Efficacy, effectiveness and side effects of medications used to prevent fractures.

There is an increasing number of effective therapies for fracture prevention in adults at risk of osteoporosis. However, shortcomings in the evidence underpinning our management of osteoporosis still exist. Evidence of antifracture efficacy in the groups of patients who most commonly use calcium and vitamin D supplements is lacking, the safety of calcium supplements is in doubt, and the safety and efficacy of high doses of vitamin D give cause for concern. Alendronate, risedronate, zoledronate and denosumab have been shown to prevent spine, nonspine and hip fractures; in addition, teriparatide and strontium ranelate prevent both spine and nonspine fractures, and raloxifene and ibandronate prevent spine fractures. However, most trials provide little information regarding long-term efficacy or safety. A particular concern at present is the possibility that oral bisphosphonates might cause atypical femoral fractures. Observational data suggest that the incidence of this type of fracture increases steeply with duration of bisphosphonate use, resulting in concern that the benefit-risk balance may become negative in the long term, particularly in patients in whom the osteoporotic fracture risk is not high. Therefore, reappraisal of ongoing use of bisphosphonates after about 5 years is endorsed by expert consensus, and 'drug holidays' should be considered at this time. Further studies are needed to guide clinical practice in this area.

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

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.

Infrared, Raman and NMR investigations of risedronate adsorption on nanocrystalline apatites.

The aim of the current work was to study the physico-chemical interactions of a bisphosphonate molecule, risedronate, with a well-characterised synthetic nanocrystalline apatite (NCA) as a model bone mineral. We adopted a global approach, using complementary physico-chemical techniques such as FTIR, RAMAN and NMR spectroscopies in order to learn more about the interaction process of risedronate with the apatitic surface. The results obtained suggest that risedronate adsorption corresponds to an ion substitution reaction with phosphate ions occurring at the crystal surface. This mechanism explains the greater amount adsorbed (N) for NCA, compared to well crystallised stoichiometric hydroxyapatite, attributable to the well-developed hydrated layer at the surface of the nanocrystals. However, most calcium ions remain attached to the solid phase and the formation of insoluble risedronate calcium salts must also be considered as a competitive reaction to the adsorption. Thus a calcium risedronate salt was synthesised and fully characterised for comparison to the solids after adsorption. Following spectroscopic results, it can be concluded that a strong interaction was established between risedronate ions and calcium ions at the apatitic surface. However, under these experimental conditions there is no nucleation of a distinct calcium risedronate salt and the apatite crystals retain their integrity.

Factors associated with bisphosphonate treatment failure in postmenopausal women with primary osteoporosis.

UNLABELLED: Among 97 postmenopausal women with primary osteoporosis, adequate calcium and vitamin D supplementation, and good compliance to a 36-month bisphosphonate treatment, the 25.8% of patients are inadequate responders. Current smoking and a bone turnover in the upper part of the normal range increase the risk of treatment failure. INTRODUCTION: To evaluate the prevalence of the bisphosphonate treatment failure and its possible associated factors in women with primary osteoporosis (PO). METHODS: We studied 97 previously untreated postmenopausal women with PO and fragility fractures and/or a FRAX® 10-year probability of a major osteoporotic fracture ≥ 7.5%, before and after a 36-month treatment with alendronate or risedronate and adequate vitamin D supplementation with good compliance. At baseline and after 36 months, lumbar spine (LS) and femoral bone mineral density (BMD) were assessed by Dual X-ray absorptiometry and vertebral fractures by spinal radiographs. Spinal deformity index (SDI) was calculated. Treatment failure was defined by the presence of ≥ 2 incident fragility fractures and/or a BMD decrease greater than the least significant change. RESULTS: Bisphosphonate treatment failure was observed in 25.8% of patients. Age, body mass index, years since menopause, familiar history of hip fracture, number of falls, type of bisphosphonate used, 25-hydroxyvitamin D levels (25OHVitD), BMD, SDI, and FRAX® score at baseline were not different between responders and inadequate responders. Treatment failure was associated with current smoking (OR 3.22, 95% CI 1.10-9.50, P = 0.034) and baseline alkaline phosphatase total activity levels ≥ 66.5 U/L (OR 4.22, 95% CI 1.48-12.01, P = 0.007), regardless of age, number of falls, LS BMD, and baseline SDI. CONCLUSIONS: The 25.8 % of PO postmenopausal women inadequately responds to bisphosphonates, despite a good compliance to therapy and normal 25OHVitD levels. The current smoking and bone turnover in the upper part of the normal range are associated with the inadequate response to bisphosphonates.

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

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

Bisphosphonates in the adjuvant setting of breast cancer therapy--effect on survival: a systematic review and meta-analysis.

BACKGROUND: The role of bisphosphonates (BP) in early breast cancer (BC) has been considered controversial. We performed a meta-analysis of all randomized controlled trials (RCTs) that appraised the effects of BP on survival in early BC. METHODS: RCTs were identified by searching the Cochrane Library, MEDLINE databases and conference proceedings. Hazard ratios (HRs) of overall survival (OS), disease-free survival (DFS) and relative risks of adverse events were estimated and pooled. RESULTS: Thirteen trials met the inclusion criteria, evaluating a total of 15,762 patients. Meta-analysis of ten trials which reported OS revealed no statistically significant benefit in OS for BP (HR 0.89, 95% CI = 0.79 to 1.01). Meta-analysis of nine trials which reported the DFS revealed no benefit in DFS (HR 0.95 (0.81-1.12)). Meta-analysis upon menopausal status showed a statistically significant better DFS in the BP-treated patients (HR 0.81(0.69-0.95)). In meta-regression, chemotherapy was negatively associated with HR of survival. CONCLUSIONS: Our meta-analysis indicates a positive effect for adjuvant BP on survival only in postmenopausal patients. Meta-regression demonstrated a negative association between chemotherapy use BP effect on survival. Further large scale RCTs are warranted to unravel the specific subgroups that would benefit from the addition of BP in the adjuvant setting.

Hydrophilic versus hydrophobic porogens for engineering of poly(lactide-co-glycolide) microparticles containing risedronate sodium.

OBJECTIVE: The aim of this study was to investigate the effect of two mechanistically different porogens, namely: the hydrophilic hydroxy-propyl-ß-cyclodextrin and the hydrophobic porogens (mineral oil and corn oil) in producing open/closed pored engineered polylactide-co-glycolic-acid microspheres suitable for pulmonary delivery of risedronate sodium (RS). MATERIALS AND METHODS: Surface morphology of the microspheres was studied and they were characterized for entrapment efficiency (%EE), particle size, and porosity as well as aerodynamic and flow properties. Selected formulae were investigated for in vitro drug release and deposition behavior using next generation impactor. Furthermore, the safety of the free drug and the selected prepared systems was assessed by MTT viability test performed on Calu-3 cell line. RESULTS AND DISCUSSION: The current work revealed that HP-ß-CD produced open-pored microspheres, while oils produced closed pored microspheres. Modulation of preparation parameters generated porous RS microspheres with high %EE, sustained drug release profile up to 15 days, suitable geometric and aerodynamic particle sizes and excellent flow properties. The safety of HP-ß-CD systems was higher than the systems utilizing oil as porogen. CONCLUSION: Porogen type affected the behavior of the microspheres as demonstrated by the various characterization experiments, with microspheres prepared using HP-ß-CD being superior to those prepared using oils as porogens.

Fourier transform infrared imaging as a tool to chemically and spatially characterize matrix-mineral deposition in osteoblasts.

Mineralizing osteoblasts are regularly used to study osteogenesis and model in vivo bone formation. Thus, it is important to verify that the mineral and matrix being formed in situ are comparable to those found in vivo. However, it has been shown that histochemical techniques alone are not sufficient for identifying calcium phosphate-containing mineral. The goal of the present study was to demonstrate the use of Fourier transform infrared imaging (FTIRI) as a tool for characterizing the spatial distribution and colocalization of the collagen matrix and the mineral phase during the mineralization process of osteoblasts in situ. MC3T3-E1 mouse osteoblasts were mineralized in culture for 28 days and FTIRI was used to evaluate the collagen content, collagen cross-linking, mineralization level and speciation, and mineral crystallinity in a spatially resolved fashion as a function of time. To test whether FTIRI could detect subtle changes in the mineralization process, cells were treated with risedronate (RIS). Results showed that collagen deposition and mineralization progressed over time and that the apatite mineral was associated with a collagenous matrix rather than ectopic mineral. The process was temporarily slowed by RIS, where the inhibition of osteoblast function caused slowed collagen production and cross-linking, leading to decreased mineralization. This study demonstrates that FTIRI is a complementary tool to histochemistry for spatially correlating the collagen matrix distribution and the nature of the resultant mineral during the process of osteoblast mineralization. It can further be used to detect small perturbations in the osteoid and mineral deposition process.

Effects of bisphosphonate treatment on circulating osteogenic endothelial progenitor cells in postmenopausal women.

OBJECTIVE: To evaluate whether bisphosphonates modulate vascular calcification by a modification in endothelial progenitor cells (EPCs) coexpressing osteoblastic surface markers and genes. PATIENTS AND METHODS: We performed a double-blind, randomized study of 20 healthy, early postmenopausal women (from February 1, 2008, through July 31, 2008) treated with placebo or risedronate sodium (35 mg/wk) for 4 months. Peripheral blood was collected at baseline and 4 months to determine serum inflammatory markers, osteoprotegerin, and receptor activator of nuclear factor-κB ligand levels and bone turnover markers. Peripheral blood mononuclear cells were stained for EPC surface markers (CD34, CD133, and vascular endothelial growth factor receptor/kinase insert domain receptor) and osteoblast markers (osteocalcin, alkaline phosphatase, and Stro-1). RESULTS: Risedronate treatment resulted in a significant down-regulation of gene sets for osteoblast differentiation and proliferation in EPCs with a trend of decreasing EPCs coexpressing osteocalcin. CONCLUSION: Our findings indicate that bisphosphonate treatment down-regulates the expression of osteogenic genes in EPCs and suggest a possible mechanism by which bisphosphonates may inhibit vascular calcification.

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.

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.

Risedronate improves bone mineral density in Crohn's disease: a two year randomized controlled clinical trial.

BACKGROUND: Patients with Crohn's disease have an increased frequency of osteopenia and osteoporosis. This randomized, controlled, double-blind study assessed the efficacy of risedronate versus placebo in treating low bone mineral density (BMD) in patients with Crohn's disease. METHODS: 88 Crohn's disease outpatients with BMD T-score<-1.0 by dual-energy X-ray absorptiometry were randomly assigned to one of two treatment groups for the two year study duration: one group received risedronate 35 mg weekly while another received placebo. Both groups received daily calcium (Ca; 500 mg) and vitamin D (D; 400 IU) supplementation. Percent change in BMD relative to baseline was compared between the two therapies at 12 and 24 months. RESULTS: Using intent-to-treat analysis, at 12 months, risedronate+Ca+D increased BMD, relative to baseline, more than placebo+Ca+D in the femoral trochanter (1.4±3.4% vs -0.1±3.1%; p=0.03) and total hip (1.1±2.7% vs -0.1±2.5%;p=0.04). This trend in greater BMD continued for the 24 month duration of the study. There was no difference between the two treatment groups for changes in spine BMD. Subgroup analysis revealed that risedronate+Ca+D resulted in significantly better improvement in femoral trochanter BMD in non-smokers (p=0.01), males (p=0.01), those with a history of corticosteroid use in the preceding year (p=0.01), and current users of immunosuppressants (p=0.04). CONCLUSIONS: Risedronate, in addition to daily calcium and vitamin D supplementation, is superior to calcium and vitamin D alone in improving femoral trochanter and total hip BMD in patients with Crohn's disease.

Preventive effect of risedronate on bone loss and frailty fractures in elderly women treated with anastrozole for early breast cancer.

The aim of this study was to assess the effect of adjuvant anastrozole, alone or associated with risedronate, on BMD and bone fracture risk in women more than 70 years old with hormone receptor-positive early breast cancer (EBC). In a group of 51 elderly women (aged 76.4 ± 5.0 years) considered for adjuvant aromatase inhibitors for EBC, 24 patients with T-scores ≥ -2 and no prevalent fractures received anastrozole 1 mg/day (group A), and 27 patients with T-scores < -2, or with T-scores ≥ -2 and prevalent fractures (group B), received anastrozole (1 mg/day) plus risedronate (35 mg/week). Both groups received supplementation with 1 g calcium carbonate and 800 IU vitamin D per day. Differences in BMD and frailty fractures were evaluated after 1 and 2 years. In group A, significant decreases in BMD were observed in the lumbar spine (Δ BMD, -0.030 ± 0.04 g/cm², P < 0.05), femoral neck (Δ BMD, -0.029 ± 0.05 g/cm², P < 0.05), and trochanter (Δ BMD, -0.026 ± 0.03 g/cm², P < 0.01) after 2 years. The greatest percent reduction in height (Hpr) emerged in the thoracic spine (3.6 ± 2.4%, P < 0.01), although only one incident vertebral fracture was observed. In group B, BMD increased in the lumbar spine (Δ BMD, 0.038 ± 0.04, P < 0.001), although no significant changes were seen in the hip regions. The decline in Hpr was negligible (about 1%). No incident fractures were observed at follow-up. In conclusion, anastrozole treatment for EBC in elderly women seems to have only mild negative effects on the femoral bone. Risedronate makes the use of anastrozole safer, even for osteopenic or osteoporotic elderly patients.

Stress fractures: diagnosis, treatment, and prevention.

Stress fractures are common injuries in athletes and military recruits. These injuries occur more commonly in lower extremities than in upper extremities. Stress fractures should be considered in patients who present with tenderness or edema after a recent increase in activity or repeated activity with limited rest. The differential diagnosis varies based on location, but commonly includes tendinopathy, compartment syndrome, and nerve or artery entrapment syndrome. Medial tibial stress syndrome (shin splints) can be distinguished from tibial stress fractures by diffuse tenderness along the length of the posteromedial tibial shaft and a lack of edema. When stress fracture is suspected, plain radiography should be obtained initially and, if negative, may be repeated after two to three weeks for greater accuracy. If an urgent diagnosis is needed, triple-phase bone scintigraphy or magnetic resonance imaging should be considered. Both modalities have a similar sensitivity, but magnetic resonance imaging has greater specificity. Treatment of stress fractures consists of activity modification, including the use of nonweight-bearing crutches if needed for pain relief. Analgesics are appropriate to relieve pain, and pneumatic bracing can be used to facilitate healing. After the pain is resolved and the examination shows improvement, patients may gradually increase their level of activity. Surgical consultation may be appropriate for patients with stress fractures in high-risk locations, nonunion, or recurrent stress fractures. Prevention of stress fractures has been studied in military personnel, but more research is needed in other populations.

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

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

In vitro and in vivo antiplasmodial activities of risedronate and its interference with protein prenylation in Plasmodium falciparum.

The increasing resistance of malarial parasites to almost all available drugs calls for the identification of new compounds and the detection of novel targets. Here, we establish the antimalarial activities of risedronate, one of the most potent bisphosphonates clinically used to treat bone resorption diseases, against blood stages of Plasmodium falciparum (50% inhibitory concentration [IC50] of 20.3±1.0 µM). We also suggest a mechanism of action for risedronate against the intraerythrocytic stage of P. falciparum and show that protein prenylation seems to be modulated directly by this drug. Risedronate inhibits the transfer of the farnesyl pyrophosphate group to parasite proteins, an effect not observed for the transfer of geranylgeranyl pyrophosphate. Our in vivo experiments further demonstrate that risedronate leads to an 88.9% inhibition of the rodent parasite Plasmodium berghei in mice on the seventh day of treatment; however, risedronate treatment did not result in a general increase of survival rates.

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

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.