Reduced mortality and subsequent fracture risk associated with oral bisphosphonate recommendation in a fracture liaison service setting: A prospective cohort study.

OBJECTIVE: Osteoporotic fragility fractures, that are common in men and women, signal increased risk of future fractures and of premature mortality. Less than one-third of postmenopausal women and fewer men are prescribed active treatments to reduce fracture risk. Therefore, in this study the association of oral bisphosphonate recommendation with subsequent fracture and mortality over eight years in a fracture liaison service setting was analysed. MATERIALS AND METHODS: In this prospective cohort study, 5011 men and women aged >50 years, who sustained a clinical fracture, accepted the invitation to attend the fracture liaison service of the West Glasgow health service between 1999 and 2007. These patients were fully assessed and all were recommended calcium and vitamin D. Based on pre-defined fracture risk criteria, 2534 (50.7%) patients were additionally also recommended oral bisphosphonates. Mortality and subsequent fracture risk were the pre-defined outcomes analysed using Cox proportional hazard models. RESULTS: Those recommended bisphosphonates were more often female (82.9 vs. 72.4%), were older (73.4 vs. 64.4 years), had lower bone mineral density T-score (-3.1 vs. -1.5) and more had sustained hip fractures (21.7 vs. 6.2%; p < 0.001). After adjustments, patients recommended bisphosphonates had lower subsequent fracture risk (Hazard Ratio (HR): 0.60; 95% confidence interval (CI): 0.49-0.73) and lower mortality risk (HR: 0.79, 95%CI: 0.64-0.97). CONCLUSION: Of the patients, who are fully assessed after a fracture at the fracture liaison service, those with higher fracture risk and a recommendation for bisphosphonates had worse baseline characteristics. However, after adjusting for these differences, those recommended bisphosphonate treatment had a substantially lower risk for subsequent fragility fracture and lower risk for mortality. These community-based data indicate the adverse public health outcomes and mortality impacts of the current low treatment levels post fracture could be improved by bisphosphonate recommendation for both subsequent fracture and mortality.

Sedentary Behavior Is Only Marginally Associated with Physical Function in Adults Aged 40-75 Years-the Maastricht Study.

Background: In an aging population, regular physical activity (PA) and exercise have been recognized as important factors in maintaining physical function and thereby preventing loss of independence and disability. However, (older) adults spent the majority of their day sedentary and therefore insight into the consequences of sedentary behavior on physical function, independent of PA, is warranted. Objective: To examine the associations of objectively measured sedentary time (ST), patterns of sedentary behavior, overall PA, and higher intensity PA (HPA) with objective measures of physical function. Methods: This is a cross-sectional study in 1,932 men and women (aged 40-75 years) participating in The Maastricht Study. The activPAL3 was used to assess daily sedentary behavior: ST (h), sedentary breaks (n), prolonged (≥30 min) sedentary bouts (n), and to assess time spent in (H)PA (h). Measures of physical function included: covered distance during a 6 min walk test [6MWD (meters)], timed chair rise stand test performance [TCSTtime (seconds)], grip strength (kg kg-1), and elbow flexion and knee extension strength (Nm kg-1). Linear regression analyses were used to examine associations between daily sedentary behavior and PA with physical function. Results: Every additional hour ST was associated with shorter 6MWD [B = -2.69 m (95% CI = -4.69; -0.69)] and lower relative elbow extension strength (B = -0.01 Nm kg-1 (-0.02; 0.00). More sedentary breaks were associated with faster TCSTtime: B = -0.55 s (-0.85; -0.26). Longer average sedentary bout duration was associated with slower TCSTtime [B = 0.17 s (0.09; 0.25)] and lower knee extension strength [B = -0.01 Nm kg-1 (-0.02; 0.00)]. Every hour of PA and HPA were associated with greater 6MWD [BPA = 15.88 m (9.87; 21.89), BHPA = 40.72 m (30.18; 51.25)], faster TCSTtime [BPA = -0.55 s (-1.03; -0.07), BHPA = -2.25 s (-3.09; -1.41)], greater elbow flexion strength [BPA = 0.03 Nm kg-1 (0.01; 0.07)], [BHPA = 0.05 Nm kg-1 (0.01; 0.08)], and greater knee extension strength [BPA = 0.04 Nm kg-1 (0.01; 0.07)], [BHPA = 0.13 Nm kg-1 (0.06; 0.20)]. Conclusion: In adults aged 40-75 years, sedentary behavior appeared to be marginally associated with lower physical function, independent of HPA. This suggests that merely reducing sedentary behavior is insufficient to improve/maintain physical function. In contrast, engaging regularly in PA, in particular HPA, is important for physical function.

Physical Activity Is Associated With Glucose Tolerance Independent of Microvascular Function: The Maastricht Study.

CONTEXT AND OBJECTIVE: Moderate-to-vigorous physical activity (MVPA) and physical fitness (PF) are positively associated with glucose tolerance. Such associations may be partly conditioned by microvascular function, which is a common correlate to MVPA, PF, and glucose tolerance. To test this hypothesis, the present study sought to investigate independent associations of MVPA and PF with glucose tolerance and to what extent these associations are mediated by microvascular function. Design, Setting, Participants, and Outcome Measures: Data from The Maastricht Study were used (n = 512 for MVPA and n = 488 for PF analyses; mean age, 59 [SD = 9] y, 52 % men). Glucose tolerance was assessed by 2-hour postload plasma glucose levels (2hPG). The total number of weekly hours of MVPA was estimated with the Community Healthy Activities Model Program for Seniors questionnaire. Walking speed during the 6-minute walk test was used to evaluate PF. Microvascular function was determined by postocclusive capillary recruitment and flowmotion with capillaroscopy and laser Doppler flowmetry in skin microcirculation. RESULTS: In univariate analyses, MVPA, PF, and microvascular function variables were associated with 2hPG. MVPA (n = 512, ß = -0.056, P = .019) and PF (n = 488, ß = -0.368, P = .006) remained associated with 2hPG after adjustment for established cardio-metabolic risk factors and history of cardiovascular disease; addition of microvascular function variables as potential mediators did not materially change the associations of MVPA (ß = -0.054, P = .024) and PF (ß = -0.364, P = .006) with 2hPG. No mediation effects of microvascular function variables were detected. CONCLUSIONS: MVPA and PF were independently associated with 2hPG, irrespective of established risk factors and generalized microvascular function. The possibility that specific microvascular functions, eg, insulin-mediated vasodilation, influence the association of MVPA and PF with 2hPG needs further investigation.

Increased fracture risk in patients with type 2 diabetes mellitus: an overview of the underlying mechanisms and the usefulness of imaging modalities and fracture risk assessment tools.

Type 2 diabetes mellitus has recently been linked to an increased fracture risk. Since bone mass seems to be normal to elevated in patient with type 2 diabetes, the increased fracture risk is thought to be due to both an increased falling frequency and decreased bone quality. The increased falling frequency is mainly a result of complications of the disease such as a retinopathy and polyneuropathy. Bone quality is affected through changes in bone shape, bone micro-architecture, and in material properties such as bone mineralization and the quality of collagen. Commonly used methods for predicting fracture risk such as dual energy X-ray absorptiometry and fracture risk assessment tools are helpful in patients with type 2 diabetes mellitus, but underestimate the absolute fracture risk for a given score. New imaging modalities such as high resolution peripheral quantitative computed tomography are promising for giving insight in the complex etiology underlying the fragility of the diabetic bone, as they can give more insight into the microarchitecture and geometry of the bone. We present an overview of the contributing mechanisms to the increased fracture risk and the usefulness of imaging modalities and risk assessment tools in predicting fracture risk in patients with type 2 diabetes.

Secondary osteoporosis and metabolic bone disease in patients 50 years and older with osteoporosis or with a recent clinical fracture: a clinical perspective.

PURPOSE OF REVIEW: The purpose of this review is to provide guidance to clinicians about which laboratory tests should be performed in patients with osteoporosis or with a recent fracture. RECENT FINDINGS: Newly diagnosed secondary osteoporosis and other metabolic bone diseases (SECOB) have been found in 5-48% of patients with osteoporosis. In patients with a recent fracture, new SECOB is found in 10-47% of patients with osteoporosis, and in 26-51% if all patients with a fracture regardless of bone mineral density (BMD) are screened. More than one SECOB can be found in the same patient, even when they have already known SECOB. In primary hyperparathyroidism, hyperthyroidism, hypercortisolism, and multiple myeloma, both SECOB and its treatment have an impact on BMD and fractures. For other SECOBs, no treatment is available, or there are no data about the effect of treatment of the SECOB on BMD and fractures. SUMMARY: We recommend performing the following tests in all patients with osteoporosis or a recent clinical fracture: calcium, phosphate, creatinine, albumin, erythrocyte sedimentation rate in all patients, 24 h urine calcium in men and serum testosterone in men less than 70 years. On indication, additional tests can be performed.

Assessment of the healing process in distal radius fractures by high resolution peripheral quantitative computed tomography.

In clinical practice, fracture healing is evaluated by clinical judgment in combination with conventional radiography. Due to limited resolution, radiographs don't provide detailed information regarding the bone micro-architecture and bone strength. Recently, assessment of in vivo bone density, architectural and mechanical properties at the microscale became possible using high resolution peripheral quantitative computed tomography (HR-pQCT) in combination with micro finite element analysis (µFEA). So far, such techniques have been used mainly to study intact bone. The aim of this study was to explore whether these techniques can also be used to assess changes in bone density, micro-architecture and bone stiffness during fracture healing. Therefore, the fracture region in eighteen women, aged 50 years or older with a stable distal radius fracture, was scanned using HR-pQCT at 1-2 (baseline), 3-4, 6-8 and 12weeks post-fracture. At 1-2 and 12 weeks post-fracture the distal radius at the contra-lateral side was also scanned as control. Standard bone density, micro-architectural and geometric parameters were calculated and bone stiffness in compression, torsion and bending was assessed using µFEA. A linear mixed effect model with time post-fracture as fixed effect was used to detect significant (p-value ≤0.05) changes from baseline. Wrist pain and function were scored using the patient-rated wrist evaluation (PRWE) questionnaire. Correlations between the bone parameters and the PRWE score were calculated by Spearman's correlation coefficient. At the fracture site, total and trabecular bone density increased by 11% and 20%, respectively, at 6-8 weeks, whereas cortical density was decreased by 4%. Trabecular thickness increased by 23-31% at 6-8 and 12 weeks and the intertrabecular area became blurred, indicating intertrabecular bone formation. Compared to baseline, calculated bone stiffness in compression, torsion and bending was increased by 31% after 12 weeks. A moderate negative correlation was found between the stiffness and the PRWE score. No changes were observed at the contra-lateral side. The results demonstrate that it is feasible to assess clinically relevant and significant longitudinal changes in bone density, micro-architecture and mechanical properties at the fracture region during the healing process of stable distal radius fractures using HR-pQCT.

Early changes in bone density, microarchitecture, bone resorption, and inflammation predict the clinical outcome 12 weeks after conservatively treated distal radius fractures: an exploratory study.

Fracture healing is an active process with early changes in bone and inflammation. We performed an exploratory study evaluating the association between early changes in densitometric, structural, biomechanical, and biochemical bone parameters during the first weeks of fracture healing and wrist-specific pain and disability at 12 weeks in postmenopausal women with a conservatively treated distal radius fracture. Eighteen patients (aged 64 ± 8 years) were evaluated at 1 to 2 and 3 to 4 weeks postfracture, using high-resolution peripheral quantitative computed tomography (HR-pQCT), micro-finite element analysis, serum procollagen type-I N-terminal propeptide (P1NP), carboxy-terminal telopeptide of type I collagen (ICTP), and high-sensitive C-reactive protein (hsCRP). After 12 weeks, patients rated their pain and disability using Patient Rated Wrist Evaluation (PRWE) questionnaire. Additionally, Quick Disability of the Arm Shoulder and Hand (QuickDASH) questionnaire and active wrist range of motion was evaluated. Linear regression models were used to study the relationship between changes in bone parameters and in hsCRP from visit 1 to 2 and PRWE score after 12 weeks. A lower PRWE outcome, indicating better outcome, was significantly related to an early increase in trabecular bone mineral density (BMD) (ß -0.96 [95% CI -1.75 to -0.16], R(2) = 0.37), in torsional stiffness (-0.14 [-0.28 to -0.004], R(2) = 0.31), and to an early decrease in trabecular separation (209 [15 to 402], R(2) = 0.33) and in ICTP (12.1 [0.0 to 24.1], R(2) = 0.34). Similar results were found for QuickDASH. Higher total dorsal and palmar flexion range of motion was significantly related to early increase in hsCRP (9.62 [3.90 to 15.34], R(2) = 0.52). This exploratory study indicates that the assessment of early changes in trabecular BMD, trabecular separation, calculated torsional stiffness, bone resorption marker ICTP, and hsCRP after a distal radius fracture provides valuable information regarding the 12-week clinical outcome in terms of pain, disability, and range of motion and validates its use in studies on the process of early fracture healing. © 2014 American Society for Bone and Mineral Research.

Fracture liaison service: impact on subsequent nonvertebral fracture incidence and mortality.

BACKGROUND: A fracture liaison service model of care is widely recommended and applied, but data on its effectiveness are scarce. Therefore, the risk of subsequent nonvertebral fractures and mortality within two years after a nonvertebral fracture was analyzed in patients who presented to a hospital with a fracture liaison service and a hospital without a fracture liaison service. METHODS: In 2005 to 2006, all consecutive patients with an age of fifty years or older presenting with a nonvertebral fracture were included. In the group that presented to a hospital without a fracture liaison service (the no-FLS group), only standard fracture care procedures were followed to address proper fracture-healing. In the group that presented to a hospital with a fracture liaison service (the FLS group), dual x-ray absorptiometry scans and laboratory testing were performed, and if applicable, patients were treated according to the Dutch guideline for osteoporosis. The risk for subsequent nonvertebral fracture and mortality were analyzed using multivariable Cox regression models with adjustments for age, sex, and baseline fracture location. RESULTS: In total, 1412 patients presented to the fracture liaison service (73.2% were women, and the mean age was 71.1 years), and 1910 underwent standard fracture care (69.8% were women, and the mean age was 69.5 years). After adjustment for age, sex, and baseline fracture location, patients who attended the fracture liaison service had a significantly lower mortality risk (hazard ratio: 0.65; 95% confidence interval [CI]: 0.53 to 0.79) over two years of follow-up. The subsequent nonvertebral fracture risk was also significantly lower in the patients in the FLS group, but this effect was time-dependent, with a hazard ratio of 0.84 (95% CI: 0.64 to 1.10) at twelve months and 0.44 (95% CI: 0.25 to 0.79) at twenty-four months. CONCLUSIONS: Patients seen at the fracture liaison service had a significantly lower mortality and subsequently a lower risk of nonvertebral fracture than those not seen at the fracture liaison service, with a reduction of 35% and 56%, respectively, over two years of follow-up. A fracture liaison service appears to be a successful approach to reduce the number of subsequent fractures and premature mortality in this cohort of patients.

The utility of absolute risk prediction using FRAX® and Garvan Fracture Risk Calculator in daily practice.

OBJECTIVES: There are two commonly used fracture risk prediction tools FRAX(®) and Garvan Fracture Risk Calculator (GARVAN-FRC). The objective of this study was to investigate the utility of these tools in daily practice. STUDY DESIGN: A prospective population-based 5-year follow-up study was conducted in ten general practice centres in the Netherlands. For the analyses, the FRAX(®) and GARVAN-FRC 10-year absolute risks (FRAX(®) does not have 5-year risk prediction) for all fractures were used. RESULTS: Among 506 postmenopausal women aged ≥60 years (mean age: 67.8±5.8 years), 48 (9.5%) sustained a fracture during follow-up. Both tools, using BMD values, distinguish between women who did and did not fracture (10.2% vs. 6.8%, respectively for FRAX(®) and 32.4% vs. 39.1%, respectively for GARVAN-FRC, p<0.0001) at group level. However, only 8.9% of those who sustained a fracture had an estimated fracture risk ≥20% using FRAX(®) compared with 53.3% using GARVAN-FRC. Although both underestimated the observed fracture risk, the GARVAN-FRC performed significantly better for women who sustained a fracture (higher sensitivity) and FRAX(®) for women who did not sustain a fracture (higher specificity). Similar results were obtained using age related cut off points. CONCLUSIONS: The discriminant value of both models is at least as good as models used in other medical conditions; hence they can be used to communicate the fracture risk to patients. However, given differences in the estimated risks between FRAX(®) and GARVAN-FRC, the significance of the absolute risk must be related to country-specific recommended intervention thresholds to inform the patient.

Comparing tolerability and efficacy of generic versus brand alendronate: a randomized clinical study in postmenopausal women with a recent fracture.

INTRODUCTION: An increasing number of generic alendronate formulations have become available. Although expected to have the same tolerability and efficacy, head-to head comparison of generic and brand alendronate was never performed. Therefore, we compared the tolerability and efficacy of generic and brand alendronate. METHODS: In a randomized double-blinded single centre cross-over study in 37 postmenopausal women (mean age 65.4±6.4 years) with osteoporosis were treated with generic and branded alendronate during 24 (2x12) weeks. Tolerance was evaluated by the Gastro intestinal Symptom Rating Scale (GSRS) and self-reported side effects. Efficacy was assessed by serum bone turnover markers, carboxy terminal telopeptide (CTX) and procollagen type I N-terminal propeptide (PINP). No wash out period was allowed (ethical reasons). Because of possible carry over effect only data of the first 12 weeks were analyzed using linear mixed models. RESULTS: There were no significant differences in overall tolerance (GSRS) between treatment groups. However, for subscale abdominal pain, patients using generic had a significantly higher mean GSRS score at week 4 (estimated mean difference (B): 0.40; 95%CI: 0.05 to 0.74, p = 0.024). The level of bone turnover markers significantly decreased over 12 weeks of follow-up for generic and branded alendronate (p < 0.001). Mean level of CTX was significantly lower with branded at week 4 (B: 121.3; 95%CI: 52.0 to 190.5), but not at week 12 (B: 53.6; 95%CI:-3.7 to 110.9). No significant differences were found for PINP at week 4 or 12. CONCLUSIONS: Bone turnover markers were significantly reduced with branded and generic alendronate. With branded, CTX was significantly lower at 4 weeks. Generic caused significantly higher abdominal pain scores in the first 4 weeks of treatment. Therefore, generic alendronate may not have the same tolerability and efficacy as branded alendronate in the first weeks after starting treatment in patients with a recent fracture. TRIAL REGISTRATION: Dutch Trial Register NTR number 1867 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1867.

The role of the combination of bone and fall related risk factors on short-term subsequent fracture risk and mortality.

BACKGROUND: We analysed whether a combination of bone- and fall-related risk factors (RFs) in addition to a recent non-vertebral fracture (NVF) contributed to subsequent NVF risk and mortality during 2-years in patients who were offered fall and fracture prevention according to Dutch fracture- and fall-prevention guidelines. METHODS: 834 consecutive patients aged ≥50 years with a recent NVF who were included. We compared subgroups of patients according to the presence of bone RFs and/or fall RFs (group 1: only bone RFs; group 2: combination of bone and fall RFs; group 3: only fall RFs; group 4: no additional RFs). Univariable and multivariable Cox regression analyses were performed adjusted for age, sex and baseline fracture location (major or minor). RESULTS: 57 (6.8%) had a subsequent NVF and 29 (3.5%) died within 2-years. Univariable Cox regression analysis showed that patients with the combination of bone and fall RFs had a 99% higher risk in subsequent fracture risk compared to all others (Hazard Ratio (HR) 1.99; 95% Confidence Interval (CI) 1.18-3.36) Multivariable analyses this was borderline not significant (HR 1.70; 95% CI: 0.99-2.93). No significant differences in mortality were found between the groups. CONCLUSION: Evaluation of fall RFs contributes to identifying patients with bone RFs at highest immediate risk of subsequent NVF in spite of guideline-based treatment. It should be further studied whether earlier and immediate prevention following a NVF can decrease fracture risk in patients with a combination of bone and fall RFs.

Contributors to secondary osteoporosis and metabolic bone diseases in patients presenting with a clinical fracture.

BACKGROUND: Previously undetected contributors to secondary osteoporosis and metabolic bone diseases (SECOB) are frequently found in patients with osteoporosis, but the prevalence in patients at the time they present with a clinical fracture is unknown. METHODS: All consecutive patients with a recent clinical vertebral or nonvertebral fracture, who were able and willing to be investigated (n = 626: 482 women, 144 men, age range 50-97 yr) had bone mineral density and laboratory investigations (serum calcium, inorganic phosphate, 25-hydroxyvitamin D, creatinine, intact PTH, TSH, free T(4), serum and urine protein electrophoresis, and in men also serum testosterone). RESULTS: Known SECOB contributors were present in 23.0% of patients and newly diagnosed SECOB contributors in 26.5%: monoclonal proteinemia (14 of 626), renal insufficiency grade III or greater (54 of 626), primary (17 of 626) and secondary (64 of 626) hyperparathyroidism, hyperthyroidism (39 of 626), and hypogonadism in men (12 of 144). Newly diagnosed SECOBs, serum 25-hydroxyvitamin D less than 50 nmol/liter (in 63.9%), and dietary calcium intake less than 1200 mg/d (in 90.6%) were found at any age, in both sexes, after any fracture (except SECOB in men with finger and toe fractures) and at any level of bone mineral density. CONCLUSION: At presentation with a fracture, 26.5% of patients have previously unknown contributors to SECOB, which are treatable or need follow-up, and more than 90% of patients have an inadequate vitamin D status and/or calcium intake. Systematic screening of patients with a recent fracture identifies those in whom potentially reversible contributors to SECOB and calcium and vitamin D deficiency are present.

Development of a simple prognostic nomogram for individualising 5-year and 10-year absolute risks of fracture: a population-based prospective study among postmenopausal women.

OBJECTIVES: Previous fracture prediction models have been based on the assumption of a stable risk of subsequent fractures over time. The aim of the present work was to develop a nomogram for prediction of 5-year and 10-year individualised absolute fracture risks for postmenopausal women taking into account the time relation between fractures. METHODS: A population-based prospective study was performed in 23 general practice centres located in the southern part of The Netherlands. At baseline (1992-1994), 4203 postmenopausal women between 50 and 80 years participated and 2372 of them also participated 10 years later. Baseline measurements included lumbar spine bone mineral density (BMD) and clinical risk factor evaluation. The incidence of fractures was ascertained. Bayesian model averaging and Cox's proportional hazards model were used. RESULTS: After enrolment, 382 (16.1%) women had a clinical fracture. Fracture risk was associated with advancing age (HR 1.09 per SD (5 years); 95% CI 1.01 to 1.17), lumbar spine BMD (HR 1.23 per -1 SD; 95% CI 1.10 to 1.37) and a prior fracture, with HR 3.27 (95% CI 2.50 to 4.30) for a recent prior fracture (≤5 years previously) and HR 1.97 (95% CI 1.43 to 2.71) for a non-recent prior fracture after menopause (>5 years previously). Women with a recent prior fracture had 66% higher risk of an incident fracture than those with a non-recent prior fracture (HR 1.66; 95% CI 1.15 to 2.40). CONCLUSIONS: The nomogram developed can help doctors to inform patients more effectively and thus better manage patient care by providing an individualised fracture risk taking into account the time relationship for fractures.

Optimal use of vitamin D when treating osteoporosis.

Inadequate serum 25-hydroxyvitamin D (25[OH]D) concentrations are associated with muscle weakness, decreased physical performance, and increased propensity in falls and fractures. This paper discusses several aspects with regard to vitamin D status and supplementation when treating patients with osteoporosis in relation to risks and prevention of falls and fractures. Based on evidence from literature, adequate supplementation with at least 700 IU of vitamin D, preferably cholecalciferol, is required for improving physical function and prevention of falls and fractures. Additional calcium supplementation may be considered when dietary calcium intake is below 700 mg/day. For optimal bone mineral density response in patients treated with antiresorptive or anabolic therapy, adequate vitamin D and calcium supplementation is also necessary. Monitoring of 25(OH)D levels during follow-up and adjustment of vitamin D supplementation should be considered to reach and maintain adequate serum 25(OH)D levels of at least 50 nmol/L, preferably greater than 75 nmol/L in all patients.

Clinical fractures cluster in time after initial fracture.

A history of fractures is a well recognised risk factor for a new clinical fracture. However, this subsequent fracture risk is not constant, but fluctuates over time, with the greatest increase in the years immediately after the initial fracture, followed by a gradual waning of risk toward the population risk. The clustering of fractures occurred regardless of age, gender and initial fracture location. It is therefore likely that fracture risk models, which take into account this fluctuation of fracture risk over time, will be more relevant in predicting an individual's subsequent fracture risk. Regardless of the cause of this clustering, these studies all strongly support the need for early action after an initial fracture to reduce the preventable risk of subsequent fractures with medical interventions that have been shown to immediately decrease the risk of fractures.

Assessment of individual fracture risk: FRAX and beyond.

The World Health Organization fracture risk assessment tool (FRAX) and the Garvan fracture risk calculator are both widely available tools for individualized fracture risk prediction in daily practice. The FRAX model is implemented in several guidelines and most widely used at present. However, clinicians should take into account the differences between the models, especially with regard to the effect of the number of falls, number and clustering of previous fractures, and the number of clinical risk factors on the outcome of predicted fracture risk. Further development will be needed for optimal integration of bone- and fall-related risks, clustering of fractures, and dosing of risk factors to validate the models in different populations and to validate the ability to select patients who will achieve fracture risk reduction with anti-osteoporosis therapy. FRAX may be used as the primary model, and in patients with recurrent fractures and falls the use of the Garvan model may be of additional value.

Timing of subsequent fractures after an initial fracture.

A prior fracture is a well-documented risk factor for a subsequent fracture and it doubles the risk of subsequent fractures. Few studies have investigated the time that elapses between the initial and subsequent fracture. These studies show that the subsequent fracture risk is not constant, but fluctuates over time. The risk of subsequent vertebral, hip, and nonvertebral non-hip fractures is highest immediately after initial hip, clinical, and radiographic vertebral fractures and nonvertebral fractures and declines afterward, regardless of gender, age, and initial fracture location. These studies indicate the need for early action after an initial fracture with medical interventions that have an effect within a short term to reduce the preventable risks of subsequent fractures.

Individualizing fracture risk prediction.

Low bone mineral density (BMD) and clinical factors (CRF) have been identified as factors associated with an increased relative risk of fractures. From this observation and for clinical decision making, the concept of prediction of the individual absolute risk of fractures has emerged. It refers to the individual's risk for fractures over a certain time period, e.g. the next 5 and 10 years. Two individualized fracture risk calculation tools that are increasingly used and are available on the web are the FRAX algorithm and the Garvan fracture risk calculator. These tools integrate BMD and CRFs for fracture risk calculation in the individual patient in daily practice. Although both tools include straightforward risk factors, such as age, sex, previous fractures, body weight and BMD, they differ in several aspects, such as the inclusion of other CRFs, fall risks and number of previous fractures. Both models still need to be validated in different populations before they can be generalized to other populations, since the background risk for fractures is population specific. Further studies will be needed to validate their contribution in selecting patients who will achieve fracture risk reduction with anti-osteoporosis therapy.

Measures of bioavailable serum testosterone and estradiol and their relationships with muscle mass, muscle strength and bone mineral density in postmenopausal women: a cross-sectional study.

OBJECTIVE: The physiologic role of circulating endogenous testosterone and estrogen concentrations in relation to lean body mass (LBM) and muscle strength is not as well documented in postmenopausal women as in elderly men. DESIGN: Three hundred and twenty-nine healthy postmenopausal women were randomly selected from a general practice population-based sample aged between 55 and 85 years. METHODS: Total testosterone and estrogen (TT and TE) and sex hormone-binding globulin (SHBG) were determined and estimates of bioavailable testosterone (free androgen index (TT/SHBG, FAI), calculated free testosterone (cFT), and estrogen (TE/SHBG, ESR) were calculated. Examinations included bone mineral density (BMD) of the spine and femoral neck (FN), LBM, maximum quadriceps extension strength (MES) and maximum handgrip strength (MGS), timed up-and-go test (TUGT), osteocalcin (OC), and urinary deoxy-pyridinoline/creatinine (DPyr). Correlations were assessed using Pearson's correlation coefficient (r). RESULTS: With advancing age, LBM, MES, MGS, BMD, and ESR significantly declined (range r: -0.356 to -0.141) and TUGT, and DPyr significantly increased (range r: 0.135 to 0.282 (P<0.05)). After age-adjustment, LBM, MES, and BMD in spine and FN were significantly related to bioavailable testosterone (range r: 0.146 to 0.193, for cFT, and 0.157 to 0.224, for FAI) and to ESR (range r: 0.162 to 0.273). OC and DPyr were significantly inversely related to ESR (r: -0.154 and -0.144 respectively). CONCLUSIONS: Age-related loss of LBM, MES and BMD in postmenopausal women is partly dependent on the presence of endogenous bioavailable testosterone and estrogen.

Risk factors for clinical fractures among postmenopausal women: a 10-year prospective study.

OBJECTIVE: Only scarce data are available on the long-term absolute risk (AR) of all clinical fractures, taking into account the time when they occurred. Therefore, we assessed during a 10-year follow-up the risk factors associated with the occurrence of any first or second clinical fracture. STUDY DESIGN: This was a population-based study in 10 general practice centres. The sample comprised 2372 postmenopausal women, aged between 50 and 80 years at baseline, who completed a questionnaire about the incidence of radiographically confirmed fractures and fracture risks, analysed by multiple Cox regression. MAIN OUTCOME MEASURE: AR for any clinical fracture. RESULTS: During the 10-year follow-up, 380 women (16%) had a fracture. A first fracture occurred in 267 women (11%). Osteoporosis at the lumbar spine (T-score <-2.5; hazard ratio (HR) 1.8, 95% confidence interval (CI) 1.4-2.3) and age over 60 years (HR1.4, 95% CI 1.1-1.8) were the only risk factors retained in the Cox analysis. The AR in the lowest-risk group was 10%, and it was 23% in the highest-risk group. A second fracture occurred in 113 women during follow-up (5%). The time when a fracture occurred was the only risk factor retained in the Cox analysis. The AR for a second fracture was 41% in the five years after any first fracture before baseline and 25% if the first fracture had occurred earlier (HR 1.8, 95% CI 1.3-2.7). CONCLUSION: In postmenopausal women, over a 10-year follow-up, the AR of a second clinical fracture is highest in the five years after any first clinical fracture. The AR for a first clinical fracture is lower and depends on osteoporosis and age.