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.

Effect of monthly high-dose vitamin D on bone density in community-dwelling older adults substudy of a randomized controlled trial.

BACKGROUND: Severe vitamin D deficiency causes osteomalacia, yet trials of vitamin D supplementation in the community have not on average demonstrated benefit to bone mineral density (BMD) or fracture risk in adults. OBJECTIVE: To determine whether monthly high-dose vitamin D supplementation influences BMD in the general population and in those with low 25-hydroxyvitamin D levels. METHODS: Two-year substudy of a trial in older community-resident adults. A total of 452 participants were randomized to receive monthly doses of vitamin D3 100 000 IU, or placebo. The primary end-point was change in lumbar spine BMD. Exploratory analyses to identify thresholds of baseline 25-hydroxyvitamin D for vitamin D effects on BMD were prespecified. RESULTS: Intention-to-treat analyses showed no significant treatment effect in the lumbar spine (between-groups difference 0.0071 g cm-2 , 95%CI: -0.0012, 0.0154) or total body but BMD loss at both hip sites was significantly attenuated by ~1/2% over 2 years. There was a significant interaction between baseline 25-hydroxyvitamin D and treatment effect (P = 0.04). With baseline 25-hydroxyvitamin D ≤ 30 nmol L-1 (n = 46), there were between-groups BMD changes at the spine and femoral sites of ~2%, significant in the spine and femoral neck, but there was no effect on total body BMD. When baseline 25-hydroxyvitamin D was >30 nmol L-1 , differences were ~1/2% and significant only at the total hip. CONCLUSIONS: This substudy finds no clinically important benefit to BMD from untargeted vitamin D supplementation of older, community-dwelling adults. Exploratory analyses suggest meaningful benefit in those with baseline 25-hydroxyvitamin D ≤ 30 nmol L-1 . This represents a significant step towards a trial-based definition of vitamin D deficiency for bone health in older adults.

Acute effects of calcium supplements on blood pressure: randomised, crossover trial in postmenopausal women.

Calcium supplements appear to increase cardiovascular risk, but the mechanism is unknown. We investigated the acute effects of calcium supplements on blood pressure in postmenopausal women. The reduction in systolic blood pressure was smaller after calcium compared with the placebo in the hours following dosing. INTRODUCTION: Calcium supplements appear to be associated with increased cardiovascular risk; however, the mechanism of this is uncertain. We previously reported that blood pressure declined over a day in older women, and that this reduction was smaller following a calcium supplement. To confirm this finding, we investigated the acute effects of calcium supplements on blood pressure. METHODS: This was a randomised controlled crossover trial in 40 healthy postmenopausal women (mean age 71 years and BMI 27.2 kg/m2). Women attended on two occasions, with visits separated by ≥7 days. At each visit, they received either 1 g of calcium as citrate, or placebo. Blood pressure and serum calcium concentrations were measured immediately before, and 2, 4 and 6 h after each intervention. RESULTS: Ionised and total calcium concentrations increased after calcium (p < 0.0001 versus placebo). Systolic blood pressure decreased after both calcium and placebo, but significantly less so after calcium (p = 0.02). The reduction in systolic blood pressure from baseline was smaller after calcium compared with placebo by 6 mmHg at 4 h (p = 0.036) and by 9 mmHg at 6 h (p = 0.002). The reduction in diastolic blood pressure was similar after calcium and placebo. CONCLUSIONS: These findings are consistent with those of our previous trial and indicate that the use of calcium supplements in postmenopausal women attenuates the post-breakfast reduction in systolic blood pressure by around 6-9 mmHg. Whether these changes in blood pressure influence cardiovascular risk requires further study.

Acute and 3-month effects of calcium carbonate on the calcification propensity of serum and regulators of vascular calcification: secondary analysis of a randomized controlled trial.

SUMMARY: Calcium supplements have been associated with increased cardiovascular risk, but the mechanism is unknown. We investigated the effects of calcium supplements on the propensity of serum to calcify, based on the transition time of primary to secondary calciprotein particles (T50). Changes in serum calcium were related to changes in T50. INTRODUCTION: Calcium supplements have been associated with increased cardiovascular risk; however, it is unknown whether this is related to an increase in vascular calcification. METHODS: We investigated the acute and 3-month effects of calcium supplements on the propensity of serum to calcify, based on the transition time of primary to secondary calciprotein particles (T50), and on three possible regulators of calcification: fetuin-A, pyrophosphate and fibroblast growth factor-23 (FGF23). We randomized 41 postmenopausal women to 1 g/day of calcium as carbonate, or to a placebo containing no calcium. Measurements were performed at baseline and then 4 and 8 h after their first dose, and after 3 months of supplementation. Fetuin-A, pyrophosphate and FGF23 were measured in the first 10 participants allocated to calcium carbonate and placebo who completed the study. RESULTS: T50 declined in both groups, the changes tending to be greater in the calcium group. Pyrophosphate declined from baseline in the placebo group at 4 h and was different from the calcium group at this time point (p = 0.04). There were no other significant between-groups differences. The changes in serum total calcium from baseline were significantly related to changes in T50 at 4 h (r = -0.32, p = 0.05) and 8 h (r = -0.39, p = 0.01), to fetuin-A at 3 months (r = 0.57, p = 0.01) and to pyrophosphate at 4 h (r = 0.61, p = 0.02). CONCLUSIONS: These correlative findings suggest that serum calcium concentrations modulate the propensity of serum to calcify (T50), and possibly produce counter-regulatory changes in pyrophosphate and fetuin-A. This provides a possible mechanism by which calcium supplements might influence vascular calcification.

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 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.

High-dose oral vitamin D3 supplementation in the elderly.

SUMMARY: Daily dosing with vitamin D often fails to achieve optimal outcomes, and it is uncertain what the target level of 25-hydroxyvitamin D should be. This study found that large loading doses of vitamin D(3) rapidly and safely normalize 25OHD levels, and that monthly dosing is similarly effective after 3-5 months. With baseline 25OHD > 50 nmol/L, vitamin D supplementation does not reduce PTH levels. INTRODUCTION: There is concern that vitamin D supplementation doses are frequently inadequate, and that compliance with daily medication is likely to be suboptimal. METHODS: This randomized double-blind trial compares responses to three high-dose vitamin D(3) regimens and estimates optimal 25-hydroxyvitamin D (25OHD) levels, from changes in parathyroid hormone (PTH), and procollagen type I amino-terminal propeptide (P1NP) in relation to baseline 25OHD. Sixty-three elderly participants were randomized to three regimens of vitamin D supplementation: a 500,000-IU loading dose; the loading dose plus 50,000 IU/month; or 50,000 IU/month. RESULTS: The Loading and Loading + Monthly groups showed increases in 25OHD of 58 +/- 28 nmol/L from baseline to 1 month. Thereafter, levels gradually declined to plateaus of 69 +/- 5 nmol/L and 91 +/- 4 nmol/l, respectively. In the Monthly group, 25OHD reached a plateau of ~80 +/- 20 nmol/L at 3-5 months. There were no changes in serum calcium concentrations. PTH and P1NP were only suppressed by vitamin D treatment in those with baseline 25OHD levels <50 and <30 nmol/L, respectively. CONCLUSIONS: Large loading doses of vitamin D(3) rapidly and safely normalize 25OHD levels in the frail elderly. Monthly dosing is similarly effective and safe, but takes 3-5 months for plateau 25OHD levels to be reached.

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.