Michigan Bone and Mineral Clinic

Detroit, MI, United States

Michigan Bone and Mineral Clinic

Detroit, MI, United States
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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.


Binkley N.,University of Wisconsin - Madison | Bone H.,Michigan Bone and Mineral Clinic | Gilligan J.P.,Tarsa Therapeutics | Krause D.S.,Tarsa Therapeutics
Osteoporosis International | Year: 2014

Summary: The effect of an investigational oral calcitonin tablet upon bone mineral density (BMD) of the spine was investigated in postmenopausal women with low bone mass and at increased risk of fracture. Compared to placebo, calcitonin tablets increased lumbar spine BMD. This agent may provide an additional choice for patients.Introduction: An investigational oral salmon calcitonin preparation was previously shown to increase lumbar spine BMD in postmenopausal women with osteoporosis. Our objective was to evaluate the use of this agent in postmenopausal women with low bone mass and at increased fracture risk but not meeting BMD criteria for osteoporosis.Methods: Treatment-naïve women were randomized to receive oral recombinant salmon calcitonin tablets or placebo once daily for 1 year. Dual-energy X-ray absorptiometry was performed at baseline and at study weeks 28 and 54. CTx-1, a bone resorption marker, was obtained at the same time points. Subjects returned periodically for tolerability assessment and adverse event (AE) recording.Results: One hundred twenty-nine women in the USA were randomized, 86 to calcitonin and 43 to placebo. Calcitonin recipients experienced a significant increase from baseline in lumbar spine BMD; the difference compared with placebo was significant. Dosing at bedtime or with dinner was equally effective. CTx-1 was suppressed in calcitonin recipients but not in placebo subjects. Gastrointestinal AEs were common, but the overall safety profile was comparable between groups.Conclusions: Oral calcitonin may provide a useful therapeutic alternative for some women with low bone mass. © 2014, The Author(s).


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.


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.


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.


Langdahl B.,Aarhus University Hospital | Binkley N.,University of Wisconsin - Madison | Bone H.,Michigan Bone and Mineral Clinic | Gilchrist N.,Princess Margaret Hospital | And 8 more authors.
Journal of Bone and Mineral Research | Year: 2012

Odanacatib (ODN) is a selective inhibitor of the collagenase cathepsin K that is highly expressed by osteoclasts. In this 2-year, phase 2, dose-ranging trial, postmenopausal women with bone mineral density (BMD) T-scores -2.0 to -3.5 at spine or hip were randomized to weekly placebo or ODN 3, 10, 25, or 50 mg plus vitamin D3 and calcium. Prespecified trial-extensions continued through 5 years. In year 3, all women were re-randomized to ODN 50 mg or placebo. For years 4 and 5, women who received placebo or ODN 3 mg in years 1 and 2 and placebo in year 3 received ODN 50 mg; others continued year 3 treatments. Endpoints included lumbar spine (primary), hip, 1/3 radius, and total body BMD; markers of bone metabolism; and safety. Women in the year 4 to 5 extension receiving placebo (n = 41) or ODN 50 mg (n = 100) had similar baseline characteristics. For women who received ODN (10-50 mg) for 5 years, spine and hip BMD increased over time. With ODN 50 mg continually for 5 years (n = 13), mean lumbar spine BMD percent change from baseline (95% confidence interval [CI]) was 11.9% (7.2% to 16.5%) versus -0.4% (-3.1% to 2.3%) for women who were switched from ODN 50 mg to placebo after 2 years (n = 14). In pooled results of women receiving continuous ODN (10-50 mg, n = 26-29), year 5 geometric mean percent changes from baseline in bone resorption markers cross-linked N-telopeptide of type I collagen (NTX)/creatinine and cross-linked C-telopeptide (CTX) were approximately -55%, but near baseline for bone formation markers bone-specific alkaline phosphatase (BSAP) and amino-terminal propeptide of type I procollagen (P1NP). In women switched from ODN 10 to 50 mg to placebo after 2 years (n = 25), bone turnover markers were near baseline. In summary, women receiving combinations of ODN (10-50 mg) for 5 years had gains in spine and hip BMD and showed larger reductions in bone resorption than bone formation markers. Discontinuation of ODN resulted in reversal of treatment effects. Treatment with ODN for up to 5 years was generally well-tolerated. © 2012 American Society for Bone and Mineral Research.


McClung M.R.,Oregon Osteoporosis Center | Grauer A.,Amgen Inc. | Boonen S.,Catholic University of Leuven | Bolognese M.A.,Bethesda Health Research Center | And 11 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND Sclerostin is an osteocyte-derived inhibitor of osteoblast activity. The monoclonal antibody romosozumab binds to sclerostin and increases bone formation. METHODS: In a phase 2, multicenter, international, randomized, placebo-controlled, parallelgroup, eight-group study, we evaluated the efficacy and safety of romosozumab over a 12-month period in 419 postmenopausal women, 55 to 85 years of age, who had low bone mineral density (a T score of -2.0 or less at the lumbar spine, total hip, or femoral neck and -3.5 or more at each of the three sites). Participants were randomly assigned to receive subcutaneous romosozumab monthly (at a dose of 70 mg, 140 mg, or 210 mg) or every 3 months (140 mg or 210 mg), subcutaneous placebo, or an open-label active comparator - oral alendronate (70 mg weekly) or subcutaneous teriparatide (20 ìg daily). The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Secondary end points included percentage changes in bone mineral density at other sites and in markers of bone turnover. RESULTS: All dose levels of romosozumab were associated with significant increases in bone mineral density at the lumbar spine, including an increase of 11.3% with the 210-mg monthly dose, as compared with a decrease of 0.1% with placebo and increases of 4.1% with alendronate and 7.1% with teriparatide. Romosozumab was also associated with large increases in bone mineral density at the total hip and femoral neck, as well as transitory increases in bone-formation markers and sustained decreases in a bone-resorption marker. Except for mild, generally nonrecurring injection-site reactions with romosozumab, adverse events were similar among groups. CONCLUSIONS: In postmenopausal women with low bone mass, romosozumab was associated with increased bone mineral density and bone formation and with decreased bone resorption. © 2014 Massachusetts Medical Society.


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.


Bone H.G.,Michigan Bone and Mineral Clinic | Lindsay R.,Helen Hayes Hospital | McClung M.R.,Oregon Osteoporosis Center | Perez A.T.,Takeda Global Research and Development Center Inc | And 2 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: Meta-analyses of clinical studies have suggested an increased incidence of peripheral fractures in postmenopausal women with type 2 diabetes mellitus taking pioglitazone. The mechanism behind this apparent increase is unknown. Objective: The objective of the study was to examine the effects of pioglitazone on bone mineral density (BMD) and turnover. Design and Setting: Twenty-five sites (in the United States) enrolled participants in this randomized, double-blind, placebo-controlled study. Participants: Postmenopausal women (n=156) with impaired fasting glucose or impaired glucose tolerance participated in the study. Interventions: The intervention consisted of pioglitazone 30 mg/d (n = 78) or placebo (n = 78), increased to 45 mg/d after 1 month, for 12 months of treatment total, followed by 6 months of washout/follow-up. Main Outcome Measures: Percentage changes from baseline to month 12 and from month 12 to month18 in BMD in total proximal femur (primary end point), total body, femoral neck, lumbar spine, and radius were measured. Results: Least squares mean changes from baseline to month 12 in total proximal femurBMDwere -0.69% for pioglitazone and -0.14% for placebo (P = .170). No statistically significant betweengroup differences were observed for anyBMDor bone remodeling marker end point.Weobserved improved glycemic control and insulin sensitivity with pioglitazone treatment. In addition, pioglitazone appeared to increase body fat, which may affect bone density measurements, especially in the lumbar spine. One pioglitazone-treated and three placebo-treated women experienced confirmed fractures. Over 18 months, one pioglitazone-treated (1.3%) and eight placebo-treated women (10.3%) developed overt type 2 diabetes mellitus. The pattern and incidence of adverse events with pioglitazone were consistent with clinical experience with thiazolidinediones. Conclusions: Maximal-dose pioglitazonehadnoeffectsonBMDorboneturnover, while improving glycemic control as expected, in postmenopausal women with impaired fasting glucose or impaired glucose tolerance. (J Clin Endocrinol Metab 98: 4691-4701, 2013) © 2013 by The Endocrine Society.


Kendler D.L.,Clinical Research Center | Roux C.,University of Paris Descartes | Benhamou C.L.,French Institute of Health and Medical Research | Brown J.P.,Laval University | And 5 more authors.
Journal of Bone and Mineral Research | Year: 2010

Patients treated with bisphosphonates for osteoporosis may discontinue or require a switch to other therapies. Denosumab binds to RANKL and is a potent inhibitor of bone resorption that has been shown to increase bone mineral density (BMD) and decrease fracture risk in postmenopausal women with osteoporosis. This was a multicenter, international, randomized, double-blind, double-dummy study in 504 postmenopausal women≥55 years of age with a BMD T-score of -2.0 or less and -4.0 or more who had been receiving alendronate therapy for at least 6 months. Subjects received open-label branded alendronate 70mg once weekly for 1 month and then were randomly assigned to either continued weekly alendronate therapy or subcutaneous denosumab 60mg every 6 months and were followed for 12 months. Changes in BMD and biochemical markers of bone turnover were evaluated. In subjects transitioning to denosumab, total hip BMD increased by 1.90% at month 12 compared with a 1.05% increase in subjects continuing on alendronate (p<.0001). Significantly greater BMD gains with denosumab compared with alendronate also were achieved at 12 months at the lumbar spine, femoral neck, and 1/3 radius (all p<.0125). Median serum CTX levels remained near baseline in the alendronate group and were significantly decreased versus alendronate (p<.0001) at all time points with denosumab. Adverse events and serious adverse events were balanced between groups. No clinical hypocalcemic adverse events were reported. Transition to denosumab produced greater increases in BMD at all measured skeletal sites and a greater reduction in bone turnover than did continued alendronate with a similar safety profile in both groups. © 2010 American Society for Bone and Mineral Research.

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