Bone mineral density changes following discontinuation of ronacaleret treatment: off-treatment extension of a randomized, dose-finding phase II trial.

CONTEXT: Parathyroidectomy in patients with hyperparathyroidism can produce subsequent increases in bone mineral density (BMD). Ronacaleret, a selective calcium-sensing receptor antagonist that stimulates endogenous parathyroid hormone release, induced mild hyperparathyroidism. OBJECTIVE: The aim of this study is to evaluate whether BMD changes after cessation of ronacaleret treatment. DESIGN: Observational, off-treatment, extension of a randomized, placebo-controlled, dose-ranging phase II trial. SETTING: Fifteen academic centers in seven countries. PATIENTS: Postmenopausal women with low BMD; 171 out of 569 women in the parent study were enrolled in the extension study. INTERVENTIONS: Subjects were treated with ronacaleret 100mg (n=16), 200mg (n=38), 300mg (n=35), or 400mg (n=32) once daily, alendronate 70mg (n=17) once weekly, or matching placebo (n=33) for 10-12months; BMD was measured after discontinuation of ronacaleret or alendronate treatment. MAIN OUTCOME MEASURE: Mean percent change in lumbar spine areal BMD by dual-energy X-ray absorptiometry at 6-12months after discontinuing ronacaleret or alendronate compared with the 10- to 12-month BMD measurement of the parent study. RESULTS: At the lumbar spine, all doses of ronacaleret resulted in gains in BMD while on treatment. These increases in BMD were maintained or increased after discontinuation of ronacaleret. All doses of ronacaleret caused bone loss at the total hip while on active treatment. However, there was an attenuation of this loss in the off-treatment extension study. CONCLUSION: The gain in BMD at the lumbar spine was maintained post-treatment and the loss of BMD at the total hip was attenuated. We hypothesize that there may have been some bone remineralization after cessation of ronacaleret.

Ronacaleret, a calcium-sensing receptor antagonist, increases trabecular but not cortical bone in postmenopausal women.

Intermittent injections of parathyroid hormone have osteoanabolic effects that increase bone mineral density (BMD). Ronacaleret is an orally administered calcium-sensing receptor antagonist that stimulates endogenous parathyroid hormone release from the parathyroid glands. Our objective was to compare the effects of ronacaleret and teriparatide on volumetric BMD (vBMD) measured by quantitative computed tomography (QCT). We conducted a randomized, placebo-controlled, dose-ranging trial at 45 academic centers with 31 sites participating in the substudy. Patients included 569 postmenopausal women with low bone mineral density; vBMD was assessed at the spine and hip in a subset of 314 women. Patients were treated for up to 12 months with open-label teriparatide 20 µg subcutaneously once daily or randomly assigned in a double-blind manner to ronacaleret 100 mg, 200 mg, 300 mg, or 400 mg once daily, alendronate 70 mg once weekly, or matching placebos. Ronacaleret increased spine integral (0.49% to 3.9%) and trabecular (1.8% to 13.3%) vBMD compared with baseline, although the increments were at least twofold lower than that attained with teriparatide (14.8% and 24.4%, respectively) but similar or superior to that attained with alendronate (5.0% and 4.9%, respectively). There were small non-dose-dependent decreases in integral vBMD of the proximal femur with ronacaleret (-0.1 to -0.8%) compared with increases in the teriparatide (3.9%) and alendronate (2.7%) arms. Parathyroid hormone (PTH) elevations with ronacaleret were prolonged relative to that seen historically with teriparatide. Ronacaleret preferentially increased vBMD of trabecular bone that is counterbalanced by small decreases in BMD at cortical sites. The relative preservation of trabecular bone and loss at cortical sites are consistent with the induction of mild hyperparathyroidism with ronacaleret therapy.

Ronacaleret, a calcium-sensing receptor antagonist, has no significant effect on radial fracture healing time: results of a randomized, double-blinded, placebo-controlled Phase II clinical trial.

BACKGROUND: Fractures cause significant morbidity, mortality, and use of health care resources. An oral agent that enhances fracture healing could reduce costs and prevent future disabilities. In Phase I studies, ronacaleret, a novel calcium-sensing receptor antagonist, stimulated parathyroid hormone (PTH) release and increased bone formation markers, suggesting that it may act as an effective oral anabolic agent to enhance fracture healing. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, clinical trial in 85 male and female subjects who had sustained a closed, unilateral, extra-articular fracture of the distal radius and were receiving conservative treatment. Subjects were randomly assigned in a double-blind manner to ronacaleret 200 mg twice daily, ronacaleret 400 mg once daily or matching placebo and followed for 12 weeks. Fracture healing was assessed by radiographs and quantitative computed tomography (CT), and bone turnover markers were measured. The study was terminated early for futility based on the results of an unplanned interim analysis. RESULTS: There were no significant differences between treatment groups in time to radiographic fracture healing (74, 65 and 68 days for placebo, 200 mg twice daily and 400 mg once daily dose groups, respectively), cortical bridging, grip strength, pain and swelling, time to cast removal, or range of motion. Markers of bone formation and levels of whole PTH, intact PTH and serum calcium increased following treatment with ronacaleret. CONCLUSION: Ronacaleret had no significant effect on duration of healing by radiograph or CT scan, time to cast removal, clinical symptoms, grip strength, or range of motion.

The effects of ronacaleret, a calcium-sensing receptor antagonist, on bone mineral density and biochemical markers of bone turnover in postmenopausal women with low bone mineral density.

CONTEXT: Ronacaleret, a calcium-sensing receptor antagonist that stimulates PTH release from the parathyroid glands, was evaluated as an oral osteoanabolic agent for the treatment of osteoporosis. OBJECTIVE: Our objective was to compare the effects of ronacaleret, teriparatide, and alendronate on bone mineral density (BMD) and markers of bone turnover. DESIGN AND SETTING: In this randomized, placebo-controlled, dose-ranging trial, spine and hip BMD were assessed by dual-energy x-ray absorptiometry and bone turnover markers were measured. PATIENTS: Patients included 569 postmenopausal women with low BMD. INTERVENTIONS: Subjects were offered open-label 20 µg teriparatide sc once daily or were randomized to 100, 200, 300, or 400 mg oral ronacaleret once daily, 70 mg alendronate once weekly, or placebo and were followed for up to 12 months. MAIN OUTCOME MEASURE: Percentage change from baseline in lumbar spine BMD was assessed at month 12. RESULTS: With ronacaleret, the increases in lumbar spine BMD at 12 months (0.3-1.6%) were significantly lower than those attained with teriparatide (9.1%) or alendronate (4.5%). There were small decreases in total hip, femoral neck, and trochanter BMD at month 12 with ronacaleret compared with increases in the teriparatide and alendronate arms. Bone turnover markers increased in the ronacaleret and teriparatide arms and decreased in the alendronate arm. PTH elevations with ronacaleret were prolonged relative to those previously reported with teriparatide. CONCLUSION: The densitometric findings in the context of prolonged PTH elevation and increased bone turnover suggest ronacaleret induces mild hyperparathyroidism. Ronacaleret only modestly increased lumbar spine BMD and decreased BMD at hip sites.