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      Effects of Long-Term Denosumab on Bone Histomorphometry and Mineralization in Women With Postmenopausal Osteoporosis

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          Abstract

          Context

          Denosumab is a potent antiresorptive agent that reduces fractures in postmenopausal women with osteoporosis.

          Objective

          Determine effects of up to 10 years of denosumab on bone histology, remodeling, and matrix mineralization characteristics.

          Design and Setting

          International, multicenter, randomized, double-blind trial [Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM)] with a long-term open-label extension.

          Patients

          Postmenopausal women with osteoporosis (92 women in FREEDOM, 46 in extension) who provided iliac bone biopsies, including 11 who provided biopsies at multiple time points.

          Interventions

          FREEDOM subjects were randomized 1:1 to subcutaneous denosumab 60 mg or placebo every 6 months for 3 years. Long-term extension subjects continued receiving denosumab, open-label, for 7 additional years.

          Outcomes

          Bone histology, histomorphometry, matrix mineralization.

          Results

          Ten-year denosumab biopsies showed normal histology. Bone histomorphometry indicated normal bone structure and reduced bone remodeling after 10 years of denosumab, similar to levels after 2 and/or 3 and 5 years of denosumab. The degree of mineralization of bone was increased and mineralization heterogeneity was reduced in the denosumab years 2/3 group vs placebo. Changes in these mineralization variables progressed from years 2/3 to year 5 of denosumab, but not thereafter.

          Conclusions

          Denosumab for 2/3, 5, and 10 years was associated with normal histology, low bone remodeling rate, increased matrix mineralization, and lower mineralization heterogeneity compared with placebo. These variables were unchanged from year 5 to year 10. These data, in combination with the maintenance of low fracture rates for up to 10 years as previously reported with denosumab therapy, suggest that strong, prolonged remodeling inhibition does not impair bone strength.

          Abstract

          After up to 10 years of denosumab therapy, iliac bone biopsies from postmenopausal women showed normal histology, reduced bone remodeling, and increased matrix mineralization that plateaued by year 5.

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          Most cited references 39

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          Severely suppressed bone turnover: a potential complication of alendronate therapy.

          Alendronate, an inhibitor of bone resorption, is widely used in osteoporosis treatment. However, concerns have been raised about potential oversuppression of bone turnover during long-term use. We report on nine patients who sustained spontaneous nonspinal fractures while on alendronate therapy, six of whom displayed either delayed or absent fracture healing for 3 months to 2 yr during therapy. Histomorphometric analysis of the cancellous bone showed markedly suppressed bone formation, with reduced or absent osteoblastic surface in most patients. Osteoclastic surface was low or low-normal in eight patients, and eroded surface was decreased in four. Matrix synthesis was markedly diminished, with absence of double-tetracycline label and absent or reduced single-tetracycline label in all patients. The same trend was seen in the intracortical and endocortical surfaces. Our findings raise the possibility that severe suppression of bone turnover may develop during long-term alendronate therapy, resulting in increased susceptibility to, and delayed healing of, nonspinal fractures. Although coadministration of estrogen or glucocorticoids appears to be a predisposing factor, this apparent complication can also occur with monotherapy. Our observations emphasize the need for increased awareness and monitoring for the potential development of excessive suppression of bone turnover during long-term alendronate therapy.
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            Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research.

            Reports linking long-term use of bisphosphonates (BPs) with atypical fractures of the femur led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address key questions related to this problem. A multidisciplinary expert group reviewed pertinent published reports concerning atypical femur fractures, as well as preclinical studies that could provide insight into their pathogenesis. A case definition was developed so that subsequent studies report on the same condition. The task force defined major and minor features of complete and incomplete atypical femoral fractures and recommends that all major features, including their location in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, minimal or no associated trauma, a medial spike when the fracture is complete, and absence of comminution, be present to designate a femoral fracture as atypical. Minor features include their association with cortical thickening, a periosteal reaction of the lateral cortex, prodromal pain, bilaterality, delayed healing, comorbid conditions, and concomitant drug exposures, including BPs, other antiresorptive agents, glucocorticoids, and proton pump inhibitors. Preclinical data evaluating the effects of BPs on collagen cross-linking and maturation, accumulation of microdamage and advanced glycation end products, mineralization, remodeling, vascularity, and angiogenesis lend biologic plausibility to a potential association with long-term BP use. Based on published and unpublished data and the widespread use of BPs, the incidence of atypical femoral fractures associated with BP therapy for osteoporosis appears to be very low, particularly compared with the number of vertebral, hip, and other fractures that are prevented by BPs. Moreover, a causal association between BPs and atypical fractures has not been established. However, recent observations suggest that the risk rises with increasing duration of exposure, and there is concern that lack of awareness and underreporting may mask the true incidence of the problem. Given the relative rarity of atypical femoral fractures, the task force recommends that specific diagnostic and procedural codes be created and that an international registry be established to facilitate studies of the clinical and genetic risk factors and optimal surgical and medical management of these fractures. Physicians and patients should be made aware of the possibility of atypical femoral fractures and of the potential for bilaterality through a change in labeling of BPs. Research directions should include development of animal models, increased surveillance, and additional epidemiologic and clinical data to establish the true incidence of and risk factors for this condition and to inform orthopedic and medical management. © 2010 American Society for Bone and Mineral Research.
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              Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab.

              Bone is a complex tissue that provides mechanical support for muscles and joints, protection for vital organs, a mineral reservoir that is essential for calcium homeostasis, and the environment and niches required for haematopoiesis. The regulation of bone mass in mammals is governed by a complex interplay between bone-forming cells termed osteoblasts and bone-resorbing cells termed osteoclasts, and is guided physiologically by a diverse set of hormones, cytokines and growth factors. The balance between these processes changes over time, causing an elevated risk of fractures with age. Osteoclasts may also be activated in the cancer setting, leading to bone pain, fracture, spinal cord compression and other significant morbidities. This Review chronicles the events that led to an increased understanding of bone resorption, the elucidation of the signalling pathway mediated by osteoprotegerin, receptor activator of NF-κB (RANK) and RANK ligand (RANKL) and its role in osteoclast biology, as well as the evolution of recombinant RANKL antagonists, which culminated in the development of the therapeutic RANKL-targeted antibody denosumab.
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                Author and article information

                Journal
                J Clin Endocrinol Metab
                J. Clin. Endocrinol. Metab
                jcem
                The Journal of Clinical Endocrinology and Metabolism
                Endocrine Society (Washington, DC )
                0021-972X
                1945-7197
                July 2018
                16 April 2018
                16 April 2018
                : 103
                : 7
                : 2498-2509
                Affiliations
                [1 ]Department of Pathology and Cell Biology, Columbia University, New York, New York
                [2 ]Helen Hayes Hospital, West Haverstraw, New York
                [3 ]Division of Rheumatology, Faculty of Medicine, Laval University and CHU de Quebec Research Centre, Quebec City, Quebec, Canada
                [4 ]Department for Endocrinology and Diabetes, Medical University Graz, Graz, Austria
                [5 ]Department of Medicine (Endocrinology), University of British Columbia, Vancouver, British Columbia, Canada
                [6 ]Bone and Chronic Diseases, INSERM, UMR 1033, Univ Lyon, Université Claude Bernard Lyon 1, Lyon, France
                [7 ]Center for Clinical and Basic Research, Tallinn, Estonia
                [8 ]Clinical Development, Amgen Inc., Thousand Oaks, California
                Author notes
                Correspondence and Reprint Requests:  David W. Dempster, BSc (Hons), PhD, FRMS, Regional Bone Center, Helen Hayes Hospital, Route 9W, West Haverstraw, New York 10993. E-mail: ddempster9@ 123456aol.com .
                Article
                jcem_201702669
                10.1210/jc.2017-02669
                6037073
                29672714
                Copyright © 2018 Endocrine Society

                This article has been published under the terms of the Creative Commons Attribution License (CC BY; https://creativecommons.org/licenses/by/4.0/).

                Page count
                Pages: 12
                Product
                Categories
                Clinical Research Articles
                Parathyroid, Bone, and Mineral Metabolism

                Endocrinology & Diabetes

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