Reduce Fracture Incidence Research Articles

Epidemiology of fractures in the United Kingdom 1988–2012: Variation with age, sex, geography, ethnicity and socioeconomic status

SummaryRates of fracture worldwide are changing. Using the Clinical Practice Research Datalink (CPRD), age, and gender, geographical, ethnic and socioeconomic trends in fracture rates across the United Kingdom were studied over a 24-year period 1988–2012. Previously observed patterns in fracture incidence by age and fracture site were evident. New data on the influence of geographic location, ethnic group and socioeconomic status were obtained. IntroductionWith secular changes in age- and sex-specific fracture incidence observed in many populations, and global shifts towards an elderly demography, it is vital for health care planners to have an accurate understanding of fracture incidence nationally. We aimed to present up to date fracture incidence data in the UK, stratified by age, sex, geographic location, ethnicity and socioeconomic status. MethodsThe Clinical Practice Research Datalink (CPRD) contains anonymised electronic health records for approximately 6.9% of the UK population. Information comes from General Practitioners, and covers 11.3 million people from 674 practices across the UK, demonstrated to be representative of the national population. The study population consisted of all permanently registered individuals aged ≥18years. Validated data on fracture incidence were obtained from their medical records, as was information on socioeconomic deprivation, ethnicity and geographic location. Age- and sex-specific fracture incidence rates were calculated. ResultsFracture incidence rates by age and sex were comparable to those documented in previous studies and demonstrated a bimodal distribution. Substantial geographic heterogeneity in age- and sex adjusted fracture incidence was observed, with rates in Scotland almost 50% greater than those in London and South East England. Lowest rates of fracture were observed in black individuals of both sexes; rates of fragility fracture in white women were 4.7 times greater than in black women. Strong associations between deprivation and fracture risk were observed in hip fracture in men, with a relative risk of 1.3 (95% CI 1.21–1.41) in Index of Multiple Deprivation category 5 (representing the most deprived) compared to category 1. ConclusionsThis study presents robust estimates of fracture incidence across the UK, which will aid decisions regarding allocation of healthcare provision to populations of greatest need. It will also assist the implementation and design of strategies to reduce fracture incidence and its personal and financial impact on individuals and health services.

The effect of bisphosphonate treatment on the biochemical and cellular events during bone remodelling in response to microinjury stimulation.

Osteoporosis is one of the most prevalent bone diseases worldwide and is characterised by high levels of bone turnover, a marked loss in bone mass and accumulation of microdamage, which leads to an increased fracture incidence that places a huge burden on global health care systems. Bisphosphonates have been used to treat osteoporosis and have shown great success in conserving bone mass and reducing fracture incidence. In spite of the existing knowledge of the in vivo responses of bone to bisphosphonates, the cellular responses to these drugs have yet to be fully elucidated. In vitro model systems that allow the decoupling of complex highly integrated events, such as bone remodelling, provide a tool whereby these biological processes may be studied in a more simplified context. This study firstly utilised an in vitro model system of bone remodelling and comprising all three major cell types of the bone (osteocytes, osteoclasts and osteoblasts), which was representative of the bone's capacity to sense microdamage and subsequently initiate a basic multicellular unit response. Secondly, this system was used to study the effect of two commonly utilised aminobisphosphonate treatments for osteoporosis, alendronate and zoledronate. We demonstrated that microinjury to osteocyte networks being treated with bisphosphonates modulates receptor activator of nuclear factor kappa-B ligand and osteoprotegerin activity, and subsequently osteoclastogenesis. Furthermore, bisphosphonates increased the osteogenic potential following microinjury. Thus, we have shown for the first time that bisphosphonates act at all three stages of bone remodelling, from microinjury to osteoclastogenesis and ultimately osteogenesis.

High incidence of fracture events in patients with Long-Gap Esophageal Atresia (LGEA): A retrospective review prompting implementation of standardized protocol

PurposeTo identify factors associated with an increased risk of fractures in Long-Gap Esophageal Atresia (LGEA) patients. Following implementation of a risk-stratified program, we hypothesized a reduction in fracture incidence within this potentially high-risk population. MethodsA retrospective review of LGEA-patients admitted between 2005 and 2014 was conducted. Symptomatic fractures with radiographic confirmation were defined as events. Univariate and multivariable analysis evaluated factors including admission weight-for-age z-score, primary versus secondary Foker process (FP), weight at Foker Stage I, days and episodes of paralysis, number of parenteral nutrition (PN) days, cumulative dose of loop diuretics adjusted for body weight and days exposed, and exposure to non-loop diuretics. A fracture-prevention protocol was initiated in 2012; incidence was evaluated pre and post-intervention. ResultsFifty-nine patients met inclusion criteria. Twenty-three (39%) patients in the entire cohort incurred at least one fracture during their hospitalization utilizing the Foker process. Given this high percentage, a targeted fracture-prevention protocol was initiated in 2012. Fracture incidence decreased from 48% prior to the protocol to 21% following the protocol (P=0.046). Several variables that were associated with an increased risk of fractures on univariate analysis included prior esophageal anastomosis attempt (P=0.008), number of separate episodes of paralysis (P=0.002), exposure to non-loop diuretics (P=0.006), cumulative loop diuretic dose (P<0.001), as well as cumulative loop diuretic over days exposed (P<0.001). Intensive care unit (ICU) stay (P=0.002) and total length of hospitalization (P<0.001) were also significantly longer among patients with a fracture. Number of separate episodes of paralysis was the only independent risk factor for the development of a fracture; patients having more than 3 episodes of paralysis had an estimated risk of fracture 15 times higher than those patients paralyzed only once or twice (O.R. 15.87, 95% C.I.: 1.47–171.23, P=0.008). ConclusionEpisodes of paralysis appeared to be the most significant risk factor for fractures in patients with LGEA who underwent the Foker procedure. The incidence of symptomatic fractures decreased significantly following implementation of a standardized protocol in this series of LGEA patients with continued prospective evaluation.

Stem cell transplantation before birth - a realistic option for treatment of osteogenesis imperfecta?

Osteogenesis imperfecta (OI) is characterized by severe bone deformities, growth retardation and bones that break easily, often from little or no apparent cause. OI is a genetic disorder primarily with defective type I collagen with a wide spectrum of clinical expression. In the more severe cases, it can be diagnosed before birth. Transplantation of mesenchymal stem cells (MSC) has the potential to improve the bone structure and stability, growth and fracture healing. Prenatal and postnatal cell transplantation has been investigated in preclinical and clinical studies of OI and suggests that this procedure is safe and has positive effects. Cell transplantation resulted in improved linear growth, mobility and reduced fracture incidence. However, the effect is transient and for this reason re-transplantation may be needed. So far there is limited experience in this area, and proper studies are required to accurately determine if MSC transplantation is of clinical benefit in the treatment of OI. In this review, we summarize what is currently known in this field.

Prenatal transplantation of mesenchymal stem cells to treat osteogenesis imperfecta.

Osteogenesis imperfecta (OI) can be a severe disorder that can be diagnosed before birth. Transplantation of mesenchymal stem cells (MSC) has the potential to improve the bone structure, growth, and fracture healing. In this review, we give an introduction to OI and MSC, and the basis for pre- and postnatal transplantation in OI. We also summarize the two patients with OI who have received pre- and postnatal transplantation of MSC. The findings suggest that prenatal transplantation of allogeneic MSC in OI is safe. The cell therapy is of likely clinical benefit with improved linear growth, mobility, and reduced fracture incidence. Unfortunately, the effect is transient. For this reason, postnatal booster infusions using same-donor MSC have been performed with clinical benefit, and without any adverse events. So far there is limited experience in this specific field and proper studies are required to accurately conclude on clinical benefits of MSC transplantation to treat OI.

Treatment of post-menopausal osteoporosis: beyond bisphosphonates.

Osteoporosis is a highly prevalent condition, characterized by compromised bone strength and fragility fractures and with an important associated socio-economic burden. Bisphosphonates are well established as the first line treatment for osteoporosis. However, while randomized control trials have in general demonstrated reasonable anti-fracture efficacy at the spine, they have shown moderate reduction in fracture incidence for non-vertebral sites. Furthermore, oral bisphosphonates are commonly associated with adverse gastrointestinal effects and both oral and parenteral bisphosphonates have been linked with osteonecrosis of the jaw and atypical femoral fracture, two rare but debilitating side effects. In addition, bisphosphonates are not recommended in patients with GFR <35 ml/min/1.73 m(2). Hence, there is a clear requirement for newer agents, which are able to reduce fracture risk further, whilst overcoming the limitations of bisphosphonates. Over the past 20 years, knowledge and a deeper understanding of the various signalling pathways involved in bone remodelling has increased, enabling identification of additional targets for therapy. This review focuses on these newer therapies and includes anti-resorptive agents such as raloxifene and other selective oestrogen receptor modulators, the monoclonal antibody denosumab (which inhibits the RANKL pathway), odanacatib, a cathepsin K inhibitor and the anabolic agents, PTH analogue; PTH (1-34) and anti-sclerostin antibodies (activator of the Wnt pathway). Strontium ranelate will not be reviewed as recent reports highlight concerns surrounding its cardiovascular safety and together with an apparent increased risk of thrombosis, its future use remains uncertain. Some of these agents such as raloxifene, denosumab and teriparatide are already in clinical use whilst others are at varying stages of development. This review will provide an overview of the mechanisms of action of these therapeutic agents on the skeleton and assess their efficacy in osteoporosis and fracture prevention.

Bone metabolism and cardiovascular function update. Effects of drugs for lifestyle-related diseases on bone metabolism

Accumulating evidence indicates that several drugs for lifestyle-related diseases are involved in bone metabolism. Drugs that might reduce fracture incidence are statins, β-blockers and thiazide diuretics, and those that might increase fractures are thiazolidinediones and loop diuretics. It is yet controversial whether ACE inhibitors, angiotensin receptor- II blockers and aldosterone receptor antagonists in addition to incretin-related drugs are indeed involved in the increase or the decrease in fracture incidence.

A calcium and vitamin D fortified food product improves bone adaptation during military training (634.3)

Stress fracture incidence during military training is high. Prior work suggests calcium (Ca) and vitamin D (vit D) intakes above the RDA may reduce fracture incidence in female trainees. How Ca and vit D affect measures of bone density and strength during initial military training (IMT) is not known. This randomized, double‐blind, placebo‐controlled trial was conducted to determine whether Ca and vit D (2000 mg and 800 IU) delivered as 2 snack bars daily throughout 9 wks of IMT improved trainee bone health. Measures of bone density pre‐ and post‐IMT and strength were assessed using peripheral quantitative computed tomography (n=20 men, n=27 women). Tibia scans were performed on the non‐dominant leg at 4, 14 and 66% of the segment length proximal to the distal end plate. Several parameters increased during training including: trabecular volumetric bone mineral density (vBMD) and bone strength index at the 4% site, cortical vBMD at the 14% and 66% sites, and stress strain index at the 66% site suggesting bone strength improved during IMT (all P&lt;0.05). Those who received Ca and vit D had greater increases in total vBMD at the 4% site (3.0 ± 3.3 vs. 1.2 ± 2.4%; P&lt;0.05) as well as cortical thickness (1.9 ± 2.2 vs. 0.6 ± 1.8%; P&lt;0.05) and bone mineral content (1.6 ± 1.6 vs 0.6 ± 1.8%; P&lt;0.05) at the 14% site. These data indicate that Ca and vit D intakes above the RDA may support bone health during periods of high turnover such as IMT.Grant Funding Source: Research supported by: ORISE and USAMRMC.

Progress and problems in oral bisphosphonate

Oral bisphosphonates are the first class of drugs other than estrogen that have been proven to reduce fracture incidence substantially. Since they are agents that inhibit bone resorption and are hardly absorbed through intestine, researchers have been focusing on augmentation of inhibitory effects of bisphosphonates on bone resorption and prolongation of the interval of drug administration. Even though they have a break-through efficacy on preventing fractures, there remain some rare problems to be solved, such as osteonecrosis of the jaw and atypical femoral fracture, after long-term exposure to bisphosphonates.

Effects of ageing, prolonged estrogen deficiency and zoledronate on bone tissue mineral distribution

The quantity and distribution of bone tissue mineral are key determinants of bone strength. Recent research revealed altered mineral distribution within sheep femora following estrogen deficiency. Rapid increases in bone remodeling occur at the onset of estrogen deficiency and abate over time. Therefore, altered tissue mineralization might be a transient characteristic of osteoporosis. Bisphosphonates reduce fracture incidence by 40–60% but increases in bone mineral density are insufficient to explain such changes. In this study the hypotheses that bone tissue mineralization is altered over prolonged estrogen depletion and bisphosphonate treatment were tested. Quantitative backscattered imaging (qBEI) was used to quantify bone mineral density distribution (BMDD) parameters (mean, FWHM) in trabeculae from the proximal femora of an ovariectomized sheep model that underwent estrogen deficiency for 31 months, an ovariectomized group administered with Zoledronic acid and age-matched controls. To assess the effects of normal ageing and prolonged estrogen deficiency, data were compared to BMDD data from sheep that were estrogen deficient for 12 months and age-matched controls. This study reports that normal ageing increases mean mineralization and mineral heterogeneity at a trabecular level. In contrast, prolonged estrogen deficiency leads to significantly decreased mean mineralization and further exacerbates increases in mineral heterogeneity. Interestingly, ZOL treatment of OVX sheep significantly reduced tissue mineral variability, both at a trabecular level and between femoral regions. Together, these findings indicate that ZOL treatment acts to reverse the increased mineral heterogeneity occurring during estrogen deficiency, which may contribute to its capacity to reduce osteoporotic fractures.

Optimal Vitamin D Status: A Critical Analysis on the Basis of Evidence-Based Medicine

Public health authorities around the world recommend widely variable supplementation strategies for adults, whereas several professional organizations, including The Endocrine Society, recommend higher supplementation. We analyzed published randomized controlled clinical trials to define the optimal intake or vitamin D status for bone and extraskeletal health. The extraskeletal effects of vitamin D are plausible as based on preclinical data and observational studies. However, apart from the beneficial effects of 800 IU/d of vitamin D3 for reduction of falls in the elderly, causality remains yet unproven in randomized controlled trials (RCTs). The greatest risk for cancer, infections, cardiovascular and metabolic diseases is associated with 25-hydroxyvitamin D (25OHD) levels below 20 ng/mL. There is ample evidence from RCTs that calcium and bone homeostasis, estimated from serum 1,25-dihydroxyvitamin D and PTH, calcium absorption, or bone mass, can be normalized by 25OHD levels above 20 ng/mL. Moreover, vitamin D supplementation (800 IU/d) in combination with calcium can reduce fracture incidence by about 20%. Such a dose will bring serum levels of 25OHD above 20 ng/mL in nearly all postmenopausal women. Based on calculations of the metabolic clearance of 25OHD, a daily intake of 500-700 IU of vitamin D3 is sufficient to maintain serum 25OHD levels of 20 ng/mL. Therefore, the recommendations for a daily intake of 1500-2000 IU/d or serum 25OHD levels of 30 ng or higher for all adults or elderly subjects, as suggested by The Endocrine Society Task Force, are premature. Fortunately, ongoing RCTs will help to guide us to solve this important public health question.

Cardiovascular Effects of Calcium Supplements

Calcium supplements reduce bone turnover and slow the rate of bone loss. However, few studies have demonstrated reduced fracture incidence with calcium supplements, and meta-analyses show only a 10% decrease in fractures, which is of borderline statistical and clinical significance. Trials in normal older women and in patients with renal impairment suggest that calcium supplements increase the risk of cardiovascular disease. To further assess their safety, we recently conducted a meta-analysis of trials of calcium supplements, and found a 27%–31% increase in risk of myocardial infarction, and a 12%–20% increase in risk of stroke. These findings are robust because they are based on pre-specified analyses of randomized, placebo-controlled trials and are consistent across the trials. Co-administration of vitamin D with calcium does not lessen these adverse effects. The increased cardiovascular risk with calcium supplements is consistent with epidemiological data relating higher circulating calcium concentrations to cardiovascular disease in normal populations. There are several possible pathophysiological mechanisms for these effects, including effects on vascular calcification, vascular cells, blood coagulation and calcium-sensing receptors. Thus, the non-skeletal risks of calcium supplements appear to outweigh any skeletal benefits, and are they appear to be unnecessary for the efficacy of other osteoporosis treatments.

AB1019 Osteoporotic fracture incidence reduction in hepatic transplanted patients

BackgroundOsteoporosis in transplanted patients is a well-documented event, and shows a multifactorial etiology. Intervention and prevention in these patients could be related to a secondary osteoporotic effect decreasing (as a...

An evaluation of the Fracture Risk Assessment Tool (FRAX®) as an indicator of treatment efficacy: the effects of bazedoxifene and raloxifene on vertebral, nonvertebral, and all clinical fractures as a function of baseline fracture risk assessed by FRAX®

The relationship between baseline Fracture Risk Assessment Tool (FRAX®) and treatment efficacy was evaluated using data from a pivotal phase 3 study. Relative risk of vertebral, nonvertebral, and all clinical fractures decreased with increasing probability of fracture for bazedoxifene (BZA) versus placebo but remained generally constant for raloxifene (RLX). To determine whether the FRAX® predicts osteoporosis treatment efficacy, we evaluated reductions in fracture incidence associated with BZA and RLX according to baseline fracture risk determined by FRAX® using data from a phase 3 osteoporosis treatment study. Hazard ratios (HRs) for effects of BZA and RLX versus placebo on incidence of vertebral, nonvertebral, and all clinical fractures were calculated using a Cox regression model. Cox regression analyses were performed in subgroups at or above 10-year fracture probability thresholds determined by FRAX®. HRs for the risk of vertebral, nonvertebral, and all clinical fractures versus placebo decreased with increasing 10-year fracture probability for BZA, while those for RLX remained stable. In all 10-year fracture probability subgroups, all BZA doses significantly reduced vertebral fracture risk versus placebo (HR = 0.22-0.66). BZA at 20, 40, and 20/40 mg significantly reduced risk of nonvertebral fractures (HR = 0.45, 0.44, and 0.45, respectively) and all clinical fractures (HR = 0.38, 0.41, and 0.40, respectively) for ≥20.0 % fracture probability. Vertebral fracture risk reductions for RLX 60 mg versus placebo were significant in subgroups at lower fracture probabilities (≥2.5- ≥ 10.0 %), but not higher (≥12.5 %), and in no subgroups for nonvertebral or all clinical fractures. The antifracture efficacy of BZA increased with increasing baseline FRAX® score, but there was no clear relationship between RLX and baseline FRAX®. These findings provide independent confirmation of current literature, suggesting that the relationship between FRAX® and treatment efficacy varies for different agents.

Endodontic instrument fracture: causes and prevention

Endodontic file fracture has traditionally been considered an uncommon event; however, a recent perception of increased fracture incidence with rotary nickel-titanium (NiTi) instruments has emerged. It is essential for the clinician to understand the likelihood of instrument fracture and the reasons for this unfortunate occurrence. Removal of fractured files is both technically difficult and time consuming and therefore it is of key importance to limit the probability of fracture. Over the last ten years, a range of NiTi alloy modifications have been made by instrument manufacturers, with varying reports of success, in an attempt to reduce the likelihood of file separation. The aim of this review was to investigate the incidence and aetiology of file fracture as well as analysing recommended prevention protocols. Additionally, the effectiveness of alloy modifications in reducing the incidence of file fracture was considered. Analysis demonstrated that the bulk of the literature relating to instrument fracture is in vitro evidence, which limits its clinical relevance. The reported incidence of NiTi instrument fracture is similar to stainless-steel (SS) files; however, inconsistent methodologies hamper accurate comparison. NiTi instruments are reported to fail by torsional overload and/or flexural fatigue, with file fracture occurring principally in the apical third of the canal or with inappropriate use. Finally, operator skill, manufacturer modifications and limiting file reuse have been demonstrated to be significant in reducing fracture incidence indicating the importance of a prevention strategy.

Evaluation of a program of integrated care to reduce recurrent osteoporotic fractures

To evaluate the outcomes of patients participating in a program of integrated care for osteoporosis in terms of medication supply, fracture incidence and expenses. Outcomes were assessed from secondary data provided by the AOK PLUS health insurance for 2455 participants of the program and the same number of matched controls who were also diagnosed with osteoporosis but did not participate in the program. Supply with Calcium and Vitamin D, antiresorptive agents and analgesics was assessed by defined daily doses. Osteoporotic fractures were identified by hospitalization data. Costs for fracture treatment, medication supply and additional expenses of the program were also included in the dataset. Patients enrolled in the program of integrated care received significantly more medication to treat osteoporosis than controls. There was no significant reduction in fracture incidence among participants of integrated care, but a reduced need of analgesics was noted. Additional costs for patients enrolled in the program were caused by a higher number of drug prescriptions, higher costs for stationary treatment and additional expenses for program related care and diagnostics. The program of integrated care was not found to be effective in reducing recurrent fractures. Cost effectiveness defined as a reduced rate of fractures in integrated care patients could not be shown by the assessed outcome measures. This missing reduction in fracture incidence may be explained by a non-sufficient improvement - compared to a placebo-controlled clinical trial - in medication supply and non-comparability of our real-world patient population with highly controlled clinical trial participants.

Reduction in the Risk of Clinical Fractures After a Single Dose of Zoledronic Acid 5 Milligrams

Annual infusions of zoledronic acid 5 mg over 3 years have been shown to reduce fracture incidence. There is now evidence that the effects of a single dose of zoledronic acid on bone mineral density and bone turnover last for much more than a year. Whether this is associated with sustained fracture prevention is not known. The objective of the study was to assess fracture incidence after only 1 infusion of zoledronic acid. The design of the study included post hoc analysis of subgroups of subjects from 2 trials, who received only 1 study infusion. The study included multicenter, randomized controlled trials. A total of 1367 subjects from HORIZON-PFT and HORIZON-RFT studies who received only 1 of the planned annual infusions participated in the study. The intervention of the study consisted of 1 infusion of zoledronic acid or placebo. Clinical fracture was the main outcome measure of the study. Mean follow-up period was 1.5 years. In patients who received only a single infusion, there was a 32% reduction in clinical fracture comparing zoledronic acid with placebo over 3 years of follow-up (95% confidence interval 2-53%, P = .04), comparable with the fracture reduction seen in those who had 3 or more annual infusions (34%; 95% confidence interval, 23-43%, P < .0001). New morphometric vertebral fractures were reduced by 68% in the single-infusion group (P = .004). The between-group differences in total hip bone mineral density at 3 years were 3.8% in those receiving 1 infusion and 6.2% in those receiving 3 infusions. In this post hoc analysis based on postrandomization subgroups, fracture risk appears to be reduced for more than 1 year after a single infusion of zoledronic acid. Prospective studies designed to assess this possibility are now warranted.

Evaluation of the clinical benefit of long-term (beyond 2 years) treatment of skeletal-related events in advanced cancers with zoledronic acid

Background:Skeletal complications of malignant bone disease are common among patients with both solid tumors and multiple myeloma (MM). Zoledronic acid (ZOL; Zometa) is an intravenous bisphosphonate with proven efficacy in reducing the incidence of skeletal complications and delaying the time to a first skeletal complication. This study was designed to assess the continued benefit of ZOL treatment over a prolonged period.Methods:This was a retrospective claims analysis study using information gathered from two national US managed-care plan databases. Patients ≥18 years of age with a single type of solid tumor or MM who were diagnosed with bone lesions and experienced at least one skeletal complication (before or after receiving ZOL) were included.Results:Of the 28,385 patients, those with lung and breast cancer composed the largest group. Greater percentages of MM and breast cancer patients were treated with ZOL. On average, those with renal cell carcinoma and lung cancer had a longer time between bone metastasis diagnosis and start of therapy with ZOL. Compared with an untreated cohort, patients treated with ZOL had a 24% reduction in incidence of fracture, a 45% reduction in incidence of spinal cord compression, and a 56% reduction in risk of mortality. Patients with persistence with ZOL over 180 days had a reduced incidence of fracture before controlling for other factors.Conclusions:Patients treated with ZOL had reduced risks of fracture, spinal cord compression, and mortality compared with patients in the no-treatment cohort. Longer persistence with ZOL was associated with better outcomes. Greatest benefits were observed for patients treated on a regular basis with ZOL for a period beyond 18 months.

Vitamin D and Calcium Supplements: What Do the Data Show? Who Should Be Treated?

Vitamin D is essential for human health. Deficiencies are associated with osteomalacia in adults and rickets in children and have been postulated to contribute to various cancers. The three major sources of vitamin D are diet; ultraviolet B radiation, primarily from the sun; and pharmacologic supplements. The extent to which vitamin D supplements, with or without calcium, can prevent various cancers and reduce fracture incidence in high-risk individuals has been controversial. The authors of this meta-analysis reviewed randomized, controlled trials and observational studies reporting incidence of or death from …

Rationale and design of the B-PROOF study, a randomized controlled trial on the effect of supplemental intake of vitamin B12and folic acid on fracture incidence

BackgroundOsteoporosis is a major health problem, and the economic burden is expected to rise due to an increase in life expectancy throughout the world. Current observational evidence suggests that an elevated homocysteine concentration and poor vitamin B12 and folate status are associated with an increased fracture risk. As vitamin B12 and folate intake and status play a large role in homocysteine metabolism, it is hypothesized that supplementation with these B-vitamins will reduce fracture incidence in elderly people with an elevated homocysteine concentration.Methods/DesignThe B-PROOF (B-Vitamins for the PRevention Of Osteoporotic Fractures) study is a randomized double-blind placebo-controlled trial. The intervention comprises a period of two years, and includes 2919 subjects, aged 65 years and older, independently living or institutionalized, with an elevated homocysteine concentration (≥ 12 μmol/L). One group receives daily a tablet with 500 μg vitamin B12 and 400 μg folic acid and the other group receives a placebo tablet. In both tablets 15 μg (600 IU) vitamin D is included. The primary outcome of the study is osteoporotic fractures. Measurements are performed at baseline and after two years and cover bone health i.e. bone mineral density and bone turnover markers, physical performance and physical activity including falls, nutritional intake and status, cognitive function, depression, genetics and quality of life. This large multi-center project is carried out by a consortium from the Erasmus MC (Rotterdam, the Netherlands), VUmc (Amsterdam, the Netherlands) and Wageningen University, (Wageningen, the Netherlands), the latter acting as coordinator.DiscussionTo our best knowledge, the B-PROOF study is the first intervention study in which the effect of vitamin B12 and folic acid supplementation on osteoporotic fractures is studied in a general elderly population. We expect the first longitudinal results of the B-PROOF intervention in the second semester of 2013. The results of this intervention will provide evidence on the efficacy of vitamin B12 and folate supplementation in the prevention of osteoporotic fractures.Trial RegistrationThe B-PROOF study is registered with the Netherlands Trial (NTR NTR1333) and with ClinicalTrials.gov (NCT00696514).