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      Combination therapy of anabolic agents and bisphosphonates on bone mineral density in patients with osteoporosis: a meta-analysis of randomised controlled trials

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          Abstract

          Objective

          We aimed to determine whether the concomitant combination therapy of anabolic agents and bisphosphonates produces more effects on bone mineral density (BMD) than anabolic agents alone in patients with osteoporosis.

          Methods

          We searched MEDLINE, EMBASE and the Cochrane Library for publications from 1 January 1980 to 1 August 2016 to identify all the randomised controlled trials (RCTs) and quasi-RCTs. The primary outcome was the mean per cent changes in BMD at the lumbar spine, the total hip and the femoral neck with an optimal period of treatment (6 to 12 months). The secondary outcome was the mean per cent changes in BMD at the same sites with the full period of recommendation (18 to 24 months). A random-effects model was used to estimate the standardised mean differences (SMDs) and the 95% CIs.

          Results

          Seven studies, with 747 patients, were included. With the optimal period, the concomitant combination therapy demonstrated a significant advantage over a monotherapy in BMD improvement at the total hip (SMD 0.42; 95% CI 0.26 to 0.58) and the femoral neck (SMD 0.30; 95% CI 0.14 to 0.46), but not for the spine BMD (SMD 0.13; 95% CI −0.17 to 0.43). With the full period, the concomitant combination therapy did not improve the BMD at the lumbar spine (SMD −0.06; 95% CI −0.71 to 0.59), the total hip (SMD 0.05; 95% CI −0.71 to 0.82) and the femoral neck (SMD −0.32; 95% CI −1.15 to 0.50).

          Conclusions

          Compared with anabolic monotherapy, the concomitant combination therapy of anabolic agents and bisphosphonates significantly improved the BMD at the total hip and femoral neck with a shorter term (6 to 12 months) and produced similar benefits on BMD for the longer term (18 to 24 months). Also, the effect of concomitant combination therapy might be affected by the dose of anabolic agents.

          PROSPERO registration number

          CRD42016041335.

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          Most cited references31

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          Osteoporosis prevention, diagnosis, and therapy.

          (2001)
          To clarify the factors associated with prevention, diagnosis, and treatment of osteoporosis, and to present the most recent information available in these areas. From March 27-29, 2000, a nonfederal, nonadvocate, 13-member panel was convened, representing the fields of internal medicine, family and community medicine, endocrinology, epidemiology, orthopedic surgery, gerontology, rheumatology, obstetrics and gynecology, preventive medicine, and cell biology. Thirty-two experts from these fields presented data to the panel and an audience of 699. Primary sponsors were the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institutes of Health Office of Medical Applications of Research. MEDLINE was searched for January 1995 through December 1999, and a bibliography of 2449 references provided to the panel. Experts prepared abstracts for presentations with relevant literature citations. Scientific evidence was given precedence over anecdotal experience. The panel, answering predefined questions, developed conclusions based on evidence presented in open forum and the literature. The panel composed a draft statement, which was read and circulated to the experts and the audience for public discussion. The panel resolved conflicts and released a revised statement at the end of the conference. The draft statement was posted on the Web on March 30, 2000, and updated with the panel's final revisions within a few weeks. Though prevalent in white postmenopausal women, osteoporosis occurs in all populations and at all ages and has significant physical, psychosocial, and financial consequences. Risks for osteoporosis (reflected by low bone mineral density [BMD]) and for fracture overlap but are not identical. More attention should be paid to skeletal health in persons with conditions associated with secondary osteoporosis. Clinical risk factors have an important but poorly validated role in determining who should have BMD measurement, in assessing fracture risk, and in determining who should be treated. Adequate calcium and vitamin D intake is crucial to develop optimal peak bone mass and to preserve bone mass throughout life. Supplementation with these 2 nutrients may be necessary in persons not achieving recommended dietary intake. Gonadal steroids are important determinants of peak and lifetime bone mass in men, women, and children. Regular exercise, especially resistance and high-impact activities, contributes to development of high peak bone mass and may reduce risk of falls in older persons. Assessment of bone mass, identification of fracture risk, and determination of who should be treated are the optimal goals when evaluating patients for osteoporosis. Fracture prevention is the primary treatment goal for patients with osteoporosis. Several treatments have been shown to reduce the risk of osteoporotic fractures, including those that enhance bone mass and reduce the risk or consequences of falls. Adults with vertebral, rib, hip, or distal forearm fractures should be evaluated for osteoporosis and given appropriate therapy.
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            The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis.

            Parathyroid hormone increases bone strength primarily by stimulating bone formation, whereas antiresorptive drugs reduce bone resorption. We conducted a randomized, double-blind clinical study of parathyroid hormone and alendronate to test the hypothesis that the concurrent administration of the two agents would increase bone density more than the use of either one alone. A total of 238 postmenopausal women (who were not using bisphosphonates) with low bone mineral density at the hip or spine (a T score of less than -2.5, or a T score of less than -2.0 with an additional risk factor for osteoporosis) were randomly assigned to daily treatment with parathyroid hormone (1-84) (100 microg; 119 women), alendronate (10 mg; 60 women), or both (59 women) and were followed for 12 months. Bone mineral density at the spine and hip was assessed by dual-energy x-ray absorptiometry and quantitative computed tomography. Markers of bone turnover were measured in fasting blood samples. The bone mineral density at the spine increased in all the treatment groups, and there was no significant difference in the increase between the parathyroid hormone group and the combination-therapy group. The volumetric density of the trabecular bone at the spine increased substantially in all groups, but the increase in the parathyroid hormone group was about twice that found in either of the other groups. Bone formation increased markedly in the parathyroid hormone group but not in the combination-therapy group. Bone resorption decreased in the combination-therapy group and the alendronate group. There was no evidence of synergy between parathyroid hormone and alendronate. Changes in the volumetric density of trabecular bone, the cortical volume at the hip, and levels of markers of bone turnover suggest that the concurrent use of alendronate may reduce the anabolic effects of parathyroid hormone. Longer-term studies of fractures are needed to determine whether and how antiresorptive drugs can be optimally used in conjunction with parathyroid hormone therapy. Copyright 2003 Massachusetts Medical Society
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              The effects of parathyroid hormone, alendronate, or both in men with osteoporosis.

              Because parathyroid hormone increases both bone formation and bone resorption, it is possible that combining parathyroid hormone with an antiresorptive agent will enhance its effect on bone mineral density. We randomly assigned 83 men who were 46 to 85 years of age and had low bone density to receive alendronate (10 mg daily; 28 men), parathyroid hormone (40 microg subcutaneously daily; 27 men), or both (28 men). Alendronate therapy was given for 30 months; parathyroid hormone therapy was begun at month 6. The bone mineral density of the lumbar spine, proximal femur, radial shaft, and total body was measured every six months with the use of dual-energy x-ray absorptiometry. Trabecular bone mineral density of the lumbar spine was measured at base line and month 30 by means of quantitative computed tomography. Serum alkaline phosphatase levels were measured every six months. The primary end point was the rate of change in the bone mineral density at the posteroanterior spine. The bone mineral density at the lumbar spine increased significantly more in men treated with parathyroid hormone alone than in those in the other groups (P<0.001 for both comparisons). The bone mineral density at the femoral neck increased significantly more in the parathyroid hormone group than in the alendronate group (P<0.001) or the combination-therapy group (P=0.01). The bone mineral density of the lumbar spine increased significantly more in the combination-therapy group than in the alendronate group (P<0.001). At 12 months, changes in the serum alkaline phosphatase level were significantly greater in the parathyroid hormone group than in the alendronate group or the combination-therapy group (P<0.001 for both comparisons). Alendronate impairs the ability of parathyroid hormone to increase the bone mineral density at the lumbar spine and the femoral neck in men. This effect may be attributable to an attenuation of parathyroid hormone-induced stimulation of bone formation by alendronate. Copyright 2003 Massachusetts Medical Society
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                Author and article information

                Journal
                BMJ Open
                BMJ Open
                bmjopen
                bmjopen
                BMJ Open
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                2044-6055
                2018
                1 March 2018
                : 8
                : 3
                : e015187
                Affiliations
                [1 ] departmentDepartment of Orthopedics , General Hospital of Chinese PLA , Beijing, China
                [2 ] departmentDepartment of Spine Surgery , First Affiliated Hospital of Harbin Medical University , Harbin, China
                Author notes
                [Correspondence to ] Dr Peifu Tang; pftang301@ 123456163.com
                Author information
                http://orcid.org/0000-0001-8826-3160
                http://orcid.org/0000-0003-4279-1704
                Article
                bmjopen-2016-015187
                10.1136/bmjopen-2016-015187
                5855398
                29500198
                7b2179df-8697-4bc2-9d93-eff5fbbf4613
                © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

                History
                : 16 November 2016
                : 02 January 2018
                : 29 January 2018
                Categories
                Diabetes and Endocrinology
                Research
                1506
                1843
                Custom metadata
                unlocked

                Medicine
                osteoporosis,combination therapy,bisphosphonates,teriparatide,parathyroid hormone
                Medicine
                osteoporosis, combination therapy, bisphosphonates, teriparatide, parathyroid hormone

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