Science.gov

Sample records for alendronate risedronate ibandronate

  1. Effects of antifracture drugs in postmenopausal, male and glucocorticoid-induced osteoporosis--usefulness of alendronate and risedronate.

    PubMed

    Iwamoto, Jun; Takeda, Tsuyoshi; Sato, Yoshihiro

    2007-11-01

    The purpose of this paper is to discuss the effects of antifracture drugs on postmenopausal, male and glucocorticoid-induced osteoporosis, focussing on the efficacy and safety of alendronate and risedronate. A search of the literature was conducted using PubMed for strictly conducted systematic reviews published from 1995 to present with homogeneity, meta-analyses with homogeneity, and randomized controlled trials (RCTs) with a narrow confidence interval. According to the results of the systematic reviews and meta-analyses, alendronate and risedronate are useful for the prevention of vertebral and non-vertebral fractures in postmenopausal women with osteoporosis. The results of RCTs have shown the antifracture efficacy of raloxifene and ibandronate against vertebral fractures and that of strontium and parathyroid hormone against vertebral and non-vertebral fractures in postmenopausal women with osteoporosis. In addition, the long-term safety of alendronate, risedronate and raloxifene has been established. On the other hand, RCTs have shown that, only alendronate prevents vertebral fractures in men with osteoporosis, and that alendronate and risedronate can prevent vertebral fractures in patients receiving glucocorticoid treatment. There seems to be less evidence of the antifracture efficacy of the drugs in male and glucocorticoid-induced osteoporosis. They have limitations related to long-term compliance, gastrointestinal intolerance and poor and variable absorption form gastrointestinal tract. Thus, intermittent intravenous administration of bisphosphonates such as ibandronate and zoledronate or subcutaneous administration of denosumab might address some of these problems, although the antifracture efficacy of these drugs needs be established. However, antifracture efficacy and long-term safety are important points in the choice of drugs for the treatment of osteoporosis. Thus, the evidence derived from the literature, based on strict evidence-based medicine

  2. Ibandronate

    MedlinePlus

    ... morning, before you eat or drink anything. Never take ibandronate at bedtime or before you wake up and get out of bed for the day. Swallow the tablets with a full glass (6 to 8 ounces [180 to 240 mL]) of plain water. Never take ibandronate with tea, coffee, juice, milk, mineral water, ...

  3. Risedronate

    MedlinePlus

    ... once a week in the morning, immediately after breakfast. The tablets are usually taken on an empty ... must take risedronate delayed-release tablets immediately after breakfast. Never take risedronate at bedtime or before you ...

  4. Clinical efficacy on fracture risk and safety of 0.5 mg or 1 mg/month intravenous ibandronate versus 2.5 mg/day oral risedronate in patients with primary osteoporosis.

    PubMed

    Nakamura, Toshitaka; Nakano, Tetsuo; Ito, Masako; Hagino, Hiroshi; Hashimoto, Junko; Tobinai, Masato; Mizunuma, Hideki

    2013-08-01

    This randomized, double-blind study assessed the antifracture efficacy and safety of intermittent intravenous (IV) ibandronate versus oral daily risedronate in Japanese patients with primary osteoporosis. Ambulatory patients aged ≥60 years were randomized to receive 0.5 or 1 mg/month IV ibandronate plus oral daily placebo or 2.5 mg/day oral risedronate, the licensed dose in Japan, plus IV placebo. The primary end point was noninferiority of ibandronate versus risedronate for first new or worsening vertebral fracture over 3 years. A total of 1,265 patients were randomized. A total of 1,134 patients formed the per-protocol set. Both ibandronate doses were noninferior to risedronate: 0.5 mg, hazard ratio (HR) 1.09 [95 % confidence interval (CI) 0.77-1.54]; 1 mg, HR 0.88 (95 % CI 0.61-1.27). The rate of first new vertebral fracture over 3 years was 16.8 % (95 % CI 12.8-20.8) for 0.5 mg ibandronate, 11.6 % (95 % CI 8.2-15.0) for 1 mg ibandronate, and 13.2 % (95 % CI 9.6-16.9) for risedronate. Significant increases in bone mineral density relative to baseline were observed with all treatments after 6 months, with substantial reductions in bone turnover markers after 3 months. Greatest efficacy was obtained with 1 mg ibandronate. Analyses in women only showed similar results to the overall population. No new safety concerns were identified. This study demonstrated the noninferiority of IV ibandronate to the licensed Japanese dose of oral risedronate and suggested that 1 mg/month is an effective dose in Japanese patients with primary osteoporosis. PMID:23644930

  5. Effectiveness of bisphosphonates on nonvertebral and hip fractures in the first year of therapy: The risedronate and alendronate (REAL) cohort study

    PubMed Central

    Watts, N. B.; Delmas, P. D.; Lange, J. L.; Lindsay, R.

    2006-01-01

    Introduction Randomized clinical trials have shown that risedronate and alendronate reduce fractures among women with osteoporosis. The aim of this observational study was to observe, in clinical practice, the incidence of hip and nonvertebral fractures among women in the year following initiation of once-a-week dosing of either risedronate or alendronate. Methods Using records of health service utilization from July 2002 through September 2004, we created two cohorts: women (ages 65 and over) receiving risedronate (n = 12,215) or alendronate (n = 21,615). Cox proportional hazard modeling was used to compare the annual incidence of nonvertebral fractures and of hip fractures between cohorts, adjusting for potential differences in risk factors for fractures. Results There were 507 nonvertebral fractures and 109 hip fractures. Through one year of therapy, the incidence of nonvertebral fractures in the risedronate cohort (2.0%) was 18% lower (95% CI 2% – 32%) than in the alendronate cohort (2.3%). The incidence of hip fractures in the risedronate cohort (0.4%) was 43% lower (95% CI 13% – 63%) than in the alendronate cohort (0.6%). These results were consistent across a number of sensitivity analyses. Conclusion Patients receiving risedronate have lower rates of hip and nonvertebral fractures during their first year of therapy than patients receiving alendronate. PMID:17106785

  6. Risedronate

    MedlinePlus

    ... acting tablets) are used to prevent and treat osteoporosis (a condition in which the bones become thin ... periods). Risedronate tablets are also used to treat osteoporosis in men, and in men and women who ...

  7. Biomechanical effects of teriparatide in women with osteoporosis treated previously with alendronate and risedronate: results from quantitative computed tomography-based finite element analysis of the vertebral body.

    PubMed

    Chevalier, Yan; Quek, Evelyn; Borah, Babul; Gross, Gary; Stewart, John; Lang, Thomas; Zysset, Philippe

    2010-01-01

    Previous antiresorptive treatment may influence the anabolic response to teriparatide. The OPTAMISE (Open-label Study to Determine How Prior Therapy with Alendronate or Risedronate in Postmenopausal Women with Osteoporosis Influences the Clinical Effectiveness of Teriparatide) study reported greater increases in biochemical markers of bone turnover and volumetric bone mineral density (BMD) when 12 months of teriparatide treatment was preceded by 2 years or more of risedronate versus alendronate treatment. The objective of this study was to use quantitative computed tomography (CT)-based nonlinear finite element modeling to evaluate how prior therapy with alendronate or risedronate in postmenopausal women with osteoporosis influences the biomechanical effectiveness of teriparatide. Finite element models of the L1 vertebra were created from quantitative CT scans, acquired before and after 12 months of therapy with teriparatide, from 171 patients from the OPTAMISE study. These models were subjected to uniaxial compression. Total BMD-derived bone volume fraction (BV/TV(d), i.e., bone volume [BV]/total volume [TV]), estimated from quantitative CT-based volumetric BMD, vertebral stiffness, and failure load (strength) were calculated for each time measurement point. The results of this study demonstrated that 12 months of treatment with teriparatide following prior treatment with either risedronate or alendronate increased BMD-derived BV/TV(d), the predicted vertebral stiffness, and failure load. However, the effects of teriparatide were more pronounced in patients treated previously with risedronate, which is consistent with the findings of the OPTAMISE study. The mean (+/-standard error) increase in stiffness was greater in the prior risedronate group than the prior alendronate group (24.6+/-3.2% versus 14.4+/-2.8%, respectively; p=0.0073). Similarly, vertebral failure load increased by 27.2+/-3.5% in the prior risedronate group versus 15.3+/-3.1% in the prior

  8. Alendronate

    MedlinePlus

    ... taking corticosteroids (a type of medication that may cause osteoporosis in some patients). Alendronate is also used ... esophagus (tube between the mouth and stomach) or cause sores in the mouth if it is not ...

  9. Adherence to alendronic or risedronic acid treatment, combined or not to calcium and vitamin D, and related determinants in Italian patients with osteoporosis

    PubMed Central

    Calabria, S; Cinconze, E; Rossini, M; Rossi, E; Maggioni, AP; Pedrini, A; De Rosa, M

    2016-01-01

    Purpose Osteoporosis is a chronic disease and an important health and social burden due to its worldwide prevalence. Literature and clinical experience report incomplete adherence to the therapy. This retrospective observational study aimed at assessing the adherence to first-line antiosteoporosis drugs (AODs; reimbursed by the National Health System, according to the Italian Medicine Agency recommendation number 79), alendronate or risedronate, with or without calcium and/or vitamin D supplements, in a real, Italian clinical setting. Patients and methods Analyses were carried out on data present in the ARNO Observatory, a population-based patient-centric Italian database. From a population of 5,808,832 inhabitants with available data, a cohort of 3.3 million of patients aged ≥40 years was selected. New users of first-line AODs as monotherapy (accrual period, 2007–2009) were followed up over 3 years to assess adherence at 6, 12, and 36 months to AODs and to supplements and related determinants. Results Approximately 40,000 new users were identified: mostly women, aged on average (standard deviation) 71±10 years. Alendronate was the most prescribed (38.2% of patients), followed by risedronate (34.9%) and alendronate with colecalciferol as a fixed-dose combination (25.8%). Adherence at the 6-month follow-up was 54%, and this constantly and significantly decreased after 1 year to 46%, and after 3 years to 33% (P<0.01). Adherence to the fixed-dose combination was higher than to plain alendronate throughout the follow-up period. Similarly, adherence to supplements constantly decreased with the duration of treatment. Women and patients aged >50 years were more likely to adhere to treatment regimen (P<0.001). The use of drugs for peptic ulcer and gastroesophageal reflux disease and of corticosteroids for systemic use were significantly associated with high adherence at different times. Polytherapy (>5 drugs), cardiovascular, and neurological therapies were

  10. Ibandronate Injection

    MedlinePlus

    ... Ibandronate is in a class of medications called bisphosphonates. It works by preventing bone breakdown and increasing ... while receiving this medication.Being treated with a bisphosphonate medication such as ibandronate injection for osteoporosis may ...

  11. Bilateral simultaneous femoral diaphyseal fractures in a patient with long-term ibandronate use.

    PubMed

    Patel, Vishal C; Lazzarini, Adam M

    2010-10-01

    Bisphosphonates are the most common medication used to treat patients with documented osteoporosis. Recently, reports have associated long-term bisphosphonate use with low-energy femur fractures. While no definitive mechanism has been associated, bisphosphonate use has been strongly implicated. This article presents the case of a 65-year-old woman with a 2-year history of ibandronate use presenting with simultaneous low-energy femoral shaft fractures. The patient reported prodromal bilateral thigh pain and was seen by a spine surgeon. A review of the literature implicates long-term ibandronate use in low-energy femur fractures. With most of the basic science studies demonstrating suppressed bone turnover after 5 years of treatment with alendronate, the significance of the present case also lies in the relatively short duration of time the patient was on ibandronate before suffering the bilateral femoral shaft fractures. Possible pathophysiology for the fractures includes suppressed bone turnover that may allow microcracks to propagate in cortical bone, which can weaken the bone and possibly predispose it to fractures. Patients who have been on bisphosphonates long term should be questioned about thigh pain and have radiographs of their femurs obtained if pain exists. Furthermore, if a patient presents with a single subtrochanteric or diaphyseal low-energy femur fracture after long-term bisphosphonate use, a radiograph of the contralateral femur should be obtained to assess for a cortical stress reaction. PMID:20954650

  12. Ibandronate

    MedlinePlus

    ... or take any other medications (including vitamins or antacids) for at least 60 minutes. Do not lie ... taking any oral medications, including supplements, vitamins, or antacids, take them at least 60 minutes after you ...

  13. Risedronate/zinc-hydroxyapatite based nanomedicine for osteoporosis.

    PubMed

    Khajuria, Deepak Kumar; Disha, Choudhary; Vasireddi, Ramakrishna; Razdan, Rema; Mahapatra, D Roy

    2016-06-01

    Targeting of superior osteogenic drugs to bone is an ideal approach for treatment of osteoporosis. Here, we investigated the potential of using risedronate/zinc-hydroxyapatite (ZnHA) nanoparticles based formulation in a rat model of experimental osteoporosis. Risedronate, a targeting moiety that has a strong affinity for bone, was loaded to ZnHA nanoparticles by adsorption method. Prepared risedronate/ZnHA drug formulation was characterized by field-emission scanning electron microscopy, X-ray diffraction analysis and fourier transform infrared spectroscopy. In vivo performance of the prepared risedronate/ZnHA nanoparticles was tested in an experimental model of postmenopausal osteoporosis. Therapy with risedronate/ZnHA drug formulation prevented increase in serum levels of bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase 5b better than risedronate/HA or risedronate. With respect to improvement in the mechanical strength of the femoral mid-shaft and correction of increase in urine calcium and creatinine levels, the therapy with risedronate/ZnHA drug formulation was more effective than risedronate/HA or risedronate therapy. Moreover, risedronate/ZnHA drug therapy preserved the cortical and trabecular bone microarchitecture better than risedronate/HA or risedronate therapy. Furthermore, risedronate/ZnHA drug formulation showed higher values of calcium/phosphorous ratio and zinc content. The results strongly implicate that risedronate/ZnHA drug formulation has a therapeutic advantage over risedronate or risedronate/HA therapy for the treatment of osteoporosis. PMID:27040198

  14. Osteonecrosis of the jaws associated with use of risedronate: report of 2 new cases.

    PubMed

    Brooks, John K; Gilson, Allen J; Sindler, Arnold J; Ashman, Steven G; Schwartz, Kevin G; Nikitakis, Nikolaos G

    2007-06-01

    Use of various bisphosphonates has been associated with the development of osteonecrosis of the jaws (ONJ). At least 865 cases of ONJ attributed to these agents have been reported in the English-language literature. Approximately 96% of these published cases were seen with administration of the intravenous agents pamidronate and zoledronate, whereas only 26 cases have been associated with oral bisphosphonates, 25 of them with alendronate. Only a single case of ONJ associated with the oral bisphosphonate risedronate has been previously cited. We report 2 cases of ONJ attributed to risedronate administration. The patients developed osteonecrosis 15 and 24 months after treatment for osteopenia. A regimen of antibiotics and chlorhexidine mouthrinse resolved the osseous defect in the mandible caused by complete exfoliation of a lingual torus in 1 patient. The other patient required sequestrectomy, repeated courses of antibiotics, surgical debridement, and steroids to promote closure of an oroantral fistula and management of sinusitis after bone grafting and implant placement in the posterior maxilla. A demographic profile of reported oral bisphosphonate users affected by ONJ is also provided. With the millions of patients receiving various oral bisphosphonates for osteopenia and osteoporosis, health care practitioners should be aware of the potential for the onset of osteonecrosis and familiar with its management. PMID:17223592

  15. Evaluation of risedronate as an antibiofilm agent.

    PubMed

    Reshamwala, Shamlan M S; Mamidipally, Chandrasekhar; Pissurlenkar, Raghuvir R S; Coutinho, Evans C; Noronha, Santosh B

    2016-01-01

    Escherichia coli cra null mutants have been reported in the literature to be impaired in biofilm formation. To develop E. coli biofilm-inhibiting agents for prevention and control of adherent behaviour, analogues of a natural Cra ligand, fructose-1,6-bisphosphate, were identified based on two-dimensional similarity to the natural ligand. Of the analogues identified, those belonging to the bisphosphonate class of drug molecules were selected for study, as these are approved for clinical use in humans and their safety has been established. Computational and in vitro studies with purified Cra protein showed that risedronate sodium interacted with residues in the fructose-1,6-bisphosphate-binding site. Using a quantitative biofilm assay, risedronate sodium, at a concentration of 300-400 μM, was found to decrease E. coli and Salmonella pullorum biofilm formation by >60 %. Risedronate drastically reduced the adherence of E. coli cells to a rubber Foley urinary catheter, demonstrating its utility in preventing the formation of biofilm communities on medical implant surfaces. The use of risedronate, either alone or in combination with other agents, to prevent the formation of biofilms on surfaces is a novel finding that can easily be translated into practical applications. PMID:26497196

  16. Integrated Model for Denosumab and Ibandronate Pharmacodynamics in Postmenopausal Women

    PubMed Central

    Marathe, Dhananjay D.; Marathe, Anshu; Mager, Donald E.

    2011-01-01

    This study aims to characterize the pharmacodynamic properties of denosumab, a RANK ligand inhibitor, and ibandronate, a bisphosphonate, using an integrated bone homeostasis model in postmenopausal women. Mean temporal profiles of denosumab, serum and urine N-telopeptide (sNTX, uNTX), lumbar spine bone mineral density (BMD) following denosumab administration, and urine C-telopeptide (uCTX) and lumbar spine BMD upon ibandronate administration were extracted from the literature. A mechanistic model was developed that integrates denosumab pharmacokinetics with binding to RANK ligand and ibandronate inhibition of osteoclast precursor differentiation to active osteoclasts (AOC). Biomarker concentrations were linked to the AOC pool. BMD was characterized by a turnover model with stimulation of bone formation and degradation by AOB (active osteoblasts) and AOC pools. The estimated basal sNTX, uNTX and uCTX concentrations were 7.24 nM, 14.4 nmol/mmolCr, and 31 μg/mmolCr. The BMD degradation rate was 0.00161 day−1 with stimulation constants associated with AOB and AOC of 1214 and 790 pM−1. Plasma ibandronate concentration producing 50% of maximum inhibition of osteoclast differentiation was 522 ng/L. The integrated model, which incorporates multiple pathways of therapeutic intervention, quantitatively describes changes in clinical biomarkers of bone turnover and BMD after denosumab and ibandronate exposures in postmenopausal women. PMID:21953540

  17. Late-onset psychosis and risedronate treatment for osteoporosis.

    PubMed

    Hirschmann, Shmuel; Gibel, Anatoly; Tsvelikhovsky, Irena; Lisker, Alexander

    2015-04-01

    As women age and enter menopause, they are sometimes more susceptible than men to certain physical and mental disorders such as osteoporosis and late-onset schizophrenia. Risedronate (Actonel©) is a bisphosphonate used for the treatment of osteopenia. Early initiation of pharmacotherapy for osteopenia is recommended to prevent greater bone loss. The most common side effects of risedronate include fever and flu-like symptoms, hypocalcemia, bone and joint pain, peripheral edema, fatigue, change in bowel movements, osteonecrosis of the jaw, and atrial fibrillation. Though reports in the professional literature of psychotic reactions to risedronate are scant, there have been FDA reports as well as patient discussions of psychiatric side effects from this medication on popular websites. We report the case of M, age 59, who was treated with risedronate for osteoporosis, and was subsequently diagnosed with atypical psychosis after other organic causes were excluded. Though it is conceivable that age-related psychosocial and physical factors triggered late-onset schizophrenia, the temporal relationship between the termination of treatment with risedronate and the improvement in her mental state suggests that the risedronate might have triggered a psychotic reaction that resolved following cessation of treatment. PMID:23644167

  18. Possible alendronate-induced polyarticular synovitis

    PubMed Central

    Gökkuş, K; Yazicioglu, G; Sagtas, E; Uyan, A; Aydin, AT

    2016-01-01

    We present a case of polyarticular synovitis following alendronate treatment for osteoporosis. The patient had no evidence of rheumatoid arthritis, pyrophosphate arthropathy, or seronegative/seropositive arthritis. Our main aim in this study is to highlight the potential adverse effects of alendronate and to warn orthopedic surgeons about the possibility of such a side effect that might lead orthopedic surgeons to administer wrong and unnecessary treatments like arthrocentesis. The withdrawal of alendronate is found to be the treatment of choice. Alendronate should be considered as a possible cause of synovitis or polyarthritis in patients treated with this agent in the absence of any other pathology. An association between alendronate and synovitis has rarely been described in the literature. We present a patient who developed polyarticular synovitis after treatment with alendronate and responded to its withdrawal. PMID:26767974

  19. Impurity profiling of ibandronate sodium by HPLC-CAD.

    PubMed

    Wahl, Oliver; Holzgrabe, Ulrike

    2015-10-10

    The modern bisphosphonate drug ibandronate sodium, a challenging candidate for impurity profiling, was analyzed using high performance liquid chromatography (HPLC) combined with corona charged aerosol detection (CAD). Separation was achieved on a mixed mode column combining hydrophobic C18 and strong anion exchange retention mechanisms using a mass spectrometer compatible volatile mobile phase consisting of trifluoroacetic acid and acetonitrile while gradient elution was applied. The method was validated following the ICH guideline Q2(R1) and found suitable for the assessment of ibandronate's related substances. The observed CAD-response for all identified impurities was linear (R(2)>0.995) over a small concentration range (0.05-0.25) and a quantification limit of at least 0.03% was found. Four batches of two different manufacturers were tested by means of the method. None of the batches contained a single impurity above 0.05%. The major impurities of all batches were the synthesis by-products N-desmethyl- and N-despentyl ibandronate as well as N,N-dimethyl pamidronate. PMID:26092222

  20. Risedronate-loaded Eudragit S100 microparticles formulated into tablets.

    PubMed

    Velasquez, Aline A; Mattiazzi, Juliane; Ferreira, Luana M; Pohlmann, Lauren; Silva, Cristiane B; Rolim, Clarice M B; Cruz, Letícia

    2014-05-01

    Risedronate, an anti-osteoporotic drug, is associated with low patient compliance due to the upper gastrointestinal side-effects and stringent dosing regimes. This study aimed to prepare and characterize risedronate-loaded Eudragit® S100 microparticles and develop a final dosage form by the compression of microparticles using direct tableting excipients. Microparticles were prepared by spray-drying and presented yield of 54%, encapsulation efficiency higher than 90%, mean diameter of 3.3 µm, moisture content around 8% and exhibited spherical shape and poor flowability. At pH 1.2, 23% of risedronate was released from microparticles in 120 min, while at pH 6.8 the drug took 90 min to reach 99.5%. Microparticles were compressed into tablets using microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide and 2 polyvinylpyrrolidone concentrations (5% and 15%). Tablets presented low variations in weight, thickness and drug content. Besides, the formulations showed sufficient hardness, low friability and disintegrated in less than 15 min. In acid medium, no more than 16% of the drug was released in 120 min, while in intestinal medium the formulations prolonged the risedronate release for 240 min. Finally, the developed tableted microparticles can be considered a promising dosage form for oral risedronate administration. PMID:23506303

  1. Update on osteoporosis management in long-term care: focus on bisphosphonates.

    PubMed

    Kamel, Hosam K

    2007-09-01

    Osteoporotic fractures are potentially devastating and associated with high morbidity and substantial economic burden. Residents of long-term care facilities are at greater risk of osteoporosis and its related fractures than those living in the community, yet osteoporosis is underdiagnosed and undertreated in these settings. Bisphosphonates are approved by the Food and Drug Administration for the treatment and prevention of osteoporosis in postmenopausal women. As a class, bisphosphonates have been shown to increase bone mineral density, decrease the markers of bone resorption, and reduce the risk of osteoporotic fractures. The 3 approved bisphosphonates are alendronate, risedronate, and ibandronate. Alendronate and risedronate are dosed daily or weekly and ibandronate, the most recently approved bisphosphonate, has been approved for monthly oral dosing or as an intravenous formulation to be given intermittently (every 3 months). In addition, other products with different mechanisms of action are in the pharmaceutical pipeline and may offer additional management options. PMID:17845945

  2. Predictors of Ibandronate Efficacy for the Management of Osteoporosis: A Meta-Regression Analysis

    PubMed Central

    Ma, Zeren; Li, Yong; Zhou, Ming; Huang, Kedi; Hu, Hejun; Liu, Xiaoping; Xu, Xiaosheng

    2016-01-01

    Background Aim of the present study was to identify the predictors of ibandronate efficacy in subjects with osteoporosis or decreased bone mineral density (BMD). Method Several electronic databases were searched by using specific keywords for the acquisition of research articles reporting the efficacy of ibandronate in subjects with osteoporosis or decreased BMD. Metaregression analyses were carried out by using changes in the BMD of lumbar spine and total hip following ibandronate treatment as dependent (outcome) variables against several independent (explanatory) variables. Results Data were extracted from 34 studies (11,090 ibandronate treated subjects) which fulfilled eligibility criteria. A history of previous fracture/s was reported by 46% of these subjects. In overall population, longer treatment duration from 1 to 5 years, increasing age, history of previous fractures, lower baseline T score, and higher baseline levels of C-terminal telopeptide of type 1 collagen (CTX) predicted higher ibandronate efficacy in improving BMD of the lumbar spine as well as of the total hip. Lower baseline levels of vitamin D and higher baseline levels of bone specific alkaline phosphatase (BSAP) predicted higher efficacy of ibandronate for lumbar spine only. In postmenopausal women with osteoporosis or decreased BMD, in addition to above-mentioned predictors, better efficacy of ibandronate was also associated with increasing time since menopause for both lumbar spine and total hip and lower body weight for lumbar spine only. Conclusion Longer treatment duration from 1 to 5 years, increasing age, lower baseline T scores, and higher serum CTX levels are identified as the predictors of better efficacy of ibandronate in the study subjects with osteoporosis or decreased BMD. PMID:26930292

  3. Clinical utility of risedronate in postmenopausal osteoporosis: patient considerations with delayed-release formulation

    PubMed Central

    Kinov, Plamen; Boyanov, Mihail

    2012-01-01

    Bisphosphonates are the most widely prescribed treatment for postmenopausal osteoporosis, secondary osteoporosis, and male osteoporosis. Notwithstanding their high effectiveness and favorable safety profile, the adherence to bisphosphonate treatment remains low. Different treatment strategies aim to improve the clinical effectiveness of bisphosphonate therapy. This review paper assesses the clinical utility of oral intermittent risedronate in the treatment of postmenopausal osteoporosis. The new delayed-release risedronate formulation is a safer and easy to use alternative to other risedronate therapy. Oral risedronate, a potent nitrogen-containing bisphosphonate, has been extensively studied using daily regimens. A new intermittent (weekly) dosing regimen confirmed its clinical effectiveness in relation to vertebral and nonvertebral fracture prevention. The absence of significant differences in the incidence of adverse effects confirmed the favorable tolerability of the weekly dosage. In efforts to improve patient adherence to treatment, an innovative, delayed-release formulation of risedronate, which ensures adequate bioavailability of the active compound when taken with food, was introduced. The once-weekly delayed-release formulation of risedronate proved to be noninferior to the daily dosage of risedronate in terms of bone mineral density and markers of bone turnover. In addition, the incidence of new morphometric vertebral fractures was comparable in both treatment regimens. The new delayed-release formulation of risedronate showed a favorable safety profile. Delayed-release risedronate is a promising, new, effective, and convenient alternative to current bisphosphonate treatments. It appears to allow better patient adherence to antiresorptive treatment. PMID:22532780

  4. Alendronate

    MedlinePlus

    ... Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for ...

  5. Local Application of Ibandronate/Gelatin Sponge Improves Osteotomy Healing in Rabbits

    PubMed Central

    Xia, Zhidao; Liu, Yueju; Peggrem, Shaun; Geng, Tao; Yang, Zhaoxu; Li, Han; Xu, Bin; Zhang, Chi; Triffitt, James T.; Zhang, Yingze

    2015-01-01

    Delayed healing or non-union of skeletal fractures are common clinical complications. Ibandronate is a highly potent anti-catabolic reagent used for treatment of osteopenia and fracture prevention. We hypothesized that local application of ibandronate after fracture fixation may improve and sustain callus formation and therefore prevent delayed healing or non-union. This study tested the effect of local application of an ibandronate/gelatin sponge composite on osteotomy healing. A right-side distal-femoral osteotomy was created surgically, with fixation using a k-wire, in forty adult male rabbits. The animals were divided into four groups of ten animals and treated by: (i) intravenous injection of normal saline (Control); (ii) local implantation of absorbable gelatin sponge (GS); (iii) local implantation of absorbable GS containing ibandronate (IB+GS), and (iv) intravenous injection of ibandronate (IB i.v.). At two and four weeks the affected femora were harvested for X-ray photography, computed tomography (CT), biomechanical testing and histopathology. At both time-points the results showed that the calluses in both the ibandronate-treated groups, but especially in the IB+GS group, were significantly larger than in the control and GS groups. At four weeks the cross sectional area (CSA) and mechanical test results of ultimate load and energy in the IB+GS group were significantly higher than in other groups. Histological procedures showed a significant reduction in osteoclast numbers in the IB+GS and IB i.v. groups at day 14. The results indicate that local application of an ibandronate/gelatin sponge biomaterial improved early osteotomy healing after surgical fixation and suggest that such treatment may be a valuable local therapy to enhance fracture repair and potentially prevent delayed or non-union. PMID:25951178

  6. Farnesyl pyrophosphate synthase inhibitor, ibandronate, improves endothelial function in spontaneously hypertensive rats.

    PubMed

    Han, Jie; Jiang, Dong-Mei; Ye, Yang; Du, Chang-Qing; Yang, Jian; Hu, Shen-Jiang

    2016-05-01

    Reactive oxygen species (ROS), originating predominantly from vascular smooth muscle cells (VSMCs), lead to vascular damage and endothelial dysfunction in rats with hypertension. The downstream signaling pathways of farnesyl pyrophosphate (FPP) synthase, Ras-related C3 botulinum toxin substrate 1 (Rac1) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, mediate the generation of ROS. The present study investigated the effect of the FPP synthase inhibitor, ibandronate, on ROS production, the possible beneficial effect on endothelial dysfunction and the underlying mechanisms in spontaneously hypertensive rats (SHRs). The SHRs were treated with ibandronate for 30 days. Endothelium‑dependent and independent vasorelaxation were measured in isolated aortic rings. Additionally, VSMCs from the SHRs and Wistar‑Kyoto (WKY) rats were cultured. The production of ROS and activation of NADPH oxidase were determined using fluorescence and chemiluminescence, respectively, in vivo and in vitro. Angiotensin II (Ang II) increased ROS production in the cultured VSMCs from the WKY rats and SHRs, in a concentration‑dependent manner. The Ang II‑induced responses were more marked in the SHR VSMCs, compare with those in the WKY VSMCs, however, the response decreased significantly following ibandronate pretreatment. Treatment with ibandronate significantly decreased the production of ROS, translocation of NADPH oxidase subunit p47phox, and activities of NADPH oxidase and Rac1 in the aorta and VSMCs, and improved the impaired endothelium‑dependent vasodilation in the SHRs. Adding geranylgeraniol, but not farnesol or mevalonate, reversed the inhibitory effects of ibandronate. In addition, inhibiting geranylgeranyl-transferase mimicked the effect of ibandronate on the excess oxidative response. Ibandronate exerted cellular antioxidant effects through the Rac1/NADPH oxidase pathway. These effects may have contributed to the vasoprotective effects on the impaired

  7. Farnesyl pyrophosphate synthase inhibitor, ibandronate, improves endothelial function in spontaneously hypertensive rats

    PubMed Central

    HAN, JIE; JIANG, DONG-MEI; YE, YANG; DU, CHANG-QING; YANG, JIAN; HU, SHEN-JIANG

    2016-01-01

    Reactive oxygen species (ROS), originating predominantly from vascular smooth muscle cells (VSMCs), lead to vascular damage and endothelial dysfunction in rats with hypertension. The downstream signaling pathways of farnesyl pyrophosphate (FPP) synthase, Ras-related C3 botulinum toxin substrate 1 (Rac1) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, mediate the generation of ROS. The present study investigated the effect of the FPP synthase inhibitor, ibandronate, on ROS production, the possible beneficial effect on endothelial dysfunction and the underlying mechanisms in spontaneously hypertensive rats (SHRs). The SHRs were treated with ibandronate for 30 days. Endothelium-dependent and independent vasorelaxation were measured in isolated aortic rings. Additionally, VSMCs from the SHRs and Wistar-Kyoto (WKY) rats were cultured. The production of ROS and activation of NADPH oxidase were determined using fluorescence and chemiluminescence, respectively, in vivo and in vitro. Angiotensin II (Ang II) increased ROS production in the cultured VSMCs from the WKY rats and SHRs, in a concentration-dependent manner. The Ang II-induced responses were more marked in the SHR VSMCs, compare with those in the WKY VSMCs, however, the response decreased significantly following ibandronate pretreatment. Treatment with ibandronate significantly decreased the production of ROS, translocation of NADPH oxidase subunit p47phox, and activities of NADPH oxidase and Rac1 in the aorta and VSMCs, and improved the impaired endothelium-dependent vasodilation in the SHRs. Adding geranylgeraniol, but not farnesol or mevalonate, reversed the inhibitory effects of ibandronate. In addition, inhibiting geranylgeranyl-transferase mimicked the effect of ibandronate on the excess oxidative response. Ibandronate exerted cellular antioxidant effects through the Rac1/NADPH oxidase pathway. These effects may have contributed to the vasoprotective effects on the impaired endothelium in

  8. On the absorption of alendronate in rats.

    PubMed

    Lin, J H; Chen, I W; deLuna, F A

    1994-12-01

    Alendronate is an antiosteolytic agent under investigation for the treatment of a number of bone disorders. Since the compound is a zwitterion with five pKa values and is completely ionized in the intestine at the physiological pH, absorption is poor; less than 1% of an oral dose is available systemically in rats. In the present studies, absorption was found to be predominantly in the upper part of the small intestine. Administration of buffered solutions of alendronate (pH 2-11) did not improve absorption. Whereas food markedly impaired the absorption of alendronate, EDTA enhanced absorption in a dose-dependent manner. Pretreatment of rats with ulcerogenic agents, mepirizole, acetylsalicylic acid, or indomethacin, resulted in a 3-7-fold increase in the oral absorption of alendronate. The absorption of phenol red, added as an indicator of intestinal tissue damage, was also increased in rats with experimental peptic ulcers. The enhanced absorption of alendronate observed in rats with experimental peptic ulcers was attributed to the alteration of the integrity of the intestinal membrane. PMID:7891304

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

    SciTech Connect

    Zhou, Qiang; Zhao, Zhi-Ning; Cheng, Jing-Tao; Zhang, Bin; Xu, Jie; Huang, Fei; Zhao, Rui-Ni; Chen, Yong-Jin

    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. They 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

  10. Combination ibandronate and radiotherapy for the treatment of bone metastases: Clinical evaluation and radiologic assessment

    SciTech Connect

    Vassiliou, Vassilios; Kalogeropoulou, Christine; Christopoulos, Christos; Solomou, Ekaterini; Leotsinides, Michael; Kardamakis, Dimitrios . E-mail: kardim@med.upatras.gr

    2007-01-01

    Purpose: Ibandronate is a single-nitrogen, noncyclic bisphosphonate with proven efficacy for reducing metastatic bone pain. In this study, we assessed the palliative effects of combined ibandronate and radiotherapy. Methods and Materials: Forty-five patients with bone metastases from various solid tumors received external-beam radiotherapy, 30-40 Gy over 3-4.5, weeks combined with 10 cycles of monthly intravenous ibandronate, 6 mg. Results: After combined therapy, mean bone pain scores (graded from 0 to 10) were reduced from 6.3 at baseline to 0.8 after 3 months, with further reductions at later time points (all p < 0.001). Opioid use decreased from 84% of patients at baseline (38/45) to 24% (11/45) at 3 months, with further subsequent reductions (all p < 0.001). Mean performance status and functioning scores also significantly improved. Bone density (assessed by computed tomography scan) increased by 20% vs. baseline at 3 months, 46% at 6 months, and 73% at 10 months (all p < 0.001). Lesion improvement was also demonstrated by magnetic resonance imaging. Treatment was well tolerated with no renal toxicity. Conclusions: In this pilot study, combined radiotherapy and ibandronate provided substantial bone pain relief and increased bone density. Computed tomography-based or magnetic resonance imaging-based evaluations offer objective methods for assessing therapeutic outcomes.

  11. Dose-Effectiveness Relationships Determining the Efficacy of Ibandronate for Management of Osteoporosis

    PubMed Central

    Hou, Yanjie; Gu, Ke; Xu, Chao; Ding, Huiyong; Liu, Changxin; Tuoheti, Yilihamu

    2015-01-01

    Abstract The purpose of this study was to perform a meta-analysis on the efficacy of ibandronate by evaluating the effect sizes of different dosing regimens. Major electronic databases were searched from 1985 to February 2015. A random effects meta-analysis was performed in STATA. Data from 34 studies (13,639 patients) were included in this meta-analysis. Ibandronate treatment significantly improved lumbar spine bone mineral density (BMD) as shown by the percent change from baseline (4.80%, P < 0.0001, 95% confidence interval [CI] [4.14, 5.45]). The respective effect sizes for oral intake and intravenous (IV) infusion were 4.57% and 5.22% (P < 0.0001, CIs [3.71, 5.42] and [4.37, 6.07]), respectively. All doses led to a significant increase in BMD except 2 oral dose regimens (1 mg/d: 4.65%, P = 0.285, 95% CI [−3.87, 13.18] and 0.5 mg/d: 3.60%, P = 0.38, 95% CI [−4.43, 11.64]. Ibandronate treatment (overall as well as dose wise) also significantly improved the total hip BMD—2.30% overall, 2.13% oral, and 2.63% IV (P < 0.0001, 95% CIs [1.96, 2.64], [1.70, 2.55], and [2.07, 3.20]), respectively. Ibandronate administration significantly decreased serum markers of bone resorption to −46.53% for C-terminal telopeptide of type 1 collagen, −24.03% for bone-specific alkaline phosphatase, and −50.17% for procollagen type I N-terminal propeptide (P < 0.0001, 95% CIs [−53.16, −39.91], [−31.28, −16.77], and [−64.13, −36.20]), respectively. Parathyroid hormone levels remained unaffected by ibandronate treatment (3.03%, P = 0.439, 95% CI [−5.06, 11.66]). There was no significant difference in the efficacy of ibandronate between oral or IV administration. Predominant dose regimens for IV administration were 1 to 3 mg/3 mo and 150 mg/mo oral and 2.5 mg/d for oral ibandronate treatment. PMID:26131800

  12. Liposomal alendronate for the treatment of restenosis.

    PubMed

    Gutman, Dikla; Golomb, Gershon

    2012-07-20

    The current treatment for coronary restenosis following balloon angioplasty involves the use of a mechanical or drug eluting stent (DES). The advent of DES systems has effectively allayed much of the challenge of restenosis that has plagued the success of percutaneous coronary interventions (PCI). However, there are certain limitations to DES use, among which is late stent thrombosis. Innate immunity and inflammation are of major importance in the overreaction of the wound healing response to PCI-induced vascular injury, which leads to restenosis. Liposomes containing alendronate have been shown to deplete circulating monocytes and reduce experimental restenosis. This review presents a unique systemic approach for treating restenosis with alendronate liposomal nano-carriers and reports on its formulation development, formulation variables affecting monocyte/macrophage targeting, pharmacokinetics (PK) and biodistribution, in vitro and in vivo anti-inflammatory effect, and the recent results of the phase II clinical trial. PMID:22178594

  13. Weekly oral alendronate in mevalonate kinase deficiency

    PubMed Central

    2013-01-01

    Background Mevalonate kinase deficiency (MKD) is caused by mutations in the MVK gene, encoding the second enzyme of mevalonate pathway, which results in subsequent shortage of downstream compounds, and starts in childhood with febrile attacks, skin, joint, and gastrointestinal symptoms, sometimes induced by vaccinations. Methods For a history of early-onset corticosteroid-induced reduction of bone mineral density in a 14-year-old boy with MKD, who also had presented three bone fractures, we administered weekly oral alendronate, a drug widely used in the management of osteoporosis and other high bone turnover diseases, which blocks mevalonate and halts the prenylation process. Results All of the patient’s MKD clinical and laboratory abnormalities were resolved after starting alendronate treatment. Conclusions This observation appears enigmatic, since alendronate should reinforce the metabolic block characterizing MKD, but is crucial because of the ultimate improvement shown by this patient. The anti-inflammatory properties of bisphosphonates are a new question for debate among physicians across various specialties, and requires further biochemical and clinical investigation. PMID:24360083

  14. Reduced food interaction and enhanced gastrointestinal tolerability of a new system based on risedronate complexed with Eudragit E100: Mechanistic approaches from in vitro and in vivo studies.

    PubMed

    Guzman, M L; Soria, E A; Laino, C; Manzo, R H; Olivera, M E

    2016-10-01

    Novel complexes consisting of Eudragit E100-risedronate are presented. The oral bioavailability of risedronate in rats was determined through its percentage excreted in urine after administration of complexed or free risedronate in fed and fasted conditions. The evaluation of the risedronate gastro-duodenal irritation potential was carried out by macroscopic and histological analyses in an experimental rat model. The degree of counterionic condensation between Eudragit E100 and risedronate was assessed by dialysis with, mechanistic information about the interaction with calcium and the release of risedronate from the complexes being obtained using physiological solution and simulated gastric fluid without pepsin. Non-significant differences were observed in the urinary excretion of risedronate when the complex or free risedronate was administered to fasted rats. However, the urinary excretion of risedronate in the complex group was 4-times higher than in the free risedronate group when animals were concomitantly administered with food. This behavior was related to the high degree of counterionic condensation in the complex (86.5%), which led to a reduction in the calcium induced rate and magnitude of risedronate precipitation and resulted in a decrease in the gastroduodenal damage from the complex, as evidenced by a lower frequency of gastric mucosae hemorrhage. A sustained release of risedronate from the complex was observed toward water, simulated gastric fluid or physiological solution, through an ionic-exchange mechanism. In conclusion, complexation with Eudragit E100 could be a useful strategy to overcome the unfavorable properties of risedronate. PMID:27418392

  15. Updates on mechanism of action and clinical efficacy of risedronate in osteoporosis

    PubMed Central

    Nuti, Ranuccio

    2014-01-01

    Summary Risedronate is a heterocyclic orally active aminobisphosphonate and it belongs to the bisphosphonate category: these drugs are powerful bone resorption inhibitors, thanks to their affinity for hydroxyapatite crystals at bone mineral matrix level and to their inhibiting effects on osteoclast activity, using the ability of inhibiting enzyme FPPS. Recent observations have reported that risedronate can decrease resorption entity, not only of the trabecular bone, but also of the cortical bone, modifying therefore the (bone compact) thickness and the cortical porosity entity, which is largely responsible of femoral fracture especially among elderly patients. Various controlled studies have proved the efficacy of risedronate in reducing fragility fracture risk significantly. In particular, it is able to lower in a very significant way the incidence of vertebral, non-vertebral and femoral fractures, with precocity of effects after only six months of therapy. The extension of protocols, moreover, has marked its efficacy even after seven years of treatment. Under the metabolic profile, these studies have also shown that risedronate activity can reduce bone resorption markers and increase bone density values at lumbar and femoral level. Results emerged from a group of women aged over 80 are relevant: risedronate has proved capable of decreasing femoral fracture risk. Also in male and steroidal osteoporosis, clinical controlled studies have shown that risedronate is effective in decreasing vertebral fracture incidence. Lastly, tolerability: the main side effects concern the gastrointestinal tract and they are usually rare, of minor entity and can be solved by sospending the treatment. Acute phase reaction is rare, due to risedronate oral administration; it is also valid for osteonecrosis of the jaw and atypical fractures. PMID:25568655

  16. Administration of bisphosphonate (ibandronate) impedes molar tooth movement in rabbits: A radiographic assessment

    PubMed Central

    Venkataramana, V.; Kumar, S. Sathesh; Reddy, B. Vishnuvardhan; Cherukuri, A. Sreekanth; Sigamani, K. Raja; Chandrasekhar, G.

    2014-01-01

    Introduction: Bisphosphonate (Bp)-ibandronate is a pharmacological agent, exhibits antiosteoclastic or antiresorptive activity and used to treat osteolytic or osteopenic disorders. BP-ibandronate may also interfere during orthodontic tooth movement. The aim of this study was to examine the influence of locally administered Bp-ibandronate on experimental tooth movement in rabbits. Materials and Methods: Twenty rabbits were divided into two groups- “10” served as Group-1 (control) and other “10” as Group-2 (experimental). Both groups received nickel-titanium closed coil springs with 100 g force between mandibular molar and incisors. Group-1 animals received 1 ml normal saline and Group-2 animals received ibandronate solution (0.3 mg/kg body weight) locally, mesial to the mandibular molar on the 1st, 7th, and 14th day of the experiment. A total of “40” lateral cephalograms were taken from both groups on the 1st and 21st day using a digital X-ray unit (Siemens X-ray systems, 300 mA Pleomophos analog, 2008, Germany). Individually, each animal's radiograph was traced manually and superimposed. The molar tooth movement was measured with the help of a standard metric scale. Results: The Student's t-test has been done to compare the mean values of Group-1 (4.650 ± 0.363) and Group-2 (2.030 ± 0.291) and the difference was statistically significant (P < 0.001). Conclusion: The retarded molar tooth movement was noticed in local drug administered rabbits, which could be beneficial in orthodontics to control the undesired tooth movement. PMID:25210364

  17. Comparative Effects of Ibandronate and Paclitaxel on Immunocompetent Bone Metastasis Model

    PubMed Central

    Chung, Yoon-Sok; Kang, Ho Chul

    2015-01-01

    Purpose Bone metastasis invariably increases morbidity and mortality. This study compares the effects of ibandronate and paclitaxel on bone structure and its mechanical properties and biochemical turnover in resorption markers using an immunocompetent Walker 256-Sprague-Dawley model, which was subjected to tumor-induced osteolysis. Materials and Methods Seventy rats were divided equally into 4 groups: 1) sham group (SHAM), 2) tumor group (CANC), 3) ibandronate treated group (IBAN), and 4) paclitaxel treated group (PAC). Morphological indices [bone volume fraction (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp)] and mechanical properties (failure load, stiffness) were evaluated after thirty days of treatment period. Bone resorption rate was analysed using serum deoxypyridinoline (Dpd) concentrations. Results Morphological indices showed that ibandronate (anti-resorptive drug) had a better effect in treating tumor-induced architectural changes in bone than paclitaxel (chemotherapeutic drug). The deterioration in bone architecture was reflected in the biomechanical properties of bone as studied with decreased failure load (Fx) and stiffness (S) of the bone on the 30th day post-surgery. Dpd concentrations were significantly lower in the IBAN group, indicating successful inhibition of bone resorption and destruction. Conclusion Ibandronate was found to be as effective as higher doses of paclitaxel in maintaining stiffness of bone. Paclitaxel treatment did not appear to inhibit osteoclast resorption, which is contrary to earlier in-vitro literature. Emphasis should be placed on the use of immunocompetent models for examining drug efficacy since it adequately reflects bone metastasis in clinical scenarios. PMID:26446649

  18. Risedronate adsorption on bioactive glass surface for applications as bone biomaterial

    NASA Astrophysics Data System (ADS)

    Mosbahi, Siwar; Oudadesse, Hassane; Lefeuvre, Bertand; Barroug, Allal; Elfeki, Hafed; Elfeki, Abdelfattah; Roiland, Claire; Keskes, Hassib

    2016-03-01

    The aim of the current work is to study the physicochemical interactions between bisphosphonates molecules, risedronate (RIS) and bioactive glass (46S6) after their association by adsorption phenomenon. To more understand the interaction processes of RIS with the 46S6 surface we have used complementary physicochemical techniques such as infrared (FTIR), Raman and nuclear magnetic resonance (NMR) spectroscopy. The obtained results suggest that risedronate adsorption corresponds to an ion substitution reaction with silicon ions occurring at the bioactive glass surface. Thus, a pure bioactive glass was synthesized and fully characterized comparing the solids after adsorption (46S6-XRIS obtained after the interaction of 46S6 and X% risedronate). Therefore, based on the spectroscopic results FTIR, Raman and MAS-NMR, it can be concluded that strong interactions have been established between RIS ions and 46S6 surface. In fact, FTIR and Raman spectroscopy illustrate the fixation of risedronate on the bioactive glass surface by the appearance of several bands characterizing risedronate. The 31P MAS-NMR of the composite 46S6-XRIS show the presence of two species at a chemical shift of 15 and 19 ppm demonstrating thus the fixation of the RIS on 46S6 surface.

  19. Evaluation of Osseointegration around Tibial Implants in Rats by Ibandronate-Treated Nanotubular Ti-32Nb-5Zr Alloy

    PubMed Central

    Nepal, Manoj; Li, Liang; Bae, Tae Sung; Kim, Byung Il; Soh, Yunjo

    2014-01-01

    Materials with differing surfaces have been developed for clinical implant therapy in dentistry and orthopedics. This study was designed to evaluate bone response to titanium alloy containing Ti-32Nb-5Zr with nanostructure, anodic oxidation, heat treatment, and ibandronate coating. Rats were randomly assigned to two groups for implantation of titanium alloy (untreated) as the control group and titanium alloy group coated with ibandronate as the experimental group. Then, the implants were inserted in both tibiae of the rats for four weeks. After implantation, bone implant interface, trabecular microstructure, mechanical fixation was evaluated by histology, micro-computed tomography (μCT) and the push-out test, respectively. We found that the anodized, heat-treated and ibandronate-coated titanium alloy triggered pronounced bone implant integration and early bone formation. Ibandronate-coated implants showed elevated values for removal torque and a higher level of BV/TV, trabecular thickness and separation upon analysis with μCT and mechanical testing. Similarly, higher bone contact and a larger percentage bone area were observed via histology compared to untreated alloy. Furthermore, well coating of ibandronate with alloy was observed by vitro releasing experiment. Our study provided evidences that the coating of bisphosphonate onto the anodized and heat-treated nanostructure of titanium alloy had a positive effect on implant fixation. PMID:25489426

  20. Photonic hydrogel beads for controlled release of risedronate

    NASA Astrophysics Data System (ADS)

    Khajuria, Deepak K.; Roy Mahapatra, D.

    2014-03-01

    pH-sensitive photonic composite hydrogel beads composed of sodium alginate and risedronate sodium (SA/RIS) was prepared crosslinked by Ca2+ owing to the ionic gelation of SA. The structure and surface morphology of the composite hydrogel beads were characterized by SEM. pH-sensitivity of these composite hydrogels beads and the release behaviors of drug from them were investigated. The results showed that the composite hydrogel beads had good pH-sensitivity. The drug loading and encapsulation efficiency were 27.7% and 92% for RIS, respectively. The cumulative release ratios of RIS from the composite hydrogel beads were 2.47% in pH 2.1 solution and 83 % in pH 6.8 solutions within 24 h, respectively. However, the cumulative release ratio of RIS in pH 7.4 solution reached 91% within 7 h. It is proposed that the novel photonic SA/RIS composite hydrogel bead could possess the potential of an increased intestinal absorption and fewer adverse effects of RIS. The pH and salt response of photonic hydrogel bead, as well as the encapsulation of macromolecules, are promising for applications in biomedicine and biotechnology.

  1. Ibandronate to treat skeletal-related events and bone pain in metastatic bone disease or multiple myeloma: a meta-analysis of randomised clinical trials

    PubMed Central

    Geng, Chun-Jing; Liang, Qian; Zhong, Jian-Hong; Zhu, Min; Meng, Fan-Ying; Wu, Ning; Liang, Rui; Yuan, Bin-Yi

    2015-01-01

    Objective Randomised controlled trials (RCTs) have given contradictory results about the efficacy and safety of ibandronate in treating metastatic bone disease (MBD) or multiple myeloma. This review meta-analysed the literature to gain a more comprehensive picture. Design Systematic review and meta-analysis of ibandronate compared with placebo or zoledronate. Data sources PubMed, EMBASE and the Cochrane Library databases were systematically searched to identify RCTs published up to March 2015 evaluating ibandronate to treat MBD or multiple myeloma. Review method 10 RCTs involving 3474 patients were included. Six RCTs were placebo-controlled and four compared ibandronate with zoledronate. The studies included in this review were mainly from European countries. Results Intravenous ibandronate (6 mg) or oral drug (50 mg) decreased the risk of skeletal-related events compared to placebo (risk ratio (RR) 0.80, 95% CI 0.71 to 0.90, p=0.002). It also reduced the bone pain score below baseline significantly more than did placebo at 96 weeks (weighted mean difference −0.41, 95% CI −0.56 to −0.27, p<0.001). The incidence of diarrhoea, nausea and adverse renal events was similar between the ibandronate and placebo groups, but ibandronate was associated with greater risk of abdominal pain. Ibandronate was associated with similar risk of skeletal-related events as another bisphosphonate drug, zoledronate (RR 1.02, 95% CI 0.82 to 1.26, p=0.87). The incidence of nausea, jaw osteonecrosis and fatigue was similar for the two drugs, but the incidence of adverse renal events was significantly lower in the ibandronate group. Conclusions Ibandronate significantly reduces the incidence of skeletal-related events and bone pain in patients with MBD or multiple myeloma relative to placebo. It is associated with a similar incidence of skeletal-related events as zoledronate. PMID:26038356

  2. Alendronate conjugated nanoparticles for calcification targeting.

    PubMed

    Li, Nanying; Song, Juqing; Zhu, Guanglin; Shi, Xuetao; Wang, Yingjun

    2016-06-01

    In this article, the synthesis of a novel calcification-targeting nanoparticle (NP) is reported, which is realized through dopamine self-polymerization on the poly(lactic-co-glycolic acid) (PLGA) particle surface and subsequent alendronate conjugation. Cell viability and proliferation tests confirmed that such particle has low cytotoxicity and good biocompatibility. Experiments were designed to observe whether the synthesized NPs can pass through an obstructive hydrogel and directly bind themselves to hydroxyapatite (HA) NPs (mimicking calcified spots) and HA porous scaffolds (mimicking calcified tissues); and the result was positive, indicating ingenious targeting of NPs on calcifications. The calcification-targeting NPs are expected to be with promising applications on calcification-related disease diagnoses and therapies. PMID:26970822

  3. Risedronate slows or partly reverses cortical and trabecular microarchitectural deterioration in postmenopausal women.

    PubMed

    Bala, Yohann; Chapurlat, Roland; Cheung, Angela M; Felsenberg, Dieter; LaRoche, Michel; Morris, Edward; Reeve, Jonathan; Thomas, Thierry; Zanchetta, Jose; Bock, Oliver; Ghasem-Zadeh, Ali; Djoumessi, Roger Martin Zebaze; Seeman, Ego; Rizzoli, René

    2014-02-01

    During early menopause, steady-state bone remodeling is perturbed; the number of basic multicellular units (BMUs) excavating cavities upon the endosteal surface exceeds the number (generated before menopause) concurrently refilling. Later in menopause, steady-state is restored; the many BMUs generated in early menopause refill as similarly large numbers of BMUs concurrently excavate new cavities. We hypothesized that risedronate reduces the number of cavities excavated. However, in younger postmenopausal women, the fewer cavities excavated will still exceed the fewer BMUs now refilling, so net porosity increases, but less than in controls. In older postmenopausal women, the fewer cavities excavated during treatment will be less than the many (generated during early menopause) now refilling, so net porosity decreases and trabecular volumetric bone mineral density (vBMD) increases. We recruited 324 postmenopausal women in two similarly designed double-blind placebo-controlled studies that included 161 younger (Group 1, ≤ 55 years) and 163 older (Group 2, ≥ 55 years) women randomized 2:1 to risedronate 35 mg/week or placebo. High-resolution peripheral computed tomography was used to image the distal radius and tibia. Cortical porosity was quantified using the StrAx1.0 software. Risedronate reduced serum carboxyterminal cross-linking telopeptide of type 1 bone collagen (CTX-1) and serum amino-terminal propeptide of type 1 procollagen (P1NP) by ∼50%. In the younger group, distal radius compact-appearing cortex porosity increased by 4.2% ± 1.6% (p = 0.01) in controls. This was prevented by risedronate. Trabecular vBMD decreased by 3.6% ± 1.4% (p = 0.02) in controls and decreased by 1.6% ± 0.6% (p = 0.005) in the risedronate-treated group. In the older group, changes did not achieve significance apart from a reduction in compact-appearing cortex porosity in the risedronate-treated group (0.9% ± 0.4%, p = 0.047). No between

  4. Lipid Profiles within the SABRE Trial of Anastrozole with and without Risedronate

    PubMed Central

    Van Poznak, Catherine; Makris, Andreas; Clack, Glen; Barlow, David H.; Eastell, Richard

    2012-01-01

    Introduction Lipid profiles in women with early breast cancer receiving anastrozole with or without risedronate were examined within an international Phase III/IV study to assess for possible treatment related changes. Methods Postmenopausal women with hormone receptor-positive breast cancer were assigned to 1 of 3 strata by risk of fragility fracture. Patients with the highest risk for fracture received anastrozole plus risedronate (A+R). Moderate-risk patients were randomized in a double-blind manner to anastrozole and risedronate (A+R) or anastrozole and placebo (A+P). Lower-risk patients received anastrozole (A) alone. Serial fasting blood samples were assessed for changes in lipid parameters relative to baseline after 12 months of treatment with anastrozole with or without risedronate. Samples were centrally analyzed for low density lipoprotein cholesterol (LDL-cholesterol), high density lipoprotein (HDL) cholesterol, total cholesterol (TC) and triglycerides (TG). Analysis was performed as primary analysis population for lipids (A plus A+P), lipid intention to treat population and secondary population (A+R). Results Of the 119 patients treated with A plus A+P, there were 66 patients eligible for inclusion in the primary analysis population. Of the 115 patients treated with secondary population (A+R) there were 65 patients eligible for lipid profiling. For LDL cholesterol, HDL cholesterol, TC and TG there were no significant changes between the baseline and 12 month assessments to suggest that any of these therapies have a negative impact on the lipid profile. Conclusions In this study of postmenopausal women with early breast cancer receiving adjuvant anastrozole with or without risedronate, there was no adverse effect on LDL cholesterol, HDL cholesterol, TC or TG values over the 12 month monitoring period. PMID:22763465

  5. No effect of risedronate on femoral periprosthetic bone loss following total hip arthroplasty

    PubMed Central

    Muren, Olle; Akbarian, Ehsan; Salemyr, Mats; Bodén, Henrik; Eisler, Thomas; Stark, André

    2015-01-01

    Background and purpose We have previously shown that during the first 2 years after total hip arthroplasty (THA), periprosthetic bone resorption can be prevented by 6 months of risedronate therapy. This follow-up study investigated this effect at 4 years. Patients and methods A single-center, double-blind, randomized placebo-controlled trial was carried out from 2006 to 2010 in 73 patients with osteoarthritis of the hip who were scheduled to undergo THA. The patients were randomly assigned to receive either 35 mg risedronate or placebo orally, once a week, for 6 months postoperatively. The primary outcome was the percentage change in bone mineral density (BMD) in Gruen zones 1 and 7 in the proximal part of the femur at follow-up. Secondary outcomes included migration of the femoral stem and clinical outcome scores. Results 61 of the 73 patients participated in this 4-year (3.9- to 4.1-year) follow-up study. BMD was similar in the risedronate group (n = 30) and the placebo group (n = 31). The mean difference was −1.8% in zone 1 and 0.5% in zone 7. Migration of the femoral stem, the clinical outcome, and the frequency of adverse events were similar in the 2 groups. Interpretation Although risedronate prevents periprosthetic bone loss postoperatively, a decrease in periprosthetic BMD accelerates when therapy is discontinued, and no effect is seen at 4 years. We do not recommend the use of risedronate following THA for osteoarthritis of the hip. PMID:25885280

  6. Dose-Effectiveness Relationships Determining the Efficacy of Ibandronate for Management of Osteoporosis: A Meta-Analysis.

    PubMed

    Hou, Yanjie; Gu, Ke; Xu, Chao; Ding, Huiyong; Liu, Changxin; Tuoheti, Yilihamu

    2015-07-01

    The purpose of this study was to perform a meta-analysis on the efficacy of ibandronate by evaluating the effect sizes of different dosing regimens.Major electronic databases were searched from 1985 to February 2015. A random effects meta-analysis was performed in STATA.Data from 34 studies (13,639 patients) were included in this meta-analysis. Ibandronate treatment significantly improved lumbar spine bone mineral density (BMD) as shown by the percent change from baseline (4.80%, P < 0.0001, 95% confidence interval [CI] [4.14, 5.45]). The respective effect sizes for oral intake and intravenous (IV) infusion were 4.57% and 5.22% (P < 0.0001, CIs [3.71, 5.42] and [4.37, 6.07]), respectively. All doses led to a significant increase in BMD except 2 oral dose regimens (1 mg/d: 4.65%, P = 0.285, 95% CI [-3.87, 13.18] and 0.5 mg/d: 3.60%, P = 0.38, 95% CI [-4.43, 11.64]. Ibandronate treatment (overall as well as dose wise) also significantly improved the total hip BMD-2.30% overall, 2.13% oral, and 2.63% IV (P < 0.0001, 95% CIs [1.96, 2.64], [1.70, 2.55], and [2.07, 3.20]), respectively. Ibandronate administration significantly decreased serum markers of bone resorption to -46.53% for C-terminal telopeptide of type 1 collagen, -24.03% for bone-specific alkaline phosphatase, and -50.17% for procollagen type I N-terminal propeptide (P < 0.0001, 95% CIs [-53.16, -39.91], [-31.28, -16.77], and [-64.13, -36.20]), respectively. Parathyroid hormone levels remained unaffected by ibandronate treatment (3.03%, P = 0.439, 95% CI [-5.06, 11.66]).There was no significant difference in the efficacy of ibandronate between oral or IV administration. Predominant dose regimens for IV administration were 1 to 3 mg/3 mo and 150 mg/mo oral and 2.5 mg/d for oral ibandronate treatment. PMID:26131800

  7. A new concept for bisphosphonate therapy: a rationale for the development of monthly oral dosing of ibandronate.

    PubMed

    Reginster, Jean-Yves; Felsenberg, Dieter; Cooper, Cyrus; Stakkestad, Jacob A; Miller, Paul D; Kendler, David L; Adami, Silvano; McClung, Michael R; Bolognese, Michael A; Civitelli, Roberto; Dumont, Etienne; Bonvoisin, Bernard; Recker, Robert R; Delmas, Pierre D

    2006-02-01

    Oral daily and weekly bisphosphonates represent the current mainstay of treatment for postmenopausal osteoporosis (PMO). However, the inconvenience of frequent dosing is known to negatively affect adherence to therapy in the long term. This has prompted the development of convenient oral bisphosphonate regimens that feature simple, less frequent dosing schedules. Such regimens require high potency agents, which can be given at low effective doses and that also have good tolerability. Ibandronate is a potent, nitrogen-containing bisphosphonate with proven efficacy when given intermittently to estrogen-depleted beagle dogs, rats and cynomolgus monkeys. Clinically, a pivotal prospective study has established that oral ibandronate has significant vertebral fracture efficacy in PMO, whether given daily (2.5 mg) or intermittently (20 mg every other day for 12 doses every 3 months; extended between-dose interval>2 months). Both oral regimens were well tolerated, which is noteworthy as patients with a history of gastrointestinal (GI) disturbance were not specifically excluded. As a result of these findings, a large, multinational, randomized, double-blind study (Monthly Oral iBandronate In LadiEs: MOBILE) is currently exploring the non-inferiority of once-monthly oral ibandronate (100 or 150 mg) to the oral daily ibandronate (2.5 mg) regimen with proven anti-fracture efficacy, in terms of lumbar spine bone mineral density (BMD) change. As with the trials investigating the weekly administration of other bisphosphonates, vertebral fracture efficacy will be inferred if the study demonstrates the non-inferiority of once-monthly ibandronate to the proven oral daily regimen in terms of spinal BMD change. The availability of this once-monthly ibandronate regimen is expected to offer benefits in terms of convenience (by having to follow dosing recommendations once a month vs. once daily or weekly) and potentially tolerability (by reducing the potential for upper GI irritation that

  8. 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.

  9. Effects of the bisphosphonate ibandronate on hyperalgesia, substance P, and cytokine levels in a rat model of persistent inflammatory pain.

    PubMed

    Bianchi, Mauro; Franchi, Silvia; Ferrario, Paolo; Sotgiu, Maria Luisa; Sacerdote, Paola

    2008-04-01

    The anti-inflammatory and analgesic properties of different bisphosphonates have been demonstrated in both animal and human studies. Ibandronate is a third-generation bisphosphonate effective in managing different types of bone pain. In this study we investigated its effects in a standard pre-clinical model of inflammatory pain. We evaluated the effects of a single injection of different doses (0.5, 1.0, and 2.0 mg/kg i.p.) of ibandronate on inflammatory oedema and cutaneous hyperalgesia produced by the intraplantar injection of complete Freund's adjuvant (CFA) in the rat hind-paw. In addition, we measured the effects of this drug (1.0 mg/kg i.p.) on hind-paw levels of different pro-inflammatory mediators (PGE-2, SP, TNF-alpha, and IL-1beta). We also measured the levels of SP protein and of its mRNA in the ipsilateral dorsal root ganglia (DRG). Ibandronate proved able to reduce the inflammatory oedema, the hyperalgesia to mechanical stimulation, and the levels of SP in the inflamed tissue as measured 3 and 7 days following CFA-injection. This drug significantly reduced the levels of TNF-alpha and IL-1beta only on day 7. On the other hand, the levels of PGE-2 in the inflamed hind-paw were unaffected by the administration of this bisphosphonate. Finally, ibandronate blocked the overexpression of SP mRNA in DRG induced by CFA-injection in the hind-paw. These data help to complete the pharmacodynamic profile of ibandronate, while also suggesting an involvement of several inflammatory mediators, with special reference to substance P, in the analgesic action of this bisphosphonate. PMID:17664076

  10. Controlled release of alendronate from nitrogen-doped mesoporous carbon

    DOE PAGESBeta

    Saha, Dipendu; Spurri, Amanda; Chen, Jihua; Hensley, Dale K.

    2016-04-13

    With this study, we have synthesized a nitrogen doped mesoporous carbon with the BET surface area of 1066 m2/g, total pore volume 0.6 cm3/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 the media withmore » 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

  11. Osteoblastic cell secretome: a novel role for progranulin during risedronate treatment.

    PubMed

    Romanello, Milena; Piatkowska, Elzbieta; Antoniali, Giulia; Cesaratto, Laura; Vascotto, Carlo; Iozzo, Renato V; Delneri, Daniela; Brancia, Francesco L

    2014-01-01

    It is well established that osteoblasts, the key cells involved in bone formation during development and in adult life, secrete a number of glycoproteins harboring autocrine and paracrine functions. Thus, investigating the osteoblastic secretome could yield important information for the pathophysiology of bone. In the present study, we characterized for the first time the secretome of human Hobit osteoblastic cells. We discovered that the secretome comprised 89 protein species including the powerful growth factor progranulin. Recombinant human progranulin (6nM) induced phosphorylation of mitogen-activated protein kinase in both Hobit and osteocytic cells and induced cell proliferation and survival. Notably, risedronate, a nitrogen-containing bisphosphonate widely used in the treatment of osteoporosis, induced the expression and secretion of progranulin in the Hobit secretome. In addition, our proteomic study of the Hobit secretome revealed that risedronate induced the expression of ERp57, HSP60 and HSC70, three proteins already shown to be associated with the prevention of bone loss in osteoporosis. Collectively, our findings unveil novel targets of risedronate-evoked biological effects on osteoblast-like cells and further our understanding of the mechanisms of action of this currently used compound. PMID:24120669

  12. Femur bone repair in ovariectomized rats under the local action of alendronate, hydroxyapatite and the association of alendronate and hydroxyapatite

    PubMed Central

    Canettieri, Antonio Carlos Victor; Colombo, Carlos Eduardo Dias; Chin, Chung Man; Faig-Leite, Horácio

    2009-01-01

    An evaluation was made of the local action of alendronate sodium (A), hydroxyapatite (HA) and the association of both substances (A + HA), in different molar concentrations, on the femur bone repair of ovariectomized rats. Ninety-eight animals were divided into seven groups: control (C), starch (S), alendronate 1 mol (A1), alendronate 2 mols (A2), hydroxyapatite 1 mol (HA1), hydroxyapatite 2 mols (HA2) and the association of alendronate + hydroxyapatite (A + HA). Rats weighing about 250 g were ovariectomized and 2.5-mm diameter bone defects were made on the left femur 30 days later. Each experimental group had defects filled with appropriate material, except for group C (control). The animals were killed 7 and 21 days after surgery. Histological, histomorphometric and statistical analyses of bone neoformation in the bone defect site were performed. From the histological standpoint, the major differences occurred after 21 days. All specimens in groups C, S, HA1 and HA2 presented linear closure of the bone defect, and most animals in groups A1, A2 and A + HA showed no bone neoformation in the central area of the defect. No statistically significant difference was found among the experimental groups after 7 days; after 21 days, group HA2 presented the highest amount of neoformed bone. There was no significant difference among groups A1, A2 and A + HA in the two study periods. It was concluded that alendronate, either isolated or in association with hydroxyapatite, had an adverse effect on bone repair in this experimental model. Moreover, the hydroxyapatite used here proved to be biocompatible and osteoconductive, with group HA2 showing the best results. PMID:19765106

  13. Efficacy of Alendronate for Preventing Collapse of Femoral Head in Adult Patients with Nontraumatic Osteonecrosis

    PubMed Central

    Hong, Yu-Cai; Luo, Ru-Bin; Zhong, Hui-Ming; Shi, Jian-Bin

    2014-01-01

    The purpose of the current review was to determine the efficacy of alendronate for preventing collapse of femoral head in adult patients with nontraumatic avascular osteonecrosis of femoral head (ANFH). Five randomized controlled trials (RCTs) involving 305 hips were included in this review, of which 3 studies investigated alendronate versus control/placebo and the other 2 studies compared the combination of alendronate and extracorporeal shockwave therapy (ESWT) with ESWT alone. Our results suggested that even the patients with extensive necrosis encountered much less collapse in the alendronate group than control group. In these RCTs, their data also indicated a positive short- and middle-term efficacy of alendronate treatment in joint function improvement and hip pain diminishment. With the presence of the outlier study, only insignificant overall efficacy of alendronate could be observed with substantial heterogeneities. In addition, we did not find any additive benefits of alendronate in combination with ESWT for preventing collapse compared to ESWT alone. In conclusion, there is still lack of strong evidence for supporting application of alendronate in adult patients with nontraumatic ANFH, which justified that large scale, randomized, and double-blind studies should be developed to demonstrate the confirmed efficacies, detailed indication, and optimized strategy of alendronate treatment. PMID:25535614

  14. Ibandronate Injection

    MedlinePlus

    ... which the bones become thin and weak and break easily) in women who have undergone menopause (''change ... osteoporosis may increase the risk that you will break your thigh bone(s). You may feel pain in ...

  15. Risedronate Prevents Bone Loss in Breast Cancer Survivors: A 2-Year, Randomized, Double-Blind, Placebo-Controlled Clinical Trial

    PubMed Central

    Greenspan, Susan L.; Brufsky, Adam; Lembersky, Barry C.; Bhattacharya, Rajib; Vujevich, Karen T.; Perera, Subashan; Sereika, Susan M.; Vogel, Victor G.

    2014-01-01

    Purpose Limited data are available on the efficacy of oral bisphosphonate therapy in breast cancer survivors. Our goal was to examine prevention of breast cancer–related bone loss in this cohort. Patients and Methods Eighty-seven postmenopausal women after chemotherapy for breast cancer were randomly assigned to once-weekly risedronate 35 mg or placebo for 24 months. Outcomes included bone mineral density (BMD) and turnover markers. Results At study initiation, 13% of patients were on an aromatase inhibitor (AI). After 24 months, there were differences of 1.6 to 2.5% (P < .05) at the spine and hip BMD between the placebo and risedronate groups. At study completion, 44% were on an AI. Adjusting for an AI, women on placebo plus AI had a decrease in BMD of (mean ± SE) 4.8% ± 0.8% at the spine and 2.8% ± 0.5% at the total hip (both P < .001). In women on risedronate + AI, the spine decreased by 2.4% ± 1.1% (P < .05) and was stable at the hip. Women in the placebo group not on an AI, maintained BMD at the spine, and had a 1.2% ± 0.5% loss at the total hip (P < .05). Women who received risedronate but no AI had the greatest improvement in BMD of 2.2% ± 0.9% (P < .05) at the total hip. Bone turnover was reduced with risedronate. There were no differences in adverse events between the groups. Conclusion We conclude that in postmenopausal women with breast cancer with or without AI therapy, once-weekly oral risedronate was beneficial for spine and hip BMD, reduced bone turnover, and was well tolerated. PMID:18427147

  16. Alendronate distributed on bone surfaces inhibits osteoclastic bone resorption in vitro and in experimental hypercalcemia models.

    PubMed

    Azuma, Y; Sato, H; Oue, Y; Okabe, K; Ohta, T; Tsuchimoto, M; Kiyoki, M

    1995-02-01

    Alendronate is an aminobisphosphonate that acts as a potent inhibitor of osteoclastic bone resorption. To understand the mechanism of action of alendronate in vivo, in this study we investigated the relationship between distribution of [14C]-alendronate in rat bone and its effects on bone resorption in vitro or in rat hypercalcemic models. A single IV dose of 0.05 approximately 1.25 mg/kg inhibited the increase in plasma calcium level induced by bovine PTH or 1 alpha(OH)D3. The minimal effective dose of pamidronate (1.25 mg/kg) and etidronate (over 31.25 mg/kg) were at least 5 times and 25 times, respectively, higher than the dose of alendronate in the rat hypercalcemic model prepared by 1 alpha(OH)D3. The relative potencies of compounds in the hypercalcemic rat models reflected those of inhibitory effects on bone resorption in vitro. We conducted the ivory-slice assay under two conditions: (a) addition of a given bisphosphonate after adherence of the osteoclasts; and (b) preincubation of the ivory slices with a given bisphosphonate. The inhibitory IC50 values of alendronate under condition (b) were similar to those under condition (a). To evaluate the interaction between osteoclasts and alendronate in bone, we investigated the localization of [14C]-alendronate in the tibia of growing rats (4-day-old rats). Alendronate did not distribute uniformly in the tibia. At 1 day after injection (0.05 mg SC), dense labeling was seen primarily under osteoclasts. We injected 0.05 mg/kg of [14C]-alendronate (single i.v.) into rats [14C]-alendronate was rapidly eliminated from plasma, and mainly distributed to the bone in rats. These data suggest that alendronate which distributed on bone surface mainly contributed to the antihypercalcemic action in vivo. PMID:7756053

  17. Experimental osteonecrosis: development of a model in rodents administered alendronate.

    PubMed

    Conte, Nicolau; Spolidorio, Luis Carlos; Andrade, Cleverton Roberto de; Esteves, Jônatas Caldeira; Marcantonio, Elcio

    2016-01-01

    The main objective of this study was to cause bisphosphonate-related osteonecrosis of the jaws to develop in a rodent model. Adult male Holtzman rats were assigned to one of two experimental groups to receive alendronate (AL; 1 mg/kg/week; n = 6) or saline solution (CTL; n = 6). After 60 days of drug therapy, all animals were subjected to first lower molar extraction, and 28 days later, animals were euthanized. All rats treated with alendronate developed osteonecrosis, presenting as ulcers and necrotic bone, associated with a significant infection process, especially at the inter-alveolar septum area and crestal regions. The degree of vascularization, the levels of C-telopeptide cross-linked collagen type I and bone-specific alkaline phosphatase, as well as the bone volume were significantly reduced in these animals. Furthermore, on radiographic analysis, animals treated with alendronate presented evident sclerosis of the lamina dura of the lower first molar alveolar socket associated with decreased radiographic density in this area. These findings indicate that the protocol developed in the present study opens new perspectives and could be a good starting model for future property design. PMID:27556684

  18. 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.

  19. Cost-utility of denosumab for the treatment of postmenopausal osteoporosis in Spain

    PubMed Central

    Darbà, Josep; Kaskens, Lisette; Sorio Vilela, Francesc; Lothgren, Mickael

    2015-01-01

    Background The objective of this study was to estimate the cost-effectiveness of denosumab for fracture prevention compared with no treatment, generic bisphosphonates, and strontium ranelate in a cohort of osteoporotic postmenopausal women in Spain. Methods A Markov model represented the possible health state transitions of Spanish postmenopausal women from initiation of fracture prevention treatment until age 100 years or death. The perspective was that of the Spanish National Health System. Fracture efficacy data for denosumab were taken from a randomized controlled trial. Fracture efficacy data for alendronate, ibandronate, risedronate, and strontium ranelate were taken from an independent meta-analysis. Data on the incidence of fractures in Spain were either taken from the published literature or derived from Swedish data after applying a correction factor based on the reported incidence from each country. Resource use in each health state was obtained from the literature, or where no data had been published, conservative assumptions were made. Utility values for the various fracture health states were taken from published sources. The primary endpoints of the model were life-years gained, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios for denosumab against the comparators. Results Denosumab reduced the risk of fractures compared with either no treatment or the other active interventions, and produced the greatest gains in life-years and QALYs. With an annual acquisition cost of €417.34 for denosumab, the incremental cost-effectiveness ratios for denosumab versus no treatment, alendronate, risedronate, and ibandronate were estimated at €6,823, €16,294, €4,895, and €2,205 per QALY gained, respectively. Denosumab dominated strontium ranelate. Sensitivity analyses confirmed the robustness of these findings. Conclusion Our analyses show that denosumab is a cost-effective intervention for fracture prevention in osteoporotic

  20. 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.

  1. Crystallization and preliminary neutron diffraction experiment of human farnesyl pyrophosphate synthase complexed with risedronate

    PubMed Central

    Yokoyama, Takeshi; Ostermann, Andreas; Mizuguchi, Mineyuki; Niimura, Nobuo; Schrader, Tobias E.; Tanaka, Ichiro

    2014-01-01

    Nitrogen-containing bisphosphonates (N-BPs), such as risedronate and zoledronate, are currently used as a clinical drug for bone-resorption diseases and are potent inhibitors of farnesyl pyrophosphate synthase (FPPS). X-ray crystallographic analyses of FPPS with N-BPs have revealed that N-BPs bind to FPPS with three magnesium ions and several water molecules. To understand the structural characteristics of N-BPs bound to FPPS, including H atoms and hydration by water, neutron diffraction studies were initiated using BIODIFF at the Heinz Maier-Leibnitz Zentrum (MLZ). FPPS–risedronate complex crystals of approximate dimensions 2.8 × 2.5 × 1.5 mm (∼3.5 mm3) were obtained by repeated macro-seeding. Monochromatic neutron diffraction data were collected to 2.4 Å resolution with 98.4% overall completeness. Here, the first successful neutron data collection from FPPS in complex with N-BPs is reported. PMID:24699741

  2. An easy and effective method for synthesis and radiolabelling of risedronate as a model for bone imaging.

    PubMed

    Motaleb, M A; Adli, A S A; El-Tawoosy, M; Sanad, M H; AbdAllah, M

    2016-04-01

    This study aimed to provide an easy method for synthesis of 1-hydroxy-2-(3-pyridyl) ethylidene bisphosphonic acid monosodium (sod. risedronate) with a high yield of 71%. The synthesized risedronate was labeled with technetium-99 m using two different reducing agents (SnCl2 .2H2 O and NaBH4 ) where NaBH4 gave stable complex and higher radiochemical yield more than SnCl2 .2H2 O. The results showed that, the radiochemical purity of (99m) Tc(NaBH4 )-risedronate was 99.2 ± 0.6% and its stability was up to 6 h. Biodistribution study showed high uptake and long retention of (99m) Tc(NaBH4 )-risedronate in bone starting from 15 min (29 ± 2.5% ID/organ) up to 4 h (35.1 ± 3.2 ID/organ) post injection. This research could introduce an easy and effective method for synthesis and labeling of risedrionate and affording a good tracer for bone imaging. PMID:26955900

  3. 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. PMID:23627045

  4. Risedronate does not reduce mechanical loading-related increases in cortical and trabecular bone mass in mice

    PubMed Central

    Sugiyama, Toshihiro; Meakin, Lee B.; Galea, Gabriel L.; Jackson, Brendan F.; Lanyon, Lance E.; Ebetino, Frank H.; Russell, R. Graham G.; Price, Joanna S.

    2011-01-01

    To establish whether the combination of anti-resorptive therapy with mechanical loading has a negative, additive or synergistic effect on bone structure, we assessed the separate and combined effects of risedronate and non-invasive dynamic loading on trabecular and cortical bone. Seventeen-week-old female C57BL/6 mice were given daily subcutaneous injections of vehicle (n = 20) or risedronate at a dose of 0.15, 1.5, 15 or 150 μg/kg/day (n = 10 in each) for 17 days. From the fourth day of treatment, the right tibiae were subjected to a single period of axial loading (40 cycles/day) for three alternate days per week for two weeks. The left tibiae were used as internal controls. Trabecular and cortical sites in the tibiae were analyzed by high-resolution micro-computed tomography and imaging of fluorochrome labels. In the non-loaded tibiae, treatment with the higher doses of risedronate at 15 or 150 μg/kg/day resulted in higher trabecular bone volume and trabecular number than in vehicle-treated controls, whereas such treatment was associated with no differences in cortical bone volume at any dose. In the loaded tibiae, loading induced increases in trabecular and cortical bone volume compared with contra-lateral controls primarily through increased trabecular thickness and periosteal expansion, respectively, independently of risedronate treatment. In conclusion, the response to mechanical loading in both trabecular and cortical bone in mice is therefore not impaired by short-term treatment with risedronate, even over a 1000-fold dose range. In considering the optimization of treatments for osteoporosis, it is reassuring that anti-resorptive therapy and mechanical loading can exert independent beneficial effects. This article is part of a Special Issue entitled Bisphosphonates. PMID:21497678

  5. Quercetin prevents experimental glucocorticoid-induced osteoporosis: a comparative study with alendronate.

    PubMed

    Derakhshanian, Hoda; Djalali, Mahmoud; Djazayery, Abolghassem; Nourijelyani, Keramat; Ghadbeigi, Sajad; Pishva, Hamideh; Saedisomeolia, Ahmad; Bahremand, Arash; Dehpour, Ahmad Reza

    2013-05-01

    Glucocorticoid-induced osteoporosis (GIO) is the most common type of secondary osteoporosis. The aim of this study was to compare the efficacy of quercetin, a plant-derived flavonoid, with alendronate in the prevention of GIO. Fifty-six Sprague-Dawley rats were randomly distributed among 7 groups (8 rats per group) and treated for 6 weeks with one of the following: (i) normal saline; (ii) 40 mg methylprednisolone sodium succinate (MP)/kg body mass; (iii) MP + 40 μg alendronate/kg; (iv) MP + 50 mg quercetin/kg; (v) MP + 40 μg alendronate/kg + 50 mg quercetin/kg; (vi) MP + 150 mg quercetin/kg; and (vii) MP + 40 μg alendronate/kg + 150 mg quercetin/kg. MP and alendronate were injected subcutaneously and quercetin was administered by oral gavage 3 days a week. At the end of the study, femur breaking strength was significantly decreased as a consequence of MP injection. This decrease was completely compensated for in groups receiving 50 mg quercetin/kg plus alendronate, and 150 mg quercetin/kg with or without alendronate. Quercetin noticeably elevated osteocalcin as a bone formation marker, while alendronate did not show such an effect. In addition, administration of 150 mg quercetin/kg increased femoral trabecular and cortical thickness by 36% and 22%, respectively, compared with the MP-treated group. These data suggest that 150 mg quercetin/kg, alone or in combination with alendronate, can completely prevent GIO through its bone formation stimulatory effect. PMID:23656499

  6. Effect of ibandronate on bending strength and toughness of rodent cortical bone

    PubMed Central

    Savaridas, T.; Wallace, R. J.; Dawson, S.; Simpson, A. H. R. W.

    2015-01-01

    Objectives There remains conflicting evidence regarding cortical bone strength following bisphosphonate therapy. As part of a study to assess the effects of bisphosphonate treatment on the healing of rat tibial fractures, the mechanical properties and radiological density of the uninjured contralateral tibia was assessed. Methods Skeletally mature aged rats were used. A total of 14 rats received 1µg/kg ibandronate (iban) daily and 17 rats received 1 ml 0.9% sodium chloride (control) daily. Stress at failure and toughness of the tibial diaphysis were calculated following four-point bending tests. Results Uninjured cortical bone in the iban group had a significantly greater mean (standard deviation (sd)), p < 0.001, stress at failure of 219.2 MPa (sd 45.99) compared with the control group (169.46 MPa (sd 43.32)) following only nine weeks of therapy. Despite this, the cortical bone toughness and work to failure was similar. There was no significant difference in radiological density or physical dimensions of the cortical bone. Conclusions Iban therapy increases the stress at failure of uninjured cortical bone. This has relevance when normalising the strength of repair in a limb when comparing it with the unfractured limb. However, the 20% increase in stress at failure with iban therapy needs to be interpreted with caution as there was no corresponding increase in toughness or work to failure. Further research is required in this area, especially with the increasing clinical burden of low-energy diaphyseal femoral fractures following prolonged use of bisphosphonates. Cite this article: Bone Joint Res 2015;4:99–104 PMID:26062566

  7. Intravenous Ibandronate Rapidly Reduces Pain, Neurochemical Indices of Central Sensitization, Tumor Burden, and Skeletal Destruction in a Mouse Model of Bone Cancer

    PubMed Central

    Halvorson, Kyle G.; Sevcik, Molly A.; Ghilardi, Joseph R.; Sullivan, Lucy J.; Koewler, Nathan J.; Bauss, Frieder; Mantyh, Patrick W.

    2008-01-01

    Over half of all chronic cancer pain arises from metastases to bone and bone cancer pain is one of the most difficult of all persistent pain states to fully control. Currently, bone pain is treated primarily by opioid-based therapies, which are frequently accompanied by significant unwanted side effects. In an effort to develop non-opioid-based therapies that could rapidly attenuate tumor-induced bone pain, we examined the effect of intravenous administration of the bisphosphonate, ibandronate, in a mouse model of bone cancer pain. Following injection and confinement of green fluorescent protein-transfected murine osteolytic 2472 sarcoma cells into the marrow space of the femur of male C3H/HeJ mice, ibandronate was administered either as a single dose (300 µg/kg), at day 7 post-tumor injection, when tumor-induced bone destruction and pain were first evident, or in three consecutive doses (100 µg/kg/day) at day 7, 8 and 9 post-tumor injection. Intravenous ibandronate administered once or in three consecutive doses reduced ongoing and movement-evoked bone cancer pain-related behaviors, neurochemical markers of central sensitization, tumor burden and tumor-induced bone destruction. These results support limited clinical trials that suggest the potential of ibandronate to rapidly attenuate bone pain and illuminate the mechanisms that may be responsible for limiting pain and disease progression. PMID:18411018

  8. 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

  9. Clinical efficacy of oral risedronate therapy in Japanese patients with Paget's disease of bone.

    PubMed

    Ohara, Masaya; Imanishi, Yasuo; Nagata, Yuki; Ishii, Akira; Kobayashi, Ikue; Mori, Katsuhito; Ito, Manabu; Miki, Takami; Nishizawa, Yoshiki; Inaba, Masaaki

    2015-09-01

    Paget's disease of bone (PDB) is a chronic disorder characterized by localized bone regions with excessive bone turnover. Although oral risedronate (17.5 mg daily for 8 weeks) was recently approved in Japan, its efficacy is not well understood. We retrospectively examined the efficacy of oral risedronate in PDB patients in a clinical setting. Eleven patients whose serum alkaline phosphatase (ALP) level exceeded the upper limit of the normal range were treated. Patients whose ALP levels normalized and remained so for 12 months after therapy initiation were defined as responders. Treatment was repeated if bone pain recurred or if serum ALP levels increased at least 25% above the nadir. Six patients (55%) were responsive to the therapy. A higher prevalence of skull lesions, higher serum calcium levels at treatment initiation and antecedent treatments of bisphosphonates were predictors of resistance against the therapy. Fresh frozen serum samples obtained from some treatment sessions were evaluated for metabolic bone markers such as bone-specific ALP (BAP), type I procollagen N-terminal pro-peptide (PINP), N-treminal crosslinking telopeptide of type I collagen and C-treminal crosslinking telopeptide of type I collagen (CTX). A significant reduction of P1NP preceded that of serum ALP levels in the responders, which was followed by a similar occurrence for BAP and osteocalcin (BGP) levels. A temporary decrease in CTX levels was noted. No significant changes in markers (including ALP level) were observed in non-responder and repeat-treatment groups. P1NP levels may be more useful than ALP levels in assessing treatment efficacy. Repeat treatment effectiveness for the repeat-treatment group was limited. PMID:25319558

  10. Prevention of Bone Loss with Risedronate in Breast Cancer Survivors: A Randomized, Controlled Clinical Trial

    PubMed Central

    Greenspan, Susan L.; Vujevich, Karen T.; Brufsky, Adam; Lembersky, Barry C.; van Londen, G.J.; Jankowitz, Rachel C.; Puhalla, Shannon L.; Rastogi, Priya; Perera, Subashan

    2016-01-01

    Purpose Aromatase inhibitors (AIs), adjuvant endocrine therapy for postmenopausal women with hormone receptor positive breast cancer, are associated with bone loss and fractures. Our objectives were to determine if 1) oral bisphosphonate therapy can prevent bone loss in women on an AI and, 2) early changes in bone turnover markers (BTM) can predict later changes in bone mineral density (BMD). Methods We conducted a 2 year double-blind, placebo-controlled, randomized trial in 109 postmenopausal women with low bone mass on an aromatase inhibitor (AI-anastrozole, letrozole, or exemestane) for hormone receptor positive breast cancer. Participants were randomized to once weekly risedronate 35 mg or placebo and all received calcium plus vitamin D. The main outcome measures included BMD, BTM [carboxy-terminal collagen crosslinks (CTX) and N-terminal propeptide of type 1 procollagen (P1NP)] and safety. Results Eighty-seven percent completed 24 months. BMD increased more in the active treatment group compared to placebo with an adjusted difference at 24 months of 3.9 ± 0.7 percentage points at the spine and 3.2 ± 0.5 percentage points at the hip (both p<0.05). The adjusted difference between the active treatment and placebo groups were 0.09 ± 0.04 nmol/LBCE for CTX and 23.3 ± 4.8 µg/mL for P1NP (both p<0.05). Women with greater 12-month decreases in CTX and P1NP in the active treatment group had a greater 24-month increase in spinal BMD (p<0.05). The oral therapy was safe and well tolerated. Conclusion In postmenopausal women with low bone mass and breast cancer on an AI, the oral bisphosphonate risedronate maintained skeletal health. PMID:25792492

  11. Prevention of hypercalciuria and stone-forming propensity during prolonged bedrest by alendronate

    NASA Technical Reports Server (NTRS)

    Ruml, L. A.; Dubois, S. K.; Roberts, M. L.; Pak, C. Y.

    1995-01-01

    The bone loss and hypercalciuria induced by immobilization or the decreased gravitational forces of space are well described. Using a model of bedrest immobilization, the ability of a potent aminobisphosphonate, alendronate, to avert hypercalciuria and stone-forming propensity was tested. Sixteen male subjects participated in a randomized, placebo-controlled trial in which they received either 20 mg of alendronate or placebo 2 weeks prior to and during 3 weeks of strict bedrest. Parameters of bone and calcium metabolism and urinary crystallization of stone-forming salts were measured before and at the end of bedrest. In the placebo group, bedrest increased urinary calcium (209 +/- 47 to 267 +/- 60 mg/day, p < 0.01) and the saturation of calcium phosphate. Before bedrest, the alendronate group had a significantly lower serum calcium (8.8 +/- 0.4 vs. 9.6 +/- 0.5 mg/dl, p < 0.01) and higher serum PTH (62.4 +/- 33.1 vs. 23.1 +/- 7.5 pg/ml, p < 0.01) compared with the placebo group. Moreover, the alendronate group had a lower urinary calcium (75 +/- 41 mg/day) and saturation of calcium oxalate and calcium phosphate. These effects of alendronate were sustained during bedrest. Following bedrest in the alendronate group, urinary calcium rose to 121 +/- 50 mg/day, a value less than that in the placebo group before or during bedrest. Similarly, urinary saturation of calcium oxalate and calcium phosphate rose with bedrest in the alendronate-treated patients but remained lower than values obtained in placebo-treated patients before or during bedrest. Alendronate inhibits bone mineral loss and averts the hypercalciuria and increased propensity for the crystallization of stone-forming calcium salts which occurs during 3 weeks of strict bedrest.

  12. 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

  13. Strontium ranelate and alendronate have differing effects on distal tibia bone microstructure in women with osteoporosis

    PubMed Central

    Laroche, Michel; Krieg, Marc-Antoine; Frieling, Isolde; Thomas, Thierry; Delmas, Pierre; Felsenberg, Dieter

    2010-01-01

    The structural basis of the antifracture efficacy of strontium ranelate and alendronate is incompletely understood. We compared the effects of strontium ranelate and alendronate on distal tibia microstructure over 2 years using HR-pQCT. In this pre-planned, interim, intention-to-treat analysis at 12 months, 88 osteoporotic postmenopausal women (mean age 63.7 ± 7.4) were randomized to strontium ranelate 2 g/day or alendronate 70 mg/week in a double-placebo design. Primary endpoints were changes in microstructure. Secondary endpoints included lumbar and hip areal bone mineral density (aBMD), and bone turnover markers. This trial is registered with http://www.controlled-trials.com, number ISRCTN82719233. Baseline characteristics of the two groups were similar. Treatment with strontium ranelate was associated with increases in mean cortical thickness (CTh, 5.3%), cortical area (4.9%) and trabecular density (2.1%) (all P < 0.001, except cortical area P = 0.013). No significant changes were observed with alendronate. Between-group differences in favor of strontium ranelate were observed for CTh, cortical area, BV/TV and trabecular density (P = 0.045, 0.041, 0.048 and 0.035, respectively). aBMD increased to a similar extent with strontium ranelate and alendronate at the spine (5.7% versus 5.1%, respectively) and total hip (3.3% versus 2.2%, respectively). No significant changes were observed in remodeling markers with strontium ranelate, while suppression was observed with alendronate. Within the methodological constraints of HR-pQCT through its possible sensitivity to X-ray attenuation of different minerals, strontium ranelate had greater effects than alendronate on distal tibia cortical thickness and trabecular volumetric density. PMID:20512336

  14. Real-Life and RCT Participants: Alendronate Users Versus FITs' Trial Eligibility Criterion.

    PubMed

    Reyes, Carlen; Pottegård, Anton; Schwarz, Peter; Javaid, M Kassim; Van Staa, Tjeerd P; Cooper, Cyrus; Diez-Perez, Adolfo; Abrahamsen, Bo; Prieto-Alhambra, Daniel

    2016-09-01

    We aimed to characterize incident users of alendronate from Denmark and Spain, and investigate their eligibility for participation in the pivotal Fracture Intervention Trial (FIT). This is an international cross-sectional study, where the data were obtained from the SIDIAP database (Sistema d'Informació per al Desenvolupament de l'Investigació en Atenció Primària) from Catalonia (Spain) and the Danish Health Registries (DHR). This study included patients who were incident users of alendronate, ≥40 years old with no history of Paget's disease. Our measurements were the proportion of incident users of alendronate who were not eligible to participate in FIT. 14,316 and 21,221 subjects initiated alendronate in 2006-2007 (SIDIAP) and 2005-2006 (DHR), respectively. SIDIAP and DHR alendronate user cohorts had 2347 (16.4 %) and 5275 (24.9 %) subjects aged >80 years old, reported 9 (0.1 %) and 91 (0.4 %) diagnoses of myocardial infarction, 423 (3 %) and 368 (1.7 %) of erosive gastro-intestinal disease, 200 (1.4 %) and 1109 (5.2 %) of dyspepsia, and 349 (2.4 %) and 149 (0.7 %) of metabolic bone disease, all of which were exclusion criteria in FIT. Men [3818 (26.7 %) in SIDIAP and 3885 (18.3 %) in DHR] and glucocorticoid users [1229 (8.6 %) in SIDIAP and 4716 (22.2 %) in DHR] were also excluded from the FIT trial. Overall, 3447 (35.4 %) SIDIAP and 6228 (44.5 %) (when not considering men and glucocorticoid users) DHR of incident alendronate users would have been excluded from FIT. One in two real-life users of alendronate exhibited one or more clinical characteristics that would have led to them being excluded from the FIT trial. PMID:27099132

  15. 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

  16. One year of alendronate treatment lowers microstructural stresses associated with trabecular microdamage initiation.

    PubMed

    O'Neal, Jessica M; Diab, Tamim; Allen, Matthew R; Vidakovic, Brani; Burr, David B; Guldberg, Robert E

    2010-08-01

    Alendronate, an anti-remodeling agent, is commonly used to treat patients suffering from osteoporosis by increasing bone mineral density. Though fracture risk is lowered, an increase in microdamage accumulation has been documented in patients receiving alendronate, leading to questions about the potentially detrimental effects of remodeling suppression on the local tissue (material) properties. In this study, trabecular bone cores from the distal femur of beagle dogs treated for one year with alendronate, at doses scaled by weight to approximate osteoporotic and Paget's disease treatment doses in humans, were subjected to uniaxial compression to induce microdamage. Tissue level von Mises stresses were computed for alendronate-treated and non-treated controls using finite element analysis and correlated to microdamage morphology. Using a modified version of the Moore and Gibson classification for damage morphology, we determined that the von Mises stress for trabeculae exhibiting severe and linear microcrack patterns was decreased by approximately 25% in samples treated with alendronate compared with non-treated controls (p<0.01), whereas there was no reduction in the von Mises stress state for diffuse microdamage formation. Furthermore, an examination of the architectural and structural characteristics of damaged trabeculae demonstrated that severely damaged trabeculae were thinner, more aligned with the loading axis, and less mineralized than undamaged trabeculae in alendronate-treated samples (p<0.01). Similar relationships with damage morphology were found only with trabecular orientation in vehicle-treated control dogs. These results indicate that changes in bone's architecture and matrix properties associated with one year of alendronate administration reduce trabecular bone's ability to resist the formation of loading-induced severe and linear microcracks, both of which dissipate less energy prior to fracture than does diffuse damage. PMID:20483387

  17. Osteogenic and anti-osteoporotic effects of risedronate-added calcium phosphate silicate cement.

    PubMed

    Gong, Tianxing; Chen, Yadong; Zhang, Yixi; Zhang, Yubiao; Liu, Xinwei; Troczynski, Tom; Häfeli, Urs O

    2016-01-01

    Osteoporosis greatly impairs bone fracture restoration with bone cement because the accelerated resorption decreases the osseointegration between bone and implants. In this study, we designed a new drug delivery system based on the third generation bisphosphonate risedronate (RA) and the osteogenic calcium phosphate silicate cement (CPSC). The impact of RA on CPSC's material properties and microstructure was evaluated by different characterization methods (μCT, XRD, FTIR, SEM and gas sorption). In addition, in vitro biocompatibility of RA-added CPSC was evaluated (MTT assay, flow cytometry, real-time PCR). In an in vivo study of osteoporotic rabbits, osteoporosis- and bone resorption-related biomarkers were measured over time (ELISA) and local osteogenic and anti-osteoporotic effects investigated (x-ray, CT, histology, PCR arrays). RA decreased the setting rate and compressive strength of CPSC by impeding the hydration of calcium silicate. The overall porosity of CPSC was also decreased with RA. The RA-added CPSC was biocompatible and improved osteoblast proliferation and differentiation. The slow release of RA from CPSC reduced the prevalence of osteoporosis in rabbits and improved peri-implant bone formation and osseointegration. In conclusion, RA-containing CPSC demonstrates its potentials to improve fractural restoration under osteoporotic conditions and should be further engineered to increase its effectiveness in fractural restoration. PMID:27388334

  18. Effect of Risedronate in a Minipig Cartilage Defect Model with Allograft

    PubMed Central

    Muehleman, Carol; Li, Jun; Abe, Yumiko; Pfister, Brian; Sah, Robert L.; Phipps, Roger; Masuda, Koichi

    2010-01-01

    Cartilage/chondrocyte transplantation is frequently utilized in the repair of focal chondral defects. It has been proposed that failure of subchondral bone maintenance or restoration is a factor contributing to the failure of cartilage-forming transplants. Some studies reveal that the transplant is associated with subchondral bone resorption, often leading to deep pits beneath the presumptive cartilage repair site. Thus, the question is raised as to the utility of agents, such as bisphosphonates, to inhibit bone remodeling at the transplant site. In the present study we show that oral administration (three times weekly) of the bisphosphonate, risedronate, inhibited the subchondral bone loss deep to the cultured allogeneic graft tissue site in attempted repair of surgically created chondral defects in a minipig model. In addition, the graft tissue, characterized by type II collagen was retained in the majority of treated animals. Untreated minipigs displayed a deep bone resorption pit, beneath the graft region, filled with type I collagen tissue as determined through immunohistochemical staining. This fibrous tissue appeared well integrated with the host tissue in the majority of cases. In the transplanted cartilage region, the overall histological score for tissue quality was significantly (p<0.05) better for the treated animals which displayed better matrix staining, cell clustering, tidemark integrity, and subchondral bone integrity (p<0.05 in each category). However, the integration of allograft with host tissue did not always occur completely. Thus, bisphosphonates might be considered in clinical treatment strategies for such procedures. PMID:18925648

  19. Treatment of Osteoporosis with Antiresoptive agent, Alendronate - warrants careful follow-up

    PubMed Central

    Jain, Sumit Kumar; Roy, Shuvendu Prosad; Nagi, Onkar Nath

    2011-01-01

    Introduction: Alendronate is the most popular bisphosphonate used to prevent fragility fracture of postmenopausal osteoporosis. There is common belief among physicians that Alendronates are very safe without many side effects and they continue it for long time. Recent papers have shown that, some patients who are on this drug from a long period suffered a rare type of fracture. We are reporting a similar type of case for the first time from Indian subcontinent but with a different associated medical condition. Case presentation: A 75 years old female presented with spontaneous fracture of right femur diaphysis. She was on Alendronate for past six years. Her bone metabolic picture also revealed vitamin D insufficiency and secondary hyperparathyroidism. Conclusion: Alendronate induced atypical fracture in association with secondary hyperparathyroidism is an unusual presentation which has not been reported in any of the case reports till date as per our knowledge. This type of presentation may need future investigation both for disease pathophysiology and future outcome in this type of fracture treatment. Treatment of osteoporosis with antiresoptive agent, alendronate; warrants careful follow-up

  20. 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.

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

    SciTech Connect

    Moon, Ho-Jin; Yun, Young-Pil; Han, Choong-Wan; Kim, Min Sung; Kim, Sung Eun; Bae, Min Soo; Kim, Gyu-Tae; Choi, Yong-Suk; Hwang, Eui-Hwan; Lee, Joon Woo; Lee, Jin-Moo; Lee, Chang-Hoon; Kim, Duck-Su; Kwon, Il Keun

    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 materials 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 enhance

  2. Alendronate functionalized mesoporous hydroxyapatite nanoparticles for drug delivery

    SciTech Connect

    Li, Dongdong; Zhu, Yuntao; Liang, Zhiqiang

    2013-06-01

    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/release 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.

  3. 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

  4. 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

  5. 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

  6. Bisphosphonates: Pharmacokinetics, bioavailability, mechanisms of action, clinical applications in children, and effects on tooth development.

    PubMed

    Soares, Ana Prates; do Espírito Santo, Renan Fernandes; Line, Sérgio Roberto Peres; Pinto, Maria das Graças Farias; Santos, Pablo de Moura; Toralles, Maria Betânia Pereira; do Espírito Santo, Alexandre Ribeiro

    2016-03-01

    Bisphosphonates (BPs) avidly bind to calcium crystals and inhibit osteoclastic bone resorption, making them useful for treatment of skeletal disorders such as osteoporosis, Paget's disease, osteogenesis imperfecta and metastatic bone diseases. BPs therapeutically act by causing toxic effects on osteoclasts or interfering with specific intracellular pathways in those cells. BPs that possess nitrogen in their composition are called nitrogen-containing BPs (NBPs) and include alendronate, pamidronate, risedronate, ibandronate, and zoledronate. Simple BPs or non-NBPs do not have nitrogen in their composition, include etiodronate and clodronate, and were the first to be tested in animals and clinically used. Because BPs may be administered to pregnant women or children during deciduous and permanent teeth development, it is expected that they might disturb tooth eruption and development. A review of current literature on pharmacokinetics, bioavailability, mechanisms of action, and clinical applications of BPs in children, and their effects on tooth eruption and development is presented. PMID:26895384

  7. Healing properties of allograft from alendronate-treated animal in lumbar spine interbody cage fusion.

    PubMed

    Xue, Qingyun; Li, Haisheng; Zou, Xuenong; Bünger, Mathias; Egund, Niels; Lind, Martin; Christensen, Finn Bjarke; Bünger, Cody

    2005-04-01

    This study investigated the healing potential of allograft from bisphosphonate-treated animals in anterior lumbar spine interbody fusion. Three levels of anterior lumbar interbody fusion with Brantigan cages were performed in two groups of five landrace pigs. Empty Brantigan cages or cages filled with either autograft or allograft were located randomly at different levels. The allograft materials for the treatment group were taken from the pigs that had been fed with alendronate, 10 mg daily for 3 months. The histological fusion rate was 2/5 in alendronate-treated allograft and 3/5 in non-treated allograft. The mean bone volume was 39% and 37.2% in alendronate-treated or non-treated allograft (NS), respectively. No statistical difference was found between the same grafted cage comparing two groups. The histological fusion rate was 7/10 in all autograft cage levels and 5/10 in combined allograft cage levels. No fusion was found at all in empty cage levels. With the numbers available, no statistically significant difference was found in histological fusion between autograft and allograft applications. There was a significant difference of mean bone volume between autograft (49.2%) and empty cage (27.5%) (P<0.01). In conclusion, this study did not demonstrate different healing properties of alendronate-treated and non-treated allograft for anterior lumbar interbody fusion in pigs. PMID:15248057

  8. A drinkable formulation of alendronate: potential to increase compliance and decrease upper GI irritation

    PubMed Central

    Brandi, Maria Luisa; Black, Dennis

    2013-01-01

    Summary Osteoporosis is a growing public health problem and several drugs have been developed in the past two decades to offer pharmacological solutions both in prevention and in therapy. Alendronate was the first compound registered as an anti-fracture agent and also the most prescribed drug worldwide for osteoporosis. Patient compliance is a major problem with alendronate, with studies demonstrating that 50–60% of patients discontinue treatment within one year. Dysphagia and swallowing difficulties are common especially among elderly people and the perceived potential for upper GI problems is a barrier to good long-term adherence. As non-persistence and non-compliance are linked to increased risk of fractures, efforts have been made to develop forms of alendronate which are more acceptable to patients. Among these, the drinkable formulations have the potential great convenience, simplicity of administration and reduction in gastro-intestinal side effects. In addition these novel soluble products are equivalent in cost to generic alendronate tablets. The approaches to improve adherence to an old and effective medication for osteoporotic patients will be reviewed in this report, with a special focus on the recently marketed product Bonasol 70 mg oral solution. PMID:24554929

  9. 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

  10. Alendronate prevents glucocorticoid-induced osteoporosis in patients with rheumatic diseases: A meta-analysis.

    PubMed

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

    2016-06-01

    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 lumbar spine, total hip, and

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

    PubMed Central

    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

    2013-01-01

    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. Results 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. Conclusion 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. PMID:26909285

  12. Bioabsorbable bone plates enabled with local, sustained delivery of alendronate for bone regeneration.

    PubMed

    Hur, Woojune; Park, Min; Lee, Jae Yeon; Kim, Myung Hun; Lee, Seung Ho; Park, Chun Gwon; Kim, Se-Na; Min, Hye Sook; Min, Hye Jeong; Chai, Jin Ho; Lee, Sang Jeong; Kim, Sukwha; Choi, Tae Hyun; Choy, Young Bin

    2016-01-28

    We prepared a bone plate enabled with the local, sustained release of alendronate, which is a drug known to inhibit osteoclast-mediated bone resorption and also expedite the bone-remodeling activity of osteoblasts. For this, we coated a bone plate already in clinical use (PLT-1031, Inion, Finland) with a blend of alendronate and a biocompatible polymer, azidobenzoic acid-modified chitosan (i.e., Az-CH) photo-crosslinked by UV irradiation. As we performed the in vitro drug release study, the drug was released from the coating at an average rate of 4.03μg/day for 63days in a sustained manner. To examine the effect on bone regeneration, the plate was fixed on an 8mm cranial critical size defect in living rats and the newly formed bone volume was quantitatively evaluated by micro-computed tomography (micro-CT) at scheduled times over 8weeks. At week 8, the group implanted with the plate enabled with sustained delivery of alendronate showed a significantly higher volume of newly formed bone (52.78±6.84%) than the groups implanted with the plates without drug (23.6±3.81%) (p<0.05). The plate enabled with alendronate delivery also exhibited good biocompatibility on H&E staining, which was comparable to the Inion plate already in clinical use. Therefore, we suggest that a bone plate enabled with local, sustained delivery of alendronate can be a promising system with the combined functionality of bone fixation and its expedited repair. PMID:26682503

  13. 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

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

    PubMed

    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 (99m)technetium-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 (99m)technetium-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

  15. Effects of risedronate on femoral bone mineral density and bone strength in sciatic neurectomized young rats.

    PubMed

    Iwamoto, Jun; Seki, Azusa; Takeda, Tsuyoshi; Sato, Yoshihiro; Yamada, Harumoto

    2005-01-01

    Immobilization induces a rapid loss of bone density and bone strength in rats. The purpose of the present study was to examine the effects of risedronate (Ris) on the femoral bone density and bone strength of sciatic neurectomized young rats. Forty male Sprague-Dawley rats, 6 weeks of age, were randomized by the stratified weight method into the following four treatment groups of 10 rats each: sham-operation, bilateral sciatic neurectomy (NX), NX + low-dose Ris (0.25 mg/kg/day, orally), and NX + high-dose Ris (0.5 mg/kg/day, orally). After 8 weeks of feeding, the volumetric bone mineral density (vBMD) and stress strain index (SSI) of the femoral distal metaphysis and middiaphysis of the rats were measured by peripheral quantitative computed tomography. The mechanical properties of the femoral distal metaphysis and middiaphysis were measured by the compression and three-point bending tests, respectively. The femoral length was also measured. As compared with the findings in the sham-operated controls, NX resulted in a loss of femoral length, cancellous vBMD, SSI, maximum load, stiffness, and breaking energy of the femoral distal metaphysis; there was also loss of cortical thickness, SSI, maximum load, and stiffness of the femoral middiaphysis, with no significant effects on the cortical vBMD or breaking energy of the femoral middiaphysis. High-dose Ris increased the vBMD to values higher than those in the sham-operated controls, and prevented the loss of SSI, maximum load, and stiffness of the femoral distal metaphysis, while low-dose Ris prevented the loss of cancellous vBMD of the femoral distal metaphysis. Neither high- nor low-dose Ris affected any of the cortical bone parameters of the femoral middiaphysis, except for cortical thickness, or the femoral length. These findings suggest that Ris may prevent immobilization-induced loss of cancellous bone density and bone strength in a dose-dependent manner without interfering with bone growth, but has no apparent

  16. 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

  17. Long-term Risedronate Treatment Normalizes Mineralization and Continues to Preserve Trabecular Architecture: Sequential Triple Biopsy Studies with Micro-Computed Tomography

    SciTech Connect

    Borah,B.; Dufresne, T.; Ritman, E.; Jorgensen, S.; Liu, S.; Chmielewski, P.; Phipps, R.; Zhou, X.; Sibonga, J.; Turner, R.

    2006-01-01

    The objective of the study was to assess the time course of changes in bone mineralization and architecture using sequential triple biopsies from women with postmenopausal osteoporosis (PMO) who received long-term treatment with risedronate. Transiliac biopsies were obtained from the same subjects (n = 7) at baseline and after 3 and 5 years of treatment with 5 mg daily risedronate. Mineralization was measured using 3-dimensional (3D) micro-computed tomography (CT) with synchrotron radiation and was compared to levels in healthy premenopausal women (n = 12). Compared to the untreated PMO women at baseline, the premenopausal women had higher average mineralization (Avg-MIN) and peak mineralization (Peak-MIN) by 5.8% (P = 0.003) and 8.0% (P = 0.003), respectively, and lower ratio of low to high-mineralized bone volume (BMR-V) and surface area (BMR-S) by 73.3% (P = 0.005) and 61.7% (P = 0.003), respectively. Relative to baseline, 3 years of risedronate treatment significantly increased Avg-MIN (4.9 {+-} 1.1%, P = 0.016) and Peak-MIN (6.2 {+-} 1.5%, P = 0.016), and significantly decreased BMR-V (-68.4 {+-} 7.3%, P = 0.016) and BMR-S (-50.2 {+-} 5.7%, P = 0.016) in the PMO women. The changes were maintained at the same level when treatment was continued up to 5 years. These results are consistent with the significant reduction of turnover observed after 3 years of treatment and which was similarly maintained through 5 years of treatment. Risedronate restored the degree of mineralization and the ratios of low- to high-mineralized bone to premenopausal levels after 3 years of treatment, suggesting that treatment reduced bone turnover in PMO women to healthy premenopausal levels. Conventional micro-CT analysis further demonstrated that bone volume (BV/TV) and trabecular architecture did not change from baseline up to 5 years of treatment, suggesting that risedronate provided long-term preservation of trabecular architecture in the PMO women. Overall, risedronate provided

  18. Phase I clinical study to select a novel oral formulation for ibandronate containing the excipient sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC).

    PubMed

    Bittner, B; McIntyre, C; Tian, H; Tang, K; Shah, N; Phuapradit, W; Ahmed, H; Chokshi, H; Infeld, M; Fotaki, N; Ma, H; Portron, A; Jordan, P; Schmidt, J

    2012-03-01

    The aim of this study was to select a novel oral formulation for ibandronate (IBN, CAS number: 13892619). In four cohorts of 28, 21, 19 and 29 healthy volunteers, the impact of the carrier molecule sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC, CAS number: 203787-91-1) on the bioavailability of IBN was investigated. Within each cohort different oral formulations with one dose of ibandronate (30 mg) and three different ratios of IBN:SNAC (1:5, 1:10 and 1:20) were compared to the approved oral IBN tablet formulations (150 and 50 mg IBN) in a 4-way cross-over design and a one week washout between the administrations. The highest mean IBN exposure was achieved with a capsule formulation containing drug-coated beadlets and an IBN:SNAC ratio of 1:5. AUC(last) and C(max) of IBN were approximately 1.3- and 2.2-fold higher compared to the reference treatment (150 mg IBN without SNAC). Increasing the post-dose fasting duration from 15 to 30 min resulted in a more than 2-fold increase in AUC(last), while superimposable IBN serum concentration-time profiles were achieved after a 30 and 60 min fast. The tolerability of the IBN/SNAC treatments in all cohorts was similar to that in the IBN reference groups and most adverse events (AEs) were of mild to moderate intensity. PMID:22530305

  19. 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

  20. Tumor necrosis factor receptor-associated periodic syndrome managed with the couple canakinumab-alendronate.

    PubMed

    Lopalco, Giuseppe; Rigante, Donato; Vitale, Antonio; Frediani, Bruno; Iannone, Florenzo; Cantarini, Luca

    2015-04-01

    Management of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is puzzling, and therapeutic choices can be complicated, due to both wide genetic heterogeneity and protean clinical phenotype. We report on a 35-year-old female who was diagnosed with TRAPS, after finding the V95M mutation on the TNFRSF1A gene; who was treated in order with etanercept, anakinra, and canakinumab (150 mg/every 8 weeks by subcutaneous injection, then increased to 150 mg every 4 weeks); and who started therapy with oral alendronate (70 mg/weekly) to control her osteoporosis. Alendronate combined with canakinumab led to the optimal clinical control of all TRAPS manifestations and normalization of inflammatory markers. Further studies should be performed to clarify bisphosphonates' role in the scenery of autoinflammatory disorders. PMID:24609716

  1. 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.

  2. The cost-effectiveness of alendronate in the management of osteoporosis.

    PubMed

    Kanis, John A; Adams, Judith; Borgström, Fred; Cooper, Cyrus; Jönsson, Bengt; Preedy, Danielle; Selby, Peter; Compston, Juliet

    2008-01-01

    The National Institute for Health and Clinical Excellence (NICE) in the UK has recently issued health economic appraisals for the primary and secondary prevention of osteoporotic fracture that are more restrictive than previous guidelines for the management of osteoporosis despite a marked reduction of the cost of intervention. The aim of the present study was to examine the cost-effectiveness of the bisphosphonate, alendronate for the prevention and treatment of fractures associated with osteoporosis. A second aim was to investigate reasons for any disparities in cost-effectiveness between our findings and the NICE appraisals. We compared the effects of alendronate 70 mg weekly by mouth for 5 years with no treatment in postmenopausal women with clinical risk factors for fracture and computed the incremental cost-effectiveness ratio (ICER) using a lifetime simulation model based on Markov cohort methodology. A sensitivity analysis examined other common interventions. Using a threshold of pound sterling 30,000 and pound sterling 20,000 per quality of life-year (QALY) gained to determine cost-effectiveness, alendronate was cost-effective for the primary prevention of fracture in women with osteoporosis irrespective of age as was treatment of women with a prior fragility fracture irrespective of BMD. Cost-effective scenarios were also found in women with strong risk factors for fracture with a bone mineral density value above the threshold for osteoporosis. The results were robust over reasonable assumptions in sensitivity analysis. We conclude that alendronate is a cost-effective agent for the prevention and treatment of fractures associated with osteoporosis. These findings, suitable for informing practice guidance, contrast with recent appraisals from NICE. PMID:18156107

  3. Effect of alendronate on endochondral ossification in mandibular condyles of growing rats

    PubMed Central

    Bradaschia-Correa, V.; Barrence, F.A.C.; Ferreira, L.B.; Massa, L.F.; Arana-Chavez, V.E.

    2012-01-01

    The replacement of the calcified cartilage by bone tissue during the endochondral ossification of the mandibular condyle is dependent of the resorbing activity of osteoclats. After partial resorption, calcified cartilage septa are covered by a primary bone matrix secreted by osteoblasts. Osteoadherin (OSAD) is a small proteoglycan present in bone matrix but absent in cartilage during the endochondral ossification. The aim of this study was to analyze the effect of alendronate, a drug known to inhibit bone resorption by osteoclasts, on the endochondral ossification of the mandibular condyle of young rats, by evaluating the distribution of osteoclasts and the presence of OSAD in the bone matrix deposited. Wistar newborn rats (n=45) received daily injections of alendronate (n=27) or sterile saline solution as control (n=18) from the day of birth until the ages of 4, 14 and 30 days. At the days mentioned, the mandibular condyles were collected and processed for transmission electron microscopy analysis. Specimens were also submitted to tartrate resistant acid phosphatase (TRAP) histochemistry and ultrastructural immunodetection of OSAD. Alendronate treatment did not impede the recruitment and fusion of osteoclasts at the ossification zone during condyle growth, but they presented inactivated phenotype. The trabeculae at the ossification area consisted of cartilage matrix covered by a layer of primary bone matrix that was immunopositive to OSAD at all time points studied. Apparently, alendronate impeded the removal of calcified cartilage and maturation of bone trabeculae in the mandibular ramus, while in controls they occurred normally. These findings highlight for giving attention to the potential side-effects of bisphosphonates administered to young patients once it may represent a risk of disturbing maxillofacial development. PMID:22688305

  4. Alendronate, a double-edged sword acting in the mevalonate pathway

    PubMed Central

    TRICARICO, PAOLA MAURA; GIRARDELLI, MARTINA; KLEINER, GIULIO; KNOWLES, ALESSANDRA; VALENCIC, ERICA; CROVELLA, SERGIO; MARCUZZI, ANNALISA

    2015-01-01

    Aminobisphosphonate aledronate is a compound commonly used clinically for the treatment of osteoporosis and other bone diseases, as a result of it preventing bone resorption. However, in previous years it has also been used to obtain cellular and animal models of a rare genetic disorder termed Mevalonate Kinase Deficiency (MKD). MKD is caused by mutations affecting the mevalonate kinase enzyme, in the cholesterol pathway and alendronate can be used to biochemically mimic the genetic defect as it inhibits farnesyl pyrophosphate synthase in the same pathway. Despite evidence in favor of the inhibition exerted on the mevalonate pathway, there is at least one clinical case of MKD in which alendronate improved not only skeletal and bone fractures, as expected, but also MKD clinical features. Based on this finding, the present study assessed the anti-inflammatory properties of this aminobisphosphonate in vitro. No anti-inflammatory effects of alendronate were observed in the in vitro experiments. Since MKD lacks specific treatments, these results may assist scientists and physicians in making the decision as to the most suitable choice of therapeutic compounds for this neglected disease. PMID:26096667

  5. 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

  6. Effects of Alendronate Sodium Content on the Interface Strengths of Composite Acrylic Bone Cement

    PubMed Central

    Song, De-Ye; Mao, Xin-Zhan; Ding, Mu-liang; Ni, Jiang-Dong

    2015-01-01

    Objective. Aim to study how the content of alendronate affected shear strengths at bone-bone cement-metal interfaces. Methods. All samples were divided into 6 groups, G0–G5. On the 1st and 60th day after surgery, bone-bone cement interface shear strengths and bone densities were examined. Interface strengths of metal-bone cement specimens were studied before immersion and 4 weeks after immersion. Results. On the 60th day, bone-bone cement interface shear strengths and bone densities showed significant differences (P < 0.05), and compared with G0, G2–G5 values increased significantly (P < 0.05), and the peak value was met in G3. Compared with the 1st day, on the 60th postoperative day both factors decreased significantly in G0 and G1 (P < 0.05). Four weeks after immersion, with the increasing dose of alendronate, the shear strengths decreased gradually and in G5 decreased significantly (P < 0.05). Compared with before immersion, the metal-bone cement interface strengths decreased significantly 4 weeks after immersion (P < 0.05). Conclusions. 50–500 mg alendronate in 50 g cement powders could prevent the decrease of shear strengths at bone-bone cement interfaces and had no effect on metal-bone cement interface strengths. While the addition dose was 100 mg, bone cement showed the best strengths. PMID:26273299

  7. 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.

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

    PubMed Central

    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

    2015-01-01

    Aim: 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. Methods: 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. Results: 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. Conclusion: 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. PMID:26051110

  9. Persistence with osteoporosis medication among newly-treated osteoporotic patients.

    PubMed

    van Boven, Job F M; de Boer, Pieter T; Postma, Maarten J; Vegter, Stefan

    2013-09-01

    Low persistence with osteoporosis medication is associated with higher fracture risk. Previous studies estimated that 1-year persistence with osteoporosis medication is low. Our aim was to study persistence with osteoporosis medication among patients with long-term follow-up (to 5 years). The InterAction Database (IADB) was used to analyze persistence of 8610 Dutch patients initiating osteoporosis drugs between 2003 and 2011. Drugs under study were alendronate, risedronate, ibandronate, etidronate, raloxifene and strontium ranelate. Cumulative persistence rates were calculated after different time frames (3 months-5 years) using survival analysis. Multivariate Cox proportional hazard analyses were used to identify determinants of non-persistence. Furthermore, switching rates of persistent patients who initiated bisphosphonate therapy were analyzed. Persistence with osteoporosis therapy was 70.7 % (95 % CI, 69.7-71.7), 58.5 % (95 % CI, 57.4-59.6 %), 25.3 % (95 % CI, 24.1-26.5) after 6 months, 1 and 5 years, respectively. Determinants associated with higher risk to non-persistence within the first year were daily dosing regimen [HR, 1.76 (95 % CI, 1.46-2.14)], age <60 years [HR, 1.26 (95 % CI, 1.19-1.34)] and use of glucocorticoids [HR, 1.16 (95 % CI, 1.07-1.26)]. Monthly dosing schedule and use of generic brands of alendronate did not show a significant association with non-persistence. Approximately 4.0 % of patients initiating therapy with weekly alendronate or weekly risedronate switched therapy. Persistence with osteoporosis medication is low. Because low persistence is strongly associated with higher fracture risk, interventions to improve persistence are recommended. This study identified several patient groups in whom such interventions may be most relevant. PMID:23575910

  10. Effects of long-term alendronate treatment on bone mineralisation, resorption parameters and biomechanics of single human vertebral trabeculae.

    PubMed

    Krause, M; Soltau, M; Zimmermann, E A; Hahn, M; Kornet, J; Hapfelmeier, A; Breer, S; Morlock, M; Wulff, B; Püschel, K; Glueer, C-C; Amling, M; Busse, B

    2014-01-01

    Due to their well-established fracture risk reduction, bisphosphonates are the most frequently used therapeutic agent to treat osteoporosis. Bisphosphonates reduce fracture risk by suppressing bone resorption, but the lower bone turnover could have a negative impact on bone quality at the tissue level. Here, we directly assess the structural and mechanical characteristics of cancellous bone from the lumbar vertebrae (L5) in non-treated osteoporotic controls (n=21), mid-term alendronate-treated osteoporotic patients (n=6), and long-term alendronate-treated osteoporotic patients (n=7). The strength and toughness of single trabeculae were evaluated, while the structure was characterised through measurements of microdamage accumulation, mineralisation distribution, and histological indices. The alendronate-treated cases had a reduced eroded surface (ES/BS, p<0.001) and a higher bone mineralisation in comparison to non-treated controls (p=0.037), which is indicative of low turnover associated with treatment. However, the amount of microdamage and the mechanical properties were similar among the control and treatment groups. As the tissue mineral density (TMD) increased significantly with alendronate treatment compared to non-treated osteoporotic controls, the reduction in resorption cavities could counterbalance the higher TMD allowing the alendronate-treated bone to maintain its mechanical properties and resist microdamage accumulation. A multivariate analysis of the possible predictors supports the theory that multiple factors (e.g., body mass index, TMD, and ES/BS) can impact the mechanical properties. Our results suggest that long-term alendronate treatment shows no adverse impact on mechanical cancellous bone characteristics. PMID:25241965

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

    PubMed

    Moon, Ho-Jin; Yun, Young-Pil; Han, Choong-Wan; Kim, Min Sung; Kim, Sung Eun; Bae, Min Soo; Kim, Gyu-Tae; Choi, Yong-Suk; Hwang, Eui-Hwan; Lee, Joon Woo; Lee, Jin-Moo; Lee, Chang-Hoon; Kim, Duck-Su; Kwon, Il Keun

    2011-09-23

    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 materials 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 enhance osteoblast differentiation and to inhibit osteoclast differentiation simultaneously. PMID:21888898

  12. Revisiting bone targeting potential of novel hydroxyapatite based surface modified PLGA nanoparticles of risedronate: Pharmacokinetic and biochemical assessment.

    PubMed

    Rawat, Purnima; Ahmad, Iqbal; Thomas, Shindu C; Pandey, Shweta; Vohora, Divya; Gupta, Sarika; Ahmad, Farhan Jalees; Talegaonkar, Sushama

    2016-06-15

    Hydroxyapatite based biodegradable mPEG-PLGA nanoparticles of risedronate (mPEG-PLGA-RIS-HA) were prepared by water miscible dialysis method for synergistic treatment of osteoporosis. The bone targeting potential of prepared nanoparticles was evaluated by performing the cell viability study and protein estimation in pre-osteoblast cell line (MC3T3E1). Biochemical and in-vivo pharmacokinetic studies on osteoporotic rat model treated with different formulations were performed. Under the biochemical study ALP, TRAP, HxP and Calcium levels were determined. Osteoporotic model treated with prepared nanoparticles indicated significant effect on bone. Pharmacokinetic studies revealed 6-fold and 4-fold increase in the relative bioavailability after intravenous and oral administration of nanoparticles respectively as compared to marketed formulation confirming better effective drug transport. Biochemical investigations also showed a significant change in biomarker level which ultimately lead to bone formation/resorption. A stability analysis has also been carried out according to ICH guidelines (Q1AR2) and shelf life was found to be 1year and 4 months for the prepared formulation. Thus the results of present studies indicated that mPEG-PLGA-RIS-HA NPs has a great potential for sustained delivery of RIS for the treatment and prevention of osteoporosis and to minimize the adverse effects of RIS typically induced by its oral administration. PMID:27113864

  13. Simultaneous, bilateral, complete atypical femoral fractures after long-term alendronate use.

    PubMed

    Higgins, Mark; Morgan-John, Sam; Badhe, Sachin

    2016-12-01

    Over the past decade there have been increasing reports of atypical femoral fractures (AFFs) associated with bisphosphonate use. Reported cases of bilateral involvement usually refer to sequential injuries, or a complete fracture with an incomplete injury to the contralateral limb. In this case report we describe simultaneous, bilateral, complete atypical femoral fractures following a simple fall. A history of prodromal pain, previous radiological evidence of cortical thickening and long term alendronate therapy for osteoporosis secondary to corticosteroid treatment paint a classical picture of the presentation of an atypical fracture pattern of which orthopaedic surgeons should be aware. PMID:27570414

  14. Fracture Prediction After Discontinuation of 4 to 5 Years of Alendronate Therapy

    PubMed Central

    Bauer, Douglas C.; Schwartz, Ann; Palermo, Lisa; Cauley, Jane; Hochberg, Marc; Santora, Art; Cummings, Steven R.; Black, Dennis M.

    2015-01-01

    IMPORTANCE Discontinuation of bisphosphonate therapy after 3 to 5 years is increasingly considered, but methods to monitor fracture risk after discontinuation have not been established. OBJECTIVE To test methods of predicting fracture risk among women who have discontinued alendronate therapy after 4 to 5 years. DESIGN, SETTING, AND PARTICIPANTS The prospective Fracture Intervention Trial Long-term Extension (FLEX) study randomized postmenopausal women aged 61 to 86 years previously treated with 4 to 5 years of alendronate therapy to 5 more years of alendronate or placebo from 1998 through 2003; the present analysis includes only the placebo group. Hip and spine dual-energy x-ray absorptiometry (DXA) were measured when placebo was begun (FLEX baseline) and after 1 to 3 years of follow-up. Two biochemical markers of bone turnover, urinary type 1 collagen cross-linked N-telopeptide (NTX) and serum bone-specific alkaline phosphatase (BAP), were measured at FLEX baseline and after 1 and 3 years. MAIN OUTCOMES AND MEASURES Symptomatic spine and nonspine fractures occurring after the follow-up measurement of DXA or bone turnover. RESULTS During 5 years of placebo, 94 of 437 women (22%) experienced 1 or more symptomatic fractures; 82 had fractures after 1 year. One-year changes in hip DXA, NTX, and BAP were not related to subsequent fracture risk, but older age and lower hip DXA at time of discontinuation were significantly related to increased fracture risk (lowest tertile of baseline femoral neck DXA vs other 2 tertiles relative hazard ratio, 2.17 [95%CI, 1.38–3.41]; total hip DXA relative hazard ratio, 1.87 [95%CI, 1.20–2.92]). CONCLUSIONS AND RELEVANCE Among postmenopausal women who discontinue alendronate therapy after 4 to 5 years, age and hip BMD at discontinuation predict clinical fractures during the subsequent 5 years. Follow-up measurements of DXA 1 year after discontinuation and of BAP or NTX 1 to 2 years after discontinuation are not associated with

  15. 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

    SciTech Connect

    Choo, Richard; Lukka, Himu; Cheung, Patrick; Corbett, Tom; Briones-Urbina, Rosario; Vieth, Reinhold; Ehrlich, Lisa; Kiss, Alex; Danjoux, Cyril

    2013-04-01

    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 > −2.5 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.

  16. 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

  17. Comparative effects of teriparatide and risedronate in glucocorticoid-induced osteoporosis in men: 18-month results of the EuroGIOPs trial.

    PubMed

    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

    2013-06-01

    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

  18. Suppression of CYP2B Induction by Alendronate-Mediated Farnesyl Diphosphate Synthase Inhibition in Primary Cultured Rat Hepatocytes

    PubMed Central

    Jackson, Nancy M.; Kocarek, Thomas A.

    2008-01-01

    We previously reported that squalestatin 1-mediated induction of CYP2B expression is attributable to squalene synthase inhibition and accumulation of an endogenous isoprenoid(s) that is capable of activating the constitutive androstane receptor. To determine whether squalestatin 1-mediated CYP2B induction is strictly dependent upon the biosynthesis of farnesyl pyrophosphate (FPP), the substrate for squalene synthase, the effects of alendronate, a nitrogen-containing bisphosphonate inhibitor of farnesyl diphosphate synthase, were determined on basal, squalestatin 1-inducible, and phenobarbital-inducible CYP2B expression in primary cultured rat hepatocytes. Alendronate treatment alone had no effect on CYP2B or CYP3A mRNA expression in the hepatocyte cultures, but alendronate co-treatment completely suppressed squalestatin 1-mediated CYP2B mRNA induction at concentrations (60 and 100 μM) that effectively inhibited cellular farnesyl diphosphate synthase activity, as assessed by reductions of squalestatin 1-mediated FPP accumulation, and that were not toxic to the cells, as indicated by a lack of effect on MTT activity. Alendronate co-treatment also partially suppressed phenobarbital-inducible CYP2B expression, and this suppressive effect was attenuated by additional co-treatment with the upstream pathway inhibitor, pravastatin. These findings demonstrate that squalestatin 1-mediated CYP2B induction cannot occur in the absence of FPP biosynthesis, but also indicate that one or more upstream isoprenoids, possibly isopentenyl pyrophosphate and/or dimethylallyl pyrophosphate, function to antagonize the CYP2B induction process. PMID:18617600

  19. Systemically alendronate was incorporated into dental tissues but did not cause morphological or mechanical changes in rats teeth.

    PubMed

    Nelson-Filho, Paulo; Lucisano, Marília Pacífico; Da Silva, Raquel Assed Bezerra; Da Silva, Roberto Santana; Serra, Mônica Campos; Gerlach, Raquel Fernanda; Neto, Francisco Carlos Rehder; Carneiro, Zumira Aparecida; Zamarioli, Ariane; Morse, Leslie; Battaglino, Ricardo

    2012-09-01

    This study evaluated the effect of the systemic use of sodium alendronate in rats in vivo. Forty-five Wistar rats aged 36 to 42 days and weighing 200 to 230 g were randomly assigned to a control group (n = 20), which received distilled water, and an experimental group (n = 25), which received 2 weekly doses of 1 mg/kg of chemically pure sodium alendronate. The animals were killed after 60 days of treatment. The tibias were removed for analysis of bone mineral density by dual-energy X-ray absorptiometry (DXA). Then, the maxillary incisors were extracted for analysis of the mineralized dental tissues using fluorescence spectroscopy (FS), scanning electron microscopy (SEM), bright field microscopy (BFM), and cross-sectional microhardness (CSMH) testing. DXA and CSMH data were subjected to statistical analysis by Kruskal-Wallis test (5% significance level). The experimental group presented higher bone mineral density than the control group by DXA. FS analysis revealed presence of alendronate in the mineralized dental tissues of the specimens of the experimental group. Significant morphological differences were not found by SEM and BFM. Enamel and dentin (100 and 300 μm from the dentinoenamel junction) CSMH data did not show significant difference between the control and experimental groups. Based on the obtained results, we conclude that while alendronate increased the bone mineral density and was incorporated into the mineralized dental tissues it did not cause significant alterations in the morphology and microhardness of rat incisor enamel and dentin. PMID:22508272

  20. 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. PMID:26445021

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

    SciTech Connect

    Deng Xue; Tamai, Riyoko; Endo, Yasuo; Kiyoura, Yusuke

    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, a 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.

  2. 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

    2015-01-01

    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. PMID:25757189

  3. Alendronate decorated nano hydroxyapatite in mesoporous silica: Cytotoxicity and osteogenic properties

    NASA Astrophysics Data System (ADS)

    Huang, Wei; Liu, Weiqiang; She, Zhending; Wu, Hongkai; Shi, Xuetao

    2011-09-01

    Mesoporous silica is a promising drug delivery vehicle due to its large surface area and order porous structure. Hydroxyapatite-modified mesoporous silica materials (MSH) have been developed, and the cytotoxicity of MSH and unmodified mesoporous silica (HMS) has also been studied in this work. The results indicated that MSH exhibited lower cytotoxicity than HMS. The drug release property of MSH was also investigated in this paper. Alendronate (AL) was laden into MSH and HMS, respectively. MSH exhibited long release period lasting over 30 days with a weak burst release in the first 5 days; however, the AL release period of HMS was just 5 days with a remarkable burst release. In addition, the osteogenic commitment induced in human marrow mesenchymal stem cells (MSCs) by MSH-alendronate (MSH-AL) was also investigated, and the osteogenesis of MSCs was evaluated by alkaline phosphatase (ALP) assay. The osteogenesis of MSCs induced by MSH-AL is comparable to that induced by the osteogenic medium. Taken together, MSH can be severed as potential bone repair materials with lower cytotoxicity.

  4. 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

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

    PubMed

    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

  6. An NMR Metabolomic Study on the Effect of Alendronate in Ovariectomized Mice

    PubMed Central

    Chen, Shin-Yu; Yu, Hui-Tzu; Kao, Ju-Po; Yang, Chung-Chun; Chiang, Shen-Shih; Mishchuk, Darya O.; Mau, Jeng-Leun; Slupsky, Carolyn M.

    2014-01-01

    Alendronate sodium (Fosamax) is most widely used for the prevention and treatment of osteoporosis. It is a type of anti-resorptive agent that reduces the risk of fractures by changing bone turnover and bone mineral density. We investigated the effect of Fosamax on a mouse model of osteoporosis. Twenty-seven female C57BL/6JNarl mice were divided into three groups: sham, ovariectomized (OVX) and OVX + Fosamax (Fosamax). After 23 weeks, bone density of femurs was analyzed using microcomputed tomography (micro-CT), and serum was analyzed for osteoblast and osteoclast activity, as well as metabolites using nuclear magnetic resonance (NMR) spectroscopy. Fosamax increased bone mineral density and cortical bone thickness, and decreased osteoblast activity slightly. Fosamax did not significantly change osteoclast activity. Serum metabolomics revealed that Fosamax had profound effects on overall metabolism, as significantly higher concentrations of metabolites associated with energy metabolism (including TCA-cycle intermediates and glucose), 3-hydroxybutyrate, taurine, allantoin, acetate, and ethanol, as well as lower concentrations of aspartate were observed in the Fosamax-treated mice compared with the OVX mice. These results suggest that alendronate may work by increasing bone density through altered metabolic activity. PMID:25184758

  7. Differential effects of statins and alendronate on cholinesterases in serum and brain of rats.

    PubMed

    Cibicková, L; Palicka, V; Cibicek, N; Cermáková, E; Micuda, S; Bartosová, L; Jun, D

    2007-01-01

    Acetylcholinesterase (AChE) inhibitors represent standard treatment of Alzheimer's disease. Cholesterol plays an important role in Alzheimer's disease development. Because cholesterol synthesis may be inhibited by statins or bisphosphonates, we hypothesized that these drugs might possibly have an influence on cholinesterases. Moreover, we also evaluated if the cholesterol-lowering agents that cross the blood-brain barrier (e.g. simvastatin) should be more effective than those which do not (e.g. atorvastatin). Four groups of rats were orally administered simvastatin, atorvastatin, alendronate or vehicle for seven days. Thereafter, blood samples were taken and the basal ganglia, septum, frontal cortex, and hippocampus were isolated from brains for measurement of acetylcholinesterase activity. In the blood, activities of neither acetyl- nor butyrylcholinesterase were influenced by any of the applied drugs. In the brain, no significant changes in AChE activity were observed after administration of atorvastatin. Both simvastatin and alendronate significantly suppressed the activity of AChE in the frontal cortex. In conclusion, our results confirmed the hypothesis that cholesterol-modifying drugs modulate AChE activity and it is more reasonable to use a blood-brain barrier penetrating drug. PMID:17087598

  8. 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.

  9. A sensitive post-column photochemical derivatization/fluorimetric detection system for HPLC determination of bisphosphonates.

    PubMed

    Pérez-Ruiz, Tomás; Martínez-Lozano, Carmen; García-Martínez, María Dolores

    2009-02-27

    A new reversed-phase ion-pair high-performance liquid chromatographic (HPLC) method has been developed for the determination of the following bisphosphonic acids: alendronic acid (ALEN), etidronic acid (ETID), ibandronic acid (IBAN) and risedronic acid (RISE). Separation was achieved on a C(18) column using a mixture of 50 mmol L(-1) borate buffer pH 9.0 containing 0.25 mmol L(-1) tetrabutylammonium chloride and 0.5 mmol L(-1) EDTA and acetonitrile (97:3) as the mobile phase. The sensitive detection of the above bisphosphonic acids was based on their oxidation to orthophosphate by the on-line peroxydisulfate-assisted photolysis followed by post-column reaction with molybdate to yield phosphomolybdate. This subsequently reacted with thiamine to generate thiochrome and, finally, the fluorescence of thiochrome was measured at 440 nm with excitation at 375 nm. The developed method is precise with a mean relative standard deviation of 1.3%, sensitive (with a detection limit at the nmol L(-1) level), accurate, specific, rapid (analysis time approximately 13 min) and inexpensive because to the low cost of the reagents. The assay was applied to the analysis of the four bisphosphonic acids in commercial dosage formulations, in which the excipients did not interfere with the determination. The method was also applied to the determination of etidronate, risedronate and ibandronate in human urine. Sample preparation involves precipitation of the analytes from urine along with endogenous phosphates such as calcium salts by addition of calcium chloride at alkaline pH and dissolution of the precipitate in 0.05 mol L(-1) ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. PMID:19150069

  10. Enteric-coated tablet of risedronate sodium in combination with phytic acid, a natural chelating agent, for improved oral bioavailability.

    PubMed

    Kim, Jeong S; Jang, Sun W; Son, Miwon; Kim, Byoung M; Kang, Myung J

    2016-01-20

    The oral bioavailability (BA) of risedronate sodium (RS), an antiresorptive agent, is less than 1% due to its low membrane permeability as well as the formation of non-absorbable complexes with multivalent cations such as calcium ion (Ca(2+)) in the gastrointestinal tract. In the present study, to increase oral BA of the bisphosphonate, a novel enteric-coated tablet (ECT) dosage form of RS in combination with phytic acid (IP6), a natural chelating agent recognized as safe, was formulated. The chelating behavior of IP6 against Ca(2+), including a stability constant for complex formulation was characterized using the continuous variation method. Subsequently, in vitro dissolution profile and in vivo pharmacokinetic profile of the novel ECT were evaluated comparatively with that of the marketed product (Altevia, Sanofi, US), an ECT containing ethylenediaminetetraacetic acid (EDTA) as a chelating agent, in beagle dogs. The logarithm of stability constant for Ca(2+)-IP6 complex, an equilibrium constant approximating the strength of the interaction between two chemicals to form complex, was 19.05, which was 3.9-fold (p<0.05) and 1.7-fold (p<0.05) higher than those of Ca(2+)-RS and Ca(2+)-EDTA complexes. The release profile of RS from both enteric-coated dosage forms was equivalent, regardless of the type of chelating agent. An in vivo absorption study in beagle dogs revealed that the maximum plasma concentration and area under the curve of RS after oral administration of IP6-containing ECT were approximately 7.9- (p<0.05) and 5.0-fold (p<0.05) higher than those of the marketed product at the same dose (35mg as RS). Therefore, our study demonstrates the potential usefulness of the ECT system in combination with IP6 for an oral therapy with the bisphosphonate for improved BA. PMID:26594027

  11. Denosumab for Elderly Men with Osteoporosis: A Cost-Effectiveness Analysis from the US Payer Perspective.

    PubMed

    Silverman, Stuart; Agodoa, Irene; Kruse, Morgan; Parthan, Anju; Orwoll, Eric

    2015-01-01

    Purpose. To evaluate the cost-effectiveness of denosumab versus other osteoporotic treatments in older men with osteoporosis from a US payer perspective. Methods. A lifetime cohort Markov model previously developed for postmenopausal osteoporosis (PMO) was used. Men in the model were 78 years old, with a BMD T-score of -2.12 and a vertebral fracture prevalence of 23%. During each 6-month Markov cycle, patients could have experienced a hip, vertebral or nonhip, nonvertebral (NHNV) osteoporotic fracture, remained in a nonfracture state, remained in a postfracture state, or died. Background fracture risks, mortality rates, persistence rates, health utilities, and medical and drug costs were derived from published sources. Previous PMO studies were used for drug efficacy in reducing fracture risk. Lifetime expected costs and quality-adjusted life-years (QALYs) were estimated for denosumab, generic alendronate, risedronate, ibandronate, teriparatide, and zoledronate. Results. Denosumab had an incremental cost-effectiveness ratio (ICER) of $16,888 compared to generic alendronate and dominated all other treatments. Results were most sensitive to changes in costs of denosumab and the relative risk of hip fracture. Conclusion. Despite a higher annual treatment cost compared to other medications, denosumab is cost-effective compared to other osteoporotic treatments in older osteoporotic US men. PMID:26783494

  12. Denosumab for Elderly Men with Osteoporosis: A Cost-Effectiveness Analysis from the US Payer Perspective

    PubMed Central

    Silverman, Stuart; Agodoa, Irene; Kruse, Morgan; Parthan, Anju; Orwoll, Eric

    2015-01-01

    Purpose. To evaluate the cost-effectiveness of denosumab versus other osteoporotic treatments in older men with osteoporosis from a US payer perspective. Methods. A lifetime cohort Markov model previously developed for postmenopausal osteoporosis (PMO) was used. Men in the model were 78 years old, with a BMD T-score of −2.12 and a vertebral fracture prevalence of 23%. During each 6-month Markov cycle, patients could have experienced a hip, vertebral or nonhip, nonvertebral (NHNV) osteoporotic fracture, remained in a nonfracture state, remained in a postfracture state, or died. Background fracture risks, mortality rates, persistence rates, health utilities, and medical and drug costs were derived from published sources. Previous PMO studies were used for drug efficacy in reducing fracture risk. Lifetime expected costs and quality-adjusted life-years (QALYs) were estimated for denosumab, generic alendronate, risedronate, ibandronate, teriparatide, and zoledronate. Results. Denosumab had an incremental cost-effectiveness ratio (ICER) of $16,888 compared to generic alendronate and dominated all other treatments. Results were most sensitive to changes in costs of denosumab and the relative risk of hip fracture. Conclusion. Despite a higher annual treatment cost compared to other medications, denosumab is cost-effective compared to other osteoporotic treatments in older osteoporotic US men. PMID:26783494

  13. 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. PMID:26381914

  14. The effect of nitrogen containing bisphosphonates, zoledronate and alendronate, on the production of pro-angiogenic factors by osteoblastic cells.

    PubMed

    Ishtiaq, S; Edwards, S; Sankaralingam, A; Evans, B A J; Elford, C; Frost, M L; Fogelman, I; Hampson, G

    2015-02-01

    Bisphosphonates (BPs) have been shown to influence angiogenesis. This may contribute to BP-associated side-effects such as osteonecrosis of the jaw (ONJ) or atypical femoral fractures (AFF). The effect of BPs on the production of angiogenic factors by osteoblasts is unclear. The aims were to investigate the effect of (1) alendronate on circulating angiogenic factors; vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANG-1) in vivo and (2) zoledronate and alendronate on the production of VEGF and ANG-1 by osteoblasts in vitro. We studied 18 post-menopausal women with T score⩽-2 randomized to calcium/vitamin D only (control arm, n=8) or calcium/vitamin D and alendronate 70mg weekly (treatment arm, n=10). Circulating concentrations of VEGF and ANG-1 were measured at baseline, 3, 6 and 12months. Two human osteoblastic cell lines (MG-63 and HCC1) and a murine osteocytic cell line (MLO-Y4) were treated with zoledronate or alendronate at concentrations of 10(-12)-10(-6)M. VEGF and ANG-1 were measured in the cell culture supernatant. We observed a trend towards a decline in VEGF and ANG-1 at 6 and 12months following treatment with alendronate (p=0.08). Production of VEGF and ANG-1 by the MG-63 and HCC1 cells decreased significantly by 34-39% (p<0.01) following treatment with zoledronate (10(-9)-10(-6)M). Treatment of the MG-63 cells with alendronate (10(-7) and 10(-6)) led to a smaller decrease (25-28%) in VEGF (p<0.05). Zoledronate (10(-10)-10(-)(6)M) suppressed the production of ANG-1 by MG-63 cells with a decrease of 43-49% (p<0.01). Co-treatment with calcitriol (10(-8)M) partially reversed this zoledronate-induced inhibition. BPs suppress osteoblastic production of angiogenic factors. This may explain, in part, the pathogenesis of the BP-associated side-effects. PMID:25461393

  15. Effects of alendronate and pamidronate on apoptosis and cell proliferation in cultured primary human gingival fibroblasts.

    PubMed

    Soydan, S S; Araz, K; Senel, F V; Yurtcu, E; Helvacioglu, F; Dagdeviren, A; Tekindal, M A; Sahin, F

    2015-11-01

    Data arising from the recent literature directed the researchers to study on the degree and extent of bisphosphonate toxicity on oral mucosa in further detail. The aim of this study is to determine the half maximal inhibitory concentration of pamidronate (PAM) and alendronate (ALN) on human gingival fibroblasts in vitro using 3-[4.5-thiazol-2-yl]-2.5-diphenyltetrazolium bromide (MTT) assay and to evaluate the effects of both agents on the proliferation and apoptotic indices. Cells used in the study were generated from human gingival specimens and divided into alendronate (n = 240), PAM (n = 240), and control groups (n = 60). Based on the MTT assay results, 10(-4), 10(-5), 10(-6), and 10(-7) M concentrations of both drugs were administered and the effects were evaluated for 6, 12, 24, 48, or 72 h periods. An indirect immunofluorescence technique was used to evaluate apoptotic (anti-caspase 3) and proliferation (anti-Ki67) indices. Toxicity of both PAM and ALN was found to be the most potent at 10(-4)-10(-5) M range. The apoptotic index of PAM group was found to be significantly higher than ALN group for all concentrations especially at 24 h incubation time (p < 0.05). The decrease in the proliferation index was found similar in first 48 h for both drugs; however, after 72 h of incubation decrease in proliferation index in PAM group was found to be significantly higher (p < 0.05). Micromolar concentrations of not only PAM but also ALN rapidly affect cells generated from human oral gingival tissue by inducing apoptosis together with inhibition of proliferation. Cytotoxic effects of both ALN and PAM on primary human gingival fibroblasts, which cause significant changes in apoptotic and proliferative indices as shown in this in vitro study, suggests that the defective epithelialization of oral mucosa is possibly a major factor on the onset of bisphosphonate-related osteonecrosis of the jaw cases. PMID:25636638

  16. Effects of denosumab, alendronate, or denosumab following alendronate on bone turnover, calcium homeostasis, bone mass and bone strength in ovariectomized cynomolgus monkeys.

    PubMed

    Kostenuik, Paul J; Smith, Susan Y; Samadfam, Rana; Jolette, Jacquelin; Zhou, Lei; Ominsky, Michael S

    2015-04-01

    Postmenopausal osteoporosis is a chronic disease wherein increased bone remodeling reduces bone mass and bone strength. Antiresorptive agents including bisphosphonates are commonly used to mitigate bone loss and fracture risk. Osteoclast inhibition via denosumab (DMAb), a RANKL inhibitor, is a newer approach for reducing fracture risk in patients at increased risk for fracture. The safety of transitioning from bisphosphonate therapy (alendronate; ALN) to DMAb was examined in mature ovariectomized (OVX) cynomolgus monkeys (cynos). One day after OVX, cynos (7-10/group) were treated with vehicle (VEH, s.c.), ALN (50 μg/kg, i.v., twice monthly) or DMAb (25 mg/kg/month, s.c.) for 12 months. Other animals received VEH or ALN for 6 months and then transitioned to 6 months of DMAb. DMAb caused significantly greater reductions in serum CTx than ALN, and transition from ALN to DMAb caused further reductions relative to continued ALN. DMAb and ALN decreased serum calcium (Ca), and transition from ALN to DMAb resulted in a lesser decline in Ca relative to DMAb or to VEH-DMAb transition. Bone histomorphometry indicated significantly reduced trabecular and cortical remodeling with DMAb or ALN. Compared with ALN, DMAb caused greater reductions in osteoclast surface, eroded surface, cortical porosity and fluorochrome labeling, and transition from ALN to DMAb reduced these parameters relative to continued ALN. Bone mineral density increased in all active treatment groups relative to VEH controls. Destructive biomechanical testing revealed significantly greater vertebral strength in all three groups receiving DMAb, including those receiving DMAb after ALN, relative to VEH controls. Bone mass and strength remained highly correlated in all groups at all tested skeletal sites, consistent with normal bone quality. These data indicate that cynos transitioned from ALN to DMAb exhibited reduced bone resorption and cortical porosity, and increased BMD and bone strength, without

  17. Bioequivalence of Alendronate and Vitamin D3 in a Combination Tablet Versus Corresponding-Dose Individual Tablets in Healthy Taiwanese Volunteers, Determined Using a Novel Plasma Alendronate Assay

    PubMed Central

    Wright, D. Hamish; Mols, Ramon; Brown, Kevin R; Yeh, Geng-Chang; Woolf, Eric; Hickey, Lisa; Zajic, Stefan

    2015-01-01

    Objective This study was designed to demonstrate that alendronate (ALN)/vitamin D3 combination tablets (ALN/D5600) are bioequivalent to corresponding doses of ALN and vitamin D3 as individual tablets in healthy Taiwanese volunteers. Methods In this open-label, randomized, 2-period, crossover study, 68 volunteers were randomized to a single ALN/D5600 combination tablet or corresponding doses of 70 mg ALN + 5600 IU vitamin D3 (2 × 2800 IU), followed by a 12-day washout period and administration of the alternate formulation. Plasma ALN levels were measured using a newly developed assay. Geometric mean ratios of ALN AUC0–last, AUC0–∞, and Cmax, and unadjusted vitamin D3 AUC0–80h and Cmax were compared and considered bioequivalent if the 90% CI was within 0.8 to 1.25. Results The geometric mean ratios were: AUC0–last, 1.084 (90% CI, 0.937–1.253); AUC0–∞, 1.081 (90% CI, 0.935–1.249); and Cmax, 1.112 (90% CI, 0.959–1.289) for ALN, and AUC0–80h 0.953 (90% CI, 0.827–1.098) and Cmax, 0.982 (90% CI, 0.854–1.130) for vitamin D3 unadjusted for endogenous levels. Conclusions The combination tablet was considered bioequivalent to coadministration based on ALN AUC0–∞ and unadjusted vitamin D3 parameters. Slight differences for ALN AUC0–last and Cmax (upper 90% CIs outside the bounds) were not considered clinically significant. The combination tablet was well tolerated. No serious adverse experiences were reported. © 2015. The Authors. Published by Elsevier Inc. All rights reserved. PMID:26843897

  18. 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. PMID:24613450

  19. 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.

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

    PubMed

    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

  1. 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

  2. Protein isoprenylation regulates osteogenic differentiation of mesenchymal stem cells: effect of alendronate, and farnesyl and geranylgeranyl transferase inhibitors

    PubMed Central

    Duque, G; Vidal, C; Rivas, D

    2011-01-01

    BACKGROUND AND PURPOSE Protein isoprenylation is an important step in the intracellular signalling pathway conducting cell growth and differentiation. In bone, protein isoprenylation is required for osteoclast differentiation and activation. However, its role in osteoblast differentiation and function remains unknown. In this study, we assessed the role of protein isoprenylation in osteoblastogenesis in a model of mesenchymal stem cells (MSC) differentiation. EXPERIMENTAL APPROACH We tested the effect of an inhibitor of farnesylation [farnesyl transferase inhibitor-277 (FTI-277)] and one of geranylgeranylation [geranylgeranyltransferase inhibitor-298 (GGTI-298)] on osteoblast differentiating MSC. In addition, we tested the effect of alendronate on protein isoprenylation in this model either alone or in combination with other inhibitors of isoprenylation. KEY RESULTS Initially, we found that levels of unfarnesylated proteins (prelamin A and HDJ-2) increased after treatment with FTI-277 concomitantly affecting osteoblastogenesis and increasing nuclear morphological changes without affecting cell survival. Furthermore, inhibition of geranylgeranylation by GGTI-298 alone increased osteoblastogenesis. This effect was enhanced by the combination of GGTI-298 and alendronate in the osteogenic media. CONCLUSIONS AND IMPLICATIONS Our data indicate that both farnesylation and geranylgeranylation play a role in osteoblastogenesis. In addition, a new mechanism of action for alendronate on protein isoprenylation in osteogenic differentiating MSC in vitro was found. In conclusion, protein isoprenylation is an important component of the osteoblast differentiation process that could constitute a new therapeutic target for osteoporosis in the future. PMID:21077849

  3. 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

  4. Alendronate-decorated biodegradable polymeric micelles for potential bone-targeted delivery of vancomycin.

    PubMed

    Cong, Yingying; Quan, Changyun; Liu, Meiqing; Liu, Jie; Huang, Gang; Tong, Guoquan; Yin, Yihua; Zhang, Chao; Jiang, Qing

    2015-01-01

    Osteomyelitis is a bone infection disease which is caused by bacteria or other germs, and could cause serious impact on the health and working capacity of the patients. Alendronate (ALN) can chelate strongly with the calcium ion of hydroxyapatite (HA) which is commonly used to treat osteoporosis. Nanomedicine has attracted a lot of attention in that the nano-sized carrier can deliver drug molecules to specific site of interest with the aid of targeting moiety and achieve sustained release, resulting in improved therapeutic effect and reduced side effect. In this study, micelles self-assembled from poly(lactic acid-co-glycolic acid)-block-poly(ethylene glycol)-alendronate (PLGA-PEG-ALN) copolymer were prepared for bone-targeted delivery of vancomycin (Van). The chemical structure of PLGA-PEG-ALN was confirmed by proton nuclear magnetic resonance ((1)H-NMR) spectroscopy. The formation of the nanoparticles was characterized by dynamic light scattering, transmission electronic microscopy as well as the critical micelle concentration measurement. Release profiles from the micelles revealed that the conjugation of ALN to the surface of micelle did not pose adverse effect on the drug-loading capacity and release behaviors. The cytotoxicity of Van-loaded PLGA-PEG-ALN micelles as well as the blank micelles was evaluated via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay toward rat bone marrow stromal cells (rBMSCs) and human embryonic hepatocytes (L02 cells), and results showed that this Van-loaded micelle possesses appropriate cytotoxicity and is safe in the potential treatment of osteomyelitis. The in vitro affinity of PLGA-PEG-ALN micelles to the HA was also confirmed in vitro. The antibacterial effect of Van-loaded PLGA-PEG-ALN micelles was tested against Staphylococcus aureus (SA) which is the main pathogenic bacteria in osteomyelitis, and the results showed that the Van-loaded micelles can effectively inhibit the growth of SA. These results

  5. Persistence with weekly and monthly bisphosphonates among postmenopausal women: analysis of a US pharmacy claims administrative database

    PubMed Central

    Fan, Tao; Zhang, Qiaoyi; Sen, Shuvayu S

    2013-01-01

    Background Bisphosphonates are available in daily, weekly, and monthly dosing formulations to treat postmenopausal osteoporosis. Some researchers suggested that adherence to monthly bisphosphonate might be different from that with weekly or daily bisphosphonate because of different dosing regimens. However, the actual persistency rates in regular practice settings are unknown. Objectives To compare persistence rates with alendronate 70 mg once weekly (AOW), risedronate 35 mg once weekly (ROW), and ibandronate 150 mg once monthly (IOM) in a US pharmacy claims database. Methods In this retrospective cohort study, pharmacy claims data of patients with new bisphosphonate prescriptions were extracted for women aged ≥ 50 years who had an AOW, ROW, or IOM prescription (index prescription) between December 30, 2004 and May 31, 2005 (the index period) and did not have the index Rx during the previous 12 months. Patients’ records were reviewed for at least 5 months from their index date to November 2, 2005 (the follow-up period). Patients were considered persistent if they neither discontinued (failed to refill the index Rx within a 45-day period following the last supply day of the previous dispensing) nor switched (changed to another bisphosphonate) during the follow-up period. Medication-possession ratio was defined as days with index prescription supplies/total days of follow-up. Results Among 44,635 patients, 25,207 (56.5%) received prescriptions of AOW, 18,689 (41.9%) ROW, and 739 (1.7%) IOM as the index prescription. In all, 35.1% of AOW patients, 32.5% of ROW patients, and 30.4% of IOM patients (P < 0.0001 AOW vs ROW or IOM) had persisted with their initial therapy, whereas 64.0% of AOW, 66.4% of ROW, and 68.2% of IOM patients discontinued (P < 0.0001) during follow-up. The medication-possession ratio (days with index prescription supplies/total days of follow-up) was significantly higher for AOW (0.55) compared with ROW (0.52) and IOM (0.51, P < 0.05). By

  6. Preparation of collagen/hydroxyapatite/alendronate hybrid hydrogels as potential scaffolds for bone regeneration.

    PubMed

    Ma, Xin; He, Zhiwei; Han, Fengxuan; Zhong, Zhiyuan; Chen, Liang; Li, Bin

    2016-07-01

    Development of biomimetic scaffolds represents a promising direction in bone tissue engineering. In this study, we designed a two-step process to prepare a type of biomimetic hybrid hydrogels that were composed of collagen, hydroxyapatite (HAP) and alendronate (ALN), an anti-osteoporosis drug. First, water-soluble ALN-conjugated HAP (HAP-ALN) containing 4.0wt.% of ALN was synthesized by treating HAP particles with ALN. Hydrogels were then formed from HAP-ALN conjugate and collagen under physiological conditions using genipin (GNP) as the crosslinker. Depending on the ALN/collagen molar ratio and GNP concentration, the gelation time of hydrogels ranged from 5 to 37min. Notably, these hybrid hydrogels exhibited markedly improved mechanical property (storage modulus G'=38-187kPa), higher gel contents, and lower swelling ratios compared to the hydrogels prepared from collagen alone under similar conditions. Moreover, they showed tunable degradation behaviors against collagenase. The collagen/HAP-ALN hybrid hydrogels supported the adhesion and growth of murine MC3T3-E1 osteoblastic cells well. Such tough yet enzymatically degradable hybrid hydrogels hold potential as scaffolds for bone tissue engineering. PMID:26998869

  7. Combinational effect of matrix elasticity and alendronate density on differentiation of rat mesenchymal stem cells.

    PubMed

    Jiang, Pengfei; Mao, Zhengwei; Gao, Changyou

    2015-06-01

    Differentiation of mesenchymal stem cells (MSCs) is regulated by multivariate physical and chemical signals in a complicated microenvironment. In this study, polymerizable double bonds (GelMA) and osteo-inductive alendronate (Aln) (Aln-GelMA) were sequentially grafted onto gelatin molecules. The biocompatible hydrogels with defined stiffness in the range of 4-40 kPa were prepared by using polyethylene glycol diacrylate (PEGDA) as additional crosslinker. The Aln density was adjusted from 0 to 4 μM by controlling the ratio between the GelMA and Aln-GelMA. The combinational effects of stiffness and Aln density on osteogenic differentiation of MSCs were then studied in terms of ALP activity, collagen type I and osteocalcin expression, and calcium deposition. The results indicated that the stiffness and Aln density could synergistically improve the expression of all these osteogenesis markers. Their osteo-inductive effects are comparable to some extent, and high Aln density could be more effective than the stiffness. PMID:25805109

  8. Primary brain calcification in patients undergoing treatment with the biphosphanate alendronate.

    PubMed

    Oliveira, J R M; Oliveira, M F

    2016-01-01

    Brain calcification might be associated with various metabolic, infectious or vascular conditions. Clinically, brain calcification can include symptoms such as migraine, parkinsonism, psychosis or dementia. The term Primary Brain Calcification was recently used for those patients without an obvious cause (formerly idiopathic) while Primary Familial Brain Calcifications was left for the cases with autosomal dominant inheritance. Recent studies found mutations in four genes (SLC20A2, PDGFRB, PDGFB and XPR1). However, these gene represent only 60% of all familial cases suggesting other genes remain to be elucidated. Studies evaluating treatments for such a devastating disease are scattered, usually appearing as single case reports. In the present study, we describe a case series of 7 patients treated with Alendronate, a widely prescribed biphosphanate. We observed good tolerance and evidence of improvements and stability by some patients. No side effects were reported and no specific symptoms related to medication. Younger patients and one individual continuing a prescription (prior to study commencement) appeared to respond more positively with some referred improvements in symptoms. Biphosphanates may represent an excellent prospect for the treatment of brain calcifications due to their being well tolerated and easily available. Conversely, prospective and controlled studies should promptly address weaknesses found in the present analysis. PMID:26976513

  9. Primary brain calcification in patients undergoing treatment with the biphosphanate alendronate

    PubMed Central

    Oliveira, J. R. M; Oliveira, M. F

    2016-01-01

    Brain calcification might be associated with various metabolic, infectious or vascular conditions. Clinically, brain calcification can include symptons such as migraine, parkinsonism, psychosis or dementia. The term Primary Brain Calcification was recently used for those patients without an obvious cause (formerly idiopathic) while Primary Familial Brain Calcifications was left for the cases with autosomal dominant inheritance. Recent studies found mutations in four genes (SLC20A2, PDGFRB, PDGFB and XPR1). However, these gene represent only 60% of all familial cases suggesting other genes remain to be elucidated. Studies evaluating treatments for such a devastating disease are scattered, usually appearing as single case reports. In the present study, we describe a case series of 7 patients treated with Alendronate, a widely prescribed biphosphanate. We observed good tolerance and evidence of improvements and stability by some patients. No side effects were reported and no specific symptoms related to medication. Younger patients and one individual continuing a prescription (prior to study commencement) appeared to respond more positively with some referred improvements in symptoms. Biphosphanates may represent an excellent prospect for the treatment of brain calcifications due to their being well tolerated and easily available. Conversely, prospective and controlled studies should promptly address weaknesses found in the present analysis. PMID:26976513

  10. Alendronate-Loaded Modified Drug Delivery Lipid Particles Intended for Improved Oral and Topical Administration.

    PubMed

    Ochiuz, Lacramioara; Grigoras, Cristian; Popa, Marcel; Stoleriu, Iulian; Munteanu, Corneliu; Timofte, Daniel; Profire, Lenuta; Grigoras, Anca Giorgiana

    2016-01-01

    The present paper focuses on solid lipid particles (SLPs), described in the literature as the most effective lipid drug delivery systems that have been introduced in the last decades, as they actually combine the advantages of polymeric particles, hydrophilic/lipophilic emulsions and liposomes. In the current study, we present our most recent advances in the preparation of alendronate (AL)-loaded SLPs prepared by hot homogenization and ultrasonication using various ratios of a self-emulsifying lipidic mixture of Compritol 888, Gelucire 44/14, and Cremophor A 25. The prepared AL-loaded SLPs were investigated for their physicochemical, morphological and structural characteristics by dynamic light scattering, differential scanning calorimetry, thermogravimetric and powder X-ray diffraction analysis, infrared spectroscopy, optical and scanning electron microscopy. Entrapment efficacy and actual drug content were assessed by a validated HPLC method. In vitro dissolution tests performed in simulated gastro-intestinal fluids and phosphate buffer solution pH 7.4 revealed a prolonged release of AL of 70 h. Additionally, release kinetics analysis showed that both in simulated gastrointestinal fluids and in phosphate buffer solution, AL is released from SLPs based on equal ratios of lipid excipients following zero-order kinetics, which characterizes prolonged-release drug systems. PMID:27367664

  11. 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

    SciTech Connect

    Deng Xue; Yu Zhiqian; Funayama, Hiromi; Shoji, Noriaki; Sasano, Takashi; Iwakura, Yoichiro; Sugawara, Shunji; Endo, Yasuo . E-mail: endo@pharmac.dent.tohoku.ac.jp

    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 HDC 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)

  12. The determination of apoptosis rates on articular cartilages of ovariectomized rats with and without alendronate treatment.

    PubMed

    Acar, Nuray; Balkarli, Huseyin; Soyuncu, Yetkin; Ozbey, Ozlem; Celik-Ozenci, Ciler; Korkusuz, Petek; Ustunel, Ismail

    2016-06-01

    Osteoporosis (OP) is a major health problem characterized by compromised bone strength. Osteoarthritis (OA) is a joint disease that progresses slowly and is characterized by breakdown of the cartilage matrix. Alendronate (ALN), a nitrogen-containing bisphosphonate (BIS), inhibits bone loss and increases bone mineralization, and has been used clinically for the treatment of OP. It is still controversial whether BIS is effective in inhibiting the progression of OA. Chondrocyte apoptosis has been described in both human and experimentally induced OA models. In our study we aimed to detect whether ALN could protect articular cartilage from degeneration and reduce apoptosis rates in experimentally OA induced rats. For this rats were ovariectomized (ovex), nine weeks after operation rats were injected 30 µg/kg/week ALN subcutaneously for six weeks. After six weeks articular cartilages were obtained. We did Safranin O staining and Mankin and Pritzker scorings to evaluate degeneration and investigated the expressions of p53, cleaved caspase 3, Poly ADP-ribose (PAR), Poly ADP-ribose polymerase 1 (PARP 1), and applied TUNEL technique to determine apoptotis rates. We found a significant decrease in glycosaminoglycan (GAG) amount and increased apoptosis which indicates damage on articular cartilages of ovex rats. GAG amount was higher and apoptosis rate was lower on articular cartilages of ALN treated ovex rats compared to the ovex group. In contrary to studies showing that early ALN treatment has a protective effect, our study shows late ALN treatment has a chondroprotective effect on articular cartilage since we treated rats nine weeks after ovariectomy. PMID:26631351

  13. Effects of 5'-azacytidine and alendronate on a hepatocellular carcinoma cell line: a proteomics perspective.

    PubMed

    Ilyas, Amber; Hashim, Zehra; Zarina, Shamshad

    2015-07-01

    Hepatocellular carcinoma (HCC) is the third leading cause of cancer related deaths around the world. Due to late diagnosis and development of drug resistance in patients suffering from HCC, development of more effective therapeutic strategies is inevitable. The aim of this study was to evaluate the combined apoptotic effect of 5'-Azacytidine (5'-AzaC) and alendronate (ALN) on Huh-7 HCC cell line and to explore differential expression at genomics and proteomics level. Incubation of HCC cell line with 5'-AzaC alone showed cell death in a time and dose dependent manner while in combination with ALN, increased cytotoxicity was observed. Up-regulation of CASP7(Caspase7) and LZTS1 (leucine zipper, putative tumor suppressor 1) and down-regulation of DNMT1(DNA (cytosine-5-)-methyltransferase 1) was noted in treated cells. Proteomic studies on the treated cells revealed altered expression of different proteins including peroxiredoxin 2 (Prx2), Annexin 5 (Anx5), Rho GTPase activating protein (RhoGAP), Nuclear factor-kappa B (NF-kB), tumor necrosis factor alpha-induced protein (TNF), triosephosphate isomerase (TPI), Glutathione S transferase (GSTP1) and Heat shock protein60 (HSP60). Our study demonstrated the cytotoxic effect of 5'-AzaC and ALN drug combination on Huh-7 HCC cells suggesting such combinations may be explored as a possible therapeutic approach. Current study revealed that Huh-7 HCC cells are sensitive to 5'-AzaC and ALN drug combination and such combination approaches could lead to the development of new therapeutic strategies. Furthermore, we also report the expression of Anx5 exclusively in untreated cancerous cell line indicating the possibility of being used as a potential therapeutic target and biomarker. PMID:25854900

  14. Acid extrusion is induced by osteoclast attachment to bone. Inhibition by alendronate and calcitonin.

    PubMed Central

    Zimolo, Z; Wesolowski, G; Rodan, G A

    1995-01-01

    Acid extrusion is essential for osteoclast (OC) activity. We examined Na+ and HCO3(-)-independent H+ extrusion in rat- and mouse OCs by measuring intracellular pH (pHi) changes, with the pHi indicator BCECF (biscarboxyethyl-5-(6) carboxyfluorescein) after H+ loading with an ammonium pulse. 90% of OCs attached to glass do not possess HCO3- and Na(+)-independent H(+)-extrusion (rate of pHi recovery = 0.043 +/- 0.007 (SEM) pH U/min, n = 26). In contrast, in OCs attached to bone, the pHi recovery rate is 0.228 +/- 0.011 pHi U/min, n = 25. OCs on bone also possess a NH(4+)-permeable pathway not seen on glass. The bone-induced H+ extrusion was inhibited by salmon calcitonin (10(-8) M, for 2 h), and was not present after pretreating the bone slices with the aminobisphosphonate alendronate (ALN). At ALN levels of 0.22 nmol/mm2 bone, H+ extrusion was virtually absent 12 h after cell seeding (0.004 +/- 0.002 pH U/min) and approximately 50% inhibition was observed at 0.022 pmol ALN/mm2 bone. The Na(+)-independent H+ extrusion was not inhibited by bafilomycin A1 (up to 10(-7) M), although a bafilomycin A1 (10(-8) M)-sensitive H+ pump was present in membrane vesicles isolated from these osteoclasts. These findings indicate that Na(+)-independent acid extrusion is stimulated by osteoclast attachment to bone and is virtually absent when bone is preincubated with ALN, or when osteoclasts are treated with salmon calcitonin. Images PMID:7593614

  15. The bone resorption inhibitors odanacatib and alendronate affect post-osteoclastic events differently in ovariectomized rabbits.

    PubMed

    Jensen, Pia Rosgaard; Andersen, Thomas Levin; Pennypacker, Brenda L; Duong, Le T; Delaissé, Jean-Marie

    2014-02-01

    Odanacatib (ODN) is a bone resorption inhibitor which differs from standard antiresorptives by its ability to reduce bone resorption without decreasing bone formation. What is the reason for this difference? In contrast with other antiresorptives, such as alendronate (ALN), ODN targets only the very last step of the resorption process. We hypothesize that ODN may therefore modify the remodeling events immediately following osteoclastic resorption. These events belong to the reversal phase and include recruitment of osteoblasts, which is critical for connecting bone resorption to formation. We performed a histomorphometric study of trabecular remodeling in vertebrae of estrogen-deficient rabbits treated or not with ODN or ALN, a model where ODN, but not ALN, was previously shown to preserve bone formation. In line with our hypothesis, we found that ODN treatment compared to ALN results in a shorter reversal phase, faster initiation of osteoid deposition on the eroded surfaces, and higher osteoblast recruitment. The latter is reflected by higher densities of mature bone forming osteoblasts and an increased subpopulation of cuboidal osteoblasts. Furthermore, we found an increase in the interface between osteoclasts and surrounding osteoblast-lineage cells. This increase is expected to favor the osteoclast-osteoblast interactions required for bone formation. Regarding bone resorption itself, we show that ODN, but not ALN, treatment results in shallower resorption lacunae, a geometry favoring bone stiffness. We conclude that, compared to standard antiresorptives, ODN shows distinctive effects on resorption geometry and on reversal phase activities which positively affect osteoblast recruitment and may therefore favor bone formation. PMID:24085265

  16. Role of connexin 43 in the mechanism of action of alendronate: dissociation of anti-apoptotic and proliferative signaling pathways.

    PubMed

    Lezcano, V; Bellido, T; Plotkin, L I; Boland, R; Morelli, S

    2012-02-15

    Bisphosphonates (BPs) inhibit osteocyte and osteoblast apoptosis via opening of connexin (Cx) 43 hemichannels and activating the extracellular signal regulated kinases ERKs. Previously, we hypothesized that intracellular survival signaling is initiated by interaction of BPs with Cx43. However, using whole cell binding assays with [(3)H]-alendronate, herein we demonstrated the presence of saturable, specific and high affinity binding sites in the Cx43-expressing ROS 17/2.8 osteoblastic cells, authentic osteoblasts and MLO-Y4 cells expressing Cx43 or not, as well as in HeLa cells lacking Cx43 expression and ROS 17/2.8 cells pretreated with agents that disassemble Cx channels. In addition, both BPs and the PTP inhibitor Na(3)VO(4) increased proliferation of cells expressing Cx43 or not. Furthermore, although BPs are internalized and inhibit intracellular enzymes in osteoclasts, whether the drugs penetrate non-resorptive bone cells is not known. To clarify this, we evaluated the osteoblastic uptake of AF-ALN, a fluorescently labeled analog of alendronate. AF-ALN was rapidly internalized in cells expressing Cx43 or not indicating that this process is not mediated via Cx43 hemichannels. Altogether, these findings suggest that although required for triggering intracellular survival signaling by BPs, Cx43 is dispensable for cellular BP binding, its uptake, as well as the proliferative effects of these agents. PMID:22230328

  17. Development of dry powder inhaler formulation loaded with alendronate solid lipid nanoparticles: solid-state characterization and aerosol dispersion performance.

    PubMed

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

    2015-01-01

    Alendronate sodium is a bisphosphonate drug used for the treatment of osteoporosis and acts as a specific inhibitor of osteoclast-mediated bone resorption. Inhalable solid lipid nanoparticles (SLNs) of the alendronate were successfully designed and developed by spray-dried and co-spray dried inhalable mannitol from aqueous solution. Emulsification technique using a simple homogenization method was used for preparation of SLNs. In vitro deposition of the aerosolized drug was studied using a Next Generation Impactor at 60 L/min following the methodology described in the European and United States Pharmacopeias. The Carr's Index, Hausner ratio and angle of repose were calculated as suitable criteria for estimation of the flow behavior of solids. Scanning electron microscopy showed spherical particle morphology of the respirable particles. The proposed spray-dried nanoparticulate-on-microparticles dry powders displayed good aerosol dispersion performance as dry powder inhalers with high values in emitted dose, fine particle fraction and mass median aerodynamic diameter. These results indicate that this novel inhalable spray-dried nanoparticulate-on-microparticles aerosol platform has great potential in systemic delivery of the drug. PMID:25220930

  18. Immunomodulatory Effect of Bisphosphonate Risedronate Sodium on CD163+ Arginase 1+ M2 Macrophages: The Development of a Possible Supportive Therapy for Angiosarcoma

    PubMed Central

    Kambayashi, Yumi; Furudate, Sadanori; Kakizaki, Aya; Aiba, Setsuya

    2013-01-01

    An imbalance of immunosuppressive cells and cytotoxic cells plays an important role in inhibiting the antitumor immune response of the tumor-bearing host. We previously reported the profiles of tumor infiltrating leukocytes in cutaneous angiosarcoma (AS) and suggested that a combination of docetaxel (DTX) with bisphosphonate risedronate sodium (RS) might be effective for MMP9-expressing AS by targeting immunosuppressive cells such as M2 macrophages. To further confirm the effect of this combination therapy, in this report we investigated the immunomodulatory effect of DTX and RS on CD163+ arginase 1 (Arg1)+ M2 macrophages in vitro. Interestingly, our present study demonstrated that DTX in combination with RS significantly upregulated the mRNA expression of CXCL10 on M2 macrophages and significantly decreased the mRNA expression of CCL17 and Arg1. Moreover, the production of CXCL10 and CXCL11 from M2 macrophages was significantly increased by DTX with RS though there was no effect of DTX with RS on the production of CCL5 and CCL17. Furthermore, DTX with RS significantly decreased the production of CCL18, which was previously reported to correlate with the severity and prognosis in cancer patients. Our present report suggests one of the possible mechanisms of DTX with RS in the supportive therapy for angiosarcoma. PMID:24489574

  19. 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. PMID:24704262

  20. The Resistance of Cortical Bone Tissue to Failure under Cyclic Loading is Reduced with Alendronate

    PubMed Central

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

    2014-01-01

    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, 1.0 mg/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, ×103 µm2; p<0.01) and the density of osteocyte lacunae (−20%; ALN1.0: 11.4±3.3, VEH: 14.3±3.6, ×102 #/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. PMID:24704262

  1. 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

  2. Aqueous extract of pomegranate seed attenuates glucocorticoid-induced bone loss and hypercalciuria in mice: A comparative study with alendronate.

    PubMed

    Zhang, Yan; Shao, Jin; Wang, Zhi; Yang, Tieyi; Liu, Shuyi; Liu, Yue; Fan, Xinbing; Ye, Weiguang

    2016-08-01

    The present study was performed in order to examine bone loss and calcium homeostasis in mice with glucocorticoid (GC)-induced osteoporosis (GIOP) following treatment with the aqueous extract of pomegranate seed (AE-PS). In addition, a comparative study with alendronate was performed. Biomarkers in the serum and the urine were measured. The tibias, kidney and duodenum were removed in order to measure the levels of bone calcium, protein expression as well as to perform histomorphological analysis of the bone. GC treatment facilitated the induction of hypercalciuria in the mice, and the AE-PS‑treated mice exhibited a greater increase in serum calcium and a decrease in urine calcium. The AE-PS reversed the deleterious effects on the trabecular bone induced by DXM and stimulated bone remodeling, including an increase in bone calcium and alkaline phosphatase‑b (ALP-b) and a decrease in a the critical bone resorption markers C-terminal telopeptide of type I collagen (CTX) and tartrate‑resistant acid phosphatase-5b (TRAP-5b). Hematoxylin and eosin (H&E) staining revealed the increased disconnections and separation between the growth plate and the trabecular bone network as well as the reduction in the trabecular bone mass of the primary and secondary spongiosa throughout the proximal metaphysis of the tibia in the DXM group. Moreover, the decreased protein expression of transient receptor potential vanilloid (TRPV)5, TRPV6 and calbindin‑D9k (CaBP‑9k) was reversed by the AE-PS or alendronate supplementation in the kidneys and the duodenum as well as plasma membrane Ca2+‑ATPase1 (PMCA1) expression in the kidneys of mice with GIOP. There was no marked difference in pharmacological effectiveness between alendronate and the AE-PS. Taken together, these findings suggest that the AE-PS may be an alternative therapy suitable for use in the management of secondary osteoporosis. PMID:27278225

  3. 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. PMID:27109613

  4. New insights into the molecular mechanisms of action of bisphosphonates.

    PubMed

    Rogers, Michael J

    2003-01-01

    Bisphosphonates are currently the most important and effective class of anti-resorptive drugs available, but the exact molecular mechanisms by which they inhibit osteoclast-mediated bone resorption have only recently been identified. Due to the targeting of bisphosphonates to bone mineral and the ability of osteoclasts to release bone-bound bisphosphonate, a direct effect on mature osteoclasts appears to be the most important route of action. As a result of recent discoveries concerning their molecular mechanism of action, bisphosphonates can be grouped into two classes. The simple bisphosphonates that closely resemble PPi (such as clodronate, etidronate and tiludronate) can be metabolically incorporated into non-hydrolysable analogues of ATP that accumulate intracellularly in osteoclasts, resulting in induction of osteoclast apoptosis. By contrast, the more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate and zoledronate) appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. Loss of bone-resorptive activity and osteoclast apoptosis is due primarily to loss of geranylgeranylated small GTPases. Identification of FPP synthase as the target of nitrogen-containing bisphosphonates has also helped explain the molecular basis for the adverse effects of these agents in the GI tract and on the immune system. PMID:14529538

  5. [Drug therapy for primary osteoporosis in men].

    PubMed

    Soen, Satoshi

    2016-07-01

    Overall, drug therapies 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. 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 and denosumab 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 and teriparatide on surrogate outcomes were similar to those reported in pivotal RCTs undertaken in postmenopausal women, in which vertebral and non-vertebral anti-fracture efficacy have been clearly demonstrated. PMID:27346317

  6. [Management of osteoporosis associated with rheumatoid arthritis and glucocorticoid-induced osteoporosis].

    PubMed

    Suzuki, Yasuo; Wakabayashi, Takayuki

    2015-12-01

    Mechanism of generalized osteoporosis associated with rheumatoid arthritis(RA)is multifactorial and following factors has been proposed:systemic effect of RA synovitis, glucocorticoids, weight loss, and endocrine changes. In addition to control of RA inflammation and management of glucocorticoid-induced osteoporosis(GIO), antiresorptive therapy, such as bisphosphonates is expected to show efficacy. Recently, anti-RANKL monoclonal antibodies have been shown to inhibit bone erosion and bone loss in combination with methotrexate in RA. GC-induced bone loss is most rapid during the initial 3 ~ 6 months and more slowly thereafter. Therefore, both primary and secondary prevention are important. The Japanese Society for Bone and Mineral Research(JSBMR)has updated the Guidelines on the Management and Treatment of GIO and has incorporated a new scoring method. By analyzing five GIO cohorts from primary and secondary prevention studies, age, GC dose, lumbar BMD, and prior fragility fractures were identified as risk factors and the fracture risk for an individual can be calculated as the sum of the scores for each risk factor. Pharmacological intervention should be started on the basis of a score of 3 as the optimal cut-off score. Both alendronate and risedronate are recommended as first-line treatment. Ibandronate,teriparatide, and active vitamin D3 derivatives are recommended as alternative option. PMID:26608858

  7. Long-term treatment with bisphosphonates and their safety in postmenopausal osteoporosis

    PubMed Central

    Pazianas, Michael; Cooper, Cyrus; Ebetino, F Hal; Russell, R Graham G

    2010-01-01

    Bisphosphonates are the leading drugs for the treatment of osteoporosis. In randomized controlled trials (RCTs), alendronate, risedronate, and zoledronate have shown to reduce the risk of vertebral, nonvertebral, and hip fractures, whereas RCTs with ibandronate show antifracture efficacy at vertebral sites. Bisphosphonates are generally well tolerated and safe. Nevertheless, adverse events have been noted, and it is important to consider the strength of the evidence for causal relationships. Effects on the gastrointestinal tract and kidney function are well recognized, as are transient acute-phase reactions. Atrial fibrillation was first identified as a potential adverse event in a zoledronate trial, but subsequent trials and analyses failed to substantiate an association with bisphosphonates. Case reports have suggested a relationship between oral bisphosphonates and esophageal cancer, but this has not been demonstrated in epidemiologic studies. A possible association between bisphosphonate use and osteonecrosis of the jaw (ONJ) has also been suggested. However, the risk of ONJ in patients with osteoporosis appears to be very low, with no evidence from prospective RCTs of a causal association. There are reports of occasional occurrence of subtrochanteric or diaphyseal fractures in osteoporotic patients, but an association with bisphosphonate therapy is not substantiated by epidemiologic studies or prospective RCTs. PMID:20668715

  8. Risk of hip, subtrochanteric, and femoral shaft fractures among mid and long term users of alendronate: nationwide cohort and nested case-control study

    PubMed Central

    Abrahamsen, Bo; Eiken, Pia; Eastell, Richard

    2016-01-01

    Objectives To determine the skeletal safety and efficacy of long term (≥10 years) alendronate use in patients with osteoporosis. Design Open register based cohort study containing two nested case control studies. Setting Nationwide study of population of Denmark. Participants 61 990 men and women aged 50-94 at the start of treatment, who had not previously taken alendronate, 1996-2007. Interventions Treatment with alendronate. Main outcome measures Incident fracture of the subtrochanteric femur or femoral shaft (ST/FS) or the hip. Non-fracture controls from the cohort were matched to fracture cases by sex, year of birth, and year of initiation of alendronate treatment. Conditional logistic regression models were fitted to calculate odds ratios with and without adjustment for comorbidity and comedications. Sensitivity analyses investigated subsequent treatment with other drugs for osteoporosis. Results 1428 participants sustained a ST/FS (incidence rate 3.4/1000 person years, 95% confidence interval 3.2 to 3.6), and 6784 sustained a hip fracture (16.2/1000 person years, 15.8 to 16.6). The risk of ST/FS was lower with high adherence to treatment with alendronate (medication possession ratio (MPR, a proxy for compliance) >80%) compared with poor adherence (MPR <50%; odds ratio 0.88, 0.77 to 0.99; P=0.05). Multivariable adjustment attenuated this association (adjusted odds ratio 0.88, 0.77 to 1.01; P=0.08). The risk was no higher in long term users (≥10 dose years; 0.70, 0.44 to 1.11; P=0.13) or in current compared with past users (0.91, 0.79 to 1.06; P=0.22). Similarly, MPR >80% was associated with a decreased risk of hip fracture (0.73, 0.68 to 0.78; P<0.001) as was longer term cumulative use for 5-10 dose years (0.74, 0.67 to 0.83; P<0.001) or ≥10 dose years (0.74, 0.56 to 0.97; P=0.03). Conclusions These findings support an acceptable balance between benefit and risk with treatment with alendronate in terms of fracture outcomes, even for over 10

  9. Efficacy, tolerability and safety of once-monthly administration of 75mg risedronate in Japanese patients with involutional osteoporosis: a comparison with a 2.5mg once-daily dosage regimen.

    PubMed

    Hagino, Hiroshi; Kishimoto, Hideaki; Ohishi, Hiroaki; Horii, Sayako; Nakamura, Toshitaka

    2014-02-01

    Oral risedronate has been shown to be effective in the treatment of osteoporosis when administered once-daily or once-weekly in Japan. This randomized, double-blind, multicenter 12-month study was conducted to compare the efficacy and tolerability of oral risedronate 75mg once-monthly with 2.5mg once-daily in Japanese patients with involutional osteoporosis. Bone mineral density (BMD), biochemical markers of bone metabolism, fractures, and adverse events (AEs) were evaluated. At the end of the study (Month 12, last observation carried forward [M12, LOCF]), mean percent change (SD) from baseline in lumbar spine (L2-L4) BMD, measured by dual energy X-ray absorptiometry (primary endpoint), was increased by 5.69 (4.00)% in the 2.5mg once-daily group (n=428), and 5.98 (4.54)% in the 75mg once-monthly group (n=422). In the non-inferiority t-test (non-inferiority margin Δ=1.5%), the 75mg once-monthly group was non-inferior to the 2.5mg once-daily group (p<0.0001). The difference between treatment groups was 0.28% (95% CI, -0.31% to 0.88%). Changes in biochemical markers of bone metabolism were generally comparable in the two groups, although decreases in the percent change from baseline in urinary NTX/CRN and CTX/CRN were statistically greater in the 2.5mg once-daily group than the 75mg once-monthly group. The frequency of new vertebral fractures (including aggravation of prevalent fractures) at the end of the study (M12, LOCF) was also similar in the two groups: 1.2% in the 2.5mg once-daily group and 1.3% in the 75mg once-monthly group. The incidence of mild/moderate/severe AEs was 75.5%/6.3%/0.5% in the 2.5mg once-daily group and 77.7%/8.1%/0.7% in the 75mg once-monthly group. AEs associated with gastrointestinal symptoms occurred in approximately 30% of subjects in each group but with no severe cases. AEs potentially associated with acute phase reaction (including symptoms of influenza-like illness or pyrexia starting within 3days of the first dose of the study drug

  10. Preparation of an injectable depot system for long-term delivery of alendronate and evaluation of its anti-osteoporotic effect in an ovariectomized rat model.

    PubMed

    Bae, Joonho; Park, Jin Woo

    2015-03-01

    We prepared an injectable depot system for the long-term delivery of alendronate using a solid/water/oil/water multiple emulsion technique with poly(lactic-co-glycolic acid) as a carrier. The microparticles were spherical with smooth surfaces, ranging from 20 to 70 μm in size. The microspheres (ALD-HA-RG504H-MC70) were optimally prepared by introducing a viscous material (hyaluronic acid) and a co-solvent system in the inner aqueous and oil phases, respectively, and showed a significantly increased drug encapsulation efficacy (>70%); the initial burst release was <10% after 1 day. In vitro drug release from ALD-HA-RG504H-MC70 followed zero-order kinetics for approximately 4 weeks and the alendronate plasma level was maintained for more than 1 month after intramuscular injection in rabbits. The ovariectomized (OVX) rats with ALD-HA-RG504H-MC70 injected intramuscularly (0.9 mg alendronate/kg/4 weeks) had 112% and 482% increased bone mineral density and trabecular area in the tibia than the OVX controls, respectively, and showed significant improvements in trabecular microarchitecture and bone strength. Furthermore, the major biomarkers of bone turnover revealed that ALD-HA-RG504H-MC70 suppressed effectively the progression of osteoporosis and facilitated new bone formation. Therefore, this sustained release depot system may improve patient compliance and therapeutic efficacy by reducing dose amounts and frequency with minimal adverse reactions. PMID:25595570

  11. Improved determination of the bisphosphonate alendronate in human plasma and urine by automated precolumn derivatization and high-performance liquid chromatography with fluorescence and electrochemical detection.

    PubMed

    Kline, W F; Matuszewski, B K

    1992-12-01

    An improved method for the determination of 4-amino-1-hydroxybutane-1,1-bisphosphonic acid (alendronate) in human urine and an assay in human plasma are described. The methods are based on co-precipitation of the bisphosphonate with calcium phosphates, automated pre-column derivatization of the primary amino group of the bisphosphonic acid with 2,3-naphthalene dicarboxyaldehyde (NDA)-N-acetyl-D-penicillamine (NAP) or cyanide (CN-) reagents, and high-performance liquid chromatography (HPLC) with electrochemical (ED) or fluorescence detection (FD). The feasibility of ED of the NDA-CN- derivative of aldendronate has been demonstrated, and a HPLC-ED assay in human urine has been validated in the concentration range 2.5-50.0 ng/ml. In order to eliminate the cyanide ion from the assay procedure, several other nucleophiles in the NDA derivatization reaction were evaluated. An NDA-NAP reagent was found to produce highly fluorescent derivatives of alendronate. The assay in urine based on NDA-NAP derivatization and HPLC-FD has been developed and fully validated in the concentration range 1-25 ng/ml. Based on the same NDA-NAP derivatization, an assay in human plasma with a limit of quantification of 5 ng/ml has also been developed. Both HPLC-FD assays were utilized to support various human pharmacokinetic studies with alendronate. PMID:1478982

  12. Asymptomatic Paget's disease of bone in a 62-year-old Nigerian man: three years post-alendronate therapy

    PubMed Central

    Ipadeola, Arinola

    2016-01-01

    Summary Paget's disease is a chronic and progressive disorder of bone characterized by focal areas of excessive osteoclastic resorption accompanied by a secondary increase in the osteoblastic activity. Paget's disease of bone (PBD) is a rare endocrine disease especially among Africans and Asians. Hence the detection of a case in a middle-aged Nigerian is of interest. We present the case of a 62-year-old Nigerian man in apparent good health who was found to have a markedly elevated serum total alkaline phosphatase (ALP) of 1179 U/l (reference range, 40–115 U/l) 4 years ago during a routine medical check-up in the USA. He had no history suggestive of PDB and also had no known family history of bone disease. Examination findings were not remarkable except for a relatively large head. A repeat ALP in our centre was 902 U/l (reference range, 40–120 U/l). Cranial CT scan showed diffuse cranial vault thickening consistent with Paget's disease which was confirmed by Tc-99m hydroxymethylene diphosphonate. He was placed on 40 mg alendronate tablets daily for 6 months. The patient has remained asymptomatic and has been in continuing biochemical remission during the 3-year follow-up period. The most recent ALP result is 88 U/l (reference range, 30–132 U/l) in April 2015. Learning points Serum total alkaline phosphatase remains a sensitive marker of bone turnover and an isolated increase above the upper limit of normal warrants more intense scrutiny in form of investigations targeted at excluding PD.Paget's disease is very rare but can occur in the Africans as seen in this Nigerian man and most patients are asymptomatic.Asymptomatic patients can benefit from treatment if disease is active, polyostotic or the lesions are located in bones with future risk of complications such as long bones, vertebrae and skull.Bisphosphonates are still the mainstay of treatment and alendronate is a useful therapeutic option for treatment. PMID:26870373

  13. The Effect of Alendronate Loaded Biphasic Calcium Phosphate Scaffolds on Bone Regeneration in a Rat Tibial Defect Model

    PubMed Central

    Park, Kwang-Won; Yun, Young-Pil; Kim, Sung Eun; Song, Hae-Ryong

    2015-01-01

    This study investigated the effect of alendronate (Aln) released from biphasic calcium phosphate (BCP) scaffolds. We evaluated the in vitro osteogenic differentiation of Aln/BCP scaffolds using MG-63 cells and the in vivo bone regenerative capability of Aln/BCP scaffolds using a rat tibial defect model with radiography, micro-computed tomography (CT), and histological examination. In vitro studies included the surface morphology of BCP and Aln-loaded BCP scaffolds visualized using field-emission scanning electron microscope, release kinetics of Aln from BCP scaffolds, alkaline phosphatase (ALP) activity, calcium deposition, and gene expression. The in vitro studies showed that sustained release of Aln from the BCP scaffolds consisted of porous microstructures, and revealed that MG-63 cells cultured on Aln-loaded BCP scaffolds showed significantly increased ALP activity, calcium deposition, and gene expression compared to cells cultured on BCP scaffolds. The in vivo studies using radiograph and histology examination revealed abundant callus formation and bone maturation at the site in the Aln/BCP groups compared to the control group. However, solid bony bridge formation was not observed at plain radiographs until 8 weeks. Micro-CT analysis revealed that bone mineral density and bone formation volume were increased over time in an Aln concentration-dependent manner. These results suggested that Aln/BCP scaffolds have the potential for controlling the release of Aln and enhance bone formation and mineralization. PMID:26561810

  14. The Effect of Alendronate Loaded Biphasic Calcium Phosphate Scaffolds on Bone Regeneration in a Rat Tibial Defect Model.

    PubMed

    Park, Kwang-Won; Yun, Young-Pil; Kim, Sung Eun; Song, Hae-Ryong

    2015-01-01

    This study investigated the effect of alendronate (Aln) released from biphasic calcium phosphate (BCP) scaffolds. We evaluated the in vitro osteogenic differentiation of Aln/BCP scaffolds using MG-63 cells and the in vivo bone regenerative capability of Aln/BCP scaffolds using a rat tibial defect model with radiography, micro-computed tomography (CT), and histological examination. In vitro studies included the surface morphology of BCP and Aln-loaded BCP scaffolds visualized using field-emission scanning electron microscope, release kinetics of Aln from BCP scaffolds, alkaline phosphatase (ALP) activity, calcium deposition, and gene expression. The in vitro studies showed that sustained release of Aln from the BCP scaffolds consisted of porous microstructures, and revealed that MG-63 cells cultured on Aln-loaded BCP scaffolds showed significantly increased ALP activity, calcium deposition, and gene expression compared to cells cultured on BCP scaffolds. The in vivo studies using radiograph and histology examination revealed abundant callus formation and bone maturation at the site in the Aln/BCP groups compared to the control group. However, solid bony bridge formation was not observed at plain radiographs until 8 weeks. Micro-CT analysis revealed that bone mineral density and bone formation volume were increased over time in an Aln concentration-dependent manner. These results suggested that Aln/BCP scaffolds have the potential for controlling the release of Aln and enhance bone formation and mineralization. PMID:26561810

  15. Synthesis, characterization and osteoconductivity properties of bone fillers based on alendronate-loaded poly(ε-caprolactone)/hydroxyapatite microspheres.

    PubMed

    Chen, Jianhong; Luo, Yun; Hong, Liangqing; Ling, You; Pang, Jun; Fang, Youqiang; Wei, Kun; Gao, Xin

    2011-03-01

    A superior drug controlled release system capable of achieving efficient osteogenesis is in imperative demand because of limited bone substitute tissue for the treatment of bone defect. In the present study, we investigated the potential of using poly(ε-caprolactone)-hydroxyapatite (PCL-HA) composite microspheres as an injectable bone repair vehicle by controlled release of alendronate (AL), a medicine that belongs to the bisphosphonates family. The PCL/HA-AL microspheres were prepared with solid/oil/water emulsion technique, which included two processes: (1) AL was loaded on the hydroxyapatite nanoparticles; (2) the HA-AL complex was built in the PCL matrix. The spherical PCL/HA-AL microspheres were characterized with its significantly improved encapsulation efficiency of hydrophilic AL and better sustained release. Human bone mesenchymal stem cells (hMSCs) were cultured on the surface of these microspheres and exhibited high proliferative profile. Specifically, in osteogenic medium, hMSCs on the surface of PCL/HA-AL microspheres displayed superior osteogenic differentiation which was verified by alkaline phosphatase activity assay. In conclusion, by presenting strong osteogenic commitment of hMSCs in vitro, the PCL/HA-AL microspheres have the potential to be used as an injectable vehicle for local therapy of bone defect. PMID:21318627

  16. Ultrastructural and immunohistochemical study of the effect of sodium alendronate in the progression of experimental periodontitis in rats.

    PubMed

    Moreira, Mariana M; Bradaschia-Correa, Vivian; Marques, Natasha D M; Ferreira, Lorraine Braga; Arana-Chavez, Victor E

    2014-11-01

    The aim of the present research was to investigate the ultrastructural aspects and the immunoexpression of receptor activator of NFκB ligand (RANKL) and osteoprotegerin (OPG) on experimental periodontal disease of alendronate (ALN)-treated rats. Male Wistar rats received daily injections of 2.5 mg/kg body weight of ALN during 7 days previously and 7, 14, and 21 days after the insertion of a 4.0 silk suture into the gingival sulcus around the right upper second molar. Specimens were fixed in 0.1% glutaraldehyde + 4% formaldehyde under microwave irradiation, decalcified in 4.13% EDTA and paraffin embedded for TRAP histochemistry and immunohistochemistry for RANKL and OPG, or embedded in Spurr epoxy resin for TEM analysis. ALN reduced the activity of osteoclasts and significantly decreased the resorption of the alveolar crest. In the control group the alveolar crest appeared resorbed by TRAP-positive osteoclasts, which presented ultrastructural features of activated cells. The immunoexpression of RANKL was not inhibited by the drug; however, the expression of OPG was increased in the treated animals. The alveolar crest of ALN-treated specimens at 21 days showed signs of osteonecrosis, like empty osteocyte lacunae, the exposed bone regions and bacterial infection. The results showed that ALN treatment in individuals with periodontal disease represents a risk of osteonecrosis because of the reduced activity of osteoclasts resultant of the increased immunoexpression of OPG. PMID:25102967

  17. Comparison of alendronate and sodium fluoride effects on cancellous and cortical bone in minipigs. A one-year study.

    PubMed Central

    Lafage, M H; Balena, R; Battle, M A; Shea, M; Seedor, J G; Klein, H; Hayes, W C; Rodan, G A

    1995-01-01

    Fluoride stimulates trabecular bone formation, whereas bisphosphonates reduce bone resorption and turnover. Fracture prevention has not been convincingly demonstrated for either treatment so far. We compared the effects of 1-yr treatment of 9-mo-old minipigs with sodium fluoride (NaF, 2 mg/kg/d p.o.) or alendronate (ALN, 4 amino-1-hydroxybutylidene bisphosphonate monosodium, 1 mg/kg/d p.o.) on the biomechanical and histomorphometric properties of pig bones. As expected, NaF increased and ALN decreased bone turnover, but in these normal animals neither changed mean bone volume. NaF reduced the strength of cancellous bone from the L4 vertebra, relative to control animals, and the stiffness (resistance to deformation) of the femora, relative to the ALN group. In the ALN-treated animals, there was a strong positive correlation between bone strength and L5 cancellous bone volume, but no such correlation was observed in the NaF group. Furthermore, the modulus (resistance to deformation of the tissue) was inversely related to NaF content and there was a relative decrease in bone strength above 0.25 mg NaF/g bone. Moreover, within the range of changes measured in this study, there was an inverse correlation between bone turnover, estimated as the percentage of osteoid surface, and modulus. These findings have relevant implications regarding the use of these agents for osteoporosis therapy. PMID:7738180

  18. Bone-targeted delivery of nanodiamond-based drug carriers conjugated with alendronate for potential osteoporosis treatment.

    PubMed

    Ryu, Tae-Kyung; Kang, Rae-Hyoung; Jeong, Ki-Young; Jun, Dae-Ryong; Koh, Jung-Min; Kim, Doyun; Bae, Soo Kyung; Choi, Sung-Wook

    2016-06-28

    This paper describes the design of alendronate-conjugated nanodiamonds (Alen-NDs) and evaluation of their feasibility for bone-targeted delivery. Alen-NDs exhibited a high affinity to hydroxyapatite (HAp, the mineral component of bone) due to the presence of Alen. Unlike NDs (without Alen), Alen-NDs were preferentially taken up by MC3T3-E1 osteoblast-like cells, compared to NIH3T3 and HepG2 cells, suggesting their cellular specificity. In addition, NDs itself increased ALP activity of MC3T3-E1 cells, compared to control group (osteogenic medium) and Alen-NDs exhibited more enhanced ALP activity. In addition, an in vivo study revealed that Alen-NDs effectively accumulated in bone tissues after intravenous tail vein injection. These results confirm the superior properties of Alen-NDs with advantages of high HAp affinity, specific uptake for MC3T3-E1 cells, positive synergistic effect for ALP activity, and in vivo bone targeting ability. The Alen-NDs can potentially be employed for osteoporosis treatment by delivering both NDs and Alen to bone tissue. PMID:27094604

  19. The effect of an alendronate-eluting titanium system to induce osteogenic differentiation in human buccal fat cells (HBFCs)

    NASA Astrophysics Data System (ADS)

    Kim, Sung Eun; Lee, Su-Young; Yun, Young-Pil; Lee, Jae Yong; Park, Kyeongsoon; Lee, Deok-Won; Song, Hae-Ryong

    2012-10-01

    The purpose of this study was to develop alendronate (Aln)-eluting Ti substrates to induce osteogenic differentiation of human buccal fat cells (HBFCs). The surface of pristine Ti was modified by dopamine (DOPA) and then heparin was grafted onto the aminated Ti surfaces to achieve the Aln-eluting Ti system. Aln was subsequently immobilized on the surface of heparinized Ti (Hep-Ti). Pristine Ti and surface-modified-Ti were characterized by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and contact angle. Osteogenic differentiation of HBFCs on the surface of pristine-Ti, Hep-Ti, Aln (1 mg)/Hep-Ti, and Aln (5 mg)/Hep-Ti was demonstrated by alkaline phosphatase (ALP) activity, calcium deposition, and osteocalcin and osteopontin mRNA expression. Successful immobilization of Aln on Hep-Ti was confirmed by XPS and contact angle. Aln/Hep-Ti showed the sustained release for up to 28 days. Additionally, HBFCs cultured on Aln/Hep-Ti substrates showed significantly induced ALP activity, calcium deposition, and osteocalcin and osteopontin mRNA expression. These results suggest that Aln-eluting Ti substrates have a potential effect on osteogenic differentiation of HBFCs and will be a promising material for bone regeneration.

  20. Doxorubicin-poly (ethylene glycol)-alendronate self-assembled micelles for targeted therapy of bone metastatic cancer

    PubMed Central

    Ye, Wei-liang; Zhao, Yi-pu; Li, Huai-qiu; Na, Ren; Li, Fei; Mei, Qi-bing; Zhao, Ming-gao; Zhou, Si-yuan

    2015-01-01

    In order to increase the therapeutic effect of doxorubicin (DOX) on bone metastases, a multifunctional micelle was developed by combining pH-sensitive characteristics with bone active targeting capacity. The DOX loaded micelle was self-assembled by using doxorubicin-poly (ethylene glycol)-alendronate (DOX-hyd-PEG-ALN) as an amphiphilic material. The size and drug loading of DOX loaded DOX-hyd-PEG-ALN micelle was 114 nm and 24.3%. In pH 5.0 phosphate buffer solution (PBS), the micelle released DOX significantly faster than in pH 7.4 PBS. In addition, with the increase of incubation time, more red DOX fluorescence was observed in tumor cells and trafficked from cytoplasm to nucleus. The IC50 of DOX loaded DOX-hyd-PEG-ALN micelle on A549 cells was obviously lower than that of free DOX in 48 h. Furthermore, the in vivo image experimental results indicated that a larger amount of DOX was accumulated in the bone metastatic tumor tissue after DOX loaded DOX-hyd-PEG-ALN micelle was intravenously administered, which was confirmed by histological analysis. Finally, DOX loaded DOX-hyd-PEG-ALN micelle effectively delayed the tumor growth, decreased the bone loss and reduced the cardiac toxicity in tumor-bearing nude mice as compared with free DOX. In conclusion, DOX loaded DOX-hyd-PEG-ALN micelle had potential in treating bone metastatic tumor. PMID:26419507

  1. Alendronate Effect on the Prevention of Bone loss in Early Stages of Ankylosing Spondylitis: A Randomized, Double-Blind, Placebo-Controlled Pilot Study

    PubMed Central

    Khabbazi, Alireza; Noshad, Hamid; Gafarzadeh, Sevil; Hajialiloo, Mehrzad; Kolahi, Susan

    2014-01-01

    Background: Ankylosing spondylitis (AS) is an inflammatory rheumatic disease that leads to a progressive ankylosis of vertebras and ossification of paravertebral ligaments. Bone loss and osteoporosis are amongst the important complications of AS, treatment of which is a challenging issue. Objectives: This study aimed to clarify the effect of alendronate on the prevention of bone loss in patients with early AS. Patients and Methods: In a randomized, double-blind, placebo-controlled study, 24 patients with early stages of AS were recruited in Emam Reza Hospital, Tabriz University of Medical Sciences. The diagnostic criteria of early AS were Schober’s index ≥ 5, normal hip joint in pelvic radiography, and absence or rarity of syndesmophytes in spine radiography (Taylor index ≤ 1). The participants were randomly allocated to the treatment and control groups and received 70 mg/week of alendronate and the same dose of placebo, respectively, for 12 months. Before and 12 months after the intervention, bone densitometry was performed from lumbar and pelvic region using the dual-energy X-ray absorptiometry (DEXA) method with Hologic QDR model instrument. Patients, physicians who prescribed the medications and those who interpreted the outcomes, and densitometry technicians were unaware of the assigned medication to each patient. Both groups received supplemental calcium (1000 mg/day) and vitamin D (400 mg/day). Results: After 12 months of treatment, hip and lumbar bone mineral density differences were not statistically significant between study groups (P = 0.061 and P = 0.112, respectively). No case of clinically apparent vertebral and nonvertebral fracture were observed in the treatment and control groups. Conclusions: Our results suggested that applying alendronate was ineffective in preventing bone loss in patients with early stages of AS. PMID:25068053

  2. 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. PMID:16422756

  3. 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.

  4. Comparative clinicoradiographical evaluation of effect of aminobisphosphonate (sodium alendronate) on peri-implant bone status: Controlled clinical trial

    PubMed Central

    Aggarwal, Rajni; Babaji, Prashant; Nathan, S. Senthil; Attokaran, George; Santosh Kumar, S. M.; Sathnoorkar, Sharanpriya

    2016-01-01

    Aim: The present study aims to compare the peri-implant bone status around immediately loaded dental implants treated with aminobisphosphonate solution and untreated control implants in terms of clinical and radiographical parameters. Materials and Methods: A total of 24 patients were randomly divided equally into two groups. This study was conducted in accordance to the Helsinki's declaration of 1975, revised in 2000, and with the approval of the institutional ethical committee. In the control group after preparation, osteotomy sites were irrigated with normal saline solution, whereas in the test group osteotomy sites were irrigated with modified bisphosphonate solution and then TRX-OP, Hi-Tec dental implants were inserted. Clinical parameters, such as modified plaque and gingival index, probing depth, mobility, and radiographic parameters were recorded at baseline (0), 3, 6, and 9 months. Data analysis was performed using the Statistical Package for the Social Sciences version 17 for windows, and the statistical techniques employed were repeated measures analysis of variance, independent sample t-test, and paired sample t-test. Results: Reduction in mean radiographic bone levels (height) was observed on the mesial and distal aspect of the control group in comparison to its baseline at all intervals. In the test group, there was reduction in mean radiographic bone levels on mesial and distal aspect of the implant site in comparison to its baseline till 6-month follow up, however, at 9 month, there was gain in bone level on both mesial and distal aspect of implant. This represents the effectiveness of sodium alendronate in enhancing the bone formation. On comparison, between both groups on mesial and distal aspect of implants, statistically significant differences were observed at 3 and 9 months on mesial and distal aspect, respectively, without any clinical evidence of mobility in the test group. Conclusion: Implant site treated with aminobisphosphonate solution

  5. Effects of Long-Term Odanacatib Treatment on Bone Gene Expression in Ovariectomized Adult Rhesus Monkeys: Differentiation From Alendronate.

    PubMed

    Muise, Eric S; Podtelezhnikov, Alexei A; Pickarski, Maureen; Loboda, Andrey; Tan, Yejun; Hu, Guanghui; Thomspon, John R; Duong, Le T

    2016-04-01

    Similar efficacy of the cathepsin K inhibitor odanacatib (ODN) and the bisphosphonate alendronate (ALN) in reducing bone turnover markers and increasing bone mineral density in spine and hip were previously demonstrated in ovariectomized (OVX)-monkeys treated for 20 months in prevention mode. Here, we profiled RNA from tibial metaphysis and diaphysis of the same study using Affymetrix microarrays, and selected 204 probe sets (p < 0.001, three-group ANOVA) that were differentially regulated by ODN or ALN versus vehicle. Both drugs produced strikingly different effects on known bone-related genes and pathways at the transcriptional level. Although ALN either reduced or had neutral effects on bone resorption-related genes, ODN significantly increased the expression of osteoclast genes (eg, APC5, TNFRSF11A, CTSK, ITGB3, and CALCR), consistent with previous findings on the effects of this agent in enhancing the number of nonresorbing osteoclasts. Conversely, ALN reduced the expression of known bone formation-related genes (eg, TGFBR1, SPP1, RUNX2, and PTH1R), whereas ODN either increased or had neutral effects on their expression. These differential effects of ODN versus ALN on bone resorption and formation were highly correlative to the changes in bone turnover markers, cathepsin K (Catk) target engagement marker serum C-terminal cross-linked telopeptide (1-CTP) and osteoclast marker tartrate resistant acid phosphatase isoform 5b (TRAP5b) in the same monkeys. Overall, the molecular profiling results are consistent with the known pharmacological actions of these agents on bone remodeling and clearly differentiate the molecular mechanisms of ODN from the bisphosphonates. © 2016 American Society for Bone and Mineral Research. PMID:26587671

  6. Early changes in biochemical markers of bone turnover predict the long-term response to alendronate therapy in representative elderly women: a randomized clinical trial.

    PubMed

    Greenspan, S L; Parker, R A; Ferguson, L; Rosen, H N; Maitland-Ramsey, L; Karpf, D B

    1998-09-01

    Although the antiresorptive agent alendronate has been shown to increase bone mineral density (BMD) at the hip and spine and decrease the incidence of osteoporotic fractures in older women, few data are available regarding early prediction of long-term response to therapy, particularly with regard to increases in hip BMD. Examining short-term changes in biochemical markers incorporates physiologic response with therapeutic compliance and should provide useful prognostic information for patients. The objective of this study was to examine whether early changes in biochemical markers of bone turnover predict long-term changes in hip BMD in elderly women. The study was a double-blind, placebo-controlled, randomized clinical trial which took place in a community-based academic hospital. One hundred and twenty community-dwelling, ambulatory women 65 years of age and older participated in the study. Intervention consisted of alendronate versus placebo for 2.5 years. All patients received appropriate calcium and vitamin D supplementation. The principal outcome measures included BMD of the hip (total hip, femoral neck, trochanter, and intertrochanter), spine (posteroanterior [PA] and lateral), total body, and radius. Biochemical markers of bone resorption included urinary N-telopeptide cross-linked collagen type I and free deoxypyridinoline; markers of bone formation included serum osteocalcin and bone-specific alkaline phosphatase. Long-term alendronate therapy was associated with increased BMD at the total hip (4.0%), femoral neck (3.1%), trochanter (5.5%), intertrochanter (3.8%), PA spine (7.8%), lateral spine (10.6%), total body (2.2%), and one-third distal radius (1.3%) in elderly women (all p < 0.01). In the placebo group, bone density increased 1.9-2.1% at the spine (p < 0.05) and remained stable at all other sites. At 6 months, there were significant decreases in all markers of bone turnover (-10% to -53%, p < 0.01) in women on alendronate. The changes in urinary

  7. Efficacy of alfacalcidol and alendronate on lumbar bone mineral density in osteoporotic patients using proton pump inhibitors

    PubMed Central

    Asaoka, Daisuke; Nagahara, Akihito; Hojo, Mariko; Matsumoto, Kenshi; Ueyama, Hiroya; Matsumoto, Kohei; Izumi, Kentaro; Takeda, Tsutomu; Komori, Hiroyuki; Akazawa, Yoichi; Shimada, Yuji; Osada, Taro; Watanabe, Sumio

    2016-01-01

    It has been indicated that proton pump inhibitor (PPI) use is associated with a loss of the anti-fracture efficacy of alendronate (AD). However, there are few prospective studies that have investigated the efficacy of AD on lumbar bone mineral density (BMD) in osteoporotic patients who are using PPIs. Thus, the aim of the present study was to investigate the efficacy of alfacalcidol (AC) and AD on lumbar BMD in osteoporotic patients using PPIs. A prospective, randomized, active control study enrolled such osteoporotic patients (age, ≥50 years). The patients were randomly assigned to receive AC (1 µg/day) or AD (35 mg/week) and were followed up for one year. Patient profiles were maintained, and lumbar BMD, bone-specific alkaline-phosphatase (BAP) and collagen type-I cross-linked N-telopeptide (NTX), upper gastrointestinal endoscopy results, and the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) were evaluated. Percentage changes in lumbar BMD, NTX, BAP, and change in FSSG score from baseline to the end of one year of treatment were investigated. Sixteen patients were eligible for analysis (eight assigned to receive AC, eight assigned to receive AD). The percentage change in lumbar BMD from baseline to the end of treatment was −0.4±4.0% for the AC group vs. 6.8±6.3% for the AD group (P=0.015). No significant percentage change of BAP and NTX between the two groups was observed. Subsequent to one year of treatment, the FSSG score did not change from the baseline values for either study group, and no new bone fractures or esophagitis were observed in either group of patients. The findings demonstrated that in osteoporotic patients using concomitant PPIs, there was a greater increase in lumbar BMD after one year of treatment with AD compared with AC. However, the number of study subjects was small; thus, further, large prospective studies are required to determine the effect of AD in osteoporotic patients using concomitant PPIs. PMID

  8. Liquid chromatography-mass spectrometry analysis of five bisphosphonates in equine urine and plasma.

    PubMed

    Wong, April S Y; Ho, Emmie N M; Wan, Terence S M; Lam, Kenneth K H; Stewart, Brian D

    2015-08-15

    Bisphosphonates are used in the management of skeletal disorder in humans and horses, with tiludronic acid being the first licensed veterinary medicine in the treatment of lameness associated with degenerative joint disease. Bisphosphonates are prohibited in horseracing according to Article 6 of the International Agreement on Breeding, Racing and Wagering (published by the International Federation of Horseracing Authorities). In order to control the use of bisphosphonates in equine sports, an effective method to detect the use of bisphosphonates is required. Bisphosphonates are difficult-to-detect drugs due to their hydrophilic properties. The complexity of equine matrices also added to their extraction difficulties. This study describes a method for the simultaneous detection of five bisphosphonates, namely alendronic acid, clodronic acid, ibandronic acid, risedronic acid and tiludronic acid, in equine urine and plasma. Bisphosphonates were first isolated from the sample matrices by solid-phase extractions, followed by methylation with trimethylsilyldiazomethane prior to liquid chromatography - tandem mass spectrometry analysis using selective reaction monitoring in the positive electrospray ionization mode. The five bisphosphonates could be detected at low ppb levels in 0.5mL equine plasma or urine with acceptable precision, fast instrumental turnaround time, and negligible matrix interferences. The method has also been applied to the excretion study of tiludronic acid in plasma and urine collected from a horse having been administered a single dose of tiludronic acid. The applicability and effectiveness of the method was demonstrated by the successful detection and confirmation of the presence of tiludronic acid in an overseas equine urine sample. To our knowledge, this is the first reported method in the successful screening and confirmation of five amino- and non-amino bisphosphonates in equine biological samples. PMID:26143477

  9. Gastrointestinal events and association with initiation of treatment for osteoporosis

    PubMed Central

    Modi, Ankita; Siris, Ethel S; Tang, Jackson; Sajjan, Shiva; Sen, Shuvayu S

    2015-01-01

    Background Preexisting gastrointestinal (GI) events may deter the use of pharmacologic treatment in patients diagnosed with osteoporosis (OP). The objective of this study was to examine the association between preexisting GI events and OP pharmacotherapy initiation among women diagnosed with OP. Methods The study utilized claims data from a large US managed care database to identify women aged ≥55 years with a diagnosis code for OP (index date) during 2002–2009. Patients with a claim for pharmacologic OP treatment in the 12-month pre-index period (baseline) were excluded. OP treatment initiation in the post-index period was defined as a claim for bisphosphonates (alendronate, ibandronate, risedronate, zoledronic acid), calcitonin, raloxifene, or teriparatide. During the post-index period (up to 12 months), GI events were identified before treatment initiation. A time-dependent Cox regression model was used to investigate the likelihood of initiating any OP treatment. Among patients initiating OP treatment, a discrete choice model was utilized to assess the relationship between post-index GI events and likelihood of initiating with a bisphosphonate versus a non-bisphosphonate. Results In total, 65,344 patients (mean age 66 years) were included; 23.7% had a GI event post diagnosis and before treatment initiation. Post-index GI events were associated with a 75% lower likelihood of any treatment initiation (hazard ratio 0.25; 95% confidence interval 0.24–0.26). Among treated patients (n=23,311), those with post-index GI events were 39% less likely to receive a bisphosphonate versus a non-bisphosphonate (odds ratio 0.61; 95% confidence interval 0.54–0.68). Conclusion GI events after OP diagnosis were associated with a decreased likelihood of OP treatment initiation and an increased likelihood of treatment initiation with a non-bisphosphonate versus a bisphosphonate. PMID:26648746

  10. Current and emerging therapies for the treatment of osteoporosis

    PubMed Central

    Waalen, Jill

    2010-01-01

    Osteoporosis represents a weakening of bone tissue due to an imbalance in the dynamic processes of bone formation and bone resorption that are continually ongoing within bone tissue. Most currently available osteoporosis therapies are antiresorptive agents. Over the past decade, bisphosphonates, notably alendronate and risedronate, have become the dominant agents with newer bisphosphonates such as ibandronate and zoledronic acid following a trend of less frequent dosing regimens. Synthetic estrogen receptor modulators (SERMs) continue to be developed as drugs that maintain the bone-protective effects of estrogen while avoiding its associated adverse side effects. Currently available agents of this class include raloxifene, the only SERM available in the United States (US), and lasofoxifene and bazedoxifene, available in Europe. Calcitonin, usually administered as a nasal spray, completes the list of currently approved antiresorptive agents, while parathyroid hormone analogs represent the only anabolic agents currently approved in both the US and Europe. Strontium ranelate is an additional agent available in Europe but not the US that has both anabolic and antiresorptive activity. New agents expected to further expand therapeutic options include denosumab, a monoclonal antibody inhibitor of the resorptive enzyme cathepsin K, which is in the final stages of Food and Drug Administration approval. Other agents in preclinical development include those targeting specific molecules of the Wnt/β-catenin pathway involved in stimulating bone formation by osteoblast cells. This review discusses the use of currently available agents as well as highlighting emerging agents expected to bring significant changes to the approach to osteoporosis therapy in the near future.

  11. 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

  12. Potency of a combined alfacalcidol-alendronate therapy to reduce the risk of falls and fractures in elderly patients with glucocorticoid-induced osteoporosis.

    PubMed

    Ringe, Johann D; Schacht, Erich; Dukas, Laurent; Mazor, Ze'ev

    2011-01-01

    This is a preplanned subgroup analysis on 318 patients with glucocorticoid-induced osteoporosis (GIOP) from an open, prospective, multi-centered, uncontrolled study on a large cohort of elderly patients with a high risk of falls and fractures. The entire group of 2579 patients was recruited by 818 practicing physicians and treated for three months with a new combination package containing 4 or 12 self-explanatory one-week blisters, each with one tablet of 70 mg alendronate (CAS 260055-05-8) and 7 capsules of 1 pg alfacalcidol (CAS 41294-56-8) (Tevabone"). The average age of the GIOP patients was 71 years and the mean body mass index 26.7 kg/m2. 58% had a diagnosis of increased risk of falls, prevalent vertebral and non-vertebral fractures were documented in 70% and 65% of the patients, respectively, and a creatinine clearance (CrCl) below 65 ml/min was documented in 55 %. Main outcome parameters were the Chair Rising Test (CRT), Timed Up and Go Test (TUG), back pain and safety at onset and after 3 months. In addition, an evaluation of the package design was done at the end of the study. The percentage of patients able to perform the CRT within 10 sec increased from 21.1% to 39.4% after 3 months (increase 87%, p < 0.0001), while successful performance of TUG within 10 sec increased by 84% (p < 0.0001) from 23.1% at onset to 42.4% after 3 months. The mean time required to perform the CRT decreased after 3 months from an average of 15.92 to 14.02 sec (p = 0.0025) (difference of 1.9 sec) and for the TUG the mean time decreased from 16.86 sec to 14.64 sec (p = 0.0056) (difference of 2.2 sec). Mean back pain measured by a 0-10 visual analogue scale decreased significantly by 43% from 6.0 to 3.4 (p < 0.0001). Throughout the study 23 adverse events (AE) were reported in 11 of the 318 GIOP patients (incidence: 3.5 %). There were no patients who experienced serious AE. Patients using the new combined regimen of alfacalcidol plus alendronate for treating GIOP achieved

  13. 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

  14. Inhibition of fibrous dysplasia via blocking Gsα with suramin sodium loaded with an alendronate-conjugated polymeric drug delivery system.

    PubMed

    Lv, Mingming; Li, Xiao; Huang, Yu; Wang, Nan; Zhu, Xinyuan; Sun, Jian

    2016-07-21

    Suramin sodium (SS), which can directly inhibit the committed step of Gsα activation, seems to be a promising drug for treating fibrous dysplasia (FD). Therefore, how to efficiently deliver SS to the lesion site becomes an urgent problem to be solved. Here a bone-targeted and pH-sensitive drug delivery system was constructed to deliver SS for treating FD with high efficiency. The novel type of bone-targeted cationic hyperbranched poly(amine-ester) (HBPAE) was synthesized by the proton-transfer polymerization of triethanolamine and glycidyl methacrylate, followed by surface carboxyl-modification and then conjugation of an alendronate (ALE) bone-targeting moiety. The resultant Suc-HBPAE-ALE formed nanoparticles in aqueous solution, and SS could be encapsulated into the Suc-HBPAE-ALE nanoparticles via electrostatic attraction. The dynamic light scattering (DLS) and transmission electron microscopy (TEM) assays showed that the SS-loaded nanoparticles had a spherical morphology with a mean diameter of 65 nm. The strong affinity of Suc-HBPAE-ALE nanoparticles to bone was verified by the hydroxyapatite (HA) adsorbing experiment. The therapeutic potential of the SS-loaded Suc-HBPAE-ALE nanoparticles was evaluated via the methylthiazoletetrazolium (MTT) assay and flow cytometry (FCM) analysis against FD cells. The experimental results indicated that the SS-loaded Suc-HBPAE-ALE nanoparticles were a highly promising drug delivery system with high efficiency for inhibiting the proliferation of diseased FD cells. PMID:27180636

  15. Preventing Nonvertebral Osteoporotic Fractures With Extended-Interval Bisphosphonates: Regimen Selection and Clinical Application

    PubMed Central

    Cole, Raymond E.; Harris, Steven T.

    2009-01-01

    Context Nonvertebral fractures (NVFs) are the most costly and disabling type of osteoporotic fractures. Bisphosphonate therapy effectively reduces the risk for NVFs; however, fracture protection depends critically on adherence and persistence. Approved bisphosphonate regimens with extended dosing intervals increase patient convenience, help patients remain on therapy, and improve fracture protection in clinical practice. Evidence Acquisition To assess evidence for NVF reduction with extended-interval bisphosphonates, we searched PubMed for phase 3 clinical trials, meta-analyses, and reviews of approved nitrogen-containing bisphosphonate regimens with monthly or less frequent dosing (monthly oral ibandronate, monthly or intermittent oral risedronate, quarterly intravenous [IV] ibandronate, and yearly IV zoledronic acid). These references were augmented by ISI Web of Science cited reference searches, ISI Proceedings searches, and hand searches of relevant conference proceedings and review bibliographies. Evidence Synthesis Monthly oral and quarterly IV ibandronate reduce NVF risk significantly more than daily oral ibandronate and placebo, as shown by meta-analyses stratified by ibandronate dose (annual cumulative exposure). Intermittent and monthly oral risedronate have shown bone density gains similar to those seen with daily oral risedronate. Incidence rates of NVF, reported as adverse events, were also similar. Yearly IV zoledronic acid reduced NVF risk by 25% and hip fracture risk by 41% compared with placebo in its pivotal trial for postmenopausal osteoporosis. Conclusions Extended-interval bisphosphonates offer similar or superior NVF protection with less lifestyle disruption compared with daily or weekly treatment. By removing obstacles to adherence and persistence, extended-interval oral and IV bisphosphonate regimens provide valuable therapeutic options to enhance real-world effectiveness and reduce NVF incidence. PMID:19295933

  16. 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

  17. 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

  18. Risk reduction of falls and fractures, reduction of back pain and safety in elderly high risk patients receiving combined therapy with alfacalcidol and alendronate: a prospective study.

    PubMed

    Schacht, Erich; Ringe, Johann D

    2011-01-01

    Efficacy and safety of a new combination package containing 4 or 12 self-explanatory one-week blisters, each with one tablet of 70 mg alendronate (CAS 260055-05-8) and 7 capsules of 1 microg alfacalcidol (CAS 41294-56-8) (Tevabone) on muscle power, muscle function, balance and back pain was investigated in an open, multi-centered, uncontrolled, prospective study on a cohort of elderly patients with a high risk of falls and fractures. 818 practicing physicians all over Germany recruited 2579 patients for a 3-month observational trial being treated with the above combination package. 92.4% were women [89.7% of the women had postmenopausal osteoporosis (PMO)]. Their average age was 74.1 years and the mean body mass index 26.4 kg/m2. 55.4% had a history of falls. Prevalent vertebral and non-vertebral fractures were documented in 62.9% and 61.4% of the patients, respectively, and a creatinine clearance below 65 ml/min was documented in 65.5%. Main outcome parameters were the Chair Rising Test (CRT), Timed Up and Go Test (TUG), back pain and safety at onset and after 3 months. In addition an evaluation of the package design was done at the end of the study. The percentage of patients able to perform the CRT within 10 sec increased from 26.3% to 42.9% after 3 months (increase 63%, p < 0.0001), while successful performance within 10 sec of TUG increased by 54% (p < 0.0001) from 30.6% at onset to 47.1% after 3 months. The average overall improvement of CRT was 2.3 sec (p < 0.0001) and of TUG amounted to 2.4 sec (p < 0.0001). It was shown in another recently published study that a mean increase of 2.6 sec in the performance of TUG results in a 24% increased risk for non-vertebral fractures. Mean back pain measured by a 0-10 visual analogue scale decreased significantly by 41% from 5.9 to 3.5 (p < 0.0001). Throughout the study, 178 adverse events (AE) were reported in 85 of the 2579 patients (incidence: 3.3 %). Only 3 patients experienced serious AE, 2 without causal

  19. Persistence of 1,25D-induced hypercalciuria in alendronate-treated genetic hypercalciuric stone-forming rats fed a low-calcium diet.

    PubMed

    Frick, Kevin K; Asplin, John R; Culbertson, Christopher D; Granja, Ignacio; Krieger, Nancy S; Bushinsky, David A

    2014-05-01

    Genetic hypercalciuric stone-forming (GHS) rats demonstrate increased intestinal Ca absorption, increased bone resorption, and reduced renal tubular Ca reabsorption leading to hypercalciuria and all form kidney stones. GHS have increased vitamin D receptors (VDR) at these sites of Ca transport. Injection of 1,25(OH)2D3 (1,25D) leads to a greater increase in urine (u)Ca in GHS than in control Sprague-Dawley (SD), possibly due to the additional VDR. In GHS the increased uCa persists on a low-Ca diet (LCD) suggesting enhanced bone resorption. We tested the hypothesis that LCD, coupled to inhibition of bone resorption by alendronate (alen), would eliminate the enhanced 1,25D-induced hypercalciuria in GHS. SD and GHS were fed LCD and half were injected daily with 1,25D. After 8 days all were also given alen until euthanasia at day 16. At 8 days, 1,25D increased uCa in SD and to a greater extent in GHS. At 16 days, alen eliminated the 1,25D-induced increase in uCa in SD. However, in GHS alen decreased, but did not eliminate, the 1,25D-induced hypercalciuria, suggesting maximal alen cannot completely prevent the 1,25D-induced bone resorption in GHS, perhaps due to increased VDR. There was no consistent effect on mRNA expression of renal transcellular or paracellular Ca transporters. Urine CaP and CaOx supersaturation (SS) increased with 1,25D alone in both SD and GHS. Alen eliminated the increase in CaP SS in SD but not in GHS. If these results are confirmed in humans with IH, the use of bisphosphonates, such as alen, may not prevent the decreased bone density observed in these patients. PMID:24573387

  20. Effect of Sequential Treatments with Alendronate, Parathyroid Hormone (1-34) and Raloxifene on Cortical Bone Mass and Strength in Ovariectomized Rats

    PubMed Central

    Amugongo, Sarah K.; Yao, Wei; Jia, Junjing; Dai, Weiwei; Lay, Yu-An E.; Jiang, Li; Harvey, Danielle; Zimmermann, Elizabeth A.; Schaible, Eric; Dave, Neil; Ritchie, Robert O.; Kimmel, Donald B.; Lane, Nancy E.

    2014-01-01

    Anti-resorptive and anabolic agents are often prescribed for the treatment of osteoporosis continuously or sequentially for many years. However their impact on cortical bone quality and bone strength is not clear. Methods Six-month old female rats were either sham operated or ovariectomized (OVX). OVX rats were left untreated for two months and then were treated with vehicle (Veh), hPTH (1-34) (PTH), alendronate (Aln), or raloxifene (Ral) sequentially for three month intervals, for a total of three periods. Mid-tibial cortical bone architecture, mass, mineralization, and strength were measured on necropsy samples obtained after each period. Bone indentation properties were measured on proximal femur necropsy samples. Results Eight or more months of estrogen deficiency in rats resulted in decreased cortical bone area and thickness. Treatment with PTH for 3 months caused the deposition of endocortical lamellar bone that increased cortical bone area, thickness, and strength. These improvements were lost when PTH was withdrawn without followup treatment, but were maintained for the maximum times tested, six months with Ral and three months with Aln. Pre-treatment with anti-resorptives was also somewhat successful in ultimately preserving the additional endocortical lamellar bone formed under PTH treatment. These treatments did not affect bone indentation properties. Summary Sequential therapy that involved both PTH and anti-resorptive agents was required to achieve lasting improvements in cortical area, thickness, and strength in OVX rats. Anti-resorptive therapy, either prior to or following PTH, was required to preserve gains attributable to an anabolic agent. PMID:25016965

  1. Polycaprolactone-Coated 3D Printed Tricalcium Phosphate Scaffolds for Bone Tissue Engineering: In Vitro Alendronate Release Behavior and Local Delivery Effect on In Vivo Osteogenesis

    PubMed Central

    2015-01-01

    The aim of this work was to evaluate the effect of in vitro alendronate (AD) release behavior through polycaprolactone (PCL) coating on in vivo bone formation using PCL-coated 3D printed interconnected porous tricalcium phosphate (TCP) scaffolds. Higher AD and Ca2+ ion release was observed at lower pH (5.0) than that at higher pH (7.4). AD and Ca2+ release, surface morphology, and phase analysis after release indicated a matrix degradation dominated AD release caused by TCP dissolution. PCL coating showed its effectiveness for controlled and sustained AD release. Six different scaffold compositions, namely, (i) TCP (bare TCP), (ii) TCP + AD (AD-coated TCP), (iii) TCP + PCL (PCL-coated TCP), (iv) TCP + PCL + AD, (v) TCP + AD + PCL, and (vi) TCP + AD + PCL + AD were tested in the distal femoral defect of Sprague–Dawley rats for 6 and 10 weeks. An excellent bone formation inside the micro and macro pores of the scaffolds was observed from histomorphology. Histomorphometric analysis revealed maximum new bone formation in TCP + AD + PCL scaffolds after 6 weeks. No adverse effect of PCL on bioactivity of TCP and in vivo bone formation was observed. All scaffolds with AD showed higher bone formation and reduced TRAP (tartrate resistant acid phosphatase) positive cells activity compared to bare TCP and TCP coated with only PCL. Bare TCP scaffolds showed the highest TRAP positive cells activity followed by TCP + PCL scaffolds, whereas TCP + AD scaffolds showed the lowest TRAP activity. A higher TRAP positive cells activity was observed in TCP + AD + PCL compared to TCP + AD scaffolds after 6 weeks. Our results show that in vivo local AD delivery from PCL-coated 3DP TCP scaffolds could further induce increased early bone formation. PMID:24826838

  2. Persistence of 1,25D-induced hypercalciuria in alendronate-treated genetic hypercalciuric stone-forming rats fed a low-calcium diet

    PubMed Central

    Asplin, John R.; Culbertson, Christopher D.; Granja, Ignacio; Krieger, Nancy S.; Bushinsky, David A.

    2014-01-01

    Genetic hypercalciuric stone-forming (GHS) rats demonstrate increased intestinal Ca absorption, increased bone resorption, and reduced renal tubular Ca reabsorption leading to hypercalciuria and all form kidney stones. GHS have increased vitamin D receptors (VDR) at these sites of Ca transport. Injection of 1,25(OH)2D3 (1,25D) leads to a greater increase in urine (u)Ca in GHS than in control Sprague-Dawley (SD), possibly due to the additional VDR. In GHS the increased uCa persists on a low-Ca diet (LCD) suggesting enhanced bone resorption. We tested the hypothesis that LCD, coupled to inhibition of bone resorption by alendronate (alen), would eliminate the enhanced 1,25D-induced hypercalciuria in GHS. SD and GHS were fed LCD and half were injected daily with 1,25D. After 8 days all were also given alen until euthanasia at day 16. At 8 days, 1,25D increased uCa in SD and to a greater extent in GHS. At 16 days, alen eliminated the 1,25D-induced increase in uCa in SD. However, in GHS alen decreased, but did not eliminate, the 1,25D-induced hypercalciuria, suggesting maximal alen cannot completely prevent the 1,25D-induced bone resorption in GHS, perhaps due to increased VDR. There was no consistent effect on mRNA expression of renal transcellular or paracellular Ca transporters. Urine CaP and CaOx supersaturation (SS) increased with 1,25D alone in both SD and GHS. Alen eliminated the increase in CaP SS in SD but not in GHS. If these results are confirmed in humans with IH, the use of bisphosphonates, such as alen, may not prevent the decreased bone density observed in these patients. PMID:24573387

  3. Difference in Bone Mineral Density Change at the Lateral Femoral Cortices according to Administration of Different Bisphosphonate Agents

    PubMed Central

    Kim, Sungjun; Bang, Hyun Hee; Yoo, Hanna; Lim, Hyunsun; Jung, Woo Seok

    2016-01-01

    Background To retrospectively assess whether the response of subtrochanteric lateral cortex (STLC) is different according to the bisphosphonate agents in terms of bone mineral density (BMD) change. Methods A total of 149 subjects, who had 2- to 4-year interval follow-up of BMD using dual energy X-ray absorptiometry (DXA), were included in this retrospective study divided into following 3 groups: control group (no consumption of any anti-osteoporotic drugs, n=38), alendronate group (naïve alendronate users, n=48), risedronate group (naïve risedronate users, n=63). BMD was measured at the STLC and subtrochanteric medial cortex (STMC) in each patient by drawing rectangular ROIs at the bone cortices. The percent change of BMD at the STLC were compared between the aforementioned 3 groups by using analysis of covariance model to control five independent variables of age, body mass index, percent change of STMC, hip axis length, time interval between DXA examinations. Results The least square mean values±standard deviation of the percent change of BMD in the control, alendronate, and risedronate groups were 1.46±1.50, 2.23±1.26, and 6.96±1.11, respectively. The risedronate group showed significantly higher change of BMD percentage compared with the control (adjusted P=0.012) or alendronate (adjusted P=0.016) groups. Conclusions The percent change of BMD at the STLC in the risedronate user group was greater than the alendronate and control groups. The implication of these changes needs to be further verified. PMID:27294080

  4. Effects of Daily or Cyclic Teriparatide on Bone Formation in the Iliac Crest in Women on No Prior Therapy and in Women on Alendronate.

    PubMed

    Dempster, David W; Cosman, Felicia; Zhou, Hua; Nieves, Jeri W; Bostrom, Mathias; Lindsay, Robert

    2016-08-01

    There is little information on the effects of combination therapy for osteoporosis at the tissue level. Using quadruple tetracycline-labeled bone biopsies, we have compared the bone formation response to teriparatide (TPTD) in treatment-naïve subjects (Rx-Naïve) and in subjects on prior and ongoing alendronate (ALN) treatment (ALN-Rx). Three bone envelopes were analyzed: cancellous, endocortical, and intracortical. TPTD was given as a standard, continuous daily injection or as a cyclic regimen (3 months on daily TPTD, 3 months off, 3 months on daily TPTD). Subjects were biopsied at 7 weeks and at 7 months to allow comparison of the bone formation response to the first and second cycles of TPTD. Baseline values for dynamic bone formation indices were lower in ALN-Rx than Rx-Naïve subjects. Both Rx-Naïve and ALN-RX subjects responded to TPTD with significant increases in bone formation indices at both time points. With cyclic TPTD treatment, the first and second cycles of TPTD stimulated bone formation rate in the cancellous and endocortical envelopes to a similar extent in ALN-Rx and Rx-Naïve subjects. However, in Rx-Naïve patients, bone formation rate (BFR/BS) was higher in patients receiving daily treatment compared with those receiving cyclic TPTD treatment in all three envelopes in the 7-month biopsies. This suggests that the cyclic approach does not provide a skeletal benefit in treatment-naive patients. In the 7-month biopsies, cortical porosity was higher in the Rx-Naïve group receiving daily TPTD than in all other groups. These data provide supporting evidence at the tissue level for previous biochemical and densitometric data suggesting that addition of either cyclic or daily TPTD to ongoing ALN treatment may be an effective approach for patients with severe osteoporosis already treated with ALN who remain at high risk of fracture. © 2016 American Society for Bone and Mineral Research. PMID:26916877

  5. 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

  6. High-resolution peripheral quantitative computed tomography and finite element analysis of bone strength at the distal radius in ovariectomized adult rhesus monkey demonstrate efficacy of odanacatib and differentiation from alendronate.

    PubMed

    Cabal, Antonio; Jayakar, Richa Y; Sardesai, Swanand; Phillips, Eual A; Szumiloski, John; Posavec, Diane J; Mathers, Parker D; Savitz, Alan T; Scott, Boyd B; Winkelmann, Christopher T; Motzel, Sherri; Cook, Lynn; Hargreaves, Richard; Evelhoch, Jeffrey L; Dardzinski, Bernard J; Hangartner, Thomas N; McCracken, Paul J; Duong, Le T; Williams, Donald S

    2013-10-01

    Translational evaluation of disease progression and treatment response is critical to the development of therapies for osteoporosis. In this study, longitudinal in-vivo monitoring of odanacatib (ODN) treatment efficacy was compared to alendronate (ALN) in ovariectomized (OVX) non-human primates (NHPs) using high-resolution peripheral computed tomography (HR-pQCT). Treatment effects were evaluated using several determinants of bone strength, density and quality, including volumetric bone mineral density (vBMD), three-dimensional structure, finite element analysis (FEA) estimated peak force and biomechanical properties at the ultradistal (UD) radius at baseline, 3, 6, 9, 12, and 18 months of dosing in three treatment groups: vehicle (VEH), low ODN (2 mg/kg/day, L-ODN), and ALN (30 μg/kg/week). Biomechanical axial compression tests were performed at the end of the study. Bone strength estimates using FEA were validated by ex-vivo mechanical compression testing experiments. After 18months of dosing, L-ODN demonstrated significant increases from baseline in integral vBMD (13.5%), cortical thickness (24.4%), total bone volume fraction BV/TV (13.5%), FEA-estimated peak force (26.6%) and peak stress (17.1%), respectively. Increases from baseline for L-ODN at 18 months were significantly higher than that for ALN in DXA-based aBMD (7.6%), cortical thickness (22.9%), integral vBMD (12.2%), total BV/TV (10.1%), FEA peak force (17.7%) and FEA peak stress (11.5%), respectively. These results demonstrate a superior efficacy of ODN treatment compared to ALN at the UD radii in ovariectomized NHPs. PMID:23791777

  7. 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

  8. Relative Effectiveness of Osteoporosis Drugs for Preventing Nonvertebral Fracture

    PubMed Central

    Cadarette, Suzanne M.; Katz, Jeffrey N.; Brookhart, M. Alan; Stürmer, Til; Stedman, Margaret R.; Solomon, Daniel H.

    2012-01-01

    Background Little information is available on the comparative effectiveness of osteoporosis pharmacotherapies. Objective To compare the relative effectiveness of osteoporosis treatments to reduce nonvertebral fracture risk among older adults. Design Cohort study. Setting Enrollees in 2 statewide pharmaceutical benefit programs for persons age 65 years or older. Patients 43 135 new recipients of oral bisphosphonates, nasal calcitonin, and raloxifene who began treatment from 2000 to 2005. The mean age was 79 years (SD, 6.9), and 96% were women. Measurements The primary outcome was nonvertebral fracture (hip, humerus, or radius or ulna) within 12 months of treatment initiation. Cox proportional hazard models stratified by state and adjusted for risk factors for fracture were used to compare fracture rates. Alendronate was the reference category in all analyses. Results A total of 1051 nonvertebral fractures were observed within 12 months (2.62 fractures per 100 person-years). No large differences in fracture risk were found between risedronate (hazard ratio [HR], 1.01 [95% CI, 0.85 to 1.21]) or raloxifene (HR, 1.18 [CI, 0.96 to 1.46]) and alendronate. However, among those with a fracture history, raloxifene recipients experienced more nonvertebral fractures within 12 months (HR, 1.78 [CI, 1.20 to 2.63]) compared with alendronate recipients. Patients who received calcitonin experienced more nonvertebral fractures than those who received alendronate (HR, 1.40, [CI, 1.20 to 1.63]). Results were similar in sensitivity analyses that examined different lengths of follow-up (6 months and 24 months), were restricted to hip fracture as the outcome, and were completed in various subgroups. Limitation Confounder adjustment was limited to health care utilization data, and the confidence bounds of some comparisons were too wide to rule out potential clinically important differences between agents. Conclusion Differences in fracture risk between risedronate or raloxifene and

  9. Identification of material parameters based on Mohr-Coulomb failure criterion for bisphosphonate treated canine vertebral cancellous bone

    PubMed Central

    Wang, Xiang; Allen, Matthew R.; Burr, David B.; Lavernia, Enrique J.; Jeremić, Boris; Fyhrie, David P.

    2008-01-01

    Nanoindentation has been widely used to study bone tissue mechanical properties. The common method and equations for analyzing nanoindentation, developed by Oliver and Pharr, are based on the assumption that the material is linearly elastic. In the present study, we adjusted the constraint of linearly elastic behavior and use nonlinear finite element analysis to determine the change in cancellous bone material properties caused by bisphosphonate treatment, based on an isotropic form of the Mohr-Coulomb failure model. Thirty-three canine lumbar vertebrae were used in this study. The dogs were treated daily for 1 year with oral doses of alendronate, risedronate, or saline vehicle at doses consistent, on a mg/kg basis, to those used clinically for the treatment of post-menopausal osteoporosis. Two sets of elastic modulus and hardness values were calculated for each specimen using the Continuous Stiffness Measurement (CSM) method (ECSM and HCSM) from the loading segment and the Oliver-Pharr method (EO-P and HO-P) from the unloading segment, respectively. Young’s modulus (EFE), cohesion (c), and friction angle (ϕ) were identified using a finite element model for each nanoindentation. The bone material properties were compared among groups and between methods for property identification. Bisphosphonate treatment had a significant effect on several of the material parameters. In particular, Oliver-Pharr hardness was larger for both the risedronate- and alendronate-treated groups compared to vehicle and the Mohr-Coulomb cohesion was larger for the risedronate-treated compared to vehicle. This result suggests that bisphosphonate treatment increases the hardness and shear strength of bone tissue. Shear strength was linearly predicted by modulus and hardness measured by the Oliver-Pharr method (r2=0.99). These results show that bisphosphonate-induced changes in Mohr-Coulomb material properties, including tissue shear cohesive strength, can be accurately calculated from

  10. Comparative effects of five bisphosphonates on apoptosis of macrophage cells in vitro.

    PubMed

    Moreau, M F; Guillet, C; Massin, P; Chevalier, S; Gascan, H; Baslé, M F; Chappard, D

    2007-03-01

    Bisphosphonates (BPs) inhibits bone resorption by reducing osteoclastic activity; they induce osteoclast apoptosis. Pathophysiology of prostheses loosening is complex and implies an inflammatory reaction secondary to the phagocytosis of wear debris by macrophages with a secondary increased bone resorption by osteoclasts. BPs inhibit proliferation and cause cell death in macrophages by induction of apoptosis. We have used mouse macrophage-like J774.1 cells to evaluate the effects of five BPs. J774A.1 cells were cultured in a standard culture medium for 2-days. BPs (alendronate, pamidronate, etidronate, risedronate, zoledronic acid) were added in the medium at concentration of 10(-6) to 10(-4)M during 3 days. Cells were studied by fluorescence microscopy after staining with the fluorescent dye Hoescht H33342 and the percentage of apoptotic cells was determined on 300 nuclei. Cells were analyzed by flow cytofluorometry after staining with annexin V-FITC (for counting apoptotic cells) and propidium iodide (for necrotic/late-apoptotic cells) on 2000 cells. Etidronate did not cause significant apoptosis or necrosis, at any concentration. Alendronate and pamidronate caused apoptosis and death only at very high concentration [10(-4)M]. On the contrary, apoptotic and necrotic cells were evidenced with risedronate or zoledronic acid at lower concentrations. These effects were dose-dependant and occurred when concentration reached [10(-5)M]. The number of apoptotic cells was higher with zoledronic acid and then with risedronate. Cytofluorometry appeared superior to cytologic analysis in the investigation of macrophage apoptosis, since necrotic cells loose contact with the glass slides and are not identifiable in cytological counts. Some amino-BPs appear to induce apoptosis in macrophages. PMID:17157266

  11. Atypical femoral fracture following zoledronic acid treatment.

    PubMed

    Ataoğlu, Baybars; Kaptan, Ahmet Yiğit; Eren, Toygun Kağan; Yapar, Ali Ekber; Berkay, Ahmet Fırat

    2016-04-01

    A 68-year-old female patient admitted to our clinic with right anterior thigh pain ongoing for six months and which increased in last two months. The patient had no trauma history. The patient had been followed-up for 15 years because of osteoporosis and administrated alendronate and ibandronate treatment for 10 years. Patient had three shots of zoledronate once a year during the last three years. Her pain was increasing when she was walking. Physical examination revealed pain in her right thigh. Radiogram showed thickened lateral cortex of the subtrochanteric area. Magnetic resonance imaging also showed thickening and edema of the same area. These images were correlated with atypical fracture in right femoral subthrochanteric zone. Dual energy X-ray absorptiometry revealed that T score was -3.3 in lumbar region and -2.5 in femoral neck. Zoledronate treatment was ended. Prophylactic surgical fixation was performed with titanium elastic nails. PMID:26874637

  12. Medical treatment of vertebral osteoporosis.

    PubMed

    Lippuner, K

    2003-10-01

    Although osteoporosis is a systemic disease, vertebral fractures due to spinal bone loss are a frequent, sometimes early and often neglected complication of the disease, generally associated with considerable disability and pain. As osteoporotic vertebral fractures are an important predictor of future fracture risk, including at the hip, medical management is targeted at reducing fracture risk. A literature search for randomized, double-blind, prospective, controlled clinical studies addressing medical treatment possibilities of vertebral fractures in postmenopausal Caucasian women was performed on the leading medical databases. For each publication, the number of patients with at least one new vertebral fracture and the number of randomized patients by treatment arm was retrieved. The relative risk (RR) and the number needed to treat (NNT, i.e. the number of patients to be treated to avoid one radiological vertebral fracture over the duration of the study), together with the respective 95% confidence intervals (95%CI) were calculated for each study. Treatment of steroid-induced osteoporosis and treatment of osteoporosis in men were reviewed separately, based on the low number of publications available. Forty-five publications matched with the search criteria, allowing for analysis of 15 different substances tested regarding their anti-fracture efficacy at the vertebral level. Bisphosphonates, mainly alendronate and risedronate, were reported to have consistently reduced the risk of a vertebral fracture over up to 50 months of treatment in four (alendronate) and two (risedronate) publications. Raloxifene reduced vertebral fracture risk in one study over 36 months, which was confirmed by 48 months' follow-up data. Parathormone (PTH) showed a drastic reduction in vertebral fracture risk in early studies, while calcitonin may also be a treatment option to reduce fracture risk. For other substances published data are conflicting (calcitriol, fluoride) or insufficient

  13. Higher Doses of Bisphosphonates Further Improve Bone Mass, Architecture, and Strength but Not the Tissue Material Properties in Aged Rats

    PubMed Central

    Shahnazari, Mohammad; Yao, Wei; Dai, WeiWei; Wang, Bob; Ionova-Martin, Sophi S.; Ritchie, Robert O.; Heeren, Daniel; Burghardt, Andrew J.; Nicolella, Daniel P.; Kimiecik, Michael G.; Lane, Nancy E.

    2010-01-01

    We report the results of a series of experiments designed to determine the effects of ibandronate (Ibn) and risedronate (Ris) on a number of bone quality parameters in aged osteopenic rats to explain how bone material and bone mass may be affected by the dose of bisphosphonates (BP) and contribute to their anti-fracture efficacy. Eighteen-month old female rats underwent either ovariectomy or sham surgery. The ovariectomized (OVX) groups were left untreated for 2 months to develop osteopenia. Treatments started at 20 months of age as follows: sham and OVX control (treated with saline), OVX+risedronate 30 and 90 (30 or 90 μg/kg/dose), and OVX+ibandronate 30 and 90 (30 or 90 μg/kg/dose). The treatments were given monthly for four months by subcutaneous injection. At sacrifice at 24 months of age the 4th lumbar vertebra was used for μCT scans (bone mass, architecture, and degree of mineralization of bone, DMB) and histomorphometry, and the 6th lumbar vertebra, tibia, and femur were collected for biomechanical testing to determine bone structural and material strength, cortical fracture toughness, and tissue elastic modulus. The compression testing of the vertebral bodies (LVB6) was simulated using finite-element analysis (FEA) to also estimate the bone structural stiffness. Both Ibn and Ris dose-dependently increased bone mass and improved vertebral bone microarchitecture and mechanical properties compared to OVX control. Estimates of vertebral maximum stress from FEA were correlated with vertebral maximum load (r=0.5, p<0.001) and maximum stress (r=0.4, p<0.005) measured experimentally. Tibial bone bending modulus and cortical strength increased compared to OVX with both BP but no dose-dependent effect was observed. DMB and elastic modulus of trabecular bone were improved with Ibn30 compared to OVX but were not affected in other BP-treated groups. DMB of tibial cortical bone showed no change with BP treatments. The fracture toughness examined in midshaft femurs did

  14. 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

  15. 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

  16. 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. PMID:24823811

  17. 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

  18. Bisphosphonate-Related Osteonecrosis of the Jaw: Historical, Ethical, and Legal Issues Associated With Prescribing

    PubMed Central

    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. PMID:25031978

  19. Bisphosphonate-related osteonecrosis of jaw (BRONJ) in Japanese population: a case series of 13 patients at our clinic.

    PubMed

    Nomura, Takeshi; Shibahara, Takahiko; Uchiyama, Takeshi; Yamamoto, Nobuharu; Shibui, Takeo; Yakushiji, Takashi; Watanabe, Akira; Muramatsu, Kyotaro; Ogane, Satoshi; Murayama, Masato; Sekine, Riyo; Nakata, Erika; Fujimoto, Yuko

    2013-01-01

    Bisphosphonate-related osteonecrosis of the jaw (BRONJ) affects quality of life and is an important problem for dentists. A Japanese position paper on BRONJ was published in 2010. The purpose of this study was to review clinical data on the treatment of BRONJ obtained at the Clinic of Oral and Maxillofacial Surgery, Tokyo Dental College, Chiba Hospital to further our understanding of this disease. A total of 13 patients (6 men and 7 women) were included. All the patients included in this study had received Bisphosphonate (BP) therapy and had BRONJ. Five of them (38.5%) had received oral BP therapy for osteoporosis, while the remaining 8 (61.5%) had received parenteral BP therapy for bone metastases from breast or prostate cancer. Osteoporosis patients were treated with risedronate or alendronate. Breast or prostate cancer patients were treated with zoledronate. Two patients with rheumatoid arthritis were treated with corticosteroid. Three patients had diabetes mellitus. Eleven patients were treated with antibiotics, while 5 underwent surgical treatment. Discontinuation of BP was recorded in 7 patients during dental treatment. Sequestration was observed in 6 patients during an 11-month follow-up. Eventually, healing and improvement of the oral mucosa were observed in 3 patients. The current standard treatment for BRONJ does not always provide good results. It is necessary to accumulate further clinical data to establish more effective treatment strategies for BRONJ. PMID:23903583

  20. Osteoporosis in the aging male: treatment options.

    PubMed

    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 exponen-tially 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

  1. [Secondary prevention of osteoporosis and identification of high risk patients].

    PubMed

    Lehmann, R; Pfeifer, M; Minne, H; Allolio, B

    2000-08-01

    Low bone mass is a major determinant of bone fragility. With respect to hip fracture risk however, there is limited contribution of BMD to the exponential age-related increase in hip fracture incidence. Large prospective studies have identified a number of additional risk factors for hip fractures independent of bone density. These can be classified as skeletal factors and fall-related factors. Body height and hip axis length are positively correlated with fracture risk. Neuromuscular impairment with low gait speed, difficulty in doing a tandem walk, lower limb dysfunction, body sway or inability to rise from a chair without using one's arms predict future fracture risk. According to the concept of evidence-based medicine (EBM) preventive strategies are now available. Supplementation with calcium and vitamin D restores bone quality through suppression of secondary hyperparathyroidism and decreases the risk of falling through improvement of neuromuscular co-ordination and body sway. Treatment with the bisphosphonates alendronate and risedronate increase bone strength and result in a significant reduction of vertebral as well as non-vertebral fractures. Hip protectors absorb energy during a fall and reduce hip fracture risk by 56%. Risk factor based patient selection may improve the cost-effectiveness of therapy. PMID:10996933

  2. 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

  3. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2002-12-01

    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: Abacavir sulfate, adalimumab, AERx morphine sulphate, alefacept, alemtuzumab, alendronic acid sodium salt, alicaforsen sodium, almotriptan, amprenavir, aripiprazole, atenolol, atorvastatin calcium; BSYX-A110; Cantuzumab mertansine, capravirine, CDP-571, CDP-870, celecoxib; Delavirdine mesilate, docetaxel, dofetilide, donepezil hydrochloride, duloxetine hydrochloride, dutasteride, dydrogesterone; Efavirenz, emtricitabine, enjuvia, enteryx, epristeride, erlotinib hydrochloride, escitalopram oxalate, etanercept, etonogestrel, etoricoxib; Fesoterodine, finasteride, flt3ligand; Galantamine hydrobromide, gemtuzumab ozogamicin, genistein, gepirone hydrochloride; Indinavir sulfate, infliximab; Lamivudine, lamivudine/zidovudine/abacavir sulfate, leteprinim potassium, levetiracetam, liposomal doxorubicin, lopinavir, lopinavir/ritonavir, losartan potassium; MCC-465, MRA; Nebivolol, nesiritide, nevirapine; Olanzapine, OROS(R)-Methylphenidate hydrochloride; Peginterferon alfa-2a, peginterferon alfa-2b, Pimecrolimus, polyethylene glycol 3350, pramlintide acetate, pregabalin, PRO-2000; Risedronate sodium, risperidone, ritonavir, rituximab, rivastigmine tartrate, rofecoxib, rosuvastatin calcium; Saquinavir mesilate, Stavudine; Tacrolimus, tadalafil, tamsulosin hydrochloride, telmisartan, tomoxetine hydrochloride, treprostinil sodium, trimegestone, trimetrexate; Valdecoxib, venlafaxine hydrochloride; Zoledronic acid monohydrate. PMID:12616965

  4. 76 FR 40735 - Joint Meeting of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-11

    ... the treatment and prevention of osteoporosis (thinning and weakening of bones that increases the... osteoporosis include: FOSAMAX (alendronate sodium) tablets and solution and FOSAMAX PLUS D (alendronate...

  5. 76 FR 21381 - Pediatric Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-15

    ... (azelastine hydrocholoride), Crestor (rosuvastatin calcium), Welchol (colesevelam hydrochloride), Intuniv (guanfacine), Lexapro (escitalopram oxalate), Actonel (risedronate), Hiberix , and Valcyte...

  6. Inflammatory eye reactions in patients treated with bisphosphonates and other osteoporosis medications: cohort analysis using a national prescription database.

    PubMed

    Pazianas, Michael; Clark, Emma M; Eiken, Pia A; Brixen, Kim; Abrahamsen, Bo

    2013-03-01

    Ocular inflammatory reactions have been described in patients on bisphosphonate treatment. We estimated the incidence rate of ocular inflammation at 3 and 12 months in patients treated for osteoporosis using a register-based cohort linked to prescription data (hospitals and private practice) and hospital data. From January 1, 1997 to December 31, 2007, a total of 88,202 patients beginning osteoporosis therapy were identified. Of those patients, 82,404 (93%) began oral bisphosphonates and 5798 (7%) nonbisphosphonates. Within the first year of treatment, 4769 (5.4%) of patients on osteoporosis therapy filled one or more prescriptions for topical eye steroids (TES). TES treatment rates (per 1000 patient-years) in the first year of osteoporosis treatment were 44 (95% confidence interval [CI] 42 to 46) for alendronate, 40 (95% CI 38 to 43) for etidronate, 45 (95% CI 35 to 57) for risedronate, 32 (95% CI 27 to 37) for raloxifene, and 64 (95% CI 49 to 83) for strontium ranelate. After adjustment for age, Charlson index, and the number of comedications, pulmonary disease in men was associated with an increased use of TES (odds ratio [OR] = 1.48; 95% CI 1.17 to 1.86; p = 0.001). In women, malignant disease (OR = 1.27; 95% CI 1.02 to 1.60; p = 0.04) and pulmonary disease (OR = 1.32; 95% CI 1.07 to 1.62; p = 0.01) were significant predictors at 3 months and rheumatic diseases at 12 months (OR = 1.20; 95% CI 1.10 to 1.31; p < 0.001). There was no significant difference between the different drug classes (bisphosphonates versus nonbisphosphonates, alendronate versus nonalendronate-bisphosphonates) for risk of ocular inflammation, with age and the number of comedications being the only significant predictors. Hospital-treated uveitis (48 patients, or 0.05%) showed a similar trend. In conclusion, after initiation of treatment for osteoporosis, the risk of inflammatory eye reactions requiring TES is relatively low and not significantly different

  7. Nitrogen-bisphosphonates block retinoblastoma phosphorylation and cell growth by inhibiting the cholesterol biosynthetic pathway in a keratinocyte model for esophageal irritation.

    PubMed

    Reszka, A A; Halasy-Nagy, J; Rodan, G A

    2001-02-01

    The surprising discovery that nitrogen-containing bisphosphonates (N-BPs) act via inhibition of the mevalonate-to-cholesterol pathway raised the possibility that esophageal irritation by N-BPs is mechanism-based. We used normal human epidermal keratinocytes (NHEKs) to model N-BP effects on stratified squamous epithelium of the esophagus. The N-BPs alendronate and risedronate inhibited NHEK growth in a dose-dependent manner without inducing apoptosis. N-BPs (30 microM) caused accumulation of cells in S phase and increased binucleation (inhibited cytokinesis). Consistent with N-BP inhibition of isoprenylation, geranylgeraniol or farnesol prevented accumulation in S phase. Binucleation was also induced by the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor lovastatin and by the squalene synthase inhibitor zaragozic acid A and was prevented by adding low-density lipoprotein. At 300 microM, N-BPs reduced expression of cyclin-dependent kinase (cdk) 2 and cdk4 and enhanced expression of p21(waf1) and p27(kip1) and their binding to cdks with corollary hypophosphorylation of retinoblastoma. Lovastatin and zaragozic acid A produced similar effects, except that p21(waf1) expression and binding to cdks was not induced. Growth inhibition, but not binucleation, was also caused by the geranylgeranyl transferase I inhibitor, GGTI-298, which also enhanced cdk2 and cdk4 association with p27(kip1). These findings are consistent with suppression of epithelial cell growth by N-BPs via inhibition of the mevalonate pathway and the consequent reduction in cholesterol synthesis, which blocks cytokinesis, and in geranylgeranylation, which interferes with progression through the cell cycle. PMID:11160853

  8. 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. PMID:16038092

  9. Risk of atypical femoral fracture during and after bisphosphonate use

    PubMed Central

    Schilcher, Jörg; Koeppen, Veronika; Aspenberg, Per; Michaëlsson, Karl

    2015-01-01

    Background and purpose Use of bisphosphonates in women is associated with higher risk of atypical femoral fractures. The risk in terms of timing of use and type of bisphosphonate, and in men, remains unclear. Patients and methods We reviewed radiographs of 5,342 Swedish women and men aged 55 years or more who had had a fracture of the femoral shaft in the 3-year period 2008–2010 (97% of those eligible), and found 172 patients with atypical fractures (93% of them women). We obtained data on medication and comorbidity. The risk of atypical fracture associated with bisphosphonate use was estimated in a nationwide cohort analysis. In addition, we performed a case-control analysis with comparison to 952 patients with ordinary shaft fractures. A short report of the findings has recently been presented (Schilcher et al. 2014a). Here we provide full details. Results The age-adjusted relative risk (RR) of atypical fracture associated with bisphosphonate use was 55 (95% CI: 39–79) in women and 54 (CI: 15–192) in men. In bisphosphonate users, women had a 3-fold higher risk than men (RR = 3.1, CI: 1.1–8.4). Alendronate users had higher risk than risedronate users (RR = 1.9, CI: 1.1–3.3). The RR after 4 years or more of use reached 126 (CI: 55–288), with a corresponding absolute risk of 11 (CI: 7–14) fractures per 10,000 person-years of use. The risk decreased by 70% per year since last use. Interpretation Women have a higher risk of atypical femoral fracture than men. The type of bisphosphonate used may affect risk estimates and the risk decreases rapidly after cessation. PMID:25582459

  10. 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.

  11. Management of osteoporosis in a pre-menopausal woman.

    PubMed

    Bhalla, Ashok K

    2010-06-01

    There is no agreed definition of osteoporosis in pre-menopausal women. The International Society for Clinical Densitometry recommends using Z-score, and women with Z-scores of -2.0 or lower should be defined as having a bone density that is 'below the expected range for age'. The diagnosis is more readily made in the presence of a low-trauma fracture. The relationship between low bone mineral density (BMD) in young pre-menopausal women and its associated fracture risk is not the same as in older women with a low BMD. Between 50% and 90% of pre-menopausal women will have an underlying secondary cause, the most common being eating disorders, anorexia nervosa and use of glucocorticoids. Management should focus on identifying the underlying cause and treating it where possible. The use of pharmacological therapy under other circumstances should be considered carefully. Women with only low BMD and no other risk factors probably require no pharmacological intervention. Those with low BMD and secondary causes or with a severely low BMD, or those who have fragility fractures, may require treatment with anti-resorptive agents, which can include oestrogen, bisphosphonates, calcitonin, calcitriol or anabolic therapy with teriparatide. Selective oestrogen receptor modulators (SERMs) should be avoided as they cause further bone loss in menstruating women. Alendronate and risedronate have been licensed for use in glucocorticoid-induced osteoporosis. These drugs accumulate in the human skeleton and have been shown to cross the placenta and accumulate in newborn rats. The effects on human pregnancy are unclear, although normal pregnancies have been reported. Pre-menopausal women with osteoporosis should be followed up until the BMD is stable, which can usually be ascertained by follow-up scans at 18-36-month intervals. PMID:20534366

  12. Community based intervention to optimize osteoporosis management: randomized controlled trial

    PubMed Central

    2010-01-01

    Background Osteoporosis-related fractures are a significant public health concern. Interventions that increase detection and treatment of osteoporosis are underutilized. This pragmatic randomised study was done to evaluate the impact of a multifaceted community-based care program aimed at optimizing evidence-based management in patients at risk for osteoporosis and fractures. Methods This was a 12-month randomized trial performed in Ontario, Canada. Eligible patients were community-dwelling, aged ≥55 years, and identified to be at risk for osteoporosis-related fractures. Two hundred and one patients were allocated to the intervention group or to usual care. Components of the intervention were directed towards primary care physicians and patients and included facilitated bone mineral density testing, patient education and patient-specific recommendations for osteoporosis treatment. The primary outcome was the implementation of appropriate osteoporosis management. Results 101 patients were allocated to intervention and 100 to control. Mean age of participants was 71.9 ± 7.2 years and 94% were women. Pharmacological treatment (alendronate, risedronate, or raloxifene) for osteoporosis was increased by 29% compared to usual care (56% [29/52] vs. 27% [16/60]; relative risk [RR] 2.09, 95% confidence interval [CI] 1.29 to 3.40). More individuals in the intervention group were taking calcium (54% [54/101] vs. 20% [20/100]; RR 2.67, 95% CI 1.74 to 4.12) and vitamin D (33% [33/101] vs. 20% [20/100]; RR 1.63, 95% CI 1.01 to 2.65). Conclusions A multi-faceted community-based intervention improved management of osteoporosis in high risk patients compared with usual care. Trial Registration This trial has been registered with clinicaltrials.gov (ID: NCT00465387) PMID:20799973

  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.

  14. Travelers' Health: Motion Sickness

    MedlinePlus

    ... morphine, meperidine Nonsteroidal analgesics Ibuprophen, naproxen, indomethacin Antidepressants Fluoxetine, paroxitene, sertraline Asthma medication Aminophylline Bisphosphonates Alendronate sodium, ...

  15. Development of Alendronate-conjugated Poly (lactic-co-glycolic acid)-Dextran Nanoparticles for Active Targeting of Cisplatin in Osteosarcoma

    NASA Astrophysics Data System (ADS)

    Liu, Ping; Sun, Liang; Zhou, Dong-Sheng; Zhang, Peng; Wang, Yong-Hui; Li, Dong; Li, Qing-Hu; Feng, Rong-Jie

    2015-12-01

    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.

  16. 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

  17. 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.

  18. Bisphosphonates do not alter the rate of secondary mineralization

    SciTech Connect

    Fuchs R. K.; Miller L.; Faillace M.E.; Allen M.R.; Phipps R.J. and Burr D.B.

    2011-05-18

    Bisphosphonates function to reduce bone turnover, which consequently increases the mean degree of tissue mineralization at an organ level. However, it is not clear if bisphosphonates alter the length of time required for an individual bone-modeling unit (BMU) to fully mineralize. We have recently demonstrated that it takes {approx}350 days (d) for normal, untreated cortical bone to fully mineralize. The aim of this study was to determine the rate at which newly formed trabecular BMUs become fully mineralized in rabbits treated for up to 414 d with clinical doses of either risedronate (RIS) or alendronate (ALN). Thirty-six, 4-month old virgin female New Zealand white rabbits were allocated to RIS (n = 12; 2.4 {micro}g/kg body weight), ALN (n = 12; 2.4 {micro}g/kg body weight), or volume-matched saline controls (CON; n = 12). Fluorochrome labels were administered at specific time intervals to quantify the rate and level of mineralization of trabecular bone from the femoral neck (FN) by Fourier transform infrared microspectroscopy (FTIRM). The organic (collagen) and inorganic (phosphate and carbonate) IR spectral characteristics of trabecular bone from undecalcified 4 micron thick tissue sections were quantified from fluorescently labels regions that had mineralized for 1, 8, 18, 35, 70, 105, 140, 210, 280, and 385 d (4 rabbits per time point and treatment group). All groups exhibited a rapid increase in mineralization over the first 18 days, the period of primary mineralization, with no significant differences between treatments. Mineralization continued to increase, at a slower rate up, to 385 days (secondary mineralization), and was not different among treatments. There were no significant differences between treatments for the rate of mineralization within an individual BMU; however, ALN and RIS both increased global tissue mineralization as demonstrated by areal bone mineral density from DXA. We conclude that increases in tissue mineralization that occur

  19. Bisphosphonates do not Alter the Rate of Secondary Mineralization

    SciTech Connect

    R Fuchs; M Faillace; M Allen; R Phipps; L Miller; D Burr

    2011-12-31

    Bisphosphonates function to reduce bone turnover, which consequently increases the mean degree of tissue mineralization at an organ level. However, it is not clear if bisphosphonates alter the length of time required for an individual bone-modeling unit (BMU) to fully mineralize. We have recently demonstrated that it takes {approx}350 days (d) for normal, untreated cortical bone to fully mineralize. The aim of this study was to determine the rate at which newly formed trabecular BMUs become fully mineralized in rabbits treated for up to 414 d with clinical doses of either risedronate (RIS) or alendronate (ALN). Thirty-six, 4-month old virgin female New Zealand white rabbits were allocated to RIS (n=12; 2.4 {mu}g/kg body weight), ALN (n=12; 2.4 {mu}g/kg body weight), or volume-matched saline controls (CON; n=12). Fluorochrome labels were administered at specific time intervals to quantify the rate and level of mineralization of trabecular bone from the femoral neck (FN) by Fourier transform infrared microspectroscopy (FTIRM). The organic (collagen) and inorganic (phosphate and carbonate) IR spectral characteristics of trabecular bone from undecalcified 4 micron thick tissue sections were quantified from fluorescently labels regions that had mineralized for 1, 8, 18, 35, 70, 105, 140, 210, 280, and 385 d (4 rabbits per time point and treatment group). All groups exhibited a rapid increase in mineralization over the first 18 days, the period of primary mineralization, with no significant differences between treatments. Mineralization continued to increase, at a slower rate up, to 385 days (secondary mineralization), and was not different among treatments. There were no significant differences between treatments for the rate of mineralization within an individual BMU; however, ALN and RIS both increased global tissue mineralization as demonstrated by areal bone mineral density from DXA. We conclude that increases in tissue mineralization that occur following a period

  20. Chronic kidney disease and the skeleton

    PubMed Central

    Miller, Paul D

    2014-01-01

    safety of specific osteoporosis therapies (alendronate, risedronate and denosumab) in stage 4 CKD. This review also discusses how to diagnose and manage fragility fractures across the five stages of CKD. PMID:26273531

  1. Bisphosphonate treatment of type I diabetic mice prevents early bone loss but accentuates suppression of bone formation

    PubMed Central

    Coe, Lindsay M.; Tekalur, Srinivasan Arjun; Shu, Yutian; Baumann, Melissa J.; McCabe, Laura R.

    2016-01-01

    Type I (T1) diabetes is an autoimmune and metabolic disease associated with bone loss. Previous studies demonstrate that T1-diabetes decreases osteoblast activity and viability. Bisphosphonate therapy, commonly used to treat osteoporosis, is demonstrated to inhibit osteoclast activity as well as osteoblast apoptosis. Therefore, we examined the effect of weekly alendronate treatments on T1-diabetes induced osteoblast apoptosis and bone loss. Bone TUNEL assays identified that alendronate therapy prevents the diabetes-induced osteoblast death observed during early stages of diabetes development. Consistent with this, alendronate treatment for 40 days was able to prevent diabetes-induced trabecular bone loss. Alendronate was also able to reduce marrow adiposity in both control diabetic mice compared to untreated mice. Mechanical testing indicated that 40 days of alendronate treatment increased bone stiffness but decreased the work required for fracture in T1-diabetic and alendronate treated mice. Of concern at this later time point, bone formation rate and osteoblast markers, which were already decreased in diabetic mice, were further suppressed in alendronate treated diabetic mice. Taken together, our results suggest that short term alendronate treatment can prevent T1-diabetes-induced bone loss in mice, possibly in part by inhibiting diabetes onset associated osteoblast death, while longer treatment enhanced bone density but at the cost of further suppressing bone formation in diabetic mice. PMID:25641511

  2. Polymer-ceramic Monolithic In-Needle Extraction (MINE) device: Preparation and examination of drug affinity.

    PubMed

    Pietrzyńska, Monika; Tomczak, Rafał; Jezierska, Katarzyna; Voelkel, Adam; Jampílek, Josef

    2016-11-01

    Polymer-ceramic materials were placed in the in-needle device. Polymer-ceramic Monolithic In-Needle Extraction (MINE) device is an extraction device used in sample preparation step but, on the other hand, it can be a tool for examination of interactions between potential antiresorptive drugs and bones. MINE device was used as tool for determination of bisphosphonate affinity to hydroxyapatite. Spectra of prepared materials containing different proportion of the ceramic part were performed with the use of Fourier transform infrared spectroscopy. The extraction of sodium risedronate as standard compound from simulated body fluids was carried out by pumping liquid samples through the MINE device. The amount of sodium risedronate in solutions was examined using UV-VIS spectroscopy. The sorption results of sodium risedronate obtained for monolithic materials containing different amount of hydroxyapatite were compared to the values determined for pure (bulk) hydroxyapatite. Sorption capacity for polymer-ceramic materials placed in the in-needle extraction device was about 0.39mg of sodium risedronate. The complete desorption process was carried out at the level over 95% using various eluents. The results of sorption-desorption experiments allow to deduce on the affinity of sodium risedronate to the ceramic part of sorbent (hydroxyapatite). PMID:27523998

  3. 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

  4. The effect of a bisphosphonate on bone volume and eggshell structure in the hen.

    PubMed

    Thorp, B H; Wilson, S; Rennie, S; Solomon, S E

    1993-12-01

    Bisphosphonates, used in the prevention and treatment of osteoporosis, in man, can prevent bone loss in experimental models of osteoporosis in mammals. In egg-laying hens there is a high incidence of bone fractures which are due to osteoporosis. Alendronate, a bisphosphonate, was given to three groups of hens in mid-lay. Different doses of alendronate were given to each group and group 4 was a control. The birds were killed after 2 weeks of treatment. The hens receiving the highest dosage of alendronate (1 mg/kg every 2nd day) ceased laying and had reduced serum calcium concentrations. Lower dosages of alendronate (0.1 and 0.01 mg/kg every 2nd day) resulted in normal egg production and serum calcium concentrations. Egg shells with ultra-structural features indicative of reduced shell quality were produced by hens on the two higher dosages, but the egg shells from the controls and from the hens on the lowest dosage were considered normal. When alendronate was administered to hens in mid-lay there was no effect on trabecular bone volumes, but there was a reduction in mean medullary bone volume in some groups. In a second experiment, pullets were treated with alendronate (0.01 mg/kg twice a week) before the onset of lay. The pullets were killed after laying their first egg. In the pullets treated with alendronate, this protocol resulted in a significantly greater volume of trabecular (structural) bone at the onset of lay. PMID:18671052

  5. In Vitro Antimalarial Activity of Different Inhibitors of the Plasmodial Isoprenoid Synthesis Pathway.

    PubMed

    da Silva, Marcia F; Saito, Alexandre Y; Peres, Valnice J; Oliveira, Antonio C; Katzin, Alejandro M

    2015-08-01

    Previous studies have shown that fosmidomycin, risedronate, and nerolidol exert antimalarial activity in vitro. We included squalestatin, an inhibitor of the isoprenoid metabolism in Erwinia uredovora, and found that combinations of compounds which act on different targets of the plasmodial isoprenoid pathway possess important supra-additivity effects. PMID:26055383

  6. In Vitro Antimalarial Activity of Different Inhibitors of the Plasmodial Isoprenoid Synthesis Pathway

    PubMed Central

    da Silva, Marcia F.; Saito, Alexandre Y.; Peres, Valnice J.; Oliveira, Antonio C.

    2015-01-01

    Previous studies have shown that fosmidomycin, risedronate, and nerolidol exert antimalarial activity in vitro. We included squalestatin, an inhibitor of the isoprenoid metabolism in Erwinia uredovora, and found that combinations of compounds which act on different targets of the plasmodial isoprenoid pathway possess important supra-additivity effects. PMID:26055383

  7. 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.

  8. Bisphosphonate release profiles from magnetite microspheres.

    PubMed

    Miyazaki, Toshiki; Inoue, Tatsuya; Shirosaki, Yuki; Kawashita, Masakazu; Matsubara, Takao; Matsumine, Akihiko

    2014-10-01

    Hyperthermia has been suggested as a novel, minimally invasive cancer treatment method. After implantation of magnetic nano- or microparticles around a tumour through blood vessels, irradiation with alternating magnetic fields facilitates the efficient in situ hyperthermia even for deep-seated tumours. On the basis of this idea, if the microspheres are capable of delivering drugs, they could be promising multifunctional biomaterials effective for chemotherapy as well as hyperthermia. In the present study, magnetite microspheres were prepared by aggregation of the iron oxide colloid in water-in-oil (W/O) emulsion. The release behaviour of alendronate, a typical bisphosphonate, from the microspheres was examined in vitro as a model of the bone tumour prevention and treatment system. The alendronate was successfully incorporated onto the porous magnetite microspheres in vacuum conditions. The drug-loaded microspheres maintained their original spherical shapes even after shaking in ultrapure water for 3 days, suggesting that they have sufficient mechanical integrity for clinical use. It was attributed to high aggregation capability of the magnetite nanoparticles through van der Waals and weak magnetic attractions. The microspheres showed slow release of the alendronate in vitro, resulting from tight covalent or ionic interaction between the magnetite and the alendronate. The release rate was diffusion-controlled type and well controlled by the alendronate concentration in drug incorporation to the microspheres. PMID:24854985

  9. Suppression of viability and acetyl-LDL metabolism in RAW 264 macrophage-like and smooth muscle cells by bisphosphonates in vitro.

    PubMed

    Tuominen, O M; Hollmén, M; Jaakkola, O; Mönkkönen, J; Ylitalo, R

    2002-10-01

    Etidronate and clodronate are bisphosphonates that inhibit the development of experimental atherosclerosis. Etidronate decreases the intimamedia thickness of carotid artery even in man. Liposome-encapsulated bisphosphonates inhibit the cellular metabolism of atherogenic, modified low-density lipoprotein (acetyl-LDL) by cultured macrophages. In the present study, the effects of new bisphosphonate tiludronate and nitrogen-containing bisphosphonate alendronate on cell viability and cellular uptake and degradation of acetyl-LDL were investigated in vitro with macrophages and arterial smooth muscle cells, which have a significant role in atherogenesis. Tiludronate and alendronate decreased the viability of RAW 264 macrophages at high concentration (1,000 microM; p < 0.05), while liposome-encapsulated drugs suppressed the viability at concentrations of 30-300 microM. At concentrations greater than or equal to 10 microM, tiludronate and alendronate inhibited the uptake and degradation of acetyl-LDL by RAW 264 cells in a concentration-dependent manner (p < 0.001). None of the bisphosphonates affected the viability of smooth muscle cells, and none but alendronate at a high concentration (1,000 microM) inhibited the uptake and degradation of acetyl-LDL by smooth muscle cells. The results show that tiludronate and alendronate inhibit the atherogenic activity of macrophages in vitro, as shown previously with etidronate and clodronate, providing further evidence for the antiatherogenic effects of bisphosphonates. PMID:12500427

  10. Systematic review of the use of bone turnover markers for monitoring the response to osteoporosis treatment: the secondary prevention of fractures, and primary prevention of fractures in high-risk groups.

    PubMed Central

    Burch, Jane; Rice, Stephen; Yang, Huiqin; Neilson, Aileen; Stirk, Lisa; Francis, Roger; Holloway, Paul; Selby, Peter; Craig, Dawn

    2014-01-01

    BACKGROUND There is currently no standard practice for the monitoring of patients receiving treatment for osteoporosis. Repeated dual-energy X-ray absorptiometry (DXA) is commonly used for monitoring treatment response, but it has its limitations. Bone turnover markers have advantages over DXA as they are non-invasive, relatively cheap and can detect changes in bone turnover rates earlier. However, they do have disadvantages, particularly high within- and between-patient variability. The ability of bone turnover markers to identify treatment non-responders and predict future fracture risk has yet to be established. OBJECTIVES We aimed to determine the clinical effectiveness, test accuracy, reliability, reproducibility and cost-effectiveness of bone turnover markers for monitoring the response to osteoporosis treatment. DATA SOURCES We searched 12 electronic databases (including MEDLINE, EMBASE, The Cochrane Library and trials registries) without language restrictions from inception to March 2012. We hand-searched three relevant journals for the 12 months prior to May 2012, and websites of five test manufacturers and the US Food and Drug Administration (FDA). Reference lists of included studies and relevant reviews were also searched. REVIEW METHODS A systematic review of test accuracy, clinical utility, reliability and reproducibility, and cost-effectiveness of two formation and two resorption bone turnover markers, in patients being treated for osteoporosis with any of bisphosphonate [alendronate (Fosamax, MSD), risedronate (Actonel, Warner Chilcott Company), zolendronate (Zometa, Novartis)], raloxifene (Evista, Eli Lilly and Company Ltd), strontium ranelate (Protelos, Servier Laboratories Ltd), denosumab (Prolia, Amgen Ltd) or teriparatide (Forsteo, Eli Lilly and Company Ltd), was undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Given the breadth of the review question, a range of study designs

  11. ONO-5334, a cathepsin K inhibitor, improves bone strength by preferentially increasing cortical bone mass in ovariectomized rats.

    PubMed

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

    2014-11-01

    This study compared the effects of ONO-5334, a cathepsin K inhibitor, with those of alendronate on bone mass and strength in ovariectomized rats. Ovariectomy resulted in significant elevation in urinary deoxypyridinoline and plasma C-terminal cross-linking telopeptide of type I collagen (CTX) 8 weeks after surgery. Peripheral quantitative computed tomography analysis showed that total, trabecular, and cortical bone mineral content (BMC) decreased in the proximal tibia, which was paralleled with a significant decline in bone strength. Treatment with ONO-5334 (0.12, 0.6, 3 or 15 mg/kg) once daily for 8 weeks dose-dependently restored the decrease in total BMC and bone mineral density (BMD) in the proximal tibia and suppressed urinary deoxypyridinoline and plasma CTX levels. Alendronate (1 mg/kg, once daily) also fully restored these bone mass parameters. Separate analysis of trabecular and cortical bones, however, showed that ONO-5334 only partially restored trabecular BMD and BMC at 15 mg/kg, whereas alendronate fully restored these parameters. On the other hand, ONO-5334 increased both cortical BMD and BMC with an effect more potent than that of alendronate. Bone geometric analysis indicated that ONO-5334 at 15 mg/kg decreased endosteal circumference without affecting periosteal circumference, resulting in marked increase in cortical thickness. Interestingly, the effects of ONO-5334 on bone strength parameters were more prominent than those of alendronate, although the two test compounds had a similar effect on total BMC. Taken together, our results indicate that ONO-5334 has pharmacological characteristics different from those of alendronate and may offer a unique therapy for patients with osteoporosis. PMID:24317478

  12. Sol-gel derived titania coating with immobilized bisphosphonate enhances screw fixation in rat tibia.

    PubMed

    Linderbäck, Paula; Areva, Sami; Aspenberg, Per; Tengvall, Pentti

    2010-08-01

    A variety of surface modifications have been tested for the enhancement of screw fixation in bone, and locally delivered anti-osteoporosis drugs such as bisphosphonates (BP) are then of interest. In this in vivo study, the impact of surface immobilized BP was compared with systemic BP delivery and screws with no BP. After due in vitro characterization, differently treated stainless steel (SS) screws were divided into four groups with 10 rats each. Three of the groups received screws coated with sol-gel derived TiO(2) and calcium phosphate (SS+TiO(2)+CaP). One of these had no further treatment, one had alendronate (BP) adsorbed to calcium phosphate mineral, and one received systemic BP treatment. The fourth group received uncoated SS screws and no BP (control). The screw pullout force was measured after 4 weeks of implantation in rat tibiae. The immobilized amount and release rate of alendronate could be controlled by different immersion times. The SS+TiO(2)+CaP coating did not increase the pullout force compared to SS alone. Surface delivered alendronate enhanced the pullout force by 93% [p = 0.000; 95% Confidence Interval (CI): 67-118%] compared to SS, and by 39% (p = 0.044; 95% CI: 7-71%) compared to systemic alendronate delivery. Both surface immobilized and systemically delivered alendronate improved implant fixation. Also, locally delivered, that is, surface immobilized alendronate showed a better fixation than systemically delivered. Using sol-gel derived TiO(2) as a platform, it is possible to administer controllable amounts of a variety of BPs. PMID:20186735

  13. Prospective study of profile of hepatic osteodystrophy in patients with non-choleastatic liver cirrhosis and impact of bisphosphonate supplementation

    PubMed Central

    Bansal, Rinkesh Kumar; Kumar, Mandhir; Kumar, Ashish

    2015-01-01

    Background and objectives Patients with liver cirrhosis are more prone to develop reduced bone mineral density (BMD), i.e. hepatic osteodystrophy (HOD). There are few data on the prevalence of HOD in the Indian population and its treatment. We aimed to determine the prevalence of HOD, factors associated with it and the impact of bisphosphonates on BMD in patients with liver cirrhosis. Patients and methods Consecutive patients with liver cirrhosis admitted at Sir Ganga Ram Hospital, New Delhi, between August 2012 and July 2013 were enrolled. Patients with chronic kidney disease, hyperparathyroidism and those on steroids were excluded. BMD was measured by dual-energy X-ray absorptiometry (DEXA) at the lumbar spine and femoral neck. Osteopenia and osteoporosis were defined according to WHO criteria. Ibandronic acid 150 mg per day orally for six months was given to patients with osteoporosis and DEXA scan repeated. Results A total of 215 patients (males 179, 83%) with a mean age of 50.9 ± 11 years were enrolled in this study. Prevalence of HOD was found to be 66% (142/215). On multivariate analysis BMI, TLC, total serum bilirubin and transient elastography values were found to be independently associated with HOD. All the patients with osteoporosis (n = 47) were treated with ibandronic acid as per protocol. Treated patients had significant improvement in DEXA scans after six months as compared to baseline. Conclusions HOD was seen in two-thirds of patients with liver cirrhosis. Higher liver stiffness as determined by transient elastography is significantly associated with HOD. Severity scores of liver disease (CTP and MELD) and etiology of liver cirrhosis did not determine HOD. Ibandronic acid is a safe drug that showed significant improvement in BMD in patients with liver disease along with osteoporosis. PMID:26966526

  14. 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.

  15. 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.

  16. Studies of the Effectiveness of Bisphosphonate and Vanadium-Bisphosphonate Compounds In Vitro against Axenic Leishmania tarentolae

    PubMed Central

    Christensen, Amy T.; McLauchlan, Craig C.; Dolbecq, Anne; Mialane, Pierre; Jones, Marjorie A.

    2016-01-01

    Leishmaniasis is a disease that is a significant problem for people, especially in tropical regions of the world. Current drug therapies to treat the disease are expensive, not very effective, and/or of significant side effects. A series of alkyl bisphosphonate compounds and one amino bisphosphonate compound, as well as alendronate and zoledronate, were tested as potential agents against Leishmania tarentolae. Also, two polyoxometalates (POMs) with nitrogen-containing bisphosphonate ligands, vanadium/alendronate (V5(Ale)2) and vanadium/zoledronate (V3(Zol)3), were tested against L. tarentolae and compared to the results of the alendronate and zoledronate ligands alone. Of the compounds evaluated in this study, the V5(Ale)2 and V3(Zol)3 complexes were most effective in inhibiting the growth of L. tarentolae. The V5(Ale)2 complex had a larger impact on cell growth than either alendronate or orthovanadate alone, whereas zoledronate itself has a significant effect on cell growth, which may contribute to the activity of the V3(Zol)3 complex. PMID:27034744

  17. Studies of the Effectiveness of Bisphosphonate and Vanadium-Bisphosphonate Compounds In Vitro against Axenic Leishmania tarentolae.

    PubMed

    Christensen, Amy T; McLauchlan, Craig C; Dolbecq, Anne; Mialane, Pierre; Jones, Marjorie A

    2016-01-01

    Leishmaniasis is a disease that is a significant problem for people, especially in tropical regions of the world. Current drug therapies to treat the disease are expensive, not very effective, and/or of significant side effects. A series of alkyl bisphosphonate compounds and one amino bisphosphonate compound, as well as alendronate and zoledronate, were tested as potential agents against Leishmania tarentolae. Also, two polyoxometalates (POMs) with nitrogen-containing bisphosphonate ligands, vanadium/alendronate (V5(Ale)2) and vanadium/zoledronate (V3(Zol)3), were tested against L. tarentolae and compared to the results of the alendronate and zoledronate ligands alone. Of the compounds evaluated in this study, the V5(Ale)2 and V3(Zol)3 complexes were most effective in inhibiting the growth of L. tarentolae. The V5(Ale)2 complex had a larger impact on cell growth than either alendronate or orthovanadate alone, whereas zoledronate itself has a significant effect on cell growth, which may contribute to the activity of the V3(Zol)3 complex. PMID:27034744

  18. Osteoporosis in women.

    PubMed

    Bowman, M A; Spangler, J G

    1997-03-01

    Many preventive and treatment strategies are now available for osteoporosis, offering many women the opportunity to forego its many complications. Exercise with calcium and vitamin D supplements is recommended for most patients. Estrogens are a preferred treatment but not acceptable to many women. Alendronate, a bisphosphonate, recently became available to treat osteoporosis. Calcitonin, subcutaneous or intranasal, also can be useful. PMID:9016728

  19. 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

  20. Which Bisphosphonate? It's the Compliance!: Decision Analysis

    PubMed Central

    Lee, You Jin; Park, Chan Ho; Ha, Yong-Chan; Koo, Kyung-Hoi

    2016-01-01

    Background The best options of several bisphosphonates for prevention of osteoporotic fractures in postmenopausal women remain controversial. We determined which bisphosphonate provides better efficacy in prevention of osteoporotic fractures using a decision analysis tool, in terms of quality of life. Methods A decision analysis model was constructed containing final outcome score and the probability of vertebral and hip fracture within 1 year. Final outcome was defined as health-related quality of life, and was used as an utility in the decision tree. Probabilities were obtained by literature review, and health-related quality of life was evaluated by consensus committee. A roll back tool was used to determine the best bisphosphonate, and sensitivity analysis was performed to compensate for decision model uncertainty. Results The decision model favored bisphosphonate with higher compliance in terms of quality of life. In one-way sensitivity analysis, ibandronate was more beneficial than the others, when probability of compliance on ibandronate was above 0.589. Conclusions In terms of quality of life, the decision analysis model showed that compliance was most important for patients in real world, regardless of type of bisphosphonate.

  1. Management of the adverse effects associated with intravenous bisphosphonates.

    PubMed

    Tanvetyanon, T; Stiff, P J

    2006-06-01

    Intravenous bisphosphonates are widely used to treat hypercalcemia and to reduce skeletal-related morbidity among cancer patients. However, serious complications, generally occurring in less than 2% of patients participated in phase III clinical trials, including acute systemic inflammatory reaction, ocular inflammation, renal failure, nephrotic syndrome, electrolyte imbalance, and osteonecrosis of the maxilla and mandible have all been increasingly reported. Yet, strategies to deal with these complications are becoming clear. Acute systemic inflammatory reaction is often self-limited and becomes less intense during subsequent treatments. For patients who develop ocular symptoms, prompt ophthalmologic evaluation is crucial to determine the safety of a subsequent bisphosphonate therapy. Patients who receive long-term pamidronate should be evaluated at intervals for early sign of nephritic syndrome as timely cessation of the agent may result in a full recovery. To reduce the risk of severe electrolyte abnormalities, particularly hypocalcemia, correcting any pre-treatment electrolyte abnormality and supplementing vitamin D and calcium may be helpful. Finally, to reduce the risk of osteonecrosis of the maxilla and mandible, obtaining a full dental evaluation before treatment and avoidance of invasive dental procedures is suggested. The three commonly used intravenous bisphosphonates (pamidronate, zoledronic acid, and ibandronate), are generally safe; ibandronate has to date been the least reported to be associated with renal side effects. As clinical indications of intravenous bisphosphonates continue to expand, prescribing clinicians should be familiar with these possible adverse effects and discuss them with patients before commencing or continuing on therapy. PMID:16547070

  2. Restoring and Maintaining Bone in Osteopenic Female Rat Skeleton. Part 1; Changes in Bone Mass and Structure

    NASA Technical Reports Server (NTRS)

    Tang, Li Ya; Jee, Webster S. S.; Ke, Hua Zhu; Kimmel, Donald B.

    1992-01-01

    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 anabolic agents to restore bone mass and architecture (+ phase) and then switches to an agent with the established ability to maintain bone mass, to keep the new bone (+/- phase). The purpose of this study was to learn whether switching to an agent known chiefly for its ability to maintain existing bone mass preserves new bone induced by PGE2, in osteopenic,estrogen-depleted rats. The current study had three phases, the bone loss (-), restore (+), and maintain (+/-) phases. We ovariectomized (OX) or sham ovariectomized (sham-OX) 5.5 month-old female rats (- phase). The OX rats were treated 5 months postovariectomy with 1-6 mg PGE2, per kg/day for 75 days to restore lost cancellous bone mass (+ phase), and then PGE2, treatment was stopped and treatment began with 1 or 5 micro-g/kg of risedronate, a bisphosphonate, twice a week for 60 days (+/- phase). During the loss (-) phase, the cancellous bone volume of the proximal tibial metaphysis in the OX rat fell to 19% of initial and 30% of age-matched control levels. During the restore (+) phase, the cancellous bone volume in OX rats doubled. When PGE2 treatment was stopped, however, and no special maintenance efforts were made during the maintain (+/-) phase, the PGE2-induced cancellous bone disappeared. In contrast, the PGE2-induced cancellous bone persisted when the PGE2 treatment was followed by either a 1 or 5 micro-g treatment of risedronate per kg given twice a week for 60 days during the maintain (+/-) phase. The tibial shaft demonstrated very little cortical bone loss during the loss (-) phase in OX rats. The tibial shaft cortical bone fell some 8%. During the restore (+) phase, new cortical bone in OX rats increased by 22%. When PGE2 treatment was stopped and nothing was given during the maintain (+/-) phase, however, all but the PGE2-induced

  3. Bisphosphonate-associated osteonecrosis of the jaw, with healing after teriparatide: a review of the literature and a case report

    PubMed Central

    Narongroeknawin, Pongthorn; Danila, Maria I.; Humphreys, Lewis G.; Barasch, Andrei; Curtis, Jeffrey R.

    2014-01-01

    This paper reports the case history of a patient who had bisphosphonate-associated osteonecrosis of the jaw (ONJ) in which adjunctive treatment with teriparatide was used. The patient was treated for 5 years with alendronate for osteoporosis and developed ONJ after extraction of maxillary teeth. An implant was placed at the site of the extracted teeth. The pathology report confirmed the clinical diagnosis of ONJ; treatment was changed from alendronate to teriparatide and the ONJ resolved. To our knowledge, this is the third case history reported in the literature in which teriparatide was successfully used as adjunct therapy in ONJ because it has an anabolic effect and presumed role in accelerating bone healing. ONJ is a serious but infrequent condition that has been recently associated with nitrogen-containing bisphosphonate therapy. Teriparatide may be a useful adjunctive therapy when ONJ develops. PMID:20415805

  4. 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; Sibonga, Jean; Keyak, Joyce; Nakamura, Toshitaka; Kohri, Kenjiro; Ohshima, Hiroshi; Moralez, Gilbert

    2014-01-01

    The bisphosphonate study is an international collaboration between the NASA and JAXA space agencies to investigate the potential value of antiresorptive drugs to mitigate the well-established bone changes associated with long-duration spaceflight. Our hypothesis is that an antiresorptive drug in combination with in-flight exercise will ameliorate bone loss and hypercalcuria during long-duration spaceflight. We have completed data analysis for 7 crewmembers treated with alendronate during flight and 3 of 10 controls without treatment. We previously reported the pre/postflight changes in bone density and the pre versus in-flight changes in various biomarkers in crewmembers taking alendronate during flight. The purpose of this report is to compare these results with the 12- month follow-up data. The table below presents these data as a percentage change from baseline either immediately postflight or in-flight (biochemical markers) with a 1-year follow-up.

  5. [Bone metastases in breast carcinoma].

    PubMed

    Teut, Michael; Warning, Albrecht

    2006-02-01

    The case of a 66-year-old patient with multiple osteolytic bone metastases caused by breast cancer is presented. The patient refused conventional pain therapy although she suffered from severe pain. A complementary therapy with homoeopathic high potencies, devil's-claw extract, enzymes, alendronate and orthomolecular substitution as well as physiotherapy resulted in effective pain relief over a period of 1 year. The case is discussed. PMID:16582551

  6. Fluoxetine-induced pill oesophagitis

    PubMed Central

    Wani, Abdul Majid; Shiekh, Abdul Gaffar; Hussain, Waleed M; Miamini, Wail Al; Khoujah, Amer M; Zayyani, Najah R

    2011-01-01

    Pill-induced oesophagitis is well reported in people of all ages (range 3–98 years), with females outnumbering males by 1.5:1. Antibiotic pills, cardiac pills and non-steroidal anti-inflammatory drugs and alendronate are the most common culprits. We report a case of fluoxetine-induced pill oesophagitis in a young adult without any underlying pathological abnormalities of the oesophagus. PMID:22693306

  7. Effect of low-level laser therapy on oral keratinocytes exposed to bisphosphonate.

    PubMed

    Lee, Jae-Yeol; Kim, In-Ryoung; Park, Bong-Soo; Kim, Yong-Deok; Chung, In-Kyo; Song, Jae-Min; Shin, Sang-Hun

    2015-02-01

    Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a side effect of bisphosphonate therapy. However, its pathophysiology is not yet fully elucidated, and effective treatment of BRONJ remains unclear. The aim of this study is to investigate the effects of alendronate on oral keratinocytes and of low-level laser therapy (LLLT) on alendronate-treated keratinocytes, specifically by evaluating their viability, apoptosis, and wound healing function after irradiation. Oral keratinocyte cells (HaCaT) were exposed to 25 μM alendronate. Then, laser irradiation was performed with a low-level Ga-Al-As laser (λ = 808 ± 3 nm, 80 mW, and 80 mA; NDLux, Seoul, Korea) using 1.2 J/cm(2) energy dose. Viability was analyzed using MTT assay. Apoptosis was measured by Hoechst staining, caspase assay. Changes in secretion of IL-8, VEGF, and collagen type I were studied by ELISA and immunofluorescence microscopy. Scratch wound assays were also performed to measure cellular migration. Our results show that alendronate inhibits keratinocyte viability, expression of IL-8, VEGF, and collagen type I which are intimately related to healing events and cell migration while promoting apoptosis. Our results serve to demonstrate the utility of LLLT in partially overcoming the inhibitory effects of this bisphosphonate. From these results, the authors believe that the present study will provide an experimental basis for a fuller explanation of the clinical effects of LLLT as a BRONJ treatment modality. PMID:23835780

  8. Differences in osteoclast formation between proximal and distal tibial osteoporosis in rats with adjuvant arthritis: inhibitory effects of bisphosphonates on osteoclasts.

    PubMed

    Shu, Goukei; Yamamoto, Kaname; Nagashima, Masakazu

    2006-01-01

    Patients with rheumatoid arthritis commonly suffer both systemic and periarticular osteoporosis. Bisphosphonates (BPs) are inhibitors of bone resorption, and several derivatives have been developed for treatment of enhanced bone resorption. We aimed to characterize osteoclast formation in two different sites, the proximal tibial and distal tibial areas, in rats with adjuvant arthritis, and to investigate the impact of amino or non-amino types of bisphosphonate. Adjuvant arthritis was initiated in rats while administering daily injections of either etidronate, a non-amino BP, or alendronate, an amino BP, for 3 weeks. On the day following the last injection, bone mineral density (BMD) was measured in the proximal tibia to assess systemic osteoporosis and in the distal tibia for periarticular osteoporosis using dual-energy X-ray absorptiometry. Subsequently, bone marrow cells from either end of the tibia were collected and incubated for 7 days before staining and counting tartrate-resistant acid phosphatase positive cells. In the rats with adjuvant arthritis, BMD of either end of the tibia was lower than in normal rats. Although etidronate prevented bone mineral loss at both ends, distal loss was significantly less than proximal. In contrast, alendronate significantly inhibited mineral loss primarily in the proximal area. Large osteoclasts, defined as having five or more nuclei, formed preferentially in the proximal tibia, while small osteoclasts with fewer than four nuclei were found mainly distally. The suppressive effect of alendronate was greater on the large osteoclasts, while etidronate had a greater effect on the small osteoclasts. These results show that the size and multinuclearity of osteoclasts and the number of osteoclasts formed are different in the distal and proximal areas of the tibia, and that alendronate and etidronate may suppress different types of osteoclasts as discriminated by the number of nuclei. PMID:17164994

  9. Bisphosphonate-Related Osteonecrosis of the Jaw After Tooth Extraction.

    PubMed

    Ribeiro, Ney Robson Bezerra; Silva, Leonardo de Freitas; Santana, Diego Matos; Nogueira, Renato Luiz Maia

    2015-10-01

    Bisphosphonates are widely used for treatment or prevention of bone diseases characterized by high osteoclastic activity. Among the oral medicines used to treat osteoporosis, alendronate has been often used. Despite of the low rate of complications on its use, cases of osteonecrosis of the jaw have been reported on literature after tooth extractions. The main symptoms include pain, tooth mobility, swelling, erythema, and ulceration. The risk factors related to osteonecrosis of the jaw associated with bisphosphonate are exposition time to the medicine, routes of administration, and oral surgical procedures performed. The aim of this work is to report a case of a patient showing osteonecrosis of the jaw associated with the use of oral bisphosphonates after tooth extractions. The patient was treated through the suspension of the alendronate with the removal of the necrotic tissue and the foci of infection. After a year's follow-up, the patient showed no recurrence signs. From the foregoing, the interruption of the alendronate use and the surgical treatment associated to antibiotic therapy showed effective on the patient's treatment. PMID:26468839

  10. The Effect of Osteoporosis Treatments on Fatigue Properties of Cortical Bone Tissue

    PubMed Central

    Brock, Garry R.; Chen, Julia T.; Ingraffea, Anthony R.; MacLeay, Jennifer; Pluhar, G. Elizabeth; Boskey, Adele L.; van der Meulen, Marjolein C.H.

    2015-01-01

    Bisphosphonates are commonly prescribed for treatment of osteoporosis. Long-term use of bisphosphonates has been correlated to atypical femoral fractures (AFF). AFFs arise from fatigue damage to bone tissue that cannot be repaired due to pharmacologic treatments. Despite fatigue being the primary damage mechanism of AFFs, the effects of osteoporosis treatments on fatigue properties of cortical bone are unknown. To examine if fatigue-life differences occur in bone tissue after different pharmacologic treatments for osteoporosis, we tested bone tissue from the femurs of sheep given a metabolic acidosis diet to induce osteoporosis, followed by treatment with a selective estrogen reception modulator (raloxifene), a bisphosphonate (alendronate or zoledronate), or parathyroid hormone (teriparatide, PTH). Beams of cortical bone tissue were created and tested in four-point bending fatigue to failure. Tissues treated with alendronate had reduced fatigue life and less modulus loss at failure compared to other treatments, while tissue treated with PTH had a prolonged fatigue life. No loss of fatigue life occurred with zoledronate treatment despite its greater binding affinity and potency compared to alendronate. Tissue mineralization measured by microCT did not explain the differences seen in fatigue behavior. Increased fatigue life with PTH suggests that current treatment methods for AFF could have beneficial effects for restoring fatigue life. These results indicate that fatigue life differs with each type of osteoporosis treatment. PMID:25642445

  11. Design and Characterization of Double Layered Mucoadhesive System Containing Bisphosphonate Derivative

    PubMed Central

    Mukherjee, Dhrubojyoti; Bharath, Srinivasan

    2013-01-01

    The objective of this study is to evaluate the effect of formulation variables on different evaluation properties such as cumulative percentage release and swelling index in development of two layered buccal mucoadhesive system consisting of a highly water soluble drug risedronate sodium. The mucoadhesive systems were developed with varied concentrations of the polymers (1-2%) using plasticizer/permeation enhancer (25–50% w/w of polymer). Two layered films comprised of risedronate sodium with chitosan (85% deacetylated) and hydroxypropylmethyl cellulose (HPMC 4KM) interpolymer complex of different ratios were prepared by solvent casting method. An impermeable backing membrane of ethyl cellulose was incorporated into the films. The study shows the effect of multipolymeric films on the release of a bisphosphonates derivative. The optimized formulations showed films with uniform drug content (90.91 ± 0.17–105.53% ± 2.15), thickness (0.22 ± 0.01 mm to 0.31 ± 0.06 mm), mucoadhesivity (26 ± 3.61–42.33 ± 2.82 g), and controlled drug release profile up to a period of 10 hours. The films were also studied for swelling index, moisture uptake, viscosity, folding endurance, water vapor transmission rate, and mucoadhesive time. PMID:24455313

  12. Successful Conservative Treatment: Multiple Atypical Fractures in Osteoporotic Patients After Bisphosphate Medication

    PubMed Central

    Kim, Hyo-Sang; Jung, Han Young; Kim, Myeong-Ok; Joa, Kyung-Lim; Kim, Yeo Ju; Kwon, Su-Yeon; Kim, Chang-Hwan

    2015-01-01

    Abstract Bisphosphonates have been commonly used for the treatment of osteoporosis. However, there have been recent case reports of atypical fractures citing their long-term use, which inhibits the turnover of bone components. A 64-year-old woman visited the outpatient clinic with pain in her right thigh and ambulation difficulty. We found fractures at both pedicles of L4 vertebra. subtrochanteric region of right femur, and left femoral shaft upon a radiologic examination. She had taken intravenous ibandronic sodium for osteoporosis over 3 years. We changed the bishophonates to a parathyroid hormone because it was suspected that the multiple fractures were caused by the medication. Further, rehabilitation, including progressive weight bearing, was started. After 3 months of the conservative treatment, she was able to walk independently. In conclusion, it is necessary to evaluate the possibility of atypical fractures in osteoporotic patients when they complain of lower extremity pain and to consider alternative treatments instead of bisphosphonates. PMID:25654380

  13. Restoring and maintaining bone in osteopenic female rat skeleton: I. Changes in bone mass and structure

    NASA Technical Reports Server (NTRS)

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

    1992-01-01

    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 anabolic agents to restore bone mass and architecture (+ phase) and then switches to an agent with the established ability to maintain bone mass, to keep the new bone (+/- phase). The purpose of this study was to learn whether switching to an agent known chiefly for its ability to maintain existing bone mass preserves new bone induced by PGE2 in osteopenic, estrogen-depleted rats. The current study had three phases, the bone loss (-), restore (+), and maintain (+/-) phases. We ovariectomized (OX) or sham ovariectomized (sham-OX) 5.5-month-old female rats (- phase). The OX rats were treated 5 months postovariectomy with 1-6 mg PGE2 per kg/day for 75 days to restore lost cancellous bone mass (+ phase), and then PGE2 treatment was stopped and treatment began with 1 or 5 micrograms/kg of risedronate, a bisphosphonate, twice a week for 60 days (+/- phase). During the loss (-) phase, the cancellous bone volume of the proximal tibial metaphysis in the OX rat fell to 19% of initial and 30% of age-matched control levels. During the restore (+) phase, the cancellous bone volume in OX rats doubled. When PGE2 treatment was stopped, however, and no special maintenance efforts were made during the maintain (+/-) phase, the PGE2-induced cancellous bone disappeared. In contrast, the PGE2-induced cancellous bone persisted when the PGE2 treatment was followed by either a 1 or 5 micrograms treatment of risedronate per kg given twice a week for 60 days during the maintain (+/-) phase. The tibial shaft demonstrated very little cortical bone loss during the loss (-) phase in OX rats. The tibial shaft cortical bone fell some 8%. During the restore (+) phase, new cortical bone in OX rats increased by 22%. When PGE2 treatment was stopped and nothing was given during the maintain (+/-) phase, however, all but the PGE2

  14. Inhibition of RuBisCO cloned from Thermosynechococcus vulcanus and expressed in Escherichia coli with compounds predicted by Molecular Operation Environment (MOE).

    PubMed

    Iwaki, Toshio; Shiota, Kazunori; Al-Taweel, Khaled; Kobayashi, Daisuke; Kobayashi, Atsushi; Suzuki, Kensaku; Yui, Toshifumi; Wadano, Akira

    2008-01-01

    Ribulose 1,5-bisphosphate carboxylase/oxygenase (RuBisCO) of a thermophilic cyanobacterium, Thermosynechococcus vulcanus, was cloned and expressed in Escherichia coli. The purified enzyme had higher thermostability than RuBisCOs isolated from mesophilic cyanobacteria. Prediction of the tertiary structure was performed using the software Molecular Operating Environment (MOE). The predicted structure did not give any clue about the basis of thermostability. Then, the molecular docking of substrates and inhibitors in the catalytic site were carried out to test analogs for consistency of ribulose 1,5-bisphosphate, a RuBisCO substrate. The analogs were searched in the Kyoto Encyclopedia of Genes and Genomes (KEGG), and 99 compounds were selected for the docking. The mol files from LIGAND Database in KEGG were changed to a three dimensional (3D) structure for use in docking simulation. The docking simulation was performed on ASEDock of MOE, and the SiteFinder command suggested about 20 candidates for the docking site of the compounds. Based on the homology of these candidate sites with the xylulose 1,5-bisphosphate (XBP)-binding site of RuBisCO isolated from Synechococcus PCC 6301, one site was selected for the docking simulation. The 40 compounds with the highest docking energies included synthetic organic substances that had never been demonstrated to be inhibitors of RuBisCO. The total docking energies were -102 kcal/mol, -104 kcal/mol, -94.0 kcal/mol, and -57.7 kcal/mol for ribulose 1,5-bisphosphate (RuBP), etidronate, risedronate, and citrate respectively. Kinetic analysis of RuBisCO revealed a K(m) value of 315 microM for RuBP, and K(i) values of 1.70, 0.93, and 2.04 mM for etidronate, risedronate, and citrate respectively. From these values, the binding energies were estimated to be -4.85, -3.84, -4.20, and -3.73 kcal/mol for RuBP, etidronate, risedronate, and citrate respectively. The differences between the values estimated from experimental data and by

  15. Minodronic acid ameliorates vertebral bone strength by increasing bone mineral density in 9-month treatment of ovariectomized cynomolgus monkeys.

    PubMed

    Tanaka, Makoto; Mori, Hiroshi; Kawabata, Kazuhito; Mashiba, Tasuku

    2016-07-01

    The effect of treatment for 9months with minodronic acid, a nitrogen-containing bisphosphonate, on vertebral mechanical strength was examined in ovariectomized (OVX) cynomolgus monkeys. Forty skeletally mature female monkeys were randomized into four OVX groups and one sham group (n=8) based on lumbar bone mineral density (BMD). OVX animals were treated orally with 15 and 150μg/kg QD of minodronic acid or 500μg/kg QD alendronate as a reference drug. Measurements of bone turnover markers and lumbar BMD were conducted at 0, 4 and 8months. Measurements of bone mechanical strength and minodronic acid concentration in vertebral bodies were also performed. OVX resulted in a decrease in lumbar BMD and an increase in bone turnover markers at 4 and 8months, compared to the sham group, and the ultimate load on the lumbar vertebra was decreased in OVX animals. Minodronic acid and alendronate prevented the OVX-induced increase in bone turnover markers and decrease in lumbar BMD. Minodronic acid at 150μg/kg increased the ultimate load on lumbar vertebra compared to untreated OVX animals. Regression analysis revealed that the ultimate load was correlated with lumbar BMD and bone mineral content (BMC), and most strongly with the increase in lumbar BMD and BMC over 8months. In a separate analysis within the sham-OVX controls and minodronic acid and alendronate treatment groups, the ultimate loads were also correlated with BMD and BMC. The load-BMD (BMC) correlation in the minodronic acid group showed a trend for a shift to a higher load from the basal relationship in the sham-OVX controls. These results indicate that treatment with minodronic acid for 9months increases vertebral mechanical strength in OVX monkeys, mainly by increasing BMD and BMC. PMID:27155564

  16. Cost-Effectiveness of Intervention Thresholds for the Treatment of Osteoporosis Based on FRAX(®) in Portugal.

    PubMed

    Marques, Andréa; Lourenço, Óscar; Ortsäter, Gustaf; Borgström, Fredrik; Kanis, John A; da Silva, José António P

    2016-08-01

    Cost-effective intervention thresholds (ITs) based on FRAX(®) were determined for Portugal. Assuming a willingness to pay (WTP) of €32,000 per quality-adjusted life years (QALYs), treatment with generic alendronate is cost effective for men and women aged 50 years or more, with 10-year probabilities for major osteoporotic fractures and hip above 8.8 and 2.5 %, respectively. The aim of the present study was to identify the 10-year probabilities of a major and hip osteoporotic fracture using FRAX(®) validated for Portugal, above which pharmacologic interventions become cost effective in the Portuguese context. A previously developed and validated state transition Markov cohort model was populated with epidemiologic, economic and quality-of-life fracture data from Portugal. Cost-effectiveness of FRAX(®)-based ITs was calculated for generic alendronate and proprietary zoledronic acid, denosumab and teriparatide were compared to "no intervention", assuming a WTP of €32,000 (two times national Gross Domestic Product per capita) per QALYs. In the Portuguese epidemiological and economic context, treatment with generic alendronate was cost effective for men and women aged 50 years or more, with 10-year probabilities at or above 8.8 % for major osteoporotic fractures and 2.5 % for hip fractures. Cost-effective threshold 10-year probabilities for major osteoporotic and hip fractures were higher for zoledronic acid (20.4 and 10.1 %), denosumab (34.9 and 10.1 %) and teriparatide (77.8 and 62.6 %), respectively. A tool is provided to perform the calculation of cost-effective ITs for different medications, according to age group and diverse levels of WTP. Cost-effective ITs, for different medications, age groups and WTP, based on 10-year probabilities of major and hip fracture probabilities calculated with FRAX are provided. PMID:27016370

  17. Periodontitis in Rats Induces Systemic Oxidative Stress That Is Controlled by Bone-Targeted Antiresorptives

    PubMed Central

    Oktay, Sehkar; Chukkapalli, Sasanka S.; Rivera-Kweh, Mercedes F.; Velsko, Irina M.; Holliday, L. Shannon; Kesavalu, Lakshmyya

    2015-01-01

    Background Periodontitis is a chronic, polymicrobial inflammatory disease that degrades connective tissue and alveolar bone and results in tooth loss. Oxidative stress has been linked to the onset of periodontal tissue breakdown and systemic inflammation, and the success of antiresorptive treatments will rely on how effectively they can ameliorate periodontal disease–induced oxidative stress during oral infection. Methods Rats were infected with polybacterial inoculum consisting of Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, as an oral lavage every other week for 12 weeks. Daily subcutaneous injections of enoxacin, bisenoxacin, alendronate, or doxycycline were administered for 6 weeks after 6 weeks of polybacterial infection in rats. The serum levels of oxidative stress parameters and antioxidant enzymes, including glutathione peroxidase, superoxide dismutase, and catalase, were evaluated in each of the infected, treated, and sham-infected rats. Results Rats infected with the periodontal pathogens displayed a five-fold increase in the oxidative stress index compared with controls as a result of increased levels of serum oxidants and decreases in total antioxidant activity. The overall decrease in antioxidant activity occurred despite increases in three important antioxidant enzymes, suggesting an imbalance between antioxidant macromolecules/small molecules production and antioxidant enzyme levels. Surprisingly, the bone-targeted antiresorptives bis-enoxacin and alendronate inhibited increases in oxidative stress caused by periodontitis. Bis-enoxacin, which has both antiresorptive and antibiotic activities, was more effective than alendronate, which acts only as an antiresorptive. Conclusion To the best of the authors’ knowledge, this is the first study to demonstrate that the increased oxidative stress induced by periodontal infection in rats can be ameliorated by bone-targeted antiresorptives. PMID:25101489

  18. Effect of recombinant human bone morphogenetic protein-2 on bisphosphonate-treated osteoblasts

    PubMed Central

    Kwon, Taek-Kyun; Song, Jae-Min; Kim, In-Ryoung; Park, Bong-Soo; Kim, Chul-Hoon; Cheong, In-Kyo

    2014-01-01

    Objectives Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a side effect of bisphophonate therapy that has been reported in recent years. Osteoclastic inactivity by bisphosphonate is the known cause of BRONJ. Bone morphogenetic protein-2 (BMP-2) plays an important role in the development of bone. Recombinant human BMP-2 (rhBMP-2) is potentially useful as an activation factor for bone repair. We hypothesized that rhBMP-2 would enhance the osteoclast-osteoblast interaction related to bone remodeling. Materials and Methods Human fetal osteoblast cells (hFOB 1.19) were treated with 100 µM alendronate, and 100 ng/mL rhBMP-2 was added. Cells were incubated for a further 48 hours, and cell viability was measured using an MTT assay. Expression of the three cytokines from osteoblasts, receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), and macrophage colony-stimulating factor (M-CSF), were analyzed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Results Cell viability was decreased to 82.75%±1.00% by alendronate and then increased to 110.43%±1.35% after treatment with rhBMP-2 (P<0.05, respectively). OPG, RANKL, and M-CSF expression were all decreased by alendronate treatment. RANKL and M-CSF expression were increased, but OPG was not significantly affected by rhBMP-2. Conclusion rhBMP2 does not affect OPG gene expression in hFOB, but it may increase RANKL and M-CSF gene expression. PMID:25551094

  19. 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.

  20. Treatment for Progressive Hearing Loss Due to Paget's Disease of Bone - A Case Report and Literature Review.

    PubMed

    Aoki, Mitsuhiro; Tanahashi, Shigeaki; Mizuta, Keisuke; Kato, Hiroki

    2015-12-01

    Paget's disease is a common bone remodeling disorder that typically begins with excessive bone resorption in the elderly. Bilateral progressive hearing loss is the most frequently encountered complication of Paget's disease. The types of hearing loss identified by audiometry are conductive, sensorineural, or both. However, the precise mechanism of hearing loss remains unclear, and the treatment has been controversial. We present a 73-year-old man who suffered from bilateral progressive hearing loss due to Paget's disease. Potent bisphosphonates, oral risedronate in daily adjusted dosages for 6 months, did not decrease or suppress the worsening of the hearing loss. The Nucleus CI24 Contour electrode array was successfully inserted on the left side without surgical and postoperative complications. The Japanese open set monosyllable word recognition test in a sound field at 65 dB had a result of 74%. This cochlear implantation can be an indication for cases of profound hearing loss due to Paget's disease. PMID:26915163

  1. 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. PMID:22222419

  2. Role of Triticum aestivum aqueous extract in glucocorticoid induced osteoporosis in rats.

    PubMed

    Banji, David; Banji, Otilia J F; Chiluka, Vijaya Laxmi; Abbagoni, Saidulu

    2014-02-01

    Administration of aqueous extract of T. aestivum (200 and 400 mg/kg/day, po, for 30 days) and risedronate (20 microg/kg, sc, five times a week for 30 days) following methyl prednisolone sodium succinate (10 mg/kg, sc, thrice a week for 4 weeks) induced osteoporosis in Wistar rats showed an increase in the serum levels of bone mineral content markers, decrease in the serum and urinary levels of bone resorption markers. An incline in strength of femur and tibia was seen particularly with 400 mg/kg of T. aestivum. Maintenance of calcium homeostasis, formation of collagen and scavenging of free radicals can plausibly be the mode of action of aqueous extract of T. aestivum thereby combating osteoporosis induced by glucocorticoids. PMID:24597148

  3. Torus Palatinus Osteonecrosis Related to Bisphosphonate: A Case Report

    PubMed Central

    Godinho, Mariana; Barbosa, Fabio; Andrade, Felipe; Cuzzi, Tullia; Ramos-e-Silva, Marcia

    2013-01-01

    Introduction Osteonecrosis of the palate is a rare condition which is even rarer when occurring on a torus palatinus and associated with bisphosphonate (BP). Case Presentation We report an uncommon case of osteonecrosis of a torus palatinus. Our patient was a 67-year-old white female who presented with a painful intraoral ulcer associated with necrotic bone tissue of her torus palatinus, due to the chronic use of alendronate. Conclusion We point out the possible causative relationship of BPs and osteonecrosis on torus growth. It is very important to know that torus palatinus and the use of BPs are risk factors for osteonecrosis of the maxilla. PMID:23687490

  4. [Treatment for hepatic osteodystrophy].

    PubMed

    Kaji, Hiroshi

    2015-11-01

    Chronic liver diseases, including liver cirrhosis, are caused by various pathogenesis, such as viral hepatitis, primary biliary cirrhosis, autoimmune hepatitis and steatohepatitis. There have not been enough clinical evidence about the treatment of hepatic osteodystrophy at the present time. Several reports suggested that bisphosphonates, such as alendronate, are effective for an increase in bone mineral density in patients with chronic liver disease. Vitamin D treatment might be useful for the frequent prevalence of vitamin D deficiency in the pathogenesis of hepatic oseodystrophy. The use of estrogens will be limited for the risk of liver dysfunction and hepatocellular carcinoma. PMID:26503875

  5. The effect of teriparatide to alleviate pain and to prevent vertebral collapse after fresh osteoporotic vertebral fracture.

    PubMed

    Tsuchie, Hiroyuki; Miyakoshi, Naohisa; Kasukawa, Yuji; Nishi, Tomio; Abe, Hidekazu; Segawa, Toyohito; Shimada, Yoichi

    2016-01-01

    Vertebral fracture is often seen in osteoporotic patients. Teriparatide is expected to promote bone union. Therefore, we evaluated the action of vertebral collapse prevention by administering teriparatide to vertebral fracture patients. Thirty-four patients with fresh vertebral fracture (48 vertebrae) participated in this study. They were administered either teriparatide (daily 20 µg/day or weekly 56.5 µg/week) or risedronate (17.5 mg/week): ten patients (20 vertebrae) received teriparatide daily (Daily group), 11 patients (15 vertebrae) received teriparatide weekly (Weekly group), and 13 patients (14 vertebrae) received risedronate (RIS group). We compared some laboratory examination items, visual analogue scale (VAS) of low back pain, vertebral collapse rate and local kyphotic angle, and the cleft frequency. In addition, we evaluated 22 vertebral fracture patients (24 vertebrae) who did not take any osteoporotic medicines (Control group). There was no significant difference in any of the scores at the start of treatment. At 8 and 12 weeks after the initial visit, VAS scores in the Daily and Weekly groups were significantly lower than in the RIS group (p < 0.05). At 8 and 12 weeks, the vertebral collapse rate and local kyphotic angle in the Daily group were significantly lower than in the RIS and Control groups (p < 0.01 and p < 0.05, respectively), and those in the Weekly group were significantly lower than in the Control group (p < 0.05). The cleft frequency in the Daily group was significantly lower than in the RIS group (p < 0.05). Teriparatide is promising for the prevention of vertebral collapse progression after vertebral fracture. PMID:25773046

  6. Bioactive glass combined with bisphosphonates provides protection against biofilms formed by the periodontal pathogen Aggregatibacter actinomycetemcomitans.

    PubMed

    Hiltunen, Anna K; Skogman, Malena E; Rosenqvist, Kirsi; Juvonen, Helka; Ihalainen, Petri; Peltonen, Jouko; Juppo, Anne; Fallarero, Adyary

    2016-03-30

    Biofilms play a pivotal role in the progression of periodontitis and they can be treated with antiseptics (i.e. chlorhexidine) or antibiotics, but these therapeutic alternatives are unable of ameliorating periodontal alveolar bone loss, which has been, on the other hand, successfully treated with bone-preserving agents. The improved bone formation achieved in animal models by the combination of two such agents: bioactive glass (BAG) and bisphosphonates has attracted the interest for further exploring dental applications. However, the antimicrobial effects that may result from combining them have not been yet investigated. Here, our aim was to explore the anti-biofilm effects that could result from combining BAG with bisphosphonates, particularly in a dental biofilm model. The experiments were performed with an oral cavity single-specie (Aggregatibacter actinomycetemcomitans) biofilm assay, which was optimized in this contribution. Risedronate displayed an intrinsic anti-biofilm effect, and all bisphosphonates, except clodronate, reduced biofilm formation when combined with BAG. In particular, the anti-biofilm activity of risedronate was significantly increased by the combination with BAG. Since it has been proposed that some of the antimicrobial effects of BAG are caused by local pH changes, studies of pH variations were performed to gain a mechanistic understanding. However, the observed anti-biofilm effects could not be explained with lowered pHs. Overall, these results do provide further support for the promising use of bisphosphonate-BAG combinations in dental applications. These findings are particularly relevant for patients undergoing cancer chemotherapy, or osteoporotic patients, which are known to be more vulnerable to periodontitis. In such cases, bisphosphonate treatment could play a double positive effect: local treatment of periodontitis (in combination with BAG) and systemic treatment of osteoporosis, prevention of hypercalcemia and metastases. PMID

  7. [Efficiency in the prescription of drugs. Impact of a health policy: automatic change to prescription by active ingredient].

    PubMed

    López de Landache, Isabel Elizondo; Braceras Izaguirre, Leire; Echeto García, Ainara; Gardeazabal Romillo, Maria José; Acevedo Heranz, Paloma

    2013-11-01

    In the Basque Country in June 2010 were changed in the electronic prescription system the treatments prescribed by a brand by active ingredients, all the patients who had prescribed these molecules: atorvastatin, clopidogrel, weekly risedronate and losartan-hydrochlorothiazide. The aim of this study was to evaluate the economic impact of this change automated done in June 2010. Retrospective study of the prescriptions made in the Basque Country of the selected active ingredients. The use of generics of these molecules from May to December 2010 increased from 64 points to 87. Particularly clopidogrel increased from 6.25% in generic prescriptions to 93.76%, losartan + hydrochlorothiazide from 17.94% to 93.83%, 18.92% for atorvastatin acid and 96.03% risedronic 1.76% to 65.97%. If we make the estimation of the amount of active ingredient in generic containers that have been dispensed from June to December 2010. If they had dispensed brand drugs you get this quantity of total savings: 8 104 762.22 euros. This work suggests that a program to promote use of generics increased efficiency in the use of drugs. To promote the use of generic drugs is an efficiency measure implemented in the NHS and in the neighboring countries, in recent figures are reached 40% in securities of U.S.A packaging and around 65% in the Basque Country the consume in early 2010 was much lower than these figures stand at 20% and at the end of the year stood at 27% thanks to the measures taken. PMID:24404717

  8. Drug holidays: the most frequent type of noncompliance with calcium plus vitamin D supplementation in persistent patients with osteoporosis

    PubMed Central

    Touskova, Tereza; Vytrisalova, Magda; Palicka, Vladimir; Hendrychova, Tereza; Fuksa, Leos; Holcova, Radka; Konopacova, Jana; Kubena, Ales Antonin

    2015-01-01

    Purpose All current recommendations include calcium and vitamin D (Ca–D) as an integrated part of osteoporosis treatment. The purpose of this pilot study was to analyze compliance with a fixed combination of Ca–D in women persistent with the treatment. Patients and methods An observational study was carried out in three osteocenters in the Czech Republic. Women with osteoporosis ≥55 years of age concurrently treated with oral ibandronate were eligible. Compliance was evaluated in a period of 3 months by Medication Event Monitoring System (MEMS), tablet count, and self-report. Nonpersistence was defined as a MEMS-based gap in the use of Ca–D to be 30 days or more. Results A total of 73 patients were monitored, of which 49 patients were analyzed (target population). Based on MEMS, mean overall compliance was 71%; good compliance (≥80%) was observed in 59% of the patients. As many as 71% of the patients took drug holidays (≥3 consecutive days without intake); overall compliance of these patients was 59% and was slightly lower on Fridays and weekends. Patients without drug holidays were fully compliant (did not omit individual doses). Compliance differed according to daily time at which the patients mostly used the Ca–D. Afternoon/evening takers showed a mean overall compliance of 82% while morning/night takers only 51% (P=0.049). Based on MEMS, tablet count, and self-report, compliance ≥75% was observed in 59%, 100%, and 87% of the patients, respectively. Outcomes obtained by the three methods were not associated with each other. Undesirable concurrent ingestion of Ca–D and ibandronate was present only twice. Conclusion Despite almost perfect self-reported and tablet count-based compliance, MEMS-based compliance was relatively poor. Consecutive supplementation-free days were common; more than two-thirds of the patients took at least one drug holiday. This pilot study showed drug holiday to be the most important type of noncompliance with Ca–D in

  9. Osteotropic therapy via targeted Layer-by-Layer nanoparticles

    PubMed Central

    Morton, Stephen W.; Shah, Nisarg J.; Quadir, Mohiuddin A.; Deng, Zhou J.; Poon, Zhiyong

    2014-01-01

    Current treatment options for debilitating bone diseases such as osteosarcoma, osteoporosis, and bone metastatic cancer are suboptimal and have low efficacy. New treatment options for these pathologies require targeted therapy that maximizes exposure to the diseased tissue and minimizes off-target side effects. This work investigates an approach for generating functional and targeted drug carriers specifically for treating primary osteosarcoma, a disease in which recurrence is common and the cure rate has remained around 20%. Our approach utilizes the modularity of Layer-by-Layer (LbL) assembly to generate tissue-specific drug carriers for systemic administration. This is accomplished via surface modification of drug-loaded nanoparticles with an aqueous polyelectrolyte, poly(acrylic acid) (PAA), side-chain functionalized with alendronate, a potent clinically-used bisphosphonate. Nanoparticles coated with PAA-Alendronate are observed to bind and internalize rapidly in human osteosarcoma 143B cells. Encapsulation of doxorubicin, a front-line chemotherapeutic, in an LbL-targeted liposome demonstrates potent toxicity in vitro. Active targeting of 143B xenografts in NCR nude mice with the LbL-targeted doxorubicin liposomes promotes enhanced, prolonged tumor accumulation and significantly improved efficacy. This report represents a tunable approach towards the synthesis of drug carriers, in which LbL can enable surface modification of nanoparticles for tissue-specific targeting and treatment. PMID:24124132

  10. 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

  11. 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. PMID:26789873

  12. 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

  13. Bilateral atypical femoral subtrochanteric fractures in a premenopausal patient receiving prolonged bisphosphonate therapy: evidence of severely suppressed bone turnover

    PubMed Central

    Kondo, Naoki; Yoda, Takuya; Fujisawa, Junichi; Arai, Katsumitsu; Sakuma, Mayumi; Ninomiya, Hiroshi; Sano, Hiroshige; Endo, Naoto

    2015-01-01

    Summary We report a case of bilateral atypical femoral fractures that occurred in a patient who had been taking bisphosphonate long-term. A 36-year-old premenopausal female diagnosed with systemic lupus erythematosus and dermatomyositis had been treated with glucocorticoid and alendronate (5 mg/day) to prevent glucocorticoid-induced osteoporosis. She was taken to our hospital because she could not walk immediately after falling down from the standing position. A plain radiograph showed a subtrochanteric fracture of the left femur. Four months later, she fell again and sustained a contralateral subtrochanteric fracture. For each fracture, a femoral intramedullary nail was inserted. Delayed union was detected in both sides, and revision surgery with an iliac bone graft was required for implant breakage in the right side. Histomorphometric findings for the ilium revealed remarkably decreased osteoid volume with no osteoclasts and a minimally eroded surface, suggesting that bone turnover was severely suppressed. However, histology of the delayed union site revealed callus formation and some osteoclast appearance, suggesting that fracture healing was occurring. In total, it took 29 months (left) and 24 months (right) until fracture healing was achieved, showing delayed union. This case is extremely rare in that patient who presented with atypical femoral fractures in spite of her premenopausal status. The bone histomorphometric findings from this case suggest that severely suppressed bone turnover is associated with atypical femoral subtrochanteric fracture and can cause delayed union in patients treated with alendronate long-term. PMID:26811712

  14. Secretion of PDGF isoforms during osteoclastogenesis and its modulation by anti-osteoclast drugs.

    PubMed

    Rahman, M Motiur; Matsuoka, Kazuhiko; Takeshita, Sunao; Ikeda, Kyoji

    2015-06-26

    In an attempt to identify secretory products of osteoclasts that mediate the coupling of bone formation to resorption, we found that along with osteoclast differentiation, PDGF-A gene expression increase occurred first, by 12 h after stimulation of bone marrow macrophages with M-CSF and RANKL, and peaked at 36 h. This was next followed by a progressive increase in PDGF-B gene expression until a peak at 60 h, when mature osteoclasts formed. Isoform-specific ELISA of the conditioned medium collected every 24 h revealed that all three of the isoforms of PDGF-AA, AB and BB were secreted, in this temporal order as differentiation proceeded. Their secretion was enhanced when osteoclasts were activated by placing them on dentin slices. The secretion of all three isoforms was decreased in cathepsin K-deficient osteoclasts compared with wild-type osteoclasts. Pharmacological inhibition of cathepsin K with odanacatib also inhibited the secretion of all three isoforms, as was also the case with alendronate treatment. The secretion of sphingosine-1-phosphate, which increased during osteoclastogenesis, was reduced from cathepsin K-deficient osteoclasts, and was inhibited by treatment with odanacatib more profoundly than with alendronate. Thus, all three isoforms of PDGF, which are secreted at distinct differentiation stages of osteoclasts, appear to have distinct roles in the cell-cell communication that takes place in the microenvironment of bone remodeling, especially from the osteoclast lineage to mesenchymal cells and vascular cells, thereby stimulating osteogenesis and angiogenesis. PMID:25951977

  15. Novel therapies for osteoporosis.

    PubMed

    Biskobing, Diane M

    2003-04-01

    Osteoporosis remains a significant clinical problem despite effective therapies. Many patients cannot or will not take currently available therapies. For this reason research continues in search of more effective and more tolerable agents. Anabolic agents offer a unique mechanism of action. The anabolic agents parathyroid hormone and strontium will be discussed. The investigational bisphosphonates ibandronate, minodronate and zoledronic acid may offer the advantage of less frequent dosing. Arzoxifene, bazedoxifene, lasofoxifene, MDL-103,323 and ospemifene are investigational selective oestrogen receptor modulators shown to be effective in animal studies and are now in clinical studies. Tibolone is a tissue-specific steroid that is currently used in Europe for prevention and treatment of osteoporosis. Multiple studies have shown efficacy in improving bone mineral density, but no fracture studies have been conducted to date. While studies of the effect of isoflavones on bone mineral density have been encouraging, a large, multi-centre study in Europe showed no effect of isoflavones on fractures. The newly described agent osteoprotegerin has been shown in early studies to inhibit bone turnover. Other agents with unique mechanisms of action in early development include cathepsin K inhibitors, integrin receptor inhibitors, nitrosylated non-steroidal anti-inflammatory agents and Src inhibitors. The efficacy of statins in bone continues to be debated with no prospective, randomised studies yet to confirm the suggestion of benefit seen in epidemiological studies. PMID:12665416

  16. Incidence and risk predictors for osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates

    PubMed Central

    2015-01-01

    Introduction The aim of this study was to establish the incidence of bisphosphonate-related osteonecrosis of the jaws (BRONJ) in oncologic patients and to determine risk predictors with respect to this condition. Material and methods This retrospective review included 197 oncologic patients treated from January 2005 to December 2010 with administration of bisphosphonates (BPs) as part of management. Sex, age, type of cancer diagnosed, period of substantial disease, oral surgery, type of bisphosphonate, number of doses, and cases of BRONJ diagnosis were recorded. The cumulative incidence and incidence rate of BRONJ were calculated. The factors that influenced BRONJ were assessed with multivariate logistic regression and with estimations of 95% confidence intervals and odd ratios. Values of p ≤ 0.05 were considered significant. Results The BRONJ appeared in 9.64% of patients. The BRONJ incidence rate was 1 in 28 patients per year of BP treatment. Logistic regression showed that the odds of osteonecrosis increased 1.0172-fold with each given dose of BP. The BRONJ risk with zoledronate was 5-fold higher than that with pamidronate or ibandronate. The risk of BRONJ increased by 40-fold after dental surgery. Conclusions Period of BP administration and type of BP used are important risk predictors for the development of BRONJ in oncologic patients treated with intravenous administration of these drugs. Patient-related factors are dental or periodontal events connected with need for oral surgery. PMID:25995747

  17. 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. PMID:25215441

  18. Inhibition of the mevalonate pathway affects epigenetic regulation in cancer cells

    PubMed Central

    Karlic, Heidrun; Thaler, Roman; Gerner, Christopher; Grunt, Thomas; Proestling, Katharina; Haider, Florian; Varga, Franz

    2015-01-01

    The mevalonate pathway provides metabolites for post-translational modifications such as farnesylation, which are critical for the activity of RAS downstream signaling. Subsequently occurring regulatory processes can induce an aberrant stimulation of DNA methyltransferase (DNMT1) as well as changes in histone deacetylases (HDACs) and microRNAs in many cancer cell lines. Inhibitors of the mevalonate pathway are increasingly recognized as anticancer drugs. Extensive evidence indicates an intense cross-talk between signaling pathways, which affect growth, differentiation, and apoptosis either directly or indirectly via epigenetic mechanisms. Herein, we show data obtained by novel transcriptomic and corresponding methylomic or proteomic analyses from cell lines treated with pharmacologic doses of respective inhibitors (i.e., simvastatin, ibandronate). Metabolic pathways and their epigenetic consequences appear to be affected by a changed concentration of NADPH. Moreover, since the mevalonate metabolism is part of a signaling network, including vitamin D metabolism or fatty acid synthesis, the epigenetic activity of associated pathways is also presented. This emphasizes the far-reaching epigenetic impact of metabolic therapies on cancer cells and provides some explanation for clinical observations, which indicate the anticancer activity of statins and bisphosphonates. PMID:25978957

  19. The synthesis of a multiblock osteotropic polyrotaxane by copper(I)-catalyzed huisgen 1,3-dipolar cycloaddition.

    PubMed

    Hein, Christopher D; Liu, Xin-Ming; Chen, Fu; Cullen, Diane M; Wang, Dong

    2010-12-01

    The design and synthesis of a novel bone-targeting polyrotaxane delivery system that utilizes alendronate (ALN) as targeting moiety is presented in this manuscript. For the introduction of ALN, it is first conjugated to α-cyclodextrin (α-CD) and subsequently threaded onto a short poly(ethylene glycol) (PEG) chain, forming a pseudopolyrotaxane. Using click chemistry, this assembly is copolymerized with bulky monomers that bear imaging and/or therapeutic agent(s) to prevent ALN-functionalized α-CD from dethreading. Overall bone affinity of this novel polymer conjugate can be easily controlled by changing the number of ALN-α-CD incorporated. The osteotropicity of the delivery system was also confirmed in vivo. PMID:20954201

  20. Effect of Long-Term Use of Bisphosphonates on Forearm Bone: Atypical Ulna Fractures in Elderly Woman with Osteoporosis.

    PubMed

    Erdem, Yusuf; Atbasi, Zafer; Emre, Tuluhan Yunus; Kavadar, Gülis; Demiralp, Bahtiyar

    2016-01-01

    Osteoporosis is a common musculoskeletal disease of the elderly population characterized by decreased bone mineral density and subsequent fractures. Bisphosphonates are a widely accepted drug therapy which act through inhibition of bone resorption and prevent fractures. However, in long-term use, atypical bisphosphonate induced fractures may occur, particularly involving the lower weight bearing extremity. Atypical ulna fracture associated with long-term bisphosphonate use is rarely reported in current literature. We present a 62-year-old woman with atypical ulna due to long-term alendronate therapy without a history of trauma or fall. Clinicians should be aware of stress fracture in a patient who has complaints of upper extremity pain and history of long-term bisphosphonate therapy. PMID:27595031

  1. Modelling the interaction of several bisphosphonates with hydroxyapatite using the generalised AMBER force field

    NASA Astrophysics Data System (ADS)

    Robinson, Janine; Cukrowski, Ignacy; Marques, Helder M.

    2006-12-01

    The ability of the Generalised AMBER Force Field (GAFF) of Kollman and co-workers to model the structures of bisphosphonate ligands, C(R 1)(R 2)(PO 32-) 2, important compounds in the treatment of bone cancer, by molecular mechanics methods is evaluated. The structure of 50 bisphosphonates and nine bisphosphonate esters were predicted and compared to their crystal structures. Partial charges were assigned from a RHF/6-31G ∗ single point calculation at the geometry of the crystal structure. Additional parameters required for GAFF were determined using the methods of the force field's developers. The structures were found to be well replicated with virtually all bond lengths reproduced to within 0.015 Å, or within 1.2 σ of the crystallographic mean. Bond angles were reproduced to within 1.9° (0.8 σ). The observed gauche or anti conformation of the molecules was reproduced, although in several instances gauche conformations observed in the solid state energy-minimised into anti conformations, and vice versa. The interaction of MDP (R 1 = R 2 = H), HEDP (R 1 = OH, R 2 = CH 3), APD (R 1 = OH, R 2 = (CH 2) 2NH 3+), alendronate (R 1 = OH, R 2 = (CH 2) 3NH 3+) and neridronate (R 1 = OH, R 2 = (CH 2) 5NH 3+) with the (001), (010) and (100) faces of hydroxyapaptite was examined by energy-minimising 20 random orientations of each ligand 20 Å from the mineral (where there is no interaction), and then at about 8 Å from the surface whereupon the ligand relaxes onto the surface. The difference in energy between the two systems is the interaction energy. In all cases interaction with hydroxyapatite caused a decrease in energy. When modelled with a dielectric constant of 78 ɛo, non-bonded interactions dominate; electrostatic interactions become important when the dielectric constant is <10 ɛo. Irrespective of the value of the dielectric constant used, the structure of the ligands on the hydroxyapatite surface is very similar. On the (001) face, both phosphonate groups

  2. The effect of metyrosine/prednisolone combination to oophorectomy-induced osteoporosis

    PubMed Central

    Salman, Suleyman; Kumbasar, Serkan; Hacimuftuoglu, Ahmet; Ozturk, Berna; Seven, Bedri; Polat, Beyzagul; Gundogdu, Cemal; Demirci, Elif; Yildirim, Kadir; Akcay, Fatih; Uslu, Turan; Tuncel Daloglu, Ferrah; Suleyman, Halis

    2012-01-01

    Background: Osteoporosis is a chronic disease characterized by a decrease in bone mineral density (BMD) and corruption of the microarchitectural structure of bone tissue. Objective: It was investigated whether methylprednisolone had a favorable effect on osteoporotic bone tissue in Oophorectomy induced osteoporotic rats whose endogenous adrenaline levels are suppressed with metyrosine. Materials and Methods: Bone Mineral Density, number of osteoblast-osteoclast, bone osteocalcin levels and alkaline phosphatase (ALP) measurements were performed. Obtained results were compared with that of alendronate. Results: Oophorectomy induced osteoporosis was exacerbated by methylprednisolone. Alentronate prevented ovariectomised induced osteoporosis, but it couldn’t prevent methylprednisolone +ovariectomised induced osteoporosis in rats. Conclusion: Combined treatment with methylprednisolon and metyrosine was the best treatment for preventing osteoporosis but metyrosine alone couldn’t prevent osteoporosis in ovariectomised rats. PMID:25246899

  3. Management of Root Resorption Using Chemical Agents: A Review.

    PubMed

    Mohammadi, Zahed; C Cehreli, Zafer; Shalavi, Sousan; Giardino, Luciano; Palazzi, Flavio; Asgary, Saeed

    2016-01-01

    Root resorption (RR) is defined as the loss of dental hard tissues because of clastic activity inside or outside of tooth the root. In the permanent dentition, RR is a pathologic event; if untreated, it might result in the premature loss of the affected tooth. Several hypotheses have been suggested as the mechanisms of root resorption such as absence of the remnants of Hertwig's epithelial root sheath (HERS) and the absence of some intrinsic factors in cementum and predentin such as amelogenin or osteoprotegerin (OPG). It seems that a barrier is formed by the less-calcified intermediate cementum or the cementodentin junction that prevents external RR. There are several chemical strategies to manage root resorption. The purpose of this paper was to review several chemical agents to manage RR such as tetracycline, sodium hypochlorite, acids (citric acid, phosphoric acid, ascorbic acid and hydrochloric acid), acetazolamide, calcitonin, alendronate, fluoride, Ledermix and Emdogain. PMID:26843869

  4. Self-assembling bisphosphonates into nanofibers to enhance their inhibitory capacity on bone resorption.

    PubMed

    Tang, Anming; Qian, Yu; Liu, Shuang; Wang, Weijuan; Xu, Bing; Qin, An; Liang, Gaolin

    2016-05-19

    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 and 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 and have better inhibitory effects on osteoclastic formation and bone resorption than Pami and Alen, respectively. We anticipate that our new drugs and could "smartly" self-assemble and locally concentrate the drugs at bone resorption lacunae in vivo and subsequently prevent/treat osteoporosis more efficiently. PMID:27153349

  5. Extracorporeal shockwave therapy for avascular necrosis of femoral head.

    PubMed

    Wang, Ching-Jen; Cheng, Jai-Hong; Huang, Chung-Cheng; Yip, Han-Kan; Russo, Sergio

    2015-12-01

    The etiology of osteonecrosis of the femoral head (ONFH) is multifactorial. Treatment of ONFH is disease stage dependent. For early stages, femoral head preservation procedures are preferred including core decompression, muscle pedicle grafting and de-rotational osteotomy. Core decompression with bone grafting is considered the gold standard. However, the results are inconsistence and unpredictable. An effective non-invasive method of treatment is imperative. Recently, extracorporeal shockwave therapy (ESWT) has shown beneficial effects in ONFH. ESWT improves pain and function of the hip and regression of the ONFH lesion. ESWT is more effective than core decompression with or without bone grafting, cocktail therapy that combined HBO, ESWT and oral alendronate is shown effective for patients with early osteonecrosis. The purpose of the article is to review, update and summarize the clinical treatment of ONFH using shockwave therapy. PMID:26188081

  6. Can long-term bisphosphonate use causes low-energy fractures? A case report.

    PubMed

    Dandinoğlu, T; Akarsu, S; Karadeniz, M; Tekin, L; Arıbal, S; Kıralp, M Z

    2014-02-01

    Bisphosphonates are inorganic pyrophosphate analog which accumulate on the bone surface, cause osteoclast apoptosis, and inhibit bone resorption. The nitrogen-containing bisphosphonates continue to be the drug of choice for the treatment of osteoporosis in both men and women. Although histomorphometric studies including bone biopsies have not shown any evidence of microcracks, recent studies have revealed that potent bisphosphonates are responsible for the oversuppression of bone turnover leading to microdamages, reduced bone strength, and increased fracture risk. There are individual cases reporting atypical femoral fractures and severely suppressed bone turnover along with long-term (≥ 5 years) use of biphosphonates. In this study, we report on a 74-year-old woman with a history of continuous alendronate use for nearly 16 years who presented to the emergency department with right proximal humerus and left femur fracture. PMID:23824297

  7. Tracking Drug Loading Capacities of Calcium Silicate Hydrate Carrier: A Comparative X-ray Absorption Near Edge Structures Study.

    PubMed

    Guo, Xiaoxuan; Wang, Zhiqiang; Wu, Jin; Yiu, Yun-Mui; Hu, Yongfeng; Zhu, Ying-Jie; Sham, Tsun-Kong

    2015-08-01

    Mesoporous spheres of calcium silicate hydrate (MS-CSH) have been prepared by an ultrasonic method. Following an earlier work in which we have revealed the interactions between ibuprofen (IBU) and CSH carriers with different morphologies by X-ray absorption near edge structures (XANES) analysis. In the present investigation, two new drug molecules, alendronate sodium (ALN) and gentamicin sulfate (GS), were incorporated into MS-CSH, and their drug loading capacities (DLCs) were measured using thermogravimetric analysis to establish the relationship between drug-carrier interactions and DLCs. The XANES spectra clearly indicate that acidic functional groups of the drug molecules linked to the active sites (Ca-OH and Si-OH groups) of MS-CSH on the surface by electrostatic interactions. In addition, it is found that the stoichiometric ratio of Ca(2+) ions of CSH carriers and the functional groups of drug molecules may significantly influence the DLCs. PMID:26162602

  8. Effect of Long-Term Use of Bisphosphonates on Forearm Bone: Atypical Ulna Fractures in Elderly Woman with Osteoporosis

    PubMed Central

    Atbasi, Zafer; Kavadar, Gülis; Demiralp, Bahtiyar

    2016-01-01

    Osteoporosis is a common musculoskeletal disease of the elderly population characterized by decreased bone mineral density and subsequent fractures. Bisphosphonates are a widely accepted drug therapy which act through inhibition of bone resorption and prevent fractures. However, in long-term use, atypical bisphosphonate induced fractures may occur, particularly involving the lower weight bearing extremity. Atypical ulna fracture associated with long-term bisphosphonate use is rarely reported in current literature. We present a 62-year-old woman with atypical ulna due to long-term alendronate therapy without a history of trauma or fall. Clinicians should be aware of stress fracture in a patient who has complaints of upper extremity pain and history of long-term bisphosphonate therapy. PMID:27595031

  9. Potential therapeutic effects of oral bisphosphonates on the intestine.

    PubMed

    Pazianas, Michael; Russell, R Graham G

    2011-12-01

    Bisphosphonates are the principal drugs prescribed for the prevention of osteoporotic fractures. They are bone specific but poorly absorbed. In oral formulations, almost 99% of the administered dose remains within the intestinal tract and reaches the small and large bowel. Although the nitrogen-containing bisphosphonates can irritate the distal esophageal/gastric mucosa, they improve drug-induced colitis in animal models and exhibit antitumor properties on intestinal cells in vitro. Several recent epidemiological studies provide evidence of a reduced risk of colorectal cancer in osteoporotic patients treated with oral bisphosphonates, notably alendronate. In this review, we will explore the possible mechanisms of action underlying these effects and raise the question of whether these agents might be used in the chemoprophylaxis against colorectal cancer. PMID:22360293

  10. Deposition of PLA/CDHA composite coating via electrospraying.

    PubMed

    Zhou, Huan; Bhaduri, Sarit B

    2013-01-01

    Composite coatings composed of carbonated calcium deficient hydroxyapatite (CDHA) and polylactic acid (PLA) were deposited on a PLA substrate surface via electrospraying. The operation parameters, structural properties, bioactivity, cell adhesion, and growth capability of as-fabricated PLA/CDHA coatings were investigated. The composite coating showed good biocompatibility and bioactivity. The deposited coating was also applied as a carrier to assist alendronate sodium (AS) local release. AS, an approved bisphosphonate drug used for the treatment of osteoporosis, was incorporated into a composite coating matrix via coelectrospraying. Its release behavior showed a long-term sustained release. This approach can be a potential coating technique for the surface modification of biopolymer implants. PMID:23594068

  11. Management of Root Resorption Using Chemical Agents: A Review

    PubMed Central

    Mohammadi, Zahed; C. Cehreli, Zafer; Shalavi, Sousan; Giardino, Luciano; Palazzi, Flavio; Asgary, Saeed

    2016-01-01

    Root resorption (RR) is defined as the loss of dental hard tissues because of clastic activity inside or outside of tooth the root. In the permanent dentition, RR is a pathologic event; if untreated, it might result in the premature loss of the affected tooth. Several hypotheses have been suggested as the mechanisms of root resorption such as absence of the remnants of Hertwig's epithelial root sheath (HERS) and the absence of some intrinsic factors in cementum and predentin such as amelogenin or osteoprotegerin (OPG). It seems that a barrier is formed by the less-calcified intermediate cementum or the cementodentin junction that prevents external RR. There are several chemical strategies to manage root resorption. The purpose of this paper was to review several chemical agents to manage RR such as tetracycline, sodium hypochlorite, acids (citric acid, phosphoric acid, ascorbic acid and hydrochloric acid), acetazolamide, calcitonin, alendronate, fluoride, Ledermix and Emdogain. PMID:26843869

  12. Epidemiological aspects of rheumatoid arthritis patients affected by oral bisphosphonate-related osteonecrosis of the jaws

    PubMed Central

    2012-01-01

    This literature review aims to evaluate the epidemiologic profile of patients with rheumatoid arthritis (RA) that developed a bisphosphonate-related osteonecrosis that affect the jaws (BRONJ), including demographic aspects, as well as clinical and therapeutic issues. A search of PUBMED/MEDLINE, Scopus, and Cochrane databases from January 2003 to September 2011 was conducted with the objective of identifying publications that contained case reports regarding oral BRONJ in RA patients. Patients with RA who develop oral BRONJ are usually women above 60 years taking steroids and long-term alendronate. Most of them have osteoporosis, and lesions, triggered by dental procedures, are usually detected at stage II in the mandible. Although there is no accepted treatment protocol, these patients seem to have better outcomes with conservative approaches that include antibiotic therapy, chlorhexidine, and drug discontinuation. PMID:22376948

  13. Phosphonated nanocelluloses from sequential oxidative-reductive treatment-Physicochemical characteristics and thermal properties.

    PubMed

    Sirviö, Juho Antti; Hasa, Tapani; Ahola, Juha; Liimatainen, Henrikki; Niinimäki, Jouko; Hormi, Osmo

    2015-11-20

    Nanocellulosic materials with good thermal stability are highly desirable for applications, such as reinforcement and filler agents in composites. In the present work, phosphonated cellulose was utilized to obtain nanocelluloses with good thermal stability and potential intumescent properties. Phosphonated cellulose was synthetized from birch pulp via sequential periodate oxidation and reductive amination using a bisphosphonate group-containing amine, sodium alendronate, as a phosphonating reagent. After high-pressure homogenization, bisphosphonate cellulose nanofibres or nanocrystals were obtained, depending on the initial oxidation degree. Nanofibres had a typical diameter of 3.8nm and length of several micrometers, whereas nanocrystals exhibited a width of about 6nm and an average length of 103-129nm. All nanocelluloses exhibited cellulose I crystalline structures and high transparency in water solutions. Phosphonated nanocelluloses exhibited good thermal stability and a greater amount of residual char was formed at 700°C compared to birch pulp and mechanically produced, non-chemically modified NFC. PMID:26344310

  14. [Pyrophosphate in medicine].

    PubMed

    Goldman, Adrian; Boije af Gennis, Gustav; Xhaard, Henri; Meri, Seppo; Yli-Kauhaluoma, Jari

    2016-01-01

    In all organisms from bacteria to humans, specific hydrolases--pyrophosphatases--hydrolyse inorganic pyrophosphate to phosphate. Without this, DNA, RNA and protein synthesis stops. Pyrophosphatases are thus essential for all life. In humans, disorders in pyrophosphate metabolism cause chondrocalcinosis and hypophosphatasia. Currently, pyrophosphate analogues, e.g. alendronate, are in clinical use in osteoporosis and Paget's disease but also for e.g. complications of prostate cancer. In bacteria and protozoan parasites, membrane-bound pyrophosphatases (mPPases), which do not occur in humans, convert pyrophosphate to a proton or sodium gradient. mPPases, which are crucial for protozoan parasites, are thus promising drug targets e.g. for malaria and leishmaniasis. PMID:27483627

  15. Atraumatic intracapsular neck of femur fractures after prolonged bisphosphonate treatment: a new atypical variant?

    PubMed Central

    Khan, Sameer Khalid; Savaridas, Terence; Hemers, Jennifer S.; Maarouf, Zouheir; Orgee, Jane M.; Orr, Michael M.

    2016-01-01

    Summary We present 2 cases of elderly females presenting with atraumatic, near-vertical (Pauwells grade 3), intracapsular neck of femur fractures. Following diagnosis of osteoporosis on DEXA scans, they had received alendronic acid for 7 and 10 years respectively. Routine blood tests and serum estimations of calcium, vitamin-D and thyroid-stimulating hormone, done at admission, were within the normal ranges. These patients were managed with a hemiarthroplasty and a dynamic hip screw (DHS) respectively, following discontinuation of bisphosphonates. We present these 2 cases in light of emerging evidence that associates long-term bisphosphonate use with atypical low energy femoral fractures. Only subtrochanteric/diaphyseal fractures have been reported to date. We present a new variant of atypical femoral neck fractures in metaphyseal bone related to prolonged bisphosphonate therapy. PMID:27252743

  16. Controlling drug delivery kinetics from mesoporous titania thin films by pore size and surface energy

    PubMed Central

    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. PMID:26185444

  17. Bisphosphonates and evidence for association with esophageal and gastric cancer: a systematic review and meta-analysis

    PubMed Central

    Wright, Ellen; Schofield, Peter T; Molokhia, Mariam

    2015-01-01

    Objectives Concerns have been raised about a possible link between bisphosphonate use, and in particular alendronate, and upper gastrointestinal (UGI) cancer. A number of epidemiological studies have been published with conflicting results. We conducted a systematic review and meta-analysis of observational studies, to determine the risk of esophageal and gastric cancer in users of bisphosphonates compared with non-users. Design We searched PubMed, MEDLINE, EMBASE, Web of Knowledge and Cochrane Database of Systematic Reviews for studies investigating bisphosphonates and esophageal or gastric cancer. We calculated pooled ORs and 95% CIs for the risk of esophageal or gastric cancer in bisphosphonate users compared with non-users. We performed a sensitivity analysis of alendronate as this was the most common single drug studied and is also the most widely used in clinical practice. Results 11 studies (from 10 papers) examining bisphosphonate exposure and UGI cancer (gastric and esophageal), met our inclusion criteria. All studies were retrospective, 6/11 (55%) case–control and 5/11(45%) cohort, and carried out using data from 5 longitudinal clinical databases. Combining 5 studies (1 from each database), we found no increased risk, OR 1.11 (95% CI 0.97 to 1.27) of esophageal cancer in bisphosphonate users compared with non-users and no increased risk of gastric cancer in bisphosphonate users, OR 0.96 (95% CI 0.82 to 1.12). Conclusion This is the fourth and most detailed meta-analysis on this topic. We have not identified any compelling evidence for a significantly raised risk of esophageal cancer or gastric cancer in male and female patients prescribed bisphosphonates. PMID:26644118

  18. 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.

  19. Increased Sclerostin Levels after Further Ablation of Remnant Estrogen by Aromatase Inhibitors

    PubMed Central

    Kim, Wonjin; Chung, Yoonjung; Kim, Se Hwa; Park, Sehee; Bae, Jae Hyun; Kim, Gyuri; Lee, Su Jin; Kim, Jo Eun; Park, Byeong-Woo; Lim, Sung-Kil

    2015-01-01

    Background Sclerostin is a secreted Wnt inhibitor produced almost exclusively by osteocytes, which inhibits bone formation. Aromatase inhibitors (AIs), which reduce the conversion of steroids to estrogen, are used to treat endocrine-responsive breast cancer. As AIs lower estrogen levels, they increase bone turnover and lower bone mass. We analyzed changes in serum sclerostin levels in Korean women with breast cancer who were treated with an AI. Methods We included postmenopausal women with endocrine-responsive breast cancer (n=90; mean age, 57.7 years) treated with an AI, and compared them to healthy premenopausal women (n=36; mean age, 28.0 years). The subjects were randomly assigned to take either 5 mg alendronate with 0.5 µg calcitriol (n=46), or placebo (n=44) for 6 months. Results Postmenopausal women with breast cancer had significantly higher sclerostin levels compared to those in premenopausal women (27.8±13.6 pmol/L vs. 23.1±4.8 pmol/L, P<0.05). Baseline sclerostin levels positively correlated with either lumbar spine or total hip bone mineral density only in postmenopausal women (r=0.218 and r=0.233; P<0.05, respectively). Serum sclerostin levels increased by 39.9%±10.2% 6 months after AI use in postmenopausal women; however, no difference was observed between the alendronate and placebo groups (39.9%±10.2% vs. 55.9%±9.13%, P>0.05). Conclusion Serum sclerostin levels increased with absolute deficiency of residual estrogens in postmenopausal women with endocrine-responsive breast cancer who underwent AI therapy with concurrent bone loss. PMID:25827459

  20. 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

  1. 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

  2. A Scoping Review of Strategies for the Prevention of Hip Fracture in Elderly Nursing Home Residents

    PubMed Central

    Sawka, Anna M.; Ismaila, Nofisat; Cranney, Ann; Thabane, Lehana; Kastner, Monika; Gafni, Amiram; Woodhouse, Linda J.; Crilly, Richard; Cheung, Angela M.; Adachi, Jonathan D.; Josse, Robert G.; Papaioannou, Alexandra

    2010-01-01

    Background Elderly nursing home residents are at increased risk of hip fracture; however, the efficacy of fracture prevention strategies in this population is unclear. Objective We performed a scoping review of randomized controlled trials of interventions tested in the long-term care (LTC) setting, examining hip fracture outcomes. Methods We searched for citations in 6 respective electronic searches, supplemented by hand searches. Two reviewers independently reviewed all citations and full-text papers; consensus was achieved on final inclusion. Data was abstracted in duplicate. Findings We reviewed 22,349 abstracts or citations and 949 full-text papers. Data from 20 trials were included: 7 - vitamin D (n = 12,875 participants), 2 - sunlight exposure (n = 522), 1 - alendronate (n = 327), 1 - fluoride (n = 460), 4 – exercise or multimodal interventions (n = 8,165), and 5 - hip protectors (n = 2,594). Vitamin D, particularly vitamin D3 ≥800 IU orally daily, reduced hip fracture risk. Hip protectors reduced hip fractures in included studies, although a recent large study not meeting inclusion criteria was negative. Fluoride and sunlight exposure did not significantly reduce hip fractures. Falls were reduced in three studies of exercise or multimodal interventions, with one study suggesting reduced hip fractures in a secondary analysis. A staff education and risk assessment strategy did not significantly reduce falls or hip fractures. In a study underpowered for fracture outcomes, alendronate did not significantly reduce hip fractures in LTC. Conclusions The intervention with the strongest evidence for reduction of hip fractures in LTC is Vitamin D supplementation; more research on other interventions is needed. PMID:20209088

  3. An experimental study to evaluate the antiosteoporotic effect of Panchatikta Ghrita in a steroid-induced osteoporosis rat model

    PubMed Central

    Munshi, Renuka; Patil, Tanvi; Garuda, Chetan; Kothari, Dushyant

    2016-01-01

    Objective: The study was conducted to develop the glucocorticoid-induced osteoporosis (GIO) model in Sprague-Dawley weanling rats using different doses of methylprednisolone (MP) and evaluate the antiosteoporotic effect of a classical ayurvedic formulation, Panchatikta Ghrita (PG), in this model. Materials and Methods: Institutional Animal Ethics Committee approval was obtained. Development of model was done by subcutaneous injection of 2 doses of MP (14 and 28 mg/kg/week) for 4 weeks in 21-day old weanlings. Following confirmation of the dose of MP that induced osteoporosis, the antiosteoporotic effect of PG was tested in this model in comparison to a known antiosteoporotic agent, alendronate. Both alendronate (2.9 mg/kg/day) and PG (1.35 g/kg/day) were administered orally 2 weeks after MP - 14 mg/kg/week injection and continued for 4 weeks. Serum and urine calcium and inorganic phosphate were analyzed at weekly intervals. Animals were sacrificed after 6 weeks, and femur bones were processed to measure bone hardness and elasticity and for histological studies. Results: Rats treated with MP - 14 mg/kg/week showed optimum osteoporotic effect with no mortality as compared to MP - 28 mg/kg/week; hence, this dose of MP was used further for the efficacy study. Osteoporotic rats treated with PG 1.35 g/kg showed increase in serum calcium and inorganic phosphate levels, whereas urine calcium and phosphate levels were significantly reduced. A significant decrease in a number of osteoclasts, whereas an increase in bone hardness and elasticity was observed as compared to diseased group demonstrating antiosteoporotic effect of PG. Conclusion: PG has an antiosteoporotic effect in GIO rat model. PMID:27298501

  4. Effects of Bisphosphonates on Glucose Transport in a Conditionally Immortalized Rat Retinal Capillary Endothelial Cell Line (TR-iBRB Cells)

    PubMed Central

    Lee, Na-Young; Park, Hyun-Joo; Kang, Young-Sook

    2016-01-01

    The objective of the present study was to elucidate the effect of bisphosphonates, anti-osteoporosis agents, on glucose uptake in retinal capillary endothelial cells under normal and high glucose conditions. The change of glucose uptake by pre-treatment of bisphosphonates at the inner blood-retinal barrier (iBRB) was determined by measuring cellular uptake of [3H]3-O-methyl glucose (3-OMG) using a conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB cells) under normal and high glucose conditions. [3H]3-OMG uptake was inhibited by simultaneous treatment of unlabeled D-glucose and 3-OMG as well as glucose transport inhibitor, cytochalasin B. On the other hand, simultaneous treatment of alendronate or pamidronate had no significant inhibitory effect on [3H]3-OMG uptake by TR-iBRB cells. Under high glucose condition of TR-iBRB cells, [3H]3-OMG uptake was increased at 48 h. However, [3H]3-OMG uptake was decreased significantly by pre-treatment of alendronate or pamidronate compared with the values for normal and high glucose conditions. Moreover, geranylgeraniol (GGOH), a mevalonate pathway intermediate, increased the uptake of [3H]3-OMG reduced by bisphosphonates pre-treatment. But, pre-treatment of histamine did not show significant inhibition of [3H]3-OMG uptake. The glucose uptake may be down regulated by inhibiting the mevalonate pathway with pre-treatment of bisphosphonates in TR-iBRB cells at high glucose condition. PMID:26759707

  5. Antioxidant effect of bisphosphonates and simvastatin on chondrocyte lipid peroxidation

    SciTech Connect

    Dombrecht, E.J.; De Tollenaere, C.B.; Aerts, K.; Cos, P.; Schuerwegh, A.J.; Bridts, C.H.; Van Offel, J.F.; Ebo, D.G.; Stevens, W.J. . E-mail: immuno@ua.ac.be; De Clerck, L.S.

    2006-09-22

    The objective of this study was to evaluate the effect of bisphosphonates (BPs) and simvastatin on chondrocyte lipid peroxidation. For this purpose, a flow cytometrical method using C11-BODIPY{sup 581/591} was developed to detect hydroperoxide-induced lipid peroxidation in chondrocytes. Tertiary butylhydroperoxide (t-BHP) induced a time and concentration dependent increase in chondrocyte lipid peroxidation. Addition of a Fe{sup 2+}/EDTA complex to t-BHP or hydrogen peroxide (H{sub 2}O{sub 2}) clearly enhanced lipid peroxidation. The lipophilic simvastatin demonstrated a small inhibition in the chondrocyte lipid peroxidation. None of three tested BPs (clodronate, pamidronate, and risedronate) had an effect on chondrocyte lipid peroxidation induced by t-BHP. However, when Fe{sup 2+}/EDTA complex was added to t-BHP or H{sub 2}O{sub 2}, BPs inhibited the lipid peroxidation process varying from 25% to 58%. This study demonstrates that BPs have antioxidant properties as iron chelators, thereby inhibiting the chondrocyte lipid peroxidation. These findings add evidence to the therapeutic potential of bisphosphonates and statins in rheumatoid arthritis.

  6. The inhibition of human farnesyl pyrophosphate synthase by nitrogen-containing bisphosphonates. Elucidating the role of active site threonine 201 and tyrosine 204 residues using enzyme mutants☆

    PubMed Central

    Tsoumpra, Maria K.; Muniz, Joao R.; Barnett, Bobby L.; Kwaasi, Aaron A.; Pilka, Ewa S.; Kavanagh, Kathryn L.; Evdokimov, Artem; Walter, Richard L.; Von Delft, Frank; Ebetino, Frank H.; Oppermann, Udo; Russell, R. Graham G.; Dunford, James E.

    2015-01-01

    Farnesyl pyrophosphate synthase (FPPS) is the major molecular target of nitrogen-containing bisphosphonates (N-BPs), used clinically as bone resorption inhibitors. We investigated the role of threonine 201 (Thr201) and tyrosine 204 (Tyr204) residues in substrate binding, catalysis and inhibition by N-BPs, employing kinetic and crystallographic studies of mutated FPPS proteins. Mutants of Thr201 illustrated the importance of the methyl group in aiding the formation of the Isopentenyl pyrophosphate (IPP) binding site, while Tyr204 mutations revealed the unknown role of this residue in both catalysis and IPP binding. The interaction between Thr201 and the side chain nitrogen of N-BP was shown to be important for tight binding inhibition by zoledronate (ZOL) and risedronate (RIS), although RIS was also still capable of interacting with the main-chain carbonyl of Lys200. The interaction of RIS with the phenyl ring of Tyr204 proved essential for the maintenance of the isomerized enzyme-inhibitor complex. Studies with conformationally restricted analogues of RIS reaffirmed the importance of Thr201 in the formation of hydrogen bonds with N-BPs. In conclusion we have identified new features of FPPS inhibition by N-BPs and revealed unknown roles of the active site residues in catalysis and substrate binding. PMID:26318908

  7. Bone Loss During Space Flights: Implication of the Vestibular System, Sex-Dependence and Countermeasure

    NASA Astrophysics Data System (ADS)

    Vignaux, G.; Besnard, S.; Philoxene, B.; Sabatier, J. P.; Allouche, S.; Denise, P.

    2008-06-01

    The decrease of mechanical load due to microgravity induces bone loss (BL) during long-term space flights. We previously postulated that vestibular system could also be involved in bone modeling. Herein, we evaluated by tomography, long-term (2 months) effects of bilateral vestibular lesion (Bilab) on BL compared to a model of diffuse osteoporosis induced by gonadectomy in male and female rats. BL (about 12%) was observed on femoral metaphysis and femoral metaphysis/diaphysis respectively in male and female Bilab groups compared to shams. Whole body and spine mineralization remained unchanged in Bilab groups while it appeared decreased in gonadectomy groups as expected. BL in Bilab groups was reported at 1 month and recovered at 2 months while it remained decreased at 2 months in our model of diffuse osteoporosis. Risedronate over counterbalanced BL in both models of BL (Bilab and gonadectomy) at 1 and 2 months. Bilateral vestibular lesions on Earth induced regional bone loss focused on bearing bones in male and female at 1 month with unknown compensatory mechanisms 2 months later.

  8. The inhibition of human farnesyl pyrophosphate synthase by nitrogen-containing bisphosphonates. Elucidating the role of active site threonine 201 and tyrosine 204 residues using enzyme mutants.

    PubMed

    Tsoumpra, Maria K; Muniz, Joao R; Barnett, Bobby L; Kwaasi, Aaron A; Pilka, Ewa S; Kavanagh, Kathryn L; Evdokimov, Artem; Walter, Richard L; Von Delft, Frank; Ebetino, Frank H; Oppermann, Udo; Russell, R Graham G; Dunford, James E

    2015-12-01

    Farnesyl pyrophosphate synthase (FPPS) is the major molecular target of nitrogen-containing bisphosphonates (N-BPs), used clinically as bone resorption inhibitors. We investigated the role of threonine 201 (Thr201) and tyrosine 204 (Tyr204) residues in substrate binding, catalysis and inhibition by N-BPs, employing kinetic and crystallographic studies of mutated FPPS proteins. Mutants of Thr201 illustrated the importance of the methyl group in aiding the formation of the Isopentenyl pyrophosphate (IPP) binding site, while Tyr204 mutations revealed the unknown role of this residue in both catalysis and IPP binding. The interaction between Thr201 and the side chain nitrogen of N-BP was shown to be important for tight binding inhibition by zoledronate (ZOL) and risedronate (RIS), although RIS was also still capable of interacting with the main-chain carbonyl of Lys200. The interaction of RIS with the phenyl ring of Tyr204 proved essential for the maintenance of the isomerized enzyme-inhibitor complex. Studies with conformationally restricted analogues of RIS reaffirmed the importance of Thr201 in the formation of hydrogen bonds with N-BPs. In conclusion we have identified new features of FPPS inhibition by N-BPs and revealed unknown roles of the active site residues in catalysis and substrate binding. PMID:26318908

  9. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2002-11-01

    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: Abacavir sulfate, abarelix, adalimumab, adefovir dipivoxil, AdGVVEGF121.10, anastrozole, anecortave acetate, aripiprazole, asulacrine isethionate, atazanavir, ATL-962, 16-Aza-epothilone B; Bevacizumab, bicalutamide, blonanserin, BMS-188667, bosentan; Celecoxib, celmoleukin, cetuximab, cilomilast, cinacalcet hydrochloride, CNTF(Ax15), colesevelam hydrochloride; Daclizumab, delavirdine mesilate, desogestrel, desoxyepothilone B, dexmethylphenidate hydrochloride, duloxetine hydrochloride; Ecogramostim, emtricitabine, epalrestat, escitalopram oxalate, examorelin, exendin-4, ezetimibe; Fidarestat, frovatriptan; HIV-1 Immunogen; Iloperidone, insulin detemir, insulin lispro, irinotecan hydrochloride; Keratinocyte growth factor; Lasofoxifene tartrate, levetiracetam, levormeloxifene, levosimendan, lumiracoxib, LY-307161 SR; Memantine hydrochloride, MEN-10755, metformin hydrochloride, metreleptin, motexafin gadolinium; Naratriptan hydrochloride, natalizumab, nesiritide, nicotine, NN-2211, NN-414; Olanzapine, omalizumab; Pegaptanib sodium, peginterferon alfa-2a, peginterferon alfa-2b, pegvisomant, pimecrolimus, pirfenidone, pramlintide acetate prasterone, pregabalin; Quetiapine fumarate; Rabeprazole sodium, raloxifene hydrochloride, raltitrexed, rDNA insulin, rFGF-2, risedronate sodium, rofecoxib, roflumilast, rosiglitazone maleate; SN-22995; Tacrolimus, tadalafil, tegaserod maleate, tiotropium bromide, tomoxetine hydrochloride, trastuzumab, trimegestone; Voglibose, Voriconazole; Ziprasidone hydrochloride. PMID:12616707

  10. Anorexia nervosa and bone.

    PubMed

    Misra, Madhusmita; Klibanski, Anne

    2014-06-01

    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 additional concerns of suboptimal peak bone mass and future bone health in this age group. Changes in lean mass and compartmental fat depots, and 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, physiological 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

  11. 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

  12. 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

  13. Synthesis and Characterization of PLGA Shell Microcapsules Containing Aqueous Cores Prepared by Internal Phase Separation.

    PubMed

    Abulateefeh, Samer R; Alkilany, Alaaldin M

    2016-08-01

    The preparation of microcapsules consisting of poly(D,L-lactide-co-glycolide) (PLGA) polymer shell and aqueous core is a clear challenge and hence has been rarely addressed in literature. Herein, aqueous core-PLGA shell microcapsules have been prepared by internal phase separation from acetone-water in oil emulsion. The resulting microcapsules exhibited mean particle size of 1.1 ± 0.39 μm (PDI = 0.35) with spherical surface morphology and internal poly-nuclear core morphology as indicated by scanning electron microscopy (SEM). The incorporation of water molecules into PLGA microcapsules was confirmed by differential scanning calorimetry (DSC). Aqueous core-PLGA shell microcapsules and the corresponding conventional PLGA microspheres were prepared and loaded with risedronate sodium as a model drug. Interestingly, aqueous core-PLGA shell microcapsules illustrated 2.5-fold increase in drug encapsulation in comparison to the classical PLGA microspheres (i.e., 31.6 vs. 12.7%), while exhibiting sustained release behavior following diffusion-controlled Higuchi model. The reported method could be extrapolated to encapsulate other water soluble drugs and hydrophilic macromolecules into PLGA microcapsules, which should overcome various drawbacks correlated with conventional PLGA microspheres in terms of drug loading and release. PMID:26416284

  14. 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

  15. 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

  16. Can Alarming Improve Compliance with Weekly Bisphosphonate in Patients with Osteoporosis?

    PubMed Central

    Nho, Jae-Hwi; Ha, Yong-Chan; Kim, Chung-Hyun; Suh, You-Sung; Koo, Kyung-Hoi

    2016-01-01

    Background Although bisphosphonate is effective for the prevention and treatment of osteoporosis, poor medication compliance is a key-limiting factor. We determined whether alarm clock could improve compliance with weekly bisphosphonate in patients with osteoporosis, by comparing with age- and gender-matched control group. Methods Fifty patients with osteoporosis were recruited and participated in alarm clock group. Patients were asked to take orally weekly risedronate for 1 year, and received alarm clock to inform the time of taking oral bisphosphonate weekly. Using the propensity score matching with age and gender, 50 patients were identified from patients with osteoporosis medication. We compared the compliance with bisphosphonate using medication possession ratio (MPR) between two groups. Results Although there was no significant difference of baseline characteristics between both groups, the mean MPR (0.80±0.33) of alarm clock group was higher than that (0.56±0.34) of control group (P<0.001). Conclusions Alarming could improve the compliance with weekly oral bisphosphonate in patients with osteoporosis. PMID:27294076

  17. Antiosteoporotic effects of Polycan in combination with calcium lactate-gluconate in ovariectomized rats

    PubMed Central

    CHOI, JAE-SUK; KIM, JOO WAN; KIM, KI YOUNG; CHO, HYUNG-RAE; CHOI, IN SOON; KU, SAE KWANG

    2014-01-01

    The aim of the present study was to investigate the optimum composition of Polycan (β-glucan complex) and calcium lactate-gluconate (CaLG) that exhibited the most beneficial effects in ovariectomy (OVX)-induced osteoporotic rats. Polycan and CaLG single formulas (100 mg/kg each), and three doses (50, 100 and 200 mg/kg) of three mixed formulas [polycan:CaLG (PCLG)=1:99, 5:95 and 10:90] were orally administered once a day for 84 days. The effects of the test materials were compared with those of a risedronate sodium-treated group. OVX resulted in an increase in body weight, decreased bone formation, elevated serum osteocalcin levels and urine deoxypyridinoline/creatinine ratio, as well as decreased serum bone-specific alkaline phosphatase levels, femur indices, bone mineral content, bone mineral density and failure load. However, these OVX-induced osteoporotic changes markedly decreased following the administration of the test materials. Continuous oral treatment of Polycan or CaLG single formulas and the PCLG mixed formulas preserved bone mass and strength. The PCLG 10:90 mixed formula exhibited the most favorable synergistic antiosteoporotic effects in the OVX-induced osteoporotic rats as compared with equal doses of the Polycan or CaLG single formulas. PMID:25120630

  18. Antiosteoporotic effects of Polycan in combination with calcium lactate-gluconate in ovariectomized rats.

    PubMed

    Choi, Jae-Suk; Kim, Joo Wan; Kim, Ki Young; Cho, Hyung-Rae; Choi, In Soon; Ku, Sae Kwang

    2014-09-01

    The aim of the present study was to investigate the optimum composition of Polycan (β-glucan complex) and calcium lactate-gluconate (CaLG) that exhibited the most beneficial effects in ovariectomy (OVX)-induced osteoporotic rats. Polycan and CaLG single formulas (100 mg/kg each), and three doses (50, 100 and 200 mg/kg) of three mixed formulas [polycan:CaLG (PCLG)=1:99, 5:95 and 10:90] were orally administered once a day for 84 days. The effects of the test materials were compared with those of a risedronate sodium-treated group. OVX resulted in an increase in body weight, decreased bone formation, elevated serum osteocalcin levels and urine deoxypyridinoline/creatinine ratio, as well as decreased serum bone-specific alkaline phosphatase levels, femur indices, bone mineral content, bone mineral density and failure load. However, these OVX-induced osteoporotic changes markedly decreased following the administration of the test materials. Continuous oral treatment of Polycan or CaLG single formulas and the PCLG mixed formulas preserved bone mass and strength. The PCLG 10:90 mixed formula exhibited the most favorable synergistic antiosteoporotic effects in the OVX-induced osteoporotic rats as compared with equal doses of the Polycan or CaLG single formulas. PMID:25120630

  19. Drugs Used in Paediatric Bone and Calcium Disorders.

    PubMed

    Cheung, Moira S

    2015-01-01

    Calcium and bone disorders in children and adolescents are treated with a wide variety of drugs. Several of these drugs have been used for many years on the basis of accepted practice, without being subjected to rigorous trials. Bisphosphonates are the mainstay treatment for children with osteoporosis, but newer, more potent compounds such as zoledronate and risedronate have begun to replace the older-generation bisphosphonates. Hypocalcaemia is managed with calcium and vitamin D and its metabolites. In difficult cases that are secondary to hypoparathyroidism, subcutaneous injections or infusions of parathyroid hormone have been used. Multiple daily phosphate supplements and calcitriol are the standard treatment for hypophosphataemic rickets, but trials of an anti-fibroblast growth factor 23 antibody appear promising, and the results are eagerly awaited. Many new medications are undergoing clinical trials and are starting to emerge as viable treatment options for children. Some of these drugs target specific diseases, such as recombinant alkaline phosphatase for hypophosphatasia and a C-type natriuretic peptide analogue for achondroplasia. Other drugs, such as denosumab and odanacatib, have been used successfully in the adult population, and the appropriate use of these drugs in children is now being evaluated. PMID:26138848

  20. Osteonecrosis of the Jaw in Patients With Metastatic Renal Cell Cancer Treated With Bisphosphonates and Targeted Agents: Results of an Italian Multicenter Study and Review of the Literature.

    PubMed

    Fusco, Vittorio; Porta, Camillo; Saia, Giorgia; Paglino, Chiara; Bettini, Giordana; Scoletta, Matteo; Bonacina, Riccardo; Vescovi, Paolo; Merigo, Elisabetta; Lo Re, Giovanni; Guglielmini, Pamela; Di Fede, Olga; Campisi, Giuseppina; Bedogni, Alberto

    2015-08-01

    Osteonecrosis of the jaw (ONJ) associated with the use of bisphosphonates has been rarely reported in metastatic renal cell cancer (RCC) patients. Since the introduction of combined therapies consisting of nitrogen-containing bisphosphonates (NBPs) and targeted agents, an increasing number of RCC patients were reported to develop ONJ, suggesting that therapeutic angiogenesis suppression might increase the risk of ONJ in NBPs users. We performed a multicenter retrospective study and reviewed literature data to assess the occurrence and to investigate the nature of ONJ in RCC patients taking NBPs and targeted agents. Nine Italian Centers contributed to the data collection. Patients with exposed and nonexposed ONJ were eligible for the study if they had been taking NBPs and were receiving targeted agents at the time of ONJ diagnosis. Forty-four RCC patients were studied. Patients were mostly male (82%), with a median age of 63 years (range, 45-85 years). Zoledronic acid (93%) and sunitinib (80%) were the most frequently used NBP and antiangiogenic agent, respectively. Other agents included Pamidronate, ibandronate, sorafenib, bevacizumab, mammalian target of rapamycin inhibitors. Forty-nine sites of ONJ were encountered, with the mandible being the preferred site of ONJ (52%); both jaws were affected in 5 cases (12%). The most common precipitating event was dental/periodontal infection (34%), followed by tooth extraction (30%). Oral triggers of ONJ were missing in 10 cases (23%). This unexpectedly high number of ONJ cases, in comparison with literature data, suggests that frequency of ONJ in RCC patients might be largely underestimated and suggests a potential role for targeted agents in the incremental risk of ONJ. PMID:25586958

  1. A predictive mechanical model for evaluating vertebral fracture probability in lumbar spine under different osteoporotic drug therapies.

    PubMed

    López, E; Ibarz, E; Herrera, A; Puértolas, S; Gabarre, S; Más, Y; Mateo, J; Gil-Albarova, J; Gracia, L

    2016-07-01

    Osteoporotic vertebral fractures represent a major cause of disability, loss of quality of life and even mortality among the elderly population. Decisions on drug therapy are based on the assessment of risk factors for fracture from bone mineral density (BMD) measurements. A previously developed model, based on the Damage and Fracture Mechanics, was applied for the evaluation of the mechanical magnitudes involved in the fracture process from clinical BMD measurements. BMD evolution in untreated patients and in patients with seven different treatments was analyzed from clinical studies in order to compare the variation in the risk of fracture. The predictive model was applied in a finite element simulation of the whole lumbar spine, obtaining detailed maps of damage and fracture probability, identifying high-risk local zones at vertebral body. For every vertebra, strontium ranelate exhibits the highest decrease, whereas minimum decrease is achieved with oral ibandronate. All the treatments manifest similar trends for every vertebra. Conversely, for the natural BMD evolution, as bone stiffness decreases, the mechanical damage and fracture probability show a significant increase (as it occurs in the natural history of BMD). Vertebral walls and external areas of vertebral end plates are the zones at greatest risk, in coincidence with the typical locations of osteoporotic fractures, characterized by a vertebral crushing due to the collapse of vertebral walls. This methodology could be applied for an individual patient, in order to obtain the trends corresponding to different treatments, in identifying at-risk individuals in early stages of osteoporosis and might be helpful for treatment decisions. PMID:27265047

  2. Osteonecrosis of the Jaw After Bisphosphonates Treatment in Patients with Multiple Myeloma

    PubMed Central

    Krstevska, Svetlana; Stavric, Sonja Genadieva; Cevrevska, Lidija; Georgjievski, Borce; Karanfilski, Oliver; Sotirova, Tatjana; Balkanov, Trajan

    2015-01-01

    Background: Bone lytic lesion in Multiple myeloma are the most commonly presented symptoms which require treatment with bisphosphonates (BPs). BPs are providing supportive care, reducing the rate of skeletal morbidity but evidently not abolishing it, the criteria for stopping their administration have to be different from those used for classic antineoplastic drugs, and they should not be stopped when metastatic bone disease is progressing. Osteonecrosis of the jaw (ONJ) has been associated recently with the use of BPs. Aim: The aim of these study is to evaluate the incidence of ONJ in patients with MM treated with mixed biphosphonates. Patients and methods: We analyzed total 296 myeloma patients (150 male and 146 female). Mostly effected age group with 58,1% is age more than 60 years up to 88 years, diagnosed in our institution in the period 2005-2015. We used intravenous or oral forms of biphosphonates such as pamidronate, ibandronate, clodronate and zolendronic acid. The patients were evaluated for ONJ. Results: The incidence of ONJ in our group of patients treated with Bps was 4,6% from our group of 260 patients 87,8% received BPs therapy and patients which haven’t received BPs 12,2%. From this group, 95,4% (248) didn’t show ONJ, and 4,6% (12) showed ONJ. The period of this treatment with BPs is an important risk factor for development of ONJ, average duration of BPs therapy in patients which show adverse effects is 26.8±13.7 months, from the total number of 12 patients that developed ONJ adverse effects, we have 8 patients which received treatment with Zolendronic acid and the remaining 4 patients which were treated with other BPs combinations without Zolendronic acid. Conclusions: All patients treated for MM must continue with the therapy with Zolendronic acid and Pamidronate, each patient must be individually treated according to his response of the treatment (dose, frequency and duration of therapy). PMID:26843726

  3. 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. PMID:23997143

  4. 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.; Sibonga, J.; Keyak, J.; Nakamura, T.; Kohri, K.; Ohshima, H.; Moralez, G.

    2015-01-01

    Elevated bone resorption is a hallmark of human spaceflight and bed rest indicating that elevated remodeling is a major factor in the etiology of space flight bone loss. In a collaborative effort between the NASA and JAXA space agencies, we are testing whether an antiresorptive drug would provide additional benefit to in-flight exercise to ameliorate bone loss and hypercalciuria during long-duration spaceflight. Measurements of bone loss include DXA, QCT, pQCT, urinary and blood biomarkers. We have completed analysis of R+1year data from 7 crewmembers treated with alendronate during flight, as well as immediate post flight (R+<2wks) data from 6 of 10 concurrent controls without treatment. The treated astronauts used the Advanced Resistive Exercise Device (ARED) during their missions. The purpose of this report is twofold: 1) to report the results of inflight, post flight and one year post flight bone measures compared with available controls with and without the use of ARED; and 2) to discuss preliminary data on concurrent controls. The figure below compares the BMD changes in ISS crewmembers exercising with and without the current ARED protocol and the alendronate treated crewmembers also using the ARED. This shows that the use of ARED prevents about half the bone loss seen in early ISS crewmembers and that the addition of an antiresorptive provides additional benefit. Resorption markers and urinary Ca excretion are not impacted by exercise alone but are significantly reduced with antiresorptive treatment. Bone measures for treated subjects, 1 year after return from space remain at or near baseline. DXA data for the 6 concurrent controls using the ARED device are similar to DXA data shown in the figure below. QCT data for these six indicate that the integral data are consistent with the DXA data, i.e., comparing the two control groups suggests significant but incomplete improvement in maintaining BMD using the ARED protocol. Biochemical data of the concurrent

  5. 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; Sibonga, Jean; Keyak, Joyce; Nakamura, Toshitaka; Kohri, Kenjiro; Ohshima, Hiroshi; Moralez, Gilbert

    2014-01-01

    The bisphosphonate study is a collaborative effort between the NASA and JAXA space agencies to investigate the potential for antiresorptive drugs to mitigate bone changes associated with long-duration spaceflight. Elevated bone resorption is a hallmark of human spaceflight and bed rest (common zero-G analog). We tested whether an antiresorptive drug in combination with in-flight exercise would ameliorate bone loss and hypercalcuria during longduration spaceflight. Measurements include DXA, QCT, pQCT, and urine and blood biomarkers. We have completed analysis of 7 crewmembers treated with alendronate during flight and the immediate postflight (R+<2 week) data collection in 5 of 10 controls without treatment. Both groups used the advanced resistive exercise device (ARED) during their missions. We previously reported the pre/postflight results of crew taking alendronate during flight (Osteoporosis Int. 24:2105-2114, 2013). The purpose of this report is to present the 12-month follow-up data in the treated astronauts and to compare these results with preliminary data from untreated crewmembers exercising with ARED (ARED control) or without ARED (Pre-ARED control). Results: the table presents DXA and QCT BMD expressed as percentage change from preflight in the control astronauts (18 Pre-ARED and the current 5 ARED-1-year data not yet available) and the 7 treated subjects. As shown previously the combination of exercise plus antiresorptive is effective in preventing bone loss during flight. Bone measures for treated subjects, 1 year after return from space remain at or near baseline values. Except in one region, the treated group maintained or gained bone 1 year after flight. Biomarker data are not currently available for either control group and therefore not presented. However, data from other studies with or without ARED show elevated bone resorption and urinary Ca excretion while bisphosphonate treated subjects show decreases during flight. Comparing the two control

  6. Bone Loss in Space: Shuttle/MIR Experience and Bed Rest Countermeasure Program

    NASA Technical Reports Server (NTRS)

    Shackelford, L. C.; LeBlanc, A.; Feiveson, A.; Oganov, V.

    1999-01-01

    exercisers, and four subjects taking alendronate (a bisphoshonate that inhibits osteoclastic resorption of bone) have completed 17 weeks bed rest. In contrast to information currently available from space flight (n=28) and bed rest (n= 12) in which all individuals experienced bone loss in at least one region, one of four subjects taking alendronate and one of five subjects performing heavy resistive exercise at bed rest fully maintained bone density in all regions of the spine and lower extremities. Overall results of both countermeasures which will be presented are encouraging. The study will be completed by mid to late 2000 with 10 subjects in each of three groups.

  7. 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; Nakamura, Toshitaka; Kohri, Kenjiro; Ohshima, Hiroshi

    2010-01-01

    Bone loss has been recognized as a potential problem from the beginning of human spaceflight. With the spaceflight missions lasting 6 months to potentially 3 years or longer this issue has assumed increased significance. Detailed measurements from the Mir and ISS long duration missions have documented losses in bone mineral density (BMD) from the total skeleton and critical sub-regions. The most important losses are from the femoral hip averaging about -1.6%/mo integral to -2.3%/mo trabecular BMD. Importantly these studies have documented the wide range in individual response from -0.5 to -5%/mo in BMD. Given the small size of any expedition crew, the wide range of responses has to be considered in the implementation of any countermeasure. Assuming that it is unlikely that the susceptibility for bone loss in any given crewmember will be known, a suite of bone loss countermeasures will likely be needed to insure protection of all crewmembers. The hypothesis for this experiment is that the combined effect of anti-resorptive drugs plus the standard in-flight exercise regimen will have a measurable effect on preventing space flight induced bone loss and strength and will reduce renal stone risk. To date, 4 crewmembers have completed the flight portion of the protocol in which crewmembers take a 70-mg alendronate tablet once a week before and during flight, starting 17 days before launch. Compared to previous ISS crewmembers (n=14) not taking alendronate, DXA measurements of the total hip BMD were significantly changed from -1.1 0.5%/mo to 0.04 0.3%/mo (p<0.01); QCT-determined trabecular BMD of the total hip was significantly changed from -2.3 1.0%/mo to -0.3 1.6%/mo (p<0.01). Significance was calculated from a one-tailed t test. While these results are encouraging, the current n (4) is small, and the large SDs indicate that while the means are improved there is still high variability in individual response. Four additional crewmembers have been recruited to participate

  8. 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; Sibonga, Jean; Nakamura, Toshitaka; Kohri, Kenjiro; Ohshima, Hiroshi

    2011-01-01

    Detailed measurements from the Mir and ISS long duration missions have documented losses in bone mineral density (BMD) from critical skeletal sub-regions. The most important BMD losses are from the femoral hip, averaging about -1.6%/mo integral to -2.3%/mo trabecular. Importantly these studies have documented the wide range in individual BMD loss from -0.5 to -5%/mo. Associated elevated urinary Ca increases the risk of renal stone formation during flight, a serious impact to mission success. To date, countermeasures have not been satisfactory. The purpose of this study is to determine if the combined effect of anti-resorptive drugs plus the standard in-flight exercise regimen will have a measurable effect on preventing space flight induced bone loss (mass and strength) and reducing renal stone risk. To date, 4 crewmembers have completed the flight portion of the protocol in which crewmembers take a 70-mg alendronate tablet once a week before and during flight, starting 17 days before launch. Compared to previous ISS crewmembers (n=14) not taking alendronate, DXA measurements of the spine, femur neck and total hip were significantly improved from -0.8 +/- 0.5%/mo to 1.0 +/- 1.1%/mo, -1.1 +/- 0.5%/mo to -0.2 +/- 0.3%/mo, -1.1 +/- 0.5%/mo to 0.04 +/- 0.3%/mo respectively. QCT-determined trabecular BMD of the femur neck, trochanter and total hip were significantly improved from -2.7 +/- 1.9%/mo to -0.2 +/- 0.8%/mo, -2.2 +/- 0.9%/mo to -0.3 +/- 1.9%/mo and -2.3 +/- 1.0%/mo to -0.2 +/- 1.8%/mo respectively. Significance was calculated from a one-tailed t test. Resorption markers were unchanged, in contrast to measurements from previous ISS crewmembers that showed typical increases of 50-100% above baseline. Urinary Ca showed no increase compared to baseline levels, also distinct from the elevated levels of 50% or greater in previous crews. While these results are encouraging, the current n (4) is small, and the large SDs indicate that, while the means are improved, there

  9. Search of antimicrobial activity of selected non-antibiotic drugs.

    PubMed

    Kruszewska, Hanna; Zareba, Tomasz; Tyski, Stefan

    2002-01-01

    A variety of pharmaceutical preparations, which are applied in the management of non-infectious diseases, have shown in vitro some antimicrobial activity. These drugs are called "non-antibiotics". The aim of this study was to detect and characterise the antimicrobial activity of non-antibiotic drugs. selected from the preparations analysed during state control performed at the Drug Institute in Poland. Over 160 pharmaceutical preparations were randomly chosen from different groups of drugs. The surveillance study was performed on standard ATCC microbial strains used for drug control: S aureus, E. coil, P. aeruginosa and C. albicans. It was shown that the drugs listed below inhibited growth of at least one of the examined strains:acyclovir (Awirol 5%, cream), alendronate (Alenato 5 mg, tabl.), alverine (Meteospasmyl 20 mg, caps.), butorphanole (Butamidor 10 mg/ml, amp.), clodronate (Sindronat 400 mg, caps), diclofenac (Olfen 75 mg, amp.), emadastine (Emadine 0.05%, eye dr.), etodolac (Febret 200 mg, caps.), fluvastatine (Lescol 40 mg, tabl.), ketamine (Ketamidor 10%, amp.), levocabastine (Histimet 0.5 mg/ml, eye dr.), losartan (Lorista 50 mg, tabl.), matipranolol (Betaman 0.3% eye dr.), mesalazine (Pentasa 1%, susp.), naproxen (Nalgesin 550 mg, tabl.), oxaprosine (Reumax 600 mg, tabl.), oxymethazoline (Nasivin 0.025%, nose dr.), proxymetacaine (Alcaine 0.5%, eye dr.), ribavirin (Rebetol 200 mg, caps.), rutoside with ascorbic acid (Cerutin 20+200 mg, tabl.), sulodexide (Vessel due F, 250 LSU, caps.), tegaserole (Zelmac 50 mg, tabl.), telmisartan (Pritor 20 mg, tabl.), temosolomide (Temodal 100 mg, caps.), ticlopidine (Ticlid 250 mg, tabl.), tolfenamic acid (Migea rapid 200 mg, tabl.), tramadole (Tramundin 100 mg, tabl.), tropicamide (Tropicamidum 1%, eye dr.). Staphylococcus aureus was susceptible to most of the drugs listed above. Ticlopidine showed activity against S. aureus, E. coli and C. albicans (MICs equal to: 0.45; 0.45 and 0.65 mg/ml, respectively

  10. Cost-effectiveness of Pharmaceutical Interventions to Prevent Osteoporotic Fractures in Postmenopausal Women with Osteopenia

    PubMed Central

    Kwon, Jin-Won; Park, Hae-Young; Kim, Ye Jee; Moon, Seong-Hwan

    2016-01-01

    Background To assess the cost-effectiveness of drug therapy to prevent osteoporotic fractures in postmenopausal women with osteopenia in Korea. Methods A Markov cohort simulation was conducted for lifetime with a hypothetical cohort of postmenopausal women with osteopenia and without prior fractures. They were assumed to receive calcium/vitamin D supplements only or drug therapy (i.e., raloxifene or risedronate) along with calcium/vitamin D for 5 years. The Markov model includes fracture-specific and non-fracture specific health states (i.e. breast cancer and venous thromboembolism), and all-cause death. Published literature was used to determine the model parameters. Local data were used to estimate the baseline incidence rates of fracture in those with osteopenia and the costs associated with each health state. Results From a societal perspective, the estimated incremental cost-effectiveness ratios (ICERs) for the base cases that had T-scores between -2.0 and -2.4 and began drug therapy at the age of 55, 60, or 65 years were $16,472, $6,741, and -$13,982 per quality-adjusted life year (QALY) gained, respectively. Sensitivity analyses for medication compliance, risk of death following vertebral fracture, and relaxing definition of osteopenia resulted in ICERs reached to $24,227 per QALY gained. Conclusions ICERs for the base case and sensitivity analyses remained within the World Health Organization's willingness-to-pay threshold, which is less than per-capita gross domestic product in Korea (about $25,700). Thus, we conclude that drug therapy for osteopenia would be a cost-effective intervention, and we recommend that the Korean National Health Insurance expand its coverage to include drug therapy for osteopenia. PMID:27294078

  11. Postpartum osteoporosis and vertebral fractures in two patients treated with enoxaparin during pregnancy.

    PubMed

    Ozdemir, D; Tam, A A; Dirikoc, A; Ersoy, R; Cakir, B

    2015-01-01

    Postpartum osteoporosis (PPO) is a rare disease associated with pregnancy and lactation period. Here, we report severe PPO and multiple vertebral compression fractures in two patients treated with enoxaparin--low-molecular-weight heparin (LMWH)--throughout their pregnancy. A 34-year-old woman who has delivered her second baby 3 months ago presented with severe low-back pain. She was treated with enoxaparin 40 mg/day for 8 months during her pregnancy. Dual-energy X-ray absorptiometry (DEXA) showed low T- and Z-scores in lumbar (L) vertebras. In magnetic resonance imaging (MRI), severe height losses in thoracic (T) 12, L1, and L2 vertebras were detected. She was diagnosed to have severe PPO and multiple vertebral compression fractures and was prescribed risedronate 35 mg/week, calcium, and vitamin D. The other patient was a 36-year-old woman diagnosed with PPO and vertebral fractures at the third week postpartum. She was also treated with enoxaparin 60 mg/day during her pregnancy. Severe osteoporosis in L vertebras and height losses indicative for compression fractures in T5-8, T11-12, and L2-5 vertebras were detected by DEXA and MRI, respectively. She was treated with calcitonin 200 U/day, calcium, and vitamin D. These findings suggest that vertebral compression fractures and PPO may be one of the causes of severe back pain in postpartum patients. Treatment with LMWH during pregnancy might be considered as a new risk factor for this rare condition. PMID:25138263

  12. Examination of antimicrobial activity of selected non-antibiotic drugs.

    PubMed

    Kruszewska, Hanna; Zareba, Tomasz; Tyski, Stefan

    2004-12-01

    A variety of pharmaceutical preparations, which are applied in the management of non-infectious diseases, have shown in vitro some antimicrobial activity. These drugs are called "non-antibiotics". The aim of this study was to detect and characterize the antimicrobial activity of non-antibiotic drugs, selected from the preparations analysed during state control performed in the National Institute of Public Health in Poland. Over 180 of pharmaceutical preparations were randomly chosen from different groups of drugs. A 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: Actonel 5 mg tabl. (risedronate), Aldan 10 mg tabl. (amlodipine), Aleras 10 mg tabl. (cetirisine), Aspicam 15 mg tabl. (meloxicam), Baikadent 6 mg/g gel (flavons of Scutellariae), Debretin 100 mg tabl. (trimebutine), Ferro-Duo 100 mg tabl. (ferrum), Gastrovent 145 mg caps. (bismuth citrate), Ibum 200 mg caps., Upfen 200 mg tabl. (ibuprofen), Lastet 100 mg caps. (etoposide), Legalon 70 mg tabl. (sylimarin), Madopar 125 tabl. (benserazide, levodopa), Moxenil 100 mg tabl. (nimesulide), Neurotin 800 mg tabl. (gabapentin), Propranolol 40 mg tabl. (propranolol), Rexetin 20 mg tabl. (paroxetine), Salipax 20 mg caps. (fluoxetine), Selofen 10 mg caps. (zaleplon) Stenorol 0.6% powder (halofuginone), Stimuloton 50 mg tabl. (sertraline), Superoptim 0.3 mg tabl. (hipericine), Uversan 50 mg tabl. (arbutine from Arctostaphylos uva ursi). S. aureus strain was susceptible to the most of the drugs listed above. The lowest inhibitory concentration was found for sertraline and hipericine (0.16 and 0.075 mg/mL, respectively). PMID:15909927

  13. Jaw bone marrow-derived osteoclast precursors internalize more bisphosphonate than long-bone marrow precursors.

    PubMed

    Vermeer, Jenny A F; Jansen, Ineke D C; Marthi, Matangi; Coxon, Fraser P; McKenna, Charles E; Sun, Shuting; de Vries, Teun J; Everts, Vincent

    2013-11-01

    Bisphosphonates (BPs) are widely used in the treatment of several bone diseases, such as osteoporosis and cancers that have metastasized to bone, by virtue of their ability to inhibit osteoclastic bone resorption. Previously, it was shown that osteoclasts present at different bone sites have different characteristics. We hypothesized that BPs could have distinct effects on different populations of osteoclasts and their precursors, for example as a result of a different capacity to endocytose the drugs. To investigate this, bone marrow cells were isolated from jaw and long bone from mice and the cells were primed to differentiate into osteoclasts with the cytokines M-CSF and RANKL. Before fusion occurred, cells were incubated with fluorescein-risedronate (FAM-RIS) for 4 or 24h and uptake was determined by flow cytometry. We found that cultures obtained from the jaw internalized 1.7 to 2.5 times more FAM-RIS than long-bone cultures, both after 4 and 24h, and accordingly jaw osteoclasts were more susceptible to inhibition of prenylation of Rap1a after treatment with BPs for 24h. Surprisingly, differences in BP uptake did not differentially affect osteoclastogenesis. This suggests that jaw osteoclast precursors are less sensitive to bisphosphonates after internalization. This was supported by the finding that gene expression of the anti-apoptotic genes Bcl-2 and Bcl-xL was higher in jaw cells than long bone cells, suggesting that the jaw cells might be more resistant to BP-induced apoptosis. Our findings suggest that bisphosphonates have distinct effects on both populations of osteoclast precursors and support previous findings that osteoclasts and precursors are bone-site specific. This study may help to provide more insights into bone-site-specific responses to bisphosphonates. PMID:23962725

  14. Evaluation of results of conservative therapy in patients with transient osteoporosis of hip.

    PubMed

    Guler, Olcay; Ozyurek, Selahattin; Cakmak, Selami; Isyar, Mehmet; Mutlu, Serhat; Mahirogullari, Mahir

    2015-09-01

    The present study aimed to review the general characteristics of 18 cases diagnosed with transient osteoporosis of the hip (TOH) in our hospital within a 3-year period and to present their follow-up results after conservative treatment. A retrospective evaluation was made of the treatment and results of follow-up of TOH cases using physical examination and laboratory findings, hip radiographs and magnetic resonance imaging (MRI) and Harris Hip Scores (HHS). The mean duration of complaints of 6 females (mean age, 34.3±4.3 years) and 12 males (mean age, 40.7±10.5 years) was 6.1±2.7 weeks before the treatment. Three female patients had a history of giving birth by cesarean delivery. None of the patients had any history of trauma. MRI revealed increased intensity in T2 sequences and decreased intensity in T1 sequences in the proximal aspect of the femur. None of the patients had subchondral collapse or intra-articular effusion. For 3 female patients who were breastfeeding, no medical therapy was given, but only hyperbaric oxygen (HBO) therapy and forearm crutches. As standard management, the other patients were prevented from weight-bearing with the use of forearm crutches and medical therapy of diclofenac sodium, acetylsalicylic acid, and risedronate sodium was administered and additional HBO therapy. Clinical and radiological improvements were observed in all patients. None of the patients had avascular necrosis (AVN) of the femoral head. There was no record of therapy-related complications. While HHS was 55.6±7.8 before the treatment, it increased to 88.8±5.8 in the 3rd month and to 96.0±1.8 in the 6th month after the treatment. This change in score over time was found to be significant. PMID:26435236

  15. The impact of an aromatase inhibitor on body composition and gonadal hormone levels in women with breast cancer

    PubMed Central

    Perera, S.; Vujevich, K.; Rastogi, P.; Lembersky, B.; Brufsky, A.; Vogel, V.; Greenspan, S. L.

    2011-01-01

    Aromatase inhibitors (AIs) have become the standard adjuvant therapy of postmenopausal breast cancer survivors. AIs induce a reduction of bioavailable estrogens by inhibiting aromatase, which would be expected to induce alterations in body composition, more extensive than induced by menopause. The objectives are to examine the impact of AIs on (1) DXA-scan derived body composition and (2) gonadal hormone levels. This is a sub-analysis of a 2-year double-blind, placebo-controlled, randomized trial of 82 women with nonmetastatic breast cancer, newly menopausal following chemotherapy, who were randomized to risedronate (35 mg once weekly) versus placebo, and stratified for their usage of AI versus no AI. Outcomes included DXA-scan derived body composition and gonadal hormone levels. As a group, total body mass increased in women over 24 months. Women on AIs gained a significant amount of lean body mass compared to baseline as well as to no-AI users (P < 0.05). Women not on an AI gained total body fat compared to baseline and AI users (P < 0.05). Free testosterone significantly increased and sex hormone binding globulin (SHBG) significantly decreased in women on AIs compared to no AIs at 24 months (P < 0.01) while total estradiol and testosterone levels remained stable. Independent of AI usage, chemotherapy-induced postmenopausal breast cancer patients demonstrated an increase of total body mass. AI users demonstrated maintenance of total body fat, an increase in lean body mass and free testosterone levels, and a decrease in SHBG levels compared to no-AI users. The mechanisms and implications of these changes need to be studied further. PMID:21046232

  16. The impact of an aromatase inhibitor on body composition and gonadal hormone levels in women with breast cancer.

    PubMed

    van Londen, G J; Perera, S; Vujevich, K; Rastogi, P; Lembersky, B; Brufsky, A; Vogel, V; Greenspan, S L

    2011-01-01

    Aromatase inhibitors (AIs) have become the standard adjuvant therapy of postmenopausal breast cancer survivors. AIs induce a reduction of bioavailable estrogens by inhibiting aromatase, which would be expected to induce alterations in body composition, more extensive than induced by menopause. The objectives are to examine the impact of AIs on (1) DXA-scan derived body composition and (2) gonadal hormone levels. This is a sub-analysis of a 2-year double-blind, placebo-controlled, randomized trial of 82 women with nonmetastatic breast cancer, newly menopausal following chemotherapy, who were randomized to risedronate (35 mg once weekly) versus placebo, and stratified for their usage of AI versus no AI. Outcomes included DXA-scan derived body composition and gonadal hormone levels. As a group, total body mass increased in women over 24 months. Women on AIs gained a significant amount of lean body mass compared to baseline as well as to no-AI users (P < 0.05). Women not on an AI gained total body fat compared to baseline and AI users (P < 0.05). Free testosterone significantly increased and sex hormone binding globulin (SHBG) significantly decreased in women on AIs compared to no AIs at 24 months (P < 0.01) while total estradiol and testosterone levels remained stable. Independent of AI usage, chemotherapy-induced postmenopausal breast cancer patients demonstrated an increase of total body mass. AI users demonstrated maintenance of total body fat, an increase in lean body mass and free testosterone levels, and a decrease in SHBG levels compared to no-AI users. The mechanisms and implications of these changes need to be studied further. PMID:21046232

  17. Pamidronate Down-regulates Tumor Necrosis Factor-alpha Induced Matrix Metalloproteinases Expression in Human Intervertebral Disc Cells

    PubMed Central

    Kang, Young-Mi; Hong, Seong-Hwan; Yang, Jae-Ho; Oh, Jin-Cheol; Park, Jin-Oh; Lee, Byung Ho; Lee, Sang-Yoon; Kim, Hak-Sun; Lee, Hwan-Mo

    2016-01-01

    Background N-containing bisphosphonates (BPs), such as pamidronate and risedronate, can inhibit osteoclastic function and reduce osteoclast number by inducing apoptotic cell death in osteoclasts. The aim of this study is to demonstrate the effect of pamidronate, second generation nitrogen-containing BPs and to elucidate matrix metallo-proteinases (MMPs) mRNA expression under serum starvation and/or tumor necrosis factor alpha (TNF-α) stimulation on metabolism of intervertebral disc (IVD) cells in vitro. Methods Firstly, to test the effect of pamidronate on IVD cells in vitro, various concentrations (10-12, 10-10, 10-8, and 10-6 M) of pamidronate were administered to IVD cells. Then DNA and proteoglycan synthesis were measured and messenger RNA (mRNA) expressions of type I collagen, type II collagen, and aggrecan were analyzed. Secondly, to elucidate the expression of MMPs mRNA in human IVD cells under the lower serum status, IVD cells were cultivated in full serum or 1% serum. Thirdly, to elucidate the expression of MMPs mRNA in IVD cells under the stimulation of 1% serum and TNF-α (10 ng/mL) In this study, IVD cells were cultivated in three dimensional alginate bead. Results Under the lower serum culture, IVD cells in alginate beads showed upregulation of MMP 2, 3, 9, 13 mRNA. The cells in lower serum and TNF-α also demonstrated upregulation of MMP-2, 3, 9, and 13 mRNA. The cells with various doses of pamidronate and lower serum and TNF-α were reveled partial down-regulation of MMPs. Conclusions Pamidronate, N-containing second generation BPs, was safe in metabolism of IVD in vitro maintaining chondrogenic phenotype and matrix synthesis, and down-regulated TNF-α induced MMPs expression. PMID:27622181

  18. Macrophage Depletion by Free Bisphosphonates and Zoledronate-Loaded Red Blood Cells

    PubMed Central

    Sabatino, Raffaella; Antonelli, Antonella; Battistelli, Serafina; Schwendener, Reto; Magnani, Mauro; Rossi, Luigia

    2014-01-01

    Bisphosphonates, besides being important drugs for the treatment of various bone diseases, could also be used to induce apoptosis in macrophage-like and cancer cells. However, their activity in vivo is limited by a short plasma half-life and rapid uptake within bone. Therefore, several delivery systems have been proposed to modify their pharmacokinetic profile and biodistribution. Among these, red blood cells (RBCs) represent one of the most promising biological carriers. The aim of this study was to select the best performing compound among Clodronate, Pamidronate, Ibandronate and Zoledronate in killing macrophages and to investigate RBCs as innovative carrier system to selectively target bisphosphonates to macrophages. To this end, the encapsulation of the selected bisphosphonates in autologous RBCs as well as the effect on macrophages, both in vitro and in vivo were studied. This work shows that, among the tested bisphosphonates, Zoledronate has proven to be the most active molecule. Human and murine RBCs have been successfully loaded with Zoledronate by a procedure of hypotonic dialysis and isotonic resealing, obtaining a dose-dependent drug entrapment with a maximal loading of 7.96±2.03, 6.95±3.9 and 7.0±1.89 µmoles of Zoledronate/ml of packed RBCs for human, Swiss and Balb/C murine RBCs, respectively. Engineered RBCs were able to detach human and murine macrophages in vitro, leading to a detachment of 66±8%, 67±8% and 60.5±3.5% for human, Swiss and Balb/C RBCs, respectively. The in vivo efficacy of loaded RBCs was tested in Balb/C mice administering 59 µg/mouse of RBC-encapsulated Zoledronate. By a single administration, depletion of 29.0±16.38% hepatic macrophages and of 67.84±5.48% spleen macrophages was obtained, confirming the ability of encapsulated Zoledronate to deplete macrophages in vivo. In conclusion, RBCs loaded with Zoledronate should be considered a suitable system for targeted delivery to macrophages, both in vitro and in vivo. PMID

  19. 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

  20. The effects of bisphosphonates on ectopic soft tissue mineralization caused by mutations in the ABCC6 gene

    PubMed Central

    Li, Qiaoli; Sundberg, John P; Levine, Michael A; Terry, Sharon F; Uitto, Jouni

    2015-01-01

    Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are heritable ectopic mineralization disorders. Most cases of PXE and many cases of GACI harbor mutations in the ABCC6 gene. There is no effective treatment for these disorders. We explored the potential efficacy of bisphosphonates to prevent ectopic calcification caused by ABCC6 mutations by feeding Abcc6−/− mice with diet containing etidronate disodium (ETD) or alendronate sodium trihydrate (AST) in quantities corresponding to 1x, 5x, or 12x of the doses used to treat osteoporosis in humans. The mice were placed on diet at 4 weeks of age, and the degree of mineralization was assessed at 12 weeks by quantitation of the calcium deposits in the dermal sheath of vibrissae, a progressive biomarker of the mineralization, by computerized morphometry of histopathologic sections and by direct chemical assay of calcium. We found that ETD, but not AST, at the 12x dosage, significantly reduced mineralization, suggesting that selected bisphosphonates may be helpful for prevention of mineral deposits in PXE and GACI caused by mutations in the ABCC6 gene, when combined with careful monitoring of efficacy and potential side-effects. PMID:25607347

  1. [The role of rank-ligand inhibition in the treatment of postmenopausal osteoporosis].

    PubMed

    Varenna, M; Gatti, D

    2010-01-01

    Osteoporosis is a skeletal disease affecting millions of people worldwide in which a decreased bone mass and a microarchitectural deterioration compromise bone strength leading to bone fragility and increased susceptibility to fracture. Bone turnover increases at menopause, with osteoclast-mediated bone resorption exceeding bone formation. Recent discoveries in bone biology have demonstrated that RANKL, a cytokine member of the tumor necrosis factor superfamily, is an essential mediator of osteoclast formation, function and survival. Denosumab is a fully human monoclonal antibody with a high affinity and specificity for human RANKL. By binding to its target, denosumab prevents the interaction of RANKL with its receptor RANK on osteoclasts and their precursors and inhibits osteoclast-mediated bone resorption. Administered as a subcutaneous injection every six months, denosumab has been shown to decrease bone turnover and to increase bone mineral density in postmenopausal women with low bone mass and osteoporosis. In these patients denosumab significantly reduced the risk of vertebral fractures, hip fractures and nonvertebral fractures. In all clinical trials published to date, denosumab was well tolerated with an incidence of adverse events, including infections and malignancy, generally similar to subjects receiving placebo or alendronate. The denosumab therapeutic regimen consisting in a subcutaneous injection every 6 months may increase patient compliance and persistence with a further benefit from treatment. By providing a new molecular target for osteoporosis treatment, denosumab is a promising drug for the treatment of postmenopausal osteoporosis and the prevention of fragility fractures. PMID:21052563

  2. 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.

  3. The effect of bisphosphonate treatment on the biochemical and cellular events during bone remodelling in response to microinjury stimulation.

    PubMed

    Mulcahy, L E; Curtin, C M; McCoy, R J; O'Brien, F J; Taylor, D; Lee, T C; Duffy, G P

    2015-01-01

    Osteoporosis is one of the most prevalent bone diseases worldwide and is characterised by high levels of bone turnover, a marked loss in bone mass and accumulation of microdamage, which leads to an increased fracture incidence that places a huge burden on global health care systems. Bisphosphonates have been used to treat osteoporosis and have shown great success in conserving bone mass and reducing fracture incidence. In spite of the existing knowledge of the in vivo responses of bone to bisphosphonates, the cellular responses to these drugs have yet to be fully elucidated. In vitro model systems that allow the decoupling of complex highly integrated events, such as bone remodelling, provide a tool whereby these biological processes may be studied in a more simplified context. This study firstly utilised an in vitro model system of bone remodelling and comprising all three major cell types of the bone (osteocytes, osteoclasts and osteoblasts), which was representative of the bone's capacity to sense microdamage and subsequently initiate a basic multicellular unit response. Secondly, this system was used to study the effect of two commonly utilised aminobisphosphonate treatments for osteoporosis, alendronate and zoledronate. We demonstrated that microinjury to osteocyte networks being treated with bisphosphonates modulates receptor activator of nuclear factor kappa-B ligand and osteoprotegerin activity, and subsequently osteoclastogenesis. Furthermore, bisphosphonates increased the osteogenic potential following microinjury. Thus, we have shown for the first time that bisphosphonates act at all three stages of bone remodelling, from microinjury to osteoclastogenesis and ultimately osteogenesis. PMID:26614482

  4. Prevention and treatment of senile osteoporosis and hip fractures.

    PubMed

    Duque, G; Demontiero, O; Troen, B R

    2009-02-01

    Osteoporosis is a major health issue worldwide, with significant economic consequences and adverse impacts on the quality of life. Hip fractures are the most devastating complication of osteoporosis, are likely to increase exponentially with an increasingly aged population, are associated with high recurrence rate, and lead to significant morbidity and mortality. This review discusses the prevalence and impact of hip fractures, the assessment of fracture risk, fall prevention, and treatment of osteoporosis with emphasis on evidence for hip fracture reduction among the various agents currently available. The aim is to provide recommendations to optimize hip fracture prevention and treatment. Ample evidence exists in the literature of many other risk factors independent from bone mineral density that increase fracture risk. These clinical risk factors have been validated in large cohorts and are incorporated into clinical tools that are invaluable in treatment decisions. In addition, strategies to prevent or reduce falls are integral to comprehensive osteoporosis management. Vitamin D combined with calcium has a role in primary prevention. Alendronate, residronate, strontium and zoledronic acid have proven efficacy in primary and secondary hip fracture prevention. An aggressive approach to investigate, assess and manage an individual's fracture risk and fall risk is paramount to reduce the high morbidity and mortality associated with hip fractures. The choice of therapy should be determined by the patient's calculated fracture risk and efficacy of the potential treatment, including long term compliance associated with the agent of choice. PMID:19277006

  5. Treatment of osteoporosis: where are we and where are we going to.

    PubMed

    Reginster, J Y

    1999-06-01

    In the past years, there has been a multiplication of drugs identified as candidates for use in the prevention or the treatment of osteoporosis. When treating established osteoporosis, the objective is to prevent further skeletal deterioration, improve bone mass and/or bone microarchitecture to provide a documented reduction of the risk of vertebral and/or peripheral fractures. Calcium and vitamin D have been shown to be particularly efficient in elderly patients, mainly to prevent non-vertebral fractures. By inhibiting osteoclastic activity, calcitonin improves bone mineral density at all sites. Preliminary results suggest that it might also decrease vertebral fracture rates. Bisphosphonates have been investigated for 20 years in the treatment of osteoporosis. Alendronate was shown to reduce spinal and extravertebral fractures. New formulations of fluoride, like monofluorophosphate appear to be particularly beneficial in women with mild to moderate osteoporosis. Several new compounds, including parathormone, strontium salts, ipriflavone or others are currently developed and subject to large investigational programs to demonstrate their ability to reduce fracture. PMID:10546235

  6. Comparison of Calipers for Matching on the Disease Risk Score.

    PubMed

    Connolly, John G; Gagne, Joshua J

    2016-05-15

    Previous studies have compared calipers for propensity score (PS) matching, but none have considered calipers for matching on the disease risk score (DRS). We used Medicare claims data to perform 3 cohort studies of medication initiators: a study of raloxifene versus alendronate in 1-year nonvertebral fracture risk, a study of cyclooxygenase 2 inhibitors versus nonselective nonsteroidal antiinflammatory medications in 6-month gastrointestinal bleeding, and a study of simvastatin + ezetimibe versus simvastatin alone in 6-month cardiovascular outcomes. The study periods for each cohort were 1998 through 2005, 1999 through 2002, and 2004 through 2005, respectively. In each cohort, we calculated 1) a DRS, 2) a prognostic PS which included the DRS as the independent variable in a PS model, and 3) the PS for each patient. We then nearest-neighbor matched on each score in a variable ratio and a fixed ratio within 8 calipers based on the standard deviation of the logit and the natural score scale. When variable ratio matching on the DRS, a caliper of 0.05 on the natural scale performed poorly when the outcome was rare. The prognostic PS did not appear to offer any consistent practical benefits over matching on the DRS directly. In general, logit-based calipers or calipers smaller than 0.05 on the natural scale performed well when DRS matching in all examples. PMID:27037270

  7. Psoralen and Isopsoralen Ameliorate Sex Hormone Deficiency-Induced Osteoporosis in Female and Male Mice

    PubMed Central

    Yuan, Xiaomei; Bi, Yanan; Yan, Zeman; Pu, Weiling; Li, Yuhong; Zhou, Kun

    2016-01-01

    Osteoporosis is a systemic skeletal disease, which is characterized by a systemic destruction of bone mass and microarchitecture. With life standard improved, the treatment of osteoporosis attracted more attention. The aim of this study is to verify the osteoprotective effect of psoralen and isopsoralen in females and males. Female and male mice were divided into 7 groups in this study: control group (sham-operation), model group (by ovariectomy or orchidectomy), positive control group (females given estradiol valerate; males given alendronate sodium), psoralen groups (10 mg/kg and 20 mg/kg), and isopsoralen groups (10 mg/kg and 20 mg/kg). After administration of psoralen and isopsoralen for 8 weeks, osteoporosis was ameliorated with increasing bone strength and improving trabecular bone microstructure as indicated by CT scan and pathology. Serum alkaline phosphatase (ALP), tartrate resistant acid phosphatase (TRACP), osteocalcin (OC), and C-terminal cross-linking telopeptides of type I collagen (CTX-1) were examined. Decreased TRACP and increased ALP/TRACP suggested restoring from bone destruction. These results suggest that psoralen and isopsoralen may be used as good natural compounds for the treatment of osteoporosis in males, as well as females. PMID:27239473

  8. Inhibition of Osteoclast Differentiation and Bone Resorption by Bisphosphonate-conjugated Gold Nanoparticles

    PubMed Central

    Lee, Donghyun; Heo, Dong Nyoung; Kim, Han-Jun; Ko, Wan-Kyu; Lee, Sang Jin; Heo, Min; Bang, Jae Beum; Lee, Jung Bok; Hwang, Deok-Sang; Do, Sun Hee; Kwon, Il Keun

    2016-01-01

    In recent years, gold nanoparticles (GNPs) have been reported to affect the regeneration of bone tissue. The goal of this study was to improve bone tissue regeneration by using targeted GNPs. We fabricated a functionalized GNPs conjugated with alendronate (ALD), of the bisphosphonate group. Subsequently, the ALD, GNPs, and ALD conjugated GNPs (GNPs-ALD) were analyzed by ultraviolet-visible absorbance (UV-vis) spectrophotometer, Attenuated total reflectance Fourier transform infrared spectrometer (ATR-FTIR), and thermo gravimetric analysis (TGA). The prepared GNPs-ALD were used to investigate their inhibitory effects on the receptor activator of nuclear factor- κb ligand (RANKL)-induced osteoclastogenesis in bone marrow-derived macrophages (BMMs). Additionally, the GNPs-ALD were applied to ovariectomy (OVX)-induced osteoporotic mice and the experiments were evaluated. ALD was found to be successfully conjugated to the GNPs surface, and it displayed significant adhesion onto the bone surface. The in-vitro study indicated that the GNPs, ALD and GNPs-ALD suppressed osteoclast formation in a dose-dependent manner. Furthermore, in the OVX mouse model, the mice treated GNPs-ALD had higher bone density as compared to other OVX mice groups. The results from these tests indicated that GNPs-ALD can be useful agents for preventing and treating osteoporosis. PMID:27251863

  9. 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

  10. Diabetes and osteoporosis: Action of gastrointestinal hormones on the bone.

    PubMed

    García-Martín, A; Reyes-García, R; García-Castro, J M; Muñoz-Torres, M

    2013-01-01

    A 62-year-old woman consulted for evaluation of treatment for her type 2 diabetes diagnosed four years ago. He had been received treatment with metformin 850mg twice, with no chronic associated complications. She had hypertension and dyslipidemia. She was being treated with candesartan/hydrochlorothiazide 32/12.5mg and atorvastatin 40mg. Her weight was 92kg and height 162cm (BMI, 35.1kg/m(2)). The last analysis showed fasting glucose 168mg/dl and glycated hemoglobin 7.5%, Microalbuminuria was negative. Blood pressure and lipid profile were within the therapeutic range. Two years ago she suffered a nontraumatic Colle's fracture in her left arm for which she was taking a daily calcium and vitamin D supplement and weekly alendronate. In summary, this is an obese female patient with type 2 diabetes mellitus and inadequate metabolic control, She also has a history of fragility fracture. How should this patient be evaluated and treated? PMID:26530941

  11. Is It a Simple Stress Fracture or Bisphosphonate-related Atypical Fracture?

    PubMed

    Kang, Soo Yong; Baek, Ji-Hoon; Kang, Bun Jung; Kim, Min Kyu; Lee, Han-Jun

    2012-11-01

    A number of reports regarding atypical fractures of the femur have raised questions concerning the possible correlation between long-term bisphosphonate treatment and the occurrence of insufficiency fractures in the proximal femur. However, clinically, it is often confused whether is it a fatigue fracture because of implant induced stress concentration or a bisphosphonate-related atypical fracture, especially in a patient with a subtrochanteric fracture who receive bisphosphonate therapy after open reduction and internal fixation, such as dynamic hip screw (DHS) fixation for previous ipsilateral femoral neck or intertrochanteric fracture. The authors experienced a case of a progressive femoral insufficiency fracture in a woman who had been on Fosamax (Alendronic acid with Vitamin D; Merck & Co. Inc, NJ, USA) therapy for four years after ipsilateral femoral neck fracture treated with a two hole DHS system. Despite a high suspicion of an insufficiency femoral subtrochanteric fracture by bone scan, the occult fracture progressed to a displaced femoral subtrochanteric fracture one year after. The fracture site was fixed with a 6 hole DHS plate, and six months after reoperation the patient had no symptoms and the fracture site had united without any complication. PMID:24524043

  12. Garré’s sclerosing osteomyelitis: case report☆☆☆

    PubMed Central

    de Moraes, Frederico Barra; Motta, Tainá Melo Vieira; Severin, Alessandra Assis; de Alencar Faria, Deniel; de Oliveira César, Fernanda; de Souza Carneiro, Siderlei

    2014-01-01

    The aim of this study was to report on a rare case of Garré’s sclerosing osteomyelitis. The patient was a 54-year-old woman with a history of treatment for lupus using corticoids for 20 years, and for osteoporosis using alendronate for five years. She presented edema and developed a limitation of left knee movement one year earlier, with mild effusion and pain on metaphyseal palpation, but without fever. She was in a good general state, without local secretion. Images of her knee showed trabecular osteolysis of the distal metaphysis of the femur and a periosteal reaction in both proximal tibias and both distal femurs, compatible with chronic osteomyelitis of low virulence and slow progression. Magnetic resonance imaging showed T2 hypersignal in the femur and tibia. Curettage was performed on the left distal femur, with release of secretion, but this was negative on culturing. A biopsy showed chronic infection and inflammation, fibrosis, xanthogranulomatous reaction and foci of suppuration. Antibiotic therapy was administered for six months. The etiology was not clarified: bacterial infection was suspected, but culturing was generally negative. The chronic process was maintained by low-virulence infection or even after treatment. The differential diagnoses were fibrous dysplasia, syphilis, pustulosis palmoplantaris, rectocolitis, Crohn's disease, SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) and Paget's disease. The unifocal diseases were osteoid osteoma, Ewing's disease, osteosarcoma and eosinophilic granuloma. PMID:26229835

  13. Garré's sclerosing osteomyelitis: case report.

    PubMed

    de Moraes, Frederico Barra; Motta, Tainá Melo Vieira; Severin, Alessandra Assis; de Alencar Faria, Deniel; de Oliveira César, Fernanda; de Souza Carneiro, Siderlei

    2014-01-01

    The aim of this study was to report on a rare case of Garré's sclerosing osteomyelitis. The patient was a 54-year-old woman with a history of treatment for lupus using corticoids for 20 years, and for osteoporosis using alendronate for five years. She presented edema and developed a limitation of left knee movement one year earlier, with mild effusion and pain on metaphyseal palpation, but without fever. She was in a good general state, without local secretion. Images of her knee showed trabecular osteolysis of the distal metaphysis of the femur and a periosteal reaction in both proximal tibias and both distal femurs, compatible with chronic osteomyelitis of low virulence and slow progression. Magnetic resonance imaging showed T2 hypersignal in the femur and tibia. Curettage was performed on the left distal femur, with release of secretion, but this was negative on culturing. A biopsy showed chronic infection and inflammation, fibrosis, xanthogranulomatous reaction and foci of suppuration. Antibiotic therapy was administered for six months. The etiology was not clarified: bacterial infection was suspected, but culturing was generally negative. The chronic process was maintained by low-virulence infection or even after treatment. The differential diagnoses were fibrous dysplasia, syphilis, pustulosis palmoplantaris, rectocolitis, Crohn's disease, SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) and Paget's disease. The unifocal diseases were osteoid osteoma, Ewing's disease, osteosarcoma and eosinophilic granuloma. PMID:26229835

  14. Structural Studies of Geosmin Synthase, a Bifunctional Sesquiterpene Synthase with αα Domain Architecture That Catalyzes a Unique Cyclization-Fragmentation Reaction Sequence.

    PubMed

    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

    2015-12-01

    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 Mg(2+) 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 three Mg(2+) 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 on the basis of ∼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

  15. Inhibition of Osteocyte Apoptosis Prevents the Increase in Osteocytic Receptor Activator of Nuclear Factor κB Ligand (RANKL) but Does Not Stop Bone Resorption or the Loss of Bone Induced by Unloading*

    PubMed Central

    Plotkin, Lilian I.; Gortazar, Arancha R.; Davis, Hannah M.; Condon, Keith W.; Gabilondo, Hugo; Maycas, Marta; Allen, Matthew R.; Bellido, Teresita

    2015-01-01

    Apoptosis of osteocytes and osteoblasts precedes bone resorption and bone loss with reduced mechanical stimulation, and receptor activator of NF-κB ligand (RANKL) expression is increased with unloading in mice. Because osteocytes are major RANKL producers, we hypothesized that apoptotic osteocytes signal to neighboring osteocytes to increase RANKL expression, which, in turn, increases osteoclastogenesis and bone resorption. The traditional bisphosphonate (BP) alendronate (Aln) or IG9402, a BP analog that does not inhibit resorption, prevented the increase in osteocyte apoptosis and osteocytic RANKL expression. The BPs also inhibited osteoblast apoptosis but did not prevent the increase in osteoblastic RANKL. Unloaded mice exhibited high serum levels of the bone resorption marker C-telopeptide fragments of type I collagen (CTX), elevated osteoclastogenesis, and increased osteoclasts in bone. Aln, but not IG9402, prevented all of these effects. In addition, Aln prevented the reduction in spinal and femoral bone mineral density, spinal bone volume/tissue volume, trabecular thickness, mechanical strength, and material strength induced by unloading. Although IG9402 did not prevent the loss of bone mass, it partially prevented the loss of strength, suggesting a contribution of osteocyte viability to strength independent of bone mass. These results demonstrate that osteocyte apoptosis leads to increased osteocytic RANKL. However, blockade of these events is not sufficient to restrain osteoclast formation, inhibit resorption, or stop bone loss induced by skeletal unloading. PMID:26085098

  16. Therapy of calcinosis universalis complicating adult dermatomyositis.

    PubMed

    Terroso, Georgina; Bernardes, Miguel; Aleixo, Abelha; Madureira, Pedro; Vieira, Romana; Bernardo, Alexandra; Costa, Lúcia

    2013-01-01

    Although frequent in juvenile dermatomyositis, calcinosis is a rare finding in adult dermatomyositis. It has been associated with disease activity and delayed treatment. It is more common in later phases of the disease, in sites under chronic stress and trauma. Calcinosis has been associated with inflammation but information about its pathogeny continues to evolve as we learn more about the underlying processes. Being uncommon, there is no standard therapy and management is guided by case studies and series. Different treatments have been used in an attempt to clear calcinosis lesions and prevent its recurrence but none has been clearly effective. The authors present the case of a 25 year-old female diagnosed with dermatomyositis who developed calcinosis universalis after stopping therapy. Immunossupressive therapy was reinitiated and therapy aiming at reduction of calcinosis was sequentially tried using: colchicine, hydroxide magnesium, diltiazem, alendronate, probenecid and pamidronate. After receiving intravenous pamidronate, calcinosis lesions decreased and the patient regained full range of movement and quality of life. No recurrence has occurred after eight years of follow-up. PMID:24131911

  17. Reproducible quantification of osteoclastic activity: characterization of a biomimetic calcium phosphate assay.

    PubMed

    Maria, Salwa M; Prukner, Christiane; Sheikh, Zeeshan; Mueller, Frank; Barralet, Jake E; Komarova, Svetlana V

    2014-07-01

    Osteoclasts are responsible for bone and joint destruction in rheumatoid arthritis, periodontitis, and osteoporosis. Animal tusk slice assays are standard for evaluating the effect of therapeutics on these cells. However, in addition to batch-to-batch variability inherent to animal tusks, their use is clearly not sustainable. Our objective was to develop and characterize a biomimetic calcium phosphate assay based on the use of phase pure hydroxyapatite coated as a thin film on the surface of culture plates, to facilitate the reproducible quantification of osteoclast resorptive activity. Osteoclasts were formed from RAW 264.7 mouse monocyte cell line using a pro-resorptive cytokine RANKL (50 ng/mL). No change in substrate appearance was noted after culture with media without cells, or undifferentiated monocytes. Only in the presence of osteoclasts localized areas of calcium phosphate dissolution were observed. The total area resorbed positively correlated with the osteoclast numbers (R(2) = 0.99). The resorbed area was significantly increased by the addition of RANKL, and decreased after application of known inhibitors of osteoclast resorptive activity, calcitonin (10 μM), or alendronate (100 μM). Thus, calcium phosphate coated substrates allow reliable monitoring of osteoclast resorptive activity and offer an alternative to animal tusk slice assays. PMID:24259122

  18. Therapeutic Effect of Oral Bisphosphonates on Choroidal Neovascularization in the Human Eye

    PubMed Central

    Honda, Shigeru; Nagai, Takayuki; Kondo, Naoshi; Fukuda, Masahide; Kusuhara, Sentaro; Tsukahara, Yasutomo; Negi, Akira

    2010-01-01

    Purpose. Choroidal neovascularization (CNV) is often associated with age-related macular degeneration (AMD) and pathological myopia (PM). Bisphosphonates, the drug of choice to treat osteoporosis, have been recently reported to have anti-angiogenic effects. The purpose of this study is to investigate the therapeutic effects of oral bisphosphonates for CNV in humans. Methods. Thirty-six consecutive cases with CNV due to AMD or PM who declined anti-VEGF therapy were recruited. The patients were prescribed 5 mg of oral alendronates daily for 6 months. The best-corrected visual-acuity (BCVA), the lesion size in fundus photographs and fluorescein angiography, foveal thickness and total macular volume in optical coherence tomography were compared between pre- and post-treatment. Results. The mean BCVA of the patients was significantly improved after a months with the treatment in the AMD group. In the PM group, the mean BCVA was maintained up to 6 months with the treatment. The mean lesion size was significantly decreased by 3 months in both groups. The averages of foveal thickness and total macular volume were significantly reduced after 1 month of treatment in the AMD group.Conclusions. Oral bisphosphonate should be further investigated as a possible therapeutic and preventive drug for CNV due to AMD and PM. PMID:20706646

  19. Bisphosphonate associated osteomyelitis of the jaw in patients with bony exposure: prevention, a new way of thinking.

    PubMed

    Tardast, Arezo; Sjöman, Reine; Løes, Sigbjørn; Abtahi, Jahan

    2015-01-01

    Objective There is strong evidence of a link between the use of systemic bisphosphonates (BPs) and osteonecrosis of the jaw, especially in cancer patients. Among risk factors for BRONJ, tooth extraction and immune suppressive drugs seem to have significant role on bone healing. Therefore, the importance of these parameters in development of BRONJ was reviewed in this retrospective study in two maxillofacial surgery units. Material and Methods From 2007 to 2012, 46 patients on bisphosphonate who had developed oral bony lesions participated in this study. The pharmacological exposure, comorbidities, maxillofacial findings, types of treatment and outcome data were collected from clinical and radiological records. Results The most frequently used BP was alendronate (67%). Tooth extraction was reported in 61% of patients with BRONJ. Systemic corticosteroids were prescribed in 35 cases (76%) as an adjuvant for BP. Patients on corticosteroids had a lower probability of bony lesion healing (p<0.05) than patients without corticosteroids. Of the 46 patients who underwent conservative treatments, only ten were completely healed (21%). Conclusions Beside tooth extraction, corticosteroids were shown to be an implant risk factor for low rate of bone healing and hence the development of BRONJ. The outcome of conservative treatment was uncertain and this emphasizes the importance of prevention. PMID:26221926

  20. Predictors of atypical femoral fractures during long term bisphosphonate therapy: A case series & review of literature

    PubMed Central

    Bhadada, Sanjay Kumar; Sridhar, Subbiah; Muthukrishnan, Jeyaram; Mithal, Ambrish; Sharma, Dinesh C.; Bhansali, Anil; Dhiman, Vandana

    2014-01-01

    Background & objectives: Bisphosphonates (BPs) are the most widely prescribed medicines for the treatment of osteoporosis because of their efficacy and favourable safety profile. There have been, several reports on an increased incidence of atypical femoral fractures after long term treatment with BPs. The objective of this study was to evaluate the clinical presentation including prodromal symptoms, skeletal radiograph findings, type and duration of BPs received and treatment outcome of patients who developed atypical femoral fractures during bisphosphonate therapy. Methods: In this retrospective study, eight patients with atypical femoral fractures were analysed based on clinical features, biochemical and radiological investigations. Results: Of the eight patients, who sustained atypical femoral fractures, six were on alendronate and two were on zoledronate therapy before the fractures. In addition to BPs, two patients were on long term corticosteroid therapy for rheumatoid arthritis and Addison's disease. Three patients had bilateral atypical femoral fractures. Except one, all of them had prodromal symptoms prior to fracture. Skeletal radiograph showed cortical thickening, pointed (beaking of) cortical margin and transverse fracture in meta-diaphyseal location. Serum calcium, phosphate, alkaline phosphatase (ALP) and intact parathyroid hormone (iPTH) concentrations were within the reference range in all patients. Interpretation & conclusions: Long term bisphosphonate therapy may increase the risk of atypical femoral fractures. Presence of prodromal pain, thickened cortex with cortical beaking may be an early clue for predicting the atypical fractures. High risk patients need periodical skeletal survey and a close follow up for early detection of cases. PMID:25222777

  1. Bisphosphonate associated osteomyelitis of the jaw in patients with bony exposure: prevention, a new way of thinking

    PubMed Central

    TARDAST, Arezo; SJÖMAN, Reine; LØES, Sigbjørn; ABTAHI, Jahan

    2015-01-01

    Objective There is strong evidence of a link between the use of systemic bisphosphonates (BPs) and osteonecrosis of the jaw, especially in cancer patients. Among risk factors for BRONJ, tooth extraction and immune suppressive drugs seem to have significant role on bone healing. Therefore, the importance of these parameters in development of BRONJ was reviewed in this retrospective study in two maxillofacial surgery units. Material and Methods From 2007 to 2012, 46 patients on bisphosphonate who had developed oral bony lesions participated in this study. The pharmacological exposure, comorbidities, maxillofacial findings, types of treatment and outcome data were collected from clinical and radiological records. Results The most frequently used BP was alendronate (67%). Tooth extraction was reported in 61% of patients with BRONJ. Systemic corticosteroids were prescribed in 35 cases (76%) as an adjuvant for BP. Patients on corticosteroids had a lower probability of bony lesion healing (p<0.05) than patients without corticosteroids. Of the 46 patients who underwent conservative treatments, only ten were completely healed (21%). Conclusions Beside tooth extraction, corticosteroids were shown to be an implant risk factor for low rate of bone healing and hence the development of BRONJ. The outcome of conservative treatment was uncertain and this emphasizes the importance of prevention. PMID:26221926

  2. Investigation of emulsified, acid and acid-alkali catalyzed mesoporous bioactive glass microspheres for bone regeneration and drug delivery.

    PubMed

    Miao, Guohou; Chen, Xiaofeng; Dong, Hua; Fang, Liming; Mao, Cong; Li, Yuli; Li, Zhengmao; Hu, Qing

    2013-10-01

    Acid-catalyzed mesoporous bioactive glass microspheres (MBGMs-A) and acid-alkali co-catalyzed mesoporous bioactive glass microspheres (MBGMs-B) were successfully synthesized via combination of sol-gel and water-in-oil (W/O) micro-emulsion methods. The structural, morphological and textural properties of mesoporous bioactive glass microspheres (MBGMs) were characterized by various techniques. Results show that both MBGMs-A and MBGMs-B exhibit regularly spherical shape but with different internal porous structures, i.e., a dense microstructure for MBGMs-A and internally porous structure for MBGMs-B. (29)Si NMR data reveal that MGBMs have low polymerization degree of silica network. The in vitro bioactivity tests indicate that the apatite formation rate of MBGMs-B was faster than that of MBGMs-A after soaking in simulated body fluid (SBF) solution. Furthermore, the two kinds of MBGMs have similar storage capacity of alendronate (AL), and the release behaviors of AL could be controlled due to their unique porous structure. In conclusion, the microspheres are shown to be promising candidates as bone-related drug carriers and filling materials of composite scaffold for bone repair. PMID:23910338

  3. A case report of a 53-year-old female with rheumatoid arthritis and osteoporosis: focus on lab testing and CAM therapies.

    PubMed

    Fitzgerald, Kara

    2011-09-01

    A 53-year-old female presented with rheumatoid arthritis and osteoporosis. Additional conditions and symptoms included Raynaud syndrome, fatigue, irritable bowel syndrome associated constipation (IBS-C), gastroesophageal reflux (GERD), menopausal symptoms, chronic urinary tract and upper respiratory infections, and weight gain. She was taking Arthrotec (a combination of diclofenac and misoprostol - for pain and inflammation), Fosamax Plus D (alendronate with vitamin D3 - recently prescribed because of low bone density), and Catapres (clonidine - for menopausal symptoms). Against the advice of her rheumatologist, she had recently discontinued taking Plaquenil (hydroxychloroquine), methotrexate, and prednisone due to significant side effects. Lab tests to identify underlying imbalances and to direct treatment were ordered. Treatment included dietary, nutritional, hormonal, and mind/body support. After one year of therapy, the patient experienced improvement with all of her presenting conditions and symptoms, which enabled her to discontinue several medications. She became versed in identifying and avoiding the environmental triggers of her disease, including foods (dairy, wheat, eggs, and soy), molds, and emotional stress. Antinuclear antibodies were normalized. She experienced a 7.5-percent improvement in left trochanteric bone density - comparable to bisphosphonate therapy. Mild improvements were also noted in the spine and bilateral femoral neck. PMID:21951026

  4. Simultaneous determination of two amino bisphosphonates drugs by micellar electrokinetic chromatography.

    PubMed

    Wu, Di; Yang, Jiajia; Cai, Yuanli; Lin, Xia; Yan, Jin; Li, Hui

    2015-01-01

    A sensitive micellar electrokinetic chromatographic method with laser-induced fluorescence detection was developed for the determination of alendronate sodium (ALN) and pamidronate disodium (PAM) after derivatization with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole. The developed method was first used for the determination of ALN and PAM in pharmaceutical preparations. After optimization, baseline separation of the analytes could be obtained in <10 min in a running buffer composed of 10 mM sodium borate and 30 mM sodium dodecyl sulfate (pH 9.0) at a voltage of 15 kV with 25°C cartridge temperature and the samples were injected by pressure (3447.5 Pa × 3 s). The method has linearity range of 0.05-70 µg/mL for the analytes (correlation coefficients: 0.9995 and 0.9997), the detection limits were 4 and 10 ng/mL for ALN and PAM, respectively. In intraday precision experiment, the relative standard deviation (RSD) values for migration time were 0.30% (ALN) and 0.27% (PAM), and the RSD values for peak areas were 1.19% (ALN) and 1.32% (PAM). The ranges of recovery were 95.5-101.8 and 94.6-105.3% for ALN and PAM, respectively. This method is not only rapid and accurate but also has the potential to be used for the quality control in pharmaceutical preparations of the two drugs. PMID:26113636

  5. Inhibition of Osteoclast Differentiation and Bone Resorption by Bisphosphonate-conjugated Gold Nanoparticles.

    PubMed

    Lee, Donghyun; Heo, Dong Nyoung; Kim, Han-Jun; Ko, Wan-Kyu; Lee, Sang Jin; Heo, Min; Bang, Jae Beum; Lee, Jung Bok; Hwang, Deok-Sang; Do, Sun Hee; Kwon, Il Keun

    2016-01-01

    In recent years, gold nanoparticles (GNPs) have been reported to affect the regeneration of bone tissue. The goal of this study was to improve bone tissue regeneration by using targeted GNPs. We fabricated a functionalized GNPs conjugated with alendronate (ALD), of the bisphosphonate group. Subsequently, the ALD, GNPs, and ALD conjugated GNPs (GNPs-ALD) were analyzed by ultraviolet-visible absorbance (UV-vis) spectrophotometer, Attenuated total reflectance Fourier transform infrared spectrometer (ATR-FTIR), and thermo gravimetric analysis (TGA). The prepared GNPs-ALD were used to investigate their inhibitory effects on the receptor activator of nuclear factor- κb ligand (RANKL)-induced osteoclastogenesis in bone marrow-derived macrophages (BMMs). Additionally, the GNPs-ALD were applied to ovariectomy (OVX)-induced osteoporotic mice and the experiments were evaluated. ALD was found to be successfully conjugated to the GNPs surface, and it displayed significant adhesion onto the bone surface. The in-vitro study indicated that the GNPs, ALD and GNPs-ALD suppressed osteoclast formation in a dose-dependent manner. Furthermore, in the OVX mouse model, the mice treated GNPs-ALD had higher bone density as compared to other OVX mice groups. The results from these tests indicated that GNPs-ALD can be useful agents for preventing and treating osteoporosis. PMID:27251863

  6. Skeletal Integrity and Visceral Transplantation

    PubMed Central

    Resnick, J.; Gupta, N.; Wagner, J.; Costa, G.; Cruz, R. J.; Martin, L.; Koritsky, D. A.; Perera, S.; Matarese, L.; Eid, K.; Schuster, B.; Roberts, M.; Greenspan, S.; Abu-Elmagd, K.

    2016-01-01

    Despite continuous improvement in long-term survival, there is no knowledge about risk of bone health impairment and management strategies before and after intestinal transplantation. Therefore, 147 adults were retrospectively studied via chart review; 70 long-term survivors, 53 candidates and 24 recipients with longitudinal follow-up. Evaluation process included measurement of bone mineral density (BMD) and allied biochemical markers. Both long-term survivors and candidates showed low bone mass with lower (p < 0.05) z-scores at hip, femoral neck and spine. Vitamin D deficiency and secondary hyperparathyroidism were observed in both groups. Prevalence of osteoporosis was 44% among long-term survivors and 36% in candidates with age, BMD, duration of parenteral nutrition, type of immunosuppression and rejection being significant risk factors. Fragility fractures occurred at a higher (p = 0.02) rate among long-term survivors (20%) compared to candidates (6%). The longitudinal study documented acceleration (p = 0.025) of bone loss after transplantation with a decline of 13.4% (femoral neck), 12.7% (hip) and 2.1% (spine). Alendronate reduced (p < 0.05) but did not prevent bone loss. In conclusion, intestinal transplant recipients are at risk of osteoporosis secondary to bone loss before and after transplantation. Accordingly, current management includes comprehensive preventive measures with prompt therapeutic intervention utilizing intravenous bisphosphonates or subcutaneous human PTH 1–34. PMID:20825384

  7. Single and Combined use of Human Parathyroid Hormone (PTH) (1-34) on Areal Bone Mineral Density (aBMD) in Postmenopausal Women with Osteoporosis: Evidence Based on 9 RCTs

    PubMed Central

    Song, Jiefu; Jing, Zhizhen; Chang, Feng; Li, Lijun; Su, Yunxing

    2014-01-01

    Background Human parathyroid hormone (PTH) (1-34) or teriparatide (TPTD) is an anabolic agent for osteoporosis. This recombinant protein stimulates positive bone formation balance and bone remodeling. However, when concomitantly used with antiresorptive (AR) agents, previous studies reported conflicting results in their potential additive and synergistic effects on bone metabolism and bone mineral density (BMD). This study aimed to integrate previous evidence to assess the effect of TPTD monotherapy and the additive effect of TPTD on AR agents in postmenopausal women with osteoporosis. Material/Methods This meta-analysis identified 9 RCTs from databases. To assess the therapeutic effect on osteoporosis, the weighted mean differences (WMDs) were used to pool the percentage change of BMD along with the 95% confidence intervals (CIs). BMD of 3 skeletal sites, including lumbar spine, total hip, and femoral neck were assessed. Results TPTD alone could significantly improve BMD of all 3 skeletal sites compared with placebo, although the effect on the femoral neck was less conclusive. The additive effect of TPTD over hormone replacement therapy (HRT) and denosumab (DEN) agents is evident in all 3 skeletal sites. But TPTD plus Alendronate (ALN) did not demonstrate additive effect in total hip and femoral neck. Conclusions TPTD alone could significantly improve BMD of lumbar spine, total hip, and femoral neck. BMD outcomes of concomitant use of TPTD and AR agents are site-dependent and vary depending on the specific AR agent used and the timing of AR therapy initiation. PMID:25503108

  8. [Bone involvement in systemic mastocytosis: Report of two cases].

    PubMed

    Florenzano, Pablo; Mezzano, Verónica; Le-Bert, Marcela; González, Gilberto

    2016-03-01

    Systemic mastocytosis (SM) is characterized by pathologic expansion and activation of mast cells. The main clinical manifestations of SM include skin involvement, gastrointestinal symptoms and anaphylaxis due to the release of its mediators. Thirty percent of pat ients with SM have a low bone mass and 20% fractures. At the same time, SM affects 10% of male patients with idiopathic osteoporosis. Measuring serum tryptase is essential for the screening of MS. We report two cases of SM with bone involvement. A 25-year- old woman with prior diagnosis of SM, based on skin involvement, flushing, high serum tryptase and compatible bone marrow (BM) biopsy and genetic study. Low bone mass was diagnosed and treatment was started with calcium and vitamin D plus oral bisphosphona tes with adequate response. A 47 years old man who presented with multiple osteoporotic vertebral fractures and low bone mass. Treatment with vitamin D and alendronate was started, but the patient developed new vertebral fractures. The study was extended w ith measurement of serum tryptase that was elevated. Diagnosis of SM was confirmed with BM biopsy and the patient was referred to hematology for specific care. These cases emphasize the importance of bone assessment in SM, as well as the need to rule out S M in patients with osteoporosis and no evident cause. PMID:27299829

  9. 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

  10. Membrane bound pyrophosphatase and P-type adenosine triphosphatase of Leishmania donovani as possible chemotherapeutic targets: similarities and differences in inhibitor sensitivities.

    PubMed

    Sen, S S; Bhuyan, N R; Lakshman, K; Roy, A K; Chakraborty, B; Bera, T

    2009-12-01

    The activities of inorganic pyrophosphatase (PPase) and adenosine triphosphatase (ATPase) were studied in the plasma membrane of Leishmania donovani promastigotes and amastigotes. It was shown that the specific activity of PPase was greater than that of ATPase in the promastigote plasma membrane. We characterized H+-PPase present in the plasma membrane of L. donovani and investigated its possible role in the survival of promastigote and amastigote. PPase activity was stimulated by K+ and sodium orthovanadate and inhibited by pyrophosphate analogs (imidodiphosphate and alendronate), KF, N,N'-dicyclohexylcarbodiimide (DCCD), thiol reagents (p-chloromercuribenzenesulfonate (PCMBS), N-ethylmaleimide (NEM), and phenylarsine oxide (PAO)), the ABC superfamily transport modulator verapamil, and also by the F(1)F(o)-ATPase inhibitor quercetin. ATPase activity was stimulated by K+ and verapamil, inhibited by DCCD, PCMBS, NEM, sodium azide, sodium orthovanadate, and quercetin, and was unaffected by PAO. We conclude that there are significant differences within promastigote, amastigote, and mammalian host in cytosolic pH homeostasis to merit the inclusion of PPase transporter as a putative target for rational drug design. PMID:19961421

  11. 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. PMID:24827162

  12. 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

  13. 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

    Li, Qiaoli; Kingman, Joshua; Sundberg, John P; Levine, Michael A; Uitto, Jouni

    2016-01-01

    Generalized arterial calcification of infancy is an intractable ectopic mineralization disorder caused by mutations in the ENPP1 gene, resulting in reduced plasma inorganic pyrophosphate (PPi) levels. We previously characterized the Enpp1(asj) mutant mouse as a model of generalized arterial calcification of infancy, and we have now explored the potential efficacy of bisphosphonates, nonhydrolyzable PPi analogs, in preventing ectopic mineralization in these mice. The 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 by microcomputed 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 generalized arterial calcification of infancy caused by ENPP1 mutations. PMID:26763447

  14. Polycan, a β-glucan from Aureobasidium pullulans SM-2001, mitigates ovariectomy-induced osteoporosis in rats

    PubMed Central

    Jung, Mi Young; Kim, Joo Wan; Kim, Ki Young; Choi, Seong Hun; Ku, Sae Kwang

    2016-01-01

    The present study aimed to investigate the protective effects of Polycan, a β-glucan from Aureobasidium pullulans SM-2001, in a rat model of ovariectomy-induced osteoporosis. Ovariectomized (OVX) rats were orally administered 31.25, 62.5 or 125 mg/kg/day Polycan for 126 days, and alterations in body weight, bone mineral content, bone mineral density, failure load, histological profiles and histomorphometric indices were analyzed. In particular, serum levels of osteocalcin, bone-specific alkaline phosphatase (bALP), calcium and phosphorus, and the urine deoxypyridinoline/creatinine ratio, were measured. Furthermore, the femur, tibia and lumbar vertebrae were harvested from all rats, and histomorphometrical analyses were conducted in order to assess the mass and structure of the bones, and the rates of bone resorption and formation. One group of rats was treated with alendronate, which served as the reference drug. The results of the present study suggested that Polycan treatment was able to inhibit ovariectomy-induced alterations in bone resorption and turnover in a dose-dependent manner. In addition, the serum expression levels of bALP and all histomorphometrical indices for bone formation were markedly increased in the Polycan-treated groups. These results indicated that Polycan was able to preserve bone mass and strength, and increase the rate of bone formation in OVX rats; thus suggesting that Polycan may be considered a potential effective anti-osteoporosis agent. PMID:27588046

  15. The Volatome of Aspergillus fumigatus

    PubMed Central

    Calvo, A. M.; Latgé, J. P.

    2014-01-01

    Early detection of invasive aspergillosis is absolutely required for efficient therapy of this fungal infection. The identification of fungal volatiles in patient breath can be an alternative for the detection of Aspergillus fumigatus that still remains problematic. In this work, we investigated the production of volatile organic compounds (VOCs) by A. fumigatus in vitro, and we show that volatile production depends on the nutritional environment. A. fumigatus produces a multiplicity of VOCs, predominantly terpenes and related compounds. The production of sesquiterpenoid compounds was found to be strongly induced by increased iron concentrations and certain drugs, i.e., pravastatin. Terpenes that were always detectable in large amounts were α-pinene, camphene, and limonene, as well as sesquiterpenes, identified as α-bergamotene and β-trans-bergamotene. Other substance classes that were found to be present in the volatome, such as 1-octen-3-ol, 3-octanone, and pyrazines, were found only under specific growth conditions. Drugs that interfere with the terpene biosynthesis pathway influenced the composition of the fungal volatome, and most notably, a block of sesquiterpene biosynthesis by the bisphosphonate alendronate fundamentally changed the VOC composition. Using deletion mutants, we also show that a terpene cyclase and a putative kaurene synthase are essential for the synthesis of volatile terpenes by A. fumigatus. The present analysis of in vitro volatile production by A. fumigatus suggests that VOCs may be used in the diagnosis of infections caused by this fungus. PMID:24906414

  16. Triclosan-loaded Tooth-binding Micelles for Prevention and Treatment of Dental Biofilm

    PubMed Central

    Chen, Fu; Rice, Kelly C.; Liu, Xin-Ming; Reinhardt, Richard A.; Bayles, Kenneth W.; Wang, Dong

    2010-01-01

    The purpose of the present study was to develop tooth-binding micelle formulations and evaluate their ability to both inhibit initial biofilm formation as well as decrease the viability of preformed biofilm using an in vitro dental biofilm model. Alendronate (ALN, a bisphosphonate) was covalently attached to the ends of different Pluronic copolymers to confer tooth-binding ability to the micelles, and triclosan was used as a model drug. Based on different micelle preparation methods, Pluronic copolymers and ALN-terminated Pluronic copolymers were used to prepare triclosan-loaded tooth-binding micelles. The formulation was optimized for triclosan solubility, particle size, hydroxyapatite (HA) binding capacity and kinetics, and in vitro drug release behavior. In vitro biofilm treatment studies demonstrated that the triclosan-loaded tooth-binding micelles were able to inhibit initial biofilm growth of Streptococcus mutans UA159 by 6-log CFU/HA disc compared to the untreated control. These tooth-binding micelles were also capable of reducing the viability of preformed biofilm by 4-log CFU/HA disc compared to untreated control biofilm. In summary, triclosan-loaded tooth-binding micelles have been successfully developed and optimized in this study. These micelles demonstrated promising anti-biofilm capabilities that have the potential for use in the future treatment and prevention of dental diseases. PMID:20387099

  17. 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

    2016-01-01

    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. PMID:26821009

  18. Bisphosphonates for cancer patients: why, how, and when?

    PubMed

    Body, J J; Mancini, I

    2002-07-01

    recommended in patients with metastatic breast cancer who have imaging evidence of lytic destruction of bone and who are concurrently receiving systemic therapy with hormonal therapy or chemotherapy. Furthermore, the ASCO Panel considered it "reasonable" to start i.v. BPs in women with localized pain whose bone scans were abnormal and plain radiographs normal, but not when an abnormal bone scan is asymptomatic. The pertinence of these criteria is discussed below. Because BPs are providing supportive care, reducing the rate of skeletal morbidity but evidently not abolishing it, the criteria for stopping their administration have to be different from those used for classic antineoplastic drugs, and they should not be stopped when metastatic bone disease is progressing. However, criteria to determine whether and for how long an individual patient benefits from their administration are lacking. New biochemical markers of bone resorption might help identify those patients continuing to benefit from therapy. Even better results have been achieved in patients with multiple myeloma, and the general consensus is that BPs should be started as soon as the diagnosis of lytic disease is made in myeloma patients. On the other hand, data are scanty in prostate cancer, but large-scale trials with potent BPs are ongoing or planned in such patients. Similar results to those achieved with pamidronate have been obtained with monthly 6-mg infusions of the newer BP ibandronate in patients with breast cancer metastatic to bone. The tolerance of ibandronate could be better, and the drug has the potential to be administered as a 15- to 30-min infusion. Zoledronate can also be administered safely as a 15-min 4-mg infusion, and large scale phase III trials have just been completed. These newer BPs will simplify the current therapeutic schemes and improve the cost-effectiveness ratio; they also have the potential to improve the therapeutic efficacy, at least in patients with an aggressive osteolytic

  19. Strategies for strengthening patent protection of pharmaceutical inventions in light of federal court decisions.

    PubMed

    Pillai, Xavier; Kinney, William A

    2010-01-01

    In this article, a brief history of patent law is presented, along with recent changes in its interpretation that are relevant in securing patents in the current landscape. Specific patent examples are presented to illustrate key issues. For example, the case of KSR International Co. v. Teleflex, Inc. is an important recent decision by the United States Supreme Court, which developed a more flexible definition of the teaching-suggestion-motivation (TSM) test in determining obviousness, which negates patentability. Although KSR case involved a mechanical invention, the ruling in this case has had implications in other areas of patent law, particularly as it applied to pharmaceutical and chemical inventions. It has had a significant impact on the outcome of patent prosecution at the United States Patent and Trademark Office (USPTO), as well as in defending patents in federal courts. If an invention is obvious to try and there are a finite number of predictable solutions in the prior art, then the invention will be considered obvious by current standards. Bayer Schering Pharma AG v. Barr Laboratories, Inc is presented as a case in which the court of appeals has applied the KSR standard of obviousness in invalidating a formulation patent claim, in which a finite number of options were available to the formulator. Unlike the formulation patent example, patents covering new molecules have survived challenges more successfully. In The Procter & Gamble Co. v. Teva Pharmaceuticals USA, Inc., the court of appeals for the Federal Circuit determined that the invention of risedronate was unobvious, although it was a mere positional isomer of a prior bisphosphonate. However in Altana Pharma AG v. Teva Pharmaceuticals USA, Inc., the court of appeals judged against the innovator company when there was a clearer case of predictable prior art. Finally, Ortho-McNeil Pharmaceutical, Inc. v. Mylan Laboratories, Inc. presents an example of a case at the Federal Circuit where topiramate

  20. Long Term Effectiveness on Prescribing of Two Multifaceted Educational Interventions: Results of Two Large Scale Randomized Cluster Trials

    PubMed Central

    Magrini, Nicola; Formoso, Giulio; Capelli, Oreste; Maestri, Emilio; Nonino, Francesco; Paltrinieri, Barbara; Giovane, Cinzia Del; Voci, Claudio; Magnano, Lucia; Daya, Lisa; Marata, Anna Maria

    2014-01-01

    Introduction Information on benefits and risks of drugs is a key element affecting doctors’ prescribing decisions. Outreach visits promoting independent information have proved moderately effective in changing prescribing behaviours. Objectives Testing the short and long-term effectiveness on general practitioners’ prescribing of small groups meetings led by pharmacists. Methods Two cluster open randomised controlled trials (RCTs) were carried out in a large scale NHS setting. Ad hoc prepared evidence based material were used considering a therapeutic area approach - TEA, with information materials on osteoporosis or prostatic hyperplasia - and a single drug oriented approach - SIDRO, with information materials on me-too drugs of 2 different classes: barnidipine or prulifloxacin. In each study, all 115 Primary Care Groups in a Northern Italy area (2.2 million inhabitants, 1737 general practitioners) were randomised to educational small groups meetings, in which available evidence was provided together with drug utilization data and clinical scenarios. Main outcomes were changes in the six-months prescription of targeted drugs. Longer term results (24 and 48 months) were also evaluated. Results In the TEA trial, one of the four primary outcomes showed a reduction (prescription of alfuzosin compared to tamsulosin and terazosin in benign prostatic hyperplasia: prescribing ratio −8.5%, p = 0.03). Another primary outcome (prescription of risedronate) showed a reduction at 24 and 48 months (−7.6%, p = 0.02; and −9,8%, p = 0.03), but not at six months (−5.1%, p = 0.36). In the SIDRO trial both primary outcomes showed a statistically significant reduction (prescription of barnidipine −9.8%, p = 0.02; prescription of prulifloxacin −11.1%, p = 0.04), which persisted or increased over time. Interpretation These two cluster RCTs showed the large scale feasibility of a complex educational program in a NHS setting, and its potentially

  1. 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

  2. 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.; Spector, E.; Nakamura, T.; Kohri, K.; Ohshima, H.

    2009-01-01

    The purpose of this research is to determine whether anti-resorptive pharmaceuticals such as bisphosphonates, in conjunction with the routine in-flight exercise program, will protect ISS crewmembers from the regional decreases in bone mineral density and bone strength and the increased renal stone risk documented on previous long-duration space flights [1-3]. Losses averaged 1 to 2 percent per month in such regions as the lumbar spine and hip. Although losses showed significant heterogeneity among individuals and between bones within a given subject, space flight-induced bone loss was a consistent finding. More than 90 percent of astronauts and cosmonauts on long-duration flights (average 171 days) aboard Mir and the ISS, had a minimum 5 percent loss in at least one skeletal site, 40 percent of them had a 10 percent or greater loss in at least one skeletal site, and 22 percent of the Mir cosmonauts experienced a 15 to 20 percent loss in at least one site. These losses occurred even though the crewmembers performed time-consuming in-flight exercise regimens. Moreover, a recent study of 16 ISS astronauts using quantitative computed tomography (QCT) demonstrated trabecular bone losses from the hip averaging 2.3 percent per month [4]. These losses were accompanied by significant losses in hip bone strength that may not be recovered quickly [5]. This rapid loss of bone mass results from a combination of increased and uncoupled remodeling, as demonstrated by increased resorption with little or no change in bone formation markers [6-7]. This elevated remodeling rate likely affects the cortical and trabecular architecture and may lead to irreversible changes. In addition to bone loss, the resulting hypercalciuria increases renal stone risk. Therefore, it is logical to attempt to attenuate this increased remodeling with anti-resorption drugs such as bisphosphonates. Success with alendronate was demonstrated in a bed rest study [8]. This work has been extended to space

  3. 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

  4. Primary biliary cirrhosis: Pathophysiology, clinical presentation and therapy

    PubMed Central

    Purohit, Treta; Cappell, Mitchell S

    2015-01-01

    Primary biliary cirrhosis (PBC) is an autoimmune, slowly progressive, cholestatic, liver disease characterized by a triad of chronic cholestasis, circulating anti-mitochondrial antibodies (AMA), and characteristic liver biopsy findings of nonsuppurative destructive cholangitis and interlobular bile duct destruction. About 10% of PBC patients, however, lack AMA. A variant, called PBC-autoimmune hepatitis (AIH) overlap, is characterized by the above findings of PBC together with findings of elevated serum alanine aminotransferase, elevated serum immunoglobulin G, and circulating anti-smooth muscle antibodies, with liver biopsy demonstrating periportal or periseptal, lymphocytic, piecemeal necrosis. PBC is hypothesized to be related to environmental exposure in genetically vulnerable individuals. It typically occurs in middle-aged females. Prominent clinical features include fatigue, pruritis, jaundice, xanthomas, osteoporosis, and dyslipidemia. The Mayo Risk score is the most widely used and best prognostic system. Ursodeoxycholic acid is the primary therapy. It works partly by reducing the concentration and injury from relatively toxic bile acids. PBC-AIH overlap syndrome is treated with ursodeoxycholic acid and corticosteroids, especially budesonide. Obeticholic acid and fibrate are promising new, but incompletely tested, therapies. Liver transplantation is the definitive therapy for advanced disease, with about 70% 10-year survival after transplantation. Management of pruritis includes local skin care, dermatologist referral, avoiding potential pruritogens, cholestyramine, and possibly opioid antagonists, sertraline, or rifaximin. Management of osteoporosis includes life-style modifications, administration of calcium and vitamin D, and alendronate. Statins are relatively safe to treat the osteopenia associated with PBC. Associated Sjogren’s syndrome is treated by artificial tears, cyclosporine ophthalmic emulsion to stimulate tear production; and saliva

  5. Molecular Design of Bisphosphonate-Modified Proteins for Efficient Bone Targeting In Vivo

    PubMed Central

    Katsumi, Hidemasa; Sano, Jun-ichi; Nishikawa, Makiya; Hanzawa, Keiko; Sakane, Toshiyasu; Yamamoto, Akira

    2015-01-01

    To establish a rational molecular design for bisphosphonate (BP)-modified proteins for efficient bone targeting, a pharmacokinetic study was performed using a series of alendronate (ALN), a nitrogen-containing BP, modified proteins with various molecular weights and varying degrees of modification. Four proteins with different molecular weight—yeast glutathione reductase (GR; MW: 112,000 Da), bovine serum albumin (BSA; MW: 67,000 Da), recombinant human superoxide dismutase (SOD; MW: 32,000 Da), and chicken egg white lysozyme (LZM; MW: 14,000 Da)—were modified with ALN to obtain ALN-modified proteins. Pharmacokinetic analysis of the tissue distribution of the ALN-modified and unmodified proteins was performed after radiolabeling them with indium-111 (111In) by using a bifunctional chelating agent. Calculation of tissue uptake clearances revealed that the bone uptake clearances of 111In-ALN-modified proteins were proportional to the degree of ALN modification. 111In-GR-ALN and BSA-ALN, the two high-molecular-weight proteins, efficiently accumulated in bones, regardless of the degree of ALN modification. Approximately 36 and 34% of the dose, respectively, was calculated to be delivered to the bones. In contrast, the maximum amounts taken up by bone were 18 and 13% of the dose for 111In-SOD-ALN(32) and LZM-ALN(9), respectively, because of their high renal clearance. 111In-SOD modified with both polyethylene glycol (PEG) and ALN (111In-PEG-SOD-ALN) was efficiently delivered to the bone. Approximately 36% of the dose was estimated to be delivered to the bones. In an experimental bone metastasis mouse model, treatment with PEG-SOD-ALN significantly reduced the number of tumor cells in the bone of the mice. These results indicate that the combination of PEG and ALN modification is a promising approach for efficient bone targeting of proteins with a high total-body clearance. PMID:26287482

  6. Effects of Sequential Osteoporosis Treatments on Trabecular Bone Mass and Strength in Osteopenic Rats

    PubMed Central

    Amugongo, Sarah K; Yao, Wei; Jia, Junjing; Lay, Yu-An E; Dai, Weiwei; Jiang, Li; Walsh, Daniel; Li, Chin-Shang; Dave, N. K. N.; Olivera, Diana; Panganiban, Brian; Ritchie, Robert O.; Lane, Nancy E

    2015-01-01

    Introduction Individual agents used to treat human osteoporosis reduce fracture risk by ~50-60%. Since agents that act with complementary mechanisms are available, sequential therapies that mix anti-resorptive and anabolic agents could improve fracture risk reduction, when compared to monotherapies. Methods We evaluated bone mass, bone microarchitecture, and bone strength in adult ovariectomized (OVX), osteopenic rats, during different sequences of vehicle (Veh), parathyroid hormone (PTH), alendronate (Aln), or raloxifene (Ral) in three 90 day treatment periods, over nine months. Differences among groups were evaluated. The interrelationships of bone mass and microarchitecture endpoints, and their relationship to bone strength were studied. Results Estrogen deficiency caused bone loss. OVX rats treated with Aln monotherapy had significantly better bone mass, microarchitecture, and bone strength than untreated OVX rats. Rats treated with an Aln drug holiday had bone mass and microarchitecture similar to the Aln monotherapy group, but with significantly lower bone strength. PTH-treated rats had markedly higher bone endpoints, but all were lost after PTH withdrawal without follow-up treatment. Rats treated with PTH followed by Aln had better bone endpoints than those treated with Aln monotherapy, PTH monotherapy, or an Aln holiday. Rats treated initially with Aln or Ral, then switched to PTH, also had better bone endpoints, than monotherapy treatment. Rats treated with Aln, then PTH, and returned to Aln had the highest values for all endpoints. Conclusion Our data indicate that anti-resorptive therapy can be coupled with an anabolic agent, to produce and maintain better bone mass, microarchitecture, and strength than can be achieved with any monotherapy. PMID:24722767

  7. Panostotic expansile bone disease with massive jaw tumor formation and a novel mutation in the signal peptide of RANK.

    PubMed

    Schafer, Anne L; Mumm, Steven; El-Sayed, Ivan; McAlister, William H; Horvai, Andrew E; Tom, Andrea M; Hsiao, Edward C; Schaefer, Frederick V; Collins, Michael T; Anderson, Mark S; Whyte, Michael P; Shoback, Dolores M

    2014-04-01

    Precise regulation of bone resorption is critical for skeletal homeostasis. We report a 32-year-old man with a panostotic expansile bone disease and a massive hemorrhagic mandibular tumor. Originally from Mexico, he was deaf at birth and became bow-legged during childhood. There was no family history of skeletal disease. Puberty occurred normally, but during adolescence he experienced difficulty straightening his limbs, sustained multiple fractures, and developed a bony tumor on his chin. By age 18 years, all limbs were misshapen. The mandibular mass grew and protruded from the oral cavity, extending to the level of the lower ribs. Other bony defects included a similar maxillary mass and serpentine limbs. Upon referral at age 27 years, biochemical studies showed serum alkaline phosphatase of 1760 U/L (Nl: 29-111) and other elevated bone turnover markers. Radiography of the limbs showed medullary expansion and cortical thinning with severe bowing. Although the jaw tumors were initially deemed inoperable, mandibular mass excision and staged partial maxillectomy were eventually performed. Tumor histopathology showed curvilinear trabeculae of woven bone on a background of hypocellular fibrous tissue. Fibrous dysplasia of bone was suspected, but there was no mutation in codon 201 of GNAS in samples from blood or tumor. His clinical and radiographic findings, elevated serum markers, and disorganized bone morphology suggested amplified receptor activator of NF-κB (RANK) signaling, even though his disorder differed from conditions with known constitutive activation of RANK signaling (eg, familial expansile osteolysis). We found a unique 12-base pair duplication in the signal peptide of TNFRSF11A, the gene that encodes RANK. No exon or splice site mutations were found in the genes encoding RANK ligand or osteoprotegerin. Alendronate followed by pamidronate therapies substantially decreased his serum alkaline phosphatase activity. This unique patient expands the

  8. Odanacatib increases mineralized callus during fracture healing in a rabbit ulnar osteotomy model.

    PubMed

    Pennypacker, Brenda L; Gilberto, David; Gatto, Nicholas T; Samadfam, Rana; Smith, Susan Y; Kimmel, Donald B; Duong, Le Thi

    2016-01-01

    The effects of the cathepsin K inhibitor odanacatib (ODN) on fracture healing were monitored for ~6 and 15 weeks post-fracture in two separate studies using the unilateral transverse mid-ulnar osteotomy model in skeletally mature female rabbits. Rabbits were pre-treated for 3-4 weeks with vehicle (Veh), ODN (2 mg/kg, po, daily), or alendronate (ALN) (0.3 mg/kg, sc, twice-weekly) prior to osteotomy. In Study 1, the animals were maintained on the same respective treatment for ~6 weeks. In Study 2, the animals were also continued on the same therapy or switched from Veh to ODN or ODN to Veh for 15 weeks. No treatment-related impairment of fracture union was seen by qualitative histological assessments in the first study. Cartilage retention was detected in the calluses of ALN-treated rabbits at week-6, while calluses in the ODN and Veh groups contained bony tissue with significantly less residual cartilage. ODN treatment also markedly increased the number of cathepsin K-(+) osteoclasts in the callus, indicating enhanced callus remodeling. From the second study, ex vivo DXA and pQCT confirmed that ODN treatment pre- and post-osteotomy increased callus bone mineral content and bone mineral density (BMD) versus Veh (p < 0.001) and discontinuation of ODN post-surgery returned callus BMD to Veh. Peak load of ODN- or ALN-treated calluses were comparable to Veh. ODN increased callus yield load (20%, p = 0.056) and stiffness (26%, p < 0.05) versus Veh. These studies demonstrated that ODN increased mineralized callus during the early phase of fracture repair without impairing callus formation or biomechanical integrity at the fracture site. PMID:26178170

  9. Effect of anti-osteoporotic agents on the prevention of bone loss in unloaded bone.

    PubMed

    Siu, Wing Sum; Ko, Chun Hay; Hung, Leung Kim; Lau, Ching Po; Lau, Clara Bik San; Fung, Kwok Pui; Leung, Ping Chung

    2013-10-01

    Pharmaceutical countermeasures to treat disuse osteoporosis are rarely studied. Pharmaceutical studies for the treatment and prevention of osteoporosis depend on the ovariectomized rat model, which is a suitable model for the disease in women. Disuse osteoporosis affects men and women, but there is lack of awareness and relevant pharmaceutical studies for this condition. The objectives of this study were to verify the validity of an unusual tail-suspension rat model in the induction of disuse osteoporosis and subsequent pharmaceutical treatments. This model was created by unloading the hind limbs of the rats in order to create a state of weightlessness in their hindlimb bones. Validation of the model was performed with non-suspended rats. This study included five groups of suspended rats fed with different agents, such as distilled water (control), high-, medium- and low-dose raloxifene and a bisphosphonate (alendronate). The experiment lasted for 28 days. Comparisons were made between the suspended control and treatment groups. Ovariectomized and sham‑operated rats were also included as a reference for bone changes during osteoporosis. Changes in bone mineral density (BMD) at the distal femur and proximal tibia, microarchitecture at the distal femur and biomechanical strength at the diaphyseal femur were studied. Reduction of BMD and deterioration of trabeculae were similar between the suspended control and ovariectomized rats. Loss of BMD induced by tail suspension was reduced most effectively by medium-dose raloxifene. Deterioration of trabecular microarchitecture was also prevented by raloxifene. The tail-suspension rat model is suitable for the study of disuse osteoporosis under the effects of various therapeutic agents. The preventive effects of raloxifene against bone loss under disuse conditions have been demonstrated using this model. PMID:23970373

  10. Denosumab: a review of its use in postmenopausal women with osteoporosis.

    PubMed

    Scott, Lesley J

    2014-07-01

    Subcutaneous denosumab (Prolia(®) [USA, Europe]; Pralia(®) [Japan]) once every 6 months is indicated in several countries for the treatment of postmenopausal women with osteoporosis at increased or high risk for fractures (featured indication). In some countries, it is also indicated for use in postmenopausal women who have failed or are intolerant to other osteoporosis treatments. In several international, phase III trials (≤3 years' duration) involving more than 12,000 women with postmenopausal osteoporosis or low bone mineral density (BMD), including Asian studies, denosumab was an effective and generally well tolerated treatment. Relative to placebo, denosumab treatment significantly reduced the risk of vertebral, nonvertebral and hip fractures and increased BMD at all skeletal sites evaluated, including the lumbar spine and total hip. Furthermore, the benefits of denosumab treatment were generally evident after the first dose and were maintained during up to 8 years of treatment in an ongoing extension study. The tolerability profile of denosumab during this extension phase was consistent with that observed during the initial 3-year FREEDOM trial. At 12 months, denosumab treatment increased BMD at the total hip, lumbar spine and/or femoral neck and reduced markers of bone turnover to a significantly greater extent than oral bisphosphonates in women who were essentially bisphosphonate-naive and in those who had switched from alendronate to denosumab treatment. Further clinical experience, including an ongoing postmarketing safety study, will more fully define the long-term safety of denosumab. In the meantime, denosumab is an important option for the treatment of women with postmenopausal osteoporosis at increased or high-risk of fractures, including in women at increased risk of fracture who are unable to take other osteoporosis treatments. PMID:24935243

  11. Norwegian Physicians’ Knowledge of the Prices of Pharmaceuticals: A Survey

    PubMed Central

    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 1 543 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. PMID:24040402

  12. What is the Best Root Surface Treatment for Avulsed Teeth?

    PubMed Central

    Tuna, Elif B; Yaman, Duygu; Yamamato, Seiko

    2014-01-01

    Dental avulsion is the most severe type of traumatic tooth injuries since it causes damage to several structures and results in avulsion of the tooth from its socket. Management protocols for avulsed teeth should include management of the pulp and periodontal ligament (PDL) cells in order to improve the long-term prognosis and survival of these teeth. The prognosis of the treatment as well as the survival of an avulsed tooth depends on intrinsic and extrinsic factors, such as the duration of the tooth’s extra-alveolar period, replantation time, the type of storage medium, PDL status and duration of splinting. Recent research has led to the development of storage media. However, there is not yet a single solution that fulfills all requirements to be considered as the ideal medium for temporary storage of avulsed teeth, and research on this field should carry on. On the other hand in case of delayed replantation, due to the great risk of tooth loss after avulsion, different root surface treatments have been proposed to prevent and delay root resorption before replantation. For this purpose, researchers have applied some different root surface treatment modalities in delayed replantation of avulsed teeth. Several protocols have been used to maintain PDL viability; some involve fluorides, steroids, sodium alendronate, enamel matrix derivatives (EMD) and basic fibroblast growth factor (bFGF, FGF-2). Among these applications, bFGF shows promising results in the regeneration of natural tooth structures and tissues. Better understanding of mechanism of bFGF may help to improve new technologies of regeneration of tooth structures. PMID:25317212

  13. Relationship between drug interactions and drug-related negative clinical outcomes

    PubMed Central

    Cremades, Javier; Gonzalo, Mario; Arrebola, Isabel

    2008-01-01

    Drug interactions may represent an iatrogenic risk that should be controlled in community pharmacies at the dispensing level. Aim We analyzed the association between potential drug-drug interactions (DDIs) and negative clinical outcomes. Methods We used dispensing data from two community pharmacies: instances where drug dispensing was associated with a potential DDI and a comparison group of randomized dispensing operations with no potential DDI. In cases where potential DDIs were detected, we analyzed the underlying negative clinical outcomes. Age and gender data were included in the analysis. Results During the study period, we registered 417 potential DDIs. The proportion of women and age were higher in the study group than in the comparison group. The average potential DDIs per patient was 1.31 (SD=0.72). The Consejo General de Colegios Oficiales de Farmacéuticos (CGCOF) database did not produce an alert in 2.4% of the cases. Over-the-counter medication use was observed in 5% of the potential DDI cases. The drugs most frequently involved in potential DDIs were acenocoumarol, calcium salts, hydrochlorothiazide, and alendronic acid, whereas the most predominant potential DDIs were calcium salts and bisphosphonates, oral antidiabetics and thiazide diuretics, antidiabetics and glucose, and oral anticoagulant and paracetamol. The existence of a drug-related negative clinical outcome was observed only in 0.96% of the potential DDI cases (50% safety cases and 50% effectiveness cases). Conclusions Only a small proportion of the detected potential DDIs lead to medication negative outcomes. Considering the drug-related negative clinical outcomes encountered, tighter control would be recommended in potential DDIs with NSAIDs or benzodiazepines. PMID:25147590

  14. Alternative treatments for oral bisphosphonate-related osteonecrosis of the jaws: A pilot study comparing fibrin rich in growth factors and teriparatide

    PubMed Central

    Pelaz, Alejandro; Gallego, Lorena; García-Consuegra, Luis; Junquera, Sonsoles; Gómez, Carlos

    2014-01-01

    Objectives: The aim of this study is to describe and compare the evolution of recurrent bisphosphonate-related osteonecrosis of the jaws (BRONJ) in patients treated with plasma rich in growth factors or teriparatide. Material and Methods: Two different types of treatments were applied in patients diagnosed of recurrent BRONJ in a referral hospital for 1.100.000 inhabitants. In the group A, plasma rich in growth factors was applied during the surgery. In the group B, the treatment consisted in the subcutaneous administration of teriparatide. All the cases of BRONJ should meet the following conditions: recurrent BRONJ, impossibility of surgery in stage 3 Ruggiero classification and absence of diagnosed neoplastic disease. Clinical and radiographic evolution of the patients from both groups was observed. Results: Nine patients were included, 5 in group A and 4 in group B. All the patients were women on oral bis-phosphonate therapy for primary osteoporosis (5 patients) or osteoporosis-related to the use of corticosteroids (4 patients). Alendronate was the most common oral bisphosphonate associated with BRONJ in our study (four patients in group A and two in group B). The mean age was 72,8 years in the group A and 73,5 years in the group B. All the patients from group A showed a complete resolution of their BRONJ. Only one patient in the group B showed the same evolution. Conclusions: In our series, the plasma rich in growth factors showed better results than the teriparatide in the treatment of recurrent BRONJ. Key words:Osteonecrosis, oral bisphosphonate, treatment, teriparatide, plasma rich in growth factors. PMID:24608203

  15. 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. PMID:27155840

  16. Incidence of Atypical Femur Fractures in Cancer Patients: The MD Anderson Cancer Center Experience.

    PubMed

    Edwards, Beatrice J; Sun, Ming; West, Dennis P; Guindani, Michele; Lin, Yan Heather; Lu, Huifang; Hu, Mimi; Barcenas, Carlos; Bird, Justin; Feng, Chun; Saraykar, Smita; Tripathy, Debasish; Hortobagyi, Gabriel N; Gagel, Robert; Murphy, William A

    2016-08-01

    Atypical femoral fractures (AFFs) are rare adverse events attributed to bisphosphonate (BP) use. Few cases of AFF in cancer have been described; the aim of this study is to identify the incidence and risk factors for AFF in a large cancer center. This retrospective study was conducted at the MD Anderson Cancer Center. The incidence rate of AFF among BP users was calculated from January 1, 2004 through December 31, 2013. The control group (n = 51) included 2 or 3 patients on BPs matched for age (≤1 year) and gender. Logistic regression analysis was used to assess the relationship between clinical characteristics and AFF. Twenty-three AFF cases were identified radiographically among 10,587 BP users, the total BP exposure was 53,789 months (4482 years), and the incidence of AFF in BP users was 0.05 cases per 100,000 person-years. Meanwhile, among 300,553 patients who did not receive BPs there were 2 cases of AFF as compared with the 23 cases noted above. The odds ratio (OR) of having AFF in BP users was 355.58 times higher (95% CI, 84.1 to 1501.4, p < 0.0001) than the risk in non-BP users. The OR of having AFF in alendronate users was 5.54 times greater (OR 5.54 [95% CI, 1.60 to 19.112, p = 0.007]) than the odds of having AFF among other BP users. Patients who were on zoledronic acid (ZOL) had smaller odds of developing AFF compared with other BP users in this matched case control sample. AFFs are rare, serious adverse events that occur in patients with cancer who receive BP therapy. Patients with cancer who receive BPs for prior osteoporosis therapy or for metastatic cancer are at higher risk of AFF. © 2016 American Society for Bone and Mineral Research. PMID:26896384

  17. 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. PMID:26549245

  18. MMP inhibition in prostate cancer.

    PubMed

    Lokeshwar, B L

    1999-06-30

    Matrix metalloproteinases (MMPs) play a significant role during the development and metastasis of prostate cancer (CaP). CaP cells secrete high levels of MMPs and low levels of endogenous MMP inhibitors (TIMPs), thus creating an excess balance of MMPs. Established CaP cell lines that express high levels of MMPs frequently metastasize to the bone and the lungs. Drugs such as Taxol and alendronate that reduce cell motility and calcium metabolism reduce bony metastasis of xenografted CaP tumors. We tested several synthetic, nontoxic inhibitors of MMPs that can be administered orally, including doxycycline (DC) and chemically modified tetracyclines (CMTs) on CaP cells in vitro and on a rat CaP model in vivo. Among several anti-MMP agents tested, CMT-3 (6-deoxy, 6-demethyl,4-de-dimethylamino tetracycline) showed highest activity against CaP cell invasion and cell proliferation. Micromolar concentration of CMT-3 and DC inhibited both the secretion and activity of MMPs by CaP cells. When tested for in vivo efficacy in the Dunning rat CaP model by daily oral gavage, CMT-3 and DC both reduced the lung metastases (> 50%). CMT-3, but not DC, inhibited tumor incidence (55 +/- 9%) and also reduced the tumor growth rate (27 +/- 9.3%). More significantly, the drugs showed minimum systemic toxicity. Ongoing studies indicate that CMT-3 may inhibit the skeletal metastases of CaP cells and delay the onset of paraplegia due to lumbar metastases. These preclinical studies provide the basis for clinical trials of CMT-3 for the treatment of metastatic disease. PMID:10415736

  19. 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. PMID:23800747

  20. Live imaging of osteoclast inhibition by bisphosphonates in a medaka osteoporosis model

    PubMed Central

    Yu, Tingsheng; Witten, Paul Eckhard; Huysseune, Ann; Buettner, Anita; To, Thuy Thanh; Winkler, Christoph

    2016-01-01

    ABSTRACT Osteoclasts are bone-resorbing cells derived from the monocyte/macrophage lineage. Excess osteoclast activity leads to reduced bone mineral density, a hallmark of diseases such as osteoporosis. Processes that regulate osteoclast activity are therefore targeted in current osteoporosis therapies. To identify and characterize drugs for treatment of bone diseases, suitable in vivo models are needed to complement cell-culture assays. We have previously reported transgenic medaka lines expressing the osteoclast-inducing factor receptor activator of nuclear factor κB ligand (Rankl) under control of a heat shock-inducible promoter. Forced Rankl expression resulted in ectopic osteoclast formation, as visualized by live imaging in fluorescent reporter lines. This led to increased bone resorption and a dramatic reduction of mineralized matrix similar to the situation in humans with osteoporosis. In an attempt to establish the medaka as an in vivo model for osteoporosis drug screening, we treated Rankl-expressing larvae with etidronate and alendronate, two bisphosphonates commonly used in human osteoporosis therapy. Using live imaging, we observed an efficient, dose-dependent inhibition of osteoclast activity, which resulted in the maintenance of bone integrity despite an excess of osteoclast formation. Strikingly, we also found that bone recovery was efficiently promoted after inhibition of osteoclast activity and that osteoblast distribution was altered, suggesting effects on osteoblast-osteoclast coupling. Our data show that transgenic medaka lines are suitable in vivo models for the characterization of antiresorptive or bone-anabolic compounds by live imaging and for screening of novel osteoporosis drugs. PMID:26704995

  1. Bisphosphonate inhibitors reveal a large elasticity of plastidic isoprenoid synthesis pathway in isoprene-emitting hybrid aspen.

    PubMed

    Rasulov, Bahtijor; Talts, Eero; Kännaste, Astrid; Niinemets, Ülo

    2015-06-01

    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

  2. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2006-05-01

    Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials 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, adenosine triphosphate, alemtuzumab, alendronate sodium/cholecalciferol, aliskiren fumarate, AMGN-0007, aminolevulinic acid methyl ester, anakinra, anidulafungin, aripiprazole, atomoxetine hydrochloride; Bevacizumab, bosentan; Calcipotriol/beta methasone dipropionate, caldaret hydrate, caspofungin acetate, cetuximab, cinacalcet hydrochloride, clopidogrel, cocaine-BSA conjugate, conivaptan hydrochloride, Cypher; Darbepoetin alfa, delmitide, desloratadine, desmoteplase, desoxyepothilone B, disufenton sodium, DU-176b, duloxetine hydrochloride, dutasteride; EBV-specific CTLs, ecogramostim, edodekin alfa, efalizumab, eletriptan, emtricitabine, entecavir, erlotinib hydrochloride, ertapenem sodium, escitalopram oxalate, etoricoxib, everolimus, ezetimibe; Fanapanel, fondaparinux sodium; Gefitinib, GTI-2040, GW-501516; Her2 E75-peptide vaccine, human insulin; Ibogaine, icatibant acetate, Id-KLH vaccine, imatinib mesylate, immune globulin subcutaneous [human], indacaterol, inolimomab, ipilimumab, i.v. gamma-globulin, ivabradine hydrochloride, ixabepilone; Lacosamide, lanthanum carbonate, lenalidomide, levocetirizine, levodopa methyl ester hydrochloride/carbidopa, levodopa/carbidopa/entacapone, lidocaine/prilocaine; Maraviroc, mecasermin, melevodopa hydrochloride, mepolizumab, mitumomab; Nesiritide; Omalizumab, oral insulin; Parathyroid hormone (human recombinant), patupilone, pegaptanib sodium, PEG-filgrastim, pemetrexed disodium, photochlor, pimecrolimus, posaconazole, prasterone, prasugrel, pregabalin, prilocaine, PRX-00023; QS-21; Ranibizumab, ranirestat, rhodamine 123, rotigaptide; Sarcosine, sirolimus

  3. Plasma CRP Levels in Premenopausal Women with Major Depression: A 12-Month Controlled Study

    PubMed Central

    Cizza, G.; Eskandari, F.; Coyle, M.; Krishnamurthy, P.; Wright, E. C.; Mistry, S.; Csako, G.

    2009-01-01

    C-reactive protein (CRP), an inflammatory marker of cardiovascular risk, is often elevated in major depressive disorder (MDD). The magnitude and consistency of this elevation have not been previously characterized in premenopausal women with MDD. The aim of the study was to prospectively assess plasma CRP levels, body composition, endocrine and metabolic parameters, and depressive status in premenopausal women with MDD (n = 77) and controls (n = 41), aged 21 to 45. Women were enrolled in a 12-month, controlled study of bone turnover, the P.O.W.E.R. (Premenopausal, Osteoporosis, Women, Alendronate, Depression) Study. Blood samples were taken at Baseline, Month 6, and Month 12. Most subjects with MDD were in clinical remission. These women tended to have consistently higher CRP levels than controls over 12 months (p = 0.077). BMI was positively related to log[CRP] in women with MDD only. Nine women with MDD had CRP levels greater than 10 mg/l, a value associated with a very high cardiovascular risk. This subset was obese and had significantly higher triglycerides, total cholesterol, LDL-cholesterol, fasting insulin, and HOMA-IR than the rest of women with MDD. The variations in CRP levels over time were high (intra- and inter-individual coefficients of variations of ∼30–50% and ∼70–140%, respectively). No control had CRP levels greater than 10 mg/l. Depression was associated with increased plasma CRP in women with MDD. The clinical significance of abnormal plasma CRP for cardiovascular risk needs to be assessed in large prospective studies of women with depression. PMID:19408214

  4. Clinical Trials Express: Fracture Risk Reduction With Denosumab in Japanese Postmenopausal Women and Men With Osteoporosis: Denosumab Fracture Intervention Randomized Placebo Controlled Trial (DIRECT)

    PubMed Central

    Matsumoto, Toshio; Sugimoto, Toshitsugu; Hosoi, Takayuki; Miki, Takami; Gorai, Itsuo; Yoshikawa, Hideki; Tanaka, Yoshiya; Tanaka, Sakae; Sone, Teruki; Nakano, Tetsuo; Ito, Masako; Matsui, Shigeyuki; Yoneda, Toshiyuki; Watanabe, Ko; Osakabe, Taisuke; Shiraki, Masataka; Fukunaga, Masao

    2014-01-01

    Context: Denosumab 60 mg sc injection every 6 months for 36 months was well tolerated and effective in reducing the incidence of vertebral, nonvertebral, and hip fracture in predominantly Caucasian postmenopausal women with osteoporosis. Objective: The objective of this phase 3 fracture study was to examine the antifracture efficacy and safety of denosumab 60 mg in Japanese women and men with osteoporosis compared with placebo. Design and Setting: A randomized, double-blind, placebo-controlled trial with an open-label active comparator as a referential arm was conducted. Patients: Subjects were 1262 Japanese patients with osteoporosis aged 50 years or older, who had one to four prevalent vertebral fractures. Intervention: Subjects were randomly assigned to receive denosumab 60 mg sc every 6 months (n = 500), placebo for denosumab (n = 511), or oral alendronate 35 mg weekly (n = 251). All subjects received daily supplements of calcium and vitamin D. Main Outcome Measure: The primary endpoint was the 24-month incidence of new or worsening vertebral fracture for denosumab vs placebo. Results: Denosumab significantly reduced the risk of new or worsening vertebral fracture by 65.7%, with incidences of 3.6% in denosumab and 10.3% in placebo at 24 months (hazard ratio 0.343; 95% confidence interval 0.194–0.606, P = .0001). No apparent difference in adverse events was found between denosumab and placebo during the first 24 months of the study. Conclusion: These results provide evidence of the efficacy and safety of denosumab 60 mg sc every 6 months in Japanese subjects with osteoporosis. PMID:24646104

  5. Bisphosphonate-induced differential modulation of immune cell function in gingiva and bone marrow in vivo: Role in osteoclast-mediated NK cell activation

    PubMed Central

    Park, So-Hyun; Park, Sil; Kozlowska, Anna; Sun, Shuting; McKenna, Charles E.; Nishimura, Ichiro; Jewett, Anahid

    2015-01-01

    The aim of this study is to establish osteoclasts as key immune effectors capable of activating the function of Natural Killer (NK) cells, and expanding their numbers, and to determine in vivo and in vitro effect of bisphosphonates (BPs) during NK cell interaction with osteoclasts and on systemic and local immune function. The profiles of 27 cytokines, chemokines and growth factors released from osteoclasts were found to be different from dendritic cells and M1 macrophages but resembling to untreated monocytes and M2 macrophages. Nitrogen-containing BPs Zoledronate (ZOL) and Alendronate (ALN), but not non-nitrogen-containing BPs Etidronate (ETI), triggered increased release of pro-inflammatory mediators from osteoclasts while all three BPs decreased pit formation by osteoclasts. ZOL and ALN mediated significant release of IL-6, TNF-` and IL-1β, whereas they inhibited IL-10 secretion by osteoclasts. Treatment of osteoclasts with ZOL inhibited NK cell mediated cytotoxicity whereas it induced significant secretion of cytokines and chemokines. NK cells lysed osteoclasts much more than their precursor cells monocytes, and this correlated with the decreased expression of MHC class I expression on osteoclasts. Intravenous injection of ZOL in mice induced pro-inflammatory microenvironment in bone marrow and demonstrated significant immune activation. By contrast, tooth extraction wound of gingival tissues exhibited profound immune suppressive microenvironment associated with dysregulated wound healing due to the effect of ZOL which could potentially be responsible for the pathogenesis of Osteonecrosis of the Jaw (ONJ). Finally, based on the data obtained in this paper we demonstrate that osteoclasts can be used as targets for the expansion of NK cells with superior function for immunotherapy of cancer. PMID:26343372

  6. Bone metabolism and renal stone risk during International Space Station missions.

    PubMed

    Smith, Scott M; Heer, Martina; Shackelford, Linda C; Sibonga, Jean D; Spatz, Jordan; Pietrzyk, Robert A; Hudson, Edgar K; Zwart, Sara R

    2015-12-01

    Bone loss and renal stone risk are longstanding concerns for astronauts. Bone resorption brought on by spaceflight elevates urinary calcium and the risk of renal stone formation. Loss of bone calcium leads to concerns about fracture risk and increased long-term risk of osteoporosis. Bone metabolism involves many factors and is interconnected with muscle metabolism and diet. We report here bone biochemistry and renal stone risk data from astronauts on 4- to 6-month International Space Station missions. All had access to a type of resistive exercise countermeasure hardware, either the Advanced Resistance Exercise Device (ARED) or the Interim Resistance Exercise Device (iRED). A subset of the ARED group also tested the bisphosphonate alendronate as a potential anti-resorptive countermeasure (Bis+ARED). While some of the basic bone marker data have been published, we provide here a more comprehensive evaluation of bone biochemistry with a larger group of astronauts. Regardless of exercise, the risk of renal stone formation increased during spaceflight. A key factor in this increase was urine volume, which was lower during flight in all groups at all time points. Thus, the easiest way to mitigate renal stone risk is to increase fluid consumption. ARED use increased bone formation without changing bone resorption, and mitigated a drop in parathyroid hormone in iRED astronauts. Sclerostin, an osteocyte-derived negative regulator of bone formation, increased 10-15% in both groups of astronauts who used the ARED (p<0.06). IGF-1, which regulates bone growth and formation, increased during flight in all 3 groups (p<0.001). Our results are consistent with the growing body of literature showing that the hyper-resorptive state of bone that is brought on by spaceflight can be countered pharmacologically or mitigated through an exercise-induced increase in bone formation, with nutritional support. Key questions remain about the effect of exercise-induced alterations in bone

  7. Effectiveness of bisphosphonate use and risk of contralateral breast cancer and recurrence in women with early-stage breast cancer treated with tamoxifen.

    PubMed

    Kwan, Marilyn L; Shi, Jiaxiao M; Habel, Laurel A; Song, Jun; Chung, Joanie W-L; Avila, Chantal C; Schottinger, Joanne E; Cheetham, T Craig; Fletcher, Suzanne W; Haque, Reina

    2016-04-01

    The effectiveness of bisphosphonates (BP) in reducing risk of second breast cancer and recurrence in observational studies has been minimally studied. We examined the association of oral BP use on risk of contralateral breast cancer (CBC) and recurrence in 16,781 women diagnosed with early-stage breast cancer from 1996 to 2007, treated with tamoxifen, and followed through December 31, 2009 at Kaiser Permanente Northern California (KPNC, n = 8857) and Southern California (KPSC, n = 7924). Sociodemographic, clinical, and pharmacy information were extracted from electronic medical records and cancer registries. CBC was identified from cancer registries, and recurrences from electronic health records and chart reviews. Multivariate Cox regression models were used to estimate hazard ratios (HR) and 95 % confidence intervals (CI) treating BP use and hormonal therapy as time-varying variables. After mean 6.4 years of follow-up, 494 (3.0 %) women developed CBC. BP use post-breast cancer diagnosis (>93 % alendronate) ranged from 14.5 to 24.9 % at both study sites. Overall, there was no association of BP use with reduced risk of CBC (ever use, HR = 0.96; 95 % CI 0.67-1.38 and continuous use, HR = 1.03; 95 % CI 0.88, 1.20). Similar null associations were observed for recurrence (ever use, HR = 0.98; 95 % CI 0.82, 1.17 and continuous use, HR = 1.00; 95 % CI 0.92, 1.09). Associations varied somewhat by site yet confidence intervals overlapped. BP use was not associated with reduced risk of recurrence or new primary disease among women diagnosed with early breast cancer and treated with tamoxifen. PMID:27002508

  8. Panostotic Expansile Bone Disease With Massive Jaw Tumor Formation and a Novel Mutation in the Signal Peptide of RANK

    PubMed Central

    Schafer, Anne L; Mumm, Steven; El-Sayed, Ivan; McAlister, William H; Horvai, Andrew E; Tom, Andrea M; Hsiao, Edward C; Schaefer, Frederick V; Collins, Michael T; Anderson, Mark S; Whyte, Michael P; Shoback, Dolores M

    2015-01-01

    Precise regulation of bone resorption is critical for skeletal homeostasis. We report a 32-year-old man with a panostotic expansile bone disease and a massive hemorrhagic mandibular tumor. Originally from Mexico, he was deaf at birth and became bow-legged during childhood. There was no family history of skeletal disease. Puberty occurred normally, but during adolescence he experienced difficulty straightening his limbs, sustained multiple fractures, and developed a bony tumor on his chin. By age 18 years, all limbs were misshapen. The mandibular mass grew and protruded from the oral cavity, extending to the level of the lower ribs. Other bony defects included a similar maxillary mass and serpentine limbs. Upon referral at age 27 years, biochemical studies showed serum alkaline phosphatase of 1760 U/L (Nl: 29-111) and other elevated bone turnover markers. Radiography of the limbs showed medullary expansion and cortical thinning with severe bowing. Although the jaw tumors were initially deemed inoperable, mandibular mass excision and staged partial maxillectomy were eventually performed. Tumor histopathology showed curvilinear trabeculae of woven bone on a background of hypocellular fibrous tissue. Fibrous dysplasia of bone was suspected, but there was no mutation in codon 201 of GNAS in samples from blood or tumor. His clinical and radiographic findings, elevated serum markers, and disorganized bone morphology suggested amplified receptor activator of NF-κB (RANK) signaling, even though his disorder differed from conditions with known constitutive activation of RANK signaling (eg, familial expansile osteolysis). We found a unique 12-base pair duplication in the signal peptide of TNFRSF11A, the gene that encodes RANK. No exon or splice site mutations were found in the genes encoding RANK ligand or osteoprotegerin. Alendronate followed by pamidronate therapies substantially decreased his serum alkaline phosphatase activity. This unique patient expands the phenotypes

  9. Osteonecrosis of the jaw in a patient with rheumatoid artritis treated with an oral aminobisphosphonate: a clinical case report.

    PubMed

    Longato, Lorena; Cavalli, Loredana; Marcucci, Gemma; Metozzi, Alessia; Giusti, Francesca; Brandi, Maria Luisa; Piscitelli, Prisco

    2013-05-01

    Osteonecrosis of the jaw (ONJ) has been recently described after intravenous administration of amino-bisphosphonates and - less frequently - in association with the use of oral bisphosphonates. Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) may affect mandible bone (65%), maxilla bone (26%) and rarely (9%) both sites simultaneously. Although causality may never be proven, emerging experimental data have established a strong association between monthly intravenous bisphosphonate administration and ONJ. Current level of evidence does not fully support a cause and effect relationship between the use of oral BPs and ONJ. In this paper, we report a clinical case of BRONJ in a 73 years old woman affected by rheumatoid arthritis (RA) and periodontitis, after three years of treatment with alendronate 70 mg one a week, plus daily calcium and vitamin D. The patient developed a tooth abscess at the lower jaw, accompanied by increased inflammatory markers, that never returned to normal range despite antibiotic therapy, inducing deterioration of joint synovium. The worsening of joint status after the onset of ONJ was reflected by the progressive increase in the number of swollen (SJ) and tender (TJ) joints, by the deterioration of the score DAS 28 (which passed from 5.46 to 7.07), pain (with VAS increasing from 60 to 90), and by a progressively impaired quality of life, as reported using the HAQ score (from 1,25 to 2,5). The patient was switched to antifracture therapy with strontium ranelate and the osteonecrosis was successfully treated with antibiotics, surgical curettage and local ultrasounds. PMID:24133533

  10. Managing Osteoporosis Patients after Long-Term Bisphosphonate Treatment

    PubMed Central

    Adler, Robert A.; Fuleihan, Ghada El-Hajj; Bauer, Douglas C.; Camacho, Pauline M.; Clarke, Bart L.; Clines, Gregory A.; Compston, Juliet E.; Drake, Matthew T.; Edwards, Beatrice J.; Favus, Murray J.; Greenspan, Susan L.; McKinney, Ross; Pignolo, Robert J.; Sellmeyer, Deborah E.

    2016-01-01

    Bisphosphonates (BPs) are the most commonly used medications for osteoporosis, but optimal duration of therapy is unknown. This ASBMR report provides guidance on BP therapy duration with a risk benefit perspective. Two trials provided evidence for long-term BP use. In the Fracture Intervention Trial Long-term Extension (FLEX), postmenopausal women receiving alendronate for 10 years had fewer clinical vertebral fractures than those switched to placebo after 5 years. In the HORIZON extension, women who received 6 annual infusions of zoledronic acid had fewer morphometric vertebral fractures compared with those switched to placebo after 3 years. Low hip T-score between −2 and −2.5 in FLEX and below −2.5 in HORIZON extension predicted a beneficial response to continued therapy. Hence, the Task Force suggests that after 5 years of oral BP or 3 years of intravenous BP, women should be reassessed. Women with previous major osteoporotic fracture, those who fracture on therapy, or others at high risk should generally continue therapy for up to 10 years (oral) or 6 years (intravenous), with periodic risk-benefit evaluation. Older women, those with a low hip T-score or high fracture risk score are considered high risk. The risk of osteonecrosis of the jaw and atypical femoral fracture increases with BP therapy duration, but such rare events are far outweighed by fracture risk reduction with BPs in high risk patients. For women not at high fracture risk after 3–5 years of BP treatment, a drug holiday of 2–3 years can be considered, with periodic reassessment. The algorithm provided for long term BP use is based on limited evidence in mostly Caucasian postmenopausal women and only for vertebral fracture reduction. It is probably applicable to men and patients with glucocorticoid-induced osteoporosis, with some adaptations. It is unlikely that future osteoporosis trials will provide data for formulating definitive recommendations. PMID:26350171

  11. Bisphosphonate-induced differential modulation of immune cell function in gingiva and bone marrow in vivo: role in osteoclast-mediated NK cell activation.

    PubMed

    Tseng, Han-Ching; Kanayama, Keiichi; Kaur, Kawaljit; Park, So-Hyun; Park, Sil; Kozlowska, Anna; Sun, Shuting; McKenna, Charles E; Nishimura, Ichiro; Jewett, Anahid

    2015-08-21

    The aim of this study is to establish osteoclasts as key immune effectors capable of activating the function of Natural Killer (NK) cells, and expanding their numbers, and to determine in vivo and in vitro effect of bisphosphonates (BPs) during NK cell interaction with osteoclasts and on systemic and local immune function. The profiles of 27 cytokines, chemokines and growth factors released from osteoclasts were found to be different from dendritic cells and M1 macrophages but resembling to untreated monocytes and M2 macrophages. Nitrogen-containing BPs Zoledronate (ZOL) and Alendronate (ALN), but not non-nitrogen-containing BPs Etidronate (ETI), triggered increased release of pro-inflammatory mediators from osteoclasts while all three BPs decreased pit formation by osteoclasts. ZOL and ALN mediated significant release of IL-6, TNF-` and IL-1β, whereas they inhibited IL-10 secretion by osteoclasts. Treatment of osteoclasts with ZOL inhibited NK cell mediated cytotoxicity whereas it induced significant secretion of cytokines and chemokines. NK cells lysed osteoclasts much more than their precursor cells monocytes, and this correlated with the decreased expression of MHC class I expression on osteoclasts. Intravenous injection of ZOL in mice induced pro-inflammatory microenvironment in bone marrow and demonstrated significant immune activation. By contrast, tooth extraction wound of gingival tissues exhibited profound immune suppressive microenvironment associated with dysregulated wound healing to the effect of ZOL which could potentially be responsible for the pathogenesis of Osteonecrosis of the Jaw (ONJ). Finally, based on the data obtained in this paper we demonstrate that osteoclasts can be used as targets for the expansion of NK cells with superior function for immunotherapy of cancer. PMID:26343372

  12. 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

  13. Possible antiosteoporotic mechanism of Cicer arietinum extract in ovariectomized rats

    PubMed Central

    Fahmy, Sohair R; Soliman, Amel M; Sayed, Amany A; Marzouk, Mohamed

    2015-01-01

    Objective: The present study aimed to throw the light on the anti-osteoprotic mechanism of Cicer arietinum extract (CAE) seeds against ovariectomized (OVX) rats. Methods: Seventy female rats were divided into two groups. The first group (14 rats/group) represented normal rats (Sham operated) while the second group (56 rats/group) underwent bilateral ovariectomy (OVX). After one week of recovery from ovariectomy surgery, the second group was randomly subdivided into 4 subgroups (14 rats/ each subgroup). The rats administered orally; distilled water (vehicle) (1st subgroup), Cicer arietinum extract (CAE) (500 or 1000 mg/kg body weight/day) (2nd and 3rd subgroups), alendronate (6.5 mg/kg mg/kg body weight) as a positive control one time/week (4rh subgroup), daily for 10 weeks. Results: The present study demonstrated that ovariectomy caused significant decrease in bone mineral; density (BMD) and content (BMC), Bone-specific alkaline phosphatase (BALP), calcium (Ca), phosphorus (P), parathyroid hormone (PTH) and calcitonin levels. Furthermore, ovariectomy induced significant elevation of tartrate-resistant acid phosphatase 5b (TRAP 5b) and receptor activator of nuclear factor (NF-kappa β) ligand (RANKL) concentration. Conversely, osteoprotegerin (OPG) and OPG/RANKL ratio were decreased following ovariectomy. The present work suggests that CAE has antiosteoporotic action against ovariectomy effects and its activity may results from its phytochemical and/or phytoestrogen contents. Conclusion: The ongoing study speculates that the CAE exerts its action through regulation of RANK/RANKL/OPG system. As, CAE not only promotes osteoblast differentiation, but also up-regulates OPG and downregulates RANKL secretion in osteoblasts, subsequently prevents bone loss and osteoporosis. PMID:26097532

  14. An osteoporotic fracture mimicking cervical dystonia in idiopathic Parkinson's disease.

    PubMed

    Ostrowski, Caroline; Ronan, Lindsay; Sheridan, Ray; Pearce, Vaughan

    2013-09-01

    We report on a case of a 65-year-old (CD) woman who sustained an atraumatic neck fracture. A combination of Parkinson's disease with motor fluctuations, chronic cervical dystonia and osteoporosis provided the basis for this interesting diagnosis. Mrs CD had progressed to complex phase idiopathic Parkinson's disease within 13 years of diagnosis. During this time she remained independent, only using a wheelchair when her motor fluctuations were bad. In 2011, she developed a sudden onset of neck spasm and occipital neuralgia, initially attributed to severe spasmodic cervical dystonia. Despite a titration regime of analgesics and weaning off of her Parkinson's disease medications, the pain persisted. An X-ray of her cervical spine showed degenerative discopathies from C4 to C7. Mrs CD underwent a trial of Botox injections to no avail and she was admitted acutely under the spinal team after an MRI of her spine showed abnormal oedema of the odontoid peg. Subsequent CT diagnosed a type II fracture of the odontoid peg on the background of severe osteoporotic bone (spinal T score -3.4 on subsequent DEXA scan) and she underwent a successful occipital cervical fusion of C1-C6. What makes this case interesting is the fact that this lady's profound powerful neck movements on a background of osteoporosis led to fracture of her neck. Post-operatively, she admitted to non-adherence to her bisphosphonates, prioritising levodopa in the morning with food rather than taking her alendronate on an empty stomach. She is now pain free and receives annual zolendronate infusions. PMID:23672934

  15. Polarized osteoclasts put marks of tartrate-resistant acid phosphatase on dentin slices--a simple method for identifying polarized osteoclasts.

    PubMed

    Nakayama, Takahiro; Mizoguchi, Toshihide; Uehara, Shunsuke; Yamashita, Teruhito; Kawahara, Ichiro; Kobayashi, Yasuhiro; Moriyama, Yoshinori; Kurihara, Saburo; Sahara, Noriyuki; Ozawa, Hidehiro; Udagawa, Nobuyuki; Takahashi, Naoyuki

    2011-12-01

    Osteoclasts form ruffled borders and sealing zones toward bone surfaces to resorb bone. Sealing zones are defined as ringed structures of F-actin dots (actin rings). Polarized osteoclasts secrete protons to bone surfaces via vacuolar proton ATPase through ruffled borders. Catabolic enzymes such as tartrate-resistant acid phosphatase (TRAP) and cathepsin K are also secreted to bone surfaces. Here we show a simple method of identifying functional vestiges of polarized osteoclasts. Osteoclasts obtained from cocultures of mouse osteoblasts and bone marrow cells were cultured for 48 h on dentin slices. Cultures were then fixed and stained for TRAP to identify osteoclasts on the slices. Cells were removed from the slices with cotton swabs, and the slices subjected to TRAP and Mayer's hematoxylin staining. Small TRAP-positive spots (TRAP-marks) were detected in the resorption pits stained with Mayer's hematoxylin. Pitted areas were not always located in the places of osteoclasts, but osteoclasts existed on all TRAP-marks. A time course experiment showed that the number of TRAP-marks was maintained, while the number of resorption pits increased with the culture period. The position of actin rings formed in osteoclasts corresponded to that of TRAP-marks on dentin slices. Immunostaining of dentin slices showed that both cathepsin K and vacuolar proton ATPase were colocalized with the TRAP-marks. Treatment of osteoclast cultures with alendronate, a bisphosphonate, suppressed the formation of TRAP-marks and resorption pits without affecting the cell viability. Calcitonin induced the disappearance of both actin rings and TRAP-marks in osteoclast cultures. These results suggest that TRAP-marks are vestiges of proteins secreted by polarized osteoclasts. PMID:21983021

  16. PTH1-34 alleviates radiotherapy-induced local bone loss by improving osteoblast and osteocyte survival.

    PubMed

    Chandra, Abhishek; Lin, Tiao; Tribble, Mary Beth; Zhu, Ji; Altman, Allison R; Tseng, Wei-Ju; Zhang, Yejia; Akintoye, Sunday O; Cengel, Keith; Liu, X Sherry; Qin, Ling

    2014-10-01

    Cancer radiotherapy is often complicated by a spectrum of changes in the neighboring bone from mild osteopenia to osteoradionecrosis. We previously reported that parathyroid hormone (PTH, 1-34), an anabolic agent for osteoporosis, reversed bone structural deterioration caused by multiple microcomputed tomography (microCT) scans in adolescent rats. To simulate clinical radiotherapy for cancer patients and to search for remedies, we focally irradiated the tibial metaphyseal region of adult rats with a newly available small animal radiation research platform (SARRP) and treated these rats with intermittent injections of PTH1-34. Using a unique 3D image registration method that we recently developed, we traced the local changes of the same trabecular bone before and after treatments, and observed that, while radiation caused a loss of small trabecular elements leading to significant decreases in bone mass and strength, PTH1-34 preserved all trabecular elements in irradiated bone with remarkable increases in bone mass and strength. Histomorphometry demonstrated that SARRP radiation severely reduced osteoblast number and activity, which were impressively reversed by PTH treatment. In contrast, suppressing bone resorption by alendronate failed to rescue radiation-induced bone loss and to block the rescue effect of PTH1-34. Furthermore, histological analyses revealed that PTH1-34 protected osteoblasts and osteocytes from radiation-induced apoptosis and attenuated radiation-induced bone marrow adiposity. Taken together, our data strongly support a robust radioprotective effect of PTH on trabecular bone integrity through preserving bone formation and shed light on further investigations of an anabolic therapy for radiation-induced bone damage. PMID:24998454

  17. PTH1-34 Alleviates Radiotherapy-induced Local Bone Loss by Improving Osteoblast and Osteocyte Survival

    PubMed Central

    Chandra, Abhishek; Lin, Tiao; Tribble, Mary Beth; Zhu, Ji; Altman, Allison R.; Tseng, Weiju; Zhang, Yejia; Akintoye, Sunday O.; Cengel, Keith; Liu, X. Sherry; Qin, Ling

    2014-01-01

    Cancer radiotherapy is often complicated by a spectrum of changes in the neighboring bone from mild osteopenia to osteoradionecrosis. We previously reported that parathyroid hormone (PTH, 1–34), an anabolic agent for osteoporosis, reversed bone structural deterioration caused by multiple microcomputed tomography (microCT) scans in adolescent rats. To simulate clinical radiotherapy for cancer patients and to search for remedies, we focally irradiated the tibial metaphyseal region of adult rats with a newly available small animal radiation research platform (SARRP) and treated these rats with intermittent injections of PTH1–34. Using a unique 3D image registration method that we recently developed, we traced the local changes of the same trabecular bone before and after treatments, and observed that, while radiation caused a loss of small trabecular elements leading to significant decreases in bone mass and strength, PTH1–34 preserved all trabecular elements in irradiated bone with remarkable increases in bone mass and strength. Histomorphometry demonstrated that SARRP radiation severely reduced osteoblast number and activity, which were impressively reversed by PTH treatment. In contrast, suppressing bone resorption by alendronate failed to rescue radiation-induced bone loss and to block the rescue effect of PTH1–34. Furthermore, histological analyses revealed that PTH1–34 protected osteoblasts and osteocytes from radiation-induced apoptosis and attenuated radiation-induced bone marrow adiposity. Taken together, our data strongly support a robust radioprotective effect of PTH on trabecular bone integrity through preserving bone formation and shed light on further investigations of an anabolic therapy for radiation-induced bone damage. PMID:24998454

  18. Oncologic Doses of Zoledronic Acid Induce Osteonecrosis of the Jaw-Like Lesions in Rice Rats (Oryzomys Palustris) with Periodontitis

    PubMed Central

    Aguirre, J. I.; Akhter, M. P.; Kimmel, D. B.; Pingel, J. E.; Williams, A.; Jorgensen, M.; Kesavalu, L.; Wronski, T. J.

    2012-01-01

    Though osteonecrosis of the jaw (ONJ) is temporally-associated with the use of nitrogen-containing bisphosphonates (N-BPs), a cause/effect relationship has not yet been established. We hypothesize that ONJ is a two-stage process in which: a) risk factors initiate pathologic processes in the oral cavity that lead to a supranormal rate of hard tissue necrosis, and b) powerful anti-resorptives reduce the rate of removal of necrotic bone sufficiently to allow its net accumulation in the jaw. To test this hypothesis, we used the rice rat model of periodontitis. At age 28 days, rats (n=15/group) were placed on a high sucrose and casein diet to exacerbate the development of periodontitis. Animals were injected SC biweekly with vehicle or alendronate (ALN, 15μg/kg), or IV once monthly with vehicle, a low dose (LD), or a high dose (HD) of zoledronic acid (ZOL) and sacrificed after 6, 12, 18, and 24 wks. Mandibles and maxillae were analyzed to determine the effects on the: a) progression of periodontitis, b) integrity of alveolar bone, c) status of bone resorption and formation, d) vascularity, and e) osteocyte viability. We found that only HD-ZOL induced ONJ-like lesions in mandibles of rice rats after 18 and 24 wks of treatment. These lesions were characterized by areas of exposed necrotic alveolar bone, osteolysis, a honey comb-like appearance of the alveolar bone, presence of bacterial colonies, and periodontal tissue destruction. In addition, inhibition of bone formation, a paradoxical abolition of the antiresorptive effect of only HD-ZOL, increased osteocyte necrosis/apoptosis, and decreased blood vessel number were found after 18 and/or 24 wks. Our study suggests that only HD-ZOL exacerbates the inflammatory response and periodontal tissue damage in rice rats, inducing bone lesions that resemble ONJ. PMID:22623376

  19. The mechanical and tribological properties of UHMWPE loaded ALN after mechanical activation for joint replacements.

    PubMed

    Gong, Kemeng; Qu, Shuxin; Liu, Yumei; Wang, Jing; Zhang, Yongchao; Jiang, Chongxi; Shen, Ru

    2016-08-01

    Ultra-high molecular weight polyethylene (UHMWPE) loaded with alendronate sodium (ALN) has tremendous potential as an orthopeadic biomaterial for joint replacements. However, poor mechanical and tribological properties of UHMWPE-ALN are still obstacle for further application. The purpose of this study was to investigate the effect and mechanism of mechanical activation on mechanical and tribological properties of 1wt% ALN-loaded UHMWPE (UHMWPE-ALN-ma). In this study, tensile test, small punch test and reciprocating sliding wear test were applied to characterize the mechanical and tribological properties of UHMWPE-ALN-ma. Scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS) and Fourier transform infrared spectroscopy (FTIR) were employed to characterize UHMWPE-ALN-ma. Tensile test and small punch test showed that Young׳s modulus, tensile strength and work-to-failure (WTF) of UHMWPE-ALN-ma increased significantly compared to those of UHMWPE-ALN. The friction coefficients and wear factors of UHMWPE-ALN-ma both decreased significantly compared to those of UHMWPE-ALN. Mechanical activation obviously reduced type 1 (void) and type 2 (the disconnected and dislocated machining marks) fusion defects of UHMWPE-ALN-ma, which were revealed by SEM images of freeze fracture surfaces after etching and lateral surfaces of specimens after extension to fracture, respectively. It was attributed to peeled-off layers and chain scission of molecular chains of UHMWPE particles after mechanical activation, which were revealed by SEM images and FTIR spectra of UHMWPE-ALN-ma and UHMWPE-ALN, respectively. Moreover, EDS spectra revealed the more homogeneous distribution of ALN in UHMWPE-ALN-ma compared to that of UHMWPE-ALN. The present results showed that mechanical activation was a potential strategy to improve mechanical and tribological properties of UHMWPE-ALN-ma as an orthopeadic biomaterial for joint replacements. PMID:27104932

  20. Interactions between active pharmaceutical ingredients and excipients affecting bioavailability: impact on bioequivalence.

    PubMed

    García-Arieta, Alfredo

    2014-12-18

    The aim of the present paper is to illustrate the impact that excipients may have on the bioavailability of drugs and to review existing US-FDA, WHO and EMA regulatory guidelines on this topic. The first examples illustrate that small amounts of sorbitol (7, 50 or 60mg) affect the bioavailability of risperidone, a class I drug, oral solution, in contrast to what is stated in the US-FDA guidance. Another example suggests, in contrast to what is stated in the US-FDA BCS biowaivers guideline, that a small amount of sodium lauryl sulphate (SLS) (3.64mg) affects the bioavailability of risperidone tablets, although the reference product also includes SLS in an amount within the normal range for that type of dosage form. These factors are considered sufficient to ensure that excipients do not affect bioavailability according to the WHO guideline. The alternative criterion, defined in the WHO guideline and used in the FIP BCS biowaivers monographs, that asserts that excipients present in generic products of the ICH countries do not affect bioavailability if used in normal amounts, is shown to be incorrect with an example of alendronate (a class III drug) tablets, where 4mg of SLS increases bioavailability more than 5-fold, although a generic product in the USA contains SLS. Finally, another example illustrates that a 2mg difference in SLS may affect bioavailability of a generic product of a class II drug, even if SLS is contained in the comparator product, and in all cases its amount was within the normal range. Therefore, waivers of in vivo bioequivalence studies (e.g., BCS biowaivers, waivers of certain dosage forms in solution at the time of administration and variations in the excipient composition) should be assessed more cautiously. PMID:25236823

  1. Acute Kidney Injury and Bisphosphonate Use in Cancer: A Report From the Research on Adverse Drug Events and Reports (RADAR) Project

    PubMed Central

    Edwards, Beatrice J.; Usmani, Sarah; Raisch, Dennis W.; McKoy, June M.; Samaras, Athena T.; Belknap, Steven M.; Trifilio, Steven M.; Hahr, Allison; Bunta, Andrew D.; Abu-Alfa, Ali; Langman, Craig B.; Rosen, Steve T.; West, Dennis P.

    2013-01-01

    Purpose: To determine whether acute kidney injury (AKI) is identified within the US Food and Drug Administration's Adverse Events and Reporting System (FDA AERS) as an adverse event resulting from bisphosphonate (BP) use in cancer therapy. Methods: A search of the FDA AERS records from January 1998 through June 2009 was performed; search terms were “renal problems” and all drug names for BPs. The search resulted in 2,091 reports. We analyzed for signals of disproportional association by calculating the proportional reporting ratio for zoledronic acid (ZOL) and pamidronate. Literature review of BP-associated renal injury within the cancer setting was conducted. Results: Four hundred eighty cases of BP-associated acute kidney injury (AKI) were identified in patients with cancer. Two hundred ninety-eight patients (56%) were female; mean age was 66 ± 10 years. Multiple myeloma (n = 220, 46%), breast cancer (n = 98, 20%), and prostate cancer (n = 24, 5%) were identified. Agents included ZOL (n = 411, 87.5%), pamidronate (n = 8, 17%), and alendronate (n = 36, 2%). Outcomes included hospitalization (n = 304, 63.3%) and death (n = 68, 14%). The proportional reporting ratio for ZOL was 1.22 (95% CI, 1.13 to 1.32) and for pamidronate was 1.55 (95% CI, 1.25 to 1.65), reflecting a nonsignificant safety signal for both drugs. Conclusion: AKI was identified in BP cancer clinical trials, although a safety signal for BPs and AKI within the FDA AERS was not detected. Our findings may be attributed, in part, to clinicians who believe that AKI occurs infrequently; ascribe the AKI to underlying premorbid disease, therapy, or cancer progression; or consider that AKI is a known adverse drug reaction of BPs and thus under-report AKI to the AERS. PMID:23814519

  2. Trends in Media Reports, Oral Bisphosphonate Prescriptions, and Hip Fractures 1996-2012: An Ecological Analysis.

    PubMed

    Jha, Smita; Wang, Zhong; Laucis, Nicholas; Bhattacharyya, Timothy

    2015-12-01

    Bisphosphonates are effective for the treatment of osteoporosis despite recent reports of safety concerns such as atypical femur fracture. We conducted an ecological analysis of relevant media reports, oral bisphosphonate use, and fracture outcomes in the United States. Trends in media reports and public interest of bisphosphonates were quantified using data from Google Trends. Data from the Medical Expenditure Panel Survey (MEPS) and the National Inpatient Sample (NIS) were used to estimate the trends in oral bisphosphonate use among patients aged 55 years and older and hospitalizations for intertrochanteric and subtrochanteric fractures, respectively. These trends in the prevalence of oral bisphosphonate use and the age-adjusted incidence rate of intertrochanteric and subtrochanteric fractures were examined from 1996 to 2012. A series of spikes in Internet search activity for alendronate (Fosamax) occurred between 2006 and 2010 immediately following media reports of safety concerns. Oral bisphosphonate use declined by greater than 50% between 2008 and 2012 (p < 0.001) after increasing use for more than a decade. The decline was more common in patients with lower education levels. Intertrochanteric hip fractures declined from 1996 through 2006 (p < 0.001) and continued to decline from 2008 to 2012 (p < 0.05). Subtrochanteric and diaphyseal fractures showed a steady and significant increase from 2002 to 2011 (p < 0.05). However, the incidence decreased from a peak of 30.5 per 100,000 in 2011 to 26.7 per 100,000 in 2012. The plateauing and subsequent decline in oral bisphosphonate use since 2006 coincided with reports of safety concerns of bisphosphonates, despite the fact that U.S. Food and Drug Administration (FDA) and American Society of Bone and Mineral Research (ASBMR) reports did not recommend any safety restrictions on their use. This decline in oral bisphosphonate use was followed by the decline in the incidence of subtrochanteric and diaphyseal fractures

  3. 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. PMID:26909487

  4. Systemic delivery of siRNA by hyaluronan-functionalized calcium phosphate nanoparticles for tumor-targeted therapy.

    PubMed

    Qiu, Chong; Wei, Wei; Sun, Jing; Zhang, Hai-Tao; Ding, Jing-Song; Wang, Jian-Cheng; Zhang, Qiang

    2016-07-14

    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. PMID:27314204

  5. Primary biliary cirrhosis: Pathophysiology, clinical presentation and therapy.

    PubMed

    Purohit, Treta; Cappell, Mitchell S

    2015-05-01

    Primary biliary cirrhosis (PBC) is an autoimmune, slowly progressive, cholestatic, liver disease characterized by a triad of chronic cholestasis, circulating anti-mitochondrial antibodies (AMA), and characteristic liver biopsy findings of nonsuppurative destructive cholangitis and interlobular bile duct destruction. About 10% of PBC patients, however, lack AMA. A variant, called PBC-autoimmune hepatitis (AIH) overlap, is characterized by the above findings of PBC together with findings of elevated serum alanine aminotransferase, elevated serum immunoglobulin G, and circulating anti-smooth muscle antibodies, with liver biopsy demonstrating periportal or periseptal, lymphocytic, piecemeal necrosis. PBC is hypothesized to be related to environmental exposure in genetically vulnerable individuals. It typically occurs in middle-aged females. Prominent clinical features include fatigue, pruritis, jaundice, xanthomas, osteoporosis, and dyslipidemia. The Mayo Risk score is the most widely used and best prognostic system. Ursodeoxycholic acid is the primary therapy. It works partly by reducing the concentration and injury from relatively toxic bile acids. PBC-AIH overlap syndrome is treated with ursodeoxycholic acid and corticosteroids, especially budesonide. Obeticholic acid and fibrate are promising new, but incompletely tested, therapies. Liver transplantation is the definitive therapy for advanced disease, with about 70% 10-year survival after transplantation. Management of pruritis includes local skin care, dermatologist referral, avoiding potential pruritogens, cholestyramine, and possibly opioid antagonists, sertraline, or rifaximin. Management of osteoporosis includes life-style modifications, administration of calcium and vitamin D, and alendronate. Statins are relatively safe to treat the osteopenia associated with PBC. Associated Sjogren's syndrome is treated by artificial tears, cyclosporine ophthalmic emulsion to stimulate tear production; and saliva