Robert Theiler

Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials

Objective To test the efficacy of supplemental vitamin D and active forms of vitamin D with or without calcium in preventing falls among older individuals. Data sources We searched Medline, the Cochrane central register of controlled trials, BIOSIS, and Embase up to August 2008 for relevant articles. Further studies were identified by consulting clinical experts, bibliographies, and abstracts. We contacted authors for additional data when necessary. Review methods Only double blind randomised controlled trials of older individuals (mean age 65 years or older) receiving a defined oral dose of supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)) or an active form of vitamin D (1α-hydroxyvitamin D3 (1α-hydroxycalciferol) or 1,25-dihydroxyvitamin D3 (1,25-dihydroxycholecalciferol)) and with sufficiently specified fall assessment were considered for inclusion. Results Eight randomised controlled trials (n=2426) of supplemental vitamin D met our inclusion criteria. Heterogeneity among trials was observed for dose of vitamin D (700-1000 IU/day v 200-600 IU/day; P=0.02) and achieved 25-hydroxyvitamin D3 concentration (25(OH)D concentration: <60 nmol/l v ≥60 nmol/l; P=0.005). High dose supplemental vitamin D reduced fall risk by 19% (pooled relative risk (RR) 0.81, 95% CI 0.71 to 0.92; n=1921 from seven trials), whereas achieved serum 25(OH)D concentrations of 60 nmol/l or more resulted in a 23% fall reduction (pooled RR 0.77, 95% CI 0.65 to 0.90). Falls were not notably reduced by low dose supplemental vitamin D (pooled RR 1.10, 95% CI 0.89 to 1.35; n=505 from two trials) or by achieved serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l (pooled RR 1.35, 95% CI 0.98 to 1.84). Two randomised controlled trials (n=624) of active forms of vitamin D met our inclusion criteria. Active forms of vitamin D reduced fall risk by 22% (pooled RR 0.78, 95% CI 0.64 to 0.94). Conclusions Supplemental vitamin D in a dose of 700-1000 IU a day reduced the risk of falling among older individuals by 19% and to a similar degree as active forms of vitamin D. Doses of supplemental vitamin D of less than 700 IU or serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l may not reduce the risk of falling among older individuals.

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.).

Muscle strength in the elderly: Its relation to vitamin d metabolites

OBJECTIVE To identify a relation between loss of muscle strength and vitamin D deficiency in ambulatory elderly persons not receiving vitamin D supplementation. DESIGN Cross-sectional study. SETTING All measurements were taken at the Department of Geriatrics, University Hospital, Basel, Switzerland. SUBJECTS Three hundred nineteen patients (103 women, 216 men) selected by random sampling from participants in an ongoing interdisciplinary study on aging (mean age for women, 74.2 yrs; for men, 76.7 yrs). OUTCOME MEASURES Leg extension power (LEP) and body mass index (BMI); serum values of 25-hydroxyvitamin D [calcidiol, 25(OH)D], 1,25-hydroxyvitamin D [calcitriol, 1,25(OH)2D], and intact parathyroid hormone (iPHT). RESULTS Twelve percent of women and 18% of men had 25(OH)D values below the normal range (<12 ng/mL). Muscle strength was lower in older subjects (female: r = -.35; p = .0005/male: r = -.48; p < .0001) and was lower in women than in men (p < .0001). In men both 25(OH)D and 1,25(OH)2D was significantly correlated with LEP (r = 0.24; p = .0004/r = .14; p = .045). In women, only 1,25(OH)2D was significantly correlated with LEP (r = 0.22; p = .034). In an ANCOVA including all participants and explaining LEP by sex, age, BMI, 1,25(OH)2D, 25(OH)D, and iPTH, all factors showed significant effects except 25(OH)D and iPTH (r2 = .41). CONCLUSION Muscle strength declined with age in ambulatory elderly people and showed modest, but significant, positive correlation with 1,25(OH)2 vitamin D in both sexes and with 25(OH)D in male subjects. Therefore vitamin D deficiency appears to contribute to the age-related loss of muscle strength, which might be more pronounced in institutionalized elderly people with a high prevalence of vitamin D deficiency.

Monthly High-Dose Vitamin D Treatment for the Prevention of Functional Decline: A Randomized Clinical Trial

IMPORTANCE Vitamin D deficiency has been associated with poor physical performance. OBJECTIVE To determine the effectiveness of high-dose vitamin D in lowering the risk of functional decline. DESIGN, SETTING, AND PARTICIPANTS One-year, double-blind, randomized clinical trial conducted in Zurich, Switzerland. The screening phase was December 1, 2009, to May 31, 2010, and the last study visit was in May 2011. The dates of our analysis were June 15, 2012, to October 10, 2015. Participants were 200 community-dwelling men and women 70 years and older with a prior fall. INTERVENTIONS Three study groups with monthly treatments, including a low-dose control group receiving 24,000 IU of vitamin D3 (24,000 IU group), a group receiving 60,000 IU of vitamin D3 (60,000 IU group), and a group receiving 24,000 IU of vitamin D3 plus 300 μg of calcifediol (24,000 IU plus calcifediol group). MAIN OUTCOMES AND MEASURES The primary end point was improving lower extremity function (on the Short Physical Performance Battery) and achieving 25-hydroxyvitamin D levels of at least 30 ng/mL at 6 and 12 months. A secondary end point was monthly reported falls. Analyses were adjusted for age, sex, and body mass index. RESULTS The study cohort comprised 200 participants (men and women ≥ 70 years with a prior fall). Their mean age was 78 years, 67.0% (134 of 200) were female, and 58.0% (116 of 200) were vitamin D deficient (<20 ng/mL) at baseline. Intent-to-treat analyses showed that, while 60,000 IU and 24,000 IU plus calcifediol were more likely than 24,000 IU to result in 25-hydroxyvitamin D levels of at least 30 ng/mL (P = .001), they were not more effective in improving lower extremity function, which did not differ among the treatment groups (P = .26). However, over the 12-month follow-up, the incidence of falls differed significantly among the treatment groups, with higher incidences in the 60,000 IU group (66.9%; 95% CI, 54.4% to 77.5%) and the 24,000 IU plus calcifediol group (66.1%; 95% CI, 53.5%-76.8%) group compared with the 24,000 IU group (47.9%; 95% CI, 35.8%-60.3%) (P = .048). Consistent with the incidence of falls, the mean number of falls differed marginally by treatment group. The 60,000 IU group (mean, 1.47) and the 24,000 IU plus calcifediol group (mean, 1.24) had higher mean numbers of falls compared with the 24,000 IU group (mean, 0.94) (P = .09). CONCLUSIONS AND RELEVANCE Although higher monthly doses of vitamin D were effective in reaching a threshold of at least 30 ng/mL of 25-hydroxyvitamin D, they had no benefit on lower extremity function and were associated with increased risk of falls compared with 24,000 IU. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01017354.

Effect of High-Dosage Cholecalciferol and Extended Physiotherapy on Complications After Hip Fracture: A Randomized Controlled Trial

BACKGROUND Care of elderly patients after hip fracture is not well established. METHODS We enrolled 173 patients with acute hip fracture who were 65 years or older (79.2% women; mean age, 84 years; 77.4% living at home). Using a factorial design, we randomly allocated patients to extended physiotherapy (PT) (supervised 60 min/d during acute care plus an unsupervised home program) vs standard PT (supervised 30 min/d during acute care plus no home program; single-blinded), and to cholecalciferol therapy, 2000 vs 800 IU/d (double-blinded). Primary outcome was rate of falls; secondary outcome was rate of hospital readmissions during the 12-month follow-up. All analyses included 173 individuals and used multivariate Poisson regression analyses. RESULTS At baseline, 50.9% of participants had 25-hydroxyvitamin D levels of less than 12 ng/mL and 97.7% of less than 30 ng/mL. We documented 212 falls and 74 hospital readmissions. Because this was a factorial design trial, all analyses tested the main effect of each treatment while controlling for the other in 173 participants. Extended vs standard PT reduced the rate of falls by 25% (95% confidence interval [CI], -44% to -1%). Cholecalciferol treatment, 2000 vs 800 IU/d, did not reduce falls (28%; 95% CI, -4% to 68%), but reduced the rate of hospital readmissions by 39% (95% CI, -62% to -1%). CONCLUSIONS Extended PT was successful in reducing falls but not hospital readmissions, whereas cholecalciferol treatment, 2000 IU/d, was successful in reducing hospital readmission but not falls. Thus, the 2 strategies may be useful together because they address 2 different and important complications after hip fracture.

Severe vitamin D deficiency in Swiss hip fracture patients

BACKGROUND Most clinical guidelines for the prevention of hip fractures recommend 800 IU vitamin D per day. This dose shifted serum 25-hydroxyvitamin D levels (25(OH)D) in previous studies to between 60 and 100 nmol/l. AIM To measure 25(OH)D levels and prevalence of vitamin D supplementation in individuals age 65+ with acute hip fracture. METHODS 222 consecutive hip fracture patients were investigated over a 12 month period. Mean age of patients was 86 years and 77% were women. RESULTS Mean serum 25(OH)D levels were low among hip fracture patients admitted from home (34.6 nmol/l), from assisted living (27.7 nmol/l), and from nursing homes (24 nmol/l). Severe vitamin D deficiency below 30 nmol/l was present in 60%, 80% were below 50 nmol/l, and less than 4% reached desirable levels of at least 75 nmol/l. Consistently, only 10% of hip fracture patients had any vitamin D supplementation on admission to acute care with significantly higher 25(OH)D levels among individuals supplemented with 800-880 IU/day (63.5 nmol/l). Controlling for age and gender, vitamin D supplementation, type of dwelling, and season were independently and significantly associated with 25(OH)D levels. CONCLUSION These data provide evidence that current guidelines for the prevention of hip fractures need further effort to be translated into clinical practice.

Prediction of Hip Fracture Risk by Quantitative Ultrasound in More Than 7000 Swiss Women ≥70 Years of Age: Comparison of Three Technologically Different Bone Ultrasound Devices in the SEMOF Study†‡

To compare the prediction of hip fracture risk of several bone ultrasounds (QUS), 7062 Swiss women ≥70 years of age were measured with three QUSs (two of the heel, one of the phalanges). Heel QUSs were both predictive of hip fracture risk, whereas the phalanges QUS was not.

Comparison of three bone ultrasounds for the discrimination of subjects with and without osteoporotic fractures among 7562 elderly women

Bone ultrasound measures (QUSs) can assess fracture risk in the elderly. We compared three QUSs and their association with nonvertebral fracture history in 7562 Swiss women 70–80 years of age. The association between nonvertebral fracture was higher for heel than phalangeal QUS.

Immobility as a Major Cause of Bone Remodeling in Residents of a Long-Stay Geriatric Ward

Residents of a long-stay geriatric ward at the University Hospital Basel were included in a study to investigate the effects of hypovitaminosis D and immobility. All 91 women (mean age 82.5 years) and 92 men (mean age 78.7 years) were enrolled in the study. Measurements included bone resorption, as measured by urinary deoxypyridinoline (dpd), serum 25-hydroxyvitamin D (25OHD), serum intact parathyroid hormone (iPTH), and their correlations with a four grade mobility score. Mobility score reflected the degree of weight bearing, ranging from walking independently to primarily bed bound. In 86% of all residents, serum 25OHD levels were below the normal limit of 12 ng/ml. Secondary hyperparathyroidism (HPT) was detected in 24% of all patients, using 55 pg/ml as the upper limit for serum iPTH. No significant correlation was found between urinary dpd and serum 25OHD or serum iPTH. Mobility index and both urinary dpd (f: P= 0.001, r = 0.37; m: P < 0.0001, r= 0.47) and serum calcium (female: P= 0.007, r = 0.28; male: P= 0.02, r= 0.24) were positively related. In institutionalized elderly people with a high prevalence of vitamin D deficiency serum intact PTH levels did not correlate with bone resorption as measured by urinary deoxypyridinolin. However, more immobile subjects had significantly higher excretion rates for urinary dpd and higher serum calcium levels. Our results suggest that in elderly people immobility may contribute to bone loss that might preempt the development of secondary HPT through elevation of serum calcium.

Clinical, biochemical and imaging methods of assessing osteoarthritis and clinical trials with agents claiming 'chondromodulating' activity.

This paper reviews, in a first part, methods used for the clinical assessment of osteoarthritis (OA) with special reference, in a second part, to trials of drugs claimed to be chondromodulating agents. The agents examined include glycosaminoglycan-peptide complex (GP-C, Rumalon) and glycosaminoglycan-polysulfate (GAGPS, Arteparon), which both showed some beneficial clinical response. However, their effect on cartilage still remains controversial. The development of a functional hip and knee OA index in clinical assessment and the role of imaging methods and biochemical markers are discussed. In future clinical trials only validated OA indices such as the Lequesne or WOMAC index and the newly established ILAR guidelines for classifying and testing drugs in OA will be accepted for registration purposes. Imaging methods including magnetic resonance imaging (MRI) offer the capacity to provide more precise information concerning cartilage destruction in OA joints. In addition, the biochemical assessment of proteoglycan fragments, bone sialoprotein (BSP), cartilage oligometric matrix protein (COMP) and the balance between stromelysin and its inhibitor (TIMP) in synovial fluid would appear to offer potential applications for the determination of joint tissue damage in the early and later stages of OA. However, these biochemical markers have yet to be validated. It is clear that in the 1990s, for a drug to be designated as disease modifying in OA, it will require a more rigorous evaluation than was hitherto required.