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Oregon City, OR, United States

McClung M.R.,Oregon Osteoporosis Center

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. Source

McClung M.R.,Oregon Osteoporosis Center
Endocrinology and Metabolism

Although several effective therapies are available for the treatment of osteoporosis in postmenopausal women and older men, there remains a need for the development of even more effective and acceptable drugs. Several new drugs that are in late-stage clinical development will be discussed. Abaloparatide (recombinant parathyroid hormone related peptide [PTHrP] analogue) has anabolic activity like teriparatide. Recent data from the phase 3 fracture prevention trial demonstrate that this agent is effective in reducing fracture risk. Inhibiting cathepsin K reduces bone resorption without decreasing the numbers or activity of osteoclasts, thereby preserving or promoting osteoblast function. Progressive increases in bone mineral density (BMD) have been observed over 5 years. Early data suggest that odanacatib effectively reduces fracture risk. Lastly, inhibiting sclerostin with humanized antibodies promotes rapid, substantial but transient increases in bone formation while inhibiting bone resorption. Marked increases in BMD have been observed in phase 2 studies. Fracture prevention studies are underway. The new therapies with novel and unique mechanisms of action may, alone or in combination, provide more effective treatment options for our patients. © 2015 Korean Endocrine Society. Source

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

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. Source

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

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. Source

McClung M.R.,Oregon Osteoporosis Center | Balske A.,Abbott Laboratories | Burgio D.E.,Procter and Gamble | Wenderoth D.,Warner Chilcott | Recker R.R.,Creighton University
Osteoporosis International

Bone mineral density response to once weekly delayed-release formulation of risedronate, given before or following breakfast, was non-inferior to that seen with traditional immediate-release risedronate given daily before breakfast. Delayed-release risedronate is a convenient dosing regimen for oral bisphosphonate therapy that might avoid poor compliance. Introduction: This 2-year, randomized, controlled, non-inferiority study assessed the efficacy and safety of a delayed-release (DR) 35-mg weekly oral formulation of risedronate that allows subjects to take their weekly risedronate dose before or immediately after breakfast. Results from the first year of the study were published previously (McClung et al. Osteoporos Int 23(1):267-276, 2012); we now report the final results after 2 years. Methods: Women with postmenopausal osteoporosis were randomly assigned to receive risedronate 5 mg immediate-release (IR) daily (n = 307) at least 30 min before breakfast, or risedronate 35 mg DR weekly, either immediately following breakfast (FB, n = 307) or at least 30 min before breakfast (BB, n = 308). Bone mineral density (BMD), bone turnover markers (BTMs), fractures, adverse events, and bone histomorphometry were evaluated. Results: A total of 248 subjects (80.8 %) in the IR daily group, 234 subjects (76.2 %) in the DR FB weekly group, and 240 subjects (77.9 %) in the DR BB weekly group completed the 2-year study. After 2 years of treatment, BMD increases at the lumbar spine and total hip with the weekly DR doses similar to or greater than that with the IR daily dose. Decreases in BTMs were similar or significantly lower in the DR groups. Bone histomorphometry results did not differ among the DR weekly and the IR daily formulations. The three regimens were similarly well tolerated. Conclusions: Risedronate 35 mg DR weekly is as effective and as well tolerated as risedronate 5 mg IR daily, and will allow subjects to take their weekly risedronate dose immediately after breakfast. © 2012 The Author(s). Source

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