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Abstract The etiology of endemic rickets was discovered a century ago. Vitamin D is the precursor of 25-hydroxyvitamin D and other metabolites, including 1,25(OH)2D, the ligand for the vitamin D receptor (VDR). The effects of the vitamin D endocrine system on bone and its growth plate are primarily indirect and mediated by its effect on intestinal calcium transport and serum calcium and phosphate homeostasis. Rickets and osteomalacia can be prevented by daily supplements of 400 IU of vitamin D. Vitamin D deficiency (serum 25-hydroxyvitamin D <50 nmol/L) accelerates bone turnover, bone loss, and osteoporotic fractures. These risks can be reduced by 800 IU of vitamin D together with an appropriate calcium intake, given to institutionalized or vitamin D–deficient elderly subjects. VDR and vitamin D metabolic enzymes are widely expressed. Numerous genetic, molecular, cellular, and animal studies strongly suggest that vitamin D signaling has many extraskeletal effects. These include regulation of cell proliferation, immune and muscle function, skin differentiation, and reproduction, as well as vascular and metabolic properties. From observational studies in human subjects, poor vitamin D status is associated with nearly all diseases predicted by these extraskeletal actions. Results of randomized controlled trials and Mendelian randomization studies are supportive of vitamin D supplementation in reducing the incidence of some diseases, but, globally, conclusions are mixed. These findings point to a need for continued ongoing and future basic and clinical studies to better define whether vitamin D status can be optimized to improve many aspects of human health. Vitamin D deficiency enhances the risk of osteoporotic fractures and is associated with many diseases. We review what is established and what is plausible regarding the health effects of vitamin D.

Abstract Background Numerous studies demonstrate associations between serum concentrations of 25-hydroxyvitamin D (25[OH]D) and a variety of common disorders, including musculoskeletal, metabolic, cardiovascular, malignant, autoimmune, and infectious diseases. Although a causal link between serum 25(OH)D concentrations and many disorders has not been clearly established, these associations have led to widespread supplementation with vitamin D and increased laboratory testing for 25(OH)D in the general population. The benefit-risk ratio of this increase in vitamin D use is not clear, and the optimal vitamin D intake and the role of testing for 25(OH)D for disease prevention remain uncertain. Objective To develop clinical guidelines for the use of vitamin D (cholecalciferol [vitamin D3] or ergocalciferol [vitamin D2]) to lower the risk of disease in individuals without established indications for vitamin D treatment or 25(OH)D testing. Methods A multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, identified and prioritized 14 clinically relevant questions related to the use of vitamin D and 25(OH)D testing to lower the risk of disease. The panel prioritized randomized placebo-controlled trials in general populations (without an established indication for vitamin D treatment or 25[OH]D testing), evaluating the effects of empiric vitamin D administration throughout the lifespan, as well as in select conditions (pregnancy and prediabetes). The panel defined “empiric supplementation” as vitamin D intake that (a) exceeds the Dietary Reference Intakes (DRI) and (b) is implemented without testing for 25(OH)D. Systematic reviews queried electronic databases for publications related to these 14 clinical questions. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and guide recommendations. The approach incorporated perspectives from a patient representative and considered patient values, costs and resources required, acceptability and feasibility, and impact on health equity of the proposed recommendations. The process to develop this clinical guideline did not use a risk assessment framework and was not designed to replace current DRI for vitamin D. Results The panel suggests empiric vitamin D supplementation for children and adolescents aged 1 to 18 years to prevent nutritional rickets and because of its potential to lower the risk of respiratory tract infections; for those aged 75 years and older because of its potential to lower the risk of mortality; for those who are pregnant because of its potential to lower the risk of preeclampsia, intra-uterine mortality, preterm birth, small-for-gestational-age birth, and neonatal mortality; and for those with high-risk prediabetes because of its potential to reduce progression to diabetes. Because the vitamin D doses in the included clinical trials varied considerably and many trial participants were allowed to continue their own vitamin D–containing supplements, the optimal doses for empiric vitamin D supplementation remain unclear for the populations considered. For nonpregnant people older than 50 years for whom vitamin D is indicated, the panel suggests supplementation via daily administration of vitamin D, rather than intermittent use of high doses. The panel suggests against empiric vitamin D supplementation above the current DRI to lower the risk of disease in healthy adults younger than 75 years. No clinical trial evidence was found to support routine screening for 25(OH)D in the general population, nor in those with obesity or dark complexion, and there was no clear evidence defining the optimal target level of 25(OH)D required for disease prevention in the populations considered; thus, the panel suggests against routine 25(OH)D testing in all populations considered. The panel judged that, in most situations, empiric vitamin D supplementation is inexpensive, feasible, acceptable to both healthy individuals and health care professionals, and has no negative effect on health equity. Conclusion The panel suggests empiric vitamin D for those aged 1 to 18 years and adults over 75 years of age, those who are pregnant, and those with high-risk prediabetes. Due to the scarcity of natural food sources rich in vitamin D, empiric supplementation can be achieved through a combination of fortified foods and supplements that contain vitamin D. Based on the absence of supportive clinical trial evidence, the panel suggests against routine 25(OH)D testing in the absence of established indications. These recommendations are not meant to replace the current DRIs for vitamin D, nor do they apply to people with established indications for vitamin D treatment or 25(OH)D testing. Further research is needed to determine optimal 25(OH)D levels for specific health benefits.

A large number of observational studies have reported harmful effects of low 25-hydroxyvitamin D (25OHD) levels on non-skeletal outcomes. We performed a systematic quantitative review on characteristics of randomized clinical trials (RCTs) included in meta-analyses (MAs) on non-skeletal effects of vitamin D supplementation. We identified systematic reviews (SR) reporting summary data in terms of MAs of RCTs on selected non-skeletal outcomes. For each outcome, we summarized the results from available SRs and scrutinized included RCTs for a number of predefined characteristics. We identified 54 SRs including data from 210 RCTs. Most MAs as well as the individual RCTs reported null-findings on risk of cardiovascular diseases, type 2 diabetes, weight-loss, and malignant diseases. Beneficial effects of vitamin D supplementation was reported in 1 of 4 MAs on depression, 2 of 9 MAs on blood pressure, 3 of 7 MAs on respiratory tract infections, and 8 of 12 MAs on mortality. Most RCTs have primarily been performed to determine skeletal outcomes, whereas non-skeletal effects have been assessed as secondary outcomes. Only one-third of the RCTs had low level of 25OHD as a criterion for inclusion and a mean baseline 25OHD level below 50 nmol/L was only present in less than half of the analyses. Published RCTs have mostly been performed in populations without low 25OHD levels. The fact that most MAs on results from RCTs did not show a beneficial effect does not disprove the hypothesis suggested by observational findings on adverse health outcomes of low 25OHD levels.

This study of pooled data from trials of oral vitamin D supplementation examined the incidence of hip and nonvertebral fractures in persons 65 years of age or older. The data suggest that high-dose vitamin D may help prevent hip and nonvertebral fractures. Approximately 75% of fractures occur in people 65 years of age or older. 1 By 2050, the worldwide incidence of hip fractures is expected to increase by 240% among women and 310% among men. 2 One strategy to prevent fractures in this population might be universal vitamin D supplementation. However, the results of several study level meta-analyses and one pooled participant-level analysis do not agree. Although one trial-level meta-analysis of double-blind, randomized, controlled trials suggested an 18% reduction in the incidence of hip fracture and a 20% reduction in the incidence of any nonvertebral fracture at a received dose of no less . . .

Vitamin D status varies across all continents and countries. Vitamin D status usually is adequate in Latin America and Australia, but in contrast it is very low in the Middle East and some countries in Asia. Trends in vitamin D status, whether it improves or declines over the years, carry important messages. Trends usually are small, but can be predictors and indicators of general health. Vitamin D status has improved in the older population in the United States, and improvement relates to dairy use and vitamin D supplements. To the contrary, vitamin D status has declined in the Inuit population of Canada due to a change from a traditional fish diet to a Western diet. A large improvement was seen in Finland after mandatory fortification of dairy products was introduced. Determinants of decline are less sun exposure, increased use of sunscreen, increase of body mass index (BMI), less physical activity, and poor socioeconomic status. Determinants of increase are food fortification with vitamin D and vitamin D supplements. Food fortification can lead to a population‐wide increase in vitamin D status as shown by the Finnish example. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Falls can have devastating consequences for older people. We determined the relationship between the likelihood of fall incidents and daily-life behavior. We used wearable sensors to assess habitual physical activity and daily-life gait quality (in terms of e.g. stability, variability, smoothness and symmetry), and determined their predictive ability for time-to-first-and-second-falls. 319 older people wore a trunk accelerometer (Dynaport MoveMonitor, McRoberts) during one week. Participants further completed questionnaires and performed grip strength and trail making tests to identify risk factors for falls. Their prospective fall incidence was followed up for six to twelve months. We determined interrelations between commonly used gait characteristics to gain insight in their interpretation and determined their association with time-to-falls. For all data -including questionnaires and tests- we determined the corresponding principal components and studied their predictive ability for falls. We showed that gait characteristics of walking speed, stride length, stride frequency, intensity, variability, smoothness, symmetry and complexity were often moderately to highly correlated (r > 0.4). We further showed that these characteristics were predictive of falls. Principal components dominated by history of falls, alcohol consumption, gait quality and muscle strength proved predictive for time-to-fall. The cross-validated prediction models had adequate to high accuracy (time dependent AUC of 0.66-0.72 for time-to-first-fall and 0.69-0.76 for -second-fall). Daily-life gait quality obtained from a single accelerometer on the trunk is predictive for falls. These findings confirm that ambulant measurements of daily behavior contribute substantially to the identification of elderly at (high) risk of falling.

Osteoporotic fractures are common in patients with chronic kidney disease (CKD). Morbidity and mortality are higher in CKD patients with a fracture than in the general population. The assessment of bone mineral density for fracture prediction may be useful at all CKD stages. It should be considered when this influences treatment decisions. Vitamin D deficiency is common in patients with CKD, particularly in patients with proteinuria, due to loss of 25-hydroxyvitamin D and its binding protein. Vitamin D supplementation should be prescribed early in the course of renal disease. For treatment and prevention of vitamin D deficiency in CKD patients cholecalciferol 800 IU/day or the equivalent per month is recommended just as in the general population.

Mechanical loading determines bone mass and bone structure, which involves many biochemical signal molecules. Of these molecules, Mepe and Fgf23 are involved in bone mineralization and phosphate homeostasis. Thus, we aimed to explore whether mechanical loading of bone affects factors of phosphate homeostasis. We studied the effect of mechanical loading of bone on the expression of Fgf23 , Mepe , Dmp1 , Phex , Cyp27b1 , and Vdr . Twelve-week old female rats received a 4-point bending load on the right tibia, whereas control rats were not loaded. RT-qPCR was performed on tibia mRNA at 4, 5, 6, 7 or 8 hours after mechanical loading for detection of Mepe , Dmp1 , Fgf23 , Phex , Cyp27b1 , and Vdr . Immunohistochemistry was performed to visualise FGF23 protein in tibiae. Serum FGF23, phosphate and calcium levels were measured in all rats. Four-point bending resulted in a reduction of tibia Fgf23 gene expression by 64% (p = 0.002) and a reduction of serum FGF23 by 30% (p<0.001), six hours after loading. Eight hours after loading, Dmp1 and Mepe gene expression increased by 151% (p = 0.007) and 100% (p = 0.007). Mechanical loading did not change Phex , Cyp27b1 , and Vdr gene expression at any time-point. We conclude that mechanical loading appears to provoke both a paracrine as well as an endocrine response in bone by modulating factors that regulate bone mineralization and phosphate homeostasis.

Severe vitamin D deficiency may cause rickets. While this point is not disputed, the use of vitamin D in the elderly to prevent fractures has been challenged recently by a meta‐analysis of 81 RCTs, suggesting that the effects of vitamin D were trivial. As is true for any review of the literature, the interpretation of a meta‐analysis can be confounded by the choice of publications to include or exclude. Indeed, the authors excluded RCTs with combined vitamin D and calcium supplementation, included futile studies of very short duration, or studies with high bolus doses known to transiently increase fracture risk. The best available data show that calcium and vitamin D supplementation of elderly subjects can decrease the risk of hip and other non‐vertebral fractures, especially in institutionalized subjects or elderly subjects with poor calcium and vitamin D status. Vitamin D deficiency is associated with many chronic diseases. The VIDA and VITAL trials did not show a protective effect on cardiovascular diseases and cancer. The D2d study also did not influence the progress of prediabetes to diabetes. However, the baseline 25OHD concentrations of the majority of the participants of all these trials were essentially normal. Post‐hoc analysis of these studies suggest some possibly beneficial health outcomes in vitamin D deficient subjects. A meta‐analysis suggested that vitamin D could partly prevent upper respiratory infections. Mendelian randomization studies suggest a causal link between lifelong low vitamin D status and multiple sclerosis. A vitamin D supplement in pregnant women may decrease maternal morbidity and improve the health of their offspring. Better‐designed studies are needed to answer all outstanding questions. However, based on all available data, it seems that correction of vitamin D and/or calcium deficiency of infants, pregnant women and elderly subjects can improve their health. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

The aim of this prospective study was to document the functional outcome and quality of life (QoL) over 1 year following hip fracture in elderly women. A total of 159 unselected elderly women with a first hip fracture were matched for age and residence with an equal number of control women. Functional status was measured by completing a Rapid Disability Rating Scale version 2 (RDRS-2) questionnaire [score ranging from 0 (best) to 54 (worse)], before hospital discharge and 12 months later. To examine longitudinal change in health-related QoL, fracture subjects and controls completed the Short Form 36 (SF-36) questionnaire. For the 134 women still alive at 1 year, the mean RDRS-2 score before hospital discharge was 16.2 (95% CI: 15.0-18.0) and 3.5 (2.6-4.3) in patients and controls, respectively ( P<0.001). During the year following hospital discharge, the mean RDRS-2 score improved to 13.0 (11.1-14.1) in hip-fracture women and worsened to 4.3 (3.3-5.0) in the control group (differences with initial scores: P<0.001 in both groups). After adjustment for potential confounders (including age and comorbidity), the estimated functional decline attributable to a hip fracture was 24% in the first year. Poor functional status upon discharge was the strongest predictor of a poor functional status at 1 year. Overall, similar trends were observed when using SF-36 scores as compared with RDRS-2 scores. However, only 51% of the study population was able to complete the SF-36 questionnaire at discharge and after 1 year, and these subjects were considerably younger ( P<0.001), had less cognitive impairment ( P<0.001), and had better functional status ( P<0.001) than those who were unable to complete the SF-36. For those women able to complete the SF-36 questionnaires, the mean SF-36 score before hospital discharge was 56.4 (95% CI: 51.9-60.9) and 71.1 (67.5-74.8) in patients and controls, respectively ( P<0.001). During the year following hospital discharge, the mean SF-36 score improved significantly to 61.1 (56.5-65.7) in hip-fracture patients ( P=0.03), but remained unchanged in the control group ( P=0.23). Overall, the results of this study indicate that women who sustain a hip fracture continue to suffer from substantial functional impairment and loss in QoL at 1 year, despite a significant recovery during this 12-month period. Function upon hospital discharge is the strongest predictor of functional status 1 year later. Assessing QoL in hip fracture women through self-administered questionnaires is subject to considerable bias due to non-response.