No abstract

Denosumab is a fully human monoclonal antibody that neutralizes the activity of RANKL, leading to the inhibition of osteoclast maturation, bone-resorbing activity, and survival. Evaluation of trans-iliac crest bone biopsy specimens in the phase 3 pivotal fracture study with denosumab in postmenopausal women with osteoporosis showed evidence of reduced bone turnover at the tissue level in subjects receiving denosumab, and up to one-third of subjects did not have evidence of tetracycline labeling in trabecular or cortical bone. Discontinuation of denosumab therapy has demonstrated that the effects of denosumab are reversible, as assessed by biochemical markers of bone turnover (BTM) and BMD. The precise nature of changes that occur at the tissue level with denosumab discontinuation have not been explored. Fifteen subjects were enrolled in a cohort study to evaluate the effects of denosumab discontinuation at the tissue level. Subjects had discontinued osteoporosis treatment for a mean time of 25.1 months (range 21 to 29 months). Bone histomorphometry results were compared with results from placebo-treated women with osteoporosis in the denosumab phase 3 pivotal fracture bone biopsy substudy, and BTMs were compared with subjects' pretreatment values. The results of this study showed normal histology and bone remodeling similar to those observed in untreated postmenopausal women with osteoporosis. With treatment cessation, 100% of biopsy specimens had evidence of tetracycline labels. Biochemical markers were comparable to and highly correlated with pretreatment levels. These data confirm that the effects of denosumab on bone turnover at the tissue level are fully reversible. ß

Background: Romosozumab is a bone-forming antibody that increases bone formation and decreases bone resorption. We conducted a double-blinded, randomized, phase-2, dose-finding trial to evaluate the effect of romosozumab on the clinical outcomes of open reduction and internal fixation of intertrochanteric or femoral neck hip fractures. Methods: Patients (55 to 94 years old) were randomized 2:3:3:3 to receive 3 subcutaneous injections of romosozumab (70, 140, or 210 mg) or a placebo postoperatively on day 1 and weeks 2, 6, and 12. The primary end point was the difference in the mean timed “Up & Go” (TUG) score over weeks 6 to 20 for romosozumab versus placebo. Additional end points included the time to radiographic evidence of healing and the score on the Radiographic Union Scale for Hip (RUSH). Results: A total of 332 patients were randomized: 243 to receive romosozumab (70 mg, n = 60; 140 mg, n = 93; and 210 mg, n = 90) and 89 to receive a placebo. Although TUG scores improved during the study, they did not differ significantly between the romosozumab and placebo groups over weeks 6 to 20 (p = 0.198). The median time to radiographic evidence of healing was 16.4 to 16.9 weeks across treatment groups. The RUSH scores improved over time across treatment groups but did not differ significantly between the romosozumab and placebo groups. The overall safety and tolerability profile of romosozumab was comparable with that of the placebo. Conclusions: Romosozumab did not improve the fracture-healing-related clinical and radiographic outcomes in the study population. Level of Evidence: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

Background: Romosozumab is an antibody that binds and inhibits sclerostin, thereby increasing bone formation and decreasing bone resorption. A double-blinded, randomized, phase-2, dose-finding trial was performed to evaluate the effect of romosozumab on the radiographic and clinical outcomes of surgical fixation of tibial diaphyseal fractures. Methods: Patients (18 to 82 years old) were randomized 3:1:1:1:1:1:1:1:1:1 to a placebo or 1 of 9 romosozumab treatment groups. Patients received subcutaneous injections of romosozumab or the placebo postoperatively on day 1 and weeks 2, 6, and 12. The primary outcome was the time to radiographic evidence of healing (“radiographic healing”) analyzed after the week-24 assessments had been completed for all patients. Results: A total of 402 patients were randomized: 299 to the romosozumab group and 103 to the placebo group. The median time to radiographic healing (the primary outcome) ranged from 14.4 to 18.6 weeks in the romosozumab groups and was 16.4 weeks (95% confidence interval [CI]: 14.6 to 18.0 weeks) in the placebo group, which was not a significant difference. There was also no significant difference in the median time to clinical healing, no relationship between romosozumab dose/frequency and unplanned revision surgery, and no apparent treatment benefit in terms of physical function. The safety and tolerability profile of romosozumab was comparable with that of the placebo. Conclusions: Romosozumab did not accelerate tibial fracture-healing in this patient population. Additional studies of patients at higher risk for delayed healing are needed to explore the potential of romosozumab to accelerate tibial fracture-healing. Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Statins are the accepted standard for lowering low‐density lipoprotein cholesterol (LDL‐C). However, 5% to 10% of statin‐treated patients report intolerance, mostly due to muscle‐related adverse effects. Challenges exist to objective identification of statin‐intolerant patients. Evolocumab is a monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in marked LDL‐C reduction. We report the design of Goal Achievement After Utilizing an Anti‐PCSK9 Antibody in Statin‐Intolerant Subjects 3 (GAUSS‐3), a phase 3, multicenter, randomized, double‐blind, ezetimibe‐controlled study to compare effectiveness of 24 weeks of evolocumab 420 mg monthly vs ezetimibe 10 mg daily in hypercholesterolemic patients unable to tolerate an effective statin dose. The study incorporates a novel atorvastatin‐controlled, double‐blind, crossover phase to objectively identify statin intolerance. Eligible patients had LDL‐C above the National Cholesterol Education Project Adult Treatment Panel III target level for the appropriate coronary heart disease risk category and were unable to tolerate ≥3 statins or 2 statins (one of which was atorvastatin ≤10 mg/d) or had a history of marked creatine kinase elevation accompanied by muscle symptoms while on 1 statin. This trial has 2 co‐primary endpoints: mean percent change from baseline in LDL‐C at weeks 22 and 24 and percent change from baseline in LDL‐C at week 24. Key secondary efficacy endpoints include change from baseline in LDL‐C, percent of patients attaining LDL‐C <70 mg/dL (1.81 mmol/L), and percent change from baseline in total cholesterol, non–high‐density lipoprotein cholesterol, and apolipoprotein B. Recruitment of 511 patients was completed on November 28, 2014.