Calcium is an essential element in the diet, but there is continuing controversy regarding its optimal intake, and its role in the pathogenesis of osteoporosis. Most studies show little evidence of a relationship between calcium intake and bone density, or the rate of bone loss. Re-analysis of data from the placebo group from the Auckland Calcium Study demonstrates no relationship between dietary calcium intake and rate of bone loss over 5 years in healthy older women with intakes varying from <400 to >1500 mg day À1 . Thus, supplements are not needed within this range of intakes to compensate for a demonstrable dietary deficiency, but might be acting as weak anti-resorptive agents via effects on parathyroid hormone and calcitonin. Consistent with this, supplements do acutely reduce bone resorption and produce small short-term effects on bone density, without evidence of a cumulative density benefit. As a result, anti-fracture efficacy remains unproven, with no evidence to support hip fracture prevention (other than in a cohort with severe vitamin D deficiency) and total fracture numbers are reduced by 0-10%, depending on which meta-analysis is considered. Five recent large studies have failed to demonstrate fracture prevention in their primary analyses. This must be balanced against an increase in gastrointestinal side effects (including a doubling of hospital admissions for these problems), a 17% increase in renal calculi and a 20-40% increase in risk of myocardial infarction. Each of these adverse events alone neutralizes any possible benefit in fracture prevention. Thus, calcium supplements appear to have a negative risk-benefit effect, and so should not be used routinely in the prevention or treatment of osteoporosis.
Some evidence suggests that Ca and vitamin D supplements affect cancer risk; however, it is uncertain whether the effects are due to Ca, vitamin D or the combination. We investigated the effect of Ca supplements without co-administered vitamin D on cancer risk. Medline, Embase and the Cochrane Central Register of Controlled Trials, reference lists of meta-analyses and two clinical trial registries were searched for randomised, placebo-controlled trials of Ca supplements ($ 500 mg/d), with $ 100 participants and duration .1 year. The lead authors of eligible trials supplied data on cancer outcomes. Trial-level data were analysed using random-effects meta-analyses and patient-level data using Cox proportional hazards models. A total of sixteen trials were eligible, six had no data available, ten provided trial-level data (n 10 496, mean duration 3·9 years), and of these, four provided patient-level data (n 7221, median duration 3·5 years). In the meta-analysis of trial-level data, allocation to Ca did not alter the risk of total cancer (relative risk 0·95, 95 % CI 0·76, 1·18, P¼ 0·63), colorectal cancer (relative risk 1·38, 95 % CI 0·89, 2·15, P¼ 0·15), breast cancer (relative risk 1·01, 95 % CI 0·64, 1·59, P¼0·97) or cancer-related mortality (relative risk 0·96, 95 % CI 0·74, 1·24, P¼ 0·75), but reduced the risk of prostate cancer (relative risk 0·54, 95 % CI 0·30, 0·96, P¼ 0·03), although there were few events. The meta-analysis of patient-level data showed similar results, with no effect of Ca on the risk of total cancer (hazard ratio 1·07, 95 % CI 0·89, 1·28, P¼ 0·50). Ca supplements without co-administered vitamin D did not alter total cancer risk over 4 years, although the meta-analysis lacked power to detect very small effects, or those with a longer latency.Key words: Calcium supplements: Cancer: Meta-analysis: Randomised trials It is possible that Ca intake has an impact on cancer risk, with some observational studies suggesting that high intakes of Ca and/or vitamin D are associated with a reduced risk of colorectal (1 -3) and breast cancer (4,5) , and an increased risk of prostate cancer (6 -8) ; however, these results are not consistent (9 -14) . To date, few randomised, placebo-controlled trials of Ca supplements with or without vitamin D have reported cancer outcomes. In a 4-year fracture prevention trial, Lappe et al. (15) reported that Ca monotherapy decreased total cancer risk by 47 % (P¼ 0·06), and Ca with vitamin D by 60 % (P¼ 0·01).In contrast, three randomised, placebo-controlled trials (16 -19) of Ca with or without vitamin D have found no evidence of an effect on cancer risk. We found no effect of Ca monotherapy on total cancer incidence in a 5-year trial in postmenopausal women (19) . The Randomised Evaluation of Calcium Or Vitamin D (RECORD) investigators found no effect of Ca with or without vitamin D on cancer mortality or incidence in older people treated for a median of 45 months (16) . The Women's Health Initiative (WHI) investigators reported no effect of Ca plus vitamin...
Ca supplements are used for bone health; however, they have been associated with increased cardiovascular risk, which may relate to their acute effects on serum Ca concentrations. Microcrystalline hydroxyapatite (MCH) could affect serum Ca concentrations less than conventional Ca supplements, but its effects on bone turnover are unclear. In the present study, we compared the acute and 3-month effects of MCH with conventional Ca supplements on concentrations of serum Ca, phosphate, parathyroid hormone and bone turnover markers. We randomised 100 women (mean age 71 years) to 1 g/d of Ca as citrate or carbonate (citrate -carbonate), one of two MCH preparations, or a placebo. Blood was sampled for 8 h after the first dose, and after 3 months of daily supplementation. To determine whether the acute effects changed over time, eight participants assigned to the citrate dose repeated 8 h of blood sampling at 3 months. There were no differences between the citrate and carbonate groups, or between the two MCH groups, so their results were pooled. The citrate -carbonate dose increased ionised and total Ca concentrations for up to 8 h, and this was not diminished after 3 months. MCH increased ionised Ca concentrations less than the citrate -carbonate dose; however, it raised the concentrations of phosphate and the Ca -phosphate product. The citrate -carbonate and MCH doses produced comparable decreases in bone resorption (measured as serum C-telopeptide (CTX)) over 8 h and bone turnover (CTX and procollagen type-I N-terminal propeptide) at 3 months. These findings suggest that Ca preparations, in general, produce repeated sustained increases in serum Ca concentrations after ingestion of each dose and that Ca supplements with smaller effects on serum Ca concentrations may have equivalent efficacy in suppressing bone turnover.
There is longstanding concern that calcium supplements might increase cardiovascular risk in patients with renal impairment. The Auckland Calcium Study suggested that the same problem occurs in older people taking these supplements for prevention of osteoporosis. Our subsequent meta-analyses, (which followed protocols finalized before the data was available) confirmed that calcium supplements, with or without vitamin D, adversely affected risk of myocardial infarction and, possibly, stroke. Several groups have re-visited these data, consistently finding an adverse effect of calcium on myocardial infarction, not always statistically significant because some meta-analyses have been under-powered. Whether or not an adverse effect of calcium plus vitamin D on myocardial infarction is found depends on whether two specific groups of subjects are included-those in the Women's Health Initiative who were already taking calcium at the time of randomization, and subjects from an open, cluster-randomized study in which baseline cardiovascular risk was different between groups. Vitamin D alone does not affect vascular risk, so it is unlikely that differences between calcium alone and calcium plus vitamin D are real, and they are more likely to result from the inclusion of studies at high risk of bias. The mechanisms of the adverse cardiovascular effects are uncertain but may be mediated by the increase in serum calcium following supplement ingestion, and the effects of this on vascular function and coagulation. Available evidence suggests the risks of calcium supplements outweigh any small benefits on fracture incidence, so the case for their use is weak.
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