Should we prescribe calcium or vitamin D supplements to treat or prevent osteoporosis?

Systematic reviews of randomized, controlled trials (RCTs) are considered the highest level of evidence to inform clinical practice. Meta-analyses of large RCTs of calcium and/or vitamin D supplements completed in the last 15 years provide strong evidence for clinical recommendations. These meta-analyses with data for > 50,000 older adults reported that calcium with or without vitamin D has only weak, inconsistent effects on fracture, and that vitamin D without calcium has no effect on fracture. Only one RCT of co-administered calcium and vitamin D in frail, institutionalized, elderly women with low dietary calcium intake and vitamin D levels showed significant reductions in fracture risk. These RCTs have also reported previously unrecognized adverse events of calcium supplements including kidney stones, myocardial infarction, hypercalcemia, and hospitalization with acute gastrointestinal symptoms. The small risk of these important adverse effects, together with the moderate risk of minor side-effects such as constipation, probably outweighs any benefits of calcium supplements on fracture. These data suggest the role for calcium and vitamin D supplements in osteoporosis management is very limited. Neither calcium nor vitamin D supplements should be recommended for fracture prevention in community-dwelling adults, although vitamin D should be considered for prevention of osteomalacia in at-risk individuals.

Bone density in healthy men after cessation of calcium supplements: 20-month follow-up of a randomized controlled trial.

UNLABELLED: Bone density has been followed up for 20 months following completion of a trial which compared calcium 1,200 mg/day with placebo, in normal older men. Following cessation of calcium supplements, there is a small residual benefit in total body bone density, but not at the hip or spine. INTRODUCTION: Calcium supplements, or supplements of calcium-rich foods, have a positive effect on bone mineral density (BMD). However, it is uncertain whether there are any residual benefits of calcium on BMD following cessation of supplementation. METHODS: In a previously published study, 323 healthy men were randomized to receive elemental calcium 600 mg/day (n = 108), calcium 1,200 mg/day (n = 108), or placebo (n = 107) over 2 years. Consenting men from the placebo and calcium 1,200 mg/day groups (85 and 87, respectively) were followed over the next 1-2 years (mean 20 months), off trial medication. RESULTS: In the core trial, BMD increased at all sites by 1.0-1.5% at 2 years in the group receiving calcium 1,200 mg/day, compared to the group receiving placebo. In post-trial follow-up, the calcium group has some residual benefit at the total body (0.41% above placebo; P = 0.04) but there was no significant between-group differences at other sites. CONCLUSION: Following cessation of calcium supplements in healthy men, there is a small residual benefit in total body BMD, but not at the hip or spine. This is unlikely to confer a clinically significant dividend in terms of ongoing fracture prevention.

Bone density is normal and does not change over 2 years in sarcoidosis.

SUMMARY: Small studies have previously suggested that sarcoidosis may be associated with low bone mineral density. In this observational study of 64 patients with sarcoidosis, bone mineral density was within the normal range at baseline, and there was no evidence of accelerated bone loss over 1-2 years. INTRODUCTION: Several small studies have suggested that sarcoidosis may be associated with low bone mineral density (BMD). METHODS: We undertook a cross-sectional study of BMD in 64 patients with sarcoidosis. Of these, 27 with 25-hydroxyvitamin D<50 nmol/L entered a 1-year intervention study of vitamin D supplements, and 37 entered a 2-year longitudinal study of BMD, with the primary endpoint of the change in lumbar spine BMD. RESULTS: The mean age of participants was 58 years, 68% were female, and 8% were currently using oral glucocorticoids. At baseline, BMD for the entire cohort was greater than the expected values for the population at the lumbar spine (mean Z-score 0.7, P<0.001) and total body (0.5, P<0.001) and similar to expected values at the femoral neck (0.2, P=0.14) and total hip (0.2, P=0.14). BMD did not change at any of these four sites (P>0.19) over 2 years in the longitudinal study. In the intervention study, vitamin D supplements had no effect on BMD, and therefore we pooled the data from all participants. BMD did not change over 1 year at the spine, total hip, or femoral neck (P>0.3), but decreased by 0.7% (95% confidence interval 0.3-1.1) at the total body (P=0.019). CONCLUSIONS: BMD was normal at baseline, and there was no consistent evidence of accelerated bone loss over 1-2 years, regardless of baseline vitamin D status. Patients with sarcoidosis not using oral glucocorticoids do not need routine monitoring of BMD.

The Auckland calcium study: 5-year post-trial follow-up.

UNLABELLED: Five years after completion of a randomised placebo-controlled trial of calcium supplements, there was no effect of calcium on total fracture incidence, a significant reduction in vertebral and forearm fractures and, in a subset, no effect on bone density. There was no increased risk of cardiovascular events after discontinuation of calcium. INTRODUCTION: The Auckland calcium study was a 5-year randomised controlled trial of 1 g/day calcium citrate in 1,471 postmenopausal women. Calcium did not reduce total, vertebral or forearm fracture incidence, increased hip fracture incidence and had beneficial effects on bone mineral density (BMD). A secondary analysis raised concerns about the cardiovascular safety of calcium. The purpose of this study was to determine whether the effects of calcium on fracture incidence, BMD and cardiovascular endpoints persisted after supplement discontinuation. METHODS: Approximately 5-years post-trial, we collected information on the 1,408 participants alive at trial completion from the national databases of hospital admissions and deaths. We contacted 1,174 women by phone, and from these we obtained information on medical events and post-trial calcium use. We undertook BMD measurements at 10 years in a selected subset of 194 women who took study medication for 5 years in the original trial, and did not take bone-active medications post-trial. RESULTS: Over the 10-year period, there was no effect on total fracture (HR 0.90, 95% CI 0.75-1.07) or hip fracture incidence (1.40, 0.89-2.21), but significant reductions in forearm (0.62, 0.43-0.89) and vertebral fractures (0.52, 0.32-0.85) in those assigned to calcium. There were no between-group differences in BMD at 10 years at any site. The adverse cardiovascular outcomes observed in the 5-year trial did not persist post-trial. CONCLUSION: Calcium supplementation for 5 years had no effect on total fracture incidence at 10 years. The positive benefits on BMD and the adverse cardiovascular effects did not persist once supplements were stopped.

The impact of dietary calcium intake and vitamin D status on the effects of zoledronate.

UNLABELLED: We investigated whether baseline dietary calcium intake or vitamin D status modified the effects of zoledronate. Neither variable influenced the effect of zoledronate on bone mineral density, bone turnover, or risk of acute phase reaction, suggesting that co-administration of calcium and vitamin D supplements with zoledronate may not always be necessary. INTRODUCTION: Calcium and vitamin D supplements are often co-administered with bisphosphonates, but it is unclear whether they are necessary for therapeutic efficacy or minimizing side effects of bisphosphonates. We investigated whether baseline dietary calcium intake or vitamin D status modified the effect of zoledronate on bone mineral density (BMD) or bone turnover at 1 year, or the risk of acute phase reactions (APR). METHODS: Data were pooled from two trials of zoledronate in postmenopausal women without vitamin D deficiency in which calcium and vitamin D were not routinely administered. The cohort (zoledronate n = 154, placebo n = 68) was divided into subgroups by baseline dietary calcium intake (<800 vs. ≥800 mg/day) and vitamin D status [25-hydroxyvitamin D (25OHD) <50 vs. ≥50 nmol/L, and <75 nmol/L vs. ≥75 nmol/L] and treatment × subgroup interactions tested. RESULTS: There were 52, 86, and 36 % of the zoledronate group and 64, 94, and 46 % of the placebo group that had dietary calcium intake ≥800 mg/day, 25OHD ≥50 nmol/L, and 25OHD ≥75 nmol/L, respectively. There were no significant interactions between treatment and either baseline dietary calcium or baseline vitamin D status for lumbar spine BMD, total hip BMD, the bone turnover markers P1NP and ß-CTx, or the risk of an APR. There was also no three-way interaction between baseline dietary calcium intake, baseline vitamin D status, and treatment for any of these variables. CONCLUSIONS: Baseline dietary calcium intake and vitamin D status did not alter the effects of zoledronate, suggesting that co-administration of calcium and vitamin D with zoledronate may not be necessary for individuals not at risk of marked vitamin D deficiency.

Differing perceptions of intervention thresholds for fracture risk: a survey of patients and doctors.

UNLABELLED: This survey suggests that patients are prepared to accept higher absolute fracture risk than doctors, before considering pharmacological therapy to be justified. Patients require that drug treatments confer substantial fracture risk reductions in order to consider long-term therapy. INTRODUCTION: Absolute fracture risk estimates are now incorporated into osteoporosis treatment guidelines. At present, little is known about how patients regard fracture risk and its management. We set out to describe and compare the views of patients and doctors on the level of fracture risk at which drug treatment is justified. METHODS: A cross-sectional survey was conducted on 114 patients referred for bone density measurement and 161 doctors whose practice includes management of osteoporosis. Participants were asked about fracture risk thresholds for pharmacological intervention. RESULTS: The absolute risk of both major osteoporotic fracture and hip fracture at which drug treatment was considered by patients to be justifiable was higher than that reported by doctors [major osteoporotic fracture, median (interquartile range): patients, 50% (25 to 60); doctors, 10% (10 to 20); P < 0.0001; hip fracture: patients, 50% (25 to 60); doctors, 10% (5 to 20); P < 0.0001]. Patients required that a drug provide a median 50% reduction in relative risk of fracture in order to consider taking long-term therapy, irrespective of the treatment mode or dosing schedule. Among doctors, there was an inverse relationship between the number of osteoporosis consultations conducted each month and threshold of risk for recommending drug treatment (r = -0.22 and r = -0.29 for major osteoporotic fracture and hip fracture, respectively, P < 0.01 for both) CONCLUSIONS: Patients are prepared to accept higher absolute fracture risk than doctors, before considering pharmacological therapy to be justified. Patients require that drug treatments confer substantial fracture risk reductions in order to consider long-term therapy.

Cardiovascular effects of calcium supplementation.

Trials in normal older women and in patients with renal impairment suggest that calcium supplements increase the risk of cardiovascular disease. To further assess their safety, we recently conducted a meta-analysis of trials of calcium supplements, and found a 27-31% increase in risk of myocardial infarction and a 12-20% increase in risk of stroke. These findings are robust because they are based on pre-specified analyses of randomized, placebo-controlled trials and show consistent risk across the trials. The fact that cardiovascular events were not primary endpoints of any of these studies will introduce noise but not bias into the data. A recent re-analysis of the Women's Health Initiative suggests that co-administration of vitamin D with calcium does not lessen these adverse effects. The increased cardiovascular risk with calcium supplements is consistent with epidemiological data relating higher circulating calcium concentrations to cardiovascular disease in normal populations. There are several possible pathophysiological mechanisms for these effects, including effects on vascular calcification, on the function of vascular cells, and on blood coagulation. Calcium-sensing receptors might mediate some of these effects. Because calcium supplements produce small reductions in fracture risk and a small increase in cardiovascular risk, there may be no net benefit from their use. Food sources of calcium appear to produce similar benefits on bone density, although their effects on fracture are unclear. Since food sources have not been associated with adverse cardiovascular effects, they may be preferable. Available evidence suggests that other osteoporosis treatments are still effective without calcium co-administration.

Effect of calcium supplementation on hip fractures.

There have been numerous studies of the effects of calcium supplementation, with or without vitamin D, on fractures. Individually, they have not provided clarity regarding calcium's anti-fracture efficacy, though they have established that calcium does have beneficial effects on bone density throughout the skeleton in women. Meta-analysis of these data suggests that total fracture numbers are diminished. However, the data from the 5,500 women involved in trials of calcium monotherapy show consistent adverse trends in numbers of hip fractures (relative risk 1.50, 95% CI 1.06-2.12). Observational data from the Study of Osteoporotic Fractures show a similar increase in risk of hip fracture associated with calcium use. We hypothesize that reduced periosteal expansion in women using calcium supplementation might account for the differences in anti-fracture efficacy of calcium at the hip, in comparison with other sites. Until there are further trial results to clarify this area, the present findings suggest that reliance on high calcium intakes to reduce the risk of hip fracture in older women is not appropriate. In addition, those at risk should be looking to other agents with a proven capacity to prevent hip fractures, such as bisphosphonates.

Determinants of vitamin D status in older men living in a subtropical climate.

INTRODUCTION: Previously we reported seasonal variation in 25-hydroxyvitamin D (25OHD) levels in postmenopausal women living in a subtropical climate. Because studies have suggested that there are gender differences in 25OHD levels, we sought to determine (1) the levels and determinants of 25OHD in men drawn from the same community, (2) whether seasonal variation of 25OHD occurs in men at this latitude (37 degrees S), and (3) whether these findings were comparable to those we previously observed in postmenopausal women. METHODS: Cross-sectional study of 378 healthy, middle-aged and older community-dwelling men in Auckland, New Zealand. RESULTS: The mean 25OHD (SD) level was 85 (31) nmol/l. We found significant seasonal variation in 25OHD levels (peak in autumn 103 nmol/l, nadir in spring 59 nmol/l). Vitamin D insufficiency (25OHD <50 nmol/l) was uncommon (prevalence in summer 0-17%, in winter 0-20%). The major determinants of 25OHD were month of blood sampling, fat percentage, physical activity, and serum albumin. Men had higher levels of 25OHD throughout the year than women did, a finding that persisted after adjusting for potential confounding factors. In men and women the determinants of 25OHD were similar. CONCLUSION: There is significant seasonal variation in 25OHD levels in men living in a subtropical climate. In contrast to postmenopausal women, men have low rates of suboptimal vitamin D status, even in winter. Routine vitamin D supplementation for this population of men is not warranted.

Calcium supplementation does not affect CRP levels in postmenopausal women--a randomized controlled trial.

INTRODUCTION: Epidemiological studies suggest that calcium supplementation may decrease the risk of cardiovascular disease. METHODS: Since the inflammatory marker C-reactive protein (CRP) is a risk factor for cardiovascular disease, and CRP production is potentially responsive to parathyroid hormone, we measured high-sensitivity CRP at baseline and 12 months in a subset of healthy postmenopausal women participating in a randomized controlled trial of the effects of 1 g of calcium daily on the incidence of fractures. RESULTS: At baseline, we found that CRP correlated positively with indices of body weight and fat and with bone mineral density (BMD) at the total body and total hip sites, but the associations between CRP and BMD were lost after adjustment for body weight. There were consistent associations between levels of CRP and markers of the metabolic syndrome (fat mass, plasma triglycerides, fasting glucose). CONCLUSION: After 1 year of calcium supplementation, there was no difference between the groups in levels of CRP. We conclude that levels of CRP correlate with anthropometric and biochemical features of insulin resistance, but that they are neither predictive of BMD nor affected by 1 g of calcium supplementation in healthy postmenopausal women.

Rapid quantitation of thermal oxidation products in fats and oils by 1H-NMR spectroscopy.

This work describes the application of high-resolution proton nuclear magnetic resonance (1H-NMR) spectroscopy to the study of the thermal peroxidation of beef tallow and corn oil under standardized conditions. The approach provides a rapid, quantitative method for determining the degree of oxidation of unsaturated fatty acids in animal and vegetable fats and oils by quantitating the decreasing intensities of 1H-NMR peaks for allylic and olefinic protons in unsaturated fatty acid chains of triglycerides and the increasing peak intensities of hydroperoxide and saturated and alpha, beta-unsaturated aldehydic protons in relation to the less labile protons in the triglyceride molecule. Two-dimensional correlation spectroscopy analysis of highly oxidized beef tallow (180 degrees C for 24 h) suggested that the unsaturated aldehydes that persisted were apparently associated with carboxy groups.

The effect of the antiestrogen tamoxifen on bone mineral density in normal late postmenopausal women.

PURPOSE: To assess the effect of the antiestrogenic agent tamoxifen on bone mineral density in normal late postmenopausal women. METHODS: A randomized, double-blind, placebo-controlled trial was performed with 57 healthy, late postmenopausal women (mean 11 +/- 7 years since menopause). Subjects were assigned to take either tamoxifen 20 mg/d or placebo for 2 years. Total body, lumbar spine, and proximal femoral (femoral neck, Ward's triangle, trochanter) bone mineral densities were measured every 6 months using dual-energy x-ray absorptiometry. Serum and urine indices of bone turnover were measured at baseline, 6 months, and 2 years. RESULTS: In the women given tamoxifen, the mean bone mineral density of the lumbar spine increased by 1.4%, while that in the women given placebo declined by 0.7% (P < 0.01 for difference between groups). Total body bone mineral density declined in both groups, but less so in the tamoxifen-treated women (P < 0.05). At both sites, the effect of tamoxifen was maximal after 1 year, with no further separation of the groups thereafter. There was no significant effect of tamoxifen on bone mineral density in the proximal femur. Tamoxifen produced significant falls in serum alkaline phosphatase (P < 0.0001), ionized calcium (P < 0.0001), and phosphate (P < 0.01), and in urinary excretion of hydroxyproline, n-telopeptides, and calcium (P < 0.05 for each). CONCLUSIONS: In normal late postmenopausal women, tamoxifen at a dose of 20 mg/d exerts a small protective effect on bone mineral density, comparable in magnitude to that of calcium supplementation and less than that of either estrogen or the bisphosphonates. Tamoxifen is unlikely to supersede any of these therapies in the management of postmenopausal osteoporosis.