanced effect on inducing osteoclast apoptosis and impairing osteoclast function when compared to unbound alendronate populations.

Effects of vitamin K2 (menatetrenone) and alendronate on bone mineral density and bone strength in rats fed a low-magnesium diet.

PubMed

Kobayashi, M; Hara, K; Akiyama, Y

2004-11-01

In this study, we examined changes in bone parameters and bone strength in rats fed low-Mg diets (experiment 1) and the effects of vitamin K2 (MK-4, experiment 3) and alendronate (ALN, experiment 2) in this model. In experiment 1, 5-week-old male Wistar rats were fed three low-Mg diets (Mg 9, 6, 3 mg/100 g diet) for 4 weeks. Although the cortical bone mineral content (CtBMC) and cortical thickness (CtTh) of the femoral diaphysis in all low-Mg-diet groups were the same as or greater than those in the intact group (Mg: 90 mg/100 g diet), the maximum load and elastic modulus were significantly reduced in the 3-mg-Mg group. In experiment 2, 4-week-old Wistar rats were fed a 6-mg-Mg diet for 8 weeks, and the effect of ALN (2, 20, and 200 microg/kg twice a week) was evaluated. The administration of ALN at 200 microg/kg increased the cortical bone mineral content (CtBMC), CtTh, and maximum load, but had no effect on the elastic modulus, as compared with the low-Mg-control group. In experiment 3, the effect of MK-4 was evaluated under the same conditions as in experiment 2. The administration of MK-4 had no effect on CtBMC, CtTh, or bone components of the femoral diaphysis. However, MK-4 inhibited the decreases in maximum load and elastic modulus due to the low-Mg diet. Since there is no other experimental model in which there is a decrease in bone mechanical properties without a decrease in bone mineral content, the low-Mg diet model is considered to be an excellent model for examining bone quality. Our results from this model suggest that MK-4 and ALN affect bone mechanical properties by different mechanisms.

Alendronate (ALN) combined with Osteoprotegerin (OPG) significantly improves mechanical properties of long bone than the single use of ALN or OPG in the ovariectomized rats

PubMed Central

2011-01-01

Background Alendronate (ALN) is the most common form of bisphosphonates used for the treatment of osteoporosis. Osteoprotegerin (OPG) has also been shown to reduce osteoporotic changes in both humans and experimental animals after systemic administration. The aim of this current study was to test if the anti-resorption effects of ALN may be enhanced when used in combination with OPG. Objectives To investigate the effects of ALN, OPG or combined on bone mass and bone mechanical properties in ovariectomized (OVX) rats. Methods OVX rats were treated with ALN, OPG-Fc, or OPG-Fc and ALN. Biochemical markers, trabecular bone mass, biomechanics, histomorphometry and RANKL expression in the bone tissues were examined following the treatments. Results The treatment of ALN, OPG-Fc and ALN+OPG-Fc all prevented bone loss in the OVX-rats, there was no statistical difference among the three treatment groups in terms of vertebrae BMD, mineralizing surfaces, mineral apposition rate, BFR/BS. The ALN+OPG-Fc treatment group had significantly increased the mechanical strength of lumber vertebral bodies and femoral shafts when compared to the ALN and OPG-Fc treatment groups. The RANKL protein expression in the vertebral bones was significantly decreased in the ALN and ALN+OPG-Fc treatment groups, suggesting the combined use of OPG-Fc and ALN might have amplified inhibition of bone resorption through inhibiting RANKL-dependent osteoclastogenesis. Conclusion The combined use of OPG-Fc and ALN may be a new treatment strategy for reversing bone loss and restoring bone quality in osteoprotic disorders. PMID:21752290

Fractures and mortality in relation to different osteoporosis treatments.

PubMed

Yun, Huifeng; Delzell, Elizabeth; Saag, Kenneth G; Kilgore, Meredith L; Morrisey, Michael A; Muntner, Paul; Matthews, Robert; Guo, Lingli; Wright, Nicole; Smith, Wilson; Colón-Emeric, Cathleen; O'Connor, Christopher M; Lyles, Kenneth W; Curtis, Jeffrey R

2015-01-01

Few studies have assessed the effectiveness of different drugs for osteoporosis (OP). We aimed to determine if fracture and mortality rates vary among patients initiating different OP medications. We used the Medicare 5% sample to identify new users of intravenous (IV) zoledronic acid (n=1.674), oral bisphosphonates (n=32.626), IV ibandronate (n=492), calcitonin (n=2.606), raloxifene (n=1.950), or parathyroid hormone (n=549). We included beneficiaries who were ≥65 years of age, were continuously enrolled in fee-for-service Medicare and initiated therapy during 2007-2009. Outcomes were hip fracture, clinical vertebral fracture, and all-cause mortality, identified using inpatient and physician diagnosis codes for fracture, procedure codes for fracture repair, and vital status information. Cox regression models compared users of each medication to users of IV zoledronic acid, adjusting for multiple confounders. During follow-up (median, 0.8-1.5 years depending on the drug), 787 subjects had hip fractures, 986 had clinical vertebral fractures, and 2.999 died. Positive associations included IV ibandronate with hip fracture (adjusted hazard ratio (HR), 2.37; 95% confidence interval (CI) 1.25-4.51), calcitonin with vertebral fracture (HR=1.59, 95%CI 1.04-2.43), and calcitonin with mortality (HR=1.31; 95%CI 1.02-1.68). Adjusted HRs for other drug-outcome comparisons were not statistically significant. IV ibandronate and calcitonin were associated with higher rates of some types of fracture when compared to IV zolendronic acid. The relatively high mortality associated with use of calcitonin may reflect the poorer health of users of this agent.

Comparison of the effects of alendronate sodium and calcitonin on bone-prosthesis osseointegration in osteoporotic rats.

PubMed

Chen, B-L; Xie, D-H; Zheng, Z-M; Lu, W; Ning, C-Y; Li, Y-Q; Li, F-B; Liao, W-M

2011-01-01

Alendronate (ALO) and calcitonin (CT), as commonly used antiosteoporosis drugs in current clinical practice, have been experimentally confirmed to produce the effectiveness of promoting osseointegration at the interface between prosthesis and host bone and enhancing the long-term stability of the prosthesis. Our current study compared these two drugs' effects on the osseointegration of prosthesis and found that both of them could promote bone attachment between prosthesis and host bone; moreover, ALO produced more pronounced effectiveness. A series of findings confirmed that ALO and CT improved bone attachment of implant in animals. However, which one shows stronger effectiveness has not yet been reported by previous researches. Our study compared the effects of the two commonly used antiosteoporosis drugs on the bone-prosthesis osseointegration so as to provide valuable reference for current clinical options of medication. Forty female SD rats aged 5 months were randomly set into A, B, C, and D groups. Except for group A, the others were ovariectomized to establish osteoporosis model (lumbar bone mineral density (BMD) decreased by 20% 4 weeks after ovariectomy). All the rats received prosthesis implantation at their tibial plateau. Then, the rats in groups C and D were given ALO (7 mg/kg/w) orally and CT (5 IU/kg/day) subcutaneously for 12 weeks, respectively. Prior to the execution, application of tetracycline hydrochloride for staining in vivo was done. After harvesting and embedding, the tibia with implants were cut into thin slides, then the bone histomorphometry was measured to observe the new bone around prosthesis and to calculate the osseointegration rate of the implants. By comparison, the effect of the two drugs on osseointegration was evaluated. (1) Both ALO and CT can effectively enhance the volume of bone mass surrounding the hydroxyapatite (HA) prosthesis and also significantly lever up osseointegration rate to 63.7% and 45.7%, respectively (p�

Gelatin Nanoparticles with Enhanced Affinity for Calcium Phosphate.

PubMed

Farbod, Kambiz; Diba, Mani; Zinkevich, Tatiana; Schmidt, Stephan; Harrington, Matthew J; Kentgens, Arno P M; Leeuwenburgh, Sander C G

2016-05-01

Gelatin nanoparticles can be tuned with respect to their drug loading efficiency, degradation rate, and release kinetics, which renders these drug carriers highly suitable for a wide variety of biomedical applications. The ease of functionalization has rendered gelatin an interesting candidate material to introduce specific motifs for selective targeting to specific organs, but gelatin nanoparticles have not yet been modified to increase their affinity to mineralized tissue. By means of conjugating bone-targeting alendronate to biocompatible gelatin nanoparticles, a simple method is developed for the preparation of gelatin nanoparticles which exhibit strong affinity to mineralized surfaces. It has been shown that the degree of alendronate functionalization can be tuned by controlling the glutaraldehyde crosslinking density, the molar ratio between alendronate and glutaraldehyde, as well as the pH of the conjugation reaction. Moreover, it has been shown that the affinity of gelatin nanoparticles to calcium phosphate increases considerably upon functionalization with alendronate. In summary, gelatin nanoparticles have been developed, which exhibit great potential for use in bone-specific drug delivery and regenerative medicine. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effect of Alendronate with β - TCP Bone Substitute in Surgical Therapy of Periodontal Intra-Osseous Defects: A Randomized Controlled Clinical Trial.

PubMed

Naineni, Rohini; Ravi, Vishali; Subbaraya, Dwijendra Kocherlakota; Prasanna, Jammula Surya; Panthula, Veerendranath Reddy; Koduganti, Rekha Rani

2016-08-01

Alendronate (ALN), an aminobisphosphonate, inhibits osteoclastic bone resorption and also stimulates osteogenesis. Beta-Tricalcium Phosphate (β-TCP) is an osteoconductive graft material which provides a scaffold for bone formation and also a widely used drug delivery vehicle for growth factors and antibiotics. Drug delivery vehicles, like β-TCP, improve the potency of the drugs by specific local site delivery of the drug, optimal release characteristics and easy handling. The aim of the this study was to evaluate the bone formation potential of 400μg ALN delivered in β-TCP in the treatment of periodontal intra-osseous defects. Thirty patients with periodontal defects were randomly assigned to 400μg ALN + β-TCP + Saline (test) group and β-TCP + Saline (active-control) group. Clinical parameters like Clinical Attachment Level (CAL) gain, Probing Depth (PD) reduction, post-operative Gingival Recession (GR) were assessed from the baseline, 3 months and 6 months recordings. Radiographic parameters like Linear Bone Growth (LBG), Percentage Bone Fill (%BF), and change in alveolar crest height (ACH) were assessed from baseline and 6 months radiographs. Mean measurements in the ALN test group for CAL gain (3.4 ± 0.74 mm), PD reduction (4.33 ± 0.82 mm), LBG (2.88 ± 0.88 mm), and %BF (51.98 ± 15.84%) were significantly greater with a p-value <0.05 compared to the mean measurements of CAL gain (2.20 ± 0.86 mm), PD reduction (3.20 ± 1.15 mm), LBG (1.70 ± 0.39 mm), and %BF (30.35 ± 6.88%) of the control group. There was mild alveolar crestal apposition (0.32 ± 0.68 mm) in the ALN test group and mild alveolar crestal resorption (-0.24 ± 0.40 mm) in the control group. 400μg ALN combined with β-TCP bone graft material was effective in improving soft tissue parameters, inhibiting alveolar crestal resorption and enhancing bone formation, compared to β-TCP alone.

A systematic review and economic evaluation of bisphosphonates for the prevention of fragility fractures.

PubMed

Davis, Sarah; Martyn-St James, Marrissa; Sanderson, Jean; Stevens, John; Goka, Edward; Rawdin, Andrew; Sadler, Susi; Wong, Ruth; Campbell, Fiona; Stevenson, Matt; Strong, Mark; Selby, Peter; Gittoes, Neil

2016-10-01

Fragility fractures are fractures that result from mechanical forces that would not ordinarily result in fracture. To evaluate the clinical effectiveness and safety of bisphosphonates [alendronic acid (Fosamax ® and Fosamax ® Once Weekly, Merck Sharp & Dohme Ltd), risedronic acid (Actonel ® and Actonel Once a Week ® , Warner Chilcott UK Ltd), ibandronic acid (Bonviva ® , Roche Products Ltd) and zoledronic acid (Aclasta ® , Novartis Pharmaceuticals UK Ltd)] for the prevention of fragility fracture and to assess their cost-effectiveness at varying levels of fracture risk. For the clinical effectiveness review, six electronic databases and two trial registries were searched: MEDLINE, EMBASE, The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Web of Science and BIOSIS Previews, Clinicaltrials.gov and World Health Organization International Clinical Trials Registry Platform. Searches were limited by date from 2008 until September 2014. A systematic review and network meta-analysis (NMA) of effectiveness studies were conducted. A review of published economic analyses was undertaken and a de novo health economic model was constructed. Discrete event simulation was used to estimate lifetime costs and quality-adjusted life-years (QALYs) for each bisphosphonate treatment strategy and a strategy of no treatment for a simulated cohort of patients with heterogeneous characteristics. The model was populated with effectiveness evidence from the systematic review and NMA. All other parameters were estimated from published sources. A NHS and Personal Social Services perspective was taken, and costs and benefits were discounted at 3.5% per annum. Fracture risk was estimated from patient characteristics using the QFracture ® (QFracture-2012 open source revision 38, Clinrisk Ltd, Leeds, UK) and FRAX ® (web version 3.9, University of Sheffield, Sheffield, UK) tools. The relationship between fracture risk and incremental net benefit (INB) was

Prevention of hip fractures by exposure to sunlight and pharmacotherapy in patients with Alzheimer's disease.

PubMed

Iwamoto, Jun; Sato, Yoshihiro; Tanaka, Kiyoshi; Takeda, Tsuyoshi; Matsumoto, Hideo

2009-01-01

Hypovitaminosis D and K due to malnutrition or sunlight deprivation, compensatory hyperparathyroidism, increased bone resorption, low bone mineral density (BMD), and an increased risk of falls may contribute to an increased risk of hip fractures in patients with Alzheimer's disease. The purpose of the present study was to clarify the efficacy of interventions against hip fractures in patients with Alzheimer's disease. With respect to randomized controlled trials (RCTs) regarding Alzheimer's disease and hip fractures, the literature was searched with PubMed. Three RCTs were identified, and the relative risk (RR) and 95% confidence interval (CI) were calculated for individual RCTs. Exposure to sunlight with calcium supplementation, menatetrenone (vitamin K2) plus calcium and vitamin D supplementation, and risedronate plus calcium and vitamin D supplementation improved hypovitaminosis D and hyperparathyroidism, contributing to a reduction in bone resorption. Risedronate itself strongly decreased bone resorption. Menatetrenone also decreased the serum level of undercarboxylated osteocalcin. The three interventions increased metacarpal BMD and reduced the incidence of hip fractures. The respective RRs (95% CI) were 0.22 (0.049-0.999), 0.13 (0.031-0.554), and 0.26 (0.100- 0.690). The present study clarified the efficacy of three interventions, including exposure to sunlight, menatetrenone, and risedronate with calcium and/or vitamin D supplementation against hip fractures in patients with Alzheimer's disease.

μCT-based, in vivo dynamic bone histomorphometry allows 3D evaluation of the early responses of bone resorption and formation to PTH and alendronate combination therapy.

PubMed

de Bakker, Chantal M J; Altman, Allison R; Tseng, Wei-Ju; Tribble, Mary Beth; Li, Connie; Chandra, Abhishek; Qin, Ling; Liu, X Sherry

2015-04-01

Current osteoporosis treatments improve bone mass by increasing net bone formation: anti-resorptive drugs such as bisphosphonates block osteoclast activity, while anabolic agents such as parathyroid hormone (PTH) increase bone remodeling, with a greater effect on formation. Although these drugs are widely used, their role in modulating formation and resorption is not fully understood, due in part to technical limitations in the ability to longitudinally assess bone remodeling. Importantly, it is not known whether or not PTH-induced bone formation is independent of resorption, resulting in controversy over the effectiveness of combination therapies that use both PTH and an anti-resorptive. In this study, we developed a μCT-based, in vivo dynamic bone histomorphometry technique for rat tibiae, and applied this method to longitudinally track changes in bone resorption and formation as a result of treatment with alendronate (ALN), PTH, or combination therapy of both PTH and ALN (PTH+ALN). Correlations between our μCT-based measures of bone formation and measures of bone formation based on calcein-labeled histology (r=0.72-0.83) confirm the accuracy of this method. Bone remodeling parameters measured through μCT-based in vivo dynamic bone histomorphometry indicate an increased rate of bone formation in rats treated with PTH and PTH+ALN, together with a decrease in bone resorption measures in rats treated with ALN and PTH+ALN. These results were further supported by traditional histology-based measurements, suggesting that PTH was able to induce bone formation while bone resorption was suppressed. Copyright © 2014 Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saha, Dipendu; Spurri, Amanda; Chen, Jihua

With this study, we have synthesized a nitrogen doped mesoporous carbon with the BET surface area of 1066 m 2/g, total pore volume 0.6 cm 3/g and nitrogen content of 0.5%. Total alendronate adsorption in this carbon was ~5%. The release experiments were designed in four different media with sequential pH values of 1.2, 4.5, 6.8 and 7.4 for 3, 1, 3 and 5 h, respectively and at 37 °C to imitate the physiological conditions of stomach, duodenum, small intestine and colon, respectively. Release of the drug demonstrated a controlled fashion; only 20% of the drug was released in themore » media with pH = 1.2, whereas 64% of the drug was released in pH = 7.4. This is in contrary to pure alendronate that was completely dissolved within 30 min in the first release media (pH = 1.2) only. The relatively larger uptake of alendronate in this carbon and its sustained fashion of release can be attributed to the hydrogen bonding between the drug and the nitrogen functionalities on carbon surface. Based on this result, it can be inferred that this formulation may lower the side effects of oral delivery of alendronate.« less

Osteogenic Activity of Locally Applied Small Molecule Drugs in a Rat Femur Defect Model

PubMed Central

Cottrell, Jessica A.; Vales, Francis M.; Schachter, Deborah; Wadsworth, Scott; Gundlapalli, Rama; Kapadia, Rasesh; O'Connor, J. Patrick

2010-01-01

The long-term success of arthroplastic joints is dependent on the stabilization of the implant within the skeletal site. Movement of the arthroplastic implant within the bone can stimulate osteolysis, and therefore methods which promote rigid fixation or bone growth are expected to enhance implant stability and the long-term success of joint arthroplasty. In the present study, we used a simple bilateral bone defect model to analyze the osteogenic activity of three small-molecule drug implants via microcomputerized tomography (micro-CT) and histomorphometry. In this study, we show that local delivery of alendronate, but not lovastatin or omeprazole, led to significant new bone formation at the defect site. Since alendronate impedes osteoclast-development, it is theorized that alendronate treatment results in a net increase in bone formation by preventing osteoclast mediated remodeling of the newly formed bone and upregulating osteoblasts. PMID:20625499

The anti-osteoporotic and anti-atherogenic effects of alendronate and simvastatin in ovariectomized rats fed high fat diet: A comparative study of combination therapy versus monotherapy.

PubMed

Mohamed, Maha Tarek; Abuelezz, Sally A; Atalla, Suzi Sobhy; El Aziz, Lobna Fouad Abd; Gorge, Sonia Salib

2017-05-01

Epidemiological studies suggest a possible link between osteoporosis and cardiovascular diseases. Mevalonate pathway was pointed to as a part of this link. This study was done to investigate the effects of Alendronate (Al) and Simvastatin (Sim), both act on the mevalonate pathway, on osteoporosis, dyslipidemia and atherosclerotic changes in ovariectomized (OVX) rats fed high fat diet (HFD). 60 female albino rats were equally divided into 5 groups: control sham, OVX-HFD untreated, OVX -HFD treated with Al (3mg/kg/d) or/and Sim (6mg/kg/d). Treatments were taken for 4 weeks by oral gavage and were started 8 weeks after ovariectomy. OVX-HFD untreated group exhibited a significant negative alteration in lipid profile and on different bone markers e.g. alkaline phosphatase, hydroxyproline and osteocalcin. A significant increase in body weights and on serum levels of TNFα, iNOS and leptin were also found compared to control sham group. Vascular reactivity studies revealed a significant decrease in effective concentration 50 of phenylephrine and in acetylcholine% of relaxation and a significant increase in maximum contractile response of phenylephrine. The atherosclerotic and osteoporotic changes were further confirmed histopathologically. Treatment of OVX-HFD with Al or/and Sim significantly improved these deleterious effects compared to OVX-HFD untreated group. Comparing the combination therapy versus the mono-therapy exhibited a significant improvement in different tested parameters which came in favor of the combination therapy. Al and Sim have anti-osteoporotic, anti-dyslipidemic and anti-atherosclerotic beneficial effects. Their combination has more promising effects in treatment of osteoporosis, dyslipidemia and atherosclerosis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

The relationship of antiresorptive drug use to structural findings and symptoms of knee osteoarthritis.

PubMed

Carbone, Laura D; Nevitt, Michael C; Wildy, Kathryn; Barrow, Karen D; Harris, Fran; Felson, David; Peterfy, Charles; Visser, Marjolein; Harris, Tamara B; Wang, Benjamin W E; Kritchevsky, Stephen B

2004-11-01

To examine the cross-sectional association between use of medications that have a bone antiresorptive effect (estrogen, raloxifene, and alendronate) and both the structural features of knee osteoarthritis (OA), assessed by magnetic resonance imaging (MRI) and radiography, and the symptoms of knee OA in elderly women. Women in the Health, Aging and Body Composition Study underwent MRI and radiography of the knee if they reported symptoms of knee OA, and women without significant knee symptoms were selected as controls. MR images of the knee were assessed for multiple features of OA using the Whole-Organ MRI scoring method, and radiographs were read for Kellgren and Lawrence grade and individual features of OA. Concurrent medication use and knee symptoms were assessed by interview, and knee pain severity was evaluated using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). There were 818 postmenopausal women from whom we obtained MR images of the knee and data on medication use. Among these women, 214 (26.2%) were receiving antiresorptive drugs. We found no significant association between overall use of antiresorptive drugs and the presence of knee pain and radiographic changes of OA of the knee. Use of alendronate, but not estrogen, was associated with less severity of knee pain as assessed by WOMAC scores. Both alendronate use and estrogen use were associated with significantly less subchondral bone attrition and bone marrow edema-like abnormalities in the knee as assessed by MRI, as compared with women who had not received these medications. Elderly women being treated with alendronate and estrogen had a significantly decreased prevalence of knee OA-related subchondral bone lesions compared with those reporting no use of these medications. Alendronate use was also associated with a reduction in knee pain according to the WOMAC scores.

Prostaglandin E2 (PGE2) and risedronate was superior to PGE2 alone in maintaining newly added bone in the cortical bone site after withdrawal in older intact rats

NASA Technical Reports Server (NTRS)

Ma, Y. F.; Lin, B. Y.; Jee, W. S.; Lin, C. H.; Chen, Y. Y.; Ke, H. Z.; Li, X. J.

1997-01-01

The objects of this study were (1) to determine the effects of risedronate (Ris) and prostaglandin E2 (PGE2) alone and in combination, on tibial diaphyses of older intact female rats; and (2) to observe the fate of any extra bone if formed after withdrawal of the treatment. Nine-month-old female Sprague-Dawley rats were treated with 6 mg of PGE2/kg/day, 1 or 5 micrograms of Ris/kg twice a week, or 6 mg of PGE2/kg/day plus 1 or 5 micrograms of Ris/kg twice a week for the first 60 days and followed by vehicle injections for another 60 days. Cross-sections of double fluorescent labeled, undecalcified tibial diaphyses proximal to the tibiofibular junction were processed for histomorphometry. We found that: (1) neither the 1 microgram nor the 5 micrograms of Ris treatment in the 60-day on/60-day off group showed any histomorphometric differences from age-related controls; (2) while the 60 days of PGE2 treatment added extra cortical bone (6%) on the tibial shaft (due to stimulation of periosteal, endocortical, and marrow trabecular bone formation), the new endocortical and most of the new marrow trabecular bone were lost when treatment was withdrawn; however, the new periosteal bone remained; (3) PGE2 with Ris added the same amount of new bone to tibial diaphysis as did PGE2 alone and upon withdrawal, new marrow trabecular bone was lost but new periosteal and endocortical bones were preserved in PGE2 + 1 microgram of Ris on/off group. In contrast, all the new bone was maintained in the PGE2 + 5 micrograms of Ris on/off group; (4) PGE2 + Ris cotreatment failed to block the increase in cortical bone porosity induced by PGE2; and (5) in the PGE2 alone and PGE2 + 1 microgram of Ris on/off groups bone turnover was higher than that in the PGE2 + 5 micrograms of Ris on/off group. These results indicate that on/off treatment with PGE2 and Ris is superior to PGE2 alone in that it forms the same amount of new bone during treatment, but preserves more cortical bone during

The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model.

PubMed

Hayami, Tadashi; Pickarski, Maureen; Wesolowski, Gregg A; McLane, Julia; Bone, Ashleigh; Destefano, James; Rodan, Gideon A; Duong, Le T

2004-04-01

It has been suggested that subchondral bone remodeling plays a role in the progression of osteoarthritis (OA). To test this hypothesis, we characterized the changes in the rat anterior cruciate ligament transection (ACLT) model of OA and evaluated the effects of alendronate (ALN), a potent inhibitor of bone resorption, on cartilage degradation and on osteophyte formation. Male Sprague-Dawley rats underwent ACLT or sham operation of the right knee. Animals were then treated with ALN (0.03 and 0.24 microg/kg/week subcutaneously) and necropsied at 2 or 10 weeks postsurgery. OA changes were evaluated. Subchondral bone volume and osteophyte area were measured by histomorphometric analysis. Coimmunostaining for transforming growth factor beta (TGF beta), matrix metalloproteinase 9 (MMP-9), and MMP-13 was performed to investigate the effect of ALN on local activation of TGF beta. ALN was chondroprotective at both dosages, as determined by histologic criteria and collagen degradation markers. ALN suppressed subchondral bone resorption, which was markedly increased 2 weeks postsurgery, and prevented the subsequent increase in bone formation 10 weeks postsurgery, in the untreated tibial plateau of ACLT joints. Furthermore, ALN reduced the incidence and area of osteophytes in a dose-dependent manner. ALN also inhibited vascular invasion into the calcified cartilage in rats with OA and blocked osteoclast recruitment to subchondral bone and osteophytes. ALN treatment reduced the local release of active TGF beta, possibly via inhibition of MMP-13 expression in articular cartilage and MMP-9 expression in subchondral bone. Subchondral bone remodeling plays an important role in the pathogenesis of OA. ALN or other inhibitors of bone resorption could potentially be used as disease-modifying agents in the treatment of OA.

Denosumab is really effective in the treatment of osteoporosis secondary to hypogonadism in prostate carcinoma patients? A prospective randomized multicenter international study.

PubMed

Doria, Carlo; Leali, Paolo Tranquilli; Solla, Federico; Maestretti, Gianluca; Balsano, Massimo; Scarpa, Robero Mario

2016-01-01

Osteoporosis is a complication of androgen deprivation therapy (ADT) in men with prostate carcinoma. The best defense against osteoporosis in prostate cancer is to identify patients with a high risk for fracture during the first clinical visit, select an effective anti-osteoporosis agent, and advise the patient to change his lifestyle and diet to prevent further bone loss. New agents include denosumab, a human monoclonal antibody that inhibits the RANK ligand (RANKL). RANKL promotes the formation, activity, and survival of osteoclasts and, thus, supports the breakdown of bone. This is a multicenter, randomized, double-blind prospective study on use of denosumab versus alendronate in the therapy of secondary osteoporosis related to ADT in prostate cancer patients in three European countries (Italy, France, Switzerland). In this 24-month observation study we enrolled 234 patients with diagnosis of osteoporosis underwent ADT for prostate cancer. All patients aged ≥55 years and had a dual-energy X-ray absorptiometry (DEXA) T-score <-1.0 (hip or spine, measured within last 2 years) and ≥ 1 fragility fracture. Patients were randomly assigned 1:1 to receive denosumab 60 mg subcutaneously every 6 months or alendronate (70 mg weekly) for 2 years. All patient received supplemental vitamin D (600 IU per day) and supplemental calcium to maintain a calcium intake of 1200 mg per day. Effectiveness of therapy in both groups (denosumab group and alendronate group) was assessed by changes in bone turnover markers (BTMs), Bone Mineral Density (BMD), fracture incidence, Visual Analogue Scale (VAS) score for back pain, and Short Form-8 (SF-8TM) health survey score for health-related quality of life (HRQoL). Percent changes from baseline in BTMs and BMD were assessed using the paired t test; a P-value 0.05). Mean changes in BMD at final follow-up differed significantly between two groups. BMD changes at the lumbar spine at 24 months were 5.6% with denosumab vs -1.1% with

Denosumab is really effective in the treatment of osteoporosis secondary to hypogonadism in prostate carcinoma patients? A prospective randomized multicenter international study

PubMed Central

Doria, Carlo; Leali, Paolo Tranquilli; Solla, Federico; Maestretti, Gianluca; Balsano, Massimo; Scarpa, Robero Mario

2016-01-01

Summary Introduction Osteoporosis is a complication of androgen deprivation therapy (ADT) in men with prostate carcinoma. The best defense against osteoporosis in prostate cancer is to identify patients with a high risk for fracture during the first clinical visit, select an effective anti-osteoporosis agent, and advise the patient to change his lifestyle and diet to prevent further bone loss. New agents include denosumab, a human monoclonal antibody that inhibits the RANK ligand (RANKL). RANKL promotes the formation, activity, and survival of osteoclasts and, thus, supports the breakdown of bone. Purpose This is a multicenter, randomized, double-blind prospective study on use of denosumab versus alendronate in the therapy of secondary osteoporosis related to ADT in prostate cancer patients in three European countries (Italy, France, Switzerland). Patients and methods In this 24-month observation study we enrolled 234 patients with diagnosis of osteoporosis underwent ADT for prostate cancer. All patients aged ≥55 years and had a dual-energy X-ray absorptiometry (DEXA) T-score <−1.0 (hip or spine, measured within last 2 years) and ≥ 1 fragility fracture. Patients were randomly assigned 1:1 to receive denosumab 60 mg subcutaneously every 6 months or alendronate (70 mg weekly) for 2 years. All patient received supplemental vitamin D (600 IU per day) and supplemental calcium to maintain a calcium intake of 1200 mg per day. Effectiveness of therapy in both groups (denosumab group and alendronate group) was assessed by changes in bone turnover markers (BTMs), Bone Mineral Density (BMD), fracture incidence, Visual Analogue Scale (VAS) score for back pain, and Short Form-8 (SF-8TM) health survey score for health-related quality of life (HRQoL). Percent changes from baseline in BTMs and BMD were assessed using the paired t test; a P-value 0.05). Mean changes in BMD at final follow-up differed significantly between two groups. BMD changes at the lumbar spine at 24

Use of Osteoporosis Medications in Older Nursing Facility Residents

PubMed Central

Wright, Rollin M.

2007-01-01

Introduction Epidemiologic studies demonstrated that 70 – 85% of nursing home residents have osteoporosis. Few studies report comprehensive information about treatment of osteoporosis in nursing facilities. Objective To determine the prevalence osteoporosis treatment and identify resident characteristics associated with the use of anti-resorptive medications or supplements indicated to treat osteoporosis in nursing homes. Methods The study design was cross-sectional. The Systematic Assessment of Geriatric Drug Use via Epidemiology database provided the data. From this database, 186,221 residents were identified as newly admitted to nursing facilities in Kansas, Maine, Missouri, Ohio, and South Dakota between 1998 and 2000. The outcome measure was the use of anti-resorptive medications (alendronate, risedronate, calcitonin, estrogen, raloxifene) or supplements (calcium with vitamin D) indicated for treatment of osteoporosis. The independent variables included demographic, health status and fracture risk factors. Results Of the overall sample, 9.1% received anti-resorptive medications and/or supplements indicated for osteoporosis treatment. The most commonly used treatment was the combination of calcium and vitamin D (5.0%). Calcitonin (2.5%) use exceeded that of any other anti-resorptive. Multivariable logistic regression analyses revealed that a diagnosis of osteoporosis and female gender were strongly associated with being more likely to receive an osteoporosis treatment (OR 6.34 with 95% CI 6.11–6.64 and OR 2.67 with 95% CI 2.53–2.83 respectively). The number of medications residents received was also strongly associated with receiving osteoporosis treatment. Being black and having four or more active diagnoses were strongly associated with lower odds of receiving treatment (OR 0.63 with 95% CI 0.57–0.68 and OR 0.71 with 95% CI 0.68–0.74 for 4 to 6 diagnoses). Discussion Newly admitted nursing facility residents infrequently received an indicated

The effects of topical application of bisphosphonates on replanted rat molars.

PubMed

Choi, Sung Chul; Kwon, Yong-Dae; Kim, Kwang Chul; Kim, Gue-Tae

2010-12-01

The purpose of this study was to evaluate the potential usefulness of two bisphosphonates (BPs) (etidronate and zoledronate), compared with that of alendronate, which is a well-known drug for delayed replantation, in decreasing or preventing inflammatory root resorption and replacement root resorption in replanted teeth. Eighty-four Sprague Dawley rat maxillary first molars were extracted, dried for 60 min and then replanted after root treatment. The rats were divided into four groups (control, alendronate, etidronate, zoledronate) as following treatments of avulsed root before replantation. At 7, 14, and 28 days postreplantation, the animals were sacrificed and the samples obtained and process for microscopic analysis. The data were statistically analyzed with the SPSS procedure, anova test and each test was complemented by the Tukey's post hoc test. The result indicated that topical application of alendronate and zoledronate, both nitrogen containing BPs, prevented inflammatory root resorption and inflammatory cell response in the delayed replantation model. Both drugs were demonstrated similar effects in the delayed tooth replantation model (P = 0.9). Etidronate did not prevent inflammatory root resorption and inflammation in the delayed replantation (P < 0.05). No significant differences in replacement root resorption were observed among all drugs. These results suggest that when teeth are dried and not replanted immediately, zoledronate, like alendronate, may prevent root resorption and facilitates the regeneration of periodontal tissues after replantation. © 2010 John Wiley & Sons A/S.

76 FR 21381 - Pediatric Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-15

... Committee will meet to discuss pediatric-focused safety reviews, as mandated by the Best Pharmaceuticals for Children Act (Pub. L. 107-109) and the Pediatric Research Equity Act (Pub. L. 110-85) for Bepreve...), Actonel (risedronate), Hiberix [Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)], and Valcyte...

Denosumab in Postmenopausal Osteoporosis: What the Clinician Needs to Know

PubMed Central

Lewiecki, E. Michael

2009-01-01

Denosumab is a subcutaneously (SC) administered investigational fully human monoclonal antibody to receptor activator of nuclear factor-kB ligand (RANKL), a cytokine member of the tumor necrosis factor family that is the principal mediator of osteoclastic bone resorption. RANKL stimulates the formation, activity, and survival of osteoclasts, and is implicated in the pathogenesis of postmenopausal osteoporosis and other skeletal disorders associated with increased bone remodeling. Denosumab binds RANKL, preventing it from binding to RANK, thereby reducing the formation, activity, and survival of osteoclasts and slowing the rate of bone resorption. Postmenopausal women with low bone mineral density (BMD) treated with denosumab have a reduction of bone turnover markers and an increase in BMD that is rapid, sustained, and reversible. In postmenopausal women with osteoporosis, denosumab reduces the risk of vertebral, hip, and nonvertebral fractures. In postmenopausal women with low BMD randomized to receive denosumab or alendronate, denosumab is associated with a significantly greater increase in BMD and further reduction in bone turnover markers compared with alendronate. In postmenopausal women with low BMD who were previously treated with alendronate, those who switched to denosumab have a significantly greater BMD increase and further reduction in bone turnover markers compared with those continuing alendronate. Denosumab is well tolerated with a favorable safety profile. It is a promising emerging drug for the prevention and treatment of osteoporosis, offering a long dosing interval of every 6 months and convenient SC dosing, with the potential of improving long-term adherence to therapy compared with current oral treatments. PMID:22870424

Vitamin D, osteoprotegerin/receptor activator of nuclear factor-kappaB ligand (OPG/RANKL) and inflammation with alendronate treatment in HIV-infected patients with reduced bone mineral density.

PubMed

Natsag, J; Kendall, M A; Sellmeyer, D E; McComsey, G A; Brown, T T

2016-03-01

The aim of the study was to determine the effect of alendronate (ALN) on inflammatory markers and osteoprotegerin (OPG)/receptor activator of nuclear factor-kappaB ligand (RANKL), and to explore the associations of baseline systemic inflammation and vitamin D status on the bone mineral density (BMD) response to ALN. Eighty-two HIV-positive patients with lumbar spine T-score ≤ -1.5 were randomized to ALN 70 mg weekly or placebo for 48 weeks; all received calcium carbonate 500 mg/vitamin D3 200 IU twice daily. Serum C-telopeptide (CTx) and BMD were assessed at baseline and week 48. Stored plasma samples in 70 subjects were assayed for levels of 25-hydroxyvitamin D (25(OH)D), OPG, RANKL, interleukin (IL)-6 and soluble receptors for tumour necrosis factor (TNF)-α 1 and 2 (sTNFR 1 and 2). ALN increased BMD more than placebo at both the lumbar spine (difference ALN - placebo 2.64%; P = 0.011) and the total hip (difference 2.27%; P = 0.016). No within- or between-arm differences in OPG, RANKL or inflammatory markers were observed over 48 weeks. High baseline CTx and sTNFR2 were associated with a more robust BMD response to ALN over 48 weeks at the lumbar spine [difference 5.66%; 95% confidence interval (CI) 3.50, 7.82; P < 0.0001] and total hip (difference 4.99%; 95% CI 2.40, 7.57; P = 0.0002), respectively. Baseline 25(OH)D < 32 ng/mL was associated with larger increases in total hip BMD over 48 weeks, independent of ALN treatment (P = 0.014). Among HIV-positive patients, higher baseline bone resorption and TNF-α activity were associated with an increased BMD response to ALN. The greater BMD response in those with lower vitamin D reinforces the importance of vitamin D supplementation with bisphosphonate treatment. © 2015 British HIV Association.

Would Be Prophylactic Administrations of Low Concentration of Alendronate an Alternative for Improving the Craniofacial Bone Repair? A Preliminary Study Focused in the Period of Cellular Differentiation and Tissue Organization.

PubMed

Göhringer, Isabella; Muller, Carmem L Storrer; Cunha, Emanuelle Juliana; Passoni, Giuliene Nunes De Souza; Vieira, Juliana Souza; Zielak, João Cesar; Scariot, Rafaela; Deliberador, Tatiana Miranda; Giovanini, Allan Fernando

2017-10-01

Alendronate (ALN) is a nitrogen-bisphosphonate that may induce an anabolic effect on craniofacial bone repair when administrated in low doses. Based on this premise, this study analyzed the influence of prophylactic low doses of ALN on bone healing in defects created in rabbit mandible. A 5 × 2-mm diameter deep defect was created in the calvaria of 28 rabbits. Fourteen of these rabbits received previously 50 μg/kg of 1% sodium ALN for 4 weeks, while the other rabbits received only 0.9% physiological saline solution (control). Animals were euthanized at 15 and 60 days postsurgery (n = 7), and the data were analyzed using histomorphometry and immunohistochemistry using the anti-CD34, bone morphogenetic protein -2 (BMP-2), and transforming growth factor (TGF)-β1 antibodies. On the 15th day postsurgery, the specimens that received previous treatment with ALN demonstrated large vascular lumen and intense positivity to CD34 either concentrated in endothelium or cells spread among the reparative tissue. These results coincided with intense positivity for BMP-2+ cells and TGF-β1 that was concentrated in both cells and perivascular area. In contrast, the control group revealed scarce cells that exhibited CD34, BMP-2+, and the TGF-β1 was restricted for perivascular area on well-formed granulation tissue. These patterns of immunohistochemical result, especially found on the 15th day of analysis, seem to be responsible for the development of larger quantities of bone matrix in the specimens that receive ALN on the 60th day postsurgery. These preliminary results showed that the prophylactic administration of low doses of ALN might be an alternative to craniofacial bone craniofacial bone repair because it increases the immunopositivity for TGF-β1 and consequently improves the CD34+ and BMP-2+ cells on reparative sites.

Effects of eight-month treatment with ONO-5334, a cathepsin K inhibitor, on bone metabolism, strength and microstructure in ovariectomized cynomolgus monkeys.

PubMed

Ochi, Yasuo; Yamada, Hiroyuki; Mori, Hiroshi; Nakanishi, Yasutomo; Nishikawa, Satoshi; Kayasuga, Ryoji; Kawada, Naoki; Kunishige, Akiko; Hashimoto, Yasuaki; Tanaka, Makoto; Sugitani, Masafumi; Kawabata, Kazuhito

2014-08-01

This study examined the effect of ONO-5334, a cathepsin K inhibitor, on bone turnover, mineral density (BMD), mechanical strength and microstructure in ovariectomized (OVX) cynomolgus monkeys. Vehicle, ONO-5334 (3, 10 or 30 mg/kg) or alendronate (0.5 mg/kg) was orally administered for eight months to sham- and OVX-operated monkeys. ONO-5334 dose-dependently suppressed OVX-induced increase in bone turnover markers (urinary C-terminal cross-linking telopeptide of type I collagen (CTX) and serum osteocalcin). At the dose of 30 mg/kg, ONO-5334 maintained urinary CTX at nearly zero level and kept serum osteocalcin around the level of the sham animals. Marker levels in the alendronate-treated animals were similar to those in the sham animals throughout the study. ONO-5334 dose-dependently reversed the effect of OVX on vertebral BMD as measured by dual-energy X-ray absorptiometry (DXA) with improvement of bone mechanical strength. Both ONO-5334 and alendronate suppressed OVX-induced changes in vertebral microstructure and turnover state. In the femoral neck, peripheral quantitative computed tomography (pQCT) analysis showed that ONO-5334 increased total and cortical BMD. In particular, ONO-5334 significantly increased cortical BMD with improvement of bone mechanical strength. In microstructural analysis, alendronate suppressed OVX-induced increase in femoral mid-shaft osteonal bone formation rate (BFR) to a level below that recorded in the sham group, whereas ONO-5334 at 30 mg/kg did not suppress periosteal, osteonal and endocortical BFR. This finding supports the significant effect of ONO-5334 on cortical BMD and mechanical strength in the femoral neck. The results of this study suggest that ONO-5334 has good therapeutic potential for the treatment of osteoporosis. Copyright © 2014 Elsevier Inc. All rights reserved.

Current and potential future drug treatments for osteoporosis.

PubMed Central

Patel, S

1996-01-01

There has been a major interest in the drug treatment of osteoporosis and an increase in the number of drugs available in most countries. The ideal drug (one which increases or restores bone density and trabecular connectivity) is still not available. However, in patients with relatively preserved trabecular connectivity and moderately reduced bone density, several agents have shown substantial clinical benefit. Oestrogens are still the mainstay of drug treatment, but the risks of breast cancer versus the cardiovascular and skeletal benefits with long term use have to be assessed in the individual. Newer tissue specific oestrogens show some promise in this respect. The bisphosphonates and possibly fluoride are likely to be the major alternatives to oestrogens in the medium term. The newer bisphosphonates, alendronate and in the future risedronate, are likely to supersede etidronate. Calcitriol probably has a limited role, confined to those patients in whom HRT or bisphosphonates are not appropriate. Calcium supplementation, or an increase in dietary intake if deficient, irrespective of which agent is used, is also of benefit. In older patients there is considerable support for using a combination of calcium and vitamin D. Whether combination treatment, for example oestrogens, bisphosphonates, and calcium together, will result in greater efficacy remains to be conclusively shown, but may be an attractive option in younger patients with higher bone turnover. Apart from fluoride, bone formation stimulators are unlikely to have a major role until the next century, although it may be possible to use growth factors as part of an ADFR regimen (A = activate remodelling, D = depress resorption, F = free formation, and R = repeat). This is still an important theoretical approach and needs further work with newer agents to see if increased efficacy can be found. In addition sequential treatment may be necessary in view of the limited time periods over which particular agents

Impact of pharmaceutical care on knowledge, quality of life and satisfaction of postmenopausal women with osteoporosis.

PubMed

Lai, Pauline Siew Mei; Chua, Siew Siang; Chan, Siew Pheng

2013-08-01

This study describes the analysis of secondary outcomes from a previously published randomised controlled trial, which assessed the effects of pharmaceutical care on medication adherence, persistence and bone turnover markers. The main focus of this manuscript is the effect of the provision of pharmaceutical care on these secondary outcomes, and details on the design of the intervention provided, the osteoporosis care plan and materials used to deliver the intervention. To evaluate the effects of pharmaceutical care on knowledge, quality of life (QOL) and satisfaction of postmenopausal osteoporotic women prescribed bisphosphonates, and their associating factors. Randomised controlled trial, performed at an osteoporosis clinic of a tertiary hospital in Malaysia. Postmenopausal women diagnosed with osteoporosis (T-score ≤-2.5/lowtrauma fracture), just been prescribed weekly alendronate/risedronate were randomly allocated to receive intervention or standard care (controls). Intervention participants received a medication review, education on osteoporosis, risk factors, lifestyle modifications, goals of therapy, side effects and the importance of medication adherence at months 0, 3, 6 and 12. Knowledge, QOL and satisfaction. A total of 198 postmenopausal osteoporotic women were recruited: intervention = 100 and control = 98. Intervention participants reported significantly higher knowledge scores at months 3 (72.50 vs. 62.50 %), 6 (75.00 vs. 65.00 %) and 12 (78.75 vs. 68.75 %) compared to control participants. QOL scores were also lower (which indicates better QOL) at months 3 (29.33 vs. 38.41), 6 (27.50 vs. 36.56) and 12 (27.53 vs. 37.56) compared to control participants. Similarly, satisfaction score was higher in intervention participants (93.67 vs. 84.83 %). More educated women, with back pain, who were provided pharmaceutical care had better knowledge levels. Similarly, older, more educated women, with previous falls and back pain tend to have poorer QOL, whilst

Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update From the American College of Physicians.

PubMed

Qaseem, Amir; Forciea, Mary Ann; McLean, Robert M; Denberg, Thomas D

2017-06-06

This guideline updates the 2008 American College of Physicians (ACP) recommendations on treatment of low bone density and osteoporosis to prevent fractures in men and women. This guideline is endorsed by the American Academy of Family Physicians. The ACP Clinical Guidelines Committee based these recommendations on a systematic review of randomized controlled trials; systematic reviews; large observational studies (for adverse events); and case reports (for rare events) that were published between 2 January 2005 and 3 June 2011. The review was updated to July 2016 by using a machine-learning method, and a limited update to October 2016 was done. Clinical outcomes evaluated were fractures and adverse events. This guideline focuses on the comparative benefits and risks of short- and long-term pharmacologic treatments for low bone density, including pharmaceutical prescriptions, calcium, vitamin D, and estrogen. Evidence was graded according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. The target audience for this guideline includes all clinicians. The target patient population includes men and women with low bone density and osteoporosis. ACP recommends that clinicians offer pharmacologic treatment with alendronate, risedronate, zoledronic acid, or denosumab to reduce the risk for hip and vertebral fractures in women who have known osteoporosis. (Grade: strong recommendation; high-quality evidence). ACP recommends that clinicians treat osteoporotic women with pharmacologic therapy for 5 years. (Grade: weak recommendation; low-quality evidence). ACP recommends that clinicians offer pharmacologic treatment with bisphosphonates to reduce the risk for vertebral fracture in men who have clinically recognized osteoporosis. (Grade: weak recommendation; low-quality evidence). ACP recommends against bone density monitoring during the 5-year pharmacologic treatment period for osteoporosis in women. (Grade: weak recommendation; low

Odanacatib Restores Trabecular Bone of Skeletally Mature Female Rabbits With Osteopenia but Induces Brittleness of Cortical Bone: A Comparative Study of the Investigational Drug With PTH, Estrogen, and Alendronate.

PubMed

Khan, Mohd Parvez; Singh, Atul Kumar; Singh, Abhishek Kumar; Shrivastava, Pragya; Tiwari, Mahesh Chandra; Nagar, Geet Kumar; Bora, Himangshu Kousik; Parameswaran, Venkitanarayanan; Sanyal, Sabyasachi; Bellare, Jayesh R; Chattopadhyay, Naibedya

2016-03-01

Cathepsin K (CK), a lysosomal cysteine protease, is highly expressed in mature osteoclasts and degrades type 1 collagen. Odanacatib (ODN) is a selective and reversible CK inhibitor that inhibits bone loss in preclinical and clinical studies. Although an antiresorptive, ODN does not suppress bone formation, which led us to hypothesize that ODN may display restorative effect on the osteopenic bones. In a curative study, skeletally mature New Zealand rabbits were ovarectomized (OVX) and after induction of bone loss were given a steady-state exposure of ODN (9 mM/d) for 14 weeks. Sham-operated and OVX rabbits treated with alendronate (ALD), 17b-estradiol (E2), or parathyroid hormone (PTH) served as various controls. Efficacy was evaluated by assessing bone mineral density (BMD), bone microarchitecture (using micro-computed tomography), fluorescent labeling of bone, and biomechanical strength. Skeletal Ca/P ratio was measured by scanning electron microscopy (SEM) with X-ray microanalysis, crystallinity by X-ray diffraction, and bone mineral density distribution (tissue mineralization) by backscattered SEM. Between the sham and ODN-treated osteopenic groups, lumbar and femur metaphyseal BMD, Ca/P ratio, trabecular microstructure and geometric indices, vertebral compressive strength, trabecular lining cells, cortical parameters (femoral area and thickness and periosteal deposition), and serum P1NP were largely comparable. Skeletal improvements in ALD-treated or E2-treated groups fell significantly short of the sham/ODN/PTH group. However, the ODN group displayed reduced ductility and enhanced brittleness of central femur, which might have been contributed by higher crytallinity and tissue mineralization. Rabbit bone marrow stromal cells expressed CK and when treated with ODN displayed increased formation of mineralized nodules and decreased apoptosis in serum-deficient medium compared with control. In vivo, ODN did not suppress remodeling but inhibited osteoclast activity

Enhancing the Breadth and Efficacy of Therapeutic Vaccines for Breast Cancer

DTIC Science & Technology

2012-10-01

this collaboration. BODY: Generate tumor lysates pooled from BC cell lines of each major subtype (luminal, HER2+, basal) [Task 4a] Given the...presented epitopes. The IEDB provides downloadable command-line driven tools for the prediction of input sequence binding affinity to MHC class I or class ...69 9 Epirubicin 317 nM 29 16 35 10 Etoposide 4 µM 60 43 48 11 Fascaplysin 167 nM 22 -19 -14 12 Ibandronate 63 µM -34 -56 -52 13 ICRF-193 11 µM

The effect of weight training on bone mineral density and bone turnover in postmenopausal breast cancer survivors with bone loss: a 24-month randomized controlled trial.

PubMed

Waltman, N L; Twiss, J J; Ott, C D; Gross, G J; Lindsey, A M; Moore, T E; Berg, K; Kupzyk, K

2010-08-01

This study examined whether 24 months of weight training exercises enhanced the effectiveness of risedronate, calcium, and vitamin D in maintaining or improving bone mineral density (BMD) in 223 postmenopausal breast cancer survivors. Subjects who were > or =50% adherent to exercise had no improvement in BMD but were less likely to lose BMD. This study examined whether (1) postmenopausal breast cancer survivors (BCS) with bone loss taking 24 months of risedronate, calcium, and vitamin D had increased bone mineral density (BMD) at the total hip, femoral neck, L1-L4 spine, total radius and 33% radius, and decreased bone turnover; (2) subjects who also participated in strength/weight training (ST) exercises had greater increases in BMD and greater decreases in bone turnover; and (3) subjects who also exercised were more likely to preserve (at least maintain) BMD. Postmenopausal BCS (223) were randomly assigned to exercise plus medication or medication only groups. Both groups received 24 months of 1,200 mg of calcium and 400 IU of vitamin D daily and 35 mg of risedronate weekly, and the exercise group additionally had ST exercises twice weekly. After 24 months, women who took medications without exercising had significant improvements in BMD at the total hip (+1.81%) and spine (+2.85%) and significant decreases in Alkphase B (-8.7%) and serum NTx (-16.7%). Women who also exercised had additional increases in BMD at the femoral neck (+0.29%), total hip (+0.34%), spine (+0.23%), total radius (+0.30%), and additional decreases in Alkphase B (-2.4%) and Serum NTx (-6.5%). Additional changes in BMD and bone turnover with exercise were not significant. Subjects who were > or =50% adherent to exercise were less likely to lose BMD at the total hip (chi-square [1] = 4.66, p = 0.03) and femoral neck (chi-square [1] = 4.63, p = 0.03). Strength/weight training exercises may prevent loss of BMD in postmenopausal BCS at risk for bone loss.

Bone mineral density changes of lumbar spine and femur in osteoporotic patient treated with bisphosphonates and beta-hydroxy-beta-methylbutyrate (HMB): Case report.

PubMed

Tatara, Marcin R; Krupski, Witold; Majer-Dziedzic, Barbara

2017-10-01

Currently available approaches to osteoporosis treatment include application of antiresorptive and anabolic agents influencing bone tissue metabolism. The aim of the study was to present bone mineral density (BMD) changes of lumbar spine in osteoporotic patient treated with bisphosphonates such as ibandronic acid and pamidronic acid, and beta-hydroxy-beta-methylbutyrate (HMB). BMD and volumetric BMD (vBMD) of lumbar spine were measured during the 6 year observation period with the use of dual-energy X-ray absorptiometry (DEXA) and quantitative computed tomography (QCT). The described case report of osteoporotic patient with family history of severe osteoporosis has shown site-dependent response of bone tissue to antiosteoporotic treatment with bisphosphonates. Twenty-five-month treatment with ibandronic acid improved proximal femur BMD with relatively poor effects on lumbar spine BMD. Over 15-month therapy with pamidronic acid was effective to improve lumbar spine BMD, while in the proximal femur the treatment was not effective. A total of 61-week long oral administration with calcium salt of HMB improved vBMD of lumbar spine in the trabecular and cortical bone compartments when monitored by QCT. Positive effects of nearly 2.5 year HMB treatment on BMD of lumbar spine and femur in the patient were also confirmed using DEXA method. The results obtained indicate that HMB may be applied for the effective treatment of osteoporosis in humans. Further studies on wider human population are recommended to evaluate mechanisms influencing bone tissue metabolism by HMB.

Desalted Duck Egg White Peptides Promote Calcium Uptake and Modulate Bone Formation in the Retinoic Acid-Induced Bone Loss Rat and Caco-2 Cell Model.

PubMed

Hou, Tao; Liu, Yanshuang; Kolba, Nikolai; Guo, Danjun; He, Hui

2017-05-12

Desalted duck egg white peptides (DPs) have been proven to promote calcium uptake in Caco-2 cells and rats treated with a calcium-deficient diet. The retinoic acid-induced bone loss model was used to evaluate the effect of DPs on calcium absorption and bone formation. Three-month-old Wistar female rats were treated with 0.9% saline, DPs (800 mg/kg), or alendronate (5 mg/kg) for three weeks immediately after retinoic acid treatment (80 mg/kg) once daily for two weeks. The model group was significantly higher in serum bone alkaline phosphatase than the other three groups ( p < 0.05), but lower in calcium absorption rate, serum osteocalcin, bone weight index, bone calcium content, bone mineral density, and bone max load. After treatment with DPs or alendronate, the absorption rate increased and some serum and bone indices recovered. The morphology results indicated bone tissue form were ameliorated and numbers of osteoclasts decreased after supplementation with DPs or alendronate. The in vitro study showed that the transient receptor potential vanilloid 6 (TRPV6) calcium channel was the main transport pathway of both DPs and Val-Ser-Glu-Glu peptitde (VSEE), which was identified from DPs. Our results indicated that DPs could be a promising alternative to current therapeutic agents for bone loss because of the promotion of calcium uptake and regulation of bone formation.

Complex regional pain syndrome type 1: Analysis of 108 patients.

PubMed

Pendón, Gisela; Salas, Adrian; García, Mercedes; Pereira, Dora

Complex regional pain syndrome (CRPS) type 1 is characterized by the presence of pain, edema, functional impotence, impaired mobility, trophic changes, vasomotor instability and bone demineralization. We carried out a retrospective and prospective, descriptive, observational study of 108 patients over 18 years of age with suspected CRPS who met Doury's criteria. We recorded demographic data, clinical characteristics, comorbidities, previous predisposing conditions and triggering factors, such as injury or fracture. We evaluated laboratory data, serial plain X-rays, 3-phase bone scintigraphy with technetium 99 and bone density scan, as well as drug treatment, rehabilitation and disease course. In all, 89% of the 108 patients were women with an average age of 54.8±12.4 years. The time between the onset of the symptoms and the first visit to a physician was 3.1 months. The most common triggering factor was injury (91.7%). The most frequent psychological factor was anxiety (42.6%). All the patients reported pain and 99.07% had impaired mobility. The most frequently affected part of the body was the hand (75%; 81/108 patients) followed by the shoulder, in the shoulder-hand syndrome. All the patients had serial X-rays and changes were observed in 93.5%. Three-phase bone scintigraphy revealed evidence of disease in all 32 of the patients who underwent this study. Bone density scanning was performed in 54 patients (50%). All the patients were treated with nonsteroidal anti-inflammatory drugs, mainly diclofenac (60%). Calcium therapy was initiated in 106 patients (98.2%) and vitamin D3 therapy in 97.2%. All the patients received bisphosphonates, primarily alendronate and ibandronate (67.6% and 27.8%, respectively). Thirty-six patients (33.3%) received corticosteroids. All of the evaluated patients underwent rehabilitation involving occupational therapy. The average time to recovery was 6.31 months (range, 4-24). The outcome was favorable in 88.9% of the patients. This

Four-year follow-up of pregnancy-associated osteoporosis: a case report.

PubMed

Takahashi, Naoto; Arai, Itaru; Kayama, Satoru; Ichiji, Kenji; Fukuda, Hironari; Handa, Jun-Ichi; Konno, Shin-Ichi

2014-01-01

A 22-year-old woman presented with complaints of severe pain in a wide region of the thoracolumbar spine. She developed severe pain in the thoracolumbar spine region 2 months after her first delivery and was referred 1 month later. A lateral thoracic X-ray showed depressed degenerative vertebrae (T7, T9). One month after the initial examination, thoracic sagittal magnetic resonance imaging showed low intensity areas on T1-weighted imaging and iso-high intensity areas on T2-weighted imaging at T5, 7, 8, 9 and 11. Bone mineral density measured by ultrasound was low (%YAM 76%). The bone metabolic markers were high, suggesting accelerated osteoclast activity. These findings prompted a diagnosis of pregnancy-associated osteoporosis. She was asked to stop breastfeeding and to wear a lumbar brace, and treatment with nutritional calcium, activated vitamin D3, and risedronate sodium was started. Her low back pain almost disappeared after treatment. Bone metabolic markers showed normalization 8 months after the initial examination. Risedronate sodium was stopped 2 years and 2 months after the initial examination. Teriparatide treatment was started because her bone mineral density remained low; however, the osteoblast marker P1NP was not increased 5 months after the start of teriparatide treatment.

Persistence with biologic therapies in the Medicare coverage gap.

PubMed

Tamariz, Leonardo; Uribe, Claudia L; Luo, Jiacong; Hanna, John W; Ball, Daniel E; Krohn, Kelly; Meadows, Eric S

2011-11-01

To describe persistence with teriparatide and other biologic therapies in Medicare Part D plans with and without a coverage gap. Retrospective (2006) cohort study of Medicare Part D prescription drug plan beneficiaries from a large benefits company. Two plans with a coverage gap (defined as "basic") were combined and compared with a single plan with coverage for generic and branded medications (defined as "complete"). Patients taking alendronate (nonbiologic comparator), teriparatide, etanercept, adalimumab, interferon β-1a, or glatiramer acetate were selected for the study. For patients with complete coverage, equivalent financial thresholds were used to define the "gap."The definition of discontinuation was failure to fill the index prescription after reaching the gap. For alendronate, 27% of 133,260 patients had enrolled in the complete plan. Patients taking biologic therapies had more commonly enrolled in complete plans: teriparatide (66% of 6221), etanercept (58% of 1469), adalimumab (52% of 824), interferon β-1a (60% of 438), and glatiramer acetate (53% of 393). For patients taking either alendronate or teriparatide, discontinuation rates were higher in the basic, versus complete, plan (adjusted odds ratios, 2.02 and 3.56, respectively). Discontinuation did not significantly vary by plan type for etanercept, adalimumab, interferon β-1a, or glatiramer acetate. For patients who reached the coverage gap, discontinuation was more likely for patients taking osteoporosis (OP) medication. Not having a coverage gap was associated with improved persistence with OP treatment.

A novel growth hormone receptor gene deletion mutation in a patient with primary growth hormone insensitivity syndrome (Laron syndrome).

PubMed

Yamamoto, Hiroyasu; Kouhara, Haruhiko; Iida, Keiji; Chihara, Kazuo; Kasayama, Soji

2008-04-01

Growth hormone (GH) insensitivity syndrome (Laron syndrome) is known to be caused by genetic disorders of the GH-IGF-1 axis. Although many mutations in the GH receptor have been identified, there have been only a few reports of deletions of the GH receptor gene. A Japanese adult female patient with Laron syndrome was subjected to chromosome analysis with basic G-banding and also with a high accuracy technique. Each exon of the GH receptor gene was amplified by means of PCR. Since this patient was diagnosed with osteoporosis, the effects of alendronate on bone mineral density (BMD) were also examined. The chromosome analysis with the high accuracy technique demonstrated a large deletion of the short arm in one allele of chromosome 5 from p11 to p13.1 [46, XX, del (5) (p11-p13.1)]. PCR amplification of exons of the GH receptor gene showed that only exons 2 and 3 were amplified. Low-dose IGF-1 administration (30microg/kg body weight) failed to increase her BMD, whereas alendronate administration resulted in an increase associated with a decrease in urinary deoxypyridinoline (DPD) and serum osteocalcin concentrations. The GH receptor gene of the patient was shown to lack exons 4-10. To the best of our knowledge, this is the third case report of Laron syndrome with large GH receptor deletion. Alendronate was effective for the enhancement of BMD.

Magnetic resonance imaging in the evaluation of clinical treatment of otospongiosis: a pilot study.

PubMed

de Oliveira Vicente, Andy; Chandrasekhar, Sujana S; Yamashita, Helio K; Cruz, Oswaldo Laercio M; Barros, Flavia A; Penido, Norma O

2015-06-01

To evaluate the applicability of magnetic resonance imaging (MRI) as a method for monitoring the activity of otospongiotic lesions before and after clinical treatment. Prospective, randomized, controlled, double-blind study. One single tertiary care institution in a large, cosmopolitan city. Twenty-six patients (n = 42 ears) with clinical, audiometric, and tomographic diagnosis of otosclerosis were enrolled. If computed tomography (CT) demonstrated active lesions, these patients underwent MRI to detect otospongiotic foci, seen as areas of gadolinium enhancement. Patients were divided into 3 groups and received treatment with placebo, sodium alendronate, or sodium fluoride for 6 months. After this period, clinical and audiometric evaluations and a second MRI were performed. Each MRI was evaluated by both a neuroradiologist and an otolaryngologist in a subjective (visual) and objective (using specific eFilm Workstation software) manner. Otospongiosis was most predominantly identified in the region anterior to the oval window, and this site was reliable for comparing pre- and posttreatment scans. The patients in the alendronate and sodium fluoride groups had MRI findings that suggested a decrease in activity of otospongiotic lesions, more relevant in the alendronate group. These findings were statistically significant for both subjective and objective MRI evaluations. MRI shows higher sensitivity than clinical or audiometric assessment for detecting reduction in activity of otospongiosis. The objective MRI evaluation based on software analysis was the most accurate method of monitoring clinical treatment response in otospongiosis. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.

The effects of pentoxifylline adminstration on fracture healing in a postmenopausal osteoporotic rat model

PubMed Central

Vashghani Farahani, Mohammad Mahdi; Ahadi, Reza; Abdollahifar, Mohammadamin

2017-01-01

Previous studies report positive effects of pentoxifylline (PTX) alone or in combination with other drugs on some pathologic bone diseases as well as an ability to accelerate osteogensis and fracture healing in both animal models and human patients. The aim of this present study was to evaluate the effects of PTX administration on Hounsfield unit and bone strength at catabolic response (bone resorbing) of a fracture in an experimental rat model of ovariectomy induced osteoporosis (OVX-D). Thirty adult female rats were divided into groups as follows: 1 (OVX, control, no treatment); 2 (OVX, sham: daily distilled water); 3 (OVX, daily alendronate: 3 mg/kg); 4 (OVX, twice daily 100 mg/kg PTX) and 5 (OVX, PTX+alenderonate). OVX was induced by bilateral ovariectomy in all rats. A complete standardized osteotomy of the right femur was made after 3.5 months. PTX and alendronate treatments were performed for eight weeks. Then, rats were euthanized and had its right femur subjected to computerized tomography scanning for measuring Hounsfield unit; eventually, the samples were sent for a three point bending test for evaluation of the bone strength. Administration of PTX with 200 mg/kg and alendronate alone and in combination showed no significant alteration in Hounsfield unit and biomechanical properties of repairing callus of the complete osteotomy compared with the control group. Results showed increased bending stiffness and stress high load mean values of repairing complete osteotomy in PTX-treated rats compared to the control OVX-D. PMID:28400835

Effect of methylprednisolone on bone mineral density in rats with ovariectomy-induced bone loss and suppressed endogenous adrenaline levels by metyrosine

PubMed Central

Yilmaz, Mehmet; Isaoglu, Unal; Uslu, Turan; Yildirim, Kadir; Seven, Bedri; Akcay, Fatih; Hacimuftuoglu, Ahmet

2013-01-01

Objectives: In this study, effect of methylprednisolone on bone mineral density (BMD) was investigated in rats with overiectomy induced bone lose and suppressed endogenous adrenalin levels, and compared to alendronate. Materials and Methods: Severity of bone loss in the examined material (femur bones) was evaluated by BMD measurement. Results: The group with the highest BMD value was metyrosinemetyrosine + methylprednisolone combination (0.151 g/cm2), while that with the lowest BMD was methylprednisolone (0.123 g/cm2). Alendronate was effective only when used alone in ovariectomized rats (0.144 g/cm2), but not when used in combination with methylprednisolone (0.124 g/cm2). In the ovariectomized rat group which received only metyrosine, BMD value was statistically indifferent from ovariectomized control group. Conclusions: Methylprednisolone protected bone loss in rats with suppressed adrenaline levels because of metyrosinemetyrosine. PMID:24014908

Vibrational bone characteristics versus bone density for the assessment of osteoporosis in ovariectomized rats.

PubMed

Anastassopoulos, G; Panteliou, S; Christopoulou, G; Stavropoulou, A; Panagiotopoulos, E; Lyritis, G; Khaldi, Lubna; Varakis, J; Karamanos, N

2010-01-01

Our previous research findings suggested this integrated study in order to monitor changes of bone properties and assess bone integrity using vibrational characteristics in osteoporosis. The method is based on measurement of the bone dynamic characteristic modal damping factor (MDF). The experimental animal model is ovariectomized rat followed by alendronate treatment. According to the experimental design, adult female Wistar rats are ovariectomized and 60 days later, with confirmed osteoporosis, the population is divided into two groups. One is administered alendronate and the second is given no treatment. Furthermore, established techniques such as pQCT and histomorphometry are applied at all time points, in order to compare and correlate to MDF. The results indicate induction of osteoporosis due to ovariectomy and render MDF capable of monitoring changes in bone material properties and architecture, with high sensitivity and repeatability.

Effect of odanacatib on bone turnover markers, bone density and geometry of the spine and hip of ovariectomized monkeys: a head-to-head comparison with alendronate.

PubMed

Williams, Donald S; McCracken, Paul J; Purcell, Mona; Pickarski, Maureen; Mathers, Parker D; Savitz, Alan T; Szumiloski, John; Jayakar, Richa Y; Somayajula, Sangeetha; Krause, Stephen; Brown, Keenan; Winkelmann, Christopher T; Scott, Boyd B; Cook, Lynn; Motzel, Sherri L; Hargreaves, Richard; Evelhoch, Jeffrey L; Cabal, Antonio; Dardzinski, Bernard J; Hangartner, Thomas N; Duong, Le T

2013-10-01

Odanacatib (ODN) is a selective and reversible Cathepsin K (CatK) inhibitor currently being developed as a once weekly treatment for osteoporosis. Here, effects of ODN compared to alendronate (ALN) on bone turnover, DXA-based areal bone mineral density (aBMD), QCT-based volumetric BMD (vBMD) and geometric parameters were studied in ovariectomized (OVX) rhesus monkeys. Treatment was initiated 10 days after ovariectomy and continued for 20 months. The study consisted of four groups: L-ODN (2 mg/kg, daily p.o.), H-ODN (8/4 mg/kg daily p.o.), ALN (15 μg/kg, twice weekly, s.c.), and VEH (vehicle, daily, p.o.). L-ODN and ALN doses were selected to approximate the clinical exposures of the ODN 50-mg and ALN 70-mg once-weekly, respectively. L-ODN and ALN effectively reduced bone resorption markers uNTx and sCTx compared to VEH. There was no additional efficacy with these markers achieved with H-ODN. Conversely, ODN displayed inversely dose-dependent reduction of bone formation markers, sP1NP and sBSAP, and L-ODN reduced formation to a lesser degree than ALN. At month 18 post-OVX, L-ODN showed robust increases in lumbar spine aBMD (11.4%, p<0.001), spine trabecular vBMD (13.7%, p<0.001), femoral neck (FN) integral (int) vBMD (9.0%, p<0.001) and sub-trochanteric proximal femur (SubTrPF) int vBMD, (6.4%, p<0.001) compared to baseline. L-ODN significantly increased FN cortical thickness (Ct.Th) and cortical bone mineral content (Ct.BMC) by 22.5% (p<0.001) and 21.8% (p<0.001), respectively, and SubTrPF Ct.Th and Ct.BMC by 10.9% (p<0.001) and 11.3% (p<0.001) respectively. Compared to ALN, L-ODN significantly increased FN Ct. BMC by 8.7% (p<0.05), and SubTrPF Ct.Th by 7.6% (p<0.05) and Ct.BMC by 6.2% (p<0.05). H-ODN showed no additional efficacy compared to L-ODN in OVX-monkeys in prevention mode. Taken together, the results from this study have demonstrated that administration of ODN at levels which approximate clinical exposure in OVX-monkeys had comparable efficacy to ALN in

Impact of equol-producing capacity and soy-isoflavone profiles of supplements on bone calcium retention in postmenopausal women: a randomized crossover trial12

PubMed Central

Pawlowski, Jessica W; Martin, Berdine R; McCabe, George P; McCabe, Linda; Jackson, George S; Peacock, Munro; Barnes, Stephen; Weaver, Connie M

2015-01-01

Background: Postmenopausal estrogen depletion is a major contributing factor to bone loss. Soy isoflavones have variable effects on the prevention of postmenopausal bone loss, which is possibly related to the specific isoflavone content or the variable equol-producing capacity of individuals. Objective: We aimed to determine the effects of the content of isoflavones in a soy supplement and the equol-producing ability of the individual on postmenopausal bone calcium retention. Design: The study was a blinded, randomized, crossover intervention trial in 24 postmenopausal women who were prescreened for their ability to convert daidzein to equol. Women were equilibrated with 41Ca before the intervention. Interventions were 5 soy isoflavone oral supplements (2 doses of a genistein-rich soy supplement and 3 doses of mixed isoflavones in various proportions) and a bisphosphonate (risedronate). Each intervention was given sequentially for 50 d followed by a 50-d washout period. The percentage of bone calcium retention was determined from the change in urinary 41Ca:calcium. Results: Interventions that ranged from 52 to 220 mg total isoflavones/d increased bone calcium retention between 3.4% and 7.6% (P < 0.05), which was a moderate effect compared with that of risedronate at 15.3% (95% CI: 7.1%, 22.7%; P = 0.0014). The most-effective soy intervention delivered 105.23 mg total isoflavones/d as genistein, daidzein, and glycitein in their natural ratios and increased bone calcium retention by 7.6% (95% CI: 4.9%, 10.2%; P < 0.0001). Genistein, at 52.85 mg/d, increased bone calcium retention by 3.4% (95% CI: 0.5%, 6.2%; P = 0.029); but there was no benefit at higher amounts (113.52 mg/d). There was no difference (P = 0.5) in bone calcium retention between equol producers and nonproducers. Conclusion: Soy isoflavones, although not as potent as risedronate, are effective bone-preserving agents in postmenopausal women regardless of their equol-producing status, and mixed

Update of the Bisphosphonate ISS Flight Experiment

NASA Technical Reports Server (NTRS)

LeBlanc, Adrian; Matsumoto, Toshio; Jones, Jeffrey; Shapiro, Jay; Lang, Thomas; Shackelford, Linda; Smith, Scott M.; Evans, Harlan; Spector, Elisabeth; Ploutz-Snyder, Robert;

Nanocomposite scaffolds with tunable mechanical and degradation capabilities: co-delivery of bioactive agents for bone tissue engineering.

PubMed

Cattalini, Juan P; Roether, Judith; Hoppe, Alexander; Pishbin, Fatemeh; Haro Durand, Luis; Gorustovich, Alejandro; Boccaccini, Aldo R; Lucangioli, Silvia; Mouriño, Viviana

2016-10-21

Novel multifunctional nanocomposite scaffolds made of nanobioactive glass and alginate crosslinked with therapeutic ions such as calcium and copper were developed for delivering therapeutic agents, in a highly controlled and sustainable manner, for bone tissue engineering. Alendronate, a well-known antiresorptive agent, was formulated into microspheres under optimized conditions and effectively loaded within the novel multifunctional scaffolds with a high encapsulation percentage. The size of the cation used for the alginate crosslinking impacted directly on porosity and viscoelastic properties, and thus, on the degradation rate and the release profile of copper, calcium and alendronate. According to this, even though highly porous structures were created with suitable pore sizes for cell ingrowth and vascularization in both cases, copper-crosslinked scaffolds showed higher values of porosity, elastic modulus, degradation rate and the amount of copper and alendronate released, when compared with calcium-crosslinked scaffolds. In addition, in all cases, the scaffolds showed bioactivity and mechanical properties close to the endogenous trabecular bone tissue in terms of viscoelasticity. Furthermore, the scaffolds showed osteogenic and angiogenic properties on bone and endothelial cells, respectively, and the extracts of the biomaterials used promoted the formation of blood vessels in an ex vivo model. These new bioactive nanocomposite scaffolds represent an exciting new class of therapeutic cell delivery carrier with tunable mechanical and degradation properties; potentially useful in the controlled and sustainable delivery of therapeutic agents with active roles in bone formation and angiogenesis, as well as in the support of cell proliferation and osteogenesis for bone tissue engineering.

Design of novel injectable in-situ forming scaffolds for non-surgical treatment of periapical lesions: In-vitro and in-vivo evaluation.

PubMed

Shamma, Rehab N; Elkasabgy, Nermeen A; Mahmoud, Azza A; Gawdat, Shaimaa I; Kataia, Mohamed M; Abdel Hamid, Mohamed A

2017-04-15

Periapical lesions are considered one of the common pathological conditions affecting alveolar bone. The primary focus of this study was to investigate the effectiveness of formulating an injectable in-situ forming scaffold-loaded with risedronate (bone resorption inhibitor) and with lornoxicam (anti-inflammatory drug) for the non-surgical treatment of periapical lesions. The scaffolds were prepared using solvent-induced phase inversion technique. Two insoluble copolymers were investigated namely; PLGA (ester-terminal) and PLGA-A (acid-terminal), additionally, SAIB was added as a high viscosity water-insoluble carrier. The addition of porogenic agents like hydrolyzed collagen was also investigated. The prepared scaffolds were characterized by analyzing their in-vitro release, DSC and rheological properties, besides their morphological properties. The results showed that the scaffolds prepared using 30% (w/v) PLGA or combined PLGA: SAIB (1:1, w/w) with total polymer concentration of 30% (w/v) possessed the most sustained drug release profile. Selected scaffolds were tested for their therapeutic effect to study the effect of porogenic agent, anti-inflammatory drug and risedronate in periapical lesions induced in dogs' teeth. Results declared that the selected scaffolds succeeded in improving the inflammation and enhancing the formation of new bony regions confirming the success of the prepared scaffolds as an innovative approach in the treatment of bone defects. Copyright © 2017 Elsevier B.V. All rights reserved.

Retreatment with teriparatide: our experience in three patients with severe secondary osteoporosis.

PubMed

Mana, D L; Zanchetta, M B; Zanchetta, J R

2017-04-01

Teriparatide is a drug for the treatment of osteoporosis which is licensed for use for up to 24 months. There is little experience with retreatment. The aim of this study was to evaluate, in three patients with severe secondary osteoporosis, the response to a second cycle of teriparatide regarding bone mineral density (BMD) and osteocalcin. Case 1 : A 62-year-old woman with multiple vertebral fractures has received corticoids for a long time. After starting teriparatide, her BMD and osteocalcin increased. She then received ibandronate for 3 years but her BMD declined. After a second treatment with teriparatide, her BMD increased again (18%). Case 2 : A 60-year-old woman with severe osteoporosis in lumbar spine (LS) (T-score - 4.5) had received corticoids for a long time and had celiac disease. After starting teriparatide, her BMD improved by 11.7%. She then received zoledronic acid for 15 months, but bone density decreased, so she was retreated with teriparatide. BMD had a slightly higher increase than after the first cycle (12.6%). Case 3 : A 60-year-old woman consulted for osteoporosis (LS T-score - 5.3), several fractures, and hyperthyroidism. She started teriparatide with improvement in BMD (39%). After 24 months, she received ibandronate for 1 year, but as her BMD declined, she was retreated with teriparatide. BMD showed an increase of 15%. The indication of a second cycle of treatment with teriparatide in three patients was effective in increasing BMD. Additional studies are needed to further identify the benefits and safety of retreatment with teriparatide.

Preparation, Biological Evaluation and Dosimetry Studies of 175Yb-Bis-Phosphonates for Palliative Treatment of Bone Pain.

PubMed

Fakhari, Ashraf; Jalilian, Amir R; Yousefnia, Hassan; Shanehsazzadeh, Saeed; Samani, Ali Bahrami; Daha, Fariba Johari; Ardestani, Mehdi Shafiee; Khalaj, Ali

2015-10-05

Optimized production and quality control of ytterbium-175 (Yb-175) labeled pamidronate and alendronate complexes as efficient agents for bone pain palliation has been presented. Yb-175 labeled pamidronate and alendronate (175Yb-PMD and 175Yb-ALN) complexes were prepared successfully at optimized conditions with acceptable radiochemical purity, stability and significant hydroxyapatite absorption. The biodistribution of complexes were evaluated up to 48 h, which demonstrated significant bone uptake ratios for 175Yb-PAM at all-time intervals. It was also detected that 175Yb-PAM mostly washed out and excreted through the kidneys. The performance of 175Yb-PAM in an animal model was better or comparable to other 175Yb-bone seeking complexes previously reported. Based on calculations, the total body dose for 175Yb-ALN is 40% higher as compared to 175Yb-PAM (especially kidneys) indicating that 175Yb-PAM is probably a safer agent than 175Yb-ALN.

Preparation, Biological Evaluation and Dosimetry Studies of 175Yb-Bis-Phosphonates for Palliative Treatment of Bone Pain

PubMed Central

Fakhari, Ashraf; Jalilian, Amir R.; Yousefnia, Hassan; Shanehsazzadeh, Saeed; Samani, Ali Bahrami; Daha, Fariba Johari; Ardestani, Mehdi Shafiee; Khalaj, Ali

2015-01-01

Objective: Optimized production and quality control of ytterbium-175 (Yb-175) labeled pamidronate and alendronate complexes as efficient agents for bone pain palliation has been presented. Methods: Yb-175 labeled pamidronate and alendronate (175Yb-PMD and 175Yb-ALN) complexes were prepared successfully at optimized conditions with acceptable radiochemical purity, stability and significant hydroxyapatite absorption. The biodistribution of complexes were evaluated up to 48 h, which demonstrated significant bone uptake ratios for 175Yb-PAM at all-time intervals. It was also detected that 175Yb-PAM mostly washed out and excreted through the kidneys. Results: The performance of 175Yb-PAM in an animal model was better or comparable to other 175Yb-bone seeking complexes previously reported. Conclusion: Based on calculations, the total body dose for 175Yb-ALN is 40% higher as compared to 175Yb-PAM (especially kidneys) indicating that 175Yb-PAM is probably a safer agent than 175Yb-ALN. PMID:27529886

Overcoming resistance to bisphosphonates through the administration of alfacalcidol: results of a 1-year, open follow-up study.

PubMed

Gaál, János; Bender, Tamás; Varga, József; Horváth, Irén; Kiss, Judit; Somogyi, Péter; Surányi, Péter

2009-11-01

This study intended to determine whether the replacement of vitamin D3 with alfacalcidol results in any bone mineral density (BMD) increase in 76 patients unresponsive to the combination of alendronate and conventional vitamin D3 treatment. In these patients the conventional vitamin D3 had been replaced with alfacalcidol (0.5 μg/day), and then the patients were followed up for a year. After treatment for 1 year, Wilcoxon test revealed a small but statistically significant (P < 0.001) increase in the BMD values of the forearm and lumbar vertebrae, in the serum calcium and urinary calcium/creatinine ratio in first-voided morning urine. However, the serum alkaline phosphatase activity, phosphorus, parathormone, osteocalcin levels and the urinary d-pyr/creatinine ratio decreased significantly (P < 0.001). As suggested by our results, combination therapy with alendronate and alfacalcidol increases bone density and improves the biochemical markers of bone turnover, without any substantial increase in the incidence of adverse effects.

Clinical Practice. Postmenopausal Osteoporosis.

PubMed

Black, Dennis M; Rosen, Clifford J

2016-01-21

Key Clinical Points Postmenopausal Osteoporosis Fractures and osteoporosis are common, particularly among older women, and hip fractures can be devastating. Treatment is generally recommended in postmenopausal women who have a bone mineral density T score of -2.5 or less, a history of spine or hip fracture, or a Fracture Risk Assessment Tool (FRAX) score indicating increased fracture risk. Bisphosphonates (generic) and denosumab reduce the risk of hip, nonvertebral, and vertebral fractures; bisphosphonates are commonly used as first-line treatment in women who do not have contraindications. Teriparatide reduces the risk of nonvertebral and vertebral fractures. Osteonecrosis of the jaw and atypical femur fractures have been reported with treatment but are rare. The benefit-to-risk ratio for osteoporosis treatment is strongly positive for most women with osteoporosis. Because benefits are retained after discontinuation of alendronate or zoledronic acid, drug holidays after 5 years of alendronate therapy or 3 years of zoledronic acid therapy may be considered for patients at lower risk for fracture.

Cost-effectiveness of osteoporosis treatments in postmenopausal women using FRAX™ thresholds for decision.

PubMed

Alzahouri, Kazem; Bahrami, Stéphane; Durand-Zaleski, Isabelle; Guillemin, Francis; Roux, Christian

2013-01-01

FRAX™ is a fracture prediction algorithm to determine a patient's absolute fracture risk. There is a growing consensus that osteoporosis treatment should be based on individual 10-year fracture probability, as calculated in the FRAX™ algorithm, rather than on T-scores alone. Our objective was to evaluate the cost-effectiveness of five years of branded alendronate therapy in postmenopausal French women with a known FRAX™ score. A Markov cohort state transition model using FRAX™ values and whenever possible population-specific data and probabilities. We estimated the incremental cost-effectiveness ratio (ICER) of alendronate versus no treatment in postmenopausal women with FRAX™ ranging from 10 to 3%. Number of women to treat (NNT) for preventing hip fracture, costs, quality-adjusted life-years, incremental cost-effectiveness ratios. The incremental cost-effectiveness ratios (ICER) compared to no treatment at age 70 ranged from €104,183 to €413,473 per QALY when FRAX™ decreased from 10 to 3%. The NNTs for preventing one hip fracture ranged from 97 to 388 according to age (50-80 years) and FRAX™. Sensitivity analyses showed that the main determinants of cost-effectiveness were adherence to therapy and cost of treatment. Using French costs of branded drug and current estimates of treatment efficacy, alendronate therapy for 70-year-old women with 10-year probability of hip fracture of 10% just meets the accepted cost-effectiveness threshold. Improving treatment adherence and/or decreasing treatment cost lowers the ICER. The model however underestimates the potential benefit by excluding other fractures. Copyright © 2012 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

The effect of dipeptidyl peptidase-IV inhibition on bone in a mouse model of type 2 diabetes

PubMed Central

Gallagher, Emily Jane; Sun, Hui; Kornhauser, Caroline; Tobin-Hess, Aviva; Epstein, Sol; Yakar, Shoshana; LeRoith, Derek

2017-01-01

Background Individuals with type 2 diabetes (T2D) are at greater risk of bone fractures than those without diabetes. Certain oral diabetic medications may further increase the risk of fracture. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are incretin-based therapies that are being increasingly used for the management of T2D. It has been hypothesized that these agents may reduce fracture risk in those with T2D. In this study, we used a mouse model of T2D to examine the effects of the DPP-IV inhibitor, MK-0626, on bone. Methods Male wild type (WT) and diabetic muscle-lysine-arginine (MKR) mice were treated with MK-0626, pioglitazone, alendronate or vehicle. The effects of treatment with MK-0626 on bone microarchitecture and turnover were compared with treatment with pioglitazone, alendronate and vehicle. Osteoblast differentiation was determined by alkaline phosphatase staining of bone marrow cells from WT and MKR mice after treatment with pioglitazone, MK-0626 or phosphate buffered saline. Results We found that MK-0626 had neutral effects on cortical and trabecular bone in diabetic mice. Pioglitazone had detrimental effects on the trabecular bone of WT but not of diabetic mice. Alendronate caused improvements in cortical and trabecular bone architecture in diabetic and WT mice. MK-0626 did not alter osteoblast differentiation, but pioglitazone impaired osteoblast differentiation in vitro. Conclusions Overall, the DPP-IV inhibitor, MK-0626, had no adverse effects on bone in an animal model of T2D or directly on osteoblasts in culture. These findings are reassuring as DPP-IV inhibitors are being widely used to treat patients with T2D who are already at an increased risk of fractures. PMID:24023014

Bi-layered nanocomposite bandages for controlling microbial infections and overproduction of matrix metalloproteinase activity.

PubMed

Anjana, J; Mohandas, Annapoorna; Seethalakshmy, S; Suresh, Maneesha K; Menon, Riju; Biswas, Raja; Jayakumar, R

2018-04-15

Chronic diabetic wounds is characterised by increased microbial contamination and overproduction of matrix metalloproteases that would degrade the extracellular matrix. A bi-layer bandage was developed, that promotes the inhibition of microbial infections and matrix metalloprotease (MMPs) activity. Bi-layer bandage containing benzalkonium chloride loaded gelatin nanoparticles (BZK GNPs) in chitosan-Hyaluronic acid (HA) as a bottom layer and sodium alendronate containing chitosan as top layer was developed. We hypothesized that the chitosan-gelatin top layer with sodium alendronate could inhibit the MMPs activity, whereas the chitosan-HA bottom layer with BZK GNPs (240±66nm) would enable the elimination of microbes. The porosity, swelling and degradation nature of the prepared Bi-layered bandage was studied. The bottom layer could degrade within 4days whereas the top layer remained upto 7days. The antimicrobial activity of the BZK NPs loaded bandage was determined using normal and clinical strains. Gelatin zymography shows that the proteolytic activity of MMP was inhibited by the bandage. Copyright © 2017 Elsevier B.V. All rights reserved.

Design, Synthesis, and Pharmacokinetics of a Bone-Targeting Dual-Action Prodrug for the Treatment of Osteoporosis.

PubMed

Xie, Haibo; Chen, Gang; Young, Robert N

2017-08-24

A dual-action bone-targeting prodrug has been designed, synthesized, and evaluated for in vitro and in vivo metabolic stability, in vivo tissue distribution, and rates of release of the active constituents after binding to bones through the use of differentially double-labeled derivatives. The conjugate (general structure 7) embodies the merger of a very potent and proven anabolic selective agonist of the prostaglandin EP4 receptor, compound 5, and alendronic acid, a potent inhibitor of bone resorption, optimally linked through a differentially hydrolyzable linker unit, N-4-carboxymethylphenyl-methyloxycarbonyl-leucinyl-argininyl-para-aminophenylmethylalcohol (Leu-Arg-PABA). Optimized conjugate 16 was designed so that esterase activity will liberate 5 and cathepsin K cleavage of the Leu-Arg-PABA element will liberate alendronic acid. Studies with doubly radiolabeled 16 provide a proof-of-concept for the use of a cathepsin K cleavable peptide-linked conjugate for targeting of bisphosphonate prodrugs to bone and slow release liberation of the active constituents in vivo. Such conjugates are potential therapies for the treatment of bone disorders such as osteoporosis.

Zoledronic Acid for the Treatment and Prevention of Primary and Secondary Osteoporosis

PubMed Central

Rizzoli, René

2010-01-01

There is increasing interest in therapies that can be administered less frequently and/or avoid gastrointestinal irritation. The efficacy of once-yearly zoledronic acid (5 mg) in the treatment and prevention of osteoporosis has been evaluated in different patient populations. In the 3-year HORIZON-Pivotal Fracture Trial in postmenopausal women with osteoporosis, zoledronic acid reduced the risk of vertebral and hip fracture by 70% and 41%, respectively, versus placebo. The efficacy of zoledronic acid in preventing subsequent fracture in patients with a hip fracture was evaluated in the HORIZON-Recurrent Fracture Trial. New vertebral and nonvertebral fractures were significantly reduced by treatment initiated within 90 days of incident hip fracture, without evidence of delayed fracture healing. Data from a 1-year study show that a single zoledronic acid 5-mg infusion is superior to oral risedronate 5 mg/day for treatment and prevention of glucocorticoid-induced osteoporosis. Increases in bone mineral density and decreases in bone turnover markers were significantly greater with zoledronic acid than with risedronate. Two different treatment regimens of zoledronic acid were found to be more effective than placebo for prevention of bone loss in postmenopausal women and reducing markers of bone turnover after 2 years. In conclusion, zoledronic acid 5 mg once-yearly infusion has demonstrated marked efficacy in the treatment and prevention of primary and secondary osteoporosis, with a combination of fracture risk reduction and prevention of bone loss at key sites. It is the only agent shown to reduce the incidence of fracture and mortality in patients with a previous low-trauma hip fracture. PMID:22870433

Effects of 16-month treatment with the cathepsin K inhibitor ONO-5334 on bone markers, mineral density, strength and histomorphometry in ovariectomized cynomolgus monkeys.

PubMed

Yamada, Hiroyuki; Ochi, Yasuo; Mori, Hiroshi; Nishikawa, Satoshi; Hashimoto, Yasuaki; Nakanishi, Yasutomo; Tanaka, Makoto; Bruce, Mark; Deacon, Steve; Kawabata, Kazuhito

2016-05-01

We examined the effects of ONO-5334, a cathepsin K inhibitor, on bone markers, BMD, strength and histomorphometry in ovariectomized (OVX) cynomolgus monkeys. ONO-5334 (1.2, 6 and 30mg/kg/day, p.o.), alendronate (0.05mg/kg/2weeks, i.v.), or vehicle was administered to OVX monkeys (all groups N=20) for 16months. A concurrent Sham group (N=20) was also treated with vehicle for 16months. OVX significantly increased bone resorption and formation markers and decreased BMD in lumbar vertebra, femoral neck, proximal tibia and distal radius. Alendronate suppressed these parameters to a level similar to that in the Sham-operated monkeys. ONO-5334 at doses 6 and 30mg/kg decreased bone resorption markers to a level roughly half of that in the Sham group, while keeping bone formation markers level above that in the Sham monkeys. Changes in DXA BMD confirmed that ONO-5334 at doses 6 and 30mg/kg increased BMD to a level greater than that in the Sham group in all examined sites. In the proximal tibia, in vivo pQCT analysis showed that ONO-5334 at doses 6 and 30mg/kg suppressed trabecular BMD loss to the sham level. However, ONO-5334 increased cortical BMD, cortical area and cortical thickness to a level greater than that in the Sham group, suggesting that ONO-5334 improves both cortical BMD and cortical geometry. Histomorphometric analysis revealed that ONO-5334 suppressed bone formation rate (BFR) at osteonal site in the midshaft femur but did not influence OVX-induced increase in BFR at either the periosteal or endocortical surfaces. Unlike alendronate, ONO-5334 increased osteoclasts surface (Oc.S/BS) and serum tartrate-resistant acid phosphatise 5b (TRAP5b) activity, highlighting the difference in the mode of action between these two drugs. Our results suggest that ONO-5334 has therapeutic potential not only in vertebral bones, but also in non-vertebral bones. Copyright © 2016 Elsevier Inc. All rights reserved.

GRAND-4: the German retrospective analysis of long-term persistence in women with osteoporosis treated with bisphosphonates or denosumab.

PubMed

Hadji, P; Kyvernitakis, I; Kann, P H; Niedhart, C; Hofbauer, L C; Schwarz, H; Kurth, A A; Thomasius, F; Schulte, M; Intorcia, M; Psachoulia, E; Schmid, T

2016-10-01

This retrospective database study assessed 2-year persistence with bisphosphonates or denosumab in a large German cohort of women with a first-time prescription for osteoporosis treatment. Compared with intravenous or oral bisphosphonates, 2-year persistence was 1.5-2 times higher and risk of discontinuation was significantly lower (P < 0.0001) with denosumab. Persistence with osteoporosis therapies is critical for fracture risk reduction. Detailed data on long-term persistence (≥2 years) with bisphosphonates and denosumab are sparse. From the German IMS® database, we included women aged 40 years or older with a first-time prescription for bisphosphonates or denosumab between July 2010 and August 2014; patients were followed up until December 2014. The main outcome was treatment discontinuation, with a 60-day permissible gap between filled prescriptions. Two-year persistence was estimated using Kaplan-Meier survival curves, with treatment discontinuation as the failure event. Denosumab was compared with intravenous (i.v.) and oral bisphosphonates separately. Cox proportional hazard ratios (HRs) for the 2-year risk of discontinuation were calculated, with adjustment for age, physician specialty, health insurance status, and previous medication use. Two-year persistence with denosumab was significantly higher than with i.v. or oral bisphosphonates (39.8 % [n = 21,154] vs 20.9 % [i.v. ibandronate; n = 20,472] and 24.8 % [i.v. zoledronic acid; n = 3966] and 16.7-17.5 % [oral bisphosphonates; n = 114,401]; all P < 0.001). Patients receiving i.v. ibandronate, i.v. zoledronic acid, or oral bisphosphonates had a significantly increased risk of treatment discontinuation than did those receiving denosumab (HR = 1.65, 1.28, and 1.96-2.02, respectively; all P < 0.0001). Two-year persistence with denosumab was 1.5-2 times higher than with i.v. or oral bisphosphonates, and risk of discontinuation was significantly lower with denosumab

Exercise and Bone Density: Meta-Analysis

DTIC Science & Technology

2003-10-01

were estimat- included in our analysis. Thus, for example, if BMD ed using previously developed methods .ŕ T- was also assessed in women performing...from 12.6% unpublished work is inappropriate because it has in the placebo group to 9.0% in the alendronate not gone through the peer review process...Olkin I. Statistical Methods for Meta-Analy- taken that could enhance BMD, cigarette smoking, 0 sis. San Diego, CA: Academic Press; 1985. take tht

Health state utility values and patient-reported outcomes before and after vertebral and non-vertebral fractures in an osteoporosis clinical trial.

PubMed

Imai, T; Tanaka, S; Kawakami, K; Miyazaki, T; Hagino, H; Shiraki, M

2017-06-01

We assessed the health state utility value (HSUV) reductions associated with vertebral fractures using data collected in the Japanese Osteoporosis Intervention Trial-03 (JOINT-03). Our analysis revealed that assessment of HSUVs after morphometric vertebral fracture is important to capture the burden of vertebral fractures. Evaluation of the HSUV after fracture is important to calculate the quality-adjusted life years (QALYs) of osteoporosis patients, which is essential information in the context of health economic evaluation. JOINT-03 study patients were aged ≥65 years and treated with risedronate and vitamin K 2 or risedronate alone. Radiographic information and patient-reported outcomes measured by EQ-5D and a visual analogue scale (VAS) were assessed at registration and followed up after 6, 12, and 24 months. According to differences among the dates of these assessments and the radiographic information, we classified the follow-up HSUVs calculated based on EQ-5D results into before or after fracture categories regardless of clinical symptoms. Among 2922 follow-up HSUVs, 201 HSUVs were categorized as HSUVs that were observed after incident vertebral fractures on X-ray films. The median time from the detection of an incident vertebral fracture until the EQ-5D assessment was 53 days (25th percentile, 0 day; 75th percentile, 357 days). The impact of incident vertebral fractures on HSUVs was quantified as -0.03. Among the five health profile domains on the EQ-5D, an incident vertebral fracture had significant effects on anxiety/depression, self-care, and usual activities. The results suggest that incident morphometric vertebral fracture was associated with impairment of the HSUV for patients with osteoporosis not only immediately but also several months after the fracture.

Influence of bone affinity on the skeletal distribution of fluorescently labeled bisphosphonates in vivo.

PubMed

Roelofs, Anke J; Stewart, Charlotte A; Sun, Shuting; Błażewska, Katarzyna M; Kashemirov, Boris A; McKenna, Charles E; Russell, R Graham G; Rogers, Michael J; Lundy, Mark W; Ebetino, Frank H; Coxon, Fraser P

2012-04-01

Bisphosphonates are widely used antiresorptive drugs that bind to calcium. It has become evident that these drugs have differing affinities for bone mineral; however, it is unclear whether such differences affect their distribution on mineral surfaces. In this study, fluorescent conjugates of risedronate, and its lower-affinity analogues deoxy-risedronate and 3-PEHPC, were used to compare the localization of compounds with differing mineral affinities in vivo. Binding to dentine in vitro confirmed differences in mineral binding between compounds, which was influenced predominantly by the characteristics of the parent compound but also by the choice of fluorescent tag. In growing rats, all compounds preferentially bound to forming endocortical as opposed to resorbing periosteal surfaces in cortical bone, 1 day after administration. At resorbing surfaces, lower-affinity compounds showed preferential binding to resorption lacunae, whereas the highest-affinity compound showed more uniform labeling. At forming surfaces, penetration into the mineralizing osteoid was found to inversely correlate with mineral affinity. These differences in distribution at resorbing and forming surfaces were not observed at quiescent surfaces. Lower-affinity compounds also showed a relatively higher degree of labeling of osteocyte lacunar walls and labeled lacunae deeper within cortical bone, indicating increased penetration of the osteocyte canalicular network. Similar differences in mineralizing surface and osteocyte network penetration between high- and low-affinity compounds were evident 7 days after administration, with fluorescent conjugates at forming surfaces buried under a new layer of bone. Fluorescent compounds were incorporated into these areas of newly formed bone, indicating that "recycling" had occurred, albeit at very low levels. Taken together, these findings indicate that the bone mineral affinity of bisphosphonates is likely to influence their distribution within the

Bisphosphonates inhibit pain, bone loss, and inflammation in a rat tibia fracture model of complex regional pain syndrome

PubMed Central

Wang, Liping; Guo, Tian-Zhi; Wei, Tzuping; Li, Wen-wu; Shi, Xiaoyou; Clark, J David; Kingery, Wade S

2016-01-01

BACKGROUND Bisphosphonates are used to prevent the bone loss and fractures associated with osteoporosis, bone metastases, multiple myeloma, and osteogenis deformans. Distal limb fractures cause regional bone loss with cutaneous inflammation and pain in the injured limb that can develop into complex regional pain syndrome (CRPS). Clinical trials have reported that anti-resorptive bisphosphonates can prevent fracture-induced bone loss, inhibit serum inflammatory cytokine levels, and alleviate CRPS pain. Previously we observed that the inhibition of inflammatory cytokines or adaptive immune responses attenuated the development of pain behavior in a rat fracture model of CRPS and we hypothesized that bisphosphonates could prevent pain behavior, trabecular bone loss, post-fracture cutaneous cytokine up-regulation, and adaptive immune responses in this CRPS model. METHODS Rats underwent tibia fracture and cast immobilization for 4 weeks and were chronically administered either subcutaneously perfused alendronate or oral zoledronate. Behavioral measurements included hindpaw von Frey allodynia, unweighting, warmth, and edema. Bone microarchitecture was measured by uCT and bone cellular activity was evaluated by static and dynamic histomorphometry. Spinal cord Fos immunostaining was performed and skin cytokine (TNF, IL-1, IL-6) and nerve growth factor (NGF) levels were determined by EIA. Skin and sciatic nerve immunoglobulin levels were determined by EIA. RESULTS Tibia fracture rats developed hindpaw allodynia, unweighting, warmth, and edema, increased spinal Fos expression, trabecular bone loss in the lumbar vertebra and bilateral distal femurs as measured by uCT, increased trabecular bone resorption and osteoclast surface with decreased bone formation rates, increased cutaneous inflammatory cytokine and NGF expression and elevated immunocomplex deposition in skin and nerve. Alendronate (60 μg/kg/day s.c.) or zoledronate (3 mg/kg/day p.o.) treatment for 28 days, started

Effects of 24 months of treatment with romosozumab followed by 12 months of denosumab or placebo in postmenopausal women with low bone mineral density: A randomized, double-blind, phase 2, parallel group study.

PubMed

McClung, Michael R; Brown, Jacques P; Diez-Perez, Adolfo; Resch, Heinrich; Caminis, John; Meisner, Paul; Bolognese, Michael A; Goemaere, Stefan; Bone, Henry G; Zanchetta, Jose R; Maddox, Judy; Bray, Sarah; Grauer, Andreas

2018-04-25

Over 12 months, romosozumab increased bone formation and decreased bone resorption, resulting in increased BMD in postmenopausal women with low BMD (NCT00896532). Herein we report the study extension evaluating 24 months treatment with romosozumab, discontinuation of romosozumab, alendronate followed by romosozumab, and romosozumab followed by denosumab. Postmenopausal women age 55-85 years with a lumbar spine (LS), total hip (TH), or femoral neck T-score ≤-2.0 and ≥-3.5 were enrolled and randomly assigned to placebo, one of five romosozumab regimens (70mg, 140mg, 210mg monthly [QM]; 140mg Q3M; 210mg Q3M) for 24 months, or open-label alendronate for 12 months followed by romosozumab 140mg QM for 12 months. Eligible participants were then re-randomized 1:1 within original treatment groups to placebo or denosumab 60mg Q6M for an additional 12 months. Percentage change from baseline in BMD and bone turnover markers (BTMs) at months 24 and 36 and safety were evaluated. Of 364 participants initially randomized to romosozumab, placebo, or alendronate, 315 completed 24 months of treatment and 248 completed the extension. Romosozumab markedly increased LS and TH BMD through month 24, with largest gains observed with romosozumab 210mg QM (LS = 15.1%; TH = 5.4%). Women receiving romosozumab who transitioned to denosumab continued to accrue BMD, whereas BMD returned toward pretreatment levels with placebo. With romosozumab 210mg QM, bone formation marker P1NP initially increased following treatment initiation and gradually decreased to below baseline by month 12, remaining below baseline through month 24; and bone resorption marker β-CTX rapidly decreased following treatment, remaining below baseline through month 24. Transition to denosumab further decreased both BTMs, while after transition to placebo, P1NP returned to baseline and β-CTX increased above baseline. Adverse events were balanced between treatment groups through month 36. These data suggest that

The effects of bisphosphonates on taurine transport in retinal capillary endothelial cells under high glucose conditions.

PubMed

Lee, Na-Young; Kang, Young-Sook

2013-01-01

Diabetic retinopathy (DR) is a major cause of blindness in diabetic patients. Elevated glucose and vascular endothelial growth factor (VEGF) in retina can trigger many of the retinal vascular changes caused by diabetes and DR. Recently, bisphosphonates, antiosteoporosis drugs, have been reported to have anti-angiogenic effect by decreasing VEGF. Taurine has several biological processes such as osmoregulation and antioxidation in retina. Therefore, the purpose of this study is to clarify the regulation of taurine transport activity by high glucose concentration and the effect of inhibitors for VEGF function, bisphosphonates, on taurine transport under high glucose condition using TR-iBRB cell lines as an in vitro model of inner blood-retinal barrier (iBRB). As a result, by exposing TR-iBRB cells to high glucose for 48 h, [(3)H]taurine uptake was decreased continuously. [(3)H]Taurine uptake was increased significantly by pretreatment of alendronate and pamidronate compared with the values for high glucose. Increased [(3)H]taurine uptake by pretreatment of alendronate and pamidronate was significantly reduced by mevalonate pathway intermediates, geranylgeraniol (GGOH). In conclusion, taurine transport through the iBRB under high glucose condition can be regulated by bisphosphonates via mevalonate pathway. Therefore, we suggest that bisphosphonates could have the beneficial effects on DR by regulation of taurine contents in retina.

Effect of bisphosphonates on root resorption after tooth replantation - a systematic review.

PubMed

Najeeb, Shariq; Siddiqui, Fahad; Khurshid, Zohaib; Zohaib, Sana; Zafar, Muhammad Sohail; Ansari, Shazia Akbar

2017-04-01

Replantation of avulsed teeth may lead to root resorption. Bisphosphonates (BPs), a class of drugs of used to treat resorptive diseases of the bone such as osteoporosis and Paget's disease, have been observed to exert an antiresorptive effect on periodontal bone as well. The antiresorptive properties of BPs could prove them useful in preventing root resorption of replanted avulsed teeth. The aim of this systematic review was to analyze and summarize the currently available literature concerning the use of BPs in preventing root resorption of avulsed teeth. PubMed/MEDLINE, Google Scholar, ISI Web of Knowledge, and Embase databases were searched using keywords 'bisphosphonate', 'replantation', and 'tooth'. Quality assessment of each study was carried out. In addition, general characteristics and outcomes of each study were summarized. After exclusion of 116 irrelevant articles, 10 animal studies were included in this review. The majority of the studies suggest that surface application of zoledronate or alendronate reduces root resorption of replanted teeth in animal models. Surface treatment with etidronate had no significant effect on root resorption, and intracanal etidronate accelerated resorption. Surface application of zoledronate and alendronate reduces root resorption of replanted teeth in animal models. However, the efficacy of intracanal usage of BPs is still debatable. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Methodological Considerations for Comparison of Brand Versus Generic Versus Authorized Generic Adverse Event Reports in the US Food and Drug Administration Adverse Event Reporting System (FAERS).

PubMed

Rahman, Md Motiur; Alatawi, Yasser; Cheng, Ning; Qian, Jingjing; Peissig, Peggy L; Berg, Richard L; Page, David C; Hansen, Richard A

2017-12-01

The US Food and Drug Administration Adverse Event Reporting System (FAERS), a post-marketing safety database, can be used to differentiate brand versus generic safety signals. To explore the methods for identifying and analyzing brand versus generic adverse event (AE) reports. Public release FAERS data from January 2004 to March 2015 were analyzed using alendronate and carbamazepine as examples. Reports were classified as brand, generic, and authorized generic (AG). Disproportionality analyses compared reporting odds ratios (RORs) of selected known labeled serious adverse events stratifying by brand, generic, and AG. The homogeneity of these RORs was compared using the Breslow-Day test. The AG versus generic was the primary focus since the AG is identical to brand but marketed as a generic, therefore minimizing generic perception bias. Sensitivity analyses explored how methodological approach influenced results. Based on 17,521 US event reports involving alendronate and 3733 US event reports involving carbamazepine (immediate and extended release), no consistently significant differences were observed across RORs for the AGs versus generics. Similar results were obtained when comparing reporting patterns over all time and just after generic entry. The most restrictive approach for classifying AE reports yielded smaller report counts but similar results. Differentiation of FAERS reports as brand versus generic requires careful attention to risk of product misclassification, but the relative stability of findings across varying assumptions supports the utility of these approaches for potential signal detection.

Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs.

PubMed

Cummings, Steven R; Karpf, David B; Harris, Fran; Genant, Harry K; Ensrud, Kristine; LaCroix, Andrea Z; Black, Dennis M

2002-03-01

To estimate how much the improvement in bone mass accounts for the reduction in risk of vertebral fracture that has been observed in randomized trials of antiresorptive treatments for osteoporosis. After a systematic search, we conducted a meta-analysis of 12 trials to describe the relation between improvement in spine bone mineral density and reduction in risk of vertebral fracture in postmenopausal women. We also used logistic models to estimate the proportion of the reduction in risk of vertebral fracture observed with alendronate in the Fracture Intervention Trial that was due to improvement in bone mineral density. Across the 12 trials, a 1% improvement in spine bone mineral density was associated with a 0.03 decrease (95% confidence interval [CI]: 0.02 to 0.05) in the relative risk (RR) of vertebral fracture. The reductions in risk were greater than predicted from improvement in bone mineral density; for example, the model estimated that treatments predicted to reduce fracture risk by 20% (RR = 0.80), based on improvement in bone mineral density, actually reduce the risk of fracture by about 45% (RR = 0.55). In the Fracture Intervention Trial, improvement in spine bone mineral density explained 16% (95% CI: 11% to 27%) of the reduction in the risk of vertebral fracture with alendronate. Improvement in spine bone mineral density during treatment with antiresorptive drugs accounts for a predictable but small part of the observed reduction in the risk of vertebral fracture.

Water-soluble polymer–drug conjugates for combination chemotherapy against visceral leishmaniasis

PubMed Central

Nicoletti, Salvatore; Seifert, Karin; Gilbert, Ian H.

2010-01-01

There is a need for new safe, effective and short-course treatments for leishmaniasis; one strategy is to use combination chemotherapy. Polymer–drug conjugates have shown promise for the delivery of anti-leishmanial agents such as amphotericin B. In this paper, we report on the preparation and biological evaluation of polymer–drug conjugates of N-(2-hydroxypropyl)methacrylamide (HPMA), amphotericin B and alendronic acid. The combinatorial polymer–drug conjugates were effective anti-leishmanial agents in vitro and in vivo, but offered no advantage over the single poly(HPMA)–amphotericin B conjugates. PMID:20338769

Osteonecrosis of the jaw: effect of bisphosphonate type, local concentration, and acidic milieu on the pathomechanism.

PubMed

Otto, Sven; Pautke, Christoph; Opelz, Christine; Westphal, Ines; Drosse, Inga; Schwager, Joanna; Bauss, Frieder; Ehrenfeld, Michael; Schieker, Matthias

2010-11-01

Osteonecrosis of the jaw has been reported in patients receiving high doses of intravenous nitrogen-containing bisphosphonates (N-BPs) because of malignant disease. The exact pathomechanisms have been elusive and questions of paramount importance remain unanswered. Recent studies have indicated toxic effects of bisphosphonates on different cell types, apart from osteoclast inhibition. Multipotent stem cells play an important role in the processes of wound healing and bone regeneration, which seem to be especially impaired in the jaws of patients receiving high doses of N-BPs. Therefore, the aim of the present study was to investigate the effects of different bisphosphonate derivatives and dose levels combined with varying pH levels on the mesenchymal stem cells in vitro. The effect of 2 N-BPs (zoledronate and ibandronate) and 1 non-N-BP (clodronate) on immortalized mesenchymal stem cells was tested at different concentrations, reflecting 1, 3, and 6 months and 1, 3, 5, and 10 years of exposure to standard oncology doses of the 2 N-BPs and equimolar concentrations of clodronate at different pH values (7.4, 7.0, 6.7, and 6.3). Cell viability and activity were analyzed using a WST assay. Cell motility was investigated using scratch wound assays and visualized using time-lapse microscopy. Both types of bisphosphonates revealed remarkable differences. Zoledronate and ibandronate showed a dose- and pH-dependent cellular toxicity. Increasing concentrations of both N-BPs and an acidic milieu led to a significant decrease in cell viability and activity (P < .01), with more pronounced effects for zoledronate. Equimolar concentrations of clodronate did not affect the cell survival or activity significantly, apart from the effect of pH reduction itself, which was also detectable in the patients in the control group who did not receive bisphosphonates. Our results have shown that high concentrations of N-BPs and a local acidic milieu, which is commonly present in infections of

[Headache case that responded to alendronate treatment in Paget's disease].

PubMed

Bozkurt, Dilek; Hiz, Fazilet; Çinar, Meral; Can, Meltem

2012-01-01

Paget's disease of the bone is a chronic, focal skeletal disease characterized by bone pain and deformity, pathological fractures and neurological symptoms such as headache, hearing loss and tinnitus, etc. The frequency of the disease increases in later ages. Viral and genetical factors play a role in the etiology. The majority of cases are asymptomatic. It is often diagnosed with an incidental finding on radiography or with an unexpected high serum alkaline phosphatase level. Bone fractures or neurological complications can negatively affect the quality of life. Early diagnosis and treatment are thus very important. Bisphosphonates are the most frequently used medication in the treatment. We present a case who sought medical help because of headache and was diagnosed as Paget's disease. Neurological complications and the diagnosis and treatment of Paget's disease are reviewed in the literature.

Controlling drug delivery kinetics from mesoporous titania thin films by pore size and surface energy.

PubMed

Karlsson, Johan; Atefyekta, Saba; Andersson, Martin

2015-01-01

The osseointegration capacity of bone-anchoring implants can be improved by the use of drugs that are administrated by an inbuilt drug delivery system. However, to attain superior control of drug delivery and to have the ability to administer drugs of varying size, including proteins, further material development of drug carriers is needed. Mesoporous materials have shown great potential in drug delivery applications to provide and maintain a drug concentration within the therapeutic window for the desired period of time. Moreover, drug delivery from coatings consisting of mesoporous titania has shown to be promising to improve healing of bone-anchoring implants. Here we report on how the delivery of an osteoporosis drug, alendronate, can be controlled by altering pore size and surface energy of mesoporous titania thin films. The pore size was varied from 3.4 nm to 7.2 nm by the use of different structure-directing templates and addition of a swelling agent. The surface energy was also altered by grafting dimethylsilane to the pore walls. The drug uptake and release profiles were monitored in situ using quartz crystal microbalance with dissipation (QCM-D) and it was shown that both pore size and surface energy had a profound effect on both the adsorption and release kinetics of alendronate. The QCM-D data provided evidence that the drug delivery from mesoporous titania films is controlled by a binding-diffusion mechanism. The yielded knowledge of release kinetics is crucial in order to improve the in vivo tissue response associated to therapeutic treatments.

Natural calcium isotopic composition of urine as a marker of bone mineral balance.

PubMed

Skulan, Joseph; Bullen, Thomas; Anbar, Ariel D; Puzas, J Edward; Shackelford, Linda; LeBlanc, Adrian; Smith, Scott M

2007-06-01

We investigated whether changes in the natural isotopic composition of calcium in human urine track changes in net bone mineral balance, as predicted by a model of calcium isotopic behavior in vertebrates. If so, isotopic analysis of natural urine or blood calcium could be used to monitor short-term changes in bone mineral balance that cannot be detected with other techniques. Calcium isotopic compositions are expressed as delta(44)Ca, or the difference in parts per thousand between the (44)Ca/(40)Ca of a sample and the (44)Ca/(40)Ca of a standard reference material. delta(44)Ca was measured in urine samples from 10 persons who participated in a study of the effectiveness of countermeasures to bone loss in spaceflight, in which 17 weeks of bed rest was used to induce bone loss. Study participants were assigned to 1 of 3 treatment groups: controls received no treatment, one treatment group received alendronate, and another group performed resistive exercise. Measurements were made on urine samples collected before, at 2 or 3 points during, and after bed rest. Urine delta(44)Ca values during bed rest were lower in controls than in individuals treated with alendronate (P <0.05, ANOVA) or exercise (P <0.05), and lower than the control group baseline (P <0.05, t-test). Results were consistent with the model and with biochemical and bone mineral density data. Results confirm the predicted relationship between bone mineral balance and calcium isotopes, suggesting that calcium isotopic analysis of urine might be refined into a clinical and research tool.

Development and validation of a Markov microsimulation model for the economic evaluation of treatments in osteoporosis.

PubMed

Hiligsmann, Mickaël; Ethgen, Olivier; Bruyère, Olivier; Richy, Florent; Gathon, Henry-Jean; Reginster, Jean-Yves

2009-01-01

Markov models are increasingly used in economic evaluations of treatments for osteoporosis. Most of the existing evaluations are cohort-based Markov models missing comprehensive memory management and versatility. In this article, we describe and validate an original Markov microsimulation model to accurately assess the cost-effectiveness of prevention and treatment of osteoporosis. We developed a Markov microsimulation model with a lifetime horizon and a direct health-care cost perspective. The patient history was recorded and was used in calculations of transition probabilities, utilities, and costs. To test the internal consistency of the model, we carried out an example calculation for alendronate therapy. Then, external consistency was investigated by comparing absolute lifetime risk of fracture estimates with epidemiologic data. For women at age 70 years, with a twofold increase in the fracture risk of the average population, the costs per quality-adjusted life-year gained for alendronate therapy versus no treatment were estimated at €9105 and €15,325, respectively, under full and realistic adherence assumptions. All the sensitivity analyses in terms of model parameters and modeling assumptions were coherent with expected conclusions and absolute lifetime risk of fracture estimates were within the range of previous estimates, which confirmed both internal and external consistency of the model. Microsimulation models present some major advantages over cohort-based models, increasing the reliability of the results and being largely compatible with the existing state of the art, evidence-based literature. The developed model appears to be a valid model for use in economic evaluations in osteoporosis.

New methodology for evaluating osteoclastic activity induced by orthodontic load

PubMed Central

ARAÚJO, Adriele Silveira; FERNANDES, Alline Birra Nolasco; MACIEL, José Vinicius Bolognesi; NETTO, Juliana de Noronha Santos; BOLOGNESE, Ana Maria

2015-01-01

Orthodontic tooth movement (OTM) is a dynamic process of bone modeling involving osteoclast-driven resorption on the compression side. Consequently, to estimate the influence of various situations on tooth movement, experimental studies need to analyze this cell. Objectives The aim of this study was to test and validate a new method for evaluating osteoclastic activity stimulated by mechanical loading based on the fractal analysis of the periodontal ligament (PDL)-bone interface. Material and Methods The mandibular right first molars of 14 rabbits were tipped mesially by a coil spring exerting a constant force of 85 cN. To evaluate the actual influence of osteoclasts on fractal dimension of bone surface, alendronate (3 mg/Kg) was injected weekly in seven of those rabbits. After 21 days, the animals were killed and their jaws were processed for histological evaluation. Osteoclast counts and fractal analysis (by the box counting method) of the PDL-bone interface were performed in histological sections of the right and left sides of the mandible. Results An increase in the number of osteoclasts and in fractal dimension after OTM only happened when alendronate was not administered. Strong correlation was found between the number of osteoclasts and fractal dimension. Conclusions Our results suggest that osteoclastic activity leads to an increase in bone surface irregularity, which can be quantified by its fractal dimension. This makes fractal analysis by the box counting method a potential tool for the assessment of osteoclastic activity on bone surfaces in microscopic examination. PMID:25760264

Effect of Bisphosphonate Use on Risk of Postmenopausal Breast Cancer

PubMed Central

Hue, Trisha F.; Cummings, Steven R.; Cauley, Jane A.; Bauer, Douglas C.; Ensrud, Kristine E.; Barrett-Connor, Elizabeth; Black, Dennis M.

2015-01-01

IMPORTANCE Studies have shown that bisphosphonates may have antitumor and antimetastatic properties. Recently, observational studies have suggested a possible protective effect of bisphosphonates on breast cancer, but the effect of bisphosphonate use on risk of breast cancer has not been tested in randomized trials. OBJECTIVE To assess the relationship of postmenopausal breast cancer incidence and bisphosphonate use using data from 2 randomized (1:1), double-blind, placebo-controlled trials. DESIGN, SETTING, AND PARTICIPANTS The Fracture Intervention Trial (FIT) randomly assigned 6459 women aged 55 to 81 years to alendronate or placebo for a mean follow-up of 3.8 years. The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly–Pivotal Fracture Trial (HORIZON-PFT) randomly assigned 7765 women aged 65 to 89 years to annual intravenous zoledronic acid or placebo for a mean follow-up of 2.8 years. Data were collected at clinical centers in the United States (FIT and HORIZON-PFT) and in Asia and the Pacific, Europe, North America, and South America (HORIZON-PFT). Women, in either study, with recurrent breast cancer or who reported a history of breast cancer were excluded from analyses. In each trial, a blinded review was conducted of each cancer adverse event report to verify incident invasive breast cancer cases. The primary analysis compared events in the active vs placebo group using a log-rank test. INTERVENTION Alendronate vs placebo (FIT) or zoledronic acid vs placebo (HORIZON-PFT). MAIN OUTCOMES AND MEASURES Hazard ratio for incident breast cancer in the bisphosphonate treatment group compared to the placebo group. RESULTS There was no significant difference in the rate of breast cancer in FIT: 1.5% (n = 46) in the placebo group and 1.8% (n = 57) in the alendronate group (hazard ratio [HR], 1.24 [95% CI, 0.84–1.83]). In HORIZON-PFT, there was also no significant difference: 0.8% (n = 29) in the placebo group and 0.9% (n = 33) in the

Natural calcium isotonic composition of urine as a marker of bone mineral balance

USGS Publications Warehouse

Skulan, J.; Bullen, T.; Anbar, A.D.; Puzas, J.E.; Shackelford, L.; LeBlanc, A.; Smith, S.M.

2007-01-01

Background: We investigated whether changes in the natural isotopic composition of calcium in human urine track changes in net bone mineral balance, as predicted by a model of calcium isotopic behavior in vertebrates. If so, isotopic analysis of natural urine or blood calcium could be used to monitor short-term changes in bone mineral balance that cannot be detected with other techniques. Methods: Calcium isotopic compositions are expressed as ??44Ca, or the difference in parts per thousand between the 44Ca/40Ca of a sample and the 44Ca/ 40Ca of a standard reference material. ??44Ca was measured in urine samples from 10 persons who participated in a study of the effectiveness of countermeasures to bone loss in spaceflight, in which 17 weeks of bed rest was used to induce bone loss. Study participants were assigned to 1 of 3 treatment groups: controls received no treatment, one treatment group received alendronate, and another group performed resistive exercise. Measurements were made on urine samples collected before, at 2 or 3 points during, and after bed rest. Results: Urine ??44Ca values during bed rest were lower in controls than in individuals treated with alendronate (P <0.05, ANOVA) or exercise (P <0.05), and lower than the control group baseline (P <0.05, Mest). Results were consistent with the model and with biochemical and bone mineral density data. Conclusion: Results confirm the predicted relationship between bone mineral balance and calcium isotopes, suggesting that calcium isotopic analysis of urine might be refined into a clinical and research tool. ?? 2007 American Association for Clinical Chemistry.

Role of zoledronic acid in the prevention and treatment of osteoporosis

PubMed Central

Räkel, Agnès; Boucher, Andrée; Ste-Marie, Louis-Georges

2011-01-01

Taken once a year, intravenous zoledronic acid (Zol) (Reclast® or Aclasta®) is a third-generation nitrogen-containing bisphosphonate that is effective compared with placebo in reducing the risk of fractures in patients with postmenopausal osteoporosis and recent low-trauma hip fracture. In glucocorticoid-induced osteoporosis, there is no significant difference between Zol and risedronate for new fractures. Improvements in bone mineral density and early reduction of bone remodeling markers are observed in postmenopausal osteoporosis, recent low-trauma hip fracture, and glucocorticoid-induced osteoporosis. Given that Zol is generally well tolerated and very convenient, it is an interesting therapeutic option for aging patients who take multiple oral drugs, who have adherence or gastrointestinal tolerance issues, and who have an indication for oral bisphosphonates. Zol is not recommended for patients with severe renal impairment. Vitamin D deficiency should be corrected before the administration of Zol. PMID:21594000

Role of zoledronic acid in the prevention and treatment of osteoporosis.

PubMed

Räkel, Agnès; Boucher, Andrée; Ste-Marie, Louis-Georges

2011-01-01

Taken once a year, intravenous zoledronic acid (Zol) (Reclast® or Aclasta®) is a third-generation nitrogen-containing bisphosphonate that is effective compared with placebo in reducing the risk of fractures in patients with postmenopausal osteoporosis and recent low-trauma hip fracture. In glucocorticoid-induced osteoporosis, there is no significant difference between Zol and risedronate for new fractures. Improvements in bone mineral density and early reduction of bone remodeling markers are observed in postmenopausal osteoporosis, recent low-trauma hip fracture, and glucocorticoid-induced osteoporosis. Given that Zol is generally well tolerated and very convenient, it is an interesting therapeutic option for aging patients who take multiple oral drugs, who have adherence or gastrointestinal tolerance issues, and who have an indication for oral bisphosphonates. Zol is not recommended for patients with severe renal impairment. Vitamin D deficiency should be corrected before the administration of Zol.

On-Demand Urine Analyzer

NASA Technical Reports Server (NTRS)

Farquharson, Stuart; Inscore, Frank; Shende, Chetan

2010-01-01

A lab-on-a-chip was developed that is capable of extracting biochemical indicators from urine samples and generating their surface-enhanced Raman spectra (SERS) so that the indicators can be quantified and identified. The development was motivated by the need to monitor and assess the effects of extended weightlessness, which include space motion sickness and loss of bone and muscle mass. The results may lead to developments of effective exercise programs and drug regimes that would maintain astronaut health. The analyzer containing the lab-on-a- chip includes materials to extract 3- methylhistidine (a muscle-loss indicator) and Risedronate (a bone-loss indicator) from the urine sample and detect them at the required concentrations using a Raman analyzer. The lab-on- a-chip has both an extractive material and a SERS-active material. The analyzer could be used to monitor the onset of diseases, such as osteoporosis.

A study of changes in bone metabolism in cases of gender identity disorder.

PubMed

Miyajima, Tsuyoshi; Kim, Yoon Taek; Oda, Hiromi

2012-07-01

The aim of this study was to determine the effect of increasing estrogen and decreasing androgen in males and increasing androgen and decreasing estrogen in females on bone metabolism in patients with gender identity disorder (GID). We measured and examined bone mineral density (BMD) and bone metabolism markers retrospectively in GID patients who were treated in our hospital. In addition, we studied the effects of treatment on those who had osteoporosis. Patients who underwent a change from male to female (MtF) showed inhibition of bone resorption and increased L2-4 BMD whereas those who underwent a change from female to male (FtM) had increased bone resorption and decreased L2-4 BMD. Six months after administration of risedronate to FtM patients with osteoporosis, L2-4 BMD increased and bone resorption markers decreased. These results indicate that estrogen is an important element with regard to bone metabolism in males.

Impact of bisphosphonate drug burden in alveolar bone during orthodontic tooth movement in a rat model: a pilot study.

PubMed

Kaipatur, Neelambar R; Wu, Yuchin; Adeeb, Samer; Stevenson, Thomas R; Major, Paul W; Doschak, Michael R

2013-10-01

The aim of this pilot study was to investigate the effect of long-term bisphosphonate drug use (bone burden) on orthodontic tooth movement in a rat model. Sprague Dawley rats were used for orthodontic protraction of the maxillary first molars with nickel-titanium coil springs and temporary anchorage devices as anchorage. Four groups of 5 rats each were included in the study; the first 2 groups were dosed with alendronate or a vehicle during concurrent orthodontic tooth movement. The third and fourth groups were pretreated for 3 months with alendronate or vehicle injections, and bisphosphonate drug treatment was discontinued before orthodontic tooth movement. Tooth movement measurements were obtained at 0, 4, and 8 weeks using high-resolution in-vivo microcomputed tomography, and the tissues were analyzed with histology and dynamic labeling of bone turnover. Appreciable tooth movement was achieved during the 8-week duration of this study with nickel-titanium coil springs and temporary anchorage devices. Both bisphosphonate treatment groups exhibited reduced tooth movement compared with the vehicle-dosed controls with a tendency toward more severe reduction in the bisphosphonate predosed group. Concurrent dosing of the bisphosphonate drug resulted in 56% and 65% reductions in tooth protraction at the 4-week and 8-week times, respectively. The impact of bisphosphonate bone burden in retarding tooth movement was even greater, with 77% and 86% reductions in tooth movement at 4 and 8 weeks, respectively. In this study, we used a robust rat model of orthodontic tooth movement with temporary anchorage devices. It has provided evidence that the bone burden of previous bisphosphonate use will significantly inhibit orthodontic tooth movement. Copyright © 2013 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.

Updated Recommendations for the Diagnosis and Management of Osteoporosis: A Local Perspective

PubMed Central

Raef, Hussein; Al-Bugami, Munira; Balharith, Sakra; Moawad, Mahmoud; El-Shaker, Mohammad; Hussain, Aneela; Al-Shaikh, Ahmad; Al-Badawi, Ismail

2011-01-01

Postmenopausal osteoporosis and osteoporosis in elderly men are major health problems, with a significant medical and economic burden. Although osteopenia and osteoporosis are more common locally than in the West, fracture rates are generally less than in Western countries. Vitamin D deficiency is common in the region and contributes adversely to bone health. Vitamin D deficiency should be suspected and treated in all subjects with ostopenia or osteoporosis. The use of risk factors to determine fracture risk has been adopted by the World Health Organization and many international societies. Absolute fracture risk methodology improves the use of resources by targeting subjects at higher risk of fractures for screening and management. The King Faisal Specialist Hospital Osteoporosis Working Group recommends screening for women 65 years and older and for men 70 years and older. Younger subjects with clinical risk factors and persons with clinical evidence of osteoporosis or diseases leading to osteoporosis should also be screened. These guidelines provide recommendations for treatment for postmenopausal women and men older than 50 years presenting with osteoporotic fractures for persons having osteoporosis—after excluding secondary causes—or for persons having low bone mass and a high risk for fracture. The Working Group has suggested an algorithm to use at King Faisal Specialist Hospital that is based on the availability, cost, and level of evidence of various therapeutic modalities. Adequate calcium and vitamin D supplement are recommended for all. Weekly alendronate (in the absence of contraindications) is recommended as first-line therapy. Alternatives to alendronate are raloxifene or strontium ranelate. Second-line therapies are zoledronic acid intravenously once yearly, when oral therapy is not feasible or complicated by side effects, or teriparatide in established osteoporosis with fractures. PMID:21403406

Self-assembling bisphosphonates into nanofibers to enhance their inhibitory capacity on bone resorption

NASA Astrophysics Data System (ADS)

Tang, Anming; Qian, Yu; Liu, Shuang; Wang, Weijuan; Xu, Bing; Qin, An; Liang, Gaolin

2016-05-01

Osteoporosis (OP) is an important aging-related disease and the effective prevention/treatment of this disease remains challenging. Considering the acidic microenvironment of bone resorption lacunae, herein, we rationally designed two pamidronate (Pami)-derivative and alendronate (Alen)-derivative hydrogelators Pami-D and Alen-D which self-assemble into nanofibers to form supramolecular hydrogels under acidic conditions. Cell viability assay, osteoclastogenesis, osteoclastic gene expression, and in vitro bone resorption results indicated that both Pami-D and Alen-D have better inhibitory effects on osteoclastic formation and bone resorption than Pami and Alen, respectively. We anticipate that our new drugs Pami-D and Alen-D could ``smartly'' self-assemble and locally concentrate the drugs at bone resorption lacunae in vivo and subsequently prevent/treat osteoporosis more efficiently.Osteoporosis (OP) is an important aging-related disease and the effective prevention/treatment of this disease remains challenging. Considering the acidic microenvironment of bone resorption lacunae, herein, we rationally designed two pamidronate (Pami)-derivative and alendronate (Alen)-derivative hydrogelators Pami-D and Alen-D which self-assemble into nanofibers to form supramolecular hydrogels under acidic conditions. Cell viability assay, osteoclastogenesis, osteoclastic gene expression, and in vitro bone resorption results indicated that both Pami-D and Alen-D have better inhibitory effects on osteoclastic formation and bone resorption than Pami and Alen, respectively. We anticipate that our new drugs Pami-D and Alen-D could ``smartly'' self-assemble and locally concentrate the drugs at bone resorption lacunae in vivo and subsequently prevent/treat osteoporosis more efficiently. Electronic supplementary information (ESI) available: Experiment methods and details; syntheses and characterization of Pami-D and Alen-D; HPLC conditions; Fig. S1-S15, Schemes S1 and S2, Tables S1 and S2

Systemic medications: clinical significance in periodontics.

PubMed

Ciancio, Sebastian G

2002-05-01

Systemic medications are of value as adjuncts to periodontal therapy. These medications can be divided into two major categories: antibiotics and agents for host modulation. Antibiotics have been shown to be valuable adjuncts in specialized types of periodontal disease, such as localized and generalized aggressive periodontitis, and of possible value in severe chronic periodontitis. Antibiotics have been studied individually, in combination and in sequential therapy. Host modulators include Periostat, non-steroidal anti-inflammatory agents, alendronate (Fosamax), hormone replacement therapy and anti-arthritic medications. These agents produce their beneficial effects by a variety of mechanisms of action, including inhibition of matrix metalloproteinases, inhibition of prostaglandin production, stimulation of osteoblasts, inhibition of osteoclasts, and other anti-inflammatory mechanisms of action.

Fabrication of a microfluidic device for studying the in situ drug-loading/release behavior of graphene oxide-encapsulated hydrogel beads.

PubMed

Veerla, Sarath Chandra; Kim, Da Reum; Yang, Sung Yun

2018-01-01

Controlled drug delivery system is highly important for not only prolonged the efficacy of drug but also cellular development for tissue engineering. A number of biopolymer composites and nanostructured carriers behave been used for the controlled drug delivery of therapeutics. Recently, in vitro microfluidic devices that mimic the human body have been developed for drug-delivery applications. A microfluidic channel was fabricated via a two-step process: (i) polydimethyl siloxane (PDMS) and curing agent were poured with a 10:2 mass ratio onto an acrylic mold with two steel pipes, and (ii) calcium alginate beads were synthesized using sodium alginate and calcium chloride solutions. Different amounts (10, 25, 50 μg) of graphene oxide (GO) were then added by Hummers method, and studies on the encapsulation and release of the model drug, risedronate (Ris), were performed using control hydrogel beads (pH 6.3), GO-containing beads (10GO, 25GO and 50GO), and different pH conditions. MC3T3 osteoblastic cells were cultured in a microchannel with Ris-loaded GO-hydrogel beads, and their proliferation, viability, attachment and spreading were assessed for a week. The spongy and textured morphology of pristine hydrogel beads was converted to flowery and rod-shaped structures in drug-loaded hydrogel beads at reduced pH (6.3) and at a lower concentration (10 μg) of GO. These latter 10GO drug-loaded beads rapidly released their cargo owing to the calcium phosphate deposited on the surface. Notably, beads containing a higher amount of GO (50GO) exhibited an extended drug-release profile. We further found that MC3T3 cells proliferated continuously in vitro in the microfluidic channel containing the GO-hydrogel system. MTT and live/dead assays showed similar proliferative potential of MC3T3 cells. Therefore, a microfluidic device with microchannels containing hydrogel beads formulated with different amounts of GO and tested under various pH conditions could be a promising system

Pregnancy- and lactation-associated osteoporosis with severe vertebral deformities: can strontium ranelate be a new alternative for the treatment?

PubMed

Tanriover, Mine Durusu; Oz, S Gul; Sozen, Tumay; Kilicarslan, Alpaslan; Guven, Gulay Sain

2009-04-01

Pregnancy- and lactation-associated osteoporosis is an uncommon condition that may be a consequence of preexisting low bone density, loss of bone mineral content during pregnancy, and increased bone turnover. To present a case of severe osteoporosis associated with pregnancy and lactation and its treatment protocol. A tertiary care hospital. A young female after twin pregnancy presenting with severe osteoporosis. The diagnosis was done on the basis of bone mineral density (BMD) measurement. The patient was treated with first alendronate and then strontium ranelate. She was considered as a candidate for kyphoplasty. A dramatic increase in the BMD and palliation of back pain were observed. Strontium ranelate may be a new alternative in the treatment of pregnancy- and lactation-associated osteoporosis.

Bilateral non-traumatic acetabular and femoral neck fractures due to pregnancy-associated osteoporosis.

PubMed

Aynaci, Osman; Kerimoglu, Servet; Ozturk, Cagatay; Saracoglu, Metehan

2008-03-01

Pregnancy-associated osteoporosis is a rare disorder and its pathophysiology remains unknown. We report a case of pregnancy-associated osteoporosis in a 27-year-old primiparous patient who revealed bilateral hip pain during early postnatal period. The plain radiographs and computerized tomography showed bilateral femoral neck and acetabular fractures. The diagnosis of osteoporosis was established by bone mineral density. Diagnostic work-up excluded a secondary osteoporosis. The case was treated successfully by bilateral cementless total hip arthroplasty. Bone mineral density increased after 2 years of treatment with calcium-vitamin D, calcitriol and alendronate. Diagnosis of pregnancy-associated osteoporosis should be suspected when hip pain occurs during pregnancy or in the post-partum period as it can lead to acetabular and femoral neck fractures.

Examination of antimicrobial activity of selected non-antibiotic medicinal preparations.

PubMed

Kruszewska, Hanna; Zareba, Tomasz; Tyski, Stefan

2012-01-01

The aim of this study was to detect and characterize the antimicrobial activity of non-antibiotic drugs, selected from the pharmaceutical products analyzed during the state control performed in National Medicines Institute, Warszawa, Poland. In 2010, over 90 pharmaceutical preparations have been randomly chosen from different groups of drugs. The surveillance study was performed on standard ATCC microbial strains used for drug control: S. aureus, E. coli, P. aeruginosa and C. albicans. It was shown that the drugs listed below inhibited growth of at least one of the examined strains: Arketis 20 mg tab. (paroxetine), Buvasodil 150 mg tab. (buflomedile), Halidor 100 mg tab. (bencyclane), Hydroxyzinum espefa 25 mg tab. (hydroxyzine), Norifaz 35 mg tab. (risedronate), Strattera 60 mg cap. (atomoxetine), Tamiflu 75 mg tab. (oseltamivir), Valpro-ratiopharm Chrono 300 mg tab. with longer dissolution (valproate), Vetminth oral paste 24 g+3 g/100 mL (niclozamide, oxybendazol). Strattera cap. showed broad activity spectrum. It inhibited growth of all examined strains (MIC of active substance -- atomoxetine ranged between 2.6-13 mg/mL).

Comparative "in vitro" evaluation of the antiresorptive activity residing in four Ayurvedic medicinal plants. Hemidesmus indicus emerges for its potential in the treatment of bone loss diseases.

PubMed

Di Pompo, Gemma; Poli, Ferruccio; Mandrone, Manuela; Lorenzi, Beatrice; Roncuzzi, Laura; Baldini, Nicola; Granchi, Donatella

2014-06-11

Four Indian plants, traditionally used in Ayurvedic medicine: Asparagus racemosus Willd., Emblica officinalis Gaertn., Hemidesmus indicus R. Br., and Rubia cordifolia L. were selected on the basis of their ethnobotanical use and of scientific evidence that suggests a potential efficacy in the treatment of bone-loss diseases. The antiresorptive properties of the four plants have been investigated. The aim was to provide adequate evidence for the exploitation of natural compounds as alternative therapeutics for the treatment of diseases caused by increased osteoclast activity. Decoctions were prepared from dried plant material according to the traditional procedure and standardization by HPLC was performed using marker compounds for each species. Total polyphenols, flavonoids and radical scavenging activity of the decoctions were also determined. The bioactivity of the plant decoctions was evaluated in subsequent phases. (1) A cytotoxicity screening was performed on the mouse monocytic RAW 264.7 cell line to define the concentrations that could be utilized in the following step. (2) The antiresorptive properties of plant decoctions were compared with that of a "gold standard" drug (alendronate) by measuring osteoclastogenesis inhibition and osteoclast apoptosis. (3) The toxic effect on bone forming cells was excluded by evaluating the impact on the proliferation of osteogenic precursors (mesenchymal stem cells, MSC). All the decoctions inhibited osteoclastogenesis similarly to alendronate at the highest doses, but Hemidesmus indicus and Rubia cordifolia were also effective at lower concentrations. Apoptosis increased significantly when cells were exposed to the highest concentration of Emblica officinalis, Hemidesmus indicus, and Rubia cordifolia. All concentrations of Emblica officinalis tested inhibited the proliferation of osteogenic precursors, while only the highest doses of Asparagus racemosus and Rubia cordifolia were toxic. On the contrary, Hemidesmus indicus

Prevention of disuse osteoporosis in rats by Cordyceps sinensis extract.

PubMed

Qi, W; Yan, Y-B; Lei, W; Wu, Z-X; Zhang, Y; Liu, D; Shi, L; Cao, P-C; Liu, N

2012-09-01

Cordyceps sinensis has been known as a traditional medicine in China, and C. sinensis plus strontium could prevent osteoporosis in ovariectomized rats. The present study shows that daily oral administration of C. sinensis at higher doses in adult hind limb suspension rats can prevent disuse-induced bone loss and deterioration of trabecular microarchitecture. Cordyceps sinensis induces estradiol production and prevents osteoporosis in ovariectomized rats. This study was to examine whether C. sinensis can prevent disuse-induced osteoporosis. Rats were randomly divided into six groups, and five groups were treated with hind limb suspension (HLS). One HLS group received alendronate (2.0 mg/kg/day) orally, and to the three other HLS groups to each group, a different amount of C. sinensis (100, 300, and 500 mg/kg/day) was orally administered for 8 weeks before and after HLS. The remaining HLS group was set as a control without treatment. Each group consisted of 10 males and females. The body weights, biochemical parameters in serum and urine, bone mineral density (BMD), bone mineral content (BMC), mechanical testing, and bone microarchitecture were examined. Treatments with higher C. sinensis dosage (300 and 500 mg/kg/day) or alendronate had a positive effect on body weights, mechanical strength, BMD, and BMC compared to the other HLS groups. C. sinensis decreased markers of bone turnover dose dependently and increased the osteocalcin levels in HLS rats. The result of micro-CT analysis from the L4 vertebra showed that C. sinensis (500 mg/kg) significantly prevented the reduction of the bone volume fraction, connectivity density, trabeculae number, and thickness as well as improved the trabeculae separation and structure model index in HLS rats. The present study demonstrates that administration of C. sinensis at higher doses over an 8-week period can prevent the disuse osteoporosis in rats. It implies that C. sinensis might be an alternative therapy for prevention

Prevention of Glucocorticoid-Induced Osteoporosis: Clinical audit to evaluate the implementation of National Osteoporosis Guideline Group 2017 guidelines in a primary care setting.

PubMed

Carter, Matthew

2018-04-12

Treatment with glucocorticoids is the leading cause of drug-induced osteoporosis. National Osteoporosis Guideline Group (NOGG) 2017 guidelines advise a case-finding strategy for patients at risk. The aims of the audit were to evaluate the implementation of the NOGG 2017 guidelines for patients receiving long-term glucocorticoid therapy in a suburban general practice, to instigate changes to ensure 90% of patients are investigated and treated appropriately, and to evaluate impact at a 6-mo re-audit. Reporting Analysis and Intelligence Delivering Results (RAIDR) is a health-care intelligence tool accessing primary care clinical data. Using RAIDR, data on relevant osteoporotic risk factors were combined to produce FRAX scores for patients who had been prescribed glucocorticoids 3 or more times in the past 12 months. FRAX data were displayed in a NOGG guidance graph for major osteoporotic fracture probability. Patients were assessed as high, intermediate, or low risk. High- and intermediate-risk patients above the NOGG threshold were recommended to start bisphosphonates; these patients were sent a prescription for alendronate and a letter of explanation. There were no intermediate patients below the NOGG threshold. Low-risk patients were recommended to have lifestyle advice; a leaflet was produced and sent to these patients. Initial results showed that only 25% of patients recommended to be on bisphosphonates were taking them. Steps were taken to educate the general practitioners in the FRAX tool and NOGG guidelines; the chronic obstructive pulmonary disease annual template was amended to aid adherence by alerting the nurse to the number of glucocorticoid courses prescribed, with additional boxes for prescribing alendronate and printing the lifestyle leaflet; and 2-monthly RAIDR searches by the practice pharmacist were started. A re-audit 6 mo later showed improvement to 92%. This audit showed that education, reminders, and simple computer prompts can greatly improve

Determination of the purity of pharmaceutical reference materials by 1H NMR using the standardless PULCON methodology.

PubMed

Monakhova, Yulia B; Kohl-Himmelseher, Matthias; Kuballa, Thomas; Lachenmeier, Dirk W

2014-11-01

A fast and reliable nuclear magnetic resonance spectroscopic method for quantitative determination (qNMR) of targeted molecules in reference materials has been established using the ERETIC2 methodology (electronic reference to access in vivo concentrations) based on the PULCON principle (pulse length based concentration determination). The developed approach was validated for the analysis of pharmaceutical samples in the context of official medicines control, including ibandronic acid, amantadine, ambroxol and lercanidipine. The PULCON recoveries were above 94.3% and coefficients of variation (CVs) obtained by quantification of different targeted resonances ranged between 0.7% and 2.8%, demonstrating that the qNMR method is a precise tool for rapid quantification (approximately 15min) of reference materials and medicinal products. Generally, the values were within specification (certified values) provided by the manufactures. The results were in agreement with NMR quantification using an internal standard and validated reference HPLC analysis. The PULCON method was found to be a practical alternative with competitive precision and accuracy to the classical internal reference method and it proved to be applicable to different solvent conditions. The method can be recommended for routine use in medicines control laboratories, especially when the availability and costs of reference compounds are problematic. Copyright © 2014 Elsevier B.V. All rights reserved.

Bisphosphonate-related osteonecrosis of the jaw: an Italian post-marketing surveillance analysis.

PubMed

Parretta, Elisabetta; Sottosanti, Laura; Sportiello, Liberata; Rafaniello, Concetta; Potenza, Simona; D'Amato, Salvatore; González-González, Rocio; Rossi, Francesco; Colella, Giuseppe; Capuano, Annalisa

2014-09-01

Although bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) is well recognized, little is known about it in terms of pathophysiology, epidemiology or management. We analyzed all suspected BRONJ reports sent to the Italian Pharmacovigilance Adverse Event Spontaneous Reporting System (Rete Nazionale Farmacovigilanza [RNF]) to determine their pattern and add new information about this relevant issue. All suspected BRONJ sent to the RNF between 2003 and 2011 were retrieved. After a case-by-case assessment procedure, we analyzed BP type, BP exposure time and time since last use. Between 2003 and 2011, 555 reports of osteonecrosis of the jaw (ONJ) after BP administration were recorded in the RNF. These events occurred mostly in patients affected by cancer (77.84%) in which zoledronate was the most frequently suspected BP. Most patients experienced ONJ after long-term use of the drug (median time of BP exposure being between 1.3 and 8.8 years). Interestingly, 139 (25.05%) cases of ONJ occurred between 2 and 121 months after BP withdrawal. This study shows that BRONJ can occur much earlier than hitherto reported, adds new data on BRONJ onset following ibandronate treatment and reveals that patients who cease BP-based therapy develop ONJ, raising the question of post-treatment monitoring strategies.

Chronic mandibular osteomyelitis with suspected underlying synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome: a case report

PubMed Central

Mochizuki, Yumi; Omura, Ken; Hirai, Hideaki; Kugimoto, Takuma; Osako, Toshimitu; Taguchi, Takahide

2012-01-01

Chronic mandibular osteomyelitis is an intractable disease. In recent years, some case reports have related this disease process to synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, which is chronic with frequent remissions and exacerbations. This report describes a case of chronic mandibular osteomyelitis suspected to be SAPHO syndrome. A 68-year-old woman presented with pain on the left side of the mandible. On the basis of clinical and radiological findings, chronic mandibular diffuse sclerosing osteomyelitis was initially diagnosed. We administrated oral clarithromycin (400 mg daily) and levofloxacin (500 mg daily), and her pain subsequently resolved. On 99mTc-labeled methylene diphosphonate scintigraphy, tracer uptake in the asymptomatic mandible was unchanged, but there was increasing tracer uptake in the sternocostal and sternoclavicular joints, compared with 99mTc-labeled methylene diphosphonate scintigraphic findings of the first visit. We diagnosed SAPHO syndrome and administrated oral sodium risedronate hydrate (2.5 mg daily). Although there has been no pain or swelling in the area of the left mandibular lesion, we have followed up on other skin and osteoarticular manifestations in conjunction with other medical departments. PMID:22427727

Synthesis of composite magnetic nanoparticles Fe3O4 with alendronate for osteoporosis treatment

PubMed Central

Lee, Ming-Song; Su, Chao-Ming; Yeh, Jih-Chao; Wu, Pei-Ru; Tsai, Tien-Yao; Lou, Shyh-Liang

2016-01-01

Osteoporosis is a result of imbalance between bone formation by osteoblasts and resorption by osteoclasts (OCs). In the present study, we investigated the potential of limiting the aggravation of osteoporosis by reducing the activity of OCs through thermolysis. The proposed method is to synthesize bisphosphonate (Bis)-conjugated iron (II, III) oxide (Fe3O4) nanoparticles and incorporate them into OCs. The cells should be subsequently exposed to radiofrequency (RF) to induce thermolysis. In this study, particles of Fe3O4 were first synthesized by chemical co-precipitation and then coated with dextran (Dex). The Dex/Fe3O4 particles were then conjugated with Bis to form Bis/Dex/Fe3O4. Transmission electron microscopy revealed that the average diameter of the Bis/Dex/Fe3O4 particles was ~20 nm. All three kinds of nanoparticles were found to have cubic inverse spinel structure of Fe3O4 by the X-ray diffraction analysis. Fourier transform infrared spectroscopy confirmed that the Dex/Fe3O4 and Bis/Dex/Fe3O4 nanoparticles possessed their respective Dex and Bis functional groups, while a superconducting quantum interference device magnetometer measured the magnetic moment to be 24.5 emu. In addition, the Bis/Dex/Fe3O4 nanoparticles were fully dispersed in double-distilled water. Osteoblasts and OCs were individually cultured with the nanoparticles, and an MTT assay revealed that they were non-cytotoxic. An RF system (42 kHz and 450 A) was used to raise the temperature of the nanoparticles for 20 minutes, and the thermal effect was found to be sufficient to destroy OCs. Furthermore, in vivo studies verified that nanoparticles were indeed magnetic resonance imaging contrast agents and that they accumulated after being injected into the body of rats. In conclusion, we developed a water-dispersible magnetic nanoparticle that had RF-induced thermogenic properties, and the results indicated that the Bis/Dex/Fe3O4 nanoparticle had the potential for controlling osteoporosis. PMID:27695319

Antiresorptive Treatment for Spaceflight Induced Bone Atrophy - Preliminary Results

NASA Technical Reports Server (NTRS)

LeBlanc, Adrian; Matsumoto, toshio; Jones, Jeff; Shapiro, Jay; Lang, Thomas; Shackelford, Linda C.; Smith, Scott M.; Evans, Harlan J.; Spector, Elisabeth R.; Ploutz-Snyder, Robert;

Update of Bisphosphonate Flight Experiment

NASA Technical Reports Server (NTRS)

LeBlanc, A.; Matsumoto, T.; Jones, J.; Shapiro, J.; Lang, T.; Shackelford, L.; Smith, S. M.; Evans, H.; Spector, E.; Snyder, R. P.;

Risk of atrial fibrillation among bisphosphonate users: a multicenter, population-based, Italian study.

PubMed

Herrera, L; Leal, I; Lapi, F; Schuemie, M; Arcoraci, V; Cipriani, F; Sessa, E; Vaccheri, A; Piccinni, C; Staniscia, T; Vestri, A; Di Bari, M; Corrao, G; Zambon, A; Gregori, D; Carle, F; Sturkenboom, M; Mazzaglia, G; Trifiro, G

2015-05-01

Bisphosphonate treatment is used to prevent bone fractures. A controversial association of bisphosphonate use and risk of atrial fibrillation has been reported. In our study, current alendronate users were associated with a higher risk of atrial fibrillation as compared with those who had stopped bisphosphonate (BP) therapy for more than 1 year. Bisphosphonates are widely used to prevent bone fractures. Controversial findings regarding the association between bisphosphonate use and the risk of atrial fibrillation (AF) have been reported. The aim of this study was to evaluate the risk of AF in association with BP exposure. We performed a nested case-control study using the databases of drug-dispensing and hospital discharge diagnoses from five Italian regions. The data cover a period ranging from July 1, 2003 to December 31, 2006. The study population comprised new users of bisphosphonates aged 55 years and older. Patients were followed from the first BP prescription until an occurrence of an AF diagnosis (index date, i.e., ID), cancer, death, or the end of the study period, whichever came first. For the risk estimation, any AF case was matched by age and sex to up to 10 controls from the same source population. A conditional logistic regression was performed to obtain the odds ratio with 95% confidence intervals (CI). The BP exposure was classified into current (<90 days prior to ID), recent (91-180), past (181-364), and distant past (≥365) use, with the latter category being used as a reference point. A subgroup analysis by individual BP was then carried out. In comparison with distant past users of BP, current users of BP showed an almost twofold increased risk of AF: odds ratio (OR) = 1.78 and 95% CI = 1.46-2.16. Specifically, alendronate users were mostly associated with AF as compared with distant past use of BP (OR, 1.97; 95% CI, 1.59-2.43). In our nested case-control study, current users of BP are associated with a higher risk of atrial

Preliminary Results of Bisphosphonate ISS Flight Experiment

NASA Technical Reports Server (NTRS)

LeBlanc, Adrian; Jones, Jeff; Shapiro, Jay; Lang, Tom; Shackelford, Linda C.; Smith, Scott M.; Evans, Harlan J.; Spector, Elisabeth R.; Sibonga, Jean; Matsumoti, Toshio;

The impact of different strategies to handle missing data on both precision and bias in a drug safety study: a multidatabase multinational population-based cohort study.

PubMed

Martín-Merino, Elisa; Calderón-Larrañaga, Amaia; Hawley, Samuel; Poblador-Plou, Beatriz; Llorente-García, Ana; Petersen, Irene; Prieto-Alhambra, Daniel

2018-01-01

Missing data are often an issue in electronic medical records (EMRs) research. However, there are many ways that people deal with missing data in drug safety studies. To compare the risk estimates resulting from different strategies for the handling of missing data in the study of venous thromboembolism (VTE) risk associated with antiosteoporotic medications (AOM). New users of AOM (alendronic acid, other bisphosphonates, strontium ranelate, selective estrogen receptor modulators, teriparatide, or denosumab) aged ≥50 years during 1998-2014 were identified in two Spanish (the Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria [BIFAP] and EpiChron cohort) and one UK (Clinical Practice Research Datalink [CPRD]) EMR. Hazard ratios (HRs) according to AOM (with alendronic acid as reference) were calculated adjusting for VTE risk factors, body mass index (that was missing in 61% of patients included in the three databases), and smoking (that was missing in 23% of patients) in the year of AOM therapy initiation. HRs and standard errors obtained using cross-sectional multiple imputation (MI) (reference method) were compared to complete case (CC) analysis - using only patients with complete data - and longitudinal MI - adding to the cross-sectional MI model the body mass index/smoking values as recorded in the year before and after therapy initiation. Overall, 422/95,057 (0.4%), 19/12,688 (0.1%), and 2,051/161,202 (1.3%) VTE cases/participants were seen in BIFAP, EpiChron, and CPRD, respectively. HRs moved from 100.00% underestimation to 40.31% overestimation in CC compared with cross-sectional MI, while longitudinal MI methods provided similar risk estimates compared with cross-sectional MI. Precision for HR improved in cross-sectional MI versus CC by up to 160.28%, while longitudinal MI improved precision (compared with cross-sectional) only minimally (up to 0.80%). CC may substantially affect relative risk estimation in EMR-based drug

A model-based cost-effectiveness analysis of osteoporosis screening and treatment strategy for postmenopausal Japanese women.

PubMed

Yoshimura, M; Moriwaki, K; Noto, S; Takiguchi, T

2017-02-01

Although an osteoporosis screening program has been implemented as a health promotion project in Japan, its cost-effectiveness has yet to be elucidated fully. We performed a cost-effectiveness analysis and found that osteoporosis screening and treatment would be cost-effective for Japanese women over 60 years. The purpose of this study was to estimate the cost-effectiveness of osteoporosis screening and drug therapy in the Japanese healthcare system for postmenopausal women with no history of fracture. A patient-level state transition model was developed to predict the outcomes of Japanese women with no previous fracture. Lifetime costs and quality-adjusted life years (QALYs) were estimated for women who receive osteoporosis screening and alendronate therapy for 5 years and those who do not receive the screening and treatments. The incremental cost-effectiveness ratio (ICER) of the screening option compared with the no screening option was estimated. Sensitivity analyses were performed to examine the influence of parameter uncertainty on the base case results. The ICERs of osteoporosis screening and treatments for Japanese women aged 50-54, 55-59, 60-64, 65-69, 70-74, and 75-79 years were estimated to be $89,242, $64,010, $40,596, $27,697, $17,027, and $9771 per QALY gained, respectively. Deterministic sensitivity analyses showed that several parameters such as the disutility due to vertebral fracture had a significant influence on the base case results. Applying a willingness to pay of $50,000 per QALY gained, the probability that the screening option became cost-effectiveness estimated to 50.9, 56.3, 59.1, and 64.7 % for women aged 60-64, 65-69, 70-74, and 75-79 years, respectively. Scenario analyses showed that the ICER for women aged 55-59 years with at least one clinical risk factor was below $50,000 per QALY. In conclusion, dual energy X-ray absorptiometry (DXA) screening and alendronate therapy for osteoporosis would be cost-effective for

Bisphosphonate ISS Flight Experiment

NASA Technical Reports Server (NTRS)

LeBlanc, Adrian; Matsumoto, Toshio; Jones, Jeffrey; Shapiro, Jay; Lang, Thomas; Shackleford, Linda; Smith, Scott M.; Evans, Harlan; Spector, Elizabeth; Ploutz-Snyder, Robert;

Diagnosis and treatment of common metabolic spinal disorders in the geriatric population.

PubMed

Eck, J C; Humphreys, S C

1998-12-01

Bone is constantly resorbed and remodeled throughout life. After approximately age 30, there is a net loss of bone mass. This places the geriatric population at an increased risk of pathologic bone disorders that can lead to fractures and deformity. In this paper, we review bone metabolism and remodeling and introduce the proper diagnostic techniques. The most common pathologic spinal disorders are introduced, with emphasis on presentation and treatment options. To prevent excessive bone loss, patients should be educated on proper nutrition (calcium and vitamin D requirements) and lifestyle (avoiding alcohol and cigarette smoking). Sex hormone and drug therapies are available to reduce bone loss. New bisphosphonates such as alendronate sodium (Fosamax) have been effective in increasing bone mass. Early diagnosis and proper treatment of pathologic bone disorders can reduce the incidence of fracture and allow the patient a more productive and comfortable life.

Bone disorders associated with the human immunodeficiency virus: pathogenesis and management.

PubMed

Qaqish, Roula B; Sims, Keri A

2004-10-01

Bone disorders such as osteopenia, osteoporosis, and osteonecrosis have been reported in patients infected with the human immunodeficiency virus (HIV), but the etiology and mechanism of these disorders are unknown. The prevalence estimates vary widely among studies and may be influenced by the presence or absence of antiretroviral therapy and lipodystrophy, severity of HIV disease, and overlapping bone loss risk factors. Addressing potential underlying bone disease risk factors (e.g., smoking and alcohol intake), evaluating calcium and vitamin D intake, and performing dual x-ray absorptiometry in patients with HIV who have risks for bone disease are important strategies in preventing osteopenia and osteoporosis in HIV-infected patients. Management of osteopenia and osteoporosis is still being evaluated. Administration of bisphosphonates (e.g., alendronate), with calcium and vitamin D supplementation, may be reasonable in treating osteoporosis; however, surgical intervention is the only method for treating symptomatic osteonecrosis.

Treatment of central giant cell lesions using bisphosphonates with intralesional corticosteroid injections

PubMed Central

2012-01-01

Central giant cell lesions are benign intraosseous proliferative lesions that have considerable local aggressiveness. Nonsurgical treatment methods, such as intralesional corticosteroid injections, systemic calcitonin and interferon have been reported. Recently, bisphosphonates have been used to treat central giant cell lesions. A case of a 36-year-old male with a central giant cell lesion crossing the mandibular midline was treated with intralesional corticosteroids combined with alendronate sodium for the control of systemic bone resorption. The steroid injections and the use of bisphosphonates were stopped after seven months when further needle penetration into the lesion was not possible due to new bone formation. After two years, the bony architecture was near normal, and only minimal radiolucency was present around the root apices of the involved teeth. The patient was followed up for four years, and panoramic radiography showed areas of new bone formation. Thus far, neither recurrence nor side effects of the medication have been detected. PMID:22913518

Targeted delivery of mesenchymal stem cells to the bone.

PubMed

Yao, Wei; Lane, Nancy E

2015-01-01

Osteoporosis is a disease of excess skeletal fragility that results from estrogen loss and aging. Age related bone loss has been attributed to both elevated bone resorption and insufficient bone formation. We developed a hybrid compound, LLP2A-Ale in which LLP2A has high affinity for the α4β1 integrin on mesenchymal stem cells (MSCs) and alendronate has high affinity for bone. When LLP2A-Ale was injected into mice, the compound directed MSCs to both trabecular and cortical bone surfaces and increased bone mass and bone strength. Additional studies are underway to further characterize this hybrid compound, LLP2A-Ale, and how it can be utilized for the treatment of bone loss resulting from hormone deficiency, aging, and inflammation and to augment bone fracture healing. This article is part of a Special Issue entitled "Stem Cells and Bone". Copyright © 2014 Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Dongdong, E-mail: lidongchem@sina.cn; Zhu, Yuntao; Liang, Zhiqiang

Highlights: ► The synthesized mesoporous hydroxyapatite has nanostructure and bioactivity. ► The materials have high surface area and amino group. ► The materials show higher drug loading and slower release rate than pure HAP. - Abstract: Mesoporous nanosized hydroxyapatite (HAP) functionalized by alendronate (ALN) was synthesized using cationic surfactant CTAB as template. The structural, morphological and textural properties were fully characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR) and N{sub 2} adsorption/desorption. Then the obtained materials were performed as drug delivery carriers using ibuprofen (IBU) as a model drug to investigate their drug storage/releasemore » properties in simulated body fluid (SBF). The materials showed relatively slower release rate compared with HAP due to the ionic interaction between -NH{sub 3}{sup +} on the matrix and -COO{sup −}belongs to IBU. The system provides a new concept for improving the drug loading or slowing down the release rate.« less

Major depressive disorder is a risk factor for low bone mass, central obesity, and other medical conditions

PubMed Central

Cizza, Giovanni

2011-01-01

Major depressive disorder (MDD) is one of the most common psychiatric illnesses in the adult population. It is often associated with an increased risk of cardiovascular disease. Osteoporosis is also a major public health threat. Multiple studies have reported an association between depression and low bone mineral density, but a causal link between these two conditions is disputed. Here the most important findings of the POWER (Premenopausal, Osteoporosis Women, Alendronate, Depression) Study, a large prospective study of bone turnover in premenopausal women with major depression, are summarized. The endocrine and immune alterations secondary to depression that might affect bone mass, and the possible role of poor lifestyle in the etiology of osteoporosis in subjects with depression, are also reviewed, as is the potential effect of antidepressants on bone loss. It is proposed that depression induces bone loss and osteoporotic fractures, primarily via specific immune and endocrine mechanisms, with poor lifestyle habits as potential contributory factors. PMID:21485748

Does Discontinuing Teriparatide Treatment and Replacing It with Bisphosphonate Maintain the Volume of the Bone Fusion Mass after Lumbar Posterolateral Fusion in Women with Postmenopausal Osteoporosis?

PubMed

Ohtori, Seiji; Orita, Sumihisa; Yamauchi, Kazuyo; Eguchi, Yawara; Aoki, Yasuchika; Nakamura, Junichi; Suzuki, Miyako; Kubota, Gou; Inage, Kazuhide; Shiga, Yasuhiro; Abe, Koki; Fujimoto, Kazuki; Kanamoto, Hirohito; Inoue, Masahiro; Kinoshita, Hideyuki; Furuya, Takeo; Koda, Masao

2017-04-01

Retrospective case series. The purpose of this study was to determine whether discontinuing teriparatide treatment and replacing it with bisphosphonate treatment maintains the volume of the fusion mass after posterolateral fusion (PLF) in women with postmenopausal osteoporosis. Clinical data support the efficacy of parathyroid hormone (PTH) for lumbar PLF. However, the use of PTH is limited to 2 years. We treated 19 women diagnosed with osteoporosis and degenerative spondylolisthesis with teriparatide (20 µg daily subcutaneously). All patients underwent one-level instrumented PLF. Teriparatide was used during 2 months prior to surgery and more than 8 months after surgery. After discontinuing teriparatide treatment, all patients used bisphosphonate (17.5 mg risedronate weekly, oral administration). Area of the fusion mass across the transverse processes at one segment was determined on an anteroposterior radiograph at 1, 2, and 3 years after surgery. We followed 19 patients for 3 years. The average duration of teriparatide treatment was 11.5 months. The bone union rate was 95%. The average area of the bone fusion mass was not significantly different between the right and left sides at 1, 2, or 3 years after surgery ( p >0.05). This study showed that replacing teriparatide treatment with bisphosphonate maintained the bone fusion mass volume after PLF in women with postmenopausal osteoporosis.

Cloning and characterization of farnesyl pyrophosphate synthase from the highly branched isoprenoid producing diatom Rhizosolenia setigera.

PubMed

Ferriols, Victor Marco Emmanuel N; Yaginuma, Ryoko; Adachi, Masao; Takada, Kentaro; Matsunaga, Shigeki; Okada, Shigeru

2015-05-21

The diatom Rhizosolenia setigera Brightwell produces highly branched isoprenoid (HBI) hydrocarbons that are ubiquitously present in marine environments. The hydrocarbon composition of R. setigera varies between C25 and C30 HBIs depending on the life cycle stage with regard to auxosporulation. To better understand how these hydrocarbons are biosynthesized, we characterized the farnesyl pyrophosphate (FPP) synthase (FPPS) enzyme of R. setigera. An isolated 1465-bp cDNA clone contained an open reading frame spanning 1299-bp encoding a protein with 432 amino acid residues. Expression of the RsFPPS cDNA coding region in Escherichia coli produced a protein that exhibited FPPS activity in vitro. A reduction in HBI content from diatoms treated with an FPPS inhibitor, risedronate, suggested that RsFPPS supplies precursors for HBI biosynthesis. Product analysis by gas chromatography-mass spectrometry also revealed that RsFPPS produced small amounts of the cis-isomers of geranyl pyrophosphate and FPP, candidate precursors for the cis-isomers of HBIs previously characterized. Furthermore, RsFPPS gene expression at various life stages of R. setigera in relation to auxosporulation were also analyzed. Herein, we present data on the possible role of RsFPPS in HBI biosynthesis, and it is to our knowledge the first instance that an FPPS was cloned and characterized from a diatom.

Endocrinology of anorexia nervosa in young people: recent insights

PubMed Central

Singhal, Vibha; Misra, Madhusmita; Klibanski, Anne

2014-01-01

Purpose of review Anorexia nervosa is among the most prevalent chronic medical conditions in young adults. It has acute as well as long-term consequences, some of which, such as low bone mineral density (BMD), are not completely reversible even after weight restoration. This review discusses our current understanding of endocrine consequences of anorexia nervosa. Recent findings Anorexia nervosa is characterized by changes in multiple neuroendocrine axes including acquired hypogonadotropic hypogonadism, growth hormone resistance with low insulin-like growth factor-1 (likely mediated by fibroblast growth factor-1), relative hypercortisolemia, alterations in adipokines such as leptin, adiponectin and resistin, and gut peptides including ghrelin, PYY and amylin. These changes in turn contribute to low BMD. Studies in anorexia nervosa have demonstrated abnormalities in bone microarchitecture and strength, and an association between increased marrow fat and decreased BMD. One study in adolescents reported an improvement in BMD following physiologic estrogen replacement, and another in adults demonstrated improved BMD following risedronate administration. Brown adipose tissue is reduced in anorexia nervosa, consistent with an adaptive response to the energy deficit state. Summary Anorexia nervosa is associated with widespread physiologic adaptations to the underlying state of undernutrition. Hormonal changes in anorexia nervosa affect BMD adversely. Further investigation is underway to optimize therapeutic strategies for low BMD. PMID:24275621

Bioactivity of Ti-6Al-4V alloy implants treated with ibandronate after the formation of the nanotube TiO2 layer.

PubMed

Moon, So-Hee; Lee, Seung-Jae; Park, Il-Song; Lee, Min-Ho; Soh, Yun-Jo; Bae, Tae-Sung; Kim, Hyung-Seop

2012-11-01

Nanostructure surface of titanium implants treated with anodic oxidation, heat, and bisphosphonates, has been introduced to improve osseointegration of the implants. However, no information could be found about the efficiency of these approaches on Ti-6Al-4V alloy surfaces. This study examined the drug loading capacity of anodized nanotubular Ti-6Al-4V alloy surfaces in vitro as well as the bone response to surface immobilized bisphosphonates (BPs) on anodized nanotubular Ti-6Al-4V alloy surface in tibiae of rats. Ti-6Al-4V alloy titanium was divided into two groups: (1) control group (nontreated); (2) test group (anodized, heat-, and bisphosphonate-treated group). In vitro, amount of the drug released from the both groups' specimens was examined; all samples were 1 × 2 cm in size. In vivo, the 10 implants were placed inside of tibias of five rats. After 4 weeks, the bone response of the implants was evaluated using a removal torque test, and measuring bone contact and bone area. In addition, the surfaces of the extracted implants were observed by FE-SEM and EDS. In vitro, the drug loading capacity of the Ti-6Al-4V alloy surfaces was enhanced by anodizing surface modification. The values of the removal torque, bone contact, and bone area were significantly higher in the test group (p < 0.05). Furthermore, according to the EDS analysis, the amounts of Ca and P on the surface of the extracted implants were higher in the test group. Within the limits of this experiment, results of this research demonstrated that bisphosphonate-treated Ti-6Al-4V alloy implants with nanotubular surfaces have positive effects in bone-to-implant contact. Copyright © 2012 Wiley Periodicals, Inc.

The impact of different strategies to handle missing data on both precision and bias in a drug safety study: a multidatabase multinational population-based cohort study

PubMed Central

Martín-Merino, Elisa; Calderón-Larrañaga, Amaia; Hawley, Samuel; Poblador-Plou, Beatriz; Llorente-García, Ana; Petersen, Irene; Prieto-Alhambra, Daniel

2018-01-01

Background Missing data are often an issue in electronic medical records (EMRs) research. However, there are many ways that people deal with missing data in drug safety studies. Aim To compare the risk estimates resulting from different strategies for the handling of missing data in the study of venous thromboembolism (VTE) risk associated with antiosteoporotic medications (AOM). Methods New users of AOM (alendronic acid, other bisphosphonates, strontium ranelate, selective estrogen receptor modulators, teriparatide, or denosumab) aged ≥50 years during 1998–2014 were identified in two Spanish (the Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria [BIFAP] and EpiChron cohort) and one UK (Clinical Practice Research Datalink [CPRD]) EMR. Hazard ratios (HRs) according to AOM (with alendronic acid as reference) were calculated adjusting for VTE risk factors, body mass index (that was missing in 61% of patients included in the three databases), and smoking (that was missing in 23% of patients) in the year of AOM therapy initiation. HRs and standard errors obtained using cross-sectional multiple imputation (MI) (reference method) were compared to complete case (CC) analysis – using only patients with complete data – and longitudinal MI – adding to the cross-sectional MI model the body mass index/smoking values as recorded in the year before and after therapy initiation. Results Overall, 422/95,057 (0.4%), 19/12,688 (0.1%), and 2,051/161,202 (1.3%) VTE cases/participants were seen in BIFAP, EpiChron, and CPRD, respectively. HRs moved from 100.00% underestimation to 40.31% overestimation in CC compared with cross-sectional MI, while longitudinal MI methods provided similar risk estimates compared with cross-sectional MI. Precision for HR improved in cross-sectional MI versus CC by up to 160.28%, while longitudinal MI improved precision (compared with cross-sectional) only minimally (up to 0.80%). Conclusion CC may substantially

Differences in rates of switchbacks after switching from branded to authorized generic and branded to generic drug products: cohort study

PubMed Central

Sarpatwari, Ameet; Dejene, Sara; Khan, Nazleen F; Lii, Joyce; Rogers, James R; Dutcher, Sarah K; Raofi, Saeid; Bohn, Justin; Connolly, John; Fischer, Michael A; Kesselheim, Aaron S; Gagne, Joshua J

2018-01-01

Abstract Objectives To compare rates of switchbacks to branded drug products for patients switched from branded to authorized generic drug products, which have the same active ingredients, appearance, and excipients as the branded product, with patients switched from branded to generic drug products, which have the same active ingredients as the branded product but may differ in appearance and excipients. Design Observational cohort study. Setting Private (a large commercial health plan) and public (Medicaid) insurance programs in the US. Participants Beneficiaries of a large US commercial health insurer between 2004 and 2013 (primary cohort) and Medicaid beneficiaries between 2000 and 2010 (replication cohort). Main outcome measures Patients taking branded products for one of the study drugs (alendronate tablets, amlodipine tablets, amlodipine-benazepril capsules, calcitonin salmon nasal spray, escitalopram tablets, glipizide extended release tablets, quinapril tablets, and sertraline tablets) were identified when they switched to an authorized generic or a generic drug product after the date of market entry of generic drug products. These patients were followed for switchbacks to the branded drug product in the year after their switch to an authorized generic or a generic drug product. Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals after adjusting for demographics, including age, sex, and calendar year. Inverse variance meta-analysis was used to pool adjusted hazard ratios across all drug products. Results A total of 94 909 patients switched from branded to authorized generic drug products and 116 017 patients switched from branded to generic drug products and contributed to the switchback analysis. Unadjusted incidence rates of switchback varied across drug products, ranging from a low of 3.8 per 100 person years (for alendronate tablets) to a high of 17.8 per 100 person years (for amlodipine

Use of Alendronate Sodium (Fosamax) to Ameliorate Osteoporosis in Renal Transplant Patients: A Case-Control Study

PubMed Central

Huang, Wen-Hung; Lee, Shen-Yang; Weng, Cheng-Hao; Lai, Ping-Chin

2012-01-01

Background Renal transplant patients often have severe bone and mineral deficiencies. While the clinical effects of immunosuppressive agents like calcineurin inhibitors (CIs) and sirolimus on bone turnover are unclear, bisphosphonates are effective in bone recovery in these patients. Gender is significantly associated with osteoporosis and affects bone turnover, which is different in women and men. The effective gender-related site of action of bisphosphonates is unknown. Methods Initially, we enrolled 84 kidney recipients who had received their transplants at least 5 months ago; of these, 8 were excluded and 76 were finally included in the study. First bone mineral density (BMD) at the lumbar spine, hip, and femoral neck was determined using dual-energy X-ray absorptiometry (DXA) between September 2008 and March 2009. These 76 patients underwent a repeat procedure after a mean period 14 months. Immunosuppressive agents, bisphosphonates, patients' characteristics, and biochemical factors were analyzed on the basis of the BMD determined using DXA. Results After the 14-month period, the BMD of lumbar spine increased significantly (from 0.9 g/cm2 to 0.92 g/cm2, p<0.001), whereas that of the hip and femoral neck did not. Ordinal logistic regression analysis was used to show that Fosamax improved bone condition, as defined by WHO (p = 0.007). The use of immunosuppressive agents did not affect bone turnover (p>0.05). Moreover, in subgroup analysis, Fosamax increased the BMD at the lumbar spine and the hipbone in males (p = 0.028 and 0.03, respectively) but only at the lumbar spine in females (p = 0.022). Conclusion After a long periods after renal transplantation, the detrimental effects of steroid and immunosuppressive agents on bone condition diminished. Short-term Fosamax administration effectively improves BMD in these patients. The efficacy of Fosamax differed between male and female renal transplant patients. PMID:23185261

Technical advance: liposomal alendronate depletes monocytes and macrophages in the nonhuman primate model of human disease.

PubMed

Burwitz, Benjamin J; Reed, Jason S; Hammond, Katherine B; Ohme, Merete A; Planer, Shannon L; Legasse, Alfred W; Ericsen, Adam J; Richter, Yoram; Golomb, Gershon; Sacha, Jonah B

2014-09-01

Nonhuman primates are critical animal models for the study of human disorders and disease and offer a platform to assess the role of immune cells in pathogenesis via depletion of specific cellular subsets. However, this model is currently hindered by the lack of reagents that safely and specifically ablate myeloid cells of the monocyte/macrophage Lin. Given the central importance of macrophages in homeostasis and host immunity, development of a macrophage-depletion technique in nonhuman primates would open new avenues of research. Here, using LA at i.v. doses as low as 0.1 mg/kg, we show a >50% transient depletion of circulating monocytes and tissue-resident macrophages in RMs by an 11-color flow cytometric analysis. Diminution of monocytes was followed rapidly by emigration of monocytes from the bone marrow, leading to a rebound of monocytes to baseline levels. Importantly, LA was well-tolerated, as no adverse effects or changes in gross organ function were observed during depletion. These results advance the ex vivo study of myeloid cells by flow cytometry and pave the way for in vivo studies of monocyte/macrophage biology in nonhuman primate models of human disease. © 2014 Society for Leukocyte Biology.

Technical Advance: Liposomal alendronate depletes monocytes and macrophages in the nonhuman primate model of human disease

PubMed Central

Burwitz, Benjamin J.; Reed, Jason S.; Hammond, Katherine B.; Ohme, Merete A.; Planer, Shannon L.; Legasse, Alfred W.; Ericsen, Adam J.; Richter, Yoram; Golomb, Gershon; Sacha, Jonah B.

2014-01-01

Nonhuman primates are critical animal models for the study of human disorders and disease and offer a platform to assess the role of immune cells in pathogenesis via depletion of specific cellular subsets. However, this model is currently hindered by the lack of reagents that safely and specifically ablate myeloid cells of the monocyte/macrophage Lin. Given the central importance of macrophages in homeostasis and host immunity, development of a macrophage-depletion technique in nonhuman primates would open new avenues of research. Here, using LA at i.v. doses as low as 0.1 mg/kg, we show a >50% transient depletion of circulating monocytes and tissue-resident macrophages in RMs by an 11-color flow cytometric analysis. Diminution of monocytes was followed rapidly by emigration of monocytes from the bone marrow, leading to a rebound of monocytes to baseline levels. Importantly, LA was well-tolerated, as no adverse effects or changes in gross organ function were observed during depletion. These results advance the ex vivo study of myeloid cells by flow cytometry and pave the way for in vivo studies of monocyte/macrophage biology in nonhuman primate models of human disease. PMID:24823811

Cloning and characterization of farnesyl pyrophosphate synthase from the highly branched isoprenoid producing diatom Rhizosolenia setigera

PubMed Central

Ferriols, Victor Marco Emmanuel N.; Yaginuma, Ryoko; Adachi, Masao; Takada, Kentaro; Matsunaga, Shigeki; Okada, Shigeru

2015-01-01

The diatom Rhizosolenia setigera Brightwell produces highly branched isoprenoid (HBI) hydrocarbons that are ubiquitously present in marine environments. The hydrocarbon composition of R. setigera varies between C25 and C30 HBIs depending on the life cycle stage with regard to auxosporulation. To better understand how these hydrocarbons are biosynthesized, we characterized the farnesyl pyrophosphate (FPP) synthase (FPPS) enzyme of R. setigera. An isolated 1465-bp cDNA clone contained an open reading frame spanning 1299-bp encoding a protein with 432 amino acid residues. Expression of the RsFPPS cDNA coding region in Escherichia coli produced a protein that exhibited FPPS activity in vitro. A reduction in HBI content from diatoms treated with an FPPS inhibitor, risedronate, suggested that RsFPPS supplies precursors for HBI biosynthesis. Product analysis by gas chromatography-mass spectrometry also revealed that RsFPPS produced small amounts of the cis-isomers of geranyl pyrophosphate and FPP, candidate precursors for the cis-isomers of HBIs previously characterized. Furthermore, RsFPPS gene expression at various life stages of R. setigera in relation to auxosporulation were also analyzed. Herein, we present data on the possible role of RsFPPS in HBI biosynthesis, and it is to our knowledge the first instance that an FPPS was cloned and characterized from a diatom. PMID:25996801

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2002-05-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables can be retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abacavir sulfate, abarelix, abciximab, acarbose, alefacept, alteplase, amisulpride, amoxicillin trihydrate, apomorphine hydrochloride, aprepitant, argatroban monohydrate, aspirin, atenolol; Betamethasone dipropionate, betamethasone valerate, bicalutamide, bleomycin sulfate; Calcium carbonate, candesartan cilexetil, celecoxib, cetirizine hydrochloride, cisplatin, clarithromycin, clavulanate potassium, clomethiazole edisilate, clopidogrel hydrogensulfate, cyclophosphamide, chorionic gonadotropin (human); Dalteparin sodium, desloratadine, dexamethasone, doxorubicin, DPC-083; Efalizumab, efavirenz, enoxaparin sodium, eprosartan mesilate, etanercept, etoposide, ezetimibe; Faropenem daloxate, fenofibrate, fluocinolone acetonide, flutamide, fluvastatin sodium, follitropin beta, fondaparinux sodium; Gabapentin, glibenclamide, goserelin, granisetron hydrochloride; Haloperidol, hydrochlorothiazide; Imiquimod, interferon beta-1a, irbesartan, iseganan hydrochloride; L-758298, lamivudine, lanoteplase, leflunomide, leuprorelin acetate, loratadine, losartan potassium; Melagatran, metformin hydrochloride, methotrexate, metronidazole, micafungin sodium, mitoxantrone hydrochloride; Nelfinavir mesilate, neutral insulin injection, nizatidine; Olopatadine hydrochloride, omeprazole, ondansetron hydrochloride; Pamidronate sodium, paracetamol, paroxetine hydrochloride, perindopril, pimecrolimus, pioglitazone hydrochloride, piroxicam, pleconaril, pralmorelin, pravastatin sodium, prednisolone, prednisone, propofol; Raloxifene hydrochloride, ranpirnase, remifentanil hydrochloride, risedronate sodium, risperidone, rofecoxib, ropinirole

Local Bisphosphonate Treatment Increases Fixation of Hydroxyapatite-Coated Implants Inserted with Bone Compaction

PubMed Central

Jakobsen, Thomas; Baas, Jørgen; Kold, Søren; Bechtold, Joan E.; Elmengaard, Brian; Søballe, Kjeld

2013-01-01

It has been shown that fixation of primary cementless joint replacement can independently be enhanced by either: (1) use of hydroxyapatite (HA) coated implants, (2) compaction of the peri-implant bone, or (3) local application of bisphosphonate. We investigated whether the combined effect ofHAcoating and bone compaction can be further enhanced with the use of local bisphosphonate treatment .HA-coated implants were bilaterally inserted into the proximal tibiae of 10 dogs. On one side local bisphosphonate was applied prior to bone compaction. Saline was used as control on the contralateral side. Implants were evaluated with histomorphometry and biomechanical pushout test. We found that bisphosphonate increased the peri-implant bone volume fraction (1.3-fold), maximum shear strength (2.1-fold), and maximum shear stiffness (2.7-fold). No significant difference was found in bone-to-implant contact or total energy absorption. This study indicates that local alendronate treatment can further improve the fixation of porous-coated implants that have also undergone HA-surface coating and peri-implant bone compaction. PMID:18752278

The Effect of Rosiglitazone on Bone Quality in a Rat Model of Insulin Resistance and Osteoporosis

NASA Astrophysics Data System (ADS)

Sardone, Laura Donata

Rosiglitazone (RSG) is an insulin-sensitizing drug used to treat Type 2 Diabetes Mellitus (T2DM). Clinical trials show that women taking RSG experience more limb fractures than patients taking other T2DM drugs. The purpose of this study is to understand how RSG (3mg/kg/day and 10mg/kg/day) and the bisphosphonate alendronate (0.7mg/kg/week) alter bone quality in the male, female and female ovariectomized (OVX) Zucker fatty rat model over a 12 week period. Bone quality was evaluated by mechanical testing of cortical and trabecular bone. Microarchitecture, bone mineral density (BMD), cortical bone porosity, bone formation/resorption and mineralization were also measured. Female OVX RSG10mg/kg rats had significantly lower vertebral BMD and compromised trabecular architecture versus OVX controls. Increased cortical porosity and decreased mechanical properties occurred in these rats. ALN treatment prevented these negative effects in the OVX RSG model. Evidence of reduced bone formation and excess bone resorption was detected in female RSG-treated rats.

The inhibition of RANK-ligand in the management of postmenopausal osteoporosis and related fractures: the role of denosumab.

PubMed

Capozzi, Anna; Lello, Stefano; Pontecorvi, Alfredo

2014-06-01

There is great interest in new treatments of osteoporosis owing to general ageing of population and increased risk for fragility fractures in the elderly. Current therapies show a good efficacy in improving bone quality and bone density, but, in spite of a certain reduction in fracture rate, according to each treatment, the problem of osteoporotic fractures is yet far from to be solved. Moreover, some treatments may produce different side effects. Denosumab (Dmab), a receptor activator of nuclear factor kappa-B ligand (RANKL)-inhibitor, is an agent recently introduced in clinical practice for treatment of osteoporosis of postmenopausal women. Dmab has improved bone mineral density and prevented new vertebral and non-vertebral fractures with a similar efficacy in comparison with alendronate. Many clinical studies showed Dmab produces also significant improvement versus placebo in bone quality as indicated by decreasing markers of bone turnover. Patients using Dmab reported less risk of AFF (Atypical Femoral Fractures) and ONJ (Osteonecrosis of the Jaw) with an increased number of cellulitis. Here, we review articles using Dmab for female post-menopausal osteoporosis.

Do bisphosphonates inhibit direct fracture healing?: A laboratory investigation using an animal model.

PubMed

Savaridas, T; Wallace, R J; Salter, D M; Simpson, A H R W

2013-09-01

Fracture repair occurs by two broad mechanisms: direct healing, and indirect healing with callus formation. The effects of bisphosphonates on fracture repair have been assessed only in models of indirect fracture healing. A rodent model of rigid compression plate fixation of a standardised tibial osteotomy was used. Ten skeletally mature Sprague-Dawley rats received daily subcutaneous injections of 1 µg/kg ibandronate (IBAN) and ten control rats received saline (control). Three weeks later a tibial osteotomy was rigidly fixed with compression plating. Six weeks later the animals were killed. Fracture repair was assessed with mechanical testing, radiographs and histology. The mean stress at failure in a four-point bending test was significantly lower in the IBAN group compared with controls (8.69 Nmm(-2) (sd 7.63) vs 24.65 Nmm(-2) (sd 6.15); p = 0.017). On contact radiographs of the extricated tibiae the mean bone density assessment at the osteotomy site was lower in the IBAN group than in controls (3.7 mmAl (sd 0.75) vs 4.6 mmAl (sd 0.57); p = 0.01). In addition, histological analysis revealed progression to fracture union in the controls but impaired fracture healing in the IBAN group, with predominantly cartilage-like and undifferentiated mesenchymal tissue (p = 0.007). Bisphosphonate treatment in a therapeutic dose, as used for risk reduction in fragility fractures, had an inhibitory effect on direct fracture healing. We propose that bisphosphonate therapy not be commenced until after the fracture has united if the fracture has been rigidly fixed and is undergoing direct osteonal healing.

The mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway

PubMed Central

Rauthan, Manish; Ranji, Parmida; Aguilera Pradenas, Nataly; Pitot, Christophe; Pilon, Marc

2013-01-01

Statins are cholesterol-lowering drugs that inhibit 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in the synthesis of cholesterol via the mevalonate pathway. This pathway also produces coenzyme Q (a component of the respiratory chain), dolichols (important for protein glycosylation), and isoprenoids (lipid moieties responsible for the membrane association of small GTPases). We previously showed that the nematode Caenorhabditis elegans is useful to study the noncholesterol effects of statins because its mevalonate pathway lacks the sterol synthesis branch but retains all other branches. Here, from a screen of 150,000 mutagenized genomes, we isolated four C. elegans mutants resistant to statins by virtue of gain-of-function mutations within the first six amino acids of the protein ATFS-1, the key regulator of the mitochondrial unfolded protein response that includes activation of the chaperones HSP-6 and HSP-60. The atfs-1 gain-of-function mutants are also resistant to ibandronate, an inhibitor of an enzyme downstream of HMG-CoA reductase, and to gliotoxin, an inhibitor acting on a subbranch of the pathway important for protein prenylation, and showed improved mitochondrial function and protein prenylation in the presence of statins. Additionally, preinduction of the mitochondrial unfolded protein response in wild-type worms using ethidium bromide or paraquat triggered statin resistance, and similar observations were made in Schizosaccharomyces pombe and in a mammalian cell line. We conclude that statin resistance through maintenance of mitochondrial homeostasis is conserved across species, and that the cell-lethal effects of statins are caused primarily through impaired protein prenylation that results in mitochondria dysfunction. PMID:23530189

The mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway.

PubMed

Rauthan, Manish; Ranji, Parmida; Aguilera Pradenas, Nataly; Pitot, Christophe; Pilon, Marc

2013-04-09

Statins are cholesterol-lowering drugs that inhibit 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in the synthesis of cholesterol via the mevalonate pathway. This pathway also produces coenzyme Q (a component of the respiratory chain), dolichols (important for protein glycosylation), and isoprenoids (lipid moieties responsible for the membrane association of small GTPases). We previously showed that the nematode Caenorhabditis elegans is useful to study the noncholesterol effects of statins because its mevalonate pathway lacks the sterol synthesis branch but retains all other branches. Here, from a screen of 150,000 mutagenized genomes, we isolated four C. elegans mutants resistant to statins by virtue of gain-of-function mutations within the first six amino acids of the protein ATFS-1, the key regulator of the mitochondrial unfolded protein response that includes activation of the chaperones HSP-6 and HSP-60. The atfs-1 gain-of-function mutants are also resistant to ibandronate, an inhibitor of an enzyme downstream of HMG-CoA reductase, and to gliotoxin, an inhibitor acting on a subbranch of the pathway important for protein prenylation, and showed improved mitochondrial function and protein prenylation in the presence of statins. Additionally, preinduction of the mitochondrial unfolded protein response in wild-type worms using ethidium bromide or paraquat triggered statin resistance, and similar observations were made in Schizosaccharomyces pombe and in a mammalian cell line. We conclude that statin resistance through maintenance of mitochondrial homeostasis is conserved across species, and that the cell-lethal effects of statins are caused primarily through impaired protein prenylation that results in mitochondria dysfunction.

[Bisphosphonate related osteonecrosis of the jaw and infection with Actinomyces].

PubMed

Arranz Caso, J Alberto; Flores Ballester, Elena; Ngo Pombe, Stephanie; López Pizarro, Victor; Dominguez-Mompello, José Luis; Restoy Lozano, Andrés

2012-12-15

Bisphosphonate related osteonecrosis of the jaw (BRONJ) has raised considerable interest since its recent description. Its pathogenesis is not yet clarified; formerly it has been considered a non-infectious complication, but recent studies seem to implicate bacteria of the genus Actinomyces. The objective of this study is to analyze the cases of BRONJ in our institution. Review of medical records of patients diagnosed of BRONJ in the Maxillofacial Surgery Unit of our hospital. We have found 11 cases of BRONJ in our hospital: 4 women taking oral alendronate or risendronate for osteoporosis and 7 cancer patients treated with intravenous zolendronic acid. All of them showed bone invasion by bacteria of the genus Actinomyces. Nine patients underwent prolonged treatment with amoxicillin with favourable clinical outcome in all of them, but 3 died of their malignancy. By contrast, one patient with beta-lactamic allergy and irregular treatment with erythromycin and tetracycline had a chronic evolution of the lesions. There was no information for other patient. Actinomyces play an important role in the development of BRONJ and specific antibiotic treatment improves the prognosis of this process. Copyright © 2012 Elsevier España, S.L. All rights reserved.

3-D bone models to improve treatment initiation among patients with osteoporosis: A randomised controlled pilot trial.

PubMed

Stephens, Melika H; Grey, Andrew; Fernandez, Justin; Kalluru, Ramanamma; Faasse, Kate; Horne, Anne; Petrie, Keith J

2016-01-01

To investigate the efficacy of 3-D printed bone models as a tool to facilitate initiation of bisphosphonate treatment among individuals who were newly diagnosed with osteoporosis. Fifty eight participants with estimated fracture risk above that at which guidelines recommend pharmacological intervention were randomised to receive either a standard physician interview or an interview augmented by the presentation of 3-D bone models. Participants' beliefs about osteoporosis and bisphosphonate treatment, initiation of bisphosphonate therapy assessed at two months using self-report and pharmacy dispensing data. Individuals in the 3-D bone model intervention condition were more emotionally affected by osteoporosis immediately after the interview (p = .04) and reported a greater understanding of osteoporosis at follow-up (p = .04), than the control group. While a greater proportion of the intervention group initiated an oral bisphosphonate regimen (alendronate) (52%) in comparison with the control group (21%), the overall initiation of medication for osteoporosis, including infusion (zoledronate), did not differ significantly (intervention group 62%, control group 45%, p = .19). The presentation of 3-D bone models during a medical consultation can modify cognitive and emotional representations relevant to treatment initiation among people with osteoporosis and might facilitate commencement of bisphosphonate treatment.

Development of Alendronate-conjugated Poly (lactic-co-glycolic acid)-Dextran Nanoparticles for Active Targeting of Cisplatin in Osteosarcoma

PubMed Central

Liu, Ping; Sun, Liang; Zhou, Dong-sheng; Zhang, Peng; Wang, Yong-hui; Li, Dong; Li, Qing-hu; Feng, Rong-jie

2015-01-01

In this study, we developed a novel poly (lactic-co-glycolic acid)-dextran (PLD)-based nanodelivery system to enhance the anticancer potential of cisplatin (CDDP) in osteosarcoma cells. A nanosized CDDP-loaded PLGA-DX nanoparticle (PLD/CDDP) controlled the release rate of CDDP up to 48 h. In vitro cytotoxicity assay showed a superior anticancer effect for PLD/CDDP and with an appreciable cellular uptake via endocytosis-mediated pathways. PLD/CDDP exhibited significant apoptosis of MG63 cancer cells compared to that of free CDDP. Approximately ~25% of cells were in early apoptosis phase after PLD/CDDP treatment comparing to ~15% for free CDDP after 48h incubation. Similarly, PLD/CDDP exhibited ~30% of late apoptosis cells comparing to only ~8% for free drug treatment. PLD/CDDP exhibited significantly higher G2/M phase arrest in MG63 cells than compared to free CDDP with a nearly 2-fold higher arrest in case of PLD/CDDP treated group (~60%). Importantly, PLD/CDDP exhibited a most significant anti-tumor activity with maximum tumor growth inhibition. The superior inhibitory effect was further confirmed by a marked reduction in the number of CD31 stained tumor blood vessels and decrease in the Ki67 staining intensity for PLD/CDDP treated animal group. Overall, CDDP formulations could provide a promising and most effective platform in the treatment of osteosarcoma. PMID:26619950

Anorexia Nervosa and Bone

PubMed Central

Misra, Madhusmita; Klibanski, Anne

2014-01-01

Anorexia nervosa (AN) is a condition of severe low weight that is associated with low bone mass, impaired bone structure and reduced bone strength, all of which contribute to increased fracture risk., Adolescents with AN have decreased rates of bone accrual compared with normal-weight controls, raising addition concerns of suboptimal peak bone mass and future bone health in this age group. Changes in lean mass and compartmental fat depots, hormonal alterations secondary to nutritional factors contribute to impaired bone metabolism in AN. The best strategy to improve bone density is to regain weight and menstrual function. Oral estrogen-progesterone combinations are not effective in increasing bone density in adults or adolescents with AN, and transdermal testosterone replacement is not effective in increasing bone density in adult women with AN. However, physiologic estrogen replacement as transdermal estradiol with cyclic progesterone does increase bone accrual rates in adolescents with AN to approximate that in normal-weight controls, leading to a maintenance of bone density Z-scores. A recent study has shown that risedronate increases bone density at the spine and hip in adult women with AN. However, bisphosphonates should be used with great caution in women of reproductive age given their long half-life and potential for teratogenicity, and should be considered only in patients with low bone density and clinically significant fractures when non-pharmacological therapies for weight gain are ineffective. Further studies are necessary to determine the best therapeutic strategies for low bone density in AN. PMID:24898127

Assessment of non‐vertebral fracture risk in postmenopausal women

PubMed Central

Roux, Christian; Briot, Karine; Horlait, Stéphane; Varbanov, Alex; Watts, Nelson B; Boonen, Steven

2007-01-01

Background Non‐vertebral (NV) fractures are responsible for a great amount of morbidity, mortality and cost attributable to osteoporosis. Objectives To identify risk factors for NV fractures in postmenopausal women with osteoporosis, and to design an assessment tool for prediction of these fractures. Methods 2546 postmenopausal women with osteoporosis included in the placebo groups of three risedronate controlled trials were included (mean age 72 years, mean femoral T‐score −2.5; 60% and 53% of patients with prevalent vertebral and NV fractures, respectively). Over 3 years, 222 NV fractures were observed. Baseline data on 14 risk factors were included in a logistic regression analysis. Results 6 risk factors were associated with NV fracture risk: prevalent NV fracture (p = 0.004), number of prevalent vertebral fractures (p<0.001), femoral T‐score (p = 0.031), serum level of 25‐hydroxyvitamin D (p<0.001), age (p = 0.012) and height (p = 0.037). An NV risk index was developed by converting the multivariate logistic equation into an additive score. In the group of women with a score ⩾2.1, the incidence of NV fracture was 13.2% (95% CI 11.1 to 15.3), 1.5 times higher than that of the general population. Conclusions The NV risk index is a convenient tool for selection of patients with osteoporosis with a high risk for NV fractures, and may help to choose from available treatments those with a proven efficacy for reduction of NV fracture risk. PMID:17314119

Photoluminescence of cerium fluoride and cerium-doped lanthanum fluoride nanoparticles and investigation of energy transfer to photosensitizer molecules.

PubMed

Cooper, Daniel R; Kudinov, Konstantin; Tyagi, Pooja; Hill, Colin K; Bradforth, Stephen E; Nadeau, Jay L

2014-06-28

CexLa1-xF3 nanoparticles have been proposed for use in nanoscintillator-photosensitizer systems, where excitation of nanoparticles by ionizing radiation would result in energy transfer to photosensitizer molecules, effectively combining the effects of radiotherapy and photodynamic therapy. Thus far, there have been few experimental investigations of such systems. This study reports novel synthesis methods for water-dispersible Ce0.1La0.9F3/LaF3 and CeF3/LaF3 core/shell nanoparticles and an investigation of energy transfer to photosensitizers. Unbound deuteroporphyrin IX 2,4-disulfonic acid was found to substantially quench the luminescence of large (>10 nm diameter) aminocaproic acid-stabilized nanoparticles at reasonable concentrations and loading amounts: up to 80% quenching at 6% w/w photosensitizer loading. Energy transfer was found to occur primarily through a cascade, with excitation of "regular" site Ce(3+) at 252 nm relayed to photosensitizer molecules at the nanoparticle surface through intermediate "perturbed" Ce(3+) sites. Smaller (<5 nm) citrate-stabilized nanoparticles were coated with the bisphosphonate alendronate, allowing covalent conjugation to chlorin e6 and resulting in static quenching of the nanoparticle luminescence: ∼50% at ∼0.44% w/w. These results provide insight into energy transfer mechanisms that may prove valuable for optimizing similar systems.

Metabolite Profiling Reveals the Effect of Dietary Rubus coreanus Vinegar on Ovariectomy-Induced Osteoporosis in a Rat Model.

PubMed

Lee, Mee Youn; Kim, Hyang Yeon; Singh, Digar; Yeo, Soo Hwan; Baek, Seong Yeol; Park, Yoo Kyoung; Lee, Choong Hwan

2016-01-26

The study was aimed at exploring the curative effects of Rubus coreanus (RC) vinegar against postmenopausal osteoporosis by using ovariectomized rats as a model. The investigations were performed in five groups: sham, ovariectomized (OVX) rats without treatment, low-dose RC vinegar (LRV)-treated OVX rats, high-dose RC vinegar (HRV)-treated OVX rats and alendronate (ALEN)-treated OVX rats. The efficacy of RC vinegar was evaluated using physical, biochemical, histological and metabolomic parameters. Compared to the OVX rats, the LRV and HRV groups showed positive effects on the aforementioned parameters, indicating estrogen regulation. Plasma metabolome analysis of the groups using gas chromatography-time of flight mass spectrometry (GC-TOF-MS) and ultra-performance liquid chromatography quadrupole-TOF-MS (UPLC-Q-TOF-MS) with multivariate analysis revealed 19 and 16 metabolites, respectively. Notably, the levels of butyric acid, phenylalanine, glucose, tryptophan and some lysophosphatidylcholines were marginally increased in RC vinegar-treated groups compared to OVX. However, the pattern of metabolite levels in RC vinegar-treated groups was found similar to ALEN, but differed significantly from that in sham group. The results highlight the prophylactic and curative potential of dietary vinegar against postmenopausal osteoporosis. RC vinegar could be an effective natural alternative for the prevention of postmenopausal osteoporosis.

Nanoparticle Tracking Analysis for the Enumeration and Characterization of Mineralo-Organic Nanoparticles in Feline Urine

PubMed Central

Mellema, M.; Stoller, M.; Queau, Y.; Ho, S. P.; Chi, T.; Larsen, J. A.; Passlack, N.; Fascetti, A. J.; Mohr, C.; Westropp, J. L.

2016-01-01

Urinary stone disease, particularly calcium oxalate, is common in both humans and cats. Calcifying nanoparticles (CNP) are spherical nanocrystallite material, and are composed of proteins (fetuin, albumin) and inorganic minerals. CNP are suggested to play a role in a wide array of pathologic mineralization syndromes including urolithiasis. We documented the development of a clinically relevant protocol to assess urinary CNP in 9 healthy cats consuming the same diet in a controlled environment using Nanoparticle Tracking Analysis (NTA®). NTA® is a novel method that allows for characterization of the CNP in an efficient, accurate method that can differentiate these particles from other urinary submicron particulates. The predominant nanoscale particles in feline urine are characteristic of CNP in terms of their size, their ability to spontaneously form under suitable conditions, and the presence of an outer layer that is rich in calcium and capable of binding to hydroxyapatite binders such as alendronate and osteopontin. The expansion of this particle population can be suppressed by the addition of citrate to urine samples. Further, compounds targeting exosomal surfaces do not label these particulates. As CNP have been associated with a number of significant urologic maladies, the method described herein may prove to be a useful adjunct in evaluating lithogenesis risk in mammals. PMID:28005930

Magnetic resonance imaging of folic acid-coated magnetite nanoparticles reflects tissue biodistribution of long-acting antiretroviral therapy.

PubMed

Li, Tianyuzi; Gendelman, Howard E; Zhang, Gang; Puligujja, Pavan; McMillan, JoEllyn M; Bronich, Tatiana K; Edagwa, Benson; Liu, Xin-Ming; Boska, Michael D

2015-01-01

Regimen adherence, systemic toxicities, and limited drug penetrance to viral reservoirs are obstacles limiting the effectiveness of antiretroviral therapy (ART). Our laboratory's development of the monocyte-macrophage-targeted long-acting nanoformulated ART (nanoART) carriage provides a novel opportunity to simplify drug-dosing regimens. Progress has nonetheless been slowed by cumbersome, but required, pharmacokinetic (PK), pharmacodynamics, and biodistribution testing. To this end, we developed a small magnetite ART (SMART) nanoparticle platform to assess antiretroviral drug tissue biodistribution and PK using magnetic resonance imaging (MRI) scans. Herein, we have taken this technique a significant step further by determining nanoART PK with folic acid (FA) decorated magnetite (ultrasmall superparamagnetic iron oxide [USPIO]) particles and by using SMART particles. FA nanoparticles enhanced the entry and particle retention to the reticuloendothelial system over nondecorated polymers after systemic administration into mice. These data were seen by MRI testing and validated by comparison with SMART particles and direct evaluation of tissue drug levels after nanoART. The development of alendronate (ALN)-coated magnetite thus serves as a rapid initial screen for the ability of targeting ligands to enhance nanoparticle-antiretroviral drug biodistribution, underscoring the value of decorated magnetite particles as a theranostic tool for improved drug delivery.

Advances in non-invasive drug delivery for atherosclerotic heart disease.

PubMed

Maranhão, Raul C; Tavares, Elaine R

2015-07-01

Apart from statins, anti-platelet agents and invasive procedures, the anti-atherosclerotic medical weaponry for coronary heart disease (CHD) is scarce and only partially protects CHD patients from major adverse cardiac events. Several novel non-invasive strategies are being developed to widen the therapeutic options. Among them, drug delivery tools were tested in vivo encompassing liposomes, micelles, polymeric, metallic and lipid nanoparticles used as carriers of statins, corticosteroids, a bisphosphonate, a glitazone, anti-cancer agents, a mycotoxin, a calcium channel blocker and a compound of traditional Chinese medicine. All preparations improved parameters related to atherosclerotic lesions induced in rabbits, rats and mice and reduced neointima formation in experiments aiming to prevent post-stenting restenosis. In subjects submitted to percutaneous coronary intervention, nanoparticle formulations of paclitaxel and alendronate showed safety but are still not conclusive regarding in-stent late loss. The experience of our group in atherosclerotic rabbits treated with non-protein lipid nanoparticles associated with anti-cancer drugs such as paclitaxel, etoposide and methotrexate is summarized, and preliminary safety data in CHD patients are anticipated. Taken together, these studies show that non-invasive drug-delivery systems may become promising tools to rescue CHD patients from the risks of severe and life-threatening lesions that should be more energetically treated.

Preferential reduction of bone mineral density at the femur reflects impairment of physical activity in patients with low-activity rheumatoid arthritis.

PubMed

Sugiguchi, Shigeru; Goto, Hitoshi; Inaba, Masaaki; Nishizawa, Yoshiki

2010-02-01

Bone mineral density (BMD) and factors influencing BMD in rheumatoid arthritis (RA) under good or moderate control were examined to assess management of osteoporosis in RA. BMD of the lumbar spine, femur, and distal radius was measured in 105 female patients with well-controlled RA. Laboratory and clinical variables associated with disease activity were measured in the same subjects, and correlations between these variables and BMD were evaluated. The RA patients showed a greater decrease in BMD of the femoral neck than of the lumbar spine. Age, Health Assessment Questionnaire (HAQ) score, and Larsen damage score had negative correlations with BMD of the femoral neck. In multiple regression analysis of the parameters associated with BMD of the femoral neck in simple regression analysis, an increase in HAQ score showed a negative correlation with BMD of the femoral neck. After initiation of treatment with alendronate (ALN), BMD of the femoral neck increased and correlated with improvement in HAQ score. A decrease in BMD of the femoral neck is a characteristic of RA. This suggests that muscle tonus has more effect than weight-bearing activity on BMD in patients with RA. BMD of the femoral neck is a useful index for general evaluation of RA patients.

Magnetic resonance imaging of folic acid-coated magnetite nanoparticles reflects tissue biodistribution of long-acting antiretroviral therapy

PubMed Central

Li, Tianyuzi; Gendelman, Howard E; Zhang, Gang; Puligujja, Pavan; McMillan, JoEllyn M; Bronich, Tatiana K; Edagwa, Benson; Liu, Xin-Ming; Boska, Michael D

2015-01-01

Regimen adherence, systemic toxicities, and limited drug penetrance to viral reservoirs are obstacles limiting the effectiveness of antiretroviral therapy (ART). Our laboratory’s development of the monocyte-macrophage-targeted long-acting nanoformulated ART (nanoART) carriage provides a novel opportunity to simplify drug-dosing regimens. Progress has nonetheless been slowed by cumbersome, but required, pharmacokinetic (PK), pharmacodynamics, and biodistribution testing. To this end, we developed a small magnetite ART (SMART) nanoparticle platform to assess antiretroviral drug tissue biodistribution and PK using magnetic resonance imaging (MRI) scans. Herein, we have taken this technique a significant step further by determining nanoART PK with folic acid (FA) decorated magnetite (ultrasmall superparamagnetic iron oxide [USPIO]) particles and by using SMART particles. FA nanoparticles enhanced the entry and particle retention to the reticuloendothelial system over nondecorated polymers after systemic administration into mice. These data were seen by MRI testing and validated by comparison with SMART particles and direct evaluation of tissue drug levels after nanoART. The development of alendronate (ALN)-coated magnetite thus serves as a rapid initial screen for the ability of targeting ligands to enhance nanoparticle-antiretroviral drug biodistribution, underscoring the value of decorated magnetite particles as a theranostic tool for improved drug delivery. PMID:26082630

Nanoparticle Tracking Analysis for the Enumeration and Characterization of Mineralo-Organic Nanoparticles in Feline Urine.

PubMed

Mellema, M; Stoller, M; Queau, Y; Ho, S P; Chi, T; Larsen, J A; Passlack, N; Fascetti, A J; Mohr, C; Westropp, J L

2016-01-01

Urinary stone disease, particularly calcium oxalate, is common in both humans and cats. Calcifying nanoparticles (CNP) are spherical nanocrystallite material, and are composed of proteins (fetuin, albumin) and inorganic minerals. CNP are suggested to play a role in a wide array of pathologic mineralization syndromes including urolithiasis. We documented the development of a clinically relevant protocol to assess urinary CNP in 9 healthy cats consuming the same diet in a controlled environment using Nanoparticle Tracking Analysis (NTA®). NTA® is a novel method that allows for characterization of the CNP in an efficient, accurate method that can differentiate these particles from other urinary submicron particulates. The predominant nanoscale particles in feline urine are characteristic of CNP in terms of their size, their ability to spontaneously form under suitable conditions, and the presence of an outer layer that is rich in calcium and capable of binding to hydroxyapatite binders such as alendronate and osteopontin. The expansion of this particle population can be suppressed by the addition of citrate to urine samples. Further, compounds targeting exosomal surfaces do not label these particulates. As CNP have been associated with a number of significant urologic maladies, the method described herein may prove to be a useful adjunct in evaluating lithogenesis risk in mammals.

Competition between isoprene emission and pigment synthesis during leaf development in aspen

PubMed Central

Rasulov, Bahtijor; Bichele, Irina; Laisk, Agu; Niinemets, Ülo

2014-01-01

In growing leaves, lack of isoprene synthase is considered responsible for delayed isoprene emission, but competition for dimethylallyl diphosphate (DMADP), the substrate for both isoprene synthesis and prenyltransferase reactions in photosynthetic pigment and phytohormone synthesis, can also play a role. We used a kinetic approach based on postillumination isoprene decay and modeling DMADP consumption to estimate in vivo kinetic characteristics of isoprene synthase and prenyltransferase reactions, and determine the share of DMADP use by different processes through leaf development in Populus tremula. Pigment synthesis rate was also estimated from pigment accumulation data, and distribution of DMADP use from isoprene emission changes due to alendronate, a selective inhibitor of prenyltransferases. Development of photosynthetic activity and pigment synthesis occurred with the greatest rate in 1-5 days old leaves when isoprene emission was absent. Isoprene emission commenced on days 5-6 and increased simultaneously with slowing down of pigment synthesis. In vivo Michaelis-Menten constant (Km) values obtained were 265 nmol m−2 (20 μM) for DMADP-consuming prenyltransferase reactions and 2560 nmol m−2 (190 μM) for isoprene synthase. Thus, despite decelerating pigment synthesis reactions in maturing leaves, isoprene emission in young leaves was limited by both isoprene synthase activity and competition for DMADP by prenyltransferase reactions. PMID:24033429

Effects of Artemisia Princeps Supplementation on Bone Metabolism in Ovariectomized Rats.

PubMed

Cho, H-J; Kim, J-W; Ju, S-Y; Park, Y-K

2016-01-01

The aim of this study was to investigate the effects of Artemisia princeps (AP) extract on bone metabolism and its potential role in the prevention of osteoporosis in ovariectomized rats. Twenty-six female Sprague-Dawley rats were divided into five groups and treated as follows: sham-operated control group (SHAM); ovariectomized control group (OVX), ovariectomized group treated by gavage with 10 mg/kg/day alendronate (ALEN); ovariectomized group treated by gavage with 100 mg/kg/day Artemisia princeps (AP100); ovariectomized group treated by gavage with 300 mg/kg/day Artemisia princeps (AP300). Treatment of ovariectomized rats with AP extracts for 15 weeks prevented the reduction in bone thickness and trabecular bone mineral density caused by urinary Ca and Cr excretion, and also prevented the increase in bone turnover by maintaining the serum Ca/P ratio. As a result, the microarchitecture of the trabecular bone and cortical bone after ovariectomy was markedly improved by administration of AP extracts. In conclusion, AP prevented bone loss and osteoclast activity associated with high bone turnover in ovariectomized rats by controlling the serum Ca/P ratio and through anti-inflammatory and anti-oxidant properties. Our data implicate AP as a promising therapeutic option for the improvement of postmenopausal osteoporosis.

Eleven years of experience with bisphosphonate plus alfacalcidol treatment in a man with osteogenesis imperfecta type I

PubMed Central

Iwamoto, Jun; Sato, Yoshihiro; Uzawa, Mitsuyoshi; Matsumoto, Hideo

2013-01-01

We report the 11-year follow-up of a man with osteogenesis imperfecta type I who was treated with bisphosphonates and alfacalcidol. A 36-year-old Japanese man with osteogenesis imperfecta type I who had frequently experienced painful fragility fractures consulted our clinic because of chronic back pain. The patient had multiple morphometric vertebral fractures and a low bone mineral density (BMD) at the lumbar spine. The patient was treated with cyclical etidronate 200 mg, for 2 weeks every 3 months, plus alfacalcidol 1 μg daily, for 2 years; and alendronate 5 mg daily or 35 mg weekly, plus alfacalcidol 1 μg daily for 9 years. After 11 years of treatment, BMD at the lumbar spine increased by 6.4%, following a 20.3% reduction in serum alkaline phosphatase. Serum calcium, phosphorus, and intact parathyroid hormone levels remained within the normal ranges. Three clinical fractures occurred at two ribs and the metacarpus, and two morphometric vertebral fractures occurred at the thoracic spine during the 11-year treatment period, but the patient experienced no adverse effects. Thus, the present case report shows the long-term outcome and safety of bisphosphonate plus alfacalcidol treatment in a man with osteogenesis imperfecta type I. PMID:23293527

Transient osteoporosis of the hip in pregnancy associated with generalized low bone mineral density--a case report.

PubMed

Anai, Takanobu; Urata, Kenichirou; Mori, Atsue; Miyazaki, Fumiko; Okamoto, Sumiaki

2013-01-01

Transient osteoporosis of the hip (TOH) in pregnancy is characterized by severe pain in unilateral or bilateral hips and has been diagnosed as localized osteopenia. However, we evaluated a case of unilateral TOH with generalized profound osteoporosis involving both the hips and the lumbar vertebrae by dual-energy X-ray absorptiometry. The diagnosis was based on the clinical course and confirmed by magnetic resonance imaging. Three-dimensional helical computed tomography (3D-CT), which has not been used in patients with TOH, revealed a markedly thin bilateral proximal femoral cortex, particularly in the symptomatic femoral head. Despite the difference in the severity of bone destruction between the two femora, they both showed the same pattern of damage on 3D-CT. Furthermore, despite continuing treatment with the same dose of alendronate and calcitriol, a high rate of bone mineral density gain, involving both the femora and lumbar vertebrae, was limited to the early postpartum months. A majority of reported female patients with TOH are pregnant. Thus, the association between TOH and pregnancy was not considered to be fortuitous, and chemical or hormonal factors related to pregnancy may play an etiologic role in this disease. The possible etiologies of TOH in pregnancy are also discussed. © 2013 S. Karger AG, Basel.

Bisphosphonate as a Countermeasure to Space Flight-Induced Bone Loss

NASA Technical Reports Server (NTRS)

Spector, Elisabeth; LeBlanc, A.; Sibonga, J.; Matsumoto, T.; Jones, J.; Smith, S. M.; Shackelford, L.; Shapiro, J.; Lang, T.; Evans, H.;

Novel and rapid osteoporosis model established in zebrafish using high iron stress.

PubMed

Zhang, Wenjuan; Xu, Jingjin; Qiu, Juhui; Xing, Cencan; Li, Xiumin; Leng, Bo; Su, Yi; Lin, Jinmei; Lin, Jiaofen; Mei, Xuqiao; Huang, Yiqun; Pan, Yutian; Xue, Yu

2018-02-05

Osteoporosis is a global public health concern and, it can result from numerous pathogenic mechanisms, many of which are closely related with age, nutritional disorders, endocrine imbalance, or adverse drug side effects presented by glucocorticoids, heparin, and anti-epileptics. Given its wide range etiologies, it is crucial to establish an animal model of osteoporosis for use in screening potential drugs quickly and effectively. Previous research has reported that an accumulation of elevated iron in the body is an independent risk factor for osteoporosis. As such, we sought to use both zebrafish larvae and adults to model an osteoporosis phenotype using high iron stress (FAC, ferric ammonium citrate). Skeletal staining results suggested that iron-overload caused a significant decrease in bone calcification as well as severe developmental cartilage defects. In addition, osteoblast and cartilage-specific mRNA expression levels were downregulated after exposure to a high-iron environment. Most importantly, we demonstrated in both larval and adult fish that high iron-induced osteogenic defects were significantly rescued using alendronate (AL), a drug known to be effective against to human osteoporosis. Even more, the repair effect of AL was achieved by facilitating osteoblast differentiation and targeting Bmp signaling. Taken together, our findings propose an rapid and effective osteoporosis model, which could be used widely for future osteoporosis drug screening. Copyright © 2018 Elsevier Inc. All rights reserved.

Oriented and Ordered Biomimetic Remineralization of the Surface of Demineralized Dental Enamel Using HAP@ACP Nanoparticles Guided by Glycine

PubMed Central

Wang, Haorong; Xiao, Zuohui; Yang, Jie; Lu, Danyang; Kishen, Anil; Li, Yanqiu; Chen, Zhen; Que, Kehua; Zhang, Qian; Deng, Xuliang; Yang, Xiaoping; Cai, Qing; Chen, Ning; Cong, Changhong; Guan, Binbin; Li, Ting; Zhang, Xu

2017-01-01

Achieving oriented and ordered remineralization on the surface of demineralized dental enamel, thereby restoring the satisfactory mechanical properties approaching those of sound enamel, is still a challenge for dentists. To mimic the natural biomineralization approach for enamel remineralization, the biological process of enamel development proteins, such as amelogenin, was simulated in this study. In this work, carboxymethyl chitosan (CMC) conjugated with alendronate (ALN) was applied to stabilize amorphous calcium phosphate (ACP) to form CMC/ACP nanoparticles. Sodium hypochlorite (NaClO) functioned as the protease which decompose amelogenin in vivo to degrade the CMC-ALN matrix and generate HAP@ACP core-shell nanoparticles. Finally, when guided by 10 mM glycine (Gly), HAP@ACP nanoparticles can arrange orderly and subsequently transform from an amorphous phase to well-ordered rod-like apatite crystals to achieve oriented and ordered biomimetic remineralization on acid-etched enamel surfaces. This biomimetic remineralization process is achieved through the oriented attachment (OA) of nanoparticles based on non-classical crystallization theory. These results indicate that finding and developing analogues of natural proteins such as amelogenin involved in the biomineralization by natural macromolecular polymers and imitating the process of biomineralization would be an effective strategy for enamel remineralization. Furthermore, this method represents a promising method for the management of early caries in minimal invasive dentistry (MID). PMID:28079165

Structural Studies of Geosmin Synthase, a Bifunctional Sesquiterpene Synthase with Alpha-Alpha Domain Architecture that Catalyzes a Unique Cyclization-Fragmentation Reaction Sequence

PubMed Central

Harris, Golda G.; Lombardi, Patrick M.; Pemberton, Travis A.; Matsui, Tsutomu; Weiss, Thomas M.; Cole, Kathryn E.; Köksal, Mustafa; Murphy, Frank V.; Vedula, L. Sangeetha; Chou, Wayne K.W.; Cane, David E.; Christianson, David W.

2015-01-01

Geosmin synthase from Streptomyces coelicolor (ScGS) catalyzes an unusual, metal-dependent terpenoid cyclization and fragmentation reaction sequence. Two distinct active sites are required for catalysis: the N-terminal domain catalyzes the ionization and cyclization of farnesyl diphosphate to form germacradienol and inorganic pyrophosphate (PPi), and the C-terminal domain catalyzes the protonation, cyclization, and fragmentation of germacradienol to form geosmin and acetone through a retro-Prins reaction. A unique αα domain architecture is predicted for ScGS based on amino acid sequence: each domain contains the metal-binding motifs typical of a class I terpenoid cyclase, and each domain requires Mg2+ for catalysis. Here, we report the X-ray crystal structure of the unliganded N-terminal domain of ScGS and the structure of its complex with 3 Mg2+ ions and alendronate. These structures highlight conformational changes required for active site closure and catalysis. Although neither full-length ScGS nor constructs of the C-terminal domain could be crystallized, homology models of the C-terminal domain were constructed based on ~36% sequence identity with the N-terminal domain. Small-angle X-ray scattering experiments yield low resolution molecular envelopes into which the N-terminal domain crystal structure and the C-terminal domain homology model were fit, suggesting possible αα domain architectures as frameworks for bifunctional catalysis. PMID:26598179

The dental implications of bisphosphonates and bone disease.

PubMed

Cheng, A; Mavrokokki, A; Carter, G; Stein, B; Fazzalari, N L; Wilson, D F; Goss, A N

2005-12-01

In 2002/2003 a number of patients presented to the South Australian Oral and Maxillofacial Surgery Unit with unusual non-healing extraction wounds of the jaws. All were middle-aged to elderly, medically compromised and on bisphosphonates for bone pathology. Review of the literature showed similar cases being reported in the North American oral and maxillofacial surgery literature. This paper reviews the role of bisphosphonates in the management of bone disease. There were 2.3 million prescriptions for bisphosphonates in Australia in 2003. This group of drugs is very useful in controlling bone pain and preventing pathologic fractures. However, in a small number of patients on bisphosphonates, intractable, painful, non-healing exposed bone occurs following dental extractions or denture irritation. Affected patients are usually, but not always, over 55 years, medically compromised and on the potent nitrogen containing bisphosphonates pamidronate (Aredia/Pamisol), alendronate (Fosamax) and zolendronate (Zometa) for non-osteoporotic bone disease. Currently, there is no simple, effective treatment and the painful exposed bone may persist for years. The main complications are marked weight loss from difficulty in eating and severe jaw and neck infections. Possible preventive and therapeutic strategies are presented although at this time there is no evidence of their effectiveness. Dentists must ask about bisphosphonate usage for bone disease when recording medical histories and take appropriate actions to avoid the development of this debilitating condition in their patients.

Treatment of Radix Dipsaci extract prevents long bone loss induced by modeled microgravity in hindlimb unloading rats.

PubMed

Niu, Yinbo; Li, Chenrui; Pan, Yalei; Li, Yuhua; Kong, Xianghe; Wang, Shuo; Zhai, YuanKun; Wu, Xianglong; Fan, Wutu; Mei, Qibing

2015-01-01

Radix Dipsaci is a kidney tonifying herbal medicine with a long history of safe use for treatment of bone fractures and joint diseases in China. Previous studies have shown that Radix Dipsaci extract (RDE) could prevent bone loss in ovariectomized rats. This study investigates the effect of RDE against bone loss induced by simulated microgravity. A hindlimb unloading rat model was established to determine the effect of RDE on bone mineral density and bone microarchitecture. Twenty-four male Sprague-Dawley rats were divided into four groups (n = 6 per group): control (CON), hindlimb unloading with vehicle (HLU), hindlimb unloading treated with alendronate (HLU-ALN, 2.0 mg/kg/d), and hindlimb unloading treated with RDE (HLU-RDE, 500 mg/kg/d). RDE or ALN was administrated orally for 4 weeks. Treatment with RDE had a positive effect on mechanical strength, BMD, BMC, bone turnover markers, and the changes in urinary calcium and phosphorus excretion. MicroCT analysis showed that RDE significantly prevented the reduction of the bone volume fraction, connectivity density, trabecular number, thickness, tissue mineral density, and tissue mineral content as well as improved the trabecular separation and structure model index. RDE was demonstrated to prevent the loss of bone mass induced by HLU treatment, which suggests the potential application of RDE in the treatment of microgravity-induced bone loss.

Oriented and Ordered Biomimetic Remineralization of the Surface of Demineralized Dental Enamel Using HAP@ACP Nanoparticles Guided by Glycine

NASA Astrophysics Data System (ADS)

Wang, Haorong; Xiao, Zuohui; Yang, Jie; Lu, Danyang; Kishen, Anil; Li, Yanqiu; Chen, Zhen; Que, Kehua; Zhang, Qian; Deng, Xuliang; Yang, Xiaoping; Cai, Qing; Chen, Ning; Cong, Changhong; Guan, Binbin; Li, Ting; Zhang, Xu

2017-01-01

Achieving oriented and ordered remineralization on the surface of demineralized dental enamel, thereby restoring the satisfactory mechanical properties approaching those of sound enamel, is still a challenge for dentists. To mimic the natural biomineralization approach for enamel remineralization, the biological process of enamel development proteins, such as amelogenin, was simulated in this study. In this work, carboxymethyl chitosan (CMC) conjugated with alendronate (ALN) was applied to stabilize amorphous calcium phosphate (ACP) to form CMC/ACP nanoparticles. Sodium hypochlorite (NaClO) functioned as the protease which decompose amelogenin in vivo to degrade the CMC-ALN matrix and generate HAP@ACP core-shell nanoparticles. Finally, when guided by 10 mM glycine (Gly), HAP@ACP nanoparticles can arrange orderly and subsequently transform from an amorphous phase to well-ordered rod-like apatite crystals to achieve oriented and ordered biomimetic remineralization on acid-etched enamel surfaces. This biomimetic remineralization process is achieved through the oriented attachment (OA) of nanoparticles based on non-classical crystallization theory. These results indicate that finding and developing analogues of natural proteins such as amelogenin involved in the biomineralization by natural macromolecular polymers and imitating the process of biomineralization would be an effective strategy for enamel remineralization. Furthermore, this method represents a promising method for the management of early caries in minimal invasive dentistry (MID).

Mechanical competence of ovariectomy-induced compromised bone after single or combined treatment with high-frequency loading and bisphosphonates

PubMed Central

Camargos G. V.; Bhattacharya P.; van Lenthe G. H.; Del Bel Cury A. A.; Naert I.; Duyck J.; Vandamme K.

2015-01-01

Osteoporosis leads to increased bone fragility, thus effective approaches enhancing bone strength are needed. Hence, this study investigated the effect of single or combined application of high-frequency (HF) loading through whole body vibration (WBV) and alendronate (ALN) on the mechanical competence of ovariectomy-induced osteoporotic bone. Thirty-four female Wistar rats were ovariectomized (OVX) or sham-operated (shOVX) and divided into five groups: shOVX, OVX-shWBV, OVX-WBV, ALN-shWBV and ALN-WBV. (Sham)WBV loading was applied for 10 min/day (130 to 150 Hz at 0.3g) for 14 days and ALN at 2 mg/kg/dose was administered 3x/week. Finite element analysis based on micro-CT was employed to assess bone biomechanical properties, relative to bone micro-structural parameters. HF loading application to OVX resulted in an enlarged cortex, but it was not able to improve the biomechanical properties. ALN prevented trabecular bone deterioration and increased bone stiffness and bone strength of OVX bone. Finally, the combination of ALN with HF resulted in an increased cortical thickness in OVX rats when compared to single treatments. Compared to HF loading, ALN treatment is preferred for improving the compromised mechanical competence of OVX bone. In addition, the association of ALN with HF loading results in an additive effect on the cortical thickness. PMID:26027958

[Orthodontic treatment of patients medicated with bisphosphonates-a clinical case report].

PubMed

Krieger, Elena; d'Hoedt, Bernd; Scheller, Herbert; Jacobs, Collin; Walter, Christian; Wehrbein, Heinrich

2013-01-01

Bisphosphonates (BP) are an established medication, e.g., for the prevention/therapy of osteoporosis. The effects of the changed bone metabolism for orthodontic treatments are unknown. A 66-year-old woman underwent a total oral rehabilitation. The therapy included (1) tooth extractions, (2) periodontal treatment, (3) insertion of dental implants, (4) provisional implant restorations, (5) orthodontic treatment, and (6) definite implant restorations. The orthodontic tooth movements were in- and retrusion of the upper frontal teeth, intrusion of the lower front teeth, using the dental implants as skeletal anchorage. After implant insertion and one month before beginning the orthodontic treatment, osteoporosis was diagnosed in this patient and, without notification to our facility, BP treatment was initiated by her general practitioner (alendronate oral, 70 mg/week), with an overall duration of intake of 7 months. After 13 months, the orthodontic treatment was successfully accomplished; however enlarged periodontal gaps, sclerotic bone areas, and mild apical root resorptions of the upper frontal teeth were found in this patient. Currently, there are no recommendations for orthodontic patients undergoing BP therapy. Orthodontic tooth movement in this low-risk patient with a short duration of intake and a low-dose BP medication was possible. Because of the reduced bone metabolism and the higher amount of side effects, the treatment should be performed with extremely light forces and frequent monitoring.

Competition between isoprene emission and pigment synthesis during leaf development in aspen.

PubMed

Rasulov, Bahtijor; Bichele, Irina; Laisk, Agu; Niinemets, Ülo

2014-03-01

In growing leaves, lack of isoprene synthase (IspS) is considered responsible for delayed isoprene emission, but competition for dimethylallyl diphosphate (DMADP), the substrate for both isoprene synthesis and prenyltransferase reactions in photosynthetic pigment and phytohormone synthesis, can also play a role. We used a kinetic approach based on post-illumination isoprene decay and modelling DMADP consumption to estimate in vivo kinetic characteristics of IspS and prenyltransferase reactions, and to determine the share of DMADP use by different processes through leaf development in Populus tremula. Pigment synthesis rate was also estimated from pigment accumulation data and distribution of DMADP use from isoprene emission changes due to alendronate, a selective inhibitor of prenyltransferases. Development of photosynthetic activity and pigment synthesis occurred with the greatest rate in 1- to 5-day-old leaves when isoprene emission was absent. Isoprene emission commenced on days 5 and 6 and increased simultaneously with slowing down of pigment synthesis. In vivo Michaelis-Menten constant (Km ) values obtained were 265 nmol m(-2) (20 μm) for DMADP-consuming prenyltransferase reactions and 2560 nmol m(-2) (190 μm) for IspS. Thus, despite decelerating pigment synthesis reactions in maturing leaves, isoprene emission in young leaves was limited by both IspS activity and competition for DMADP by prenyltransferase reactions. © 2013 John Wiley & Sons Ltd.

Dual Effects of Bisphosphonates on Ectopic Skin and Vascular Soft Tissue Mineralization versus Bone Microarchitecture in a Mouse Model of Generalized Arterial Calcification of Infancy

PubMed Central

Li, Qiaoli; Kingman, Joshua; Sundberg, John P.; Levine, Michael A.; Uitto, Jouni

2015-01-01

Generalized arterial calcification of infancy (GACI) is an intractable ectopic mineralization disorder caused by mutations in the ENPP1 gene resulting in reduced plasma inorganic pyrophosphate levels. We previously characterized the Enpp1asj mutant mouse as a model of GACI, and we have now explored the potential efficacy of bisphosphonates, non-hydrolyzable PPi analogs, in preventing ectopic mineralization in these mice. These mice were maintained on either basic diet (control) or diets containing etidronate or alendronate in three different concentrations (experimental). Considering low bioavailability of bisphosphonates when administered orally, subsequent studies tested the mice with subcutaneous injections of etidronate. The treatments were initiated at 4 weeks of age, and the degree of mineralization was assessed at 12 weeks of age by quantitation of calcium deposits in the muzzle skin containing dermal sheath of vibrissae and in aorta. We found that bisphosphonate treatments significantly reduced mineralization in skin and aorta. These changes in treated mice were accompanied with restoration of their bone microarchitecture, determined bymicrocomputed tomography. The inhibitory capacity of bisphosphonates, with mechanistic implications, was confirmed in a cell-based mineralization assay in vitro. Collectively, these results suggest that bisphosphonate treatment may be beneficial by a dual effect for preventing ectopic soft tissue mineralization while correcting decreased bone mineralization in GACI caused by ENPP1 mutations. PMID:26763447

Bisphosphonate-associated osteonecrosis of jaw reoccurrence after methotrexate therapy: a case report.

PubMed

Alsalleeh, Fahd; Keippel, Jeffery; Adams, Lyde; Bavitz, Bruce

2014-09-01

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-known complication caused by amino-bisphosphonate therapy. We document one case of BRONJ associated with oral administration of methotrexate, a known immunosuppressive drug used to treat rheumatoid arthritis. A 66-year-old woman was referred for evaluation and endodontic surgery of recently re-treated tooth 13. Tooth 14 was extracted 3 months prior, and the extraction site had not completely healed. Her medical history revealed rheumatoid arthritis and osteoporosis. She had been taking Fosamax (alendronate) 70 mg daily. Because of adequate root canal therapy of tooth 13, endodontic surgery was performed. Five months after apicoectomy, her symptoms had not changed. Tooth 13 was extracted, and the socket healed without complications. The socket of extracted tooth 14 was also healing. At the 3-month recall visit, bone exposure and purulent discharge at the site of extracted tooth 14 were noted. The patient had recently received methotrexate. The methotrexate was discontinued, and she was given course of amoxicillin. At the 18-month follow-up, the healing progressed, and the wound was closed. A medication that suppresses the immune system such as methotrexate may complicate the management of BRONJ. Once a diagnosis of BRONJ is made, a closely monitored conservative approach is recommended. Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

ALX 111: ALX1-11, parathyroid hormone (1-84) - NPS Allelix, PREOS, PTH, recombinant human parathyroid hormone, rhPTH (1-84).

PubMed

2003-01-01

Parathyroid Hormone; TOP) has been designed to assess the bone-building and fracture-reducing potential of the drug, and over 2600 postmenopausal women with osteoporosis who have not received previous drug therapy for osteoporosis have been enrolled. Treatment will be completed in September 2003, but more than 75% of patients enrolled in the TOP study have chosen to enrol in an Open Label Extension Study (OLES), which allows for a total treatment period of up to 24 months. NPS Pharmaceuticals has signed an agreement with Bio-Imaging Technologies, which will provide all image handling and analysis for this trial. In September 2002, NPS Pharmaceuticals announced that it has met its patient enrolment target (n > 150) for its POWER (PTH for Osteoporotic Women on Estrogen Replacement) study; a 24-month phase III trial initiated in Europe in November 2001. In this trial, women with osteoporosis receive SC injections of ALX 111 or placebo, in combination with their existing hormone replacement therapies, to test the bone building potential of the drug. In addition to the POWER study, a clinical trial sponsored by the National Institutes of Health (NIH) is being conducted to evaluate the potential of ALX 111 to build bone in combination with another osteoporosis medication. The 'PaTH' study (PTH/alendronate) is designed to assess the effect of various combinations and sequential uses of ALX 111 and Merck's Fosamax, a drug for slowing the loss of bone due to osteoporosis. The PaTH study, initiated in May 2000 and scheduled to conclude in September 2003, involved 238 patients with postmenopausal osteoporosis. It is thought that alendronic acid and ALX 111, when administered in combination, may act in an additive manner to treat osteoporosis because they act in different ways; alendronic acid acts to inhibit resorption and ALX 111 speeds up bone formation and resorption, with a net increase in formation. Results of this study are still being analysed but preliminary results appear to be

Poly(vinyl alcohol)/hydroxyapatite Monolithic In-Needle Extraction (MINE) device: Preparation and examination of drug affinity.

PubMed

Pietrzyńska, Monika; Czerwiński, Michał; Voelkel, Adam

2017-07-15

Polymer-ceramic materials based on poly(vinyl alcohol) (PVA) and hydroxyapatite were applied as sorption material in Monolithic In-Needle Extraction (MINE) device. The presented device provides new possibilities for the examination of bisphosphonates affinity for bone and will be a helpful tool in evaluation of potential antiresorptive drugs suitability. A ceramic part of monoliths was prepared by incorporation of hydroxyapatite (HA) into the reaction mixture or by using a soaking method (mineralization of HA on the PVA). The parameters of synthesis conditions were optimized to achieve a monolithic material having the appropriate dimensions after the soaking process enabling placing of the monolithic material inside the needle. Furthermore, the material must have had optimal dimensions after the re-soaking process to fit perfectly to the needle. Among the sixteen monolithic materials, eight of them were selected for further study, and then four of them were selected as a sorbent material for the MINE device. The material properties were examined on the basis of several parameters: swelling ratio, initial mass reversion and initial diameter reversion, mass growth due to the HA formation, and antiresorptive drug sorption. The MINE device might be then used as a tool for examination of interactions between bisphosphonate and bone. The simulated body fluid containing sodium risedronate (RSD) as a standard compound was passed through the MINE device. The obtained device allowed for sorption about 0.38mg of RSD. The desorption process was carried out in five steps allowing insightful analysis. The MINE device turned out to be a helpful tool for determination of the bisphosphonates affinity to the ceramic part of sorbent (hydroxyapatite) and to assess the usefulness of them as antiresorptive drugs in the future. Copyright © 2017 Elsevier B.V. All rights reserved.

Cranial base pathology in pediatric osteogenesis imperfecta patients treated with bisphosphonates.

PubMed

Arponen, Heidi; Vuorimies, Ilkka; Haukka, Jari; Valta, Helena; Waltimo-Sirén, Janna; Mäkitie, Outi

2015-03-01

Cranial base pathology is a serious complication of osteogenesis imperfecta (OI). Our aim was to analyze whether bisphosphonate treatment, used to improve bone strength, could also prevent the development of craniocervical junction pathology (basilar impression, basilar invagination, or platybasia) in children with OI. In this single-center retrospective study the authors analyzed the skull base morphology from lateral skull radiographs and midsagittal MR images (total of 94 images), obtained between the ages of 0 and 25 years in 39 bisphosphonate-treated OI patients. The results were compared with age-matched normative values and with findings in 70 OI patients who were not treated with bisphosphonates. In addition to cross-sectional data, longitudinal data were available from 22 patients with an average follow-up period of 7.6 years. The patients, who had OI types I, III, IV, VI, and VII, had been treated with zoledronic acid, pamidronate, or risedronate for 3.2 years on average. Altogether 33% of the 39 bisphosphonate-treated patients had at least 1 cranial base anomaly, platybasia being the most prevalent diagnosis (28%). Logistic regression analysis suggested a higher risk of basilar impression or invagination in patients with severe OI (OR 22.04) and/or older age at initiation of bisphosphonate treatment (OR 1.45), whereas a decreased risk was associated with longer duration of treatment (OR 0.28). No significant associations between age, height, or cumulative bisphosphonate dose and the risk for cranial base anomaly were detected. In longitudinal evaluation, Kaplan-Meier curves suggested delayed development of cranial base pathology in patients treated with bisphosphonates but the differences from the untreated group were not statistically significant. These findings indicate that cranial base pathology may develop despite bisphosphonate treatment. Early initiation of bisphosphonate treatment may delay development of craniocervical junction pathology

Osteoporotic vertebral fractures during pregnancy: be aware of a potential underlying genetic cause.

PubMed

Campos-Obando, Natalia; Oei, Ling; Hoefsloot, Lies H; Kiewiet, Rosalie M; Klaver, Caroline C W; Simon, Marleen E H; Zillikens, M Carola

2014-04-01

Although the baby growing in its mother's womb needs calcium for skeletal development, osteoporosis and fractures very rarely occur during pregnancy. A 27-year-old woman in the seventh month of her first pregnancy contracted midthoracic back pain after lifting an object. The pain was attributed to her pregnancy, but it remained postpartum. Her past medical history was uneventful, except for severely reduced vision of her left eye since birth. Family history revealed that her maternal grandmother had postmenopausal osteoporosis and her half-brother had three fractures during childhood after minor trauma. Her height was 1.58 m; she had no blue sclerae or joint hyperlaxity. Laboratory examination including serum calcium, phosphate, alkaline phosphatase, creatinine, β-carboxyterminal cross-linking telopeptide of type I collagen, 25-hydroxyvitamin D, and TSH was normal. Multiple thoracic vertebral fractures were diagnosed on x-ray examination, and dual-energy x-ray absorptiometry scanning showed severe osteoporosis (Z-scores: L2-L4, -5.6 SD; femur neck, -3.9 SD). DNA analyses revealed two compound heterozygous missense mutations in LRP5. The patient's mother carried one of the LRP5 mutations and was diagnosed with osteoporosis. Her half-brother, treated with cabergoline for a microprolactinoma, also had osteoporosis of the lumbar spine on dual-energy x-ray absorptiometry and carried the same LRP5 mutation. The patient was treated with risedronate for 2.5 years. Bone mineral density and back pain improved. She stopped bisphosphonate use 6 months before planning a second pregnancy. Our patient was diagnosed with osteoporosis pseudoglioma syndrome/familial exudative vitreoretinopathy. Potential underlying genetic causes should be considered in pregnancy-associated osteoporosis with implications for patients and relatives. More studies regarding osteoporosis treatment preceding conception are desirable.

1H NMR-based metabonomic study on the effects of Epimedium on glucocorticoid-induced osteoporosis.

PubMed

Pan, Sina; Chen, Ali; Han, Zhihui; Wang, Yaling; Lu, Xin; Yang, Yongxia

2016-12-01

Glucocorticoids are widely used in clinical practice for the treatment of many immune-mediated and inflammatory diseases, and glucocorticoid-induced osteoporosis (GIO) is the most common type of secondary osteoporosis. Epimedium is one of the most commonly used traditional Chinese medicines for treating osteoporosis. In the present study, we systematically analysed the metabonomic characteristics of GIO model rats and elucidated the therapeutic effect of Epimedium by using a 1 H NMR-based metabonomic approach in conjunction with multivariate data analysis. Rats in treatment and model groups were injected with dexamethasone (0.1mg/kg/day) for 5 weeks. Simultaneously, two treatment groups were orally administered Epimedium (10g/kg/day) or Alendronate (1.2mg/kg/day) for 5 weeks. In GIO model rats, lipid and lactate levels in serum were increased, while creatine/creatinine, PC/GPC, taurine, glycine and β-glucose levels were decreased. In urine, GIO rats had higher levels of phenylacetylglycine but lower levels of 2-oxoglutarate, citrate, creatine/creatinine, taurine, PC/GPC and hippurate than controls. Epimedium reversed the aforementioned metabolic alterations in multiple metabolic pathways involved in energy, lipid, amino acid and phospholipid metabolism and gut microbiota derangement. Our results indicated that Epimedium had significant effects in the prevention and treatment of osteoporosis. It is concluded that 1 H NMR metabonomics is a useful method for studying the metabolic effects of traditional Chinese medicine from a systematic and holistic view. Copyright © 2016 Elsevier B.V. All rights reserved.

A polymorphism at the translation start site of the vitamin D receptor gene is associated with the response to anti-osteoporotic therapy in postmenopausal women from southern Italy.

PubMed

Conti, Valeria; Russomanno, Giusy; Corbi, Graziamaria; Toro, Giuseppe; Simeon, Vittorio; Filippelli, Walter; Ferrara, Nicola; Grimaldi, Michela; D'Argenio, Valeria; Maffulli, Nicola; Filippelli, Amelia

2015-03-10

The present study investigated the effect of two single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) gene, rs1544410 A/G and rs2228570 C/T, in modulating bone mineral density (BMD) and the response to treatment with bisphosphonates or strontium ranelate in postmenopausal osteoporosis (PMO). Four hundred eighteen postmenopausal women from Southern Italy treated with bisphosphonates or strontium ranelate for three years were enrolled and stratified according to their genotype. Changes in BMD were expressed as the delta t-score (Δt-score). Allelic frequencies for rs1544410 A/GSNP were 11.2% AA, 50.0% GA and 38.8% GG; for rs2228570 C/TSNP were 54.8% CC, 39.5% TC and 5.7% TT. TT carriers showed a lower t-score than TC and CC (both p < 0.02) genotypes and were more responsive to the therapy when compared to both TC (p < 0.02) and CC (p < 0.05) carriers. Specifically, TT carriers receiving alendronate demonstrated a significant improvement of the Δt-score compared to TC and CC (both p < 0.0001) carriers. After adjustment for confounders, the Δt-score showed evidence of a statistically significant positive association with TT in all treatments considered. Therapy response was independent of rs1544410 A/G SNP; instead, rs2228570 C/TSNP was associated with a better response to antiresorptive treatment, thus suggesting that the therapy for PMO should be personalized.

A Polymorphism at the Translation Start Site of the Vitamin D Receptor Gene Is Associated with the Response to Anti-Osteoporotic Therapy in Postmenopausal Women from Southern Italy

PubMed Central

Conti, Valeria; Russomanno, Giusy; Corbi, Graziamaria; Toro, Giuseppe; Simeon, Vittorio; Filippelli, Walter; Ferrara, Nicola; Grimaldi, Michela; D’Argenio, Valeria; Maffulli, Nicola; Filippelli, Amelia

2015-01-01

The present study investigated the effect of two single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) gene, rs1544410 A/G and rs2228570 C/T, in modulating bone mineral density (BMD) and the response to treatment with bisphosphonates or strontium ranelate in postmenopausal osteoporosis (PMO). Four hundred eighteen postmenopausal women from Southern Italy treated with bisphosphonates or strontium ranelate for three years were enrolled and stratified according to their genotype. Changes in BMD were expressed as the delta t-score (Δt-score). Allelic frequencies for rs1544410 A/GSNP were 11.2% AA, 50.0% GA and 38.8% GG; for rs2228570 C/TSNP were 54.8% CC, 39.5% TC and 5.7% TT. TT carriers showed a lower t-score than TC and CC (both p < 0.02) genotypes and were more responsive to the therapy when compared to both TC (p < 0.02) and CC (p < 0.05) carriers. Specifically, TT carriers receiving alendronate demonstrated a significant improvement of the Δt-score compared to TC and CC (both p < 0.0001) carriers. After adjustment for confounders, the Δt-score showed evidence of a statistically significant positive association with TT in all treatments considered. Therapy response was independent of rs1544410 A/G SNP; instead, rs2228570 C/TSNP was associated with a better response to antiresorptive treatment, thus suggesting that the therapy for PMO should be personalized. PMID:25764158

Hydroxyapatite-anchored dendrimer for in situ remineralization of human tooth enamel.

PubMed

Wu, Duo; Yang, Jiaojiao; Li, Jiyao; Chen, Liang; Tang, Bei; Chen, Xingyu; Wu, Wei; Li, Jianshu

2013-07-01

In situ remineralization of hydroxyapatite (HA) on human tooth enamel surface induced by organic matrices is of great interest in the fields of material science and stomatology. In order to mimic the organic matrices induced biomineralization process in developing enamel and enhance the binding strength at the remineralization interface, carboxyl-terminated poly(amido amine) (PAMAM-COOH)-alendronate (ALN) conjugate (ALN-PAMAM-COOH) was synthesized and characterized. PAMAM-COOH has a highly ordered architecture and is capable of promoting the HA crystallization process. ALN is conjugated on PAMAM-COOH due to its specific adsorption on HA (the main component of tooth enamel), resulting in increased binding strength which is tight enough to resist phosphate buffered saline (PBS) rinsing as compared with that of PAMAM-COOH alone. While incubated in artificial saliva, ALN-PAMAM-COOH could induce in situ remineralization of HA on acid-etched enamel, and the regenerated HA has the nanorod-like crystal structure similar to that of human tooth enamel. The hardness of acid-etched enamel samples treated by ALN-PAMAM-COOH can recover up to 95.5% of the original value with strong adhesion force. In vivo experiment also demonstrates that ALN-PAMAM-COOH is effective in repairing acid-etched enamel in the oral cavity. Overall, these results suggest that ALN-PAMAM-COOH is highly promising as a restorative biomaterial for in situ remineralization of human tooth enamel. Copyright © 2013 Elsevier Ltd. All rights reserved.

Relative binding affinity of carboxylate-, phosphonate-, and bisphosphonate-functionalized gold nanoparticles targeted to damaged bone tissue

NASA Astrophysics Data System (ADS)

Ross, Ryan D.; Cole, Lisa E.; Roeder, Ryan K.

2012-10-01

Functionalized Au NPs have received considerable recent interest for targeting and labeling cells and tissues. Damaged bone tissue can be targeted by functionalizing Au NPs with molecules exhibiting affinity for calcium. Therefore, the relative binding affinity of Au NPs surface functionalized with either carboxylate ( l-glutamic acid), phosphonate (2-aminoethylphosphonic acid), or bisphosphonate (alendronate) was investigated for targeted labeling of damaged bone tissue in vitro. Targeted labeling of damaged bone tissue was qualitatively verified by visual observation and backscattered electron microscopy, and quantitatively measured by the surface density of Au NPs using field-emission scanning electron microscopy. The surface density of functionalized Au NPs was significantly greater within damaged tissue compared to undamaged tissue for each functional group. Bisphosphonate-functionalized Au NPs exhibited a greater surface density labeling damaged tissue compared to glutamic acid- and phosphonic acid-functionalized Au NPs, which was consistent with the results of previous work comparing the binding affinity of the same functionalized Au NPs to synthetic hydroxyapatite crystals. Targeted labeling was enabled not only by the functional groups but also by the colloidal stability in solution. Functionalized Au NPs were stabilized by the presence of the functional groups, and were shown to remain well dispersed in ionic (phosphate buffered saline) and serum (fetal bovine serum) solutions for up to 1 week. Therefore, the results of this study suggest that bisphosphonate-functionalized Au NPs have potential for targeted delivery to damaged bone tissue in vitro and provide motivation for in vivo investigation.

Pyrophosphate Supplementation Prevents Chronic and Acute Calcification in ABCC6-Deficient Mice.

PubMed

Pomozi, Viola; Brampton, Christopher; van de Wetering, Koen; Zoll, Janna; Calio, Bianca; Pham, Kevin; Owens, Jesse B; Marh, Joel; Moisyadi, Stefan; Váradi, András; Martin, Ludovic; Bauer, Carolin; Erdmann, Jeanette; Aherrahrou, Zouhair; Le Saux, Olivier

2017-06-01

Soft tissue calcification occurs in several common acquired pathologies, such as diabetes and hypercholesterolemia, or can result from genetic disorders. ABCC6, a transmembrane transporter primarily expressed in liver and kidneys, initiates a molecular pathway inhibiting ectopic calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into pyrophosphate (PPi), a major calcification inhibitor. Heritable mutations in ABCC6 underlie the incurable calcification disorder pseudoxanthoma elasticum and some cases of generalized arterial calcification of infancy. Herein, we determined that the administration of PPi and the bisphosphonate etidronate to Abcc6 -/- mice fully inhibited the acute dystrophic cardiac calcification phenotype, whereas alendronate had no significant effect. We also found that daily injection of PPi to Abcc6 -/- mice over several months prevented the development of pseudoxanthoma elasticum-like spontaneous calcification, but failed to reverse already established lesions. Furthermore, we found that the expression of low amounts of the human ABCC6 in liver of transgenic Abcc6 -/- mice, resulting in only a 27% increase in plasma PPi levels, led to a major reduction in acute and chronic calcification phenotypes. This proof-of-concept study shows that the development of both acute and chronic calcification associated with ABCC6 deficiency can be prevented by compensating PPi deficits, even partially. Our work indicates that PPi substitution represents a promising strategy to treat ABCC6-dependent calcification disorders. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Influence of social competence of physicians on patient compliance with osteoporosis medications--a study on Polish postmenopausal women.

PubMed

Bryl, Nadia; Horst-Sikorska, Wanda; Ignaszak-Szczepaniak, Magdalena; Marcinkowska, Michalina; Michalak, Michał; Sewerynek, Ewa

2012-07-01

The aim of the study was to examine the impact of social competence of physicians on the effectiveness of patient compliance and persistence with therapy. The study included physicians and their patients, previously diagnosed with osteoporosis, and eligible to receive pharmacological treatment. The physicians were evaluated with the social competence questionnaire involving three dimensions: social exposure, intimacy and assertiveness, as well as in the combined scale. All patients in the study group were prescribed the same medication: alendronate once a week. Compliance and persistence of the patients were juxtaposed with social interaction skills of physicians during 7 scheduled appointments at 2-month intervals. Doctor's effectiveness in situations demanding close interpersonal contact was higher in the group with good compliance--group A (p < 0.001), as well as in the situations of social exposure, (p < 0.001). On the other hand, their assertiveness was higher in the group with poor compliance--group B (p < 0.001). Co-morbid conditions (group A: 76%, group B: 74%), as well as earlier fractures (40.43% vs. 36.78%) were comparable in both groups. Disease acceptance and suggested methods of treatment were more often accepted by patients from group A than group B (56% vs. 33%, respectively). (1) Disease acceptance is essential for effective treatment. (2) Social skills of physicians influence patient adherence to therapy recommendations. (3) Close interpersonal contact between physicians and their patients eliminates the feeling of fear and

A 12-year follow-up study of combined treatment of post-severe acute respiratory syndrome patients with femoral head necrosis.

PubMed

Liu, Tiansheng; Ma, Jinchao; Su, Bin; Wang, Hao; Wang, Qi; Ma, Xinlong

2017-01-01

To investigate the long-term efficacy of a combination treatment of alendronate, extracorporeal shock and hyperbaric oxygen for osteonecrosis of the femoral head (ONFH) of post-severe acute respiratory syndrome (SARS) patients. The retrospective study was performed including a total of 37 post-SARS ONFH patients (66 hip joints) in the Department of Orthopedics of the General Hospital of Tianjin Medical University between November 2003 and November 2015, consisting of 6 males (11 hip joints) and 31 females (55 hip joints), with age between 19 and 47 years (average 29.9 years). Visual analog scale (VAS) score, Harris score and Association Research Circulation Osseous (ARCO) stage of imaging examination were compared among those before treatment, and at 1, 3, 6, 9 and 12 years after treatment. Paired t -test was used for statistical analysis of VAS and Harris score before and after treatment. Difference of effective rate on all stages was analyzed with Chi-square test. With 12-year follow-up, significant improvements on VAS (6.81 of pre-treatment vs 3.94 of 12-year post-treatment) and Harris score (74.54 of pre-treatment vs 80.14 of 12-year post-treatment) were observed (all p <0.05). Effective rate showed statistical significance among three stages of ARCO ( p <0.05). The combined treatment showed different efficacies on different ARCO stages; the best was on ARCO Phase I. The combined treatment may delay or discontinue the development of ONFH in post-SARS patients.

Bisphosphonates and Nonhealing Femoral Fractures: Analysis of the FDA Adverse Event Reporting System (FAERS) and International Safety Efforts

PubMed Central

Edwards, Beatrice J.; Bunta, Andrew D.; Lane, Joseph; Odvina, Clarita; Rao, D. Sudhaker; Raisch, Dennis W.; McKoy, June M.; Omar, Imran; Belknap, Steven M.; Garg, Vishvas; Hahr, Allison J.; Samaras, Athena T.; Fisher, Matthew J.; West, Dennis P.; Langman, Craig B.; Stern, Paula H.

2013-01-01

Background: In the United States, hip fracture rates have declined by 30% coincident with bisphosphonate use. However, bisphosphonates are associated with sporadic cases of atypical femoral fracture. Atypical femoral fractures are usually atraumatic, may be bilateral, are occasionally preceded by prodromal thigh pain, and may have delayed fracture-healing. This study assessed the occurrence of bisphosphonate-associated nonhealing femoral fractures through a review of data from the U.S. FDA (Food and Drug Administration) Adverse Event Reporting System (FAERS) (1996 to 2011), published case reports, and international safety efforts. Methods: We analyzed the FAERS database with use of the proportional reporting ratio (PRR) and empiric Bayesian geometric mean (EBGM) techniques to assess whether a safety signal existed. Additionally, we conducted a systematic literature review (1990 to February 2012). Results: The analysis of the FAERS database indicated a PRR of 4.51 (95% confidence interval [CI], 3.44 to 5.92) for bisphosphonate use and nonhealing femoral fractures. Most cases (n = 317) were attributed to use of alendronate (PRR = 3.32; 95% CI, 2.71 to 4.17). In 2008, international safety agencies issued warnings and required label changes. In 2010, the FDA issued a safety notification, and the American Society for Bone and Mineral Research (ASBMR) issued recommendations about bisphosphonate-associated atypical femoral fractures. Conclusions: Nonhealing femoral fractures are unusual adverse drug reactions associated with bisphosphonate use, as up to 26% of published cases of atypical femoral fractures exhibited delayed healing or nonhealing. PMID:23426763

The Impact of Efflux Pump Inhibitors on the Activity of Selected Non-Antibiotic Medicinal Products against Gram-Negative Bacteria.

PubMed

Laudy, Agnieszka E; Kulińska, Ewa; Tyski, Stefan

2017-01-11

The potential role of non-antibiotic medicinal products in the treatment of multidrug-resistant Gram-negative bacteria has recently been investigated. It is highly likely that the presence of efflux pumps may be one of the reasons for the weak activity of non-antibiotics, as in the case of some non-steroidal anti-inflammatory drugs (NSAIDs), against Gram-negative rods. The activity of eight drugs of potential non-antibiotic activity, active substance standards, and relevant medicinal products were analysed with and without of efflux pump inhibitors against 180 strains of five Gram-negative rod species by minimum inhibitory concentration (MIC) value determination in the presence of 1 mM MgSO₄. Furthermore, the influence of non-antibiotics on the susceptibility of clinical strains to quinolones with or without PAβN (Phe-Arg-β-naphthylamide) was investigated. The impacts of PAβN on the susceptibility of bacteria to non-antibiotics suggests that amitriptyline, alendronate, nicergoline, and ticlopidine are substrates of efflux pumps in Gram-negative rods. Amitriptyline/Amitriptylinum showed the highest direct antibacterial activity, with MICs ranging 100-800 mg/L against all studied species. Significant decreases in the MIC values of other active substances (acyclovir, atorvastatin, and famotidine) tested with pump inhibitors were not observed. The investigated non-antibiotic medicinal products did not alter the MICs of quinolones in the absence and in the presence of PAβN to the studied clinical strains of five groups of species.

Systemic delivery of siRNA by hyaluronan-functionalized calcium phosphate nanoparticles for tumor-targeted therapy

NASA Astrophysics Data System (ADS)

Qiu, Chong; Wei, Wei; Sun, Jing; Zhang, Hai-Tao; Ding, Jing-Song; Wang, Jian-Cheng; Zhang, Qiang

2016-06-01

In this study, hyaluronan (HA)-functionalized calcium phosphate nanoparticles (CaP-AHA/siRNA NPs) were developed for an injectable and targetable delivery of siRNA, which were prepared by coating the alendronate-hyaluronan graft polymer (AHA) around the surface of calcium phosphate-siRNA co-precipitates. The prepared CaP-AHA/siRNA NPs had a uniform spherical core-shell morphology with an approximate size of 170 nm and zeta potential of -12 mV. The coating of hydrophilic HA improved the physical stability of nanoparticles over one month due to the strong interactions between phosphonate and calcium. In vitro experiments demonstrated that the negatively charged CaP-AHA/siRNA NPs could effectively deliver EGFR-targeted siRNA into A549 cells through CD44-mediated endocytosis and significantly down-regulate the level of EGFR expression. Also, the internalized CaP-AHA/siRNA NPs exhibited a pH-responsive release of siRNA, indicating that the acidification of lysosomes probably facilitated the disassembling of nanoparticles and the resultant ions sharply increased the inner osmotic pressure and thus expedited the release of siRNA from late lysosomes into the cytoplasm. Furthermore, in vivo tumor therapy demonstrated that high accumulation of CaP-AHA/siEGFR NPs in tumor led to a significant tumor growth inhibition with a specific EGFR gene silencing effect after intravenous administration in nude mice xenografted with A549 tumor, along with a negligible body weight loss. These results suggested that the CaP-AHA/siRNA NPs could be an effective and safe systemic siRNA delivery system for a RNAi-based tumor targeted therapy strategy.In this study, hyaluronan (HA)-functionalized calcium phosphate nanoparticles (CaP-AHA/siRNA NPs) were developed for an injectable and targetable delivery of siRNA, which were prepared by coating the alendronate-hyaluronan graft polymer (AHA) around the surface of calcium phosphate-siRNA co-precipitates. The prepared CaP-AHA/siRNA NPs had a uniform

Temporal course of avascular femoral head necrosis in patients with pemphigus vulgaris.

PubMed

Balighi, Kamran; Daneshpazhooh, Maryam; Aghazadeh, Nessa; Saeidi, Vahide; Shahpouri, Farzam; Hejazi, Pardis; Chams-Davatchi, Cheyda

2016-10-01

Pemphigus vulgaris (PV) is typically treated with systemic corticosteroids and immunosuppressive agents. Avascular necrosis (AVN) of the femoral head is a well-recognized major complication of corticosteroid therapy. The characteristics of this serious complication in PV remain unknown. Uncontrolled, retrospective study of all PV-related AVN cases diagnosed at an Iranian autoimmune bullous disease clinic between 1985 and 2013. Of the 2,321 medical records of PV patients reviewed, 45 (1.93 %) cases showed femoral AVN, with 30 (66.7 %) individuals being male. The mean age at diagnosis of AVN was 47.4 ± 14.2 years. The mean interval between the diagnosis of PV and the onset of AVN was 25.3 ± 18.3 months. With the exception of eight cases (17.8 %), the majority of patients developed AVN within three years after the diagnosis of PV. The mean cumulative dose of prednisolone in patients with AVN was 13,115.8 ± 7041.1 mg. There was a strong correlation between the total prednisolone dose and the time of onset of AVN (p = 0.001). In patients with a history of alendronate intake, that interval was significantly shorter (p = 0.01). Occurring in about 2 % of patients, AVN is a serious complication of corticosteroid treatment in patients with PV, predominantly in the first three years of treatment. In individuals receiving higher doses of prednisolone, AVN tends to occur earlier. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

Influence of the teaching program on the learning in knowledge and practice of osteonecrosis of the jaws produced by antireasorptives in dental students of the Principality of Asturias (Spain)

PubMed Central

Escobedo, Matias-Ferrán; García-Consuegra, Luis; Gay, Silvia; Álvarez, Lorena; Olay, Sonsoles; Ascani, Giuliano

2017-01-01

Background This study aims to evaluate the influence of changes in the teaching contents on medication-related osteonecrosis of the jaw may have on the knowledge and the capacity for practical case resolution about this pathology. Material and Methods A cross-sectional descriptive study was conducted through a survey divided into four sections: degree of means of knowledge acquisition, habitual practice and ability to solve clinical cases. The total number of respondents (n = 225) was divided into two groups: Group A (Year 2015-2016) and Group B (Year 2016-2017). The students in Group B received more teaching content on the subject than group A. Results A total of 175 survey responses were collected. The internet was the preferred tool for continuing education in both groups. The best known bisphosphonates (BPs) were Alendronate (Fosamax®: 56.9% Group A, 67.5% Group B) and Zoledronic Acid (Zometa®: 56.9% Group A, 51.8% Group B). A low percentage of students (37.9% Group A, 43.4% Group B) acknowledged the existence of other drugs that could also cause osteonecrosis of the jaws. Regarding the correct resolution of practical cases, the respondents of Group B reached a significantly higher score (5.67) than the score observed in Group A (4.04). Conclusions Training on medication-related osteonecrosis among dental students is susceptible to improvement. Introducing minor changes in the teachings allows this goal to be successfully achieved. Key words:Osteonecrosis of the jaw (ONJ), bisphosphonate-related osteonecrosis of the jaws (BRONJ), medication-related osteonecrosis of the jaw (MRONJ), dental education. PMID:29410755

Increasing Kyphosis Predicts Worsening Mobility in Older Community-Dwelling Women: A Prospective Cohort Study

PubMed Central

Katzman, Wendy B.; Vittinghoff, Eric; Ensrud, Kris; Black, Dennis M.; Kado, Deborah M.

2013-01-01

OBJECTIVES To determine whether increasing kyphosis angle was independently associated with poorer mobility as measured according to the Timed Up and Go Test (TUG), after controlling for other established risk factors. DESIGN Prospective cohort study. SETTING Eleven clinical centers in the United States. PARTICIPANTS Two thousand seven hundred seventy-seven women aged 55 to 80 randomized to the placebo arms of the Fracture Intervention Trial, a randomized controlled trial of the effect of alendronate on risk for osteoporotic fractures. MEASUREMENTS The primary predictor was change in kyphosis angle, measured using the Debrunner Kyphometer; the outcome was change in mobility, measured as performance time on the TUG. Covariates were baseline age, kyphosis angle, body mass index (BMI), self-reported health status, grip strength, change in total hip bond mineral density (BMD), and number of vertebral fractures over a mean of 4.4 years. RESULTS Greater kyphosis angle predicted longer mobility performance times (P<.001), independent of other significant predictors of worsening mobility including age, baseline kyphosis, health status, grip strength, BMI, change in hip BMD, and new vertebral fractures. TUG performance times increased by 0.02 seconds (95% confidence interval (CI) =0.01–0.03) for every 5° increase in kyphosis angle, more than the increase in mobility time of 0.01 seconds (95% CI =0.005–0.03) over 1 year observed in this cohort. CONCLUSION Increasing kyphosis angle is independently associated with worsening mobility. Interventions are needed to prevent or reduce increasing kyphosis and mobility decline. PMID:21198460

A case report of disabling bone pain after long-term kidney transplantation.

PubMed

Myint, T M M; Vucak-Dzumhur, M; Ebeling, P R; Elder, G J

2014-02-01

A 77-year-old man, who received a renal transplant 13 years before for IgA glomerulonephritis, was referred after he developed bilateral mid-tibial aching pain that did not improve with simple analgesia. He had recently been changed from low-dose cyclosporine to tacrolimus, but the pain did not improve when this was reversed. He had a history of focal prostatic adenocarcinoma, cryptococcal lung infection, osteoporosis treated with alendronate for 2 years and multiple squamous cell carcinomas, including one requiring left neck dissection and radiotherapy. Upon physical examination, he had gouty tophi and marked bilateral tibial tenderness but had no other clinical findings. Laboratory investigations included an elevated intact parathyroid hormone value of 7.9 pmol/L (1.6 to 6.9), bone specific alkaline phosphatase of 22 µg/L (3.7 to 20.9), urinary deoxypyridinoline/creatinine ratio of 7.2 nmol/mmol (2.5 to 5.4) and C-reactive protein. Chest X-ray and tibial X-rays were normal, but there was marrow oedema and a prominent periosteal reaction on magnetic resonance imaging. A radionuclide bone scan showed increased symmetrical, linear uptake in both tibiae and the left femur, and uptake was also noted in both clinically asymptomatic humeri. Tibial bone biopsy disclosed small deposits of poorly differentiated metastatic cancer and a follow-up chest CT revealed a lung lesion. It was concluded that the bone pain and periostitis was caused by primary lung cancer with metastatic disease to bone, and an associated hypertrophic osteoarthropathy.

Could zoledronic acid prevent root resorption in replanted rat molar?

PubMed

Yoo, Jung Eun; Kim, Mi Sun; Kwon, Yong-Dae; Kim, Eun-Cheol; Kim, Kwang Chul; Choi, Sung Chul

2015-12-01

In this study, we evaluated whether zoledronate could suppress the progression of external root resorption in rat due to delayed replantation by inhibiting osteoclastic activity. Also, we estimated the optimal dosage of zoledronate in root treatment of the rat model for a maximum effect of zoledronate. Maxillary first molars in Sprague Dawley rats (N = 84) were extracted, dried for 60 min, and then replanted. The rats were divided into 6 groups (1 mM alendronate, and 1, 5, 10, 20, 40 μM zoledronate). At 4 and 8 weeks postreplantation, the animals were sacrificed and evaluated by radiographic and histological analysis. There were no significant differences at 4 weeks. However, at 8 weeks, 10, 20, and 40 μM ZOL showed more increased radiopaque and smaller periapical lesion in radiographic analysis. In histological analysis, all groups showed similar inflammatory root resorption rate at 4 weeks. However, at 8 weeks, 20 and 40 μM ZOL showed lower rate than those of other groups (P < 0.05). In concerning of replacement resorption, there were no significant differences statistically. In this animal experiment, zoledronate was capable of limiting the occurrence of root resorption in delayed replantation model. In particular, 20 μM dosage of zoledronate solution showed the most effective dose in long-term follow up and might be suitable for inhibition of root resorption in delayed tooth replantation. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Parathyroid hormone-related protein (PTHrP) as a causative factor of cancer-associated wasting: possible involvement of PTHrP in the repression of locomotor activity in rats bearing human tumor xenografts.

PubMed

Onuma, Etsuro; Tsunenari, Toshiaki; Saito, Hidemi; Sato, Koh; Yamada-Okabe, Hisafumi; Ogata, Etsuro

2005-09-01

Nude rats bearing the LC-6-JCK human lung cancer xenograft displayed cancer-associated wasting syndrome in addition to humoral hypercalcemia of malignancy. In these rats, not only PTHrP but also several other human proinflammatory cytokines, such as IL-6, leukemia-inducing factor, IL-8, IL-5 and IL-11, were secreted to the bloodstream. Proinflammatory cytokines induce acute-phase reactions, as evidenced by a decrease of serum albumin and an increase in alpha1-acid glycoprotein. Tumor resection abolished the production of proinflammatory cytokines and improved acute-phase reactions, whereas anti-PTHrP antibody affected neither proinflammatory cytokine production nor acute-phase reactions. Nevertheless, tumor resection and administration of anti-PTHrP antibody similarly and markedly attenuated not only hypercalcemia but also loss of fat, muscle and body weight. Body weight gain by anti-PTHrP antibody was associated with increased food consumption; increased body weight from anti-PTHrP antibody was observed when animals were freely fed but not when they were given the same feeding as those that received only vehicle. Furthermore, nude rats bearing LC-6-JCK showed reduced locomotor activity, less eating and drinking and low blood phosphorus; and anti-PTHrP antibody restored them. Although alendronate, a bisphosphonate drug, decreased blood calcium, it affected neither locomotor activity nor serum phosphorus level. These results indicate that PTHrP represses physical activity and energy metabolism independently of hypercalcemia and proinflammatory cytokine actions and that deregulation of such physiologic activities and functions by PTHrP is at least in part involved in PTHrP-induced wasting syndrome.

Clinical utility of a wheat-germ precipitation assay for determination of bone alkaline phosphatase concentrations in patients with different metabolic bone diseases.

PubMed

Braga, V; Dorizzi, R; Brocco, G; Rossini, M; Zamberlan, N; Gatti, D; Adami, S

1995-07-01

Bone alkaline phosphatase was evaluated by wheat-germ lectin precipitation in several clinical conditions. The study included 33 premenopausal healthy women, 46 postmenopausal apparently healthy women, 19 growing children, 24 patients with Paget's disease, 31 patients with primary hyperparathyroidism and 66 patients with hepatobiliary diseases. In postmenopausal women the mean T score (i.e.: the number of SD below or above the mean for premenopausal women) was 2.6 +/- 1.3 (SD) for bone alkaline phosphatase and 1.61 +/- 1.21 for total alkaline phosphatase (p < 0.001). The T score for bone alkaline phosphatase provided a better discrimination from normals for both Paget's disease (22.1 +/- 27.8 versus 12.8 +/- 16 p < 0.001) and primary hyperparathyroidism (8.2 +/- 4.3 versus 4.6 +/- 3.7 p < 0.005 for bone alkaline phosphatase and total alkaline phosphatase respectively). After treatment with intravenous bisphosphonate the percent decrease of bone alkaline phosphatase was larger than that of total alkaline phosphatase both in patients with Paget's disease (-46% versus -72% p < 0.01) and in patients with primary hyperparathyroidism (-21% versus -47% p < 0.02) and an estimate of the precision (delta mean/SD of the delta mean) for bone alkaline phosphatase was 1.9-3.7 times higher than that of total alkaline phosphatase. In twelve osteoporotic patients treated for six months with oral alendronate the decrease in bone turnover was detected with significantly higher precision with bone alkaline phosphatase than with total alkaline phosphatase (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Management of the Patient with Aggressive and Resistant Papillary Thyroid Carcinoma

PubMed Central

Miftari, Rame; Topçiu, Valdete; Nura, Adem; Haxhibeqiri, Valdete

2016-01-01

Purpose: Papillary carcinoma is the most frequent type of thyroid cancer and was considered the most benign of all thyroid carcinomas, with a low risk of distant metastases. However, there are some variants of papillary thyroid carcinoma that have affinity to spread in many organs, such as: lymph nodes, lungs and bones. Aim: The aim of this study was presentation of a case with papillary carcinoma of the thyroid gland, very persistent and resistant in treatment with I 131. Material and results: A man 56 years old were diagnosed with papillary carcinoma of thyroid gland. He underwent a surgical removal of the tumor and right lobe of thyroid gland. With histopathology examination, were confirmed follicular variant of papillary carcinoma pT4. Two weeks later he underwent total thyroidectomy and was treated with 100 mCi of J 131. Six months later, the value of thyroglobulin was found elevated above upper measured limits (more than 500 ng/ml). Patient underwent surgical removal of 10 metastatic lymph nodes in the left side of the neck and has been treated with 145 mCi of radioiodine I 131. The examination after 5 months shows elevation of thyroglobulin, more than 20000 ng/ml and focally uptake of J 131 in the left lung. Patient was treated once again with 150 mCi radioiodine J 131. Whole body scintigraphy was registered focal uptake of radioiodine in the middle of the left collarbone. After a month, patient refers the enlargement of the lymph node in the right side of the neck. Currently patient is being treated with kinase inhibitor drug sorafenib and ibandronate. We have identified first positive response in treatment. Enlarged lymph node in the neck was reduced and the patient began feeling better. Conclusion: This study suggests that some subtypes of papillary thyroid carcinoma appear to have more aggressive biological course. Subtypes of papillary thyroid carcinoma such as diffuse sclerosing carcinoma, tall cell or columnar cell and insular variants, appears to

Synergistic Effects of Ethanol and Isopentenyl Pyrophosphate on Expansion of γδ T Cells in Synovial Fluid from Patients with Arthritis

PubMed Central

Laurent, Agneta J.; Bindslev, Niels; Johansson, Björn; Berg, Louise

2014-01-01

Low to moderate ethanol consumption has been associated with protective effects in autoimmune diseases such as rheumatoid arthritis, RA. An expansion of γδ T cells induced by isopentenyl pyrophosphate, IPP, likewise seems to have a protective role in arthritis. The aim of this project was to test the hypothesis that low doses of ethanol can enhance IPP-induced expansion of synovial fluid γδ T cells from patients with arthritis and may thereby potentially account for the beneficial effects of ethanol on symptoms of the arthritic process. Thus, mononuclear cells from synovial fluid (SF) from 15 patients with arthritis and from peripheral blood (PB) from 15 healthy donors were stimulated with low concentrations of ethanol and IPP for 7 days in vitro. IPP in combination with ethanol 0.015%, 2.5 mM, equivalent to the decrease per hour in blood ethanol concentration due to metabolism, gave a significantly higher fractional expansion of SF γδ T cells compared with IPP alone after 7 days (ratio 10.1+/−4.0, p<0.0008, n = 12) in patients with arthritis. Similar results were obtained for PB γδ T cells from healthy controls (ratio 2.0+/−0.4, p<0.011, n = 15). The augmented expansion of γδ T cells in SF is explained by a higher proliferation (p = 0.0034, n = 11) and an increased survival (p<0.005, n = 11) in SF cultures stimulated with IPP plus ethanol compared to IPP alone. The synergistic effects of IPP and ethanol indicate a possible allosteric effect of ethanol. Similar effects could be seen when stimulating PB with ethanol in presence of risedronate, which has the ability to increase endogenous levels of IPP. We conclude that expansion of γδ T cells by combinatorial drug effects, possibly in fixed-dose combination, FDC, of ethanol in the presence of IPP might give a protective role in diseases such as arthritis. PMID:25090614

A mechanistic study of the interaction of water-soluble borate glass with apatite-bound heterocyclic nitrogen-containing bisphosphonates.

PubMed

Pramanik, Chandrani; Sood, Parveen; Niu, Li-Na; Yuan, He; Ghoshal, Sushanta; Henderson, Walter; Liu, Yaodong; Jang, Seung Soon; Kumar, Satish; Pashley, David H; Tay, Franklin R

2016-02-01

Long-term oral and intravenous use of nitrogen-containing bisphosphonates (N-BPs) is associated with osteonecrosis of the jaw. Although N-BPs bind strongly to bone surfaces via non-covalent bonds, it is possible for extrinsic ions to dissociate bound N-BPs from mineralized bone by competitive desorption. Here, we investigate the effects and mechanism of using an ionic cocktail derived from borate bioactive glass for sequestration of heterocyclic N-BPs bound to apatite. By employing solid-state and solution-state analytical techniques, we confirmed that sequestration of N-BPs from bisphosphonate-bound apatite occurs in the presence of the borate-containing ionic cocktail. Simulations by density functional theory computations indicate that magnesium cation and borate anion are well within the extent of the risedronate or zoledronate anion to form precipitate complexes. The sequestration mechanism is due to the borate anion competing with bisphosphonates for similar electron-deficient sites on the apatite surface for binding. Thus, application of the borate-containing ionic cocktail represents a new topical lavage approach for removing apatite-bound heterocyclic N-BPs from exposed necrotic bone in bisphosphonate-related osteonecrosis of the jaw. Long-term oral consumption and injections of nitrogen-containing bisphosphonates (N-BPs) may result in death of the jaw bone when there is traumatic injury to the bone tissues. To date, there is no effective treatment for such a condition. This work reported the use of an ionic cocktail derived from water-soluble borate glass microfibers to displace the most potent type of N-BPs that are bound strongly to the mineral component on bone surfaces. The mechanism responsible for such an effect has been identified to be cation-mediated complexation of borate anions with negatively-charged N-BPs, allowing them to be released from the mineral surface. This borate-containing cocktail may be developed into a novel topical rinse for

Pleiotropic effects of bisphosphonates on osteosarcoma.

PubMed

Ohba, Tetsuro; Cates, Justin M M; Cole, Heather A; Slosky, David A; Haro, Hirotaka; Ichikawa, Jiro; Ando, Takashi; Schwartz, Herbert S; Schoenecker, Jonathan G

2014-06-01

Osteosarcoma is the most common primary malignant tumor of bone and accounts for half of all primary skeletal malignancies in children and teenagers. The prognosis for patients who fail or progress on first-line chemotherapy protocols is poor, therefore, additional adjuvant therapeutic strategies are needed. A recent feasibility study has demonstrated that the nitrogen-containing bisphosphonate zoledronic acid (ZOL) can be combined safely with conventional chemotherapy. However, the pharmacodynamics of bisphosphonate therapy is not well characterized. Osteosarcoma is a highly angiogenic tumor. Recent reports of the anti-angiogenic effects of bisphosphonates prompted us to determine whether nitrogen-containing bisphosphonate (ZOL and alendronate) treatment attenuates osteosarcoma growth by inhibition of osteoclast activity, tumor-mediated angiogenesis, or direct inhibitory effects on osteosarcoma. Here, we demonstrate that bisphosphonates directly inhibit VEGFR2 expression in endothelial cells, as well as endothelial cell proliferation and migration. Additionally, bisphosphonates also decrease VEGF-A expression in osteosarcoma (K7M3) cells, resulting in reduced stimulation of endothelial cell migration in co-culture assays. ZOL also decreases VEGFR1 expression in aggressive osteosarcoma cell lines (K7M3, 143B) and induces apoptosis of these cells, but has negligible effects on less aggressive osteosarcoma cell lines (K12 and TE85). In vivo ZOL treatment results in significant reduction in osteosarcoma-initiated angiogenesis and tumor growth in a murine model of osteosarcoma. In conclusion, bisphosphonates have diverse growth inhibitory effects on osteosarcoma through: (1) activation of apoptosis and inhibition of cell proliferation, (2) inhibition of VEGF-A and VEGFR1 expression by tumor cells, (3) inhibition of tumor-induced angiogenesis, and (4) direct inhibitory actions on endothelial cells. Published by Elsevier Inc.

Lycopene treatment against loss of bone mass, microarchitecture and strength in relation to regulatory mechanisms in a postmenopausal osteoporosis model.

PubMed

Ardawi, Mohammed-Salleh M; Badawoud, Mohammed H; Hassan, Sherif M; Rouzi, Abdulrahim A; Ardawi, Jumanah M S; AlNosani, Nouf M; Qari, Mohammed H; Mousa, Shaker A

2016-02-01

Lycopene supplementation decreases oxidative stress and exhibits beneficial effects on bone health, but the mechanisms through which it alters bone metabolism in vivo remain unclear. The present study aims to evaluate the effects of lycopene treatment on postmenopausal osteoporosis. Six-month-old female Wistar rats (n=264) were sham-operated (SHAM) or ovariectomized (OVX). The SHAM group received oral vehicle only and the OVX rats were randomized into five groups receiving oral daily lycopene treatment (mg/kg body weight per day): 0 OVX (control), 15 OVX, 30 OVX, and 45 OVX, and one group receiving alendronate (ALN) (2μg/kg body weight per day), for 12weeks. Bone densitometry measurements, bone turnover markers, biomechanical testing, and histomorphometric analysis were conducted. Micro computed tomography was also used to evaluate changes in microarchitecture. Lycopene treatment suppressed the OVX-induced increase in bone turnover, as indicated by changes in biomarkers of bone metabolism: serum osteocalcin (s-OC), serum N-terminal propeptide of type 1 collagen (s-PINP), serum crosslinked carboxyterminal telopeptides (s-CTX-1), and urinary deoxypyridinoline (u-DPD). Significant improvement in OVX-induced loss of bone mass, bone strength, and microarchitectural deterioration was observed in lycopene-treated OVX animals. These effects were observed mainly at sites rich in trabecular bone, with less effect in cortical bone. Lycopene treatment down-regulated osteoclast differentiation concurrent with up-regulating osteoblast together with glutathione peroxidase (GPx) catalase (CAT) and superoxide dismutase (SOD) activities. These findings demonstrate that lycopene treatment in OVX rats primarily suppressed bone turnover to restore bone strength and microarchitecture. Copyright © 2015. Published by Elsevier Inc.

Activation of Src kinase by protein-tyrosine phosphatase-PEST in osteoclasts: comparative analysis of the effects of bisphosphonate and protein-tyrosine phosphatase inhibitor on Src activation in vitro.

PubMed

Chellaiah, Meenakshi A; Schaller, Michael D

2009-08-01

PTP-PEST is involved in the regulation of sealing ring formation in osteoclasts. In this article, we have shown a regulatory role for PTP-PEST on dephosphorylation of c-Src at Y527 and phosphorylation at Y418 in the catalytic site. Activation of Src in osteoclasts by over-expression of PTP-PEST resulted in the phosphorylation of cortactin at Y421 and WASP at Y294. Also enhanced as a result, is the interaction of Src, cortactin, and Arp2 with WASP. Moreover, the number of osteoclasts displaying sealing ring and bone resorbing activity was increased in response to PTP-PEST over-expression as compared with control osteoclasts. Cells expressing constitutively active-Src (527YDeltaF) simulate the effects mediated by PTP-PEST. Treatment of osteoclasts with a bisphosphonate alendronate or a potent PTP inhibitor PAO decreased the activity and phosphorylation of Src at Y418 due to reduced dephosphorylation state at Y527. Therefore, Src-mediated phosphorylation of cortactin and WASP as well as the formation of WASP.cortactin.Arp2 complex and sealing ring were reduced in these osteoclasts. Similar effects were observed in osteoclasts treated with an Src inhibitor PP2. We have shown that bisphosphonates could modulate the function of osteoclasts by inhibiting downstream signaling mediated by PTP-PEST/Src, in addition to its effect on the inhibition of the post-translational modification of small GTP-binding proteins such as Rab, Rho, and Rac as shown by others. The promising effects of the inhibitors PP2 and PAO on osteoclast function suggest a therapeutic approach for patients with bone metastases and osteoporosis as an alternative to bisphosphonates.

Improved Mobilization of Exogenous Mesenchymal Stem Cells to Bone for Fracture Healing and Sex Difference

PubMed Central

Yao, Wei; Evan Lay, Yu-An; Kot, Alexander; Liu, Ruiwu; Zhang, Hongliang; Chen, Haiyan; Lam, Kit; Lane, Nancy E.

2017-01-01

Mesenchymal stem cell (MSC) transplantation has been tested in animal and clinical fracture studies. We have developed a bone-seeking compound, LLP2A-Alendronate (LLP2A-Ale) that augments MSC homing to bone. The purpose of this study was to determine whether treatment with LLP2A-Ale or a combination of LLP2A-Ale and MSCs would accelerate bone healing in a mouse closed fracture model and if the effects are sex dependent. A right mid-femur fracture was induced in two-month-old osterix-mCherry (Osx-mCherry) male and female reporter mice. The mice were subsequently treated with placebo, LLP2A-Ale (500 µg/kg, IV), MSCs derived from wild-type female Osx-mCherry adipose tissue (ADSC, 3 × 105, IV) or ADSC + LLP2A-Ale. In phosphate buffered saline-treated mice, females had higher systemic and surface-based bone formation than males. However, male mice formed a larger callus and had higher volumetric bone mineral density and bone strength than females. LLP2A-Ale treatment increased exogenous MSC homing to the fracture gaps, enhanced incorporation of these cells into callus formation, and stimulated endochondral bone formation. Additionally, higher engraftment of exogenous MSCs in fracture gaps seemed to contribute to overall fracture healing and improved bone strength. These effects were sex-independent. There was a sex-difference in the rate of fracture healing. ADSC and LLP2A-Ale combination treatment was superior to on callus formation, which was independent of sex. Increased mobilization of exogenous MSCs to fracture sites accelerated endochondral bone formation and enhanced bone tissue regeneration. PMID:27334693

Effects of Teriparatide Retreatment in Osteoporotic Men and Women

PubMed Central

Finkelstein, Joel S.; Wyland, Jason J.; Leder, Benjamin Z.; Burnett-Bowie, Sherri-Ann M.; Lee, Hang; Jüppner, Harald; Neer, Robert M.

2009-01-01

Context: The stimulatory effect of teriparatide on bone mineral density (BMD) and bone turnover is initially exuberant, but then diminishes. Objective: Our objective was to determine whether retreating with teriparatide after a drug-free period can restore the initial exuberant response to teriparatide. Design and Setting: This was a planned extension of a randomized controlled trial conducted in a single university hospital. Patients and Intervention: Subjects previously participated in a 30-month randomized trial comparing the effects of alendronate (group 1), teriparatide (group 2), or both (group 3) on BMD and bone turnover in men and women with low BMD (phase 1). Subjects who completed phase 1 on their assigned therapy entered phase 2 (months 30–42), during which teriparatide was stopped in groups 2 and 3. Teriparatide was administered to all subjects during months 42 to 54 (phase 3). Main Outcome Measures: We compared changes in BMD and markers of bone turnover (serum osteocalcin, N-terminal propeptide of type 1 collagen, and N-telopeptide) between phase 1 and 3 in subjects receiving teriparatide alone. Results: Posterior-anterior and lateral spine BMD increased 12.5 ± 1.5 and 16.9 ± 1.7%, respectively, during the first 12 months of teriparatide administration and 5.2 ± 0.8 and 6.2 ± 1.8%, respectively, during teriparatide retreatment (P < 0.001 and P = 0.001). Increases in osteocalcin (P < 0.001), N-terminal propeptide of type 1 collagen (P < 0.001), and N-telopeptide (P < 0.001) were greater during the first period of teriparatide administration. Conclusion: The response to teriparatide is attenuated when readministered after a 12-month hiatus. PMID:19401368

Population screening for osteoporosis risk: a randomised control trial of medication use and fracture risk.

PubMed

Barr, R J; Stewart, A; Torgerson, D J; Reid, D M

2010-04-01

Randomised control trial of osteoporosis screening in 4,800 women aged 45-54 years was carried out. Screened group observed an increase of 7.9% in hormone replacement therapy (HRT) use (p < 0.001), 15% in other osteoporosis treatments (p < 0.001) and a 25.9% reduction in fracture risk compared with control. Screening for osteoporosis significantly increases treatment use and reduces fracture incidence. Population screening programmes can identify menopausal women with low bone mineral density (BMD) and elevated risk of future fracture but require to be proven effective by a randomised control trial. A total of 4,800 women, 45-54 years, were randomised in equal numbers to screening or no screening (control) groups. Following screening, those in the lowest quartile of BMD were advised to consider HRT. Nine years later, the effect of screening on the uptake of treatment and the incidence of fractures were assessed by postal questionnaire. Categorical differences were assessed using chi(2) test. Cox regression was used to assess hazard ratio (HR). Of the screened and the control groups, 52.4% vs 44.5%, respectively, reported taking HRT (p < 0.001). In addition, 36.6% of the screened vs 21.6% of the control groups reported the use of vitamin D, calcium, alendronate, etidronate or raloxifene (p < 0.001). In a per protocol analysis of verified incident fractures, a 25.9% reduction in risk of fractures (of any site) in the screened group was observed (HR = 0.741, 95% CI = 0.551-0.998 adjusted age, weight and height). Screening for osteoporosis as assessed by low bone density significantly increases the use of HRT and other treatments for osteoporosis and reduces fracture incidence.

Experimental models for cancellous bone healing in the rat

PubMed Central

Bernhardsson, Magnus; Sandberg, Olof; Aspenberg, Per

2015-01-01

Background and purpose — Cancellous bone appears to heal by mechanisms different from shaft fracture healing. There is a paucity of animal models for fractures in cancellous bone, especially with mechanical evaluation. One proposed model consists of a screw in the proximal tibia of rodents, evaluated by pull-out testing. We evaluated this model in rats by comparing it to the healing of empty drill holes, in order to explain its relevance for fracture healing in cancellous bone. To determine the sensitivity to external influences, we also compared the response to drugs that influence bone healing. Methods — Mechanical fixation of the screws was measured by pull-out test and related to the density of the new bone formed around similar, but radiolucent, PMMA screws. The pull-out force was also related to the bone density in drill holes at various time points, as measured by microCT. Results — The initial bone formation was similar in drill holes and around the screw, and appeared to be reflected by the pull-out force. Both models responded similarly to alendronate or teriparatide (PTH). Later, the models became different as the bone that initially filled the drill hole was resorbed to restore the bone marrow cavity, whereas on the implant surface a thin layer of bone remained, making it change gradually from a trauma-related model to an implant fixation model. Interpretation — The similar initial bone formation in the different models suggests that pull-out testing in the screw model is relevant for assessment of metaphyseal bone healing. The subsequent remodeling would not be of clinical relevance in either model. PMID:26200395

Vanishing testes syndrome-related osteoporosis and high cardio-metabolic risk in an adult male with long term untreated hypergonadotropic hypogonadism.

PubMed

Carsote, Mara; Capatina, Cristina; Valea, Ana; Dumitrascu, Anda

2016-02-01

The male hypogonadism-related bone mass loss is often under diagnosed. Peak bone mass is severely affected if the hypogonadism occurs during puberty and is left untreated. We present an interesting; almost bizarre case of a male with non-functional testes early during childhood and undiagnosed and untreated hypogonadism until his fifth decade of life. Forty six year male is referred for goitre, complaining of back pain. Phenotype suggested intersexuality: gynoid proportions, micropenis, no palpable testes into the scrotum, no facial or truncal hair. His medical history had been unremarkable until the previous year when primary hypothyroidism was diagnosed and levothyroxine replacement was initiated. Later, he was diagnosed with ischemic heart disease, with inaugural unstable angina. On admission, the testosterone was 0.2 ng/mL (normal: 1.7-7.8 ng/mL), FSH markedly increased (56 mUI/mL), with normal adrenal axis, and TSH (under thyroxine replacement). High bone turnover markers, and blood cholesterol, and impaired glucose tolerance were diagnosed. The testes were not present in the scrotum. Abdominal computed tomography suggested bilateral masses of 1.6 cm diameter within the abdominal fat that were removed but no gonadal tissue was confirmed histopathologically. Vanishing testes syndrome was confirmed. The central DXA showed lumbar bone mineral density of 0.905 g/cm2, Z-score of -2.9SD. The spine profile X-Ray revealed multiple thoracic vertebral fractures. Alendronate therapy together with vitamin D and calcium supplements and trans-dermal testosterone were started. Four decades of hypogonadism associate increased cardiac risk, as well as decreased bone mass and high fracture risk.

Acrylic injectable and self-curing formulations for the local release of bisphosphonates in bone tissue.

PubMed

Rodríguez-Lorenzo, L M; Fernández, M; Parra, J; Vázquez, B; López-Bravo, A; Román, J San

2007-11-01

Two bisphosphonates (BPs), namely 1-hydroxy-2-[4-aminophenyl]ethane-1,1-diphosphonic acid (APBP) and 1-hydroxy-2-[3-indolyl]ethane-1,1-diphosphonic acid (IBP), have been synthesized and incorporated to acrylic injectable and self-curing formulations. Alendronic acid monosodium trihydrated salt (ALN) containing cement was formulated as control. These systems have potential applications in low density hard tissues affected by ailments characterized by a high osteoclastic resorption, i.e. osteoporosis and osteolysis. Values of curing parameters of APBP and IBP were acceptable to obtain pastes with enough fluency to be injected through a biopsy needle into the bone cavity. Working times ranged between 8 and 15 min and maximum temperature was around 50 degrees C. Cured systems stored for a month in synthetic body fluid had compressive strengths between 90 and 96 MPa and modulus between 1.2 and 1.3 GPa, which suggest mechanical stabilization after setting and in the short time. BPs were released in PBS at an initial rate depending on the corresponding chemical structure in the order ALN > APBP > IBP to give final concentrations in PBS of 2.21, 0.44, and 0.19 mol/mL for ALN, APBP, and IBP, respectively. Cytotoxicities of bisphosphonates were evaluated, IC(50) values being in the order APBP > ALN > IBP. Absence of cytotoxicity coming from leachables of the cured systems was observed in all cases independently of the BP. An improved cell growth and proliferation for the systems loaded with APBP and IBP compared with that loaded with ALN was observed, as assessed by measuring cell adhesion and proliferation, and total DNA content.

Bisphosphonate Inhibitors Reveal a Large Elasticity of Plastidic Isoprenoid Synthesis Pathway in Isoprene-Emitting Hybrid Aspen1

PubMed Central

2015-01-01

Recently, a feedback inhibition of the chloroplastic 1-deoxy-d-xylulose 5-phosphate (DXP)/2-C-methyl-d-erythritol 4-phosphate (MEP) pathway of isoprenoid synthesis by end products dimethylallyl diphosphate (DMADP) and isopentenyl diphosphate (IDP) was postulated, but the extent to which DMADP and IDP can build up is not known. We used bisphosphonate inhibitors, alendronate and zoledronate, that inhibit the consumption of DMADP and IDP by prenyltransferases to gain insight into the extent of end product accumulation and possible feedback inhibition in isoprene-emitting hybrid aspen (Populus tremula × Populus tremuloides). A kinetic method based on dark release of isoprene emission at the expense of substrate pools accumulated in light was used to estimate the in vivo pool sizes of DMADP and upstream metabolites. Feeding with fosmidomycin, an inhibitor of DXP reductoisomerase, alone or in combination with bisphosphonates was used to inhibit carbon input into DXP/MEP pathway or both input and output. We observed a major increase in pathway intermediates, 3- to 4-fold, upstream of DMADP in bisphosphonate-inhibited leaves, but the DMADP pool was enhanced much less, 1.3- to 1.5-fold. In combined fosmidomycin/bisphosphonate treatment, pathway intermediates accumulated, reflecting cytosolic flux of intermediates that can be important under strong metabolic pull in physiological conditions. The data suggested that metabolites accumulated upstream of DMADP consist of phosphorylated intermediates and IDP. Slow conversion of the huge pools of intermediates to DMADP was limited by reductive energy supply. These data indicate that the DXP/MEP pathway is extremely elastic, and the presence of a significant pool of phosphorylated intermediates provides an important valve for fine tuning the pathway flux. PMID:25926480

Differential effects of biologic versus bisphosphonate inhibition of wear debris-induced osteolysis assessed by longitudinal micro-CT.

PubMed

Tsutsumi, Ryosuke; Hock, Colleen; Bechtold, C Dustin; Proulx, Steven T; Bukata, Susan V; Ito, Hiromu; Awad, Hani A; Nakamura, Takashi; O'Keefe, Regis J; Schwarz, Edward M

2008-10-01

Aseptic loosening of total joint replacements is caused by wear debris-induced osteoclastic bone resorption, for which bisphosphonates (BPs) and RANK antagonists have been developed. Although BPs are effective in preventing metabolic bone loss, they are less effective for inflammatory bone loss. Because this difference has been attributed to the antiapoptotic inflammatory signals that protect osteoclasts from BP-induced apoptosis, but not RANK antagonists, we tested the hypothesis that osteoprotegerin (OPG) is more effective in preventing wear debris-induced osteolysis than zoledronic acid (ZA) or alendronate (Aln) in the murine calvaria model using in vivo micro-CT and traditional histology. Although micro-CT proved to be incompatible with titanium (Ti) particles, we were able to demonstrate a 3.2-fold increase in osteolytic volume over 10 days induced by polyethylene (PE) particles versus sham controls (0.49 +/- 0.23 mm(3) versus 0.15 +/- 0.067 mm(3); p < 0.01). Although OPG and high-dose ZA completely inhibited this PE-induced osteolysis (p < 0.001), pharmacological doses of ZA and Aln were less effective but still reached statistical significance (p < 0.05). Traditional histomorphometry of the sagital suture area of calvaria from both Ti and PE-treated mice confirmed the remarkable suppression of resorption by OPG (p < 0.001) versus the lack of effect by physiological BPs. The differences in drug effects on osteolysis were largely explained by the significant difference in osteoclast numbers observed between OPG versus BPs in both Ti- and PE-treated calvaria; and linear regression analyses that demonstrated a highly significant correlation between osteolysis volume and sagittal suture area versus osteoclast numbers (p < 0.001). (c) 2008 Orthopaedic Research Society.

Bone microenvironment-mediated resistance of cancer cells to bisphosphonates and impact on bone osteocytes/stem cells.

PubMed

Alasmari, Abeer; Lin, Shih-Chun; Dibart, Serge; Salih, Erdjan

2016-08-01

Anti-resorptive bisphosphonates (BPs) have been clinically used to prevent cancer-bone metastasis and cancer-induced bone pathologies despite the fact that the phenotypic response of the cancer-bone interactions to BP exposure is "uncharted territory". This study offers unique insights into the interplay between cancer stem cells and osteocytes/osteoblasts and mesenchymal stem cells using a three-dimensional (3D) live cancer-bone interactive model. We provide extraordinary cryptic details of the biological events that occur as a result of alendronate (ALN) treatment using 3D live cancer-bone model systems under specific bone remodeling stages. While cancer cells are susceptible to BP treatment in the absence of bone, they are totally unaffected in the presence of bone. Cancer cells colonize live bone irrespective of whether the bone is committed to bone resorption or formation and hence, cancer-bone metastasis/interactions are though to be "independent of bone remodeling stages". In our 3D live bone model systems, ALN inhibited bone resorption at the osteoclast differentiation level through effects of mineral-bound ALN on osteocytes and osteoblasts. The mineral-bound ALN rendered bone incapable of osteoblast differentiation, while cancer cells colonize the bone with striking morphological adaptations which led to a conclusion that a direct anti-cancer effect of BPs in a "live or in vivo" bone microenvironment is implausible. The above studies were complemented with mass spectrometric analysis of the media from cancer-bone organ cultures in the absence and presence of ALN. The mineral-bound ALN impacts the bone organs by limiting transformation of mesenchymal stem cells to osteoblasts and leads to diminished endosteal cell population and degenerated osteocytes within the mineralized bone matrix.

Local administration of bone morphogenetic protein-2 and bisphosphonate during non-weight-bearing treatment of ischemic osteonecrosis of the femoral head: an experimental investigation in immature pigs.

PubMed

Kim, Harry K W; Aruwajoye, Olumide; Du, Justin; Kamiya, Nobuhiro

2014-09-17

Non-weight-bearing decreases the femoral head deformity but increases bone resorption without increasing bone formation in an experimental animal model of Legg-Calvé-Perthes disease. We sought to determine if local administration of bone morphogenetic protein (BMP)-2 with or without bisphosphonate can increase the bone formation during the non-weight-bearing treatment in the large animal model of Legg-Calvé-Perthes disease. Eighteen piglets were surgically induced with femoral head ischemia. Immediately following the surgery, all animals received an above-the-knee amputation to enforce local non-weight-bearing (NWB). One to two weeks later, six animals received local BMP-2 to the necrotic head (BMP group), six received local BMP-2 and ibandronate (BMP+IB group), and the remaining six received no treatment (NWB group). All animals were killed at eight weeks after the induction of ischemia. Radiographic, microcomputed tomography (micro-CT), and histomorphometric assessments were performed. Radiographic assessment showed that the femoral heads in the NWB, BMP, and BMP+IB groups had a decrease of 20%, 14%, and 10%, respectively, in their mean epiphyseal quotient in comparison with the normal control group. Micro-CT analyses showed significantly higher femoral head bone volume in the BMP+IB group than in the BMP group (p = 0.02) and the NWB group (p < 0.001). BMP+IB and BMP groups had a significantly higher trabecular number (p < 0.01) and lower trabecular separation (p < 0.02) than the NWB group. In addition, the osteoclast number per bone surface was significantly lower in the BMP+IB group compared with the NWB group. Calcein labeling showed significantly higher bone formation in the BMP and BMP+IB groups than in the NWB group (p < 0.05). Heterotopic ossification was found in the capsule of four hips in the BMP+IB group but not in the BMP group. Administration of BMP-2 with bisphosphonate best decreased bone resorption and increased new bone formation during non

Norwegian physicians' knowledge of the prices of pharmaceuticals: a survey.

PubMed

Eriksen, Ida Iren; Melberg, Hans Olav; Bringedal, Berit

2013-01-01

The objectives of this study are to measure physicians' knowledge of the prices of pharmaceuticals, and investigate whether there are differences in knowledge of prices between groups of physicians. This article reports on a survey study of physicians' knowledge of the prices of pharmaceuticals conducted on a representative sample of Norwegian physicians in the autumn of 2010. The importance of physicians' knowledge of costs derives from their influence on total spending and allocation of limited health-care resources. Physicians are important drivers in the effort to contain costs in health care, but only if they have the knowledge needed to choose the most cost-effective treatment options. A survey was sent to 1543 Norwegian physicians, asking them for price estimates and their opinions on the importance of considering the cost of treatment to society as a decision factor when treating their patients. This article deals with a subsection in which the physicians were asked to estimate the price of five pharmaceuticals: simvastatin, alendronate (Fosamax), infliximab (Remicade), natalizumab (Tysabri) and escitalopram (Cipralex). The response rate was 65%. For all the five pharmaceuticals, more than 50% and as many as 83% gave responses that differed more than 50% from the actual drug price. The price of more expensive pharmaceuticals was underestimated, while the opposite was the case for less expensive medicines. The data show that physicians in general have poor knowledge of the prices of the pharmaceuticals they offer their patients. However, the physicians who frequently deal with a drug have better knowledge of its price than those who do not handle a medication as often. The data also suggest that those physicians who agree that cost of care to society is an important decision factor have better knowledge of drug prices.