Kerrie M. Sanders

Annual high-dose oral vitamin D and falls and fractures in older women: A randomized controlled trial

CONTEXT Improving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor. OBJECTIVE To determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture. DESIGN, SETTING, AND PARTICIPANTS A double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008. INTERVENTION 500,000 IU of cholecalciferol or placebo. MAIN OUTCOME MEASURES Falls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels. RESULTS Women in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing. CONCLUSION Among older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures. TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12605000658617; isrctn.org Identifier: ISRCTN83409867.

A Pooled Analysis of Vitamin D Dose Requirements for Fracture Prevention

BACKGROUND The results of meta-analyses examining the relationship between vitamin D supplementation and fracture reduction have been inconsistent. METHODS We pooled participant-level data from 11 double-blind, randomized, controlled trials of oral vitamin D supplementation (daily, weekly, or every 4 months), with or without calcium, as compared with placebo or calcium alone in persons 65 years of age or older. Primary end points were the incidence of hip and any nonvertebral fractures according to Cox regression analyses, with adjustment for age group, sex, type of dwelling, and study. Our primary aim was to compare data from quartiles of actual intake of vitamin D (including each individual participants adherence to the treatment and supplement use outside the study protocol) in the treatment groups of all trials with data from the control groups. RESULTS We included 31,022 persons (mean age, 76 years; 91% women) with 1111 incident hip fractures and 3770 nonvertebral fractures. Participants who were randomly assigned to receive vitamin D, as compared with those assigned to control groups, had a nonsignificant 10% reduction in the risk of hip fracture (hazard ratio, 0.90; 95% confidence interval [CI], 0.80 to 1.01) and a 7% reduction in the risk of nonvertebral fracture (hazard ratio, 0.93; 95% CI, 0.87 to 0.99). By quartiles of actual intake, reduction in the risk of fracture was shown only at the highest intake level (median, 800 IU daily; range, 792 to 2000), with a 30% reduction in the risk of hip fracture (hazard ratio, 0.70; 95% CI, 0.58 to 0.86) and a 14% reduction in the risk of any nonvertebral fracture (hazard ratio, 0.86; 95% CI, 0.76 to 0.96). Benefits at the highest level of vitamin D intake were fairly consistent across subgroups defined by age group, type of dwelling, baseline 25-hydroxyvitamin D level, and additional calcium intake. CONCLUSIONS High-dose vitamin D supplementation (≥800 IU daily) was somewhat favorable in the prevention of hip fracture and any nonvertebral fracture in persons 65 years of age or older. (Funded by the Swiss National Foundations and others.).

Age- and Gender-Specific Rate of Fractures in Australia: A Population-Based Study

Abstract: There is little population-based data concerning fracture rates in Australia. We ascertained all fractures occurring during 2 years in adults aged 35 years and over residing within a defined region (population 218 000), representative of the Australian population. The major strength of this study is the comprehensive ascertainment of fractures, which was ensured by regular searches of the only two radiologic providers in the Geelong Osteoporosis Study region. Nevertheless, vertebral fractures are likely to be underestimated since our ascertainment relied on a clinical indication for a medical imaging procedure. Among those aged 35 – 55 years, the fracture rate (persons per 10 000/year) in men was about double the rate in women (65 vs 35). The fracture rate was almost 7 times higher in women over 60 years versus women less than 55 years of age. In contrast, the fracture rate in men over 60 years was only 50% higher than in men less than 55 years of age (72 vs 104). Fracture rates in women and men were highest at the hip (28 and 10 respectively), spine (21 and 7), distal forearm (Colles’) (18 and 4) and humerus (11 and 3), and were 3–4 times higher in women than men. These fractures accounted for 63% of all fractures in women and 32% in men. By contrast, the rate of lower leg and ankle fractures was less than 10 per 10 000 in both women and men and did not increase to the same extent with age. Hip fracture rates appear high, particularly among the older age strata, compared with retrospective ascertainment in other populations. In Australia, as in many other countries, there is an increasing longevity of the population. The number of women aged 90 years and over increased by 32% and the number of men of this age increased by 48% in the 5 years between the Australian national census of 1991 and 1996. Given stable fracture rates, the substantial health burden imposed by age-related fractures, particularly hip fractures, will continue to escalate in both women and men.

The Exclusion of High Trauma Fractures May Underestimate the Prevalence of Bone Fragility Fractures in the Community: The Geelong Osteoporosis Study

Fractures associated with severe trauma are generally excluded from estimates of the prevalence of osteoporotic fractures in the community. Because the degree of trauma is difficult to quantitate, low bone mass may contribute to fractures following severe trauma. We ascertained all fractures in a defined population and compared the bone mineral density (BMD) of women who sustained fractures in either “low” or “high” trauma events with the BMD of a random sample of women from the same population. BMD was measured by dual‐energy X‐ray absorptiometry and expressed as a standardized deviation (Z score) adjusted for age. The BMD Z scores (mean ± SEM) were reduced in both the low and high trauma groups, respectively: spine‐posterior‐anterior (−0.50 ± 0.05 and −0.21 ± 0.08), spine‐lateral (−0.28 ± 0.06 and −0.19 ± 0.10), femoral neck (−0.42 ± 0.04 and −0.26 ± 0.09), Wards triangle (−0.44 ± 0.04 and −0.28 ± 0.08), trochanter (−0.44 ± 0.05 and −0.32 ± 0.08), total body (−0.46 ± 0.06 and −0.32 ± 0.08), ultradistal radius (−0.47 ± 0.05 and −0.42 ± 0.07), and midradius (−0.52 ± 0.06 and −0.33 ± 0.09). Except at the PA spine, the deficits were no smaller in the high trauma group. Compared with the population, the age‐adjusted odds ratio for osteoporosis (t‐score < −2.5) at one or more scanning sites was 3.1 (95% confidence interval 1.9, 5.0) in the high trauma group and 2.7 (1.9, 3.8) in the low trauma group. The data suggest that the exclusion of high trauma fractures in women over 50 years of age may result in underestimation of the contribution of osteoporosis to fractures in the community. Bone density measurement of women over 50 years of age who sustain fractures may be warranted irrespective of the classification of trauma.

Vitamin D and health in adults in Australia and New Zealand: a position statement

The prevalence of vitamin D deficiency varies, with the groups at greatest risk including housebound, community‐dwelling older and/or disabled people, those in residential care, dark‐skinned people (particularly those modestly dressed), and other people who regularly avoid sun exposure or work indoors. Most adults are unlikely to obtain more than 5%–10% of their vitamin D requirement from dietary sources. The main source of vitamin D for people residing in Australia and New Zealand is exposure to sunlight. A serum 25‐hydroxyvitamin D (25‐OHD) level of ≥ 50 nmol/L at the end of winter (10–20 nmol/L higher at the end of summer, to allow for seasonal decrease) is required for optimal musculoskeletal health. Although it is likely that higher serum 25‐OHD levels play a role in the prevention of some disease states, there is insufficient evidence from randomised controlled trials to recommend higher targets. For moderately fair‐skinned people, a walk with arms exposed for 6–7 minutes mid morning or mid afternoon in summer, and with as much bare skin exposed as feasible for 7–40 minutes (depending on latitude) at noon in winter, on most days, is likely to be helpful in maintaining adequate vitamin D levels in the body. When sun exposure is minimal, vitamin D intake from dietary sources and supplementation of at least 600 IU (15 μg) per day for people aged ≤ 70 years and 800 IU (20 μg) per day for those aged > 70 years is recommended. People in high‐risk groups may require higher doses. There is good evidence that vitamin D plus calcium supplementation effectively reduces fractures and falls in older men and women.

Seasonal Periodicity of Serum Vitamin D and Parathyroid Hormone, Bone Resorption, and Fractures: The Geelong Osteoporosis Study

In this population‐based study, seasonal periodicity was seen with reduced serum vitamin D, increased serum PTH, and increased bone resorption in winter. This was associated with an increased proportion of falls resulting in fracture and an increased risk of wrist and hip fractures.

Vitamin D with Calcium Reduces Mortality: Patient Level Pooled Analysis of 70,528 Patients from Eight Major Vitamin D Trials

INTRODUCTION Vitamin D may affect multiple health outcomes. If so, an effect on mortality is to be expected. Using pooled data from randomized controlled trials, we performed individual patient data (IPD) and trial level meta-analyses to assess mortality among participants randomized to either vitamin D alone or vitamin D with calcium. SUBJECTS AND METHODS Through a systematic literature search, we identified 24 randomized controlled trials reporting data on mortality in which vitamin D was given either alone or with calcium. From a total of 13 trials with more than 1000 participants each, eight trials were included in our IPD analysis. Using a stratified Cox regression model, we calculated risk of death during 3 yr of treatment in an intention-to-treat analysis. Also, we performed a trial level meta-analysis including data from all studies. RESULTS The IPD analysis yielded data on 70,528 randomized participants (86.8% females) with a median age of 70 (interquartile range, 62-77) yr. Vitamin D with or without calcium reduced mortality by 7% [hazard ratio, 0.93; 95% confidence interval (CI), 0.88-0.99]. However, vitamin D alone did not affect mortality, but risk of death was reduced if vitamin D was given with calcium (hazard ratio, 0.91; 95% CI, 0.84-0.98). The number needed to treat with vitamin D plus calcium for 3 yr to prevent one death was 151. Trial level meta-analysis (24 trials with 88,097 participants) showed similar results, i.e. mortality was reduced with vitamin D plus calcium (odds ratio, 0.94; 95% CI, 0.88-0.99), but not with vitamin D alone (odds ratio, 0.98; 95% CI, 0.91-1.06). CONCLUSION Vitamin D with calcium reduces mortality in the elderly, whereas available data do not support an effect of vitamin D alone.

Annual high-dose vitamin D3 and mental well-being: randomised controlled trial

BACKGROUND Epidemiological evidence supports a relationship between vitamin D and mental well-being, although evidence from large-scale placebo-controlled intervention trials is lacking. AIMS To examine if vitamin D supplementation has a beneficial effect on mood in community-dwelling older women; if a single annual large dose of vitamin D has a role in the prevention of depressive symptoms; and if there is an association between serum 25-hydroxyvitamin D levels and mental health. METHOD A double-blind, randomised, placebo-controlled trial of women aged 70 or older (the Vital D Study: ISRCTN83409867 and ACTR12605000658617). Participants were randomly assigned to receive 500 000 IU vitamin D(3) (cholecalciferol) orally or placebo every autumn/winter for 3-5 consecutive years. The tools utilised at various time points were the General Health Questionnaire, the 12-item Short Form Health Survey, the Patient Global Impression-Improvement scale and the WHO Well-Being Index. Serum 25-hydroxyvitamin D levels were measured in a subset of 102 participants. RESULTS In this non-clinical population, no significant differences between the vitamin D and placebo groups were detected in any of the measured outcomes of mental health. Serum 25-hydroxyvitamin D levels in the vitamin D group were 41% higher than the placebo group 12 months following their annual dose. Despite this difference, scores from the questionnaires did not differ. Furthermore, there was no interaction between those on antidepressant/anxiety medication at baseline and the treatment groups. CONCLUSIONS The lack of improvement in indices of mental well-being in the vitamin D group does not support the hypothesis that an annual high dose of vitamin D(3) is a practical intervention to prevent depressive symptoms in older community-dwelling women.

Effects of resistance exercise and fortified milk on skeletal muscle mass, muscle size, and functional performance in middle-aged and older men: an 18-mo randomized controlled trial

Limited data have suggested that the consumption of fluid milk after resistance training (RT) may promote skeletal muscle hypertrophy. The aim of this study was to assess whether a milk-based nutritional supplement could enhance the effects of RT on muscle mass, size, strength, and function in middle-aged and older men. This was an 18-mo factorial design (randomized control trial) in which 180 healthy men aged 50-79 yr were allocated to the following groups: 1) exercise + fortified milk, 2) exercise, 3) fortified milk, or 4) control. Exercise consisted of progressive RT with weight-bearing impact exercise. Men assigned to the fortified milk consumed 400 ml/day of low-fat milk, providing an additional 836 kJ, 1000 mg calcium, 800 IU vitamin D(3), and 13.2 g protein per day. Total body lean mass (LM) and fat mass (FM) (dual-energy X-ray absorptiometry), midfemur muscle cross-sectional area (CSA) (quantitative computed tomography), muscle strength, and physical function were assessed. After 18 mo, there was no significant exercise by fortified milk interaction for total body LM, muscle CSA, or any functional measure. However, main effect analyses revealed that exercise significantly improved muscle strength ( approximately 20-52%, P < 0.001), LM (0.6 kg, P < 0.05), FM (-1.1 kg, P < 0.001), muscle CSA (1.8%, P < 0.001), and gait speed (11%, P < 0.05) relative to no exercise. There were no effects of the fortified milk on muscle size, strength, or function. In conclusion, the daily consumption of low-fat fortified milk does not enhance the effects of RT on skeletal muscle size, strength, or function in healthy middle-aged and older men with adequate energy and nutrient intakes.

Fracture rates lower in rural than urban communities: the Geelong Osteoporosis Study

Background: Urban and rural communities differ in the incidence of several diseases including coronary heart disease and some cancers. Lower hip fracture rates among rural than urban populations have been reported but few studies have compared rural and urban fractures at sites other than the hip. Objective: To compare total and site specific fracture rates among adult residents of rural and urban communities within the same population. Design and setting: This is a population based study on osteoporosis in Australia. All fractures occurring in adult residents over a two year period were ascertained using radiological reports. The rural and urban areas are in close proximity, with the same medical, hospital, and radiological facilities permitting uniform fracture ascertainment. Main outcome measures: All fracture rates were age adjusted and sex adjusted to the Australian population according to the 1996 census of the Australian Bureau of Statistics and described as the rate per 10 000 person years. The p values refer to the adjusted rate difference. Results: The hip fracture rate (incidence per 10 000 person years) was 32% lower (39 v 57, p<0.001), and the total fracture rate 15% lower (160 v 188, p=0.004) among rural than urban residents, respectively. The lower fracture rates in the rural population were also apparent for pelvic fractures. Conclusion: In the older rural population, lower fracture rates at sites typically associated with osteoporosis suggest environmental factors may have a different impact on bone health in this community. If the national rate of hip fracture could be reduced to that of the rural population, the projected increase in hip fracture number attributable to aging of the population could be prevented.