Anti-fracture efficacy of zoledronate in subgroups of osteopenic postmenopausal women: secondary analysis of a randomized controlled trial.

BACKGROUND: We recently reported that the administration of zoledronate every 18 months to osteopenic older women reduces the incidence of fractures. OBJECTIVE: Here, we present a more detailed analysis of that trial to determine whether baseline clinical characteristics impact on the anti-fracture efficacy of this intervention. METHODS: This is a prospective, randomized, placebo-controlled, double-blind trial in osteopenic postmenopausal women aged ≥ 65 years, to determine the anti-fracture efficacy of zoledronate. 2000 women were recruited using electoral rolls and randomized to receive 4 infusions of either zoledronate 5 mg or normal saline, at 18-month intervals. Each participant was followed for 6 years. Calcium supplements were not supplied. RESULTS: Fragility fractures (either vertebral or nonvertebral) occurred in 190 women in the placebo group (227 fractures) and in 122 women in the zoledronate group (131 fractures), odds ratio (OR) 0.59 (95%CI 0.46, 0.76; P < 0.0001). There were no significant interactions between baseline variables (age, anthropometry, BMI, dietary calcium intake, baseline fracture status, recent falls history, bone mineral density, calculated fracture risk) and the treatment effect. In particular, the reduction in fractures appeared to be independent of baseline fracture risk, and numbers needed to treat (NNT) to prevent one woman fracturing were not significantly different across baseline fracture risk tertiles. CONCLUSIONS: The present analyses indicate that the decrease in fracture numbers is broadly consistent across this cohort. The lack of relationship between NNTs and baseline fracture risk calls into question the need for BMD measurement and precise fracture risk assessment before initiating treatment in older postmenopausal women.

Circulating calcium concentrations, vascular disease and mortality: a systematic review.

Associations between serum calcium and vascular disease have been reported, but the consistency of these findings is unknown. We conducted a systematic review to determine whether circulating calcium concentrations are associated with risks of cardiovascular disease and death in normocalcaemic populations. We conducted PubMed searches up to 18 December 2014 and scrutinized reference lists of papers. Eligible studies related serum calcium to mortality or cardiovascular events in humans. A follow-up of at least one year was required for longitudinal studies. Studies in populations selected on the basis of renal disease or abnormal serum calcium were excluded. Two investigators performed independent data extraction. The results were tabulated and, where possible, meta-analysed. Five of 11 studies reported a statistically significant positive association between serum calcium and mortality. Meta-analysis of eight of these studies showed a hazard ratio of death of 1.13 (1.09, 1.18) per standard deviation of serum calcium. Eight of 13 studies reported a statistically significant positive association between serum calcium and cardiovascular disease. Meta-analysis of eight studies showed a hazard ratio of cardiovascular disease of 1.08 (1.04, 1.13) per standard deviation of serum calcium. For two studies reporting odds ratios, the pooled odds ratio per standard deviation was 1.22 (1.11, 1.32). When hazard ratios adjusted for cardiovascular risk factors were meta-analysed, the pooled hazard ratio was 1.04 (1.01, 1.08). Other studies demonstrated associations between serum calcium and stroke and between serum calcium and direct measurements of arterial disease and calcification. These observational data indicate that serum calcium is associated with vascular disease and death, but they cannot determine causality.

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.

Calcium supplements: benefits and risks.

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(-1) . 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.

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.

Incidence of ocular side effects with intravenous zoledronate: secondary analysis of a randomized controlled trial.

SUMMARY: This prospective study showed that the incidence of acute anterior uveitis, confirmed by ophthalmic examination, in patients receiving intravenous zoledronate infusions as part of a randomized controlled trial for fracture prevention is 1.1%. INTRODUCTION: We prospectively investigated the incidence of ocular side effects after a single intravenous zoledronate infusion. METHODS: In a secondary analysis of a double-blind, placebo-controlled trial in which early post-menopausal women (N=1054) with normal bone density or osteopenia were randomized to infusion of zoledronate 5 mg (N=703) or placebo (N=351), we analyzed significant adverse ocular events occurring within 3 months. RESULTS: Fourteen participants reported ocular symptoms after the infusion. All were examined by an ophthalmologist and eight were diagnosed with acute anterior uveitis (AAU) and one with sectoral episcleritis. The incidence of AAU and episcleritis was 1.1% (95% CI 0.5-2.1) and 0.1% (95% CI 0.0-0.7), respectively, in the zoledronate group and 0% for both conditions in the placebo group (95% CI 0.0-0.8). The mean time from infusion to symptom onset for AAU was 3 days (range 2-4). Three cases were bilateral. AAU was mild-moderate in seven participants and severe in one. All affected eyes were treated with topical cyclopentolate 1% (to break, or minimize, posterior synechiae), and intensive, potent, topical corticosteroids with a tapering regime based on treatment response. The mean duration of topical corticosteroid was 26±10 days (range 17-44). The mean, best corrected visual acuity was 20/20 (range 20/20-20/40) at presentation, which remained unchanged after AAU resolution. None of the participants lost vision, and no long-term sequelae were reported at last follow-up (range 3-13 months post-infusion). CONCLUSIONS: Prescribers should inform patients about the possibility of ocular side effects with zoledronate infusions and refer promptly to an ophthalmologist if symptoms develop.

Skeletal and nonskeletal effects of vitamin D: is vitamin D a tonic for bone and other tissues?

The vitamin D endocrine system is critical for the maintenance of circulating calcium concentrations, but recently, there has been advocacy for the widespread use of vitamin D supplements to improve skeletal and nonskeletal health. Recent studies of tissue-selective vitamin D receptor knockout mice indicate that the principal action of vitamin D responsible for the maintenance of calcium homoeostasis is the regulation of intestinal calcium absorption. High levels of vitamin D can increase bone resorption and impair mineralization, consistent with its role in maintaining circulating calcium concentrations. These findings suggest that circumspection is appropriate in its clinical use. There is now substantial clinical trial data with vitamin D supplements, which fails to establish their efficacy on bone density or the prevention of falls or fractures. However, some trials in frail and/or vitamin D-deficient populations have produced positive outcomes. Where there are positive effects of vitamin D supplementation on skeletal outcomes, these are mainly seen in cohorts with baseline circulating 25-hydroxyvitamin D (25(OH)D) levels in the range 25-40 nmol/L or lower. A great diversity of nonskeletal conditions have been associated with low 25(OH)D, but there is little evidence for efficacy of vitamin D supplementation for such end-points. At present, supplements should be advised for populations with risk factors (e.g., lifestyle, skin color, and frailty) for having serum 25(OH)D levels in the 25- to 40-nmol/L range or below. A dose of ≤800 IU/day is adequate. This approach will maintain 25(OH)D levels well above the threshold for osteomalacia and makes allowance for the poor accuracy and precision of some 25(OH)D assays.

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.