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      Treatment options for postmenopausal osteoporosis

      Therapeutics and Clinical Risk Management

      Dove Medical Press

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          Abstract

          To serve our readership better, future editions of Therapeutics and Clinical Risk Management will once again feature the Editor’s comments and views on some of the articles published in that issue of the journal. Bone is a complex tissue that, in addition to protecting vital organs and giving mechanical support for muscles and joints, provides a mineral reservoir essential for calcium homeostasis, together with the microenvironment essential for hematopoiesis. Osteoporosis is the most common metabolic bone disease, with up to a third of postmenopausal women suffering from this increasingly important public health problem. Key characteristics include low bone mineral density with microarchitectural deterioration of bone tissue leading to increased susceptibility to fragility fractures. Bone remodeling is vital for a healthy skeleton through removal of damaged tissue by the reabsorptive action of osteoclasts, with osteoblasts accounting for generation of new bone matrix. In recent years, our knowledge of the molecular pathways involved in bone formation and resorption has greatly improved, and it is now appreciated that the interplay between osteoclasts and osteoblasts is controlled by a complex array of hormones, cytokines, and growth factors. This has led to the development of new drugs to treat osteoporosis and these have been classified according to their mode of action on this remodeling process. For example, antiresorptive drugs include bisphosphonates and raloxifene, while anabolic drugs such as teriparatide or parathyroid hormone enhance remodelling.1 Bone resorption is regulated by a transmembranous and soluble protein highly expressed by osteoclasts known as receptor activator of nuclear factor-κB (RANK), a member of the tumor necrosis factor receptor superfamily essential for osteoclastogenesis. Denosumab is a fully humanized monoclonal antibody specific for RANK-ligand. Binding of the latter by denosumab prevents its interaction with RANK, thereby leading to a reduction in osteoclast activity and consequently bone resorption. The place of denosumab in the treatment of osteoporosis, particularly in the context of postmenopausal women, has been comprehensively reviewed in the current issue of the journal.2 Treatment with denosumab was characterized by rapid, sustained, and reversible reduction in bone turnover markers, a marked increase in bone mineral density at all sites, and a marked decrease in the risk of vertebral, hip, and nonvertebral fractures in women with postmenopausal osteoporosis. The safety and long-term treatment issues associated with denosumab use in osteoporosis was also reviewed by Anastasilakis et al3 in the same issue. These authors point out that although to date the majority of studies report that denosumab has a favorable safety profile in large-scale clinical trials, vigilance is required in relation to long-term adverse effects, particularly those related to oversuppression of bone turnover. Other important areas to be considered in osteoporosis include the effect of treatment on bone quality and patient characteristics, compliance, and potential side effects. Both review articles complement two original papers on postmenopausal osteoporosis and these were from the same group. The first presented an interesting case report of a young woman who was followed up for 5 years after developing vertebral fractures subsequent to pregnancy and lactation. The authors reported that after 5 years of treatment with a daily dose of alfacalcidol 1 μg, bone mineral density at the patient’s lumbar spine (L1, L3, L4) increased by 21.4%, and this was associated with marked reductions in bone turnover markers.4 Quantitative ultrasound is a potentially useful noninvasive method for studying bone density and structure in vivo, and quantitative ultrasound parameters, such as speed of sound, may represent a useful tool for measuring responses to treatment for postmenopausal osteoporosis. The bisphosphonate, alendronate, is widely used as a first-line drug for the treatment of postmenopausal osteoporosis, with established efficacy for vertebral, nonvertebral, hip, and wrist fractures.5 Therefore, it is of interest that the second original research paper on osteoporosis from this group examined 45 postmenopausal women who had received treatment for more than one year with alendronate. The authors found that treatment resulted in significant decreases in bone turnover markers that were associated with a modest but clinically significant increase in speed of sound at the calcaneus in postmenopausal Japanese women with osteoporosis.6 There were limitations to this study which the authors acknowledge, the most important of which is the relatively small sample size and retrospective nature of the study. Therefore, it would be interesting if larger randomized controlled trials were performed to confirm the usefulness or otherwise of speed of sound for measuring responses to treatment for postmenopausal osteoporosis with established and emerging therapies.

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          Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.

          Osteoporosis is an abnormal reduction in bone mass and bone deterioration leading to increased fracture risk. Alendronate belongs to the bisphosphonate class of drugs, which act to inhibit bone resorption by interfering with the activity of osteoclasts. To assess the efficacy of alendronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women. We searched CENTRAL, MEDLINE and EMBASE for relevant randomized controlled trials published between 1966 to 2007. Women receiving at least one year of alendronate, for postmenopausal osteoporosis, were compared to those receiving placebo and/or concurrent calcium/vitamin D. The outcome was fracture incidence. We undertook study selection and data abstraction in duplicate. We performed meta-analysis of fracture outcomes using relative risks and a > 15% relative change was considered clinically important. We assessed study quality through reporting of allocation concealment, blinding and withdrawals. Eleven trials representing 12,068 women were included in the review. Relative (RRR) and absolute (ARR) risk reductions for the 10 mg dose were as follows. For vertebral fractures, a significant 45% RRR was found (RR 0.55, 95% CI 0.45 to 0.67). This was significant for both primary prevention, with 45% RRR (RR 0.55, 95% CI 0.38 to 0.80) and 2% ARR, and secondary prevention with 45% RRR (RR 0.55, 95% CI 0.43 to 0.69) and 6% ARR. For non-vertebral fractures, a significant 16% RRR was found (RR 0.84, 95% CI 0.74 to 0.94). This was significant for secondary prevention, with 23% RRR (RR 0.77, 95% CI 0.64 to 0.92) and 2% ARR, but not for primary prevention (RR 0.89, 95% CI 0.76 to 1.04). There was a significant 40% RRR in hip fractures (RR 0.60, 95% CI 0.40 to 0.92), but only secondary prevention was significant with 53% RRR (RR 0.47, 95% CI 0.26 to 0.85) and 1% ARR. The only significance found for wrist was in secondary prevention, with a 50% RRR (RR 0.50 95% CI 0.34 to 0.73) and 2% ARR. For adverse events, we found no statistically significant differences in any included study. However, observational data raise concerns regarding potential risk for upper gastrointestinal injury and, less commonly, osteonecrosis of the jaw. At 10 mg per day, both clinically important and statistically significant reductions in vertebral, non-vertebral, hip and wrist fractures were observed for secondary prevention ('gold' level evidence, www.cochranemsk.org). We found no statistically significant results for primary prevention, with the exception of vertebral fractures, for which the reduction was clinically important ('gold' level evidence).
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            New understanding and treatments for osteoporosis.

            To summarize promising areas of investigation in osteoporosis and to stimulate further research in this area, as discussed in a recent international conference. Over the recent years, there has been an improvement in the knowledge of molecular pathways involved in bone formation and resorption with the development of new drugs to treat osteoporosis. Intact parathyroid hormone, teriparatide, and anti-sclerostin monoclonal antibody are anabolic drugs, whereas denosumab and odanacatib are anti-resorptive drugs with more reversible effects as compared to bisphosphonates. Anabolic and anti-resorptive agents have different effects on bone, and research in this area includes the efficacy of combination and sequential therapies with them. New insights in the molecular pathways of bone remodeling have clarified the mechanisms responsible for skeletal fragility in several forms of secondary osteoporosis, such as that occurring in type 2 diabetes, following drug exposure and systemic inflammatory diseases. Future research is needed to address the efficacy of anti-osteoporotic drugs in these more recently recognized conditions of skeletal fragility. Osteoporosis continues to be an important field of biomedical research.
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              Long-term treatment of osteoporosis: safety and efficacy appraisal of denosumab

              Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-κB ligand (RANKL), a member of the tumor necrosis factor receptor superfamily essential for osteoclastogenesis. Denosumab treatment is associated with a rapid, sustained, and reversible reduction in bone turnover markers, a continuous marked increase in bone mineral density at all sites, and a marked decrease in the risk of vertebral, hip, and nonvertebral fractures in women with postmenopausal osteoporosis. Therefore, it could be considered as an effective alternative to previous bisphosphonate treatment as well as first-line treatment of severe osteoporosis. Cost-effectiveness studies support this suggestion. In addition, denosumab seems to be the safest treatment option in patients with impaired renal function. Denosumab is characterized by reversibility of its effect after treatment discontinuation, in contrast with bisphosphonates. Large-scale clinical trials, including the extension of FREEDOM trial for up to 5 years, are reassuring for its safety. However, given its brief post-market period, vigilance regarding adverse events related to putative RANKL inhibition in tissues other than bone, as well as those related to bone turnover oversuppression, is advised.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2012
                2012
                28 August 2012
                : 8
                : 367-368
                Affiliations
                Division of Applied Medicine, School of Medicine and Dentistry, Institute of Medical Sciences, University of Aberdeen, United Kingdom
                Author notes
                Correspondence: Garry M Walsh, Division of Applied Medicine, School of Medicine and Dentistry, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom
                Article
                tcrm-8-367
                10.2147/TCRM.S36280
                3431956
                22956875
                © 2012 Walsh, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

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                Medicine

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