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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.

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., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: Most longitudinal studies of bone mineral density (BMD) in HIV-infected cohorts have been of short duration, typically 1-2 years. Some studies, especially of cohorts treated with highly active antiretroviral therapy (HAART), report short-term stable or increasing BMD, but other studies, often in cohorts initiating HAART, report short-term losses in BMD. We assessed BMD changes over the medium term in HIV-infected men already established on HAART at baseline., Design: Six-year, prospective, longitudinal study., Subjects: Forty-four HIV-infected men treated with HAART and 37 uninfected, healthy controls., Measurements: Participants had measurements of BMD at baseline, 2 and 6 years., Results: In the HIV-infected men at baseline, the mean age was 49 years, the mean duration of infection was 8 years, and the mean duration of HAART was 50 months. Over 6 years of follow-up, there was a greater increase in lumbar spine BMD (5·3%, 95% CI 3·8-6·5%) in the HIV-infected men compared with controls (0·3%, 95% CI -1·0 to 1·6%), P < 0·001. There was no difference between the groups in the change in BMD over time at the total hip (HIV group: -0·6%, 95% CI -1·7 to 0·4%, controls -1·0%, 95% CI -2·2 to 0%, P = 0·8) or at the total body (HIV group, 0·3%, 95% CI -0·3 to 1·0%; controls, 0·5%, 95% CI -0·2 to 1·1%, P = 0·15). Lean mass increased in the HIV group, but not in the controls., Conclusions: There was no evidence of accelerated bone loss over 6 years in middle-aged, HIV-infected men treated with HAART. For such patients, routine monitoring of BMD is not necessary over the short/medium term., (© 2012 Blackwell Publishing Ltd.)

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.

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.

Objective: To determine the association, if any, between male-pattern hair loss (baldness) and serum 25-hydroxyvitamin D (25-OHD) levels., Design and Participants: A cross-sectional study of 296 healthy middle-aged and older men., Main Outcome Measures: Degree of baldness was independently assessed by two researchers using the Hamilton-Norwood scale and serum 25-OHD was measured in all men., Results: Classification of the degree of baldness by the two researchers showed a high level of agreement (kappa = 0.93). Forty-eight per cent of men had no hair loss or mild frontotemporal recession, 15% had predominant vertex loss, and 37% had significant scalp and vertex loss. After data were adjusted for potential confounding factors - including age, month of 25-OHD measurement, exercise levels, use of sunscreen, skin type and frequency of outdoor hat wearing - no significant differences in 25-OHD levels between these groups was detected (P = 0.60)., Conclusions: The degree of baldness does not appear to influence serum 25-OHD levels. The high prevalence of baldness in older men does not explain sex differences in 25-OHD levels. Other novel hypotheses are required to help determine whether baldness serves any physiological purpose.

Aims: To explore the effects of seasonal variation on the diagnosis of vitamin D sufficiency and to determine whether age, gender, and ethnicity modify these effects., Methods: 21,987 adults had a measurement of serum 25-hydroxyvitamin D (25OHD) at Labplus, Auckland City Hospital, between January 2002 and September 2003, and sine curves were fitted for 25OHD versus day of year to predict the 25OHD nadir for each individual., Results: 48% (range: 30-63%) of individuals had 25OHD <50 nmol/L in the month of measurement, but 63% were predicted to have 25OHD <50 nmol/L in late winter or early spring based on expected seasonal variation. The 25OHD levels required to ensure 25OHD levels >50 nmol/L throughout the year varied substantially by season (in summer at least 60-75 nmol/L), and tended to be higher in men than women, decrease with age, and vary with ethnicity. Mean 25OHD levels were very low (<40 nmol/L) in people of Indian, Middle Eastern, and African descent., Conclusion: Seasonal variation in 25OHD affects the diagnosis of vitamin D sufficiency. Clinicians should consider the month of sampling when interpreting the results of 25OHD measurements. In New Zealand, a summertime 25OHD <60-75 nmol/L is generally required to ensure year-round 25OHD levels <50 nmol/L.

Background: The effect of season on vitamin D status is often overlooked in studies of optimal vitamin D concentrations and in clinical practice., Objectives: We aimed to determine the effects of seasonal variation of 25-hydroxyvitamin D [25(OH)D] on a previously selected minimum concentration for vitamin D sufficiency (50 nmol/L) and to determine whether fat mass modifies these effects., Design: A cross-sectional study evaluated 1606 healthy postmenopausal women and 378 older men from Auckland, New Zealand, who were undergoing single measurements of 25(OH)D., Results: Concentrations of <50 nmol 25(OH)D/L were seen in 49% (range: 23%-74%) of women and 9% (range: 0%-26%) of men when measured, but 73% of women and 39% of men were predicted to have trough 25(OH)D concentrations < 50 nmol/L, according to the demonstrated seasonal variation. The predicted duration of 25(OH)D concentrations < 50 nmol/L was 250 d/y in women and 165 d/y in men., Conclusion: Seasonal variation significantly affects the diagnosis of vitamin D sufficiency, which requires seasonally adjusted thresholds individualized for different locations. Clinicians should consider the month of sampling and the amount of body fat when interpreting 25(OH)D measurements.

Objective: 25-hydroxyvitamin D (25OHD) levels are inversely related to body weight, and have been reported to decline with age and be lower in women than men. We hypothesized that these findings might be explained by effects of these variables on vitamin D binding protein (DBP) levels. We set out to determine the relationships between DBP and gender, 25OHD, body weight and body composition., Design: Cross-sectional analysis., Patients: One hundred healthy, middle-aged and older, community-dwelling men and women., Measurements: All participants were measured for 25OHD, DBP, body weight, bone mineral density and body composition., Results: Women had higher mean DBP levels than men but lower total 25OHD levels [DBP: women, mean (SD) 339 (36) mg/l, men 307 (71) mg/l, P = 0.005; 25OHD: women 67 (23) nmol/l, men 91 (39) nmol/l, P < 0.001]. In women, there were significant positive relationships between DBP and albumin (r = 0.33) and 25OHD (r = 0.34) whereas in men there were no significant relationships between DBP and any measured variables. There was no significant relationship between DBP and age, body weight, body mass index, fat mass or percentage fat in men or women., Conclusion: We found no evidence to support the hypothesis that DBP levels are related to age, or adiposity. The changes in 25OHD levels with age, gender, or fat mass are not due to underlying relationships between DBP and these variables. This suggests that the relationships consistently observed between 25OHD and body composition and gender are of biological origin and not due to adaptation to changes in transport proteins.

Studies performed in the Northern Hemisphere and in areas distant from the equator have demonstrated significant seasonal variation in 25-hydroxyvitamin D (25OHD) levels. Whether such variation occurs in a subtropical area such as Australasia is not clear. We performed a cross-sectional study of 1,606 healthy, postmenopausal women recruited over a 33-month period. The study had three goals: to determine the normal levels of 25OHD in healthy postmenopausal women living in Auckland, New Zealand; to determine whether seasonal variation of 25OHD occurs at this latitude; to assess the relationship between 25OHD, biochemical indices, anthropometric variables and bone mineral density (BMD). We found significant seasonal variation in 25OHD levels, with the change in monthly ultraviolet dose from summer to winter being followed 6-8 weeks later by a corresponding change in 25OHD levels. Vitamin D insufficiency (25OHD <50 nmol/l) was common. During summer, 28-58% of participants had suboptimal vitamin D status, while in winter, the frequency increased to 56-74%. 25OHD levels correlated with participants' age (r=-0.15), weight (r=-0.11), body mass index (r=-0.13), fat mass (r=-0.14), percentage body fat (r=-0.16), physical activity (r=0.10) and the month of blood sampling (all P<0.0001). Collectively, age, fat mass, physical activity, and month of sampling explained 21% of the variance in 25OHD. No significant relationships were noted between 25OHD and BMD at any site. Other variables that showed significant monthly variation were glucose (P=0.002), serum phosphate, alkaline phosphatase, and albumin (all P<0.0001). There was no monthly variation in BMD at the lumbar spine or proximal femur. In conclusion, there is significant seasonal variation in 25OHD levels, even in a subtropical climate. Furthermore, despite generous amounts of sunlight, considerable numbers of women have suboptimal vitamin D status, even in summer. Our findings support the suggestion that vitamin D supplementation should become standard practice in this population of women, particularly during winter.

Two letters to the editor in response to articles published in previous issues including an article on the Women's Health Initiative calcium and vitamin D study, published in a previous issue and its response and an editorial on calcium, vitamin D and cardiovascular risk, published in a previous issue are presented.

A response by Mark J Bolland and colleagues to a letter to the editor about their article "Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set" in the previous issue is presented.