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  1. Tan VP, Macdonald HM, Kim S, Nettlefold L, Gabel L, Ashe MC, et al.
    J. Bone Miner. Res., 2014 Oct;29(10):2161-81.
    PMID: 24737388 DOI: 10.1002/jbmr.2254
    A preponderance of evidence from systematic reviews supports the effectiveness of weight-bearing exercises on bone mass accrual, especially during the growing years. However, only one systematic review (limited to randomized controlled trials) examined the role of physical activity (PA) on bone strength. Thus, our systematic review extended the scope of the previous review by including all PA intervention and observational studies, including organized sports participation studies, with child or adolescent bone strength as the main outcome. We also sought to discern the skeletal elements (eg, mass, structure, density) that accompanied significant bone strength changes. Our electronic-database, forward, and reference searches yielded 14 intervention and 23 observational studies that met our inclusion criteria. We used the Effective Public Health Practice Project (EPHPP) tool to assess the quality of studies. Due to heterogeneity across studies, we adopted a narrative synthesis for our analysis and found that bone strength adaptations to PA were related to maturity level, sex, and study quality. Three (of five) weight-bearing PA intervention studies with a strong rating reported significantly greater gains in bone strength for the intervention group (3% to 4%) compared with only three significant (of nine) moderate intervention studies. Changes in bone structure (eg, bone cross-sectional area, cortical thickness, alone or in combination) rather than bone mass most often accompanied significant bone strength outcomes. Prepuberty and peripuberty may be the most opportune time for boys and girls to enhance bone strength through PA, although this finding is tempered by the few available studies in more mature groups. Despite the central role that muscle plays in bones' response to loading, few studies discerned the specific contribution of muscle function (or surrogates) to bone strength. Although not the focus of the current review, this seems an important consideration for future studies.
  2. Lau EM, Suriwongpaisal P, Lee JK, Das De S, Festin MR, Saw SM, et al.
    J. Bone Miner. Res., 2001 Mar;16(3):572-80.
    PMID: 11277276 DOI: 10.1359/jbmr.2001.16.3.572
    The objectives of the Asian Osteoporosis Study (AOS) were to determine risk factors for hip fracture in men and women in four Asian countries, that is, Singapore, Malaysia, Thailand, and the Philippines. A total of 451 men and 725 women (aged 50 years and over) with hip fractures were compared with an equal number of community controls. A standardized questionnaire was administered by interview. The following relative risks (RRs) were found in women and men by multiple logistic regression: dietary calcium intake < 498 mg/day, 2.0 for women (95% CI, 1.5-2.8) and 1.5 for men (95% CI, 1.0-2.2); no load bearing activity in the immediate past, 2.0 for women (95% CI, 1.4-2.7) and 3.4 for men (95% CI, 2.3-5.1); no vigorous sport activities in young adulthood, 7.2 for women (95% CI, 4.0-13.0) and 2.4 for men (95% CI, 1.6-3.6); cigarette smoking, 1.5 for men (95% CI, 1.0-2.1); alcohol consumption 7 days a week, 2.9 for women (95% CI, 1.0-8.6) and 1.9 for men (95% CI, 1.1-3.2); fell twice or more in the last 12 months, 3.0 for women (95% CI, 1.8-4.8) and 3.4 for men (95% CI, 1.8-6.6); a history of fractures after 50 years of age, 1.8 for women (95% CI, 1.1-2.9) and 3.0 for men (95% CI, 1.6-5.6); a history of stroke, 3.8 for women (95% CI, 2.0-7.1) and 3.6 for men (95% CI, 1.8-7.1); use of sedatives, 2.5 for women (95% CI, 1.0-6.3) and 3.0 for men (95% CI, 1.0-9.7); and use of thyroid drugs, 7.1 for women (95% CI, 2.0-25.9) and 11.8 for men (95% CI, 1.3-106.0). Women who were 1.56 m or taller had an RR of 2.0 (95% CI, 1.3-3.0) for hip fracture and men who were 1.69 m or taller had an RR of 1.9 (95% CI, 1.2-3.1) for hip fracture. Based on these findings, primary preventive programs for hip fracture could be planned in Asia.
  3. Roberts MS, Gafni RI, Brillante B, Guthrie LC, Streit J, Gash D, et al.
    J. Bone Miner. Res., 2019 09;34(9):1609-1618.
    PMID: 31063613 DOI: 10.1002/jbmr.3747
    Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism caused by heterozygous, gain-of-function mutations of the calcium-sensing receptor gene (CAR). Individuals are hypocalcemic with inappropriately low parathyroid hormone (PTH) secretion and relative hypercalciuria. Calcilytics are negative allosteric modulators of the extracellular calcium receptor (CaR) and therefore may have therapeutic benefits in ADH1. Five adults with ADH1 due to four distinct CAR mutations received escalating doses of the calcilytic compound NPSP795 (SHP635) on 3 consecutive days. Pharmacokinetics, pharmacodynamics, efficacy, and safety were assessed. Parallel in vitro testing with subject CaR mutations assessed the effects of NPSP795 on cytoplasmic calcium concentrations (Ca2+i ), and ERK and p38MAPK phosphorylation. These effects were correlated with clinical responses to administration of NPSP795. NPSP795 increased plasma PTH levels in a concentration-dependent manner up to 129% above baseline (p = 0.013) at the highest exposure levels. Fractional excretion of calcium (FECa) trended down but not significantly so. Blood ionized calcium levels remained stable during NPSP795 infusion despite fasting, no calcitriol supplementation, and little calcium supplementation. NPSP795 was generally safe and well-tolerated. There was significant variability in response clinically across genotypes. In vitro, all mutant CaRs were half-maximally activated (EC50 ) at lower concentrations of extracellular calcium (Ca2+o ) compared to wild-type (WT) CaR; NPSP795 exposure increased the EC50 for all CaR activity readouts. However, the in vitro responses to NPSP795 did not correlate with any clinical parameters. NPSP795 increased plasma PTH levels in subjects with ADH1 in a dose-dependent manner, and thus, serves as proof-of-concept that calcilytics could be an effective treatment for ADH1. Albeit all mutations appear to be activating at the CaR, in vitro observations were not predictive of the in vivo phenotype or the response to calcilytics, suggesting that other parameters impact the response to the drug. © 2019 American Society for Bone and Mineral Research.
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