By Jeffrey T. Jensen, MD, MPH
Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland
Dr. Jensen is a consultant for and receives grant/research support from HRA Pharma, Bayer Healthcare, Merck, Agile Pharm, Population Council, AbbVie, Evofem, and ContraMed; and is a consultant for Teva Pharmaceuticals and Microchips.
A systematic review of randomized, controlled trials of calcium supplementation found only small non-progressive increases in bone mineral density. This supports the clinical conclusion that supplementation alone is insufficient to prevent fracture risk.
Tai V, et al. Calcium intake and bone mineral density: Systematic review and meta-analysis. BMJ 2015;351;h4183. doi: 10.1136/bmj.h4183.
The authors conducted a systematic review of published randomized trials to evaluate the effects of increasing calcium intake on bone mineral density (BMD). Eligible studies recruited participants > 50 years of age and randomized subjects to receive increased dietary sources of calcium or calcium supplements (with or without vitamin D) or no additional calcium. Most of the studies enrolled only women. Studies could assess the outcome of BMD at the lumbar spine, total hip, femoral neck, total body, or forearm. They identified 15 trials that evaluated dietary sources of calcium (n = 1533 subjects). Of these, 10 used milk or milk powder, two used dairy products, and three used hydroxyapatite preparations. Calcium supplements (typically 1000 mg/day) were evaluated in 51 trials (n = 12,257); 36 studied calcium monotherapy, 13 co-administered calcium and vitamin D, and two compared both approaches. Most of the studies evaluated calcium without vitamin D in women < 70 years of age and had a duration of at least 2 years.
Overall, calcium supplements increased BMD at all five skeletal sites at 1 year (0.7-1.4%) and 2 years (0.8-1.5%). In studies that followed subjects longer, the size of the increase in BMD was similar to the increase at 1 year. Augmenting calcium intake from dietary sources also increased BMD at the total hip and total body at 1 year (0.6-1.0%) as well as the lumbar spine/femoral neck at 2 years (0.7-1.8%), but there was no effect on BMD at the forearm at either time point. Similar increases in BMD were observed in the trials comparing calcium to co-administered calcium and vitamin D, in trials with calcium doses of ≥ 1000 mg/day vs < 1000 mg/day, and in trials where the baseline dietary calcium intake was < 800 mg/day vs ≥ 800 mg/day. The authors concluded that increasing calcium intake from either dietary sources or supplements results in only small and non-progressive increases in BMD that are unlikely to lead to a clinically significant reduction in risk of fracture.
COMMENTARY
In early menopause, rapid bone loss occurs due to the absence of estrogen-regulated modulation of bone remodeling. In addition to direct effects on bone, estrogen also has important effects on vitamin D metabolism and the intestinal absorption and renal excretion of calcium.1 Since serum calcium levels actually decline in postmenopausal women in the setting of this massive turnover of calcium,2 calcium supplementation is a routine recommendation. However, given the poor absorption and rapid excretion of calcium, I have always questioned whether the net effect of ingestion of an oral calcium supplement on calcium balance is similar to the effect of dropping a 10-pound bag of salt in the bay on ocean salinity.
Although this meta-analysis provides no new information, the authors do raise a valid question. Since the overall impact of calcium supplementation on BMD is small and non-progressive, can this actually improve health by reducing fracture risk?
Clinical trials measure BMD as a surrogate for fracture risk, as large numbers of subjects must be followed for many years to actually evaluate fracture as a clinical endpoint. The studies evaluated in this meta-analysis have insufficient numbers to address the risk of facture. We also know little about the effect of age and, in particular, whether early replacement could be more impactful. When I discussed this paper with Leon Speroff, he was also careful to point out that “while the increase from baseline was not progressive, we typically expect to see a progressive bone loss accumulating with age, so prevention of that loss may well be meaningful in terms of fracture protection, particularly with long-term exposure.”
The most important clinical point to stress is that calcium and calcium/vitamin D should not be recommended for fracture prevention, in keeping with standard practice. In contrast, we have level 1A evidence that postmenopausal estrogen replacement therapy does prevent hip and other fractures.3,4 Although women using raloxifene had a reduction in spinal compression fractures, an important reduction in hip fracture was not observed.5,6 A reduction of non-vertebral fracture has also been reported with bazedoxifene, but the absolute number of hip fractures was small and not different from placebo or raloxifene.7 Bisphosphonates have been shown to reduce vertebral and non-vertebral fracture risk, but the data are less convincing8 for primary prevention of hip fracture. This leads me to conclude that women at risk for fracture without contraindications to estrogen therapy should be strongly counseled to consider this benefit.
So calcium might help, but it should not be relied upon to prevent fracture in high-risk women. In my opinion, this information should be part of the discussion of initiation of estrogen therapy in healthy menopausal women.
REFERENCES
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Fritz MA, Speroff L. Clinical Gynecologic Endocrinology and Infertility. 8th Ed: Lippincott Williams & Wilkins; 2011.
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Bhattarai T, et al. Correlation of common biochemical markers for bone turnover, serum calcium, and alkaline phosphatase in post-menopausal women. Malays J Med Sci 2014;21:58-61.
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Rossouw JE, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-333.
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Anderson GL, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative randomized controlled trial. JAMA 2004;291:1701-1712.
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Ensrud KE, et al. Effects of raloxifene on fracture risk in postmenopausal women: The Raloxifene Use for the Heart Trial. J Bone Miner Res 2008;23:112-120.
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Agnusdei D, Iori N. Raloxifene: Results from the MORE study. J Musculoskelet Neuronal Interact 2000;1:127-132.
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Silverman SL, et al. Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: Results from a 3-year, randomized, placebo-, and active-controlled clinical trial. J Bone Miner Res 2008;23:1923-1934.
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Wells GA, et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev 2008:CD001155.
