Oregon Osteoporosis Center

Oregon City, OR, United States

Oregon Osteoporosis Center

Oregon City, OR, United States
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McClung M.R.,Oregon Osteoporosis Center
Bone | Year: 2017

Based on a platform of strong preclinical data, several studies in humans have demonstrated that inhibiting sclerostin with specific antibodies results in a brisk albeit transient anabolic response in the skeleton without an accompanying increase in bone resorption. Impressive increases in bone mineral density and bone strength have been demonstrated. Other than mild injection site reactions, therapy for up to 2 years has been well tolerated. The restriction of sclerostin expression almost exclusively to skeletal tissues, coupled with the absence of recognized medical problems in patients with heterozygous sclerostin deficiency, provides promise that the drug can be used safely. Recent results from a Phase 3 fracture trial suggest that anti-sclerostin therapy will be a useful and welcomed new treatment for patients with severe osteoporosis in need of skeletal reconstruction. © 2016

McClung M.R.,Australian Catholic University | McClung M.R.,Oregon Osteoporosis Center
Current Osteoporosis Reports | Year: 2017

Purpose of review: The objective of this review is to update evidence regarding the use of osteoporosis drugs in sequence or in combination to optimize increases in bone mass and strength. Recent findings: Simultaneous use of denosumab plus teriparatide produces larger increases in BMD than does monotherapy. The use of bisphosphonates or denosumab after teriparatide results in progressive gains in BMD. When switching from bisphosphonates and especially denosumab to teriparatide, an overlap of 6-12 months may prevent the transient loss of BMD in cortical sites. Phase 3 trials document fracture risk reduction with anabolic therapy for 12-18 months followed by an anti-remodeling drug. Summary: With the exception of adding teriparatide to ongoing denosumab therapy, there is little evidence to support the use of more than one osteoporosis drug at a time. In contrast, sequential therapy regimens of anabolic drugs followed by potent anti-remodeling agents will be the new standard for treating patients at imminent risk of fracture. © 2017 Springer Science+Business Media New York

Keaveny T.M.,University of California at Berkeley | McClung M.R.,Oregon Osteoporosis Center | Wan X.,Eli Lilly and Company | Kopperdahl D.L.,O.N. Diagnostics | And 2 more authors.
Bone | Year: 2012

To gain insight into the clinical effect of teriparatide and alendronate on the hip, we performed non-linear finite element analysis of quantitative computed tomography (QCT) scans from 48 women who had participated in a randomized, double-blind clinical trial comparing the effects of 18-month treatment of teriparatide 20. μg/d or alendronate 10. mg/d. The QCT scans, obtained at baseline, 6, and 18. months, were analyzed for volumetric bone mineral density (BMD) of trabecular bone, the peripheral bone (defined as all the cortical bone plus any endosteal trabecular bone within 3. mm of the periosteal surface), and the integral bone (both trabecular and peripheral), and for overall femoral strength in response to a simulated sideways fall. At 18. months, we found in the women treated with teriparatide that trabecular volumetric BMD increased versus baseline (+. 4.6%, p. <. 0.001), peripheral volumetric BMD decreased (-1.1%, p. <. 0.05), integral volumetric BMD (+. 1.0%, p = 0.38) and femoral strength (+. 5.4%, p = 0.06) did not change significantly, but the ratio of strength to integral volumetric BMD ratio increased (+. 4.0%, p = 0.04). An increase in the ratio of strength to integral volumetric BMD indicates that overall femoral strength, compared to baseline, increased more than did integral density. For the women treated with alendronate, there were small (<. 1.0%) but non-significant changes compared to baseline in all these parameters. The only significant between-treatment difference was in the change in trabecular volumetric BMD (p. <. 0.005); related, we also found that, for a given change in peripheral volumetric BMD, femoral strength increased more for teriparatide than for alendronate (p = 0.02). We conclude that, despite different compartmental volumetric BMD responses for these two treatments, we could not detect any overall difference in change in femoral strength between the two treatments, although femoral strength increased more than integral volumetric BMD after treatment with teriparatide. © 2011 Elsevier Inc.

Zerbini C.A.F.,Hospital Heliopolis | McClung M.R.,Oregon Osteoporosis Center
Therapeutic Advances in Musculoskeletal Disease | Year: 2013

Human bones are in a continuous process of remodeling that ensures renovation and maintenance of the skeletal mass. Bone remodeling has two phases that are normally coupled and balanced: bone resorption mediated by osteoclasts and bone formation mediated by osteoblasts. An increase in bone resorption over bone formation results in a progressive loss of bone mass and impairment of bone microarchitecture leading to osteoporosis and its associated fractures. Recent advances in the understanding of the molecular and cellular mechanisms involved in the remodeling process have allowed the development of new targets for osteoporosis treatment. Cathepsin K, a cysteine protease, is found in osteoclasts along the bone resorption surfaces and very efficiently degrades type I collagen, the major component of the organic bone matrix. Inhibition of cathepsin K reduces bone resorption but does not impair bone formation particularly at cortical sites. Odanacatib, a potent and highly selective cathepsin K inhibitor, showed prevention of bone loss without reduction of bone formation in preclinical and clinical trials (phase I and II). Odanacatib is currently in a phase III fracture outcome international trial for the treatment of postmenopausal osteoporosis. © The Author(s), 2013.

El-Hajj Fuleihan G.,American University of Beirut | Bouillon R.,Catholic University of Leuven | Clarke B.,Mayo Clinic Foundation | Chakhtoura M.,American University of Beirut | And 3 more authors.
Journal of Bone and Mineral Research | Year: 2015

Hypovitaminosis D is prevalent worldwide but proportions vary widely between regions, depending on genetic and lifestyle factors, the threshold to define deficiency, and accuracy of 25-hydroxyvitamin D (25OHD) assays used. Latitude, pollution, concealing clothing, sun exposure, gender, dietary habits, and lack of government regulation account for up to 50% in variations in serum 25OHD levels, whereas genetic polymorphisms in the vitamin D pathway account for less than 5%. Organizations/societies have developed guidelines for recommended desirable 25OHD levels and vitamin D doses to reach them, but their applicability across age groups and populations are still debated. This article and the accompanying online Supporting Information highlight sources of variations in circulating 25OHD levels, uncertainties and knowledge gaps, and analytical problems facing 25OHD assays, while keeping efficacy and safety data as the dominant factors when defining a desirable range for 25OHD levels. We propose a desirable range of 20 to 40ng/mL (50 to 100nmol/L), provided precise and accurate assays are used. Although slightly lower levels, 15 to 20ng/mL, may be sufficient for some infants and adults, higher levels, 40 to 60ng/mL, may still be safe. This desirable range allows physicians to tailor treatment while taking season, lifestyle, vitamin D intake, and other sources of variation into account. We reserve 25OHD measurements for at-risk patients, defined by disease or lifestyle, and the use of 25OHD assays calibrated against the recommended international standards. Most target groups reach desirable target levels by a daily intake of 400 to 600IU for children and 800IU for adults. A total daily allowance of vitamin D of up to 1000IU in the pediatric age groups, and up to 2000IU in adults, tailored to an individual patient risk profile, is probably safe over long durations. Additional data are needed to validate the proposed range and vitamin D doses, especially in children, pregnant women, and non-white populations. © 2015 American Society for Bone and Mineral Research. © 2015 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.

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.

Poole K.E.S.,University of Cambridge | Treece G.M.,University of Cambridge | Gee A.H.,University of Cambridge | Brown J.P.,Laval University | And 3 more authors.
Journal of Bone and Mineral Research | Year: 2015

Women with osteoporosis treated for 36 months with twice-yearly injections of denosumab sustained fewer hip fractures compared with placebo. Treatment might improve femoral bone at locations where fractures typically occur. To test this hypothesis, we used 3D cortical bone mapping of postmenopausal women with osteoporosis to investigate the timing and precise location of denosumab versus placebo effects in the hips. We analyzed clinical computed tomography scans from 80 female participants in FREEDOM, a randomized trial, wherein half of the study participants received subcutaneous denosumab 60mg twice yearly and the others received placebo. Cortical 3D bone thickness maps of both hips were created from scans at baseline, 12, 24, and 36 months. Cortical mass surface density maps were also created for each visit. After registration of each bone to an average femur shape model followed by statistical parametric mapping, we visualized and quantified statistically significant treatment effects. The technique allowed us to pinpoint systematic differences between denosumab and control and to display the results on a 3D average femur model. Denosumab treatment led to an increase in femoral cortical mass surface density and thickness, already evident by the third injection (12 months). Overall, treatment with denosumab increased femoral cortical mass surface density by 5.4% over 3 years. One-third of the increase came from increasing cortical density, and two-thirds from increasing cortical thickness, relative to placebo. After 36 months, cortical mass surface density and thickness had increased by up to 12% at key locations such as the lateral femoral trochanter versus placebo. Most of the femoral cortex displayed a statistically significant relative difference by 36 months. Osteoporotic cortical bone responds rapidly to denosumab therapy, particularly in the hip trochanteric region. This mechanism may be involved in the robust decrease in hip fractures observed in denosumab-treated women at increased risk of fracture. © 2014 American Society for Bone and Mineral Research.

McClung M.R.,Oregon Osteoporosis Center
Climacteric | Year: 2015

Albright was the first of many to show that loss of bone mass due to estrogen deficiency is an important part of the pathogenesis of postmenopausal osteoporosis. This led to the use of estrogen therapy which was shown to prevent bone loss at menopause and to reduce the risk of important fragility fractures. Selective estrogen receptor modulators (SERMs), with salutary estrogen-like skeletal effects and with protection from breast cancer, have important roles in the management of young postmenopausal women. New members of the SERM family may approach the effectiveness of estrogen in preventing bone loss and reducing fracture risk. When combined with estrogen, new SERMs prevent endometrial hyperplasia, and that combination reduces menopausal symptoms and prevents bone loss. Drugs that reduce bone turnover or stimulate bone formation by non-estrogen pathways have also been developed to treat osteoporosis. Emerging therapies, with unique mechanisms of action, may provide improved efficacy in treating women who already have osteoporosis. © 2015 International Menopause Society.

Mcclung M.,Oregon Osteoporosis Center
Clinical Obstetrics and Gynecology | Year: 2013

Bisphosphonates are effective treatments for osteoporosis. The pharmacology and observance of atypical femoral fractures in patients on long-term therapy raise questions about the need for intermittent discontinuation of treatment, a "drug holiday." Fracture protection benefits of bisphosphonate therapy far outweigh the risk of atypical fractures for the first 10 years of therapy. However, because the fracture probability of therapy abates slowly after stopping the treatment while the risk of atypical fracture appears to decrease quickly, a "drug holiday" of 1 to 2 years should be considered after 3 to 5 years of bisphosphonate therapy except in those patients who remain at very high fracture risk. © 2013, Lippincott Williams & Wilkins.

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