Patient level pooled analysis of 68,500 patients from seven major vitamin D fracture trials in the US and Europe

Objectives To identify participants’ characteristics that influence the anti-fracture efficacy of vitamin D or vitamin D plus calcium with respect to any fracture, hip fracture, and clinical vertebral fracture and to assess the influence of dosing regimens and co-administration of calcium. Design Individual patient data analysis using pooled data from randomised trials. Data sources Seven major randomised trials of vitamin D with calcium or vitamin D alone, yielding a total of 68 517 participants (mean age 69.9 years, range 47-107 years, 14.7% men). Study selection Studies included were randomised studies with at least one intervention arm in which vitamin D was given, fracture as an outcome, and at least 1000 participants. Data synthesis Logistic regression analysis was used to identify significant interaction terms, followed by Cox’s proportional hazards models incorporating age, sex, fracture history, and hormone therapy and bisphosphonate use. Results Trials using vitamin D with calcium showed a reduced overall risk of fracture (hazard ratio 0.92, 95% confidence interval 0.86 to 0.99, P=0.025) and hip fracture (all studies: 0.84, 0.70 to 1.01, P=0.07; studies using 10 μg of vitamin D given with calcium: 0.74, 0.60 to 0.91, P=0.005). For vitamin D alone in daily doses of 10 μg or 20 μg, no significant effects were found. No interaction was found between fracture history and treatment response, nor any interaction with age, sex, or hormone replacement therapy. Conclusion This individual patient data analysis indicates that vitamin D given alone in doses of 10-20 μg is not effective in preventing fractures. By contrast, calcium and vitamin D given together reduce hip fractures and total fractures, and probably vertebral fractures, irrespective of age, sex, or previous fractures.The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. AA acknowledges personal funding from the UK Medical Research Council and Chief Scientist Office of the Scottish Government Health Directorates

Vitamin D and Foot and Ankle Trauma: An individual or societal problem?

Background Vitamin D deficiency is a worldwide health concern. Hypovitaminosis D may adversely affect recovery from bone injury. The authors aimed to perform an audit of the Vitamin D status of patients in three centres in the United Kingdom presenting with foot and ankle osseous damage. Methods Serum 25-hydroxyvitamin-D (vitamin D) levels were obtained in patients presenting with imaging confirmed foot and ankle osseous trauma. Variables including age, gender, ethnicity, location, season, month, anatomical location and type of bone injury were recorded. Results 308 patients were included from three different centres. 66.6% were female. The average age was 47.7 (range; 10–85). The mean hydroxyvitamin-D levels were 52.0 nmol/L (SD 28.5). 18.8% were grossly deficient, 23.7% deficient, 34.7% insufficient and 22.7% within normal range. 351 separate bone injuries were identified of which 104 were categorised as stress reactions, 134 as stress fractures, 105 as fractures and 8 non-unions. Age, gender, anatomical location and fracture type did not statistically affect vitamin D levels. Ethnicity did affect Vitamin D levels: non-Caucasians mean levels were 32.4 nmols/L compared to Caucasian levels of 53.2 nmol/L (p = 0.0026). Conclusion Only 18.8% of our trauma patients had a normal Vitamin D level and 22.7% were grossly deficient. Patient age, gender, anatomical location and injury type did not statistically affect vitamin D levels. No difference between trauma and elective patients were found. Hypovitaminosis D is a problem of society in general rather than specific to certain foot and ankle injury patterns or particular patient groups sustaining trauma. Level of evidence 2b

Hip fracture risk in relation to vitamin D supplementation and serum 25-hydroxyvitamin D levels: a systematic review and meta-analysis of randomised controlled trials and observational studies

<p>Abstract</p> <p>Background</p> <p>Vitamin D supplementation for fracture prevention is widespread despite conflicting interpretation of relevant randomised controlled trial (RCT) evidence. This study summarises quantitatively the current evidence from RCTs and observational studies regarding vitamin D, parathyroid hormone (PTH) and hip fracture risk.</p> <p>Methods</p> <p>We undertook separate meta-analyses of RCTs examining vitamin D supplementation and hip fracture, and observational studies of serum vitamin D status (25-hydroxyvitamin D (25(OH)D) level), PTH and hip fracture. Results from RCTs were combined using the reported hazard ratios/relative risks (RR). Results from case-control studies were combined using the ratio of 25(OH)D and PTH measurements of hip fracture cases compared with controls. Original published studies of vitamin D, PTH and hip fracture were identified through PubMed and Web of Science databases, searches of reference lists and forward citations of key papers.</p> <p>Results</p> <p>The seven eligible RCTs identified showed no significant difference in hip fracture risk in those randomised to cholecalciferol or ergocalciferol supplementation versus placebo/control (RR = 1.13[95%CI 0.98-1.29]; 801 cases), with no significant difference between trials of <800 IU/day and ≥800 IU/day. The 17 identified case-control studies found 33% lower serum 25(OH)D levels in cases compared to controls, based on 1903 cases. This difference was significantly greater in studies with population-based compared to hospital-based controls (χ²₁(heterogeneity) = 51.02, p < 0.001) and significant heterogeneity was present overall (χ²₁₆(heterogeneity) = 137.9, p < 0.001). Serum PTH levels in hip fracture cases did not differ significantly from controls, based on ten case-control studies with 905 cases (χ²₉(heterogeneity) = 149.68, p < 0.001).</p> <p>Conclusions</p> <p>Neither higher nor lower dose vitamin D supplementation prevented hip fracture. Randomised and observational data on vitamin D and hip fracture appear to differ. The reason for this is unclear; one possible explanation is uncontrolled confounding in observational studies. Post-fracture PTH levels are unrelated to hip fracture risk.</p

Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe.

ObjectivesTo identify participants' characteristics that influence the anti-fracture efficacy of vitamin D or vitamin D plus calcium with respect to any fracture, hip fracture, and clinical vertebral fracture and to assess the influence of dosing regimens and co-administration of calcium.DesignIndividual patient data analysis using pooled data from randomised trials.Data sourcesSeven major randomised trials of vitamin D with calcium or vitamin D alone, yielding a total of 68 517 participants (mean age 69.9 years, range 47-107 years, 14.7% men).Study selectionStudies included were randomised studies with at least one intervention arm in which vitamin D was given, fracture as an outcome, and at least 1000 participants.Data synthesisLogistic regression analysis was used to identify significant interaction terms, followed by Cox's proportional hazards models incorporating age, sex, fracture history, and hormone therapy and bisphosphonate use.ResultsTrials using vitamin D with calcium showed a reduced overall risk of fracture (hazard ratio 0.92, 95% confidence interval 0.86 to 0.99, P=0.025) and hip fracture (all studies: 0.84, 0.70 to 1.01, P=0.07; studies using 10 microg of vitamin D given with calcium: 0.74, 0.60 to 0.91, P=0.005). For vitamin D alone in daily doses of 10 microg or 20 microg, no significant effects were found. No interaction was found between fracture history and treatment response, nor any interaction with age, sex, or hormone replacement therapy.ConclusionThis individual patient data analysis indicates that vitamin D given alone in doses of 10-20 microg is not effective in preventing fractures. By contrast, calcium and vitamin D given together reduce hip fractures and total fractures, and probably vertebral fractures, irrespective of age, sex, or previous fractures

Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe.

ObjectivesTo identify participants' characteristics that influence the anti-fracture efficacy of vitamin D or vitamin D plus calcium with respect to any fracture, hip fracture, and clinical vertebral fracture and to assess the influence of dosing regimens and co-administration of calcium.DesignIndividual patient data analysis using pooled data from randomised trials.Data sourcesSeven major randomised trials of vitamin D with calcium or vitamin D alone, yielding a total of 68 517 participants (mean age 69.9 years, range 47-107 years, 14.7% men).Study selectionStudies included were randomised studies with at least one intervention arm in which vitamin D was given, fracture as an outcome, and at least 1000 participants.Data synthesisLogistic regression analysis was used to identify significant interaction terms, followed by Cox's proportional hazards models incorporating age, sex, fracture history, and hormone therapy and bisphosphonate use.ResultsTrials using vitamin D with calcium showed a reduced overall risk of fracture (hazard ratio 0.92, 95% confidence interval 0.86 to 0.99, P=0.025) and hip fracture (all studies: 0.84, 0.70 to 1.01, P=0.07; studies using 10 microg of vitamin D given with calcium: 0.74, 0.60 to 0.91, P=0.005). For vitamin D alone in daily doses of 10 microg or 20 microg, no significant effects were found. No interaction was found between fracture history and treatment response, nor any interaction with age, sex, or hormone replacement therapy.ConclusionThis individual patient data analysis indicates that vitamin D given alone in doses of 10-20 microg is not effective in preventing fractures. By contrast, calcium and vitamin D given together reduce hip fractures and total fractures, and probably vertebral fractures, irrespective of age, sex, or previous fractures

Effects of three monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility and muscle strength in older postmenopausal women: a randomised controlled trial

Daily vitamin D in addition to calcium supplementation reduces falls and fractures in older women. However, poor adherence to therapy is a common clinical problem. To examine the effects of supervised oral 3 monthly vitamin D therapy on falls, muscle strength and mobility, we conducted a nine-month randomised, double-blind, placebo-controlled trial in 686 community-dwelling ambulant women aged over 70 years. Participants received either oral cholecalciferol 150,000 IU every 3 months (n = 353) or an identical placebo (n = 333). All participants were advised to increase dietary calcium intake. Falls data were collected three monthly. At baseline, 3, 6 and 9 months, muscle strength was measured by a handheld dynamometer and mobility by the Timed Up and Go (TUG) test. Serum 25 hydroxyvitamin D (25OHD) was measured in a subgroup of 40 subjects. Mean age at baseline was 76.7 ± 4.1 years. The average serum 25OHD value at baseline was 65.8 ± 22.7 nmol/L.By three, six and nine months after supplementation, 25OHD levels of the vitamin D group were approximately 15 nmol/L higher than the placebo group. Calcium intake did not change significantly between baseline (864 ± 412 mg/day) and 9 months (855 ± 357 mg/day). Faller rates in the two groups did not differ: vitamin D group 102/353(29%); placebo group 89/333(27%). At 9 months, compared to placebo or baseline, muscle strength and TUG were not altered by vitamin D. In conclusion, oral cholecalciferol 150,000 IU therapy administered three monthly had neither beneficial nor adverse effects on falls or physical function. These data together with previous findings confirm that intermittent large doses of vitamin D are ineffective or have a deleterious effect on falls. Thus despite adherence issues with daily vitamin D replacement, an intermittent, high dose vitamin D regimen cannot be supported as a strategy to reduce falls and fractures