Review: Calcium supplementation and risk for fracture in persons >50 years of age
Question Does increased dietary calcium or calcium supplementation (CaS) affect risk for fracture in participants >50 years of age? Review scope Included studies assessed dietary sources of calcium (milk, dairy products, dietary calcium intake from food, or hydroxyapatite) or CaS, alone or combined with other treatment (e.g. vitamin D) as long as the other treatment was given to both groups, in participants >50 years of age. Exclusion criteria were major systemic pathology (e.g. renal failure or caancer) Primary outcome was fractures. Review methods MEDLINE and EMBASE/Excerpta Medica (both to Sept 2014) and reference lists were searched for randomized controlled trials (RCTs) and cohort, casecontrol, or cross sectional studies. 2 RCTs (n =293) assessed dietary calcium and were not combined for analysis. 26 RCTs (n =69107, mean age 52 to 86 y, 0 to 100% women, follow up 1 to 7 y) assessed CaS as monotherapy (14 RCTs) calcium plus vitamin D (8 RCTs) or had multiple groups (4 RCTs) In 20 of these RCTs, calcium dose was 1000 mg/d. Risk for bias was low for 3 RCTs, moderate for 9 RCTs, and high for 13 RCTs; it was high for hip fracture but low for other outcomes for 1 RCT. Results of meta analyses for CaS are reported in this abstract. Main results Meta analysis of trials with low risk for bias showed that CaS did not differ from control for total fractures (Table) When all studies were combined, CaS reduced fracture risk (Table) Conclusion Meta analysis of trials with low risk for bias showed that in participants >50 years of age, calcium supplementation does not reduce risk for total fractures. Calcium supplementation vs control for participants >50 years of age* Outcome Risk for bias Number of trials (n) Weighted event rates At 1 to 7 y Calcium Control RRR (95% CI) NNT (CI) Total fracture All 20 (58573) 11% 12% 11% (4 to 19) 77 (45 to 212) Low 4 (44505) 12.2% 12.7% 4% (1 to 9) NS Moderate 8 (11539) 7.2% 8.6% 17% (7 to 27) 69 (43 to 166) High 8 (2529) 8.3% 11% 23% (11 to 47) NS *NS not significant; other abbreviations defined in Glossary. Weighted event rates, RRR, NNT, and CI calculated from control event rates and relative risks in article using a random effects model. Commentary In the Women's Health Initiative (WHI) CaS showed a 15% increased risk for myocardial infarction or stroke compared with placebo (1) similar to that found in a meta analysis of CaS in older persons of both sexes (1) A longitudinal observational study of 388229 men and women 50 to 71 years of age followed for 12 years found that CaS was associated with a 20% increased risk for mortality in men, overwhelmingly due to coronary heart disease (CHD) (relative risk increase 19% (2) CaS was not linked to cardiovascular (CV) mortality in women (2) Increased CV morbidity and mortality raise legitimate concern that the potential harms of CaS outweigh the potential benefits, namely protection against osteoporotic fractures. This challenges current public health recommendations for calcium intake of 1200 mg/d (3) and has led the US Preventive Services Task Force to conclude that the available evidence is insufficient to assess the balance of benefits and harms of vitamin D and CaS in men and postmenopausal women (4) Tai and colleagues showed that dietary or CaS produce a clinically insignificant increase in BMD of 1.8% which plateaus at 2 years. Bolland and colleagues found that dietary or CaS did not reduce any type of osteoporotic fracture based on meta analysis of 4 trials with low risk for bias. These results seem to bolster the argument not to recommend CaS. Risk for osteoporotic fracture increases with age and is influenced by the levels of 25 OH vitamin D (25 OHD) and parathyroid hormone (PTH) BMD, and fall risk. Real life dietary intake of calcium falls below currently recommended levels in many elderly people, with ingested Ca inversely proportionate to age (5) Further, calcium absorption, after adjusting for vitamin D levels, drops significantly in postmenopausal women after 75 years of age (6) PTH is a principal driver of bone resorption. With increasing age, the ability of 25 OHD to suppress PTH declines; after age 60, 30% of persons with a therapeutic 25 OHD of 30 ng/mL have a clinically significantly elevated PTH >65 pg/mL (7) The lower the calcium intake, the higher the level of 25 OHD required to maintain PTH within normal limits (8) Vitamin D supplementation alone, without CaS, seems to be ineffective in lowering risk for osteoporotic fractures (9) A reversal of current guidelines for CaS should be accompanied by research to explore the reasons behind the paradox of beneficial physiologic effects unaccompanied by fracture prevention. Could the formulation of the CaS have influenced outcomes? Large clinical trials, including 3 of the low bias trials cited by Bolland and colleagues used calcium carbonate, which has intestinal absorption about 25% less than that of calcium citrate (110) Are there women who would benefit because of very low total calcium intake or low net absorption? In a subgroup analysis of the WHI study of women ingesting <800 mg/day of calcium, fracture rates were similar between the calcium plus vitamin D and the placebo groups (111) The physiologic benefits of calcium intake in later life seem too small and too late to counteract the cumulative and interacting risk factors for osteoporotic fractures, such as low BMD and fall risk. In the very old, fall prevention may be the single best intervention to prevent osteoporotic fractures. CaS should be based on the individual patient's medical conditions, not merely age and sex.
Annals of Internal Medicine