Call to action: a five nations consensus on the use of intravenous zoledronate after hip fracture.

Currently in the UK and Ireland, after a hip fracture most patients do not receive bone protection medication to reduce the risk of refracture. Yet randomised controlled trial data specifically examining patients with hip fracture have shown that intravenous zoledronate reduces refracture risk by a third. Despite this evidence, use of intravenous zoledronate is highly variable following a hip fracture; many hospitals are providing this treatment, whilst most are currently not. A range of clinical uncertainties, doubts over the evidence base and practical concerns are cited as reasons. This paper discusses these concerns and provides guidance from expert consensus, aiming to assist orthogeriatricians, pharmacists and health services managers establish local protocols to deliver this highly clinically and cost-effective treatment to patients before they leave hospital, in order to reduce costly re-fractures in this frail population.

Vitamin D status in postmenopausal women living at higher latitudes in the UK in relation to bone health, overweight, sunlight exposure and dietary vitamin D.

For 5 months a year the UK has insufficient sunlight for cutaneous synthesis of vitamin D and winter requirements are met from stores made the previous summer. Although there are few natural dietary sources, dietary intake may help maintain vitamin D status. We investigated the relationship between 25-hydroxyvitamin D (25(OH)D), bone health, overweight, sunlight exposure and dietary vitamin D in 3113 women (age 54.8 [SD 2.3] years) living at latitude 57 degrees N between 1998-2000. Serum 25(OH)D was measured by high performance liquid chromatography (HPLC), dietary intakes (food frequency questionnaire, n=2598), sunlight exposure (questionnaire, n=2402) and bone markers were assessed. Bone mineral density (BMD) was measured by dual x-ray absorptiometry in all women at the sampling visit and 6 years before. Seasonal variation in 25(OH)D was not substantial with a peak in the autumn (23.7 [9.9] ng/ml) and a nadir in spring (19.7 [7.6] ng/ml). Daily intake of vitamin D was 4.2 [2.5] mug from food only and 5.8 [4.0] mug including vitamin D from cod liver oil and multivitamins. The latter was associated with 25(OH)D at each season whereas vitamin D simply from food was associated with 25(OH)D in winter and spring only. Sunlight exposure was associated with 25(OH)D in summer and autumn. 25(OH)D was negatively associated with increased bone resorption and bone loss (P<0.05) remaining significant after adjustment for confounders (age, weight, height, menopausal status/HRT use, physical activity and socio-economic status). Using an insufficiency cut-off of <28 ng/ml 25(OH)D, showed lower concentrations of bone resorption markers in the upper category (fDPD/Cr 5.1 [1.7] nmol/mmol compared to 5.3 [2.1] nmol/mmol, P=0.03) and no difference in BMD or bone loss. 25(OH)D was lower (P<0.01) and parathyroid hormone higher (P<0.01) in the top quintile of body mass index. In conclusion, low vitamin D status is associated with greater bone turnover, bone loss and obesity. Diet appears to attenuate the seasonal variation of vitamin D status in early postmenopausal women at northerly latitude where quality of sunlight for production of vitamin D is diminished.

A high anticholinergic burden is associated with a history of falls in the previous year in middle-aged women: findings from the Aberdeen Prospective Osteoporosis Screening Study.

PURPOSE: To examine the cross-sectional association between anticholinergic medication burden (ACB) and a history of falls, bone mineral density, and low trauma fractures in middle-aged women aged under 65 years from the Aberdeen Prospective Osteoporosis Screening Study. METHODS: ACB (0 = none, 1 = possible, ≥2 = definite) was calculated from medication use for 3883 Caucasian women [mean age (SD) = 54.3 (2.3) years] attending the second Aberdeen Prospective Osteoporosis Screening Study visit (1997-2000). Outcomes were examined using logistic regression. Model adjustments were selected a priori based on expert opinion. RESULTS: Of 3883 participants, 3293 scored ACB = 0, 328 scored ACB = 1, and 262 scored ACB ≥2. High ACB burden (≥2) was associated with increased odds (ACB = 0 reference) for falls (fully adjusted odds ratio [95% confidence intervals] = 1.81 [1.25-2.62]; P = 0.002) and having low bone mineral density (lowest quintile-20%) at Ward's triangle (3.22 [1.30-7.99]; P = 0.01). A history of falls over the year prior to the study visit in participants with ACB score ≥2 was 32 per 100. For ACB categories 1 and 0, a history of falls per 100 was 21 and 22, respectively. CONCLUSIONS: The risk of falling associated with ACB observed in older age may also extend to middle-aged women.

Large-scale population-based study shows no evidence of association between common polymorphism of the VDR gene and BMD in British women.

UNLABELLED: The VDR is a candidate gene for osteoporosis. Here we studied five common polymorphisms of VDR in relation to calcium intake and vitamin D status in a population-based cohort of 3100 British women, but found no significant association with bone mass, bone loss, or fracture. INTRODUCTION: Population studies of vitamin D receptor (VDR) polymorphisms have produced conflicting results. We performed a comprehensive study dealing with all potential confounders in a large population to determine whether polymorphisms in the VDR gene influence bone health. MATERIALS AND METHODS: We studied 3100 women (50-63 years old) with bone markers, 25-hydroxyvitamin D, calcium, PTH, diet, and physical activity collected in 1998-2000. BMD was measured in 1990-1994 and 1998-2000. Fracture prevalence was assessed in 2002. Women were genotyped for five polymorphisms in the VDR gene: Cdx-2, Fok1, Bsm1, Apa1, and Taq1. The relationship between VDR and BMD, and interactions between VDR genotype, dietary calcium, and 25-hydroxyvitamin D, were examined using analysis of covariance. RESULTS: Compared with carriers of the G allele, homozygotes for the rare Cdx-2 A polymorphism (n = 136) had less bone loss (-0.5 +/- 1.2 versus -0.7 +/- 1.0%/year [SD]; p = 0.01) and lower PTH (3.0 +/- 1.6 versus 3.4 +/- 2.0 pM; p = 0.03) despite similar vitamin D status. The association was not significant after correction for multiple testing or adjustment for confounders. At low calcium intakes, AA homozygotes had greater femoral neck (FN) BMD compared with carriers of the G allele, but at higher calcium intakes, the association was reversed. At low calcium intake, homozygotes for the b allele of Bsm1 had greater BMD compared with carriers of the B allele, but at higher calcium intakes, there was no difference. Similar results were seen for the Taq1 polymorphism. There was no evidence of gene-nutrient interaction when adjusted for body weight. No interactions between genotypes and vitamin D status on BMD were observed. CONCLUSIONS: VDR does not seem to influence BMD or bone turnover in early postmenopausal white women with adequate calcium intake. Gene-nutrient interactions on BMD may be an indirect consequence of interactions between genotype and calcium intake on weight.

Seasonal variation in 25(OH)D at Aberdeen (57°N) and bone health indicators--could holidays in the sun and cod liver oil supplements alleviate deficiency?

Vitamin D has been linked with many health outcomes. The aim of this longitudinal study, was to assess predictors of seasonal variation of 25-hydroxy-vitamin D (25(OH)D) (including use of supplements and holidays in sunny destinations) at a northerly latitude in the UK (57°N) in relation to bone health indicators. 365 healthy postmenopausal women (mean age 62.0 y (SD 1.4)) had 25(OH)D measurements by immunoassay, serum C-telopeptide (CTX), estimates of sunlight exposure (badges of polysulphone film), information regarding holidays in sunny destinations, and diet (from food diaries, including use of supplements such as cod liver oil (CLO)) at fixed 3-monthly intervals over 15 months (subject retention 88%) with an additional 25(OH)D assessment in spring 2008. Bone mineral density (BMD) at the lumbar spine (LS) and dual hip was measured in autumn 2006 and spring 2007 (Lunar I-DXA). Deficiency prevalence (25(OH)D<25 nmol/L) was reduced in women who went on holiday to sunny destinations 3 months prior to their visit, compared to women who did not go on holidays [5.4% vs. 24.6% in Spring (p<0.001) and 3.8% vs. 25.6% in Winter (p = 0.001), respectively]. Similarly deficiency was lower amongst those who took CLO supplements compared to women that did not consume these supplements [2.0% vs. 23.7% in Spring (p = 0.001) and 4.5% vs. 24.8% in winter (p = 0.005), respectively]. There was no seasonal variation in CTX; 25(OH)D predicted a small proportion (1.8% variation) of LS BMD in spring 2007 [unstandardized ß (SE): 0.039 (0.016), p = 0.017]. Seasonal variation of 25(OH)D had little effect on BMD and no effect on CTX. It appears that small increments in vitamin D (e.g. those that can be achieved by cod liver oil supplements of 5 µg/day) are sufficient to ensure that 25(OH)D is above 25 nmol/L for most people throughout the year. Similarly, holidays in sunny destinations show benefit.

Hip bone loss is attenuated with 1000 IU but not 400 IU daily vitamin D3: a 1-year double-blind RCT in postmenopausal women.

Few year-long vitamin D supplementation trials exist that match seasonal changes. The aim of this study was to determine whether daily oral vitamin D3 at 400 IU or 1000 IU compared with placebo affects annual bone mineral density (BMD) change in postmenopausal women in a 1-year double-blind placebo controlled trial in Scotland. White women aged 60 to 70 years (n = 305) were randomized to one of two doses of vitamin D or placebo. All participants started simultaneously in January/February 2009, attending visits at bimonthly intervals with 265 (87%) women attending the final visit and an additional visit 1 month after treatment cessation. BMD (Lunar iDXA) and 1,25-dihydroxyvitamin D[1,25(OH)2 D], N-terminal propeptide of type 1 collagen [P1NP], C-terminal telopeptide of type I collagen [CTX], and fibroblast growth factor-23 [FGF23] were measured by immunoassay at the start and end of treatment. Circulating PTH, serum Ca, and total 25-hydroxyvitamin D [25(OH)D] (latter by tandem mass spectrometry) were measured at each visit. Mean BMD loss at the hip was significantly less for the 1000 IU vitamin D group (0.05% ± 1.46%) compared with the 400 IU vitamin D or placebo groups (0.57% ± 1.33% and 0.60% ± 1.67%, respectively) (p < 0.05). Mean (± SD) baseline 25(OH)D was 33.8 ± 14.6 nmol/L; comparative 25(OH)D change for the placebo, 400 IU, and 1000 IU vitamin D groups was -4.1 ± 11.5 nmol/L, +31.6 ± 19.8 nmol/L, and +42.6 ± 18.9 nmol/L, respectively. Treatment did not change markers of bone metabolism, except for a small reduction in PTH and an increase in serum calcium (latter with 1000 IU dose only). The discordance between the incremental increase in 25(OH)D between the 400 IU and 1000 IU vitamin D and effect on BMD suggests that 25(OH)D may not accurately reflect clinical outcome, nor how much vitamin D is being stored.

Vitamin D3 supplementation has no effect on conventional cardiovascular risk factors: a parallel-group, double-blind, placebo-controlled RCT.

CONTEXT: Observational studies show an association between low vitamin D status assessed by circulating 25-hydroxyvitamin D and cardiovascular events and mortality. Data from randomized controlled trials are limited. OBJECTIVE: The aim of this study was to test whether daily doses of vitamin D(3) at 400 or 1000 IU/d for 1 yr affected conventional markers of cardiovascular disease (CVD) risk. DESIGN: We conducted a parallel-group, double-blind, placebo-controlled randomized controlled trial. Randomization was computer generated. Participants and study investigators were blinded to intervention groupings throughout the trial. SETTING: The study was conducted at the Clinical Research Facility, University of Aberdeen, United Kingdom. PARTICIPANTS: A total of 305 healthy postmenopausal women aged 60-70 yr were recruited for the study. INTERVENTION: Each woman received a daily capsule of 400 or 1000 IU vitamin D(3) or placebo randomly allocated. MAIN OUTCOME MEASURES: Primary outcomes were serum lipid profile [total, high-density lipoprotein, and low-density lipoprotein cholesterol; triglycerides; and apolipoproteins A-1 and B100], insulin resistance (homeostatic model assessment), inflammatory biomarkers (high-sensitivity C-reactive protein, IL-6, soluble intracellular adhesion molecule-1), and blood pressure. RESULTS: A total of 265 (87%) participants completed all study visits. Small differences between groups for serum apolipoprotein B100 change [repeated measures ANOVA, P=0.04; mean (sd), -1.0 (10.0) mg/dl (400 IU); -1.0 (10.0) mg/dl (1000 IU); and +0.02 (10.0) mg/dl (placebo)] were not considered clinically significant. Other systemic markers for CVD risk remained unchanged. There was significant seasonal variation in systolic and diastolic blood pressure independent of vitamin D dose (P<0.001, linear mixed model). Mean (sd) reduction in systolic blood pressure from winter to summer was -6.6 (10.8) mm Hg. CONCLUSIONS: Improving vitamin D status through dietary supplementation is unlikely to reduce CVD risk factors. Confounding of seasonality should be recognized and addressed in future studies of vitamin D.

Effect of potassium citrate supplementation or increased fruit and vegetable intake on bone metabolism in healthy postmenopausal women: a randomized controlled trial.

BACKGROUND: Alkali provision may explain why fruit and vegetables benefit bone health. OBJECTIVE: We aimed to determine the effects of alkali-providing potassium citrate (double-blind) and fruit and vegetable intake (single-blind) on bone turnover over 2 y. DESIGN: We conducted a randomized placebo-controlled trial in 276 postmenopausal women (aged 55-65 y). Women were randomly assigned to 4 groups: high-dose potassium citrate (55.5 mEq/d), low-dose potassium citrate (18.5 mEq/d), placebo, and 300 g additional fruit and vegetables/d (equivalent of 18.5 mEq alkali). Serum and fasted urine for bone markers were collected at baseline and at 3, 6, 12, 18, and 24 mo. An additional urine sample was collected at 4-6 wk. Bone mineral density (BMD) was measured at baseline and 2 y. RESULTS: Repeated-measures ANOVA showed no difference between groups for urinary free deoxypyridinoline cross-links relative to creatinine (fDPD/Cr), serum N-terminal propeptide of type 1 collagen, or beta C-terminal telopeptide, although, at 4-6 wk, fDPD/Cr was lower in the high-dose potassium citrate group (P = 0.04). Mean +/- SD spine BMD loss in the placebo group (1.8 +/- 3.9%) did not differ significantly from that in the treatment groups (2.1 +/- 3.2%; P = 0.88). Hip BMD loss in the placebo and low-dose potassium citrate groups was 1.3 +/- 2.3% and 2.2 +/- 2.3%, respectively (P = 0.14). CONCLUSIONS: Two-year potassium citrate supplementation does not reduce bone turnover or increase BMD in healthy postmenopausal women, which suggests that alkali provision does not explain any long-term benefit of fruit and vegetable intake on bone.