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ABSTRACT: The fracture risk assessment tool from the World Health Organization (FRAX®) estimates 10-yr major osteoporotic and hip fracture probabilities from multiple clinical risk factors and optionally femoral neck bone mineral density (BMD). FRAX without BMD has been proposed as a method to select postmenopausal women younger than 65yr for BMD measurement, but the efficiency of this strategy and its concordance with National Osteoporosis Foundation (NOF) treatment guidelines is unknown. The osteoporosis self-assessment test (OST) is another simple screening tool based on age and weight alone. A historical cohort of 18,315 women aged 50-64yr, drawn from the Manitoba Bone Density Program database, which contains clinical BMD results for the Province of Manitoba, Canada, was used to determine the performance of these screening tools in selecting postmenopausal women younger than 65yr for BMD testing. FRAX was closely aligned with indicators of high fracture risk (area under the receiver operating characteristic curve [AUROC]: 0.89), whereas OST was better for detecting women with osteoporotic BMD (AUROC: 0.72). The combination of major fracture probability 10% or higher from FRAX without BMD or OST less than 1 identified 42% of women for BMD testing, capturing 72% of women meeting any NOF treatment criteria (90% of women with NOF criteria for high risk from FRAX or prior fracture). The negative predictive value to exclude qualification for treatment under the NOF criteria was 90%. These data may help to inform an evidence-based approach for targeting BMD testing in postmenopausal women younger than 65yr under the NOF treatment guidelines.
Journal of Clinical Densitometry 02/2013; · 1.29 Impact Factor
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ABSTRACT: A FRAX(®) model for Romania calibrated to the total Romanian population was released June 1, 2011. This article describes the data used to develop the Romanian FRAX model and illustrates its features compared to models for other countries. Age- and sex-stratified hip fracture incidence rates and mortality rates for 2010 were extracted from nationwide databases from the age of 40 years. For other major fractures, Romanian incidence rates were imputed, using Swedish ratios for hip to other major osteoporotic fracture (humerus, forearm, and clinically symptomatic vertebral fractures). Fracture incidence rates increased with increasing age: for hip fracture, incidence rates were higher among younger men than women but with a female preponderance from the age of 65 years. The 10-year probability of hip or major fracture was increased in patients with a clinical risk factor (CRF), lower BMI, female gender, higher age, and decreased BMD T score. Of the CRFs, a parental hip fracture accounted for the greatest increase in 10-year fracture probability. The Romanian FRAX tool is the first country-specific fracture prediction model. It is based on the original FRAX methodology, which has been externally validated in several independent cohorts. Despite some limitations, the strengths make the Romanian FRAX tool a good candidate for implementation into clinical practice.
Calcified Tissue International 01/2013; · 2.38 Impact Factor
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Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 01/2013; · 6.04 Impact Factor
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BMJ (Clinical research ed.). 01/2013; 346:f1427.
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ABSTRACT: BACKGROUND: Subjects with inflammatory bowel disease (IBD) are at increased risk for hip and other major osteoporotic fractures. However, previous analyses have not fully accounted for differences in bone mineral density (BMD) and other clinical factors that affect the risk of fracture. The World Health Organization Fracture Risk Assessment tool (FRAX®) can be used to predict the 10-year fracture riskfrom BMD and clinical risk factors. METHODS: A population based database containing clinical information on all IBD subjects in the province of Manitoba, Canada, was linked with the Manitoba Bone Mineral Density Database, which contains results of all dual X-ray absorptiometry (DXA) scans in the province. FRAX probabilities were calculated for all subjects aged50 years or more undergoing baseline DXA testing. Subjects were followed for occurrence of major osteoporotic fractures (MOF; hip, clinical spine, wrist, humerus). Cox proportional hazards models were used to determine whether IBD was independently predictive of MOF or hip fracture. RESULTS: After controlling for FRAX fracture probability computed with BMD, IBD was not associated with a significantly increased risk for MOF (HR 1.12, 95%CI 0.83-1.55) but was associated with an increased risk for hip fracture (HR 2.14, 95%CI 1.26-3.65).The addition of femoral neck T-score to FRAX probability without knowledge of BMD had a negligible effect on the estimated hazard ratios for IBD, suggesting that IBD mediates any effect on fracture risk independently of femoral neck BMD CONCLUSION: After controlling for FRAX probability, subjects with IBD are not at an increased risk for overall MOF, but may be at increased risk of hip fracture. © 2012 American Society for Bone and Mineral Research.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 12/2012; · 6.04 Impact Factor
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ABSTRACT: INTRODUCTION: With the development of country-specific FRAX® tools to estimate fracture probability, guidance is required on the fracture probability at which treatment can be recommended. OBJECTIVES: The aim of the present study was to determine FRAX-based intervention thresholds in men and women from Turkey and determine their population impact. PATIENTS AND METHODS: Intervention thresholds for treatment and assessment thresholds for measuring BMD were devised using the strategy adopted by the National Osteoporosis Guideline Group of the UK but applied to the fracture probabilities in Turkey. The number of men and women potentially eligible for treatment was determined from the distribution of FRAX-based probabilities of a major fracture (Turkish model, version 3.6) in a representative sample of 26,394 men and women aged 50 years or more. RESULTS: Intervention thresholds, set at the probability equivalents of a woman with a prior fragility fracture rose with age from 7.0 % at the age of 50 years to 31 % at the age of 90 years. Approximately 8.6 % of the female Turkish population aged 50 years or more had a prior fragility fracture and would be eligible for treatment. A further 13.6 % without a prior fracture would be eligible for treatment. In contrast, the number of men aged 50 years or more eligible for treatment was 3.1 % CONCLUSIONS: FRAX-based guidelines can be developed and are expected to avoid unnecessary treatment of individuals at low fracture risk and direct treatments to those at high risk. The adoption of FRAX-based intervention thresholds will demand a reappraisal of the criteria for reimbursement of interventions and health economic assessment.
Archives of Osteoporosis 09/2012;
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ABSTRACT: There is an increasing recognition that the management of osteoporosis requires the characterization of fracture risk to be based on absolute risk rather than single measures such as bone mineral density (BMD). FRAX, the most widely used tool that incorporates clinical risk factors with or without BMD, was launched in 2008. This brief review addresses the development of FRAX since then and describes some of the issues that continue to be discussed as FRAX plays an increasing role in clinical practice.
FRAX is a platform technology that will continue to develop. High-quality updated epidemiology of fracture and mortality can lead to recalibration of models. The addition of new risk factors is complex as the process requires validation in an international setting as well as a comprehensive assessment of how such new factors interact with the existing FRAX variables. Nonetheless, clinical interpretation can be enhanced by taking into account the potential adjustments of FRAX probabilities and several of these are described.
FRAX is being incorporated in an increasing number of clinical guidelines, and assessment and intervention thresholds have been provided to instruct clinical decision-making. There is an increasing body of evidence that patients deemed at highest risk of fracture by FRAX, with or without the use of BMD, will overlap significantly with those identified by previous guidelines and will respond to appropriate osteoporosis therapy.
Current opinion in rheumatology 07/2012; 24(5):554-60. · 4.60 Impact Factor
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ABSTRACT: Having traditionally relied on measurements of bone mineral density, it is now established that the consideration of other risk variables improves the categorisation of fracture risk. Whereas several models are available, the FRAX models are the most extensively used. The approach uses easily obtained clinical risk factors to estimate 10 year fracture probability, with or without femoral neck bone mineral density (BMD), to enhance fracture risk prediction. It has been constructed and validated using primary data from population based cohorts around the world, including centres from North America, Europe, Asia and Australia. The FRAX® tool should not be considered as a gold standard, but rather as a platform technology on which to build as new validated risk indicators become available. Notwithstanding, the present models provide an aid to enhance patient assessment by the integration of clinical risk factors alone and/or in combination with BMD.
Clinical biochemistry 05/2012; 45(12):887-93. · 2.02 Impact Factor
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ABSTRACT: Ten-year fracture risk assessment with the fracture risk assessment system (FRAX) is increasingly used to guide treatment decisions. Osteoporosis pharmacotherapy reduces fracture risk, but the effect is greater than can be explained from the increase in bone mineral density (BMD). Whether this invalidates fracture predictions with FRAX is uncertain. A total of 35,764 women (age ≥50 years) and baseline BMD testing (1996–2007) had FRAX probabilities retroactively calculated. A provincial pharmacy database was used to identify osteoporosis medication use. Women were categorized as untreated, current high adherence users [medication possession ratio (MPR) ≥0.80 in the year after BMD testing], current low adherence users (MPR <0.80), and past users. Fractures outcomes to 10 years were established form a population-based health data repository. FRAX and femoral neck BMD alone stratified major osteoporotic and hip fracture risk within untreated and each treated subgroup (all p-values <0.001) with similar area under the receiver operating characteristic curve. In untreated and each treated subgroup, a stepwise gradient in observed 10-year major osteoporotic and hip fracture incidence was found as a function of the predicted probability tertile (all p-values <0.001 for linear trend). Concordance (calibration) plots for major osteoporotic fractures and hip fractures showed good agreement between the predicted and observed 10-year fracture incidence in untreated women and each treated subgroup. Only in the highest risk tertile of women highly adherent to at least 5 years of bisphosphonate use was observed hip fracture risk significantly less than predicted, though major osteoporotic fracture risk was similar to predicted. In summary, this work suggests that the FRAX tool can be used to predict fracture probability in women currently or previously treated for osteoporosis. Although FRAX should not be used to assess the reduction in fracture risk in individuals on treatment, it may still have value for guiding the need for continued treatment or treatment withdrawal
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 02/2012; 27(6):1243-51. · 6.04 Impact Factor
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ABSTRACT: The use of FRAX, particularly in the absence of BMD, has been the subject of some debate and is the focus of this review. The clinical risk factors used in FRAX have high validity as judged from an evidence-based assessment and identify a risk that is responsive to pharmaceutical intervention. Moreover, treatment effects, with the possible exception of alendronate, are not dependent on baseline BMD and strongly suggest that FRAX identifies high-risk patients who respond to pharmaceutical interventions. In addition, the selection of high-risk individuals with FRAX, without knowledge of BMD, preferentially selects for low BMD. The prediction of fractures with the use of clinical risk factors alone in FRAX is comparable to the use of BMD alone to predict fractures and is suitable, therefore, in the many countries where DXA facilities are sparse. In countries where access to BMD is greater, FRAX can be used without BMD in the majority of cases and BMD tests reserved for those close to a probability-based intervention threshold. Whereas the efficacy for agents to reduce fracture risk has not been tested prospectively in randomized controlled trials in patients selected on the basis of FRAX probabilities, there is compelling evidence that FRAX with or without the use of BMD provides a well-validated instrument for targeting patients most likely to benefit from an intervention.
Calcified Tissue International 11/2011; 90(1):1-13. · 2.38 Impact Factor
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Eugene McCloskey
Nature Reviews Endocrinology 01/2011; 7(7):383-4. · 9.97 Impact Factor
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Eugene McCloskey
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ABSTRACT: While fractures at the spine, wrist and hip are regarded as classical osteoporotic fractures, all fragility fractures in the elderly should be considered as osteoporotic once pathological fracture (e.g. metastatic disease) has been excluded. The assessment of fracture risk should take account of specific risk factors in addition to bone mineral density (BMD). The WHO has produced FRAX, a well validated tool that estimates the probability of a major osteoporotic fracture in the next 10 years. The algorithm is specifically designed for primary care. After age and prior fragility fracture, BMD is the next major determinant of fracture risk. Rather than scanning all individuals with a risk factor, measurements should be targeted to those whose probability of fracture lies close to the intervention threshold where knowledge of BMD will influence management. Individuals with a low trauma vertebral fracture or low BMD for age should be investigated for underlying causes of osteoporosis. Secondary causes account for up to 40% of cases of osteoporosis in women and 60% in men. The goal of osteoporosis management is to reduce the future risk of fracture. Lifestyle modification includes measures to reduce falls risk and bone loss such as exercise, adequate dietary calcium and avoidance of smoking and excessive alcohol consumption. All patients with an osteoporotic fracture and those at high risk should be assessed for falls risk. Combined therapy, with calcium and vitamin D, has been shown to reduce hip fracture risk in the frail elderly and should be considered in all older patients who are housebound or in residential care. Alendronate and risedronate are available as once-weekly preparations with evidence for significant reductions in vertebral and non-vertebral fractures. Denosumab is approved for osteoporosis in postmenopausal women at increased risk of fractures. Strontium ranelate has been shown to reduce fracture risk significantly in postmenopausal women.
The Practitioner 01/2011; 255(1736):19-22, 2-3.
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ABSTRACT: Advances in management have resulted in a dramatic decline in mortality for individuals infected with human immunodeficiency virus (HIV). This decrease in mortality, initially the result of improved prophylaxis and treatment of opportunistic infections but later mediated by the use of highly-active antiretroviral therapy (HAART) has led to the need to consider long-term complications of the disease itself, or its treatment. Bone disease is increasingly recognised as a concern. The prevalence of reduced BMD and possibly also fracture incidence are increased in HIV-positive individuals compared with HIV-negative controls. There are many potential explanations for this - an increased prevalence of established osteoporosis risk factors in the HIV-positive population, a likely direct effect of HIV infection itself and a possible contributory role of ARV therapy. At present, the assessment of bone disease and fracture risk remains patchy, with little or no guidance on identifying those at increased risk of reduced BMD or fragility fracture. Preventative and therapeutic strategies with bone specific treatments need to be developed. Limited data suggest bisphosphonates may be beneficial in conjunction with vitamin D and calcium supplementation in the treatment of reduced BMD in HIV-infected patients but larger studies of longer duration are needed. The safety and cost-effectiveness of these and other treatments needs to be evaluated.
Archives of Biochemistry and Biophysics 11/2010; 503(1):66-77. · 2.93 Impact Factor
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ABSTRACT: A FRAX model for Canada was constructed for prediction of osteoporotic and hip fracture risk using national hip fracture data with and without the use of femoral neck bone mineral density (BMD). Performance of this system was assessed independently in a large clinical cohort of 36,730 women and 2873 men from the Manitoba Bone Density Program database that tracks all clinical dual-energy X-ray absorptiometry (DXA) test results for the Province of Manitoba, Canada. Linkage with other provincial health databases allowed for the direct comparison of fracture risk estimates from the Canadian FRAX model with observed fracture rates to 10 years (549 individuals with incident hip fractures and 2543 with incident osteoporotic fractures). The 10-year Kaplan-Meier estimate for hip fractures in women was 2.7% [95% confidence interval (CI) 2.1-3.4%] with a predicted value of 2.8% for FRAX with BMD, and in men the observed risk was 3.5% (95% CI 0.8-6.2%) with predicted value of 2.9%. The 10-year estimate of osteoporotic fracture risk for all women was 12.0% (95% CI 10.8-13.4%) with a predicted value of 11.1% for FRAX with BMD, and in men, the observed risk was 10.7% (95% CI 6.6-14.9%) with a predicted value of 8.4%. Discrepancies were observed within some subgroups but generally were small. Fracture discrimination based on receiver operating characteristic curve analysis was comparable with published meta-analyses with area under the curve for osteoporotic fracture prediction of 0.694 (95% CI 0.684-0.705) for FRAX with BMD and for hip fractures 0.830 (95% CI 0.815-0.846), both of which were better than FRAX without BMD or BMD alone. Individual risk factors considered by FRAX made significant independent contributions to fracture prediction in one or more of the models. In conclusion, a Canadian FRAX tool calibrated on national hip fracture data generates fracture risk predictions that generally are consistent with observed fracture rates across a wide range of risk categories.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 04/2010; 25(11):2350-8. · 6.04 Impact Factor
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ABSTRACT: Breast cancer treatments have been associated with accelerated bone loss and increased osteoporosis risk. In a subgroup analysis of a randomised, double-blind, placebo-controlled study, we compared the changes in spine and total hip bone mineral density (BMD) and biochemical markers of bone turnover in women with primary breast cancer who had received standard therapy plus either oral clodronate 1600 mg/d (n=419) or placebo (n=432) for 2 years. After 2 years, spine BMD was 1.92% higher in patients who received clodronate instead of placebo (P<0.0001) and total hip BMD was 1.29% higher (P=0.002 versus placebo). Patients who received clodronate had a median 26% reduction in levels of serum N-terminal pro-peptide of type I procollagen (PINP)--a marker of bone turnover--after 2 years of therapy. This compares with a median 5% increase in patients who received placebo (P<0.0001). Effects on BMD, but not biochemical markers, persisted for up to 3 years post-treatment. Early changes in PINP were associated with changes in BMD and the likelihood of developing bone metastases. This study shows the use of oral clodronate during primary breast cancer treatment is associated with reduced bone turnover and protection against bone metastases.
European journal of cancer (Oxford, England: 1990) 02/2010; 46(3):558-65. · 4.12 Impact Factor
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ABSTRACT: The introduction of the WHO FRAX algorithms has facilitated the assessment of fracture risk on the basis of fracture probability. FRAX integrates the influence of several well validated risk factors for fracture with or without the use of BMD. Its use in fracture risk prediction poses challenges for patient assessment, the development of practice guidelines, the evaluation of drug efficacy and reimbursement, as well as for health economics which are the topics outlined in this review.
Bone 03/2009; 44(5):734-43. · 4.02 Impact Factor
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ABSTRACT: Bisphosphonates play a central role in the management of bone loss due to a range of disorders, including metastatic bone disease, cancer treatment-induced bone loss, and postmenopausal osteoporosis. With potent bisphosphonates, such as zoledronic acid, it may be possible to maintain efficacy with relatively infrequent administration.
Sixty-six patients who were osteopenic at >1 year following curative cancer therapy received a single i.v. 4 mg dose of the bisphosphonate zoledronic acid. Bone mineral density (BMD) was measured using double-beam X-ray absorptiometry scan and the bone resorption marker N-telopeptide of type II collagen was determined using a chemiluminescence ELISA assay.
The single dose of zoledronic acid induced mean increases in bone BMD at the lumbar spine of 3.1%, 5.2%, and 5.3% and at the total hip of 2.7%, 3.5%, and 4.3% after 12, 24, and 36 months of follow-up, respectively (P < 0.001 at all time points). By 36 months, 84% of patients had achieved increase in BMD at the spine and 90% at the hip. The mean percentage decrease in the bone resorption marker N-telopeptide was approximately 58% at 6 weeks and 42%, 33%, and 31% at 12, 24, and 36 months, respectively (P < 0.001).
A single dose of zoledronic acid in patients with low BMD results in a sustained increase in BMD and a corresponding decrease in bone resorption. Very infrequent administration of zoledronic acid may have clinical benefits in terms of convenience, reduced toxicity, improved compliance, and cost.
Clinical Cancer Research 09/2007; 13(18 Pt 1):5406-10. · 7.74 Impact Factor
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Eugene McCloskey
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ABSTRACT: Low oestradiol levels in women are associated with decreased bone mineral density (BMD) and increased fracture risk. The third-generation aromatase inhibitors (AIs; anastrozole, letrozole, and exemestane) are used in the treatment of early and advanced breast cancer and act by substantially reducing oestrogen synthesis in postmenopausal women. However, due to their mechanism of action, there is concern regarding the long-term effects of these agents on bone, particularly when used in the adjuvant setting. In this paper, the currently available data on the effects of the third-generation AIs on markers of bone turnover, BMD, and fracture risk are reviewed, with the emphasis on results in the adjuvant treatment of early breast cancer. These data suggest that both the steroidal (exemestane) and non-steroidal (anastrozole and letrozole) AIs appear to affect bone turnover. Conclusions regarding any clinically relevant differences between these agents are difficult to make, and further data are awaited from long-term adjuvant use of these three agents in ongoing clinical studies. Postmenopausal women are at increased risk of osteoporosis and fracture, and the increasing use of AIs in the adjuvant treatment of postmenopausal breast cancer patients will require appropriate consideration of fracture risk, with the use of anti-osteoporotic therapies, if necessary.
European Journal of Cancer 06/2006; 42(8):1044-51. · 5.54 Impact Factor
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ABSTRACT: Experimental and clinical data show that the oral bisphosphonate clodronate (Bonefos) can inhibit tumor-induced osteoclastic bone resorption. This randomized, double-blind, placebo-controlled, multicenter trial was designed to determine if the addition of oral clodronate to standard treatment for primary operable breast cancer could reduce the subsequent occurrence of bone metastases and thereby improve overall survival.
1,069 patients with primary operable stage I-III breast cancer were randomized to receive oral clodronate (1,600 mg/day) or placebo for 2 years, in conjunction with standard treatment for primary breast cancer including surgery, radiotherapy, adjuvant chemotherapy, and/or tamoxifen. All patients were assessed for bone metastases at two and five years and additionally when clinically indicated. Survival status was determined as of the close of the study on 30 June 2000 with a median follow up of 5.6 years. The treatment arms were compared using the unstratified log-rank test. Hazard ratios (HRs) with 95% confidence intervals were calculated.
Oral clodronate significantly reduced the risk of bone metastases in all patients over the 5 year study period (51 patients versus 73 patients with placebo; HR = 0.692, P = 0.043); the difference was also statistically significant over the 2 year medication period (19 patients versus 35 patients with placebo; HR = 0.546, P = 0.031). These differences were most pronounced in patients with stage II/III disease (39 patients versus 64 patients with placebo, HR = 0.592, P = 0.009 over 5 years; 16 patients versus 32 patients with placebo, HR= 0.496, P = 0.020 over 2 years). Survival data also favoured the clodronate arm (HR for all patients = 0.768, P = 0.048; HR for stage II/III disease = 0.743, P = 0.041), although this was not significant due to multiple analyses. Oral clodronate was well tolerated, with mild-to-moderate diarrhoea being the most frequently reported adverse event.
These results confirm that oral clodronate will significantly improve the 5 year bone relapse free survival when used as a supplementary adjuvant treatment for patients receiving standard treatment for primary operable breast cancer.
Breast cancer research: BCR 02/2006; 8(2):R13. · 5.24 Impact Factor
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ABSTRACT: There is debate about the possible deleterious effect of excessive vitamin A exposure on fracture risk. In this nested case control study in older women (312 cases and 934 controls), serum retinol, retinyl palmitate, and beta-carotene were not associated with fracture risk, and there was no evidence of excess risk with multivitamin or cod liver oil supplementation.
Recent studies have suggested that higher vitamin A intake may account for a component of fracture risk within the general population and that supplemental vitamin A may be harmful even within recommended limits. No studies have examined the relationship between biochemical retinol status and fracture in older women.
We examined serum retinol, retinyl palmitate, and beta-carotene as predictors of incident hip and other fractures in a large prospective study of British women over the age of 75 years (n = 2606, 312 incident osteoporotic fractures, 92 incident hip fractures; mean follow-up duration, 3.7 years). Fasting blood samples (9:00-11:00 a.m.) were collected at baseline. Using a case-control design (three controls per case), serum retinol, retinyl palmitate, and beta-carotene were assessed as univariate predictors of incident osteoporotic fracture or hip fracture. Baseline BMD at the total hip, age, 25(OH)D, serum beta Crosslaps, bone-specific alkaline phosphatase, weight, height, and smoking were considered as covariates in a multivariate model.
Serum retinol, retinyl palmitate, and beta-carotene were not significant univariate predictors of either hip fracture or any fracture (all p > 0.05; Cox proportional hazards regression). For all osteoporotic fractures, the hazard ratio (HR) was 0.92 (95% CI, 0.81-1.05) per 1 SD increase in serum retinol. Risk of any osteoporotic fracture was slightly less in the highest quartile of serum retinol compared with the lowest quartile (HR, 0.85; 95% CI, 0.69-1.05; p = 0.132) There was a tendency for increased serum retinol to predict benefit rather than harm in terms of BMD (r = 0.09, p = 0.002). Multivitamin or cod liver oil supplementation was associated with a significantly lower risk of any fracture (HR, 0.76; 95% CI, 0.60-0.96; p = 0.021). In multivariate analysis, only age, total hip BMD, and weight were associated with fracture risk (p < 0.05).
We found no evidence to support any skeletal harm associated with increased serum indices of retinol exposure or modest retinol supplementation in this population.
Journal of Bone and Mineral Research 07/2005; 20(6):913-20. · 6.37 Impact Factor
