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      Calcium and vitamin D supplementation with 3-year denosumab treatment is beneficial to enhance bone mineral density in postmenopausal patients with osteoporosis and rheumatoid arthritis

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          Abstract

          Background

          This 3-year retrospective study compared the outcomes of bisphosphonate-pretreated denosumab therapy with or without vitamin D and calcium supplementation in postmenopausal osteoporosis (OP) patients with rheumatoid arthritis (RA).

          Materials and methods

          Fifty-eight patients under long-term denosumab treatment were divided into groups without (denosumab group; 31 cases) or with (combination group; 27 cases) vitamin D and calcium supplementation. The bone markers of BAP, TRACP-5b, and urinary NTX were measured at baseline and every year for 3 years. We also evaluated bone mineral density (BMD) of the lumbar 1–4 vertebrae (L-BMD) and bilateral total hips (H-BMD) at the same time points.

          Results

          There were no significant differences in the percent changes of serum albumin-corrected calcium between the groups. The percent change in TRACP-5b was significantly higher in the combination group at 2 years. Serum 25-hydroxyvitamin D status was persistently high during therapy in both groups, with significant percent increases over baseline at 2 and 6 months in both groups and at 24 months in the combination group. The percent increase from baseline of serum zinc was significantly higher at 3 years in the combination group over the denosumab group. L-BMD and H-BMD were significantly increased at every time point for 3 years vs pretreatment levels in both groups and were significantly higher in the combination group at all time points.

          Conclusion

          Compared with denosumab monotherapy, the combination group displayed significantly increased serum zinc, L-BMD, and H-BMD at 3 years in OP patients with RA. Thus, calcium and vitamin D supplementation may be beneficial to enhance BMD gains, but not necessarily 25-hydroxyvitamin D status, in patients with OP and RA under denosumab.

          Most cited references29

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          Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit.

          Coupling between bone formation and bone resorption refers to the process within basic multicellular units in which resorption by osteoclasts is met by the generation of osteoblasts from precursors, and their bone-forming activity, which needs to be sufficient to replace the bone lost. There are many sources of activities that contribute to coupling at remodeling sites, including growth factors released from the matrix, soluble and membrane products of osteoclasts and their precursors, signals from osteocytes and from immune cells and signaling taking place within the osteoblast lineage. Coupling is therefore a process that involves the interaction of a wide range of cell types and control mechanisms. As bone remodeling occurs at many sites asynchronously throughout the skeleton, locally generated activities comprise very important control mechanisms. In this review, we explore the potential roles of a number of these factors, including sphingosine-1-phosphate, semaphorins, ephrins, interleukin-6 (IL-6) family cytokines and marrow-derived factors. Their interactions achieve the essential tight control of coupling within individual remodeling units that is required for control of skeletal mass.
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            The role of vitamin D in the endocrinology controlling calcium homeostasis.

            Vitamin D and its' metabolites are a crucial part of the endocrine system that controls whole body calcium homeostasis. The goal of this hormonal control is to regulate serum calcium levels so that they are maintained within a very narrow range. To achieve this goal, regulatory events occur in coordination at multiple tissues, e.g. the intestine, kidney, bone, and parathyroid gland. Production of the vitamin D endocrine hormone, 1,25 dihydroxyvitamin D (1,25(OH)2 D) is regulated by habitual dietary calcium intake and physiologic states like growth, aging, and the menopause. The molecular actions of 1,25(OH)2 D on calcium regulating target tissues are mediated predominantly by transcription controlled by the vitamin D receptor. A primary role for 1,25(OH)2 D during growth is to increase intestinal calcium absorption so that sufficient calcium is available for bone mineralization. However, vitamin D also has specific actions on kidney and bone.
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              Crucial Role of Vitamin D in the Musculoskeletal System

              Vitamin D is well known to exert multiple functions in bone biology, autoimmune diseases, cell growth, inflammation or neuromuscular and other immune functions. It is a fat-soluble vitamin present in many foods. It can be endogenously produced by ultraviolet rays from sunlight when the skin is exposed to initiate vitamin D synthesis. However, since vitamin D is biologically inert when obtained from sun exposure or diet, it must first be activated in human beings before functioning. The kidney and the liver play here a crucial role by hydroxylation of vitamin D to 25-hydroxyvitamin D in the liver and to 1,25-dihydroxyvitamin D in the kidney. In the past decades, it has been proven that vitamin D deficiency is involved in many diseases. Due to vitamin D’s central role in the musculoskeletal system and consequently the strong negative impact on bone health in cases of vitamin D deficiency, our aim was to underline its importance in bone physiology by summarizing recent findings on the correlation of vitamin D status and rickets, osteomalacia, osteopenia, primary and secondary osteoporosis as well as sarcopenia and musculoskeletal pain. While these diseases all positively correlate with a vitamin D deficiency, there is a great controversy regarding the appropriate vitamin D supplementation as both positive and negative effects on bone mineral density, musculoskeletal pain and incidence of falls are reported.
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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
                2019
                18 December 2018
                : 15
                : 15-22
                Affiliations
                [1 ]Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Japan, yxn14@ 123456aol.jp
                [2 ]Department of Orthopaedic Surgery, Showa Inan General Hospital, Komagane, Japan, yxn14@ 123456aol.jp
                Author notes
                Correspondence: Yukio Nakamura, Department of Orthopaedic Surgery, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto 390-8621, Japan, Tel +81 263 37 2659, Fax +81 263 35 8844, Email yxn14@ 123456aol.jp
                Article
                tcrm-15-015
                10.2147/TCRM.S182858
                6302805
                30588001
                efe77452-153a-4aea-bc1d-6b33e3312263
                © 2019 Suzuki et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Original Research

                Medicine
                25(oh)d,bone mineral density,bone-related minerals,denosumab,osteoporosis,rheumatoid arthritis

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