Effects of various squalene epoxides on coenzyme Q and cholesterol synthesis.

2,3-Oxidosqualene is an intermediate in cholesterol biosynthesis and 2,3:22,23-dioxidosqualene act as the substrate for an alternative pathway that produces 24(S),25-epoxycholesterol which effects cholesterol homeostasis. In light of our previous findings concerning the biological effects of certain epoxidated all-trans-polyisoprenes, the effects of squalene carrying epoxy moieties on the second and third isoprene residues were investigated here. In cultures of HepG2 cells both monoepoxides of squalene and one of their hydrolytic products inhibited cholesterol synthesis and stimulated the synthesis of coenzyme Q (CoQ). Upon prolonged treatment the cholesterol content of these cells and its labeling with [(3)H]mevalonate were reduced, while the amount and labeling of CoQ increased. Injection of the squalene monoepoxides into mice once daily for 6days elevated the level of CoQ in their blood, but did not change the cholesterol level. The same effects were observed upon treatment of apoE-deficient mice and diabetic GK-rats. This treatment increased the hepatic level of CoQ10 in mice, but the amount of CoQ9, which is the major form, was unaffected. The presence of the active compounds in the blood was supported by the finding that cholesterol synthesis in the white blood cells was inhibited. Since the ratio of CoQ9/CoQ10 varies depending on the experimental conditions, the cells were titrated with substrate and inhibitors, leading to the conclusion that the intracellular isopentenyl-PP pool is a regulator of this ratio. Our present findings indicate that oxidosqualenes may be useful for stimulating both the synthesis and level of CoQ both in vitro and in vivo.

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.

Timing of the initiation of bisphosphonates after surgery for fracture healing: a systematic review and meta-analysis of randomized controlled trials.

SUMMARY: We performed a systematic review and meta-analysis of randomized clinical trials. Early administration of bisphosphonates (BPs) after surgery did not appear to delay fracture healing time either radiologically or clinically. Furthermore, the anti-resorptive efficacy of BPs given immediately after surgical repair should positively affect the rate of subsequent fractures. INTRODUCTION: Bisphosphonates (BPs) are widely used in the prophylaxis and treatment of osteoporosis. However, early administration of BPs after surgical repair of a fracture may limit the reserve capacity of bone to heal. The aim of this review and meta-analysis was to analyze the benefits and adverse effects of early administration of BPs and give recommendations regarding when BPs should be utilized. METHODS: We identified randomized controlled trials comparing the early administration of BPs to placebo, delayed BP treatment, or no therapy in adult patients after surgery. The search was performed in PubMed, the Cochrane Library, and Embase. RESULTS: Ten studies with 2888 patients were included. Four trials used alendronate, three trials used zoledronic, two trials used risedronate, and one trial used etidronate. Early administration of BPs was considered less than 3 months after surgery. Patients treated with BP therapy had no significant differences in radiological fracture healing times compared with patients in the control group (mean difference [MD] 0.47, 95% confidence interval [CI] -2.75 to 3.69). There were also no significant differences in the rate of delay or nonunion of fracture healing (odds ratio [OR] 0.98, 95% CI 0.64 to 1.50). However, the bone mineral density (BMD) of total hips did significantly improve after 12 months of treatment with BPs. And most bone turnover markers of patients in the study group were significantly decreased. CONCLUSIONS: Early administration of BPs after surgery did not appear to delay fracture healing time either radiologically or clinically. Furthermore, according to the changes in BMD and bone turnover markers, the anti-resorptive efficacy of BPs given immediately after surgical repair should positively affect the rate of subsequent fractures.

Residual effect after oral bisphosphonate treatment and healthy adherer effects--the Swedish Adherence Register Analysis (SARA).

UNLABELLED: Little is known of the effect of alendronate and risedronate on osteoporotic fractures after discontinuation of therapy. We found that time on treatment was significantly inversely associated with the incidence of hospitalized fractures during posttreatment follow-up. Our results will inform health economic analysis of osteoporosis interventions. INTRODUCTION: Real-world persistence to treatment of osteoporosis is well-understood, but little is known of the posttreatment residual effect on fractures. The objective of this study was to investigate the residual effect of alendronate and risedronate on fractures and assess whether a healthy adherer effect confounds the association between persistence and residual anti-fracture effect. METHODS: A treatment-naïve cohort from the Swedish Prescribed Drug Register was identified through prescriptions for alendronate or risedronate between 2005 and 2009. Persistence was estimated, and patients were stratified by time on treatment (<1 month, 1-6 months, 7-12 months, and >12 months). Survival analysis was used to study hospitalized fractures and mortality up to 18 months after treatment discontinuation. RESULTS: The crude incidence proportion of fractures the first 6 months after treatment discontinuation ranged from 2.26% (<1 month of treatment) to 1.16% (>12 months). The corresponding estimates for month 7 to 12 after discontinuation was 3.18 to 1.96%, and for month 13 to 18 after discontinuation 2.69 to 1.95%. Adjusted regression results showed that patients persisting with therapy for >12 months had 60% lower fracture risk the first six months after treatment discontinuation (RR 0.40, p = 0.001). Patient characteristics, including prevalent fractures and co-morbidities, and posttreatment mortality were comparable across persistence durations, and we found no evidence of a healthy adherer effect. CONCLUSIONS: Time on bisphosphonate treatment was significantly inversely associated with the incidence of hospitalized fractures during posttreatment follow-up. We found no evidence of a healthy adherer effect confounding the relationship between treatment persistence and fracture risk.

Bone safety with risedronate: histomorphometric studies at different dose levels and exposure.

UNLABELLED: This report describes bone safety and histomorphometric data across different dose levels and dosing frequencies of risedronate. Normal bone structure and histomorphometric data were observed, with ongoing bone remodeling and mineralization regardless of dose. These data are reassuring and do not suggest compromised bone remodeling during treatment with established risedronate regimens. INTRODUCTION: The efficacy and bone safety of risedronate 5 mg daily were established in pivotal phase III randomized, placebo-controlled clinical studies. Histomorphometric analysis of paired biopsies demonstrated bone safety as reflected by presence of fluorescent tetracycline double-labels in all evaluable biopsies. This report describes bone safety and histomorphometric data across studies of various dose regimens of risedronate. METHODS: Bridging studies, with bone mineral density as the primary endpoint, demonstrated non-inferiority of risedronate 35 mg and 50 mg once a week, risedronate 150 mg once a month, and a risedronate 75-mg dose on two consecutive days a month versus risedronate 5 mg daily. The low oral bioavailability and known dosing limitations due to food interactions of bisphosphonates have led to development of an oral delayed-release dose form of risedronate 35 mg to be taken weekly, before or after breakfast. Bone biopsies were collected at 24 months in studies involving these risedronate dosing regimens; bone safety and histomorphometric data were evaluated. RESULTS: Qualitative bone histology showed normal mineralization of newly formed bone without evidence of pathological findings, such as osteomalacia, bone marrow dyscrasia, or bone marrow fibrosis. Importantly, ongoing bone remodeling, based on fluorochrome labeling, was observed in all patients regardless of dose and exposure. Key histomorphometric variables were comparable to those observed with the risedronate 5 mg daily dose and were within the range seen in healthy pre- and post-menopausal women. CONCLUSIONS: Overall, the results are reassuring with respect to bone safety and histomorphometric data, and do not suggest oversuppression of bone remodeling during treatment with these established risedronate regimens.

Bridging the osteoporosis treatment gap: performance and cost-effectiveness of a fracture liaison service.

Individuals who sustain fragility fractures are at high risk of refracture. However, osteoporosis treatment rates remain low for these patients. Therefore, we aimed to assess the performance and cost-effectiveness of introducing a fracture liaison service (FLS) into a tertiary hospital. In "nonhospitalized" ambulatory patients who had sustained fragility fractures, we assessed baseline osteoporosis investigation and treatment rates, and subsequently, the impact of introducing an orthopedic osteoporosis policy and an FLS. Outcomes measured were uptake of osteoporosis intervention, patient satisfaction, and quality-adjusted life years (QALYs) gained. QALYs were calculated over 5 years using predicted fracture risks without intervention and estimated fracture risk reduction with intervention. At baseline (n = 49), 2% of ambulatory patients who had sustained fragility fractures underwent dual-energy X-ray absorptiometry (DXA) and 6% received osteoporosis-specific medication. After introduction of an osteoporosis policy (n = 58), 28% were investigated with DXA (p < 0.0001). However, treatment rates were unchanged. An FLS was introduced, reviewing 203 new patients over the inaugural 2 years (mean age [standard deviation], 67 (11) years; 77% female). All underwent DXA, and criteria for osteoporosis and osteopenia were identified in 44% and 40%, respectively. Osteoporosis medications were prescribed to 61% patients (risedronate: 22%, alendronate: 16%, strontium ranelate: 13%, zoledronic acid: 8%, other: 2%). Eighty-five of 90 questionnaire respondents were very satisfied or satisfied with the FLS. With the treatment prescribed over 5 years, we conservatively estimated that this FLS would reduce nonvertebral refractures from 59 to 50, improving QALYs by 0.054 and costing $1716 per patient (incremental cost-effectiveness ratio: $31749). This FLS model improves uptake of osteoporosis intervention guidelines, is popular among patients, and improves cost-effectiveness. Thus, it has the capacity to substantially improve health in a cost-effective way.

Lipophilic analogs of zoledronate and risedronate inhibit Plasmodium geranylgeranyl diphosphate synthase (GGPPS) and exhibit potent antimalarial activity.

We report the results of an in vitro screening assay targeting the intraerythrocytic form of the malaria parasite Plasmodium falciparum using a library of 560 prenyl-synthase inhibitors. Based on "growth-rescue" and enzyme-inhibition experiments, geranylgeranyl diphosphate synthase (GGPPS) is shown to be a major target for the most potent leads, BPH-703 and BPH-811, lipophilic analogs of the bone-resorption drugs zoledronate and risedronate. We determined the crystal structures of these inhibitors bound to a Plasmodium GGPPS finding that their head groups bind to the [Mg(2+)](3) cluster in the active site in a similar manner to that found with their more hydrophilic parents, whereas their hydrophobic tails occupy a long-hydrophobic tunnel spanning both molecules in the dimer. The results of isothermal-titration-calorimetric experiments show that both lipophilic bisphosphonates bind to GGPPS with, on average, a ΔG of -9 kcal mol(-1), only 0.5 kcal mol(-1) worse than the parent bisphosphonates, consistent with the observation that conversion to the lipophilic species has only a minor effect on enzyme activity. However, only the lipophilic species are active in cells. We also tested both compounds in mice, finding major decreases in parasitemia and 100% survival. These results are of broad general interest because they indicate that it may be possible to overcome barriers to cell penetration of existing bisphosphonate drugs in this and other systems by simple covalent modification to form lipophilic analogs that retain their enzyme-inhibition activity and are also effective in vitro and in vivo.

Risk of atypical femoral fracture during and after bisphosphonate use.

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.

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.

Changes in bone mineral density at 3 years in postmenopausal women receiving anastrozole and risedronate in the IBIS-II bone substudy: an international, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Aromatase inhibitors prevent breast cancer in postmenopausal women at high risk of the disease but are associated with accelerated bone loss. We assessed effectiveness of oral risedronate for prevention of reduction in bone mineral density (BMD) after 3 years of follow-up in a subset of patients in the IBIS-II trial. METHODS: The double-blind IBIS-II trial recruited 3864 healthy, postmenopausal women at increased risk of breast cancer and randomly allocated them oral anastrozole (1 mg/day) or matched placebo. 1410 (36%) postmenopausal women were then enrolled in a bone substudy and stratified at baseline according to their lowest baseline T score at spine or femoral neck (stratum I: T score at least -1·0; stratum II: T score at least -2·5 but less than -1·0; stratum III: T score less than -2·5 but greater than -4·0). Women in stratum I were monitored only; women in stratum III were all given risedronate (35 mg/week). Women in stratum II were randomly assigned (1:1) to risedronate (35 mg/week) or matched placebo by use of a block randomisation schedule via a web-based programme. The primary outcome of this per-protocol analysis (done with all women with a baseline and 3 year DXA assessment) was the effect of risedronate versus placebo for osteopenic women in stratum II randomly allocated to anastrozole (1 mg/day). Secondary outcomes included effect of anastrozole (1 mg/day) on BMD in women not receiving risedronate (strata I and II) and in osteoporotic women who were all treated with risedronate (stratum III). The trial is ongoing, but no longer recruiting. This trial is registered, number ISRCTN31488319. FINDINGS: Between Feb 2, 2003, and Sept 30, 2010, 150 (58%) of 260 women in stratum II who had been randomly allocated to anastrozole and either risedronate or placebo had baseline and 3 year assessments. At the lumbar spine, 3 year mean BMD change for the 77 women receiving anastrozole/risedronate was 1·1% (95% CI 0·2 to 2·1) versus -2·6% (-4·0 to -1·3) for the 73 women receiving anastrozole/placebo (p<0·0001). For the total hip, 3 year mean BMD change for women receiving anastrozole/risedronate was -0·7% (-1·6 to 0·2) versus -3·5% (-4·6 to -2·3) for women receiving anastrozole/placebo (p=0·0001). 652 (65%) of 1008 women in strata I and II who were not randomly allocated to risedronate had both baseline and 3 year assessments. Women not receiving risedronate in stratum I and II who received anastrozole (310 women) had a significant BMD decrease after 3 years of follow-up compared with women who received placebo (342 women) at the lumbar spine (-4·0% [-4·5 to -3·4] vs -1·2% [-1·7 to -0·7], p<0·0001) and total hip (-4·0% [-4·4 to -3·6] vs -1·8% [-2·1 to -1·4], p<0·0001). 106 (79%) of 149 women in stratum III had a baseline and a 3 year assessment. The 46 women allocated to anastrozole had a modest BMD increase of 1·2% (-0·1 to 2·6) at the spine compared with a 3·9% (2·6 to 5·2) increase for the 60 women allocated to placebo (p=0·006). For the total hip, a small 0·3% (-0·9 to 1·5) increase was noted for women allocated anastrozole compared with a 1·5% (0·5 to 2·5) increase for women allocated placebo, but the difference was not significant (p=0·12). The most common adverse event reported was arthralgia (stratum I: 94 placebo and 114 anastrozole; stratum II: 39 placebo/placebo, 25 placebo/risedronate, 34 anastrozole/placebo, and 34 anastrozole/risedronate; stratum III: 21 placebo/risedronate, 17 anastrozole/risedronate). Other adverse events included hot flushes, alopecia, abdominal pain, and back pain. INTERPRETATION: Risedronate counterbalances the effect of anastrozole-induced bone loss in osteopenic and osteoporotic women and might be offered in combination with anastrozole treatment to provide an improved risk-benefit profile. FUNDING: Cancer Research UK (C569/A5032), National Health and Medical Research Council Australia (GNT300755, GNT569213), Sanofi-Aventis, and AstraZeneca.

Probenecid as a sensitizer of bisphosphonate-mediated effects in breast cancer cells.

BACKGROUND: Anti-resorptive bisphosphonates (BP) are used for the treatment of osteoporosis and bone metastases. Clinical studies indicated a benefit in survival and tumor relapse in subpopulations of breast cancer patients receiving zoledronic acid, thus stimulating the debate about its anti-tumor activity. Amino-bisphosphonates in nM concentrations inhibit farnesyl pyrophosphate synthase leading to accumulation of isopentenyl pyrophosphate (IPP) and the ATP/pyrophosphate adduct ApppI, which induces apoptosis in osteoclasts. For anti-tumor effects µM concentrations are needed and a sensitizer for bisphosphonate effects would be beneficial in clinical anti-tumor applications. We hypothesized that enhancing intracellular pyrophosphate accumulation via inhibition of probenecid-sensitive channels and transporters would sensitize tumor cells for bisphosphonates anti-tumor efficacy. METHOD: MDA-MB-231, T47D and MCF-7 breast cancer cells were treated with BP (zoledronic acid, risedronate, ibandronate, alendronate) and the pyrophosphate channel inhibitors probenecid and novobiocin. We determined cell viability and caspase 3/7 activity (apoptosis), accumulation of IPP and ApppI, expression of ANKH, PANX1, ABCC1, SLC22A11, and the zoledronic acid target gene and tumor-suppressor KLF2. RESULTS: Treatment of MDA-MB-231 with BP induced caspase 3/7 activity, with zoledronic acid being the most effective. In MCF-7 and T47D either BP markedly suppressed cell viability with only minor effects on apoptosis. Co-treatment with probenecid enhanced BP effects on cell viability, IPP/ApppI accumulation as measurable in MCF-7 and T47D cells, caspase 3/7 activity and target gene expression. Novobiocin co-treatment of MDA-MB-231 yielded identical results on viability and apoptosis compared to probenecid, rendering SLC22A family members as candidate modulators of BP effects, whereas no such evidence was found for ANKH, ABCC1 and PANX1. CONCLUSIONS: In summary, we demonstrate effects of various bisphosphonates on caspase 3/7 activity, cell viability and expression of tumor suppressor genes in breast cancer cells. Blocking probenecid and novobiocin-sensitive channels and transporters enhances BP anti-tumor effects and renders SLC22A family members as good candidates as BP modulators. Further studies will have to unravel if treatment with such BP-sensitizers translates into preclinical and clinical efficacy.

Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Children with osteogenesis imperfecta are often treated with intravenous bisphosphonates. We aimed to assess the safety and efficacy of risedronate, an orally administered third-generation bisphosphonate, in children with the disease. METHODS: In this multicentre, randomised, parallel, double-blind, placebo-controlled trial, children aged 4-15 years with osteogenesis imperfecta and increased fracture risk were randomly assigned by telephone randomisation system in a 2:1 ratio to receive either daily risedronate (2·5 or 5 mg) or placebo for 1 year. Study treatment was masked from patients, investigators, and study centre personnel. Thereafter, all children received risedronate for 2 additional years in an open-label extension. The primary efficacy endpoint was percentage change in lumbar spine areal bone mineral density (BMD) at 1 year. The primary efficacy analysis was done by ANCOVA, with treatment, age group, and pooled centre as fixed effects, and baseline as covariate. Analyses were based on the intention-to-treat population, which included all patients who were randomly assigned and took at least one dose of assigned study treatment. The trial is registered with ClinicalTrials.gov, number NCT00106028. FINDINGS: Of 147 patients, 97 were randomly assigned to the risedronate group and 50 to the placebo group. Three patients from the risedronate group and one from the placebo group did not receive study treatment, leaving 94 and 49 in the intention-to-treat population, respectively. The mean increase in lumbar spine areal BMD after 1 year was 16·3% in the risedronate group and 7·6% in the placebo group (difference 8·7%, 95% CI 5·7-11·7; p<0·0001). After 1 year, clinical fractures had occurred in 29 (31%) of 94 patients in the risedronate group and 24 (49%) of 49 patients in the placebo group (p=0·0446). During years 2 and 3 (open-label phase), clinical fractures were reported in 46 (53%) of 87 patients in the group that had received risedronate since the start of the study, and 32 (65%) of 49 patients in the group that had been given placebo during the first year. Adverse event profiles were otherwise similar between the two groups, including frequencies of reported upper-gastrointestinal and selected musculoskeletal adverse events. INTERPRETATION: Oral risedronate increased areal BMD and reduced the risk of first and recurrent clinical fractures in children with osteogenesis imperfecta, and the drug was generally well tolerated. Risedronate should be regarded as a treatment option for children with osteogenesis imperfecta. FUNDING: Alliance for Better Bone Health (Warner Chilcott and Sanofi).

Use of strontium ranelate and risk of acute coronary syndrome: cohort study.

BACKGROUND: A recent pooled analysis of randomised trials found an increased risk of myocardial infarction with use of the antiosteoporotic drug strontium ranelate. We conducted a nationwide cohort study in Denmark, 2005-2011, to investigate the risk of acute coronary syndrome among postmenopausal women treated with strontium ranelate. METHODS: The study involved two analytic setups. The first analysis included new users of either strontium ranelate (n=1798) or one of the two first-line bisphosphonates in Denmark (alendronate and risedronate; n=65 236). The second analysis included patients who had first been treated with a first-line bisphosphonate and subsequently switched to either strontium ranelate (n=1219) or ibandronate (n=2290). The primary outcome was acute coronary syndrome (unstable angina or myocardial infarction). The secondary outcome was any-cause mortality. Cox regression was used to estimate HRs, with adjustment using a disease risk score. RESULTS: Compared with use of alendronate/risedronate, use of strontium was not associated with significantly increased risk of acute coronary syndrome (rate per 1000 person-years 5.7 for strontium vs 6.3 for alendronate/risedronate; adjusted HR 0.89, 95% CI 0.52 to 1.55) or any-cause mortality (adjusted HR 0.96, 95% CI 0.76 to 1.21). In the analysis of switchers, strontium was not associated with significantly increased risk of acute coronary syndrome (rate per 1000 person-years 9.9 for strontium vs 9.9 for ibandronate; adjusted HR 1.00, 95% CI 0.49 to 2.05) or of any-cause mortality (adjusted HR 1.45, 95% CI 0.95 to 2.21). INTERPRETATION: These real-world data of antiosteoporotic drug users do not support a significant association between use of strontium ranelate and acute coronary syndrome.

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.

Denosumab significantly increases bone mineral density and reduces bone turnover compared with monthly oral ibandronate and risedronate in postmenopausal women who remained at higher risk for fracture despite previous suboptimal treatment with an oral bisphosphonate.

UNLABELLED: Managing osteoporotic patients suboptimally adherent to bisphosphonates (BPs) is difficult. Such patients who remained at higher risk for fracture (≥1 risk factor) were transitioned to denosumab or a monthly oral BP. Denosumab-treated subjects had significantly greater increases in bone mineral density and decreases in bone turnover in this 12-month study. INTRODUCTION: A clinical need exists to manage patients who are suboptimally adherent to oral BPs and remain at higher risk for fracture. Here, we compare the effects on bone mineral density (BMD) and bone turnover of transitioning such patients to denosumab or monthly oral BP (ibandronate or risedronate). METHODS: In two previous multicenter, open-label studies, postmenopausal women ≥55 years previously treated with, though suboptimally adherent to, a daily or weekly BP were randomized to denosumab 60 mg subcutaneously every 6 months (N = 852) or oral BP 150 mg monthly (N = 851) for 12 months. In this combined post-hoc analysis, a subset of higher risk subjects was identified, and the percentage changes from baseline in BMD and serum C-telopeptide of type I collagen (sCTX-1) were assessed. RESULTS: In the overall population, denosumab was associated with greater gains in BMD at 12 months than monthly oral BP at the total hip, femoral neck, and lumbar spine (p < 0.0001 for all). In higher risk subjects, denosumab led to greater gains in BMD than oral BPs at the total hip (2.2 vs 0.8 %), femoral neck (1.8 vs 0.3 %), and lumbar spine (3.7 vs 1.4 %) (p < 0.0001 for all). Denosumab also led to greater decreases in sCTX-1 in the overall population and higher risk subjects at months 1 and 6 (p < 0.0001 for both). Adverse events and serious adverse events were generally similar between treatment groups. CONCLUSIONS: Transitioning to denosumab was well tolerated and more effective in increasing BMD and reducing bone turnover than cycling to a monthly oral BP treatment in subjects who remained at higher fracture risk despite suboptimal BP treatment.

Increased bone mineral density with monthly intravenous ibandronate contributes to fracture risk reduction in patients with primary osteoporosis: three-year analysis of the MOVER study.

The relationship between gains in bone mineral density (BMD) in the hip and the incidence of vertebral fractures in the MOVER study was examined. Japanese patients from the ibandronate and risedronate treatment groups whose hip BMD had increased during the 3-year treatment period were classified into those with or without vertebral fractures. In both the ibandronate group and the risedronate group, hip BMD gains in the patients who had developed no vertebral fractures during the treatment period were greater than in the patients who developed vertebral fractures. We categorized the gains in hip BMD at 6 months into 3 groups (≤0, >0 to ≤3, and >3%), and used logistic regression analysis to estimate odds ratios and the probabilities of incidence of vertebral fractures at 12, 24, and 36 months. The current study demonstrated that greater gains in hip BMD during the first 6 months of treatment were associated with a reduction in the risk of subsequent vertebral fractures during the duration of treatment, and suggested that measurement of hip BMD gain at that time could lead to a prediction of the risk of the future vertebral fracture incidence.

Risedronate improves bone architecture and strength faster than alendronate in ovariectomized rats on a low-calcium diet.

Clinical evidence suggests that, compared with alendronate, risedronate reduces fracture risk faster and more potently, with less bone mass gain. We tested the hypothesis that risedronate improves bone quality faster than alendronate using calcium-deficient, ovariectomized (OVX) rats. Female Sprague-Dawley rats at 24 weeks of age were divided into sham-operated and OVX groups and fed a low-calcium (0.05%) diet under paired feeding. After 12 weeks, OVX rats were divided into five groups and treated with vehicle, risedronate (3.5 and 17.5 µg/kg/week, s.c.) or alendronate (7 and 35 µg/kg/week, s.c.). Rats were killed 6-8 weeks later and the bone architecture and strength of the left femur were evaluated by micro-computed tomography and a three-point bending test. Trabecular bone mineral density (BMD), number and thickness were significantly lower in OVX rats than in the sham-operated group. Cortical BMD, bone area (Ct.Ar), and thickness (Ct.Th) were similarly decreased. Risedronate significantly improved Ct.Ar (+8%) and Ct.Th (+9%) at 6 weeks, while alendronate only caused a significant improvement in Ct.Ar (+8% at 6 weeks) and only at the higher dose. At 8 weeks, both risedronate and alendronate significantly increased trabecular BMD compared with the vehicle. Bone strength parameters showed a significant correlation between Ct.Ar and Ct.Th. Risedronate significantly improved maximum load at 6 weeks, while alendronate failed to produce any significant changes. Our results suggest that risedronate is superior to alendronate at improving cortical bone architecture and strength, and that enhanced bone quality partly accounts for risedronate's efficacy.

Effect of parathyroidectomy versus risedronate on volumetric bone mineral density and bone geometry at the tibia in postmenopausal women with primary hyperparathyroidism.

The objective of the study was to evaluate the effect of parathyroidectomy (PTX) versus 35 mg once-weekly (ow) risedronate administration on volumetric bone mineral density (vBMD) and bone geometry at the tibia in postmenopausal women with primary hyperparathyroidism (PHPT). Our open-label prospective observational study included 32 postmenopausal women with PHPT as the study group: 16 underwent PTX and 16 were treated with 35 mg ow risedronate for 2 years. We assessed areal BMD (aBMD) by DXA, and vBMD and bone mineral content (BMC) (cortical and trabecular area) by peripheral quantitative computed tomography (pQCT) at the tibia at baseline and at 2 years. Risedronate did not result in any significant change on vBMD and structural pQCT indices. PTX resulted in significant increase in trabecular (trab) BMC (6.44 %) and vBMD (4.64 %), with percent increase being significantly higher than risedronate (p < 0.05). At cortical sites, there was no significant change following PTX. However, the percent change in cortical (cort) vBMD was higher following PTX versus risedronate (0.39 % vs. -0.26 %, p < 0.05). In conclusion, in postmenopausal women with PHPT, PTX is superior to ow risedronate, in terms of improvement of trabecular mineralization and vBMD at the tibia, whereas the effect at cortical sites is less pronounced.

Effects of risedronate alone or combined with vitamin K2 on serum undercarboxylated osteocalcin and osteocalcin levels in postmenopausal osteoporosis.

Risedronate decreases osteoporotic fracture incidence; however, its effects remain unclear in elderly osteoporotic patients. Vitamin K mediates carboxylation of osteocalcin (OC), and high undercarboxylated osteocalcin (ucOC) levels indicate vitamin K deficiency and increased osteoporotic fracture risk. We aimed to evaluate the effects of risedronate alone or combined with vitamin K2 on serum ucOC, OC, and incidence of vertebral fractures in elderly osteoporotic patients. A total of 101 women with postmenopausal osteoporosis aged >60 years were randomly stratified into two groups-R group (n = 51), treated with risedronate alone; and R + K group (n = 50), treated with risedronate and vitamin K2. Serum ucOC, OC and incidence of vertebral fractures were evaluated before treatment and at 6 and 12 months post-treatment. Decreased ucOC rates at 6 and 12 months were not significant between groups. However, at 6 and 12 months, decreased OC rates in the R group (p < 0.01 and 0.05, respectively) were significantly higher than in the R + K group, and ucOC/OC change rates in the R group (p < 0.05 and 0.001, respectively) were significantly lower than in the R + K group. Vertebral fracture incidence was not significantly different between the groups at 6 and 12 months. ucOC levels in patients with incident vertebral fractures were significantly higher than in patients without incident vertebral fractures in the R group at 6 months (p < 0.05). Although no significant difference was observed for ucOC decrease rate and incidence of vertebral fractures between treatments, ucOC levels in patients with incident vertebral fractures were significantly greater than in patients without when using risedronate alone.

Design of a randomized clinical trial of concurrent treatment with vitamin K2 and risedronate compared to risedronate alone in osteoporotic patients: Japanese Osteoporosis Intervention Trial-03 (JOINT-03).

Concurrent treatments with bisphosphonates and vitamin K are promising given that bisphosphonates possibly interfere with vitamin K activation. This is a prospective, multi-center, open-labeled, randomized trial of the efficacy of concurrent treatment with vitamin K2 and risedronate compared with risedronate alone and to explore subsets of patients for which concurrent treatment is particularly efficacious (trial identification number UMIN000000991). Inclusion criteria are women who meet the criteria for pharmacological therapy for osteoporosis, aged ≥65 years, have any of pre-specified risk factors, can walk unassisted, and are able to answer questionnaires. Exclusion criteria are prior warfarin use, secondary osteoporosis or non-osteoporotic metabolic bone diseases, contraindication for vitamin K2 and risedronate, hyper- or hypoparathyroidism, mental disorders, prevalent vertebral fracture at ≥6 sites, severe degenerative spinal deformation between T4 and L4, serious heart, liver, or kidney disease, or bisphosphonate use within the previous 6 months. Patients were recruited from 123 institutes between January 2008 and February 2010, and allocated to vitamin K2 (45 mg/day) and risedronate (2.5 mg/day or 17.5 mg/week) or risedronate alone (2.5 mg/day or 17.5 mg/week) groups. Primary endpoint is a vertebral or non-vertebral fracture. Secondary endpoints are bone mineral density, height, undercarboxylated osteocalcin, JOQOL, EQ-5D and safety. A sample size of 910 subjects per group and 2-year follow-up will provide 80 % power to detect 35 % risk reduction for fracture, with a two-sided significance level of 5 %. Subgroup analysis stratified to adjustment factors for random allocation, body mass index, 25-hydroxyvitamin D, estimated glomerular filtration rate, grade of vertebral fracture, JOQOL, EQ-5D, and co-morbidity is pre-specified.