odanacatib and Fractures--Bone

Osteoporosis is a metabolic bone disease that commonly results in middle-aged and elderly people following fractures. Odanacatib (ODN), a potential osteoporosis medication, was stopped in the Long-term Odanacatib Fracture Trial (LOFT) phase III study because it increased the risk of stroke. Herein, we conducted a systematic review and meta-analysis to further assess the efficacy and safety of ODN in osteoporosis treatment.. We searched the PubMed, EMBASE, Cochrane Library, and Web of Science, using the core search terms "osteoporosis" and "odanacatib." The primary outcomes were the percentage change in markers of bone turnover and bone formation as well as that in the bone mineral density (BMD) of the lumbar spine, hip, femoral neck, and greater trochanter. The secondary outcome was the risk of adverse events (AEs), used to explore the safety of ODN.. Ten articles-all double-blinded, randomized, placebo-controlled trials-were included. All trials were considered to be of high quality if they met the inclusion and exclusion criteria. We found that ODN increases BMD in the lumbar spine, total hip, and femoral neck, whereas it decreases the concentration of serum C-telopeptides of type I collagen (sCTx) and urinary N-telopeptide/creatinine ratio (uNTx/Cr). We found no significant differences in total, drug-related, serious, or skin AEs between the ODN and control groups. However, significant differences in fracture and stroke AEs were found between the ODN and control groups.. ODN is an appealing long-term osteoporosis treatment method; however, further research should focus on the potential increased risk of fracture and stroke.

Topics: Aged; Bone Density; Bone Density Conservation Agents; Double-Blind Method; Female; Fractures, Bone; Humans; Middle Aged; Osteoporosis; Osteoporosis, Postmenopausal; Stroke

Osteoporosis and fragility fractures are important public health concerns. Cathepsin K inhibitors, including odanacatib , are a novel class of medications for osteoporosis whose mechanism of action is to directly inhibit bone resorption without killing osteoclasts, thereby permitting the complex coupling between bone resorption and formation to continue.. The physiological basis for the mechanism of action of cathepsin K inhibitors is covered in addition to a review of the preclinical, Phase I, Phase II and preliminary Phase III trial data of odanacatib.. Evidence suggests that odanacatib has similar efficacy to bisphosphonates at increasing bone mineral density and decreasing risk of fragility fractures. Although odanacatib may preferentially inhibit bone resorption more than formation, the clinical significance of this difference in mechanism of action is not yet known. A careful analysis of the Phase III trial data is needed with specific attention to adverse events.

Topics: Animals; Biphenyl Compounds; Bone Density; Bone Density Conservation Agents; Bone Resorption; Cathepsin K; Clinical Trials as Topic; Diphosphonates; Fractures, Bone; Humans; Osteoporosis; Risk

Odanacatib (ODN), a selective cathepsin-K inhibitor, was found to increase bone mineral density (BMD); the effect on fractures is based on adverse event reports.. To estimate current effects and predict future effects of ODN on BMD and fractures.. Electronic databases (Medline, EMBASE, Cochrane Library), conference proceedings, and bibliographies.. Trials that compared ODN 50 mg/wk to placebo for at least 1 year and reported changes in BMD or fractures. Meta-analysis: Two bone outcomes were pooled as independent and as joint outcomes in Bayesian univariate and bivariate random-effects models.. Of 32 potentially eligible articles, six citations describing four trials (993 patients) were included. ODN for 3 years increased mean BMD at the lumbar spine by 5.0% (95% credible interval [CrI], 2.7, 7.5), total hip by 3.6% (95% CrI, 1.6, 5.9), and femoral neck (FN) by 3.6% (95% CrI, 1.6, 5.7). In a future trial of 3-year duration, the predicted mean increase in BMD, adjusted for the effect on fractures, was 4.9% for lumbar spine (95% CrI, 2.5, 7.4), 3.4% for total hip (95% CrI, 1.7, 5.2), and 3.5% for FN (95% CrI, 1.8, 5.3). After accounting for the effect on FN BMD, ODN for 3 years was associated with a population odds ratio of 0.38 (95% CrI, 0.1, 0.8). In a future trial, the odds ratio was 0.41 (95% CrI, 0.1, 1.1). The probability of benefit on fractures was 96-99%. The estimates remained robust in sensitivity analyses.. Our analyses suggest that ODN will increase BMD and decrease all fractures in the fracture outcome trial; however, direct demonstration of this antifracture efficacy is needed.

Topics: Bayes Theorem; Biphenyl Compounds; Bone Density; Cathepsin K; Fractures, Bone; Humans; Osteoporosis; Randomized Controlled Trials as Topic

Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis.. The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between -2·5 and -4·0 if no previous radiographic vertebral fracture, or between -1·5 and -4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than -4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66).. Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43-40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45-60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40-0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39-0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68-0·87; all p<0·0001. Combined results from LOFT plus LOFT Extension for cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 4·9% (341/6909) versus 9·6% (675/7011), HR 0·48, 95% CI 0·42-0·55; hip fractures 1·1% (86/8043) versus 2·0% (162/8028), 0·52, 0·40-0·67; non-vertebral fractures 6·4% (512/8043) versus 8·4% (675/8028), 0·74, 0·66-0·83; all p<0·0001. In LOFT, the composite cardiovascular endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 273 (3·4%) of 8043 patients in the odanacatib group versus 245 (3·1%) of 8028 in the placebo group (HR 1·12, 95% CI 0·95-1·34; p=0·18). New-onset atrial fibrillation or flutter occurred in 112 (1·4%) of 8043 patients in the odanacatib group versus 96 (1·2%) of 8028 in the placebo group (HR 1·18, 0·90-1·55; p=0·24). Odanacatib was associated with an increased risk of stroke (1·7% [136/8043] vs 1·3% [104/8028], HR 1·32, 1·02-1·70; p=0·034), but not myocardial infarction (0·7% [60/8043] vs 0·9% [74/8028], HR 0·82, 0·58-1·15; p=0·26). The HR for all-cause mortality was 1·13 (5·0% [401/8043] vs 4·4% [356/8028], 0·98-1·30; p=0·10). When data from LOFT Extension were included, the composite of cardiovascular death, myocardial infarction, or stroke occurred in significantly more patients in the odanacatib group than in the placebo group (401 [5·0%] of 8043 vs 343 [4·3%] of 8028, HR 1·17, 1·02-1·36; p=0·029, as did stroke (2·3% [187/8043] vs 1·7% [137/8028], HR 1·37, 1·10-1·71; p=0·0051).. Odanacatib reduced the risk of fracture, but was associated with an increased risk of cardiovascular events, specifically stroke, in postmenopausal women with osteoporosis. Based on the overall balance between benefit and risk, the study's sponsor decided that they would no longer pursue development of odanacatib for treatment of osteoporosis.. Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.

Topics: Aged; Aged, 80 and over; Biphenyl Compounds; Bone Density; Bone Density Conservation Agents; Double-Blind Method; Female; Fractures, Bone; Hip Fractures; Humans; Osteoporosis, Postmenopausal; Osteoporotic Fractures; Spinal Fractures; Treatment Outcome

Topics: Biphenyl Compounds; Cathepsin K; Clinical Trials as Topic; Drug Approval; Enzyme Inhibitors; Fractures, Bone; Humans; Osteoporosis; United States; United States Food and Drug Administration

Topics: Biphenyl Compounds; Female; Fractures, Bone; Humans; Osteoporosis; Osteoporosis, Postmenopausal; Placebos; Postmenopause; Practice Patterns, Physicians'; Randomized Controlled Trials as Topic; Selective Estrogen Receptor Modulators; Time Factors; Treatment Outcome