Sex-Specific Effects of Nutritional Supplements for Infants Born Early or Small: An Individual Participant Data Meta-Analysis (ESSENCE IPD-MA) I-Cognitive Function and Metabolic Risk.

Neonatal nutritional supplements are widely used to improve growth and development but may increase risk of later metabolic disease, and effects may differ by sex. We assessed effects of supplements on later development and metabolism. We searched databases and clinical trials registers up to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter cognitive impairment in toddlers (13 trials, n = 1410; adjusted relative risk (aRR) 0.88 [95% CI 0.68, 1.13]; p = 0.31) or older ages, nor alter metabolic risk beyond 3 years (5 trials, n = 438; aRR 0.94 [0.76, 1.17]; p = 0.59). However, supplementation reduced motor impairment in toddlers (13 trials, n = 1406; aRR 0.76 [0.60, 0.97]; p = 0.03), and improved motor scores overall (13 trials, n = 1406; adjusted mean difference 1.57 [0.14, 2.99]; p = 0.03) and in girls not boys (p = 0.03 for interaction). Supplementation lowered triglyceride concentrations but did not affect other metabolic outcomes (high-density and low-density lipoproteins, cholesterol, fasting glucose, blood pressure, body mass index). Macronutrient supplementation for infants born small may not alter later cognitive function or metabolic risk, but may improve early motor function, especially for girls.

Sex-Specific Effects of Nutritional Supplements for Infants Born Early or Small: An Individual Participant Data Meta-Analysis (ESSENCE IPD-MA) II: Growth.

Neonatal nutritional supplements may improve early growth for infants born small, but effects on long-term growth are unclear and may differ by sex. We assessed the effects of early macronutrient supplements on later growth. We searched databases and clinical trials registers from inception to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter BMI in childhood (kg/m2: adjusted mean difference (aMD) -0.11[95% CI -0.47, 0.25], p = 0.54; 3 trials, n = 333). Supplementation increased length (cm: aMD 0.37[0.01, 0.72], p = 0.04; 18 trials, n = 2008) and bone mineral content (g: aMD 10.22[0.52, 19.92], p = 0.04; 6 trials, n = 313) in infancy, but not at older ages. There were no differences between supplemented and unsupplemented groups for other outcomes. In subgroup analysis, supplementation increased the height z-score in male toddlers (aMD 0.20[0.02, 0.37], p = 0.03; 10 trials, n = 595) but not in females, and no significant sex interaction was observed (p = 0.21). Macronutrient supplementation for infants born small may not alter BMI in childhood. Supplementation increased growth in infancy, but these effects did not persist in later life. The effects did not differ between boys and girls.

Dietary calcium intake and change in bone mineral density in older adults: a systematic review of longitudinal cohort studies.

Many older adults do not achieve recommended intakes of calcium and there is some concern over the potential impact of this on bone health. The objective of this review was to examine evidence from cohort studies on the relationship between calcium intake and change in bone mineral density (BMD) in older adults, something not undertaken in the last two decades. Data sources included Ovid Medline, Embase, and PubMed and references from retrieved reviews and articles. The final search was performed in February 2021. We included cohort studies of calcium intake in participants aged >50 years with change in BMD over ≥1 year as an outcome. We identified 23 studies of women and 7 of men. Most studies found no association between calcium intake and change in BMD in women (71%) or men (71%). Among women, five studies reported high rates (>30% of participants) of hormone treatment or osteoporosis therapy (HT/OT) use; 80% of these studies reported a positive association between calcium intake and change in BMD, compared with 10% of studies in which HT/OT use was low. No study in women in which the mean age was >60 years reported a positive association between calcium intake and change in BMD. We conclude that calcium intake across the ranges consumed in these studies (mean intake in all but one study >500 mg/day) is not an important determinant of bone loss, particularly among women >60 years. The positive findings in studies with high rates of HT/OT use are likely to arise from confounding as a result of co-administration of calcium supplements with these medications.

Dietary Calcium Intake and Bone Loss Over 6 Years in Osteopenic Postmenopausal Women.

CONTEXT: Calcium intakes are commonly lower than the recommended levels, and increasing calcium intake is often recommended for bone health. OBJECTIVE: To determine the relationship between dietary calcium intake and rate of bone loss in older postmenopausal women. PARTICIPANTS: Analysis of observational data collected from a randomized controlled trial. Participants were osteopenic (hip T-scores between -1.0 and -2.5) women, aged >65 years, not receiving therapy for osteoporosis nor taking calcium supplements. Women from the total cohort (n = 1994) contributed data to the analysis of calcium intake and bone mineral density (BMD) at baseline, and women from the placebo group (n = 698) contributed data to the analysis of calcium intake and change in BMD. BMD and bone mineral content (BMC) of the spine, total hip, femoral neck, and total body were measured three times over 6 years. RESULTS: Mean calcium intake was 886 mg/day. Baseline BMDs were not related to quintile of calcium intake at any site, before or after adjustment for baseline age, height, weight, physical activity, alcohol intake, smoking status, and past hormone replacement use. There was no relationship between bone loss and quintile of calcium intake at any site, with or without adjustment for covariables. Total body bone balance (i.e., change in BMC) was unrelated to an individuals' calcium intake (P = 0.99). CONCLUSIONS: Postmenopausal bone loss is unrelated to dietary calcium intake. This suggests that strategies to increase calcium intake are unlikely to impact the prevalence of and morbidity from postmenopausal osteoporosis.

Serum phosphate is related to adiposity in healthy adults.

BACKGROUND: Inorganic phosphate is a crucial component of cellular energy metabolism. We have identified an inverse relationship between serum phosphate concentration and fat mass in a cohort of healthy men. This study reports those data and determines whether this association is present in two female populations. METHODS: Cross-sectional data from three independent cohorts, consisting of healthy adult males (Male Cohort, n = 323) and healthy postmenopausal women (Female Cohort 1, n = 185; and Female Cohort 2, n = 1471), are reported. Associations between serum phosphate and weight, body mass index (BMI), fat mass and bone mineral density (BMD) were assessed. In a fourth cohort of postmenopausal women (FGF23 Cohort, n = 20), associations between fibroblast growth factor 23 (FGF23), weight and BMI were assessed. RESULTS: Serum phosphate correlated inversely with weight, BMI and fat mass across all three cohorts (r = -0·13 to -0·31, P < 0·0001-0·02). Associations were diminished after adjustment for PTH, but remained significant. In the FGF23 Cohort, FGF23 was positively correlated with weight (r = 0·60, P = 0·007) and BMI (r = 0·49, P = 0·03). Phosphate was inversely associated with BMD in Female Cohorts 1 and 2 (r = -0·08 to -0·29, P < 0·0001-0·02). This relationship was attenuated, but remained significant at most sites, following adjustment for age, fat mass, renal function and 25-hydroxyvitamin D. CONCLUSIONS: Serum phosphate is inversely associated with measures of adiposity in both women and men, largely independently of PTH. FGF23 might mediate these associations. This relationship may be an unrecognized confounder in some of the correlates of serum phosphate already described.

Concordance of Results from Randomized and Observational Analyses within the Same Study: A Re-Analysis of the Women's Health Initiative Limited-Access Dataset.

BACKGROUND: Observational studies (OS) and randomized controlled trials (RCTs) often report discordant results. In the Women's Health Initiative Calcium and Vitamin D (WHI CaD) RCT, women were randomly assigned to CaD or placebo, but were permitted to use personal calcium and vitamin D supplements, creating a unique opportunity to compare results from randomized and observational analyses within the same study. METHODS: WHI CaD was a 7-year RCT of 1g calcium/400IU vitamin D daily in 36,282 post-menopausal women. We assessed the effects of CaD on cardiovascular events, death, cancer and fracture in a randomized design- comparing CaD with placebo in 43% of women not using personal calcium or vitamin D supplements- and in a observational design- comparing women in the placebo group (44%) using personal calcium and vitamin D supplements with non-users. Incidence was assessed using Cox proportional hazards models, and results from the two study designs deemed concordant if the absolute difference in hazard ratios was ≤0.15. We also compared results from WHI CaD to those from the WHI Observational Study(WHI OS), which used similar methodology for analyses and recruited from the same population. RESULTS: In WHI CaD, for myocardial infarction and stroke, results of unadjusted and 6/8 covariate-controlled observational analyses (age-adjusted, multivariate-adjusted, propensity-adjusted, propensity-matched) were not concordant with the randomized design results. For death, hip and total fracture, colorectal and total cancer, unadjusted and covariate-controlled observational results were concordant with randomized results. For breast cancer, unadjusted and age-adjusted observational results were concordant with randomized results, but only 1/3 other covariate-controlled observational results were concordant with randomized results. Multivariate-adjusted results from WHI OS were concordant with randomized WHI CaD results for only 4/8 endpoints. CONCLUSIONS: Results of randomized analyses in WHI CaD were concordant with observational analyses for 5/8 endpoints in WHI CaD and 4/8 endpoints in WHI OS.

Calcium intake and risk of fracture: systematic review.

OBJECTIVE: To examine the evidence underpinning recommendations to increase calcium intake through dietary sources or calcium supplements to prevent fractures. DESIGN: Systematic review of randomised controlled trials and observational studies of calcium intake with fracture as an endpoint. Results from trials were pooled with random effects meta-analyses. DATA SOURCES: Ovid Medline, Embase, PubMed, and references from relevant systematic reviews. Initial searches undertaken in July 2013 and updated in September 2014. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials or cohort studies of dietary calcium, milk or dairy intake, or calcium supplements (with or without vitamin D) with fracture as an outcome and participants aged >50. RESULTS: There were only two eligible randomised controlled trials of dietary sources of calcium (n=262), but 50 reports from 44 cohort studies of relations between dietary calcium (n=37), milk (n=14), or dairy intake (n=8) and fracture outcomes. For dietary calcium, most studies reported no association between calcium intake and fracture (14/22 for total, 17/21 for hip, 7/8 for vertebral, and 5/7 for forearm fracture). For milk (25/28) and dairy intake (11/13), most studies also reported no associations. In 26 randomised controlled trials, calcium supplements reduced the risk of total fracture (20 studies, n=58,573; relative risk 0.89, 95% confidence interval 0.81 to 0.96) and vertebral fracture (12 studies, n=48,967. 0.86, 0.74 to 1.00) but not hip (13 studies, n=56,648; 0.95, 0.76 to 1.18) or forearm fracture (eight studies, n=51,775; 0.96, 0.85 to 1.09). Funnel plot inspection and Egger's regression suggested bias toward calcium supplements in the published data. In randomised controlled trials at lowest risk of bias (four studies, n=44,505), there was no effect on risk of fracture at any site. Results were similar for trials of calcium monotherapy and co-administered calcium and vitamin D. Only one trial in frail elderly women in residential care with low dietary calcium intake and vitamin D concentrations showed significant reductions in risk of fracture. CONCLUSIONS: Dietary calcium intake is not associated with risk of fracture, and there is no clinical trial evidence that increasing calcium intake from dietary sources prevents fractures. Evidence that calcium supplements prevent fractures is weak and inconsistent.

Acute effects of calcium supplements on blood pressure and blood coagulation: secondary analysis of a randomised controlled trial in post-menopausal women.

Recent evidence suggests that Ca supplements increase the risk of cardiovascular events, but the mechanism(s) by which this occurs is uncertain. In a study primarily assessing the effects of various Ca supplements on blood Ca levels, we also investigated the effects of Ca supplements on blood pressure and their acute effects on blood coagulation. We randomised 100 post-menopausal women to 1 g/d of Ca or a placebo containing no Ca. Blood pressure was measured at baseline and every 2 h up to 8 h after their first dose and after 3 months of supplementation. Blood coagulation was measured by thromboelastography (TEG) in a subgroup of participants (n 40) up to 8 h only. Blood pressure declined over 8 h in both the groups, consistent with its normal diurnal rhythm. The reduction in systolic blood pressure was smaller in the Ca group compared with the control group by >5 mmHg between 2 and 6 h (P≤0·02), and the reduction in diastolic blood pressure was smaller at 2 h (between-groups difference 4·5 mmHg, P=0·004). Blood coagulability, assessed by TEG, increased from baseline over 8 h in the calcium citrate and control groups. At 4 h, the increase in the coagulation index was greater in the calcium citrate group compared with the control group (P=0·03), which appeared to be due to a greater reduction in the time to clot initiation. These data suggest that Ca supplements may acutely influence blood pressure and blood coagulation. Further investigation of this possibility is required.

Acute and 3-month effects of microcrystalline hydroxyapatite, calcium citrate and calcium carbonate on serum calcium and markers of bone turnover: a randomised controlled trial in postmenopausal women.

Ca supplements are used for bone health; however, they have been associated with increased cardiovascular risk, which may relate to their acute effects on serum Ca concentrations. Microcrystalline hydroxyapatite (MCH) could affect serum Ca concentrations less than conventional Ca supplements, but its effects on bone turnover are unclear. In the present study, we compared the acute and 3-month effects of MCH with conventional Ca supplements on concentrations of serum Ca, phosphate, parathyroid hormone and bone turnover markers. We randomised 100 women (mean age 71 years) to 1 g/d of Ca as citrate or carbonate (citrate-carbonate), one of two MCH preparations, or a placebo. Blood was sampled for 8 h after the first dose, and after 3 months of daily supplementation. To determine whether the acute effects changed over time, eight participants assigned to the citrate dose repeated 8 h of blood sampling at 3 months. There were no differences between the citrate and carbonate groups, or between the two MCH groups, so their results were pooled. The citrate-carbonate dose increased ionised and total Ca concentrations for up to 8 h, and this was not diminished after 3 months. MCH increased ionised Ca concentrations less than the citrate-carbonate dose; however, it raised the concentrations of phosphate and the Ca-phosphate product. The citrate-carbonate and MCH doses produced comparable decreases in bone resorption (measured as serum C-telopeptide (CTX)) over 8 h and bone turnover (CTX and procollagen type-I N-terminal propeptide) at 3 months. These findings suggest that Ca preparations, in general, produce repeated sustained increases in serum Ca concentrations after ingestion of each dose and that Ca supplements with smaller effects on serum Ca concentrations may have equivalent efficacy in suppressing bone turnover.

Vitamin D supplementation and falls: a trial sequential meta-analysis.

BACKGROUND: Vitamin D supplementation is often recommended to prevent falls, although vitamin D trials and meta-analyses of these trials have reported conflicting results for this outcome. We aimed to assess if there was a need for further research. METHODS: We explored the value of doing further randomised controlled trials assessing the effects of vitamin D supplements on falls with trial sequential analysis with a risk reduction threshold of 15%. All analyses were done using the numbers of participants who had a fall in intention-to-treat analyses. Trial sequential analysis performs a cumulative meta-analysis, but reduces the risk of false-positive results from repetitive statistical testing by maintaining the overall risk of type 1 error at 5%. FINDINGS: In 20 existing randomised controlled trials (n=29,535), the effect estimate for vitamin D with or without calcium on falls lay within the futility boundary, providing evidence that vitamin D supplementation does not alter the relative risk by 15% or more. In a sensitivity analysis using a risk reduction threshold of 10%, the effect estimate also lay within the futility boundary. In subgroup analyses using a risk reduction threshold of 15%, the effect estimate also lay within the futility boundary for trials of vitamin D supplementation (16 trials, n=22,291) and trials of vitamin D with calcium (six trials, n=9919). INTERPRETATION: In pooled analyses, supplementation with vitamin D, with or without calcium, does not reduce falls by 15% or more. Future trials with similar designs are unlikely to alter these conclusions. At present, there is little justification for prescribing vitamin D supplements to prevent falls. FUNDING: Health Research Council of New Zealand.

The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis.

BACKGROUND: Vitamin D insufficiency is associated with many disorders, leading to calls for widespread supplementation. Some investigators suggest that more clinical trials to test the effect of vitamin D on disorders are needed. METHODS: We did a trial sequential meta-analysis of existing randomised controlled trials of vitamin D supplements, with or without calcium, to investigate the possible effect of future trials on current knowledge. We estimated the effects of vitamin D supplementation on myocardial infarction or ischaemic heart disease, stroke or cerebrovascular disease, cancer, total fracture, hip fracture, and mortality in trial sequential analyses using a risk reduction threshold of 5% for mortality and 15% for other endpoints. FINDINGS: The effect estimate for vitamin D supplementation with or without calcium for myocardial infarction or ischaemic heart disease (nine trials, 48 647 patients), stroke or cerebrovascular disease (eight trials 46 431 patients), cancer (seven trials, 48 167 patients), and total fracture (22 trials, 76 497 patients) lay within the futility boundary, indicating that vitamin D supplementation does not alter the relative risk of any of these endpoints by 15% or more. Vitamin D supplementation alone did not reduce hip fracture by 15% or more (12 trials, 27 834 patients). Vitamin D co-administered with calcium reduced hip fracture in institutionalised individuals (two trials, 3853 patients) but did not alter the relative risk of hip fracture by 15% or more in community-dwelling individuals (seven trials, 46 237 patients). There is uncertainty as to whether vitamin D with or without calcium reduces the risk of death (38 trials, 81 173). INTERPRETATION: Our findings suggest that vitamin D supplementation with or without calcium does not reduce skeletal or non-skeletal outcomes in unselected community-dwelling individuals by more than 15%. Future trials with similar designs are unlikely to alter these conclusions. FUNDING: Health Research Council of New Zealand.

Randomised controlled trial of vitamin D supplementation in sarcoidosis.

OBJECTIVES: The role vitamin D intake/production plays in sarcoidosis-associated hypercalcaemia is uncertain. However, authoritative reviews have recommended avoiding sunlight exposure and vitamin D supplements, which might lead to adverse skeletal outcomes from vitamin D insufficiency. We investigated the effects of vitamin D supplementation on surrogate measures of skeletal health in patients with sarcoidosis and vitamin D insufficiency. DESIGN: Randomised, placebo-controlled trial. SETTING: Clinical research centre. PARTICIPANTS: 27 normocalcaemic patients with sarcoidosis and 25-hydroxyvitamin D (25OHD) <50 nmol/L. INTERVENTION: 50 000 IU weekly cholecalciferol for 4 weeks, then 50 000 IU monthly for 11 months or placebo. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was the change in serum calcium over 12 months, and secondary endpoints included measurements of calcitropic hormones, bone turnover markers and bone mineral density (BMD). RESULTS: The mean age of participants was 57 years and 70% were women. The mean (SD) screening 25OHD was 35 (12) and 38 (9) nmol/L in the treatment and control groups, respectively. Vitamin D supplementation increased 25OHD to 94 nmol/L after 4 weeks, 84 nmol/L at 6 months and 78 nmol/L at 12 months, while levels remained stable in the control group. 1,25-Dihydroxy vitamin D levels were significantly different between the groups at 4 weeks, but not at 6 or 12 months. There were no between-groups differences in albumin-adjusted serum calcium, 24 h urine calcium, markers of bone turnover, parathyroid hormone or BMD over the trial. One participant developed significant hypercalcaemia after 6 weeks (total cholecalciferol dose 250 000 IU). CONCLUSIONS: In patients with sarcoidosis and 25OHD <50 nmol/L, vitamin D supplements did not alter average serum calcium or urine calcium, but had no benefit on surrogate markers of skeletal health and caused one case of significant hypercalcaemia. TRIAL REGISTRATION: This trial is registered at the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au). The registration number is ACTRN12607000364471, date of registration 5/7/2007.

Subgroup analysis for the risk of cardiovascular disease with calcium supplements.

Calcium supplements have been reported to increase the risk of myocardial infarction (MI). We wished to determine whether the effects of calcium supplements on cardiovascular risk vary across different population groups. We modeled the effect of calcium (with or without vitamin D) on the time to incident cardiovascular events in pre-specified subgroups based on age, dietary calcium intake, body mass index, smoking history, history of hypertension, diabetes and prevalent cardiovascular disease, using interaction terms in Cox proportional hazards models in two randomized controlled trial data sets-our re-analysis of the Women's Health Initiative Calcium and Vitamin D study (WHI CaD), and our pooled patient-level meta-analysis of trials of calcium supplements with or without vitamin D. For women in WHI CaD not taking calcium supplements at randomization (n=16 718), we found no significant interactions between treatment allocation, the risk of MI, stroke or coronary revascularization, or any of the baseline variables. In the pooled patient-level data set of six trials of calcium with or without vitamin D (n=24 869), there were also no significant interactions between treatment allocation, risk of MI or stroke, and any of the baseline variables. We found no evidence that the increased cardiovascular risk from calcium supplements differs across varying patient subpopulations. These findings suggest that targeted prescription of calcium supplements to specific population subgroups, such as younger people and those with low dietary calcium intake, should not be endorsed.

Calcium supplements and cancer risk: a meta-analysis of randomised controlled trials.

Some evidence suggests that Ca and vitamin D supplements affect cancer risk; however, it is uncertain whether the effects are due to Ca, vitamin D or the combination. We investigated the effect of Ca supplements without co-administered vitamin D on cancer risk. Medline, Embase and the Cochrane Central Register of Controlled Trials, reference lists of meta-analyses and two clinical trial registries were searched for randomised, placebo-controlled trials of Ca supplements ( ≥ 500 mg/d), with ≥ 100 participants and duration >1 year. The lead authors of eligible trials supplied data on cancer outcomes. Trial-level data were analysed using random-effects meta-analyses and patient-level data using Cox proportional hazards models. A total of sixteen trials were eligible, six had no data available, ten provided trial-level data (n 10,496, mean duration 3·9 years), and of these, four provided patient-level data (n 7221, median duration 3·5 years). In the meta-analysis of trial-level data, allocation to Ca did not alter the risk of total cancer (relative risk 0·95, 95% CI 0·76, 1·18, P= 0·63), colorectal cancer (relative risk 1·38, 95% CI 0·89, 2·15, P= 0·15), breast cancer (relative risk 1·01, 95% CI 0·64, 1·59, P= 0·97) or cancer-related mortality (relative risk 0·96, 95% CI 0·74, 1·24, P= 0·75), but reduced the risk of prostate cancer (relative risk 0·54, 95 % CI 0·30, 0·96, P= 0·03), although there were few events. The meta-analysis of patient-level data showed similar results, with no effect of Ca on the risk of total cancer (hazard ratio 1·07, 95% CI 0·89, 1·28, P= 0·50). Ca supplements without co-administered vitamin D did not alter total cancer risk over 4 years, although the meta-analysis lacked power to detect very small effects, or those with a longer latency.

Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set.

BACKGROUND: Frequent use of personal, nonprotocol calcium supplements obscured an adverse effect of coadministered calcium and vitamin D (CaD) on cardiovascular risk in the Women's Health Initiative (WHI). OBJECTIVE: We investigated the effects of the use of personal calcium or vitamin D supplements on other outcomes in the WHI CaD Study (WHI CaD) by using the WHI limited-access clinical trials data set. DESIGN: The WHI CaD was a 7-y, randomized, placebo-controlled trial of CaD (1 g Ca/400 IU vitamin D daily) in 36,282 community-dwelling, postmenopausal women. The incidence of total cancer (excluding nonmelanoma skin cancers), breast and colorectal cancers, hip and total fracture, and mortality was assessed by using Cox proportional hazards models. RESULTS: In the WHI CaD, interactions between the use of either personal calcium or vitamin D supplements and CaD were found for total, breast, and colorectal cancers but not for fracture or mortality. In 15,646 women (43%) who were not taking personal calcium or vitamin D supplements at randomization, CaD significantly decreased the risk of total, breast, and invasive breast cancers by 14-20% and nonsignificantly reduced the risk of colorectal cancer by 17%. In women taking personal calcium or vitamin D supplements, CaD did not alter cancer risk (HR: 1.06-1.26). CONCLUSIONS: For women in the WHI CaD who were not taking personal calcium or vitamin D supplements at randomization, CaD decreased the risk of total, breast, and colorectal cancers and did not change the risk of fractures or total mortality. The nonskeletal effects of CaD may be more important than the skeletal effects and should be considered when evaluating these supplements. The WHI CaD trial is registered at clinicaltrials.gov as NCT00000611.

Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access dataset and meta-analysis.

OBJECTIVES: To investigate the effects of personal calcium supplement use on cardiovascular risk in the Women's Health Initiative Calcium/Vitamin D Supplementation Study (WHI CaD Study), using the WHI dataset, and to update the recent meta-analysis of calcium supplements and cardiovascular risk. DESIGN: Reanalysis of WHI CaD Study limited access dataset and incorporation in meta-analysis with eight other studies. Data source WHI CaD Study, a seven year, randomised, placebo controlled trial of calcium and vitamin D (1g calcium and 400 IU vitamin D daily) in 36,282 community dwelling postmenopausal women. Main outcome measures Incidence of four cardiovascular events and their combinations (myocardial infarction, coronary revascularisation, death from coronary heart disease, and stroke) assessed with patient-level data and trial-level data. RESULTS: In the WHI CaD Study there was an interaction between personal use of calcium supplements and allocated calcium and vitamin D for cardiovascular events. In the 16,718 women (46%) who were not taking personal calcium supplements at randomisation the hazard ratios for cardiovascular events with calcium and vitamin D ranged from 1.13 to 1.22 (P = 0.05 for clinical myocardial infarction or stroke, P = 0.04 for clinical myocardial infarction or revascularisation), whereas in the women taking personal calcium supplements cardiovascular risk did not alter with allocation to calcium and vitamin D. In meta-analyses of three placebo controlled trials, calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.21 (95% confidence interval 1.01 to 1.44), P = 0.04), stroke (1.20 (1.00 to 1.43), P = 0.05), and the composite of myocardial infarction or stroke (1.16 (1.02 to 1.32), P = 0.02). In meta-analyses of placebo controlled trials of calcium or calcium and vitamin D, complete trial-level data were available for 28,072 participants from eight trials of calcium supplements and the WHI CaD participants not taking personal calcium supplements. In total 1384 individuals had an incident myocardial infarction or stroke. Calcium or calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.24 (1.07 to 1.45), P = 0.004) and the composite of myocardial infarction or stroke (1.15 (1.03 to 1.27), P = 0.009). CONCLUSIONS: Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, a finding obscured in the WHI CaD Study by the widespread use of personal calcium supplements. A reassessment of the role of calcium supplements in osteoporosis management is warranted.

Evaluation of the FRAX and Garvan fracture risk calculators in older women.

Fracture risk calculators estimate the absolute risk of osteoporotic fractures. We investigated the performance of the FRAX and Garvan Institute fracture risk calculators in healthy, older, New Zealand, postmenopausal women with normal bone mineral density (BMD) for their age. Fractures were ascertained in women initially enrolled in a 5-year trial of calcium supplements and followed on average for 8.8 years. Baseline data (1422 women, mean age 74 years, mean femoral neck BMD T-score -1.3) were used to estimate fracture risk during follow-up using the FRAX and Garvan calculators. The FRAX-New Zealand tool was used both with and without baseline BMD. The discrimination of the calculators was assessed using the area under the curve (AUC) of receiver operating characteristic curves. The calibration was assessed by comparing estimated risk of fracture with fracture incidence across a range of estimated fracture risks and clinical factors. For each fracture subtype, the calculators had comparable moderate predictive discriminative ability (AUC range: hip fracture 0.67-0.70; osteoporotic fracture 0.62-0.64; any fracture 0.60-0.63) that was similar to that of models using only age and BMD. The Garvan calculator was well calibrated for osteoporotic fractures but overestimated hip fractures. FRAX with BMD underestimated osteoporotic and hip fractures. FRAX without BMD underestimated osteoporotic and overestimated hip fractures. In summary, none of the calculators provided better discrimination than models based on age and BMD, and their discriminative ability was only moderate, which may limit their clinical utility. The calibration varied, suggesting that the calculators should be validated in local cohorts before clinical use.

Imatinib mesylate does not increase bone volume in vivo.

Imatinib mesylate is a tyrosine kinase inhibitor used in the management of disorders in which activation of c-Abl, PDGFR, or c-Kit signaling plays a critical role. In vitro, imatinib stimulates osteoblast differentiation, inhibits osteoblast proliferation and survival, and decreases osteoclast development. Patients treated with imatinib exhibit altered bone and mineral metabolism, with stable or increased bone mass. However, recovery from the underlying disease and/or weight gain might contribute to these effects. We therefore investigated the skeletal effects of imatinib in healthy rats. We evaluated the effects of imatinib on bone volume, markers of bone turnover, and bone histomorphometry in mature female rats treated for 5 weeks with either vehicle, imatinib 40 mg/kg daily, or imatinib 70 mg/kg daily. Compared to vehicle, imatinib reduced trabecular bone volume/tissue volume (mean [SD]: vehicle 26.4% [5.4%], low-dose imatinib 24.8% [4.9%] [P = 0.5], high-dose imatinib 21.1% [5.7%] [P = 0.05]), reduced osteoblast surface (mean [SD]: vehicle 12.8% [5.8%], low-dose 6.8% [1.9%] [P < 0.01], high-dose 7.8 [3.1%] [P < 0.05]), and reduced serum osteocalcin (mean change from baseline [95% CI]: vehicle -8.2 [-26.6 to 10.2] ng/ml, low dose -79.7 [-97.5 to -61.9] ng/ml [P < 0.01 vs. vehicle], high-dose -66.0 [-82.0 to -50.0] ng/ml [P < 0.05 vs. vehicle]). Imatinib did not affect biochemical or histomorphometric indices of bone resorption. These results suggest that, in healthy animals, treatment with imatinib does not increase bone mass and that the improvements in bone density reported in patients receiving imatinib may not be a direct effect of the drug.

Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis.

OBJECTIVE: To investigate whether calcium supplements increase the risk of cardiovascular events. DESIGN: Patient level and trial level meta-analyses. DATA SOURCES: Medline, Embase, and Cochrane Central Register of Controlled Trials (1966-March 2010), reference lists of meta-analyses of calcium supplements, and two clinical trial registries. Initial searches were carried out in November 2007, with electronic database searches repeated in March 2010. STUDY SELECTION: Eligible studies were randomised, placebo controlled trials of calcium supplements (>or=500 mg/day), with 100 or more participants of mean age more than 40 years and study duration more than one year. The lead authors of eligible trials supplied data. Cardiovascular outcomes were obtained from self reports, hospital admissions, and death certificates. RESULTS: 15 trials were eligible for inclusion, five with patient level data (8151 participants, median follow-up 3.6 years, interquartile range 2.7-4.3 years) and 11 with trial level data (11 921 participants, mean duration 4.0 years). In the five studies contributing patient level data, 143 people allocated to calcium had a myocardial infarction compared with 111 allocated to placebo (hazard ratio 1.31, 95% confidence interval 1.02 to 1.67, P=0.035). Non-significant increases occurred in the incidence of stroke (1.20, 0.96 to 1.50, P=0.11), the composite end point of myocardial infarction, stroke, or sudden death (1.18, 1.00 to 1.39, P=0.057), and death (1.09, 0.96 to 1.23, P=0.18). The meta-analysis of trial level data showed similar results: 296 people had a myocardial infarction (166 allocated to calcium, 130 to placebo), with an increased incidence of myocardial infarction in those allocated to calcium (pooled relative risk 1.27, 95% confidence interval 1.01 to 1.59, P=0.038). CONCLUSIONS: Calcium supplements (without coadministered vitamin D) are associated with an increased risk of myocardial infarction. As calcium supplements are widely used these modest increases in risk of cardiovascular disease might translate into a large burden of disease in the population. A reassessment of the role of calcium supplements in the management of osteoporosis is warranted.