Therapeutics Review: In postmenopausal women and older men, vitamin D plus calcium reduces some fractures Avenell A, Mak JC, O’Connell D. Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men. Cochrane Database Syst Rev. 2014;4:CD000227. Clinical impact ratings: F ★★★★★★✩ G ★★★★★★✩ Conclusions In postmenopausal women and older men, vitamin D supple- mentation alone does not reduce risk for fractures. Vitamin D plus calcium reduces hip fractures compared with control or placebo but not compared with calcium alone. Source of funding: Scottish Government Health Directories, UK. For correspondence: A. Avenell, University of Aberdeen, Aberdeen, Scotland, UK. E-mail a.avenell@abdn.ac.uk. ■ Commentary Approximately 9 million osteoporotic fractures occur worldwide each year, and many women take calcium and vitamin D supple- ments (CaD) for prevention. Avenell and colleagues did a systematic review of 91 791 partici- pants from 53 trials. Among postmenopausal women and older adults at risk for osteoporotic fractures, vitamin D alone did not reduce any new fractures compared with no vitamin D. CaD lowered the risk for hip fracture by 16% compared with no supplementation, but CaD was no more effective than calcium supplementation alone for preventing fractures. Neither vitamin D alone nor CaD reduced mortality. Vitamin D supplementation, with or without calcium, increased the frequency of mild hyper- calcemia. CaD also increased risk for gastrointestinal symptoms and renal disease. Overall, the beneficial effect of CaD seems to originate from calcium rather than vitamin D. Vitamin D may have a differential effect on fractures in persons who have osteoporosis. The review included trials with postmenopausal women or older men regardless of whether they had osteoporosis. The results and clinical implications could have been different if the study populations were stratified by presence or absence of osteoporosis. Chung and colleagues found that CaD reduced risk for fracture in older adults, but the beneficial effect was primarily in institutionalized older adults and not in community- dwelling individuals (1); this finding led to the US Preventive Services Task Force recommendation against low-dose CaD in community-dwelling postmenopausal women (2). Many bisphosphonate trials co-administered CaD. There are concerns about bisphosphonates unmasking subclinical vitamin D deficiency and leading to hypocalcemia (3). Cli- nicians should therefore continue to prescribe bisphospho- nates with concurrent CaD until future trials show nonin- feriority of bisphosphonates plus calcium alone compared with bisphosphonates plus CaD. KoKo Aung, MD, MPH University of Texas Health Science Center San Antonio, Texas, USA Reference 1. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Ann Intern Med. 2011;155:827-38. 2. Moyer VA; U.S. Preventive Services Task Force. Ann Intern Med. 2013;158:691-6. 3. Mouyis M,Ostor A,Crisp A, et al. Rheumatology 2008;47:1348-51. Vitamin D (Vit D), alone or with calcium (Ca), vs control, placebo, or calcium alone in postmenopausal women or older men* Outcomes Number of Weighted event rates At 12 wk to 7 y trials (n) Vit D Control or RRI (95% CI) NNH alone placebo Hip fracture 11 (27 693) 2.9% 2.6% 12% (−2 to 29) NS New vertebral fracture 6 (11 396) 1.45% 1.41% 3% (−24 to 39) NS Vit D + Ca Ca alone RRR (CI) NNT Hip fracture 7 (7411) 2.1% 2.5% 16% (−13 to 37) NS New vertebral fracture† 2 (2681) 0.03% 0.22% 86% (−177 to 99) NS Vit D + Ca Control or RRR (CI) NNT (CI) placebo Hip fracture 9 (49 853) 1.5% 1.8% 16% (4 to 26) 341 (210 to 1364) New vertebral fracture 4 (42 185) 0.9% 1.0% 11% (−9 to 26) NS *NS = not significant; other abbreviations defined in Glossary. RRI, RRR, NNT, and CI calculated from control event rates and risk ratios in article using a fixed-effect model. Vitamin D–related com- pounds were vitamin D 2 , vitamin D 3 , or 25-hydroxyvitamin D. †Trials included only patients with previous osteoporotic fracture. 16 September 2014 | ACP Journal Club | Volume 161 • Number 6 JC5 © 2014 American College of Physicians Question In postmenopausal women and older men, does vitamin D sup- plementation, with or without calcium, prevent fractures? Review scope Included studies compared vitamin D (D 2 , D 3 , or 25-hydroxyvit- amin D), alone or combined with calcium, with placebo, no inter- vention (control), or calcium alone in postmenopausal women or older men (mean or median population age > 65 y) and could include patients with impaired mobility due to neurologic disease. Exclusion criteria included use of corticosteroids, eldecalcitol, or vitamin D treatment based on renal failure. Outcomes included hip fracture, any new vertebral fracture, and adverse events. Review methods Cochrane Bone, Joint, and Muscle Trauma Group Specialized Register, Cochrane Central Register of Controlled Trials, and CINAHL (all to Dec 2012); MEDLINE and EMBASE/Excerpta Medica (both to Nov 2012); BIOSIS (to Jan 2013); abstracts in Journal of Bone and Mineral Research, Bone, Calcified Tissue International, and Osteoporosis International (all to Dec 2012); and reference lists were searched for randomized controlled trials (RCTs) and quasi-RCTs. 53 trials (n = 91 791) met selection criteria; 50 were RCTs, and 3 were quasi-RCTs. Risk for bias for randomization was low for 21 trials, unclear for 28, and high for 4. Risk for bias for allocation concealment was low for 22 trials, unclear for 28, and high for 2. Thirteen trials did not report blinding; 32 blinded participants, and 30 blinded providers. Main results The Main results are in the Table. Vitamin D, alone or with calcium, increased risk for gastrointestinal effects (relative risk increase [RRI] 4%, 95% CI 0 to 8) and renal calculi or insufficiency (RRI 16%, CI 2 to 33) compared with control, placebo, or calcium alone. DownloadedFrom:http://annals.org/byaUniversityofCaliforniaSanDiegoUseron12/25/2016