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Detroit, MI, United States

Eisman J.A.,University of New South Wales | Bone H.G.,Michigan Bone and Mineral Clinic | Hosking D.J.,Nottingham City Hospital | McClung M.R.,Oregon Osteoporosis Center | And 10 more authors.
Journal of Bone and Mineral Research | Year: 2011

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 50mg weekly. After 2 years, patients (n=189) were rerandomized to ODN 50mg 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 50mg 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. Source

Fitzpatrick L.A.,Glaxosmithkline | Dabrowski C.E.,Glaxosmithkline | Cicconetti G.,Glaxosmithkline | Gordon D.N.,Glaxosmithkline | And 3 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

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 alendrona tearms. Bone turn over 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. Copyright © 2011 by The Endocrine Society. Source

Bone H.G.,Michigan Bone and Mineral Clinic | Bolognese M.A.,Bethesda Health Research Center | Yuen C.K.,University of Manitoba | Kendler D.L.,Clinical Research Center | And 5 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: Denosumab treatment for 24 months increased bone mineral density (BMD) and reduced bone turnover markers (BTM) in postmenopausal women. Objective: The aim was to determine the effects of prior denosumab or placebo injections on BMD, BTM, and safety over 24 months after treatment discontinuation. Design: We conducted an off-treatment extension of a phase 3, randomized, double-blind, parallel- group study. Participants: A total of 256 postmenopausal women with a mean age of 59 yr and a mean lumbar spine T-score of ≤1.61 at randomization participated in the study. Interventions: Participants received placebo or 60 mg denosumab every 6 months for 24 months, followed by 24 months off treatment. Main Outcome Measures: We measured the percentage changes in BMD and BTM, and evaluated safety. Results: Of the 256 participants enrolled in the posttreatment phase, 87% completed the study. During 24 months of denosumab treatment, BMD increased (lumbar spine, 6.4%; total hip, 3.6%; 1/3 radius, 1.4%), and BTM decreased (serum C-terminal telopeptide of type 1 collagen, 63%; and N-terminal propeptide of type 1 procollagen, 47%),comparedwith placebo. After discontinuation, BMD declined, but the previously treated denosumab group maintained higher BMD than the previously treated placebo group at these sites (P= 0.05). Final BMD at month 48 strongly correlated with month 0 BMD. After denosumab discontinuation, BTM increased above baseline within 3 months (serum C-terminal telopeptide of type 1 collagen) or 6 months (N-terminal propeptide of type 1 procollagen) and returned to baseline by month 48. Adverse event rates during the off-treatment phase were similar between groups. Conclusions: In postmenopausalwomenwith lowBMD,the effects of 60mgdenosumabtreatment for 24 months on BMD and BTM are reversible upon discontinuation, reflecting its biological mechanism of action. Residual BMD measurements remained above those of the group previously treated with placebo. Copyright © 2011 by The Endocrine Society. Source

Bone H.G.,Michigan Bone and Mineral Clinic | McClung M.R.,Oregon Osteoporosis Center | Roux C.,University of Paris Descartes | Recker R.R.,Creighton University | And 6 more authors.
Journal of Bone and Mineral Research | Year: 2010

Cathepsin K, a cysteine protease expressed in osteoclasts, degrades type 1 collagen. Odanacatib selectively and reversibly inhibited cathepsin K and rapidly decreased bone resorption in preclinical and phase I studies. A 1-year dose-finding trial with a 1-year extension on the same treatment assignment was performed in postmenopausal women with low bone mineral density (BMD) to evaluate the safety and efficacy of weekly doses of placebo or 3, 10, 25, or 50mg of odanacatib on BMD and biomarkers of skeletal remodeling. Women with BMD T-scores of -2.0 or less but not less than -3.5 at the lumbar spine or femoral sites were randomly assigned to receive placebo or one of four doses of odanacatib; all received vitamin D with calcium supplementation as needed. The primary endpoint was percentage change from baseline lumbar spine BMD. Other endpoints included percentage change in BMD at hip and forearm sites, as well as changes in biomarkers of skeletal remodeling. Twenty-four months of treatment produced progressive dose-related increases in BMD. With the 50-mg dose of odanacatib, lumbar spine and total-hip BMD increased 5.5% and 3.2%, respectively, whereas BMD at these sites was essentially unchanged with placebo (-0.2% and -0.9%). Biochemical markers of bone turnover exhibited dose-related changes. The safety and tolerability of odanacatib generally were similar to those of placebo, with no dose-related trends in any adverse experiences. In summary, 2 years of weekly odanacatib treatment was generally well-tolerated and increased lumbar spine and total-hip BMD in a dose-related manner in postmenopausal women with low BMD. © 2010 American Society for Bone and Mineral Research. Source

Block G.A.,Clinical Research Division | Bone H.G.,Michigan Bone and Mineral Clinic | Fang L.,Amgen Inc. | Fang L.,Genentech | And 2 more authors.
Journal of Bone and Mineral Research | Year: 2012

This 16-week study evaluated pharmacokinetics and pharmacodynamics of denosumab in 55 subjects with renal function ranging from normal to dialysis-dependent kidney failure. Participants received a single 60-mg subcutaneous dose of denosumab. Kidney function groups were based on calculations using the Cockcroft-Gault equation and U.S. Food and Drug Administration (FDA) guidance in place when the study was designed. Renal function did not have a significant effect on denosumab pharmacokinetics or pharmacodynamics. These findings suggest denosumab dose adjustment based on glomerular filtration rate is not required. Rapid decreases in serum C-telopeptide in all groups were sustained throughout the study. The most common adverse events were hypocalcemia (15%), pain in extremity (15%), and nausea (11%). Most adverse events were mild to moderate in severity. Calcium and vitamin D supplementation was not initially required by the study protocol, but was added during the trial. No subject who received adequate calcium and vitamin D supplementation became hypocalcemic. Seven subjects had nadir serum calcium concentrations between 7.5 and <8.0 mg/dL (1.9 and <2.0 mmol/L), and 5 subjects (4 with advanced renal disease) had nadir serum calcium <7.5 mg/dL (<1.9 mmol/L). Two subjects (1 symptomatic, 1 asymptomatic) were hospitalized for intravenous calcium gluconate treatment. At the recommended dose, denosumab is a useful therapeutic option for patients with impaired renal function. Supplementation of calcium and vitamin D is strongly recommended when patients initiate denosumab therapy, particularly in patients with reduced renal function. © 2012 American Society for Bone and Mineral Research. Source

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