Advocacy for the use of calcium supplements arose at a time when there were no other effective interventions for the prevention of osteoporosis. Their promotion was based on the belief that increasing calcium intake would increase bone formation. Our current understandings of the biology of bone suggest that this does not occur, though calcium does act as a weak antiresorptive. Thus, it slows postmenopausal bone loss but, despite this, recent meta-analyses suggest no significant prevention of fractures. In sum, there is little substantive evidence of benefit to bone health from the use of calcium supplements. Against this needs to be balanced the likelihood that calcium supplement use increases cardiovascular events, kidney stones, gastrointestinal symptoms, and admissions to hospital with acute gastrointestinal problems. Thus, the balance of risk and benefit seems to be consistently negative. As a result, current recommendations are to obtain calcium from the diet in preference to supplements. Dietary calcium intake has not been associated with the adverse effects associated with supplements, probably because calcium is provided in smaller boluses, which are absorbed more slowly since they come together with quantities of protein and fat, resulting in a slower gastric transit time. These findings suggest that calcium supplements have little role to play in the modern therapeutics of osteoporosis, which is based around the targeting of safe and effective anti-resorptive drugs to individuals demonstrated to be at increased risk of future fractures.
For many decades there has been advocacy for the use of calcium supplements in the prevention and treatment of osteoporosis. In the 1960s and 1970s, this was in the context of having no proven medications for osteoporosis management, a situation which has now changed dramatically. The rationale for advocating calcium is that it is one of the principal constituents of bone, though it should always be remembered that bone is a connective tissue, so its fundamental framework is a protein matrix (type I collagen) which is laid down by osteoblasts (bone forming cells) and remodelled and removed by osteoclasts (bone resorbing cells). In adult life, this cell-mediated process of bone remodelling takes place at intervals across the skeletal surface, and involves the removal and replacement of small packets of bone. Once osteoblasts have laid down new type 1 collagen, calcium and phosphate crystalize between the collagen fibres, providing bone with its compressive strength. Thus, bone balance, or the change in bone density over time, is driven by the balance of activities of bone forming cells and bone resorbing cells. Providing excess calcium and phosphate will not lead to the creation of more bone, since the amount of bone laid down is determined by the number and activity of osteoblasts. While an adequate supply of calcium and phosphate is important to ensure that bone laid down by osteoblasts is normally mineralised, an oversupply is unlikely to be helpful.
It is often assumed that higher calcium intakes result in greater bone density and fewer fractures. However, there are very few data to support this belief, and it is notable that calcium intake does not figure in any of the fracture risk calculators (e.g. fracture risk assessment tool [FRAX], Garvan) currently used. Thus, cross-sectional studies that relate customary calcium intake to bone density show no relationship between these variables (in the National Health and Nutrition Examination Survey [NHANES] the
Many clinical trials have now been carried out to determine whether calcium supplements can improve bone density and reduce fractures. There is consistent evidence that the use of calcium supplements reduces bone turnover by about 20%, and this is associated with a reduction in postmenopausal bone loss.[
A number of observational studies have assessed whether there is a relationship between
The Women's Health Initiative (WHI) investigators also addressed this question in their large trial in which the intervention was calcium plus vitamin D.[
In spite of the consistency of the data presented in
The publication of our meta-analyses has led to a large number of observational analyses assessing the relationship between calcium supplement use and cardiovascular risk. A number of positive and a number of negative analyses have resulted, reflecting the much lower power of observational studies to address such questions, and the problem of residual confounding which always makes interpretation of observational data difficult. It is noteworthy that the studies which have suggested a significant adverse effect of calcium supplements have not been balanced by a similar number of studies suggesting a significant benefit. Thus, on balance, the observational data are generally consistent with the randomised, controlled trial findings.
While there is no randomised, controlled trial of calcium supplements which has cardiovascular events as its endpoint (and neither is there likely to be), there have been several other recent studies which reinforce the suggestion that calcium supplementation may have adverse cardiovascular effects. Calcium supplements have long been used in patients with renal failure for their phosphate binding properties, including in patients not yet requiring dialysis. Jamal et al.[
The immediate biochemical consequence of taking a calcium supplement is an increase in circulating calcium levels, which persists for >8 hours.[
The third recent piece of data relates to the finding that the use of the calcimimetic ion, strontium, is associated with a 60% increase in the risk of myocardial infarction.[
As discussed above, circulating calcium levels in the upper part of the normal range are associated with increased cardiovascular risk.[
The WHI demonstrated a 17% increase in the risk of kidney stones associated with randomisation to calcium plus vitamin D.[
Advocacy for the use of calcium supplements arose at a time when there were no other effective interventions for the prevention of osteoporosis. Their promotion was based on the belief that increasing calcium intake would increase bone formation. Our current understandings of the biology of bone suggest that this is not likely to occur. There is evidence that calcium acts as a weak antiresorptive, through its suppression of parathyroid hormone secretion. This is likely to be the mechanism that contributes to the slowing of postmenopausal bone loss with the use of calcium supplements. Despite this, recent meta-analyses suggest no benefit from the use of calcium supplements in fracture prevention, and in fact there is evidence of adverse effects of calcium supplementation on hip fracture risk. In sum, there is little substantive evidence of benefit to bone health from the use of calcium supplements.
Against this needs to be balanced the likelihood that calcium supplement use increases the risk of cardiovascular events, formation of kidney stones, and gastrointestinal symptoms, including the risk of admission to hospital with acute gastrointestinal problems. Thus, the balance of risk and benefit seems to be consistently negative. As a result, most organisations providing advice regarding optimisation of bone health, recommend that individuals should obtain their calcium requirement from diet in preference to supplements. Dietary calcium intake has not been associated with the adverse effects associated with supplements, probably because calcium is provided in much less concentrated boluses, and these boluses are absorbed more slowly from the gastrointestinal tract since they come together with quantities of protein and fat, resulting in a slower gastric transit time. It is also important to note that we now have much more effective antiresorptive agents than calcium supplements, which prevent fractures and are safe in long-term use. Therefore, osteoporosis prevention should centre on the quantitative assessment of fracture risk, and the targeting of appropriate fracture prevention therapies to those found to be at increased risk. As a result, calcium supplements have little role to play in the context of the modern therapeutics of osteoporosis.
Dr. Reid has received research grants or speaking/consulting fees from Merck, Amgen, Sanofi and Novartis.
Supported by the Health Research Council of New Zealand.
Meta-analysis of the effects of calcium alone or with vitamin D, on hip fracture risk in randomised controlled trials. Studies have been divided according to the residential status of their participants. The classification of the Harwood study is debatable since subjects were in hospital following fractures at trial entry, though most had been community dwelling previously. [Reprinted from "Calcium risk.benefit updated.New WHI analyses", by Reid, IR, Bolland, MJ, 2013, Maturitas, 77(1), pp. 1-3. Copyright 2013 by the Elsevier. Reprinted with permission].
Kaplan.Meier survival curves for time to incident myocardial infarction or stroke by treatment allocation in a meta-analysis of patient-level data from five trials of calcium supplements used as monotherapy (n=8,151) and in women in the Women's Health Initiative (WHI) calcium and vitamin D trial not using personal calcium supplements at randomization (n=16,718). The magnitude and time-course of the effects of calcium supplements on the two classes of vascular events were very similar in these independent databases. CI, confidence interval; HR, hazard ratio. [Reprinted from "Subgroup analysis for the risk of cardiovascular disease with calcium supplements", by Radford LT, Bolland MJ, Gamble GD, Grey A, Reid IR, 2013, Bonekey Rep, 77(1), pp. 1-3. Copyright 2013 by the Nature Publishing Group. Reprinted with permission].
The association of serum calcium, phosphate, and calcium.phosphate product (CPP) with the presence of coronary artery disease, divided into calcified or mixed plaque, and non-calcified plaque. Plaque was measured by cardiac computed tomography in 7553 Korean adults. [Reprinted from "Impact of serum calcium and phosphate on coronary atherosclerosis detected by cardiac computed tomography", by Shin S, Kim KJ, Chang HJ, Cho I, Kim YJ, Choi BW, Rhee Y, Lim SK, Yang WI, Shim CY, Ha JW, Jang Y, Chung N, 2012, Eur Heart J, 33(22), pp.2873-81. Copyright 2012 by the Oxford University Press. Reprinted with permission].