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We prospectively assessed, with predefined criteria, the location and rates of all femur fractures (hip, subtrochanteric/femoral shaft [ST/FS], including atypical [AFF] and distal fractures) in women at increased fracture risk during treatment with the cathepsin K inhibitor, odanacatib (ODN), or placebo over 5 years in the Long-Term ODN Fracture Trial (LOFT and LOFT Extension [NCT00529373, EudraCT 2007-002693-66]). ODN was an investigational antiresorptive agent previously in development as an osteoporosis treatment that, unlike bisphosphonates, reduces bone formation only transiently. Women aged >= 65 years with a bone mineral density (BMD) T-score

Odanacatib (ODN) was investigated as an osteoporosis treatment in 292 men. Compared with placebo, odanacatib improved bone mineral density and led to sustained bone resorption decreases while producing relatively little bone formation reduction that leveled off with time. However, increased risk of stroke in another study stopped further odanacatib development.INTRODUCTION: ODN, a selective oral cathepsin K inhibitor, was in development for osteoporosis treatment. This phase 3, double-blind, randomized, placebo-controlled, 24-month study investigated ODN safety and efficacy in men with osteoporosis.METHODS: Men with idiopathic osteoporosis or osteoporosis due to hypogonadism and a lumbar spine or hip (total hip [TH], femoral neck [FN], or trochanter) bone mineral density (BMD) T-score of ≤ - 2.5 to ≥ - 4.0 without prior vertebral fracture or ≤ - 1.5 to ≥ - 4.0 with one prior vertebral fracture were randomized (1:1) to once-weekly ODN 50 mg or placebo. All received 5600 IU vitamin D3 weekly and calcium supplementation as needed (≥ 1200 mg daily). The primary efficacy outcome was changed from baseline in lumbar spine BMD versus placebo.RESULTS: Overall, 292 men, mean age 68.8 years, were randomly assigned to ODN or placebo. Versus placebo, ODN increased BMD from baseline at the lumbar spine, TH, FN, and trochanter by 5.6%, 2.0%, 1.7%, and 2.1%, respectively (all p CONCLUSION: Though a promising osteoporosis therapy for men, ODN development was discontinued due to increased risk of stroke in the LOFT phase 3 trial.TRIAL REGISTRATION: Clinicaltrials.gov NCT01120600 (registered May 11, 2010).

Summary Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial. Introduction Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN. Methods The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score ≤−2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score ≤−1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D3 (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg. Results Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension. Conclusions This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants. Electronic supplementary material The online version of this article (doi:10.1007/s00198-014-2944-6) contains supplementary material, which is available to authorized users.

MK-5442 is an orally bioavailable calcium-sensing receptor antagonist that is hypothesized to stimulate bone formation by stimulating endogenous secretion of a pulse of PTH. Earlier clinical and preclinical studies demonstrated increased bone mineral density (BMD) after treatment.Our objective was to identify a dose of MK-5442 that produces osteoanabolic effects without excessive hypercalcemia.This was a randomized, double-blind, placebo-controlled, parallel-group trial of private or institutional practice.In total, 383 postmenopausal women with osteoporosis were administered daily oral MK-5442 (2.5, 5, 7.5, 10, or 15 mg) or placebo.Serum PTH and calcium, bone turnover markers, areal BMD, and safety were evaluated.A dose-dependent transient increase in PTH occurred after an MK-5442 dose and lasted more than 3.5 hours. Compared with placebo, significant increases in bone formation markers (serum procollagen 1 N-terminal peptide and bone-specific alkaline phosphatase) were observed by 6 months, whereas bone resorption markers (serum C-telopeptide of type 1 collagen, urine N-telopeptides of type 1 collagen) initially decreased but were also significantly increased by 6 months. Despite the biochemical marker changes suggestive of an anabolic response, there were no statistically significant differences between any dose of MK-5442 and placebo in percent change from baseline at month 6 in any of the BMD endpoints. The frequency of hypercalcemia (trough serum calcium ≥ 10.8 mg/dL) was greater with higher MK-5442 doses.In postmenopausal women with low bone mass, treatment with MK-5442 resulted in transient pulses of PTH. Bone formation markers increased quickly and bone resorption markers decreased temporarily, suggestive of an anabolic window. However, there were no increases in BMD versus placebo.

Summary In this meta-analysis of all Merck-conducted, placebo-controlled clinical trials of alendronate, the occurrence of AF was uncommon, with most studies reporting two or fewer events. Across all studies, no clear association between overall bisphosphonate exposure and the rate of serious or non-serious AF was observed. Introduction To explore the incidence of atrial fibrillation (AF) and other cardiovascular endpoints in clinical trials of alendronate. Methods All double-blind, placebo-controlled studies of alendronate 5, 10, or 20 mg daily, 35 mg once-weekly, 35 mg twice-weekly, and 70 mg once-weekly of at least 3 months duration conducted by Merck were included in this meta-analysis. The primary method of analysis was exact Poisson regression. Estimated relative risk (RR) of alendronate versus placebo and the associated 95% confidence interval was derived from a model that included number of episodes with factors for treatment group and study and an offset parameter for number of person-years on study. Results Of 41 studies considered, 32 met all criteria for inclusion in the analysis (participants—9,518 alendronate, 7,773 placebo). Estimated RR for all AF events was 1.16 (95% CI = 0.87, 1.55; p = 0.33). Most trials had two or fewer AF events. The RR of AF classified as a serious adverse event was 1.25 (95% CI = 0.82, 1.93; p = 0.33), but became 0.97 (95% CI = 0.51, 1.85) when the clinical fracture cohort of the Fracture Intervention Trial was excluded, indicating that results were driven by events in that study. Estimated RRs for other cardiovascular endpoints were less than 1. Conclusions The incidence of atrial fibrillation was low in Merck clinical trials of alendronate and was not significantly increased in any single trial nor in the meta-analysis. Based on this analysis, alendronate use does not appear to be associated with an increased risk of atrial fibrillation. Electronic supplementary material The online version of this article (doi:10.1007/s00198-011-1546-9) contains supplementary material, which is available to authorized users.

The selective cathepsin K inhibitor odanacatib (ODN) progressively increased bone mineral density (BMD) and decreased bone-resorption markers during 2 years of treatment in postmenopausal women with low BMD. A 1-year extension study further assessed ODN efficacy and safety and the effects of discontinuing therapy. In the base study, postmenopausal women with BMD T-scores between −2.0 and −3.5 at the lumbar spine or femur received placebo or ODN 3, 10, 25, or 50 mg weekly. After 2 years, patients (n = 189) were rerandomized to ODN 50 mg weekly or placebo for an additional year. Endpoints included BMD at the lumbar spine (primary), total hip, and hip subregions; levels of bone turnover markers; and safety assessments. Continued treatment with 50 mg of ODN for 3 years produced significant increases from baseline and from year 2 in BMD at the spine (7.9% and 2.3%) and total hip (5.8% and 2.4%). Urine cross-linked N-telopeptide of type I collagen (NTx) remained suppressed at year 3 (−50.5%), but bone-specific alkaline phosphatase (BSAP) was relatively unchanged from baseline. Treatment discontinuation resulted in bone loss at all sites, but BMD remained at or above baseline. After ODN discontinuation at month 24, bone turnover markers increased transiently above baseline, but this increase largely resolved by month 36. There were similar overall adverse-event rates in both treatment groups. It is concluded that 3 years of ODN treatment resulted in progressive increases in BMD and was generally well tolerated. Bone-resorption markers remained suppressed, whereas bone-formation markers returned to near baseline. ODN effects were reversible: bone resorption increased transiently and BMD decreased following treatment discontinuation. © 2011 American Society for Bone and Mineral Research.

Adherence to anti-osteoporosis medications is currently low and is associated with poor anti-fracture efficacy. This manuscript reviews the potential design of clinical studies that aim to demonstrate improved adherence, with new chemical entities to be used in the management of osteoporosis.Several medications have been unequivocally shown to decrease fracture rates in clinical trials. However, in real life settings, long-term persistence and compliance to anti-osteoporosis medication is poor, hence decreasing the clinical benefits for patients.An extensive search of Medline from 1985 to 2006 retrieved all trials including the keywords osteoporosis, compliance, persistence or adherence followed by a critical appraisal of the data obtained through a consensus expert meeting.The impact of non-adherence on the clinical development of interventions is reviewed, so that clinicians, regulatory agencies and reimbursement agencies might be better informed of the problem, in order to stimulate the necessary research to document adherence.Adherence to therapy is a major problem in the treatment of osteoporosis. Both patients and medication factors are involved. Adherence studies are an important aspect of outcomes studies, but study methodologies are not well developed at the moment and should be improved. Performing adherence studies will be stimulated when registration authorities accept the result of these studies and include the relevant information in Sect. 5.1 of the summary of product characteristics. Reimbursement authorities might also consider such studies as important information for decisions on reimbursement.

Objective This paper describes the rationale and supporting data for once-weekly dosing of alendronate. Background Alendronate sodium, a bisphosphonate that potently inhibits bone resorption, has been shown to increase bone mass and substantially reduce the incidence of osteoporotic fractures, including fractures of the hip. The standard regimen of daily administration has generally been well tolerated. However, weekly administration may provide greater convenience to patients without compromising efficacy or tolerability. The pharmacokinetics of alendronate and bone remodeling theory predict similar efficacy for weekly and daily administration if the cumulative dose is the same. Bone resorption in individual remodeling units normally proceeds for ~2 weeks; alendronate inhibits the rate and extent of resorption. Because the half-life of residence on bone surfaces is several weeks, weekly administration of alendronate should inhibit bone resorption to an overall extent similar to that of daily dosing, thereby producing similar effects on bone mass and strength. Animal studies demonstrate that both weekly and daily parenteral administration of alendronate effectively increase bone mass and strength, but confirmation of efficacy is needed for weekly oral dosing in humans. Although daily bisphosphonates (alendronate and risedronate) elicited esophageal irritation in a canine model of gastroesophageal reflux, weekly dosing with alendronate at a higher unit dose did not. Thus, the lower frequency of weekly dosing with a higher unit dose may actually reduce the risk of upper gastrointestinal irritation compared with daily administration of a lower dose. Conclusions Current safety and efficacy data justify further investigation of once-weekly dosing of alendronate. Two positive-control, double-blind, randomized trials of osteoporosis treatment and prevention are currently being performed to assess the comparability of weekly, biweekly, and daily dosing of alendronate with regard to effects on bone density, safety, and tolerability.