Prior Fragility Fracture Research Articles

Fracture prediction and calibration of a Canadian FRAX® tool: a population-based report from CaMos

A new Canadian WHO fracture risk assessment (FRAX®) tool to predict 10-year fracture probability was compared with observed 10-year fracture outcomes in a large Canadian population-based study (CaMos). The Canadian FRAX tool showed good calibration and discrimination for both hip and major osteoporotic fractures. The purpose of this study was to validate a new Canadian WHO fracture risk assessment (FRAX®) tool in a prospective, population-based cohort, the Canadian Multicentre Osteoporosis Study (CaMos). A FRAX tool calibrated to the Canadian population was developed by the WHO Collaborating Centre for Metabolic Bone Diseases using national hip fracture and mortality data. Ten-year FRAX probabilities with and without bone mineral density (BMD) were derived for CaMos women (N = 4,778) and men (N = 1,919) and compared with observed fracture outcomes to 10 years (Kaplan-Meier method). Cox proportional hazard models were used to investigate the contribution of individual FRAX variables. Mean overall 10-year FRAX probability with BMD for major osteoporotic fractures was not significantly different from the observed value in men [predicted 5.4% vs. observed 6.4% (95%CI 5.2-7.5%)] and only slightly lower in women [predicted 10.8% vs. observed 12.0% (95%CI 11.0-12.9%)]. FRAX was well calibrated for hip fracture assessment in women [predicted 2.7% vs. observed 2.7% (95%CI 2.2-3.2%)] but underestimated risk in men [predicted 1.3% vs. observed 2.4% (95%CI 1.7-3.1%)]. FRAX with BMD showed better fracture discrimination than FRAX without BMD or BMD alone. Age, body mass index, prior fragility fracture and femoral neck BMD were significant independent predictors of major osteoporotic fractures; sex, age, prior fragility fracture and femoral neck BMD were significant independent predictors of hip fractures. The Canadian FRAX tool provides predictions consistent with observed fracture rates in Canadian women and men, thereby providing a valuable tool for Canadian clinicians assessing patients at risk of fracture.

Construction and validation of a simplified fracture risk assessment tool for Canadian women and men: results from the CaMos and Manitoba cohorts

A procedure for creating a simplified version of fracture risk assessment tool (FRAX®) is described. Calibration, fracture prediction, and concordance were compared with the full FRAX tool using two large, complementary Canadian datasets. The Canadian Association of Radiologists and Osteoporosis Canada (CAROC) system for fracture risk assessment is based upon sex, age, bone mineral density (BMD), prior fragility fracture, and glucocorticoid use. CAROC does not require computer or web access, and categorizes 10-year major osteoporotic fracture risk as low (<10%), moderate (10-20%), or high (>20%). Basal CAROC fracture risk tables (by age, sex, and femoral neck BMD) were constructed from Canadian FRAX probabilities for major osteoporotic fractures (adjusted for prevalent clinical risk factors). We assessed categorization and fracture prediction with the updated CAROC system in the CaMos and Manitoba BMD cohorts. The new CAROC system demonstrated high concordance with the Canadian FRAX tool for risk category in both the CaMos and Manitoba cohorts (89% and 88%). Ten-year fracture outcomes in CaMos and Manitoba BMD cohorts showed good discrimination and calibration for both CAROC (6.1-6.5% in low-risk, 13.5-14.6% in moderate-risk, and 22.3-29.1% in high-risk individuals) and FRAX (6.1-6.6% in low-risk, 14.4-16.1% in moderate-risk, and 23.4-31.0% in high-risk individuals). Reclassification from the CAROC risk category to a different risk category under FRAX occurred in <5% for low-risk, 20-24% for moderate-risk, and 27-30% for high-risk individuals. Reclassified individuals had 10-year fracture outcomes that were still within or close to the original nominal-risk range.. The new CAROC system is well calibrated to the Canadian population and shows a high degree of concordance with the Canadian FRAX tool. The CAROC system provides s a simple alternative when it is not feasible to use the full Canadian FRAX tool.

Fracture Types and Risk Factors in Men With Prostate Cancer on Androgen Deprivation Therapy: A Matched Cohort Study of 19,079 Men

Accumulating evidence shows that androgen deprivation therapy is associated with osteoporosis and fragility fractures of the spine, hip and wrist. One study suggested that androgen deprivation therapy may also be associated with nonfragility fractures in older men. Whether other clinical risk factors independently increase the risk of fractures is not certain. Using linked administrative databases in Ontario, Canada, we matched 19,079 men 66 years old or older with prostate cancer with at least 6 months of continuous androgen deprivation therapy or bilateral orchiectomy with men with prostate cancer who had never received androgen deprivation. Matching variables were age, prior cancer treatment, diagnosis year, comorbidity, medication, prior fractures and socioeconomic variables. Primary outcomes were a typical fragility fracture of the spine, hip or wrist and any fracture. Independent predictors of fracture outcomes were assessed with Cox proportional hazards models. At a mean 6.47-year followup androgen deprivation therapy was associated with an increased risk of fragility fracture (HR 1.65, 95% CI 1.53-1.78) and any fracture (HR 1.46, 95% CI 1.39-1.54). Independent predictors of fragility and any fracture were increasing age, prior bone thinning medications, chronic kidney disease, prior dementia, prior fragility fracture and prior osteoporosis diagnosis or treatment (p <0.05). Continuous androgen deprivation therapy for at least 6 months is associated with an increased risk of fracture. Increasing age, prior osteoporotic fracture and dementia are important clinical factors that may warrant greater consideration of anti-osteoporotic therapy in these men.

Simplified 10-Year Absolute Fracture Risk Assessment: A Comparison of Men and Women

A simplified (semiquantitative) approach developed by the Canadian Association of Radiologists and Osteoporosis Canada (denoted as CAROC) for absolute fracture risk assessment incorporates age, sex, prior fragility fracture, and systemic corticosteroid use, together with bone mineral density (BMD) to define absolute fracture risk. The CAROC system has been shown to predict fracture rates in women referred for clinical BMD testing, but it is uncertain how this system performs in routine clinical practice in men who are much less likely to undergo BMD testing with potential for referral biases. Thirty-six thousand seven hundred and thirty women and 2873 men aged 50 yr or older at the time of baseline BMD testing were identified in a database containing all clinical dual-energy X-ray absorptiometry test results for the Province of Manitoba, Canada. Population-based health service records from 1987 to 2008 were assessed for fracture codes and medication use. Fracture risk under the CAROC model was categorized as low (<10%), moderate (10–20%), or high (>20%). Ten-year fracture risk estimated by the Kaplan-Meier method showed the same gradient in observed fracture risk for men and women. Despite evidence of greater referral bias in men resulting in a higher rate of clinical risk factors, the performance of the prediction algorithm was not affected.

A FRAX® model for the assessment of fracture probability in Belgium

A country-specific FRAX® model was developed from the epidemiology of fracture and death in Belgium. Fracture probabilities were identified that corresponded to currently accepted reimbursement thresholds. The objective of this study was to evaluate a Belgian version of the WHO fracture risk assessment (FRAX®) tool to compute 10-year probabilities of osteoporotic fracture in men and women. A particular aim was to determine fracture probabilities that corresponded to the reimbursement policy for the management of osteoporosis in Belgium and the clinical scenarios that gave equivalent fracture probabilities. Fracture probabilities were computed from published data on the fracture and death hazards in Belgium. Probabilities took account of age, sex, the presence of clinical risk factors and femoral neck bone mineral density (BMD). Fracture probabilities were determined that were equivalent to intervention (reimbursement) thresholds currently used in Belgium. Fracture probability increased with age, lower BMI, decreasing BMD T-score and all clinical risk factors used alone or combined. The 10-year probabilities of a major osteoporosis-related fracture that corresponded to current reimbursement guidelines ranged from approximately 7.5% at the age of 50 years to 26% at the age of 80 years where a prior fragility fracture was used as an intervention threshold. For women at the threshold of osteoporosis (femoral neck T-score = -2.5 SD), the respective probabilities ranged from 7.4% to 15%. Several combinations of risk-factor profiles were identified that gave similar or higher fracture probabilities than those currently accepted for reimbursement in Belgium. The FRAX® tool has been used to identify possible thresholds for therapeutic intervention in Belgium, based on equivalence of risk with current guidelines. The FRAX® model supports a shift from the current DXA-based intervention strategy, towards a strategy based on fracture probability of a major osteoporotic fracture that in turn may improve identification of patients at increased fracture risk. The approach will need to be supported by health economic analyses.

Hip and fragility fracture prediction by 4-item clinical risk score and mobile heel BMD: a women cohort study

BackgroundOne in four Swedish women suffers a hip fracture yielding high morbidity and mortality. We wanted to revalidate a 4-item clinical risk score and evaluate a portable heel bone mineral density (BMD) technique regarding hip and fragility fracture risk among elderly women.MethodsIn a population-based prospective cohort study we used clinical risk factors from a baseline questionnaire and heel BMD to predict a two-year hip and fragility fracture outcome for women, in a fracture preventive program. Calcaneal heel BMD was measured by portable dual X-ray laser absorptiometry (DXL) and compared to hip BMD, measured with stationary dual X-ray absorptiometry (DXA) technique.ResultsSeven women suffered hip fracture and 14 women fragility fracture/s (at hip, radius, humerus and pelvis) among 285 women; 60% having heel BMD ≤ -2.5 SD. The 4-item FRAMO (Fracture and Mortality) Index combined the clinical risk factors age ≥80 years, weight <60 kg, prior fragility fracture, and impaired rise-up ability. Women having 2-4 risk factors showed odds ratio (OR) for hip fracture of 5.9 and fragility fracture of 4.4. High risk group hip fracture risk was 2.8% annually compared to 0.5% for the low risk majority (69%). Heel BMD showed hip fracture OR of 3.1 and fragility fracture OR of 2.6 per SD decrease. For 30 DXA assessed participants mean hip BMD at -2.5 SD level corresponded to a lower BMD at the heel. Five of seven hip fractures occurred within a small risk group of 32 women, identified by high FRAMO Index + prior fragility fracture + heel T-score ≤-3.5 SD.ConclusionsIn a follow-up study we identified high risk groups for hip and fragility fracture with our plain 4-item risk model. Increased fracture risk was also related to decreasing heel BMD in calcaneal bone, measured with a mobile DXL technique. A combination of high FRAMO Index, prior fragility fracture, and very low BMD restricted the high risk group to 11%, among whom most hip fractures occurred (71%). These practical screening methods could eventually reduce hip fracture incidence by concentrating preventive resources to high fracture risk women.

Assessment of fracture risk

Fractures are a common complication of osteoporosis. Although osteoporosis is defined by bone mineral density at the femoral neck, other sites and validated techniques can be used for fracture prediction. Several clinical risk factors contribute to fracture risk independently of BMD. These include age, prior fragility fracture, smoking, excess alcohol, family history of hip fracture, rheumatoid arthritis and the use of oral glucocorticoids. These risk factors in conjunction with BMD can be integrated to provide estimates of fracture probability using the FRAX ® tool. Fracture probability rather than BMD alone can be used to fashion strategies for the assessment and treatment of osteoporosis.

The cost-effectiveness of risedronate in the UK for the management of osteoporosis using the FRAX®

The study estimated the cost-effectiveness of risedronate compared to no treatment in UK women using the FRAX algorithm for fracture risk assessment. A Markov cohort model was used to estimate the cost-effectiveness. Risedronate was found cost-effective from the age of 65 years, assuming a willingness to pay for a QALY of 30,000 pounds. The aim of this study was to assess the cost-effectiveness of risedronate for the prevention and treatment in a UK setting using the FRAX algorithm for fracture risk assessment. A further aim was to establish intervention thresholds with risedronate treatment. The cost-effectiveness of risedronate was compared to no treatment in post-menopausal women with clinical risk factors for fracture using a Markov cohort model populated with data relevant for the UK. The model incorporated the features of FRAX (the WHO risk assessment tool). The analysis had a health care perspective and quality adjusted life years was used as the main outcome measure. Treatment was cost-effective from the age of 65 years, assuming a willingness to pay for a QALY of 30,000 pounds. Treatment was also cost-effective at all ages in women who had previously sustained a fragility fracture or in women with a parental history of hip fracture with a bone mineral density set at the threshold of osteoporosis. At the 30,000 pounds threshold value for a QALY, risedronate was on average found to cost-effective below the 10-year probability of a major osteoporotic fractures of 13.0%. Risedronate is a cost-effective agent for the treatment of established osteoporosis (osteoporosis and a prior fragility fracture) in women from the age of 50 years and older and above 65 years in women with osteoporosis alone. The results support the treatment recommendations in recent UK guidelines for osteoporosis.

Bone health practices in men on androgen deprivation therapy (ADT): A population-based analysis of 25,802 patients

9631 Background: ADT is used in up to 1 in 2 men with prostate cancer. Osteoporosis and fragility fractures are important side effects of ADT. Guidelines recommend 2 important bone health practices for men on ADT - measurement of bone mineral density with dual x-ray absorptiometry (DEXA) and use of bisphosphonates in men at risk of osteoporosis. The implementation of these guidelines in practice is not well known. Methods: Using linked administrative databases, we identified 25,802 men (mean age 75.9 y, range 66–100 y) with prostate cancer who were treated with at least 6 months of ADT or who underwent bilateral orchiectomy in Ontario, Canada between 1995 and 2005. Performance of DEXA and prescription of bisphosphonates were captured using specific procedure codes and drug identification numbers, respectively. Prior use of DEXA and bisphosphonates, as well as prior diagnoses of osteoporosis and fragility fracture, were captured with specific diagnostic codes and a 3 y look-back period. Annual rates per 100 person-years were determined for both outcomes. Results: Among 25,802 men, 3.09% had a DEXA more than one year prior to starting ADT, and 3.14% had a prior diagnosis of osteoporosis. Within 2 years of starting ADT, the rate of undergoing DEXA rose from 0.50 per 100 person-years in 1995 to 19.47 in 2005. Rates of DEXA testing were higher among those with a prior diagnosis of osteoporosis, prior DEXA test, or prior fragility fracture but did not reach rates above 50 per 100 person-years in any of these groups. Bisphosphonate use increased from 0.27 per 100 person-years in 1995 to 3.18 in 2005 among prior non-users. More men on ADT were started on a bisphosphonate in the third year after starting ADT as compared to the second year, and rates were higher in year 2 than year 1. Less than one-third of men starting a bisphosphonate underwent any DEXA testing within 12 months of bisphosphonate initiation. Conclusions: Rates of DEXA testing and bisphosphonate use have increased over time among older men starting ADT, but significant gaps and delays remain in the quality of bone health care in this population. No significant financial relationships to disclose.

Ten-year fracture probability identifies women who will benefit from clodronate therapy—additional results from a double-blind, placebo-controlled randomised study

Fracture risk prediction can be enhanced by the concurrent assessment of other clinical risk factors. This study demonstrates that the estimation of an individual's 10-year probability of fracture by the FRAX algorithm identifies patients at high risk of fracture who will respond to bisphosphonate therapy. Treatments for osteoporosis are targeted largely to patients with low bone density (BMD) or a prior fragility fracture. Fracture risk prediction can be enhanced by the concurrent assessment of other clinical risk factors, but it is important to determine whether the risk so identified can be reduced by intervention. We determined the effect of a bisphosphonate on fracture rates when risk was calculated using a new risk algorithm (FRAX). Women aged 75 years or more were recruited to a randomised, double-blind controlled trial of 800 mg oral clodronate (Bonefos) daily over 3 years. Baseline clinical risk factors were entered in the FRAX model to compute the 10-year probability of major osteoporotic fractures with or without input of femoral neck BMD. The interaction between fracture probability and treatment efficacy was examined by Poisson regression. In 3,974 women, the interaction between fracture probability and treatment efficacy was significant when probability was assessed without BMD (p = 0.043), but not when BMD was included (p = 0.10). Efficacy was more evident in those deemed at highest risk. For example women lying at the 75th percentile of fracture probability in the absence of BMD (10-year probability 24%) treatment reduced fracture risk by 27% (HR 0.73, 95%CI 0.58-0.92). In those with a fracture probability of 30% (90th percentile), the fracture risk reduction was 38% (HR 0.62, 0.46-0.84). The estimation of an individual's 10-year probability of fracture by the FRAX algorithm identifies patients at high risk of fracture who will respond to bisphosphonate therapy.

Comment on: NICE guidance does not tally with clinical practice--a district general experience: reply

SIR, Many thanks for giving us the opportunity to comment on the observations of Yeap [1] on our letter [2]. His observations are valid about BMD not being the best marker for osteoporosis. It is, however, a flawed assumption that a prior fragility fracture is the only marker for future fracture. We know that what is frequently reported as a fragility fracture in the elderly might not be so [3]. Yeap advocates the recently published European guidance for the management of osteoporosis in post-menopausal women, which propose that treatment can be instigated after a fragility fracture, with or without BMD assessment [4]. This is pragmatic advice that may be partly related to the limited provision of dual energy X-ray absorbtiometry services. Our data included all fragility fractures including hip, wrist, vertebra and rib, while most of the data quoted in the literature is based on vertebral and or hip fractures, but did not include all other fractures. Many studies have shown that BMD is still a good marker for future fracture risk [5], and therefore finding a normal BMD in a patient who has sustained a fracture should make us re-evaluate the fracture and determine whether it was indeed low trauma. Fractures themselves are sometimes due to a combination of skeletal fragility and fall risk [6] and a possible unmeasured confounder in our findings was fall risk. This was emphasized in the European Prospective Osteoporosis Study [7]. It could be argued that falls risk should be assessed separately when new guidelines are produced.

Daily practice using the guidelines for prevention and treatment of osteoporosis. Use of clinical risk factors for osteoporotic fractures in the evaluation of risk of future fracture

A number of clinical risk factors that provide information on fracture risk over and above that given by BMD have been defined. WHO proposed FRAX (fracture risk assessment tool) in which the fracture probability could be calculated by the use of risk factors with or without BMD. The proposed independent risk factors are age, a prior fragility fracture, a parental history of hip fracture, smoking, use of systemic corticosteroids, excess alcohol intake, secondary osteoporosis, and rheumatoid arthritis. Management algorithms in postmenopausal women based on an health analysis have been proposed in several countries including UK, Sweden, Germany, USA and Canada.

Bone density and fragility fractures in patients with developmental disabilities

We investigated prior fractures, osteoporosis risk factors, and bone mineral density (BMD) in 107 institutionalized adults with developmental disabilities. We found a very high prevalence of BMD in the osteoporotic range and a significant correlation between lower BMD and prior fragility fractures. The purpose of this study was to investigate factors contributing to osteoporosis and fragility fractures among developmentally disabled adults. Adults from a residential center participated in a prospective study in which bone mineral density (BMD) at the forearm and heel were measured with a portable X-ray densitometer. Prior fragility fractures were identified from chart review. Among 107 participants, 84 (78.5%) had a measurement within the osteoporotic range. The heel was more severely abnormal (mean T-score -3.1 +/- 1.5) than the forearm (-1.6 +/- 1.3, p < .0.0001). Radiographically confirmed prior fragility fractures (17 [16.3%]) were associated with lower heel (p = 0.0155) and forearm (p = 0.0172) T-scores. In multiple regression analysis, there were independent associations between forearm BMD and prior fragility fractures (p = 0.0126) and between heel BMD and prior fragility fractures (p = 0.0291). The odds ratio for prior fracture increased by 2.02 (95% CI 1.12-3.64) for each standard deviation (SD) decrease in heel T-score and by 2.39 (95% CI 1.08-5.32) for each SD decrease in forearm T-score. We found a very high prevalence of osteoporotic BMD measurements in institutionalized adults with developmental disabilities. Lower heel and forearm BMD measurements were significantly and independently associated with prior fragility fractures in this population.

Hip fractures in users of first- vs. second-generation bisphosphonates

This study compared population hip fracture rates for women with a prior fragility fracture who were treated with first-generation versus second-generation bisphosphonate therapies. The observational study found that, relative to women treated with etidronate, a first-generation bisphosphonate, women treated with the second-generation therapies 'alendronate' or 'risedronate' were equally likely to be admitted to hospital for hip fracture. Our findings must be confirmed in large randomized head-to-head controlled trials. Few studies have examined hip fracture outcomes among users of first- versus second-generation bisphosphonates. We compared hip fracture rates among elderly women with a history of fracture dispensed first- and second-generation bisphosphonates, hypothesizing that hip fracture rates would be higher among users of first- versus second-generation bisphosphonates after adjusting for confounders. Administrative data from Ontario, Canada from 01 April 1998 to 31 March 2002 was used to identify population-based bisphosphonate-naïve cohorts of subjects age 66 years and older initiated on first- (etidronate plus calcium; n = 19,127) or second-generation (alendronate or risedronate; n = 1,460) bisphosphonates. Multivariate Cox proportional hazard models were used for analysis. During over 23,000 person-years of follow-up, we observed 293 hospital admissions for first hip fracture. The unadjusted event rates yielded approximately 12.5 hospital admissions for hip fracture per 1,000 person-years of follow-up in each study group. Relative to the etidronate plus calcium group, females in the alendronate or risedronate group were equally likely to be admitted for hip fracture (adjusted rate ratio [aRR] = 1.0; 95% CI 0.6-1.6). The findings of this study suggest similar rates of hip fracture between the first- and second-generation bisphosphonates when used continuously among elderly females with a prior history of fracture.

Glucocorticoid-induced osteoporosis: a systematic review and cost-utility analysis

To determine whether strategies can be devised for the assessment and treatment of glucocorticoid-induced osteoporosis (GIO). Electronic databases were searched up to October 2002. A systematic review of interventions was undertaken of all randomised controlled trials in which fracture was measured as an outcome. Effectiveness was compared with effectiveness in postmenopausal osteoporosis. The risk of osteoporotic fractures at any given T-score for bone mineral density (BMD) was determined from published meta-analyses of the relationship between BMD and fracture risk. The risk of an osteoporotic fracture in the presence of a prior osteoporotic fracture was computed from a published meta-analysis of the relationship between the prior occurrence of fracture of each type and the risk of a future fracture of each type. The additional risk due to exposure to glucocorticoids was determined by meta-analysis of prospectively studied population-based cohorts. The consequences of fracture on mortality were assessed for each fracture type. Costs and utilities were determined for osteoporosis in the UK by updating systematic reviews of the literature. A model was prepared that comprised an individual patient-based approach that simulated whether or not events occurred in each subsequent year for each patient. Effectiveness was populated from a systematic review of interventions in GIO and postmenopausal osteoporosis. Treatments were given for 5 years using a 5-year offset time (in this context, offset time is the duration for which an effect on fracture persists after the treatment stops). The analytic framework was set at 10 years. Because of the many uncertainties, extensive sensitivity analysis was undertaken. Evidence of anti-fracture efficacy was confined to a minority of agents used in the management of GIO. Only risedronate (a bisphosphonate) and calcidiol (vitamin D) were shown to have significant effects on vertebral fracture risk, but neither had significant effects on non-vertebral fracture risk. In further meta-analyses, the effects of bisphosphonates in GIO were compared with effects combining all available data for bisphosphonates in GIO and in postmenopausal osteoporosis. Since calcidiol is not licensed for use in the UK, cost-effectiveness analysis was confined to risedronate and to a pooled bisphosphonate effect. Analysis of cost-effectiveness of risedronate using the empirical data in GIO showed better cost-effectiveness with increasing age, but at no age did cost-effectiveness ratios fall below the threshold value of 30,000 pounds per quality-adjusted life-year gained. When account was taken of BMD, cost-effectiveness was confined to less than 10% of patients with very low T-scores for BMD. Assuming that bisphosphonate efficacy on fracture risk was comparable to that observed with bisphosphonates in postmenopausal osteoporosis, cost-effectiveness was shown in patients with a prior fracture. In patients with no prior fracture, cost-effectiveness was observed in individuals aged 75 years or more. In younger patients without a prior fracture, cost-effective scenarios were found contingent upon a T-score for BMD that was 2.0 SD or less. Cost-effective scenarios for risedronate in the management of GIO were identified, but only at the extremes of age and T-score, such that less than 10% of patients aged 50 years or more would be eligible for treatment. Greater cost-effectiveness was observed assuming that the effects of bisphosphonate in GIO were similar to those observed in postmenopausal osteoporosis, an assumption tested by meta-analysis. An assessment algorithm is proposed based on age, the presence of a prior fragility fracture and BMD tests in individuals aged 50 years or more with no fracture. The conclusions derived are conservative, mainly because of the assumptions that were made in the absence of sufficient data. Thus, conclusions that treatment scenarios are cost-effective are reasonably secure. By contrast, scenarios shown not to be cost-effective are less secure. As information in these areas becomes available, the implications for cost-effectiveness of interventions should be reappraised. Health economic assessment based on probability of fracture is an important area for further research. Other areas for further research arise from gaps in empirical knowledge on utilities and side-effects that are amenable to primary research. Further secondary research is recommended to evaluate more closely the impact of all vertebral fractures (rather than clinically overt vertebral fractures) on cost-effectiveness and methods of monitoring treatment.

Estimates of fracture probability in Denmark

Dear Editors, The predictive value of DXA for fracture risk assessment has been established in many studies. The meta-analysis of Marshall et al. [1] found that the risk of any osteoporotic fracture increased 1.6-fold for each standard deviation decrease in bone mineral density. More recently it has become evident that there are important interactions that modulate the performance characteristics of BMD. For example, age provides an element of risk not captured by BMD. Thus, the 10-year probability of hip fracture in women aged 80 years with a T-score of −2.5 SD at the femoral neck is fivefold higher than that found in a woman at the age of 50 years with an identical T-score [2]. There is also a complex interaction of age with BMD. Whereas the average gradient of risk for hip fracture in men and women is approximately 2.6 per SD decrease in BMD at the femoral neck [1], it is significantly higher at the age of 50 years (3.68) than at the age of 85 years (1.93) [3]. More recently it has been possible to combine the primary data from a large number of population-based cohorts to elucidate the independent contribution of other clinical risk factors for fracture over and above that provided by age and BMD. Candidate risk factors include low body mass index, the long-term use of glucocorticoids, a prior fragility fracture, a parental history of hip fracture, secondary causes of osteoporosis, cigarette use and excess alcohol consumption [4]. Because of the multiplicity of independent risk factors and their complex interactions, there is a growing view that for clinical purposes, fracture risk should be expressed as fracture probability. The approach takes into account both the risk of fracture and of death [5]. In a recent paper Abrahamsen et al. [6] present their findings on the 10-year absolute risk of osteoporotic fractures according to the T-score for BMD at the total hip. They found that absolute risk in young postmenopausal women in Denmark was higher for any BMD value than that presented by us for Sweden in 2001 [2]. We would agree with this finding. The authors also suggest that the gradient of risk between BMD and fracture risk (i.e., the increase in risk for each standard deviation decrease in BMD) differs from our findings as illustrated in their figure (Fig. 2 of their paper). On this basis, the authors state that “the Kanis algorithm is of limited use at the time of the menopause”, and “is certainly true in healthy North European women not only because the gradient of risk differs from our work but also because the absolute risk differs”. The ‘Kanis algorithm’ is a term commonly associated with the models for fracture risk assessment that our WHO Collaborating Centre is developing. In this context, the statements of Abrahamsen are misleading and should not go unchallenged. Osteoporos Int (2007) 18:1141–1143 DOI 10.1007/s00198-007-0346-8

Clodronate Reduces the Incidence of Fractures in Community-Dwelling Elderly Women Unselected for Osteoporosis: Results of a Double-Blind, Placebo-Controlled Randomized Study

A 3-year prospective, randomized, placebo-controlled trial of oral clodronate 800 mg showed that the incidence of clinical fractures was decreased by 20% in 5596 elderly women unselected for osteoporosis. The effect occurred in the absence of systematic calcium and vitamin D supplementation and was observed across a wide range of BMDs. To date, most studies with bisphosphonates have reported on their use in individuals selected to be at high risk for fracture usually by the presence of low BMD or a prior fragility fracture, usually of the spine. We wished to determine the effect of the bisphosphonate, clodronate, on the rate of fractures in women > or =75 years of age living in the community. Women > or =75 years of age living in the general community in South Yorkshire and North Derbyshire, identified from general practice registers, were recruited by letter of invitation to a randomized, double-blind, controlled trial of 800 mg oral clodronate (Bonefos) or matching placebo daily over 3 years. The main outcomes were the incidences of hip and any clinical fracture. Of the 5579 elderly women included in the intention-to-treat analysis of efficacy, 114 had a new hip fracture during the 3-year treatment phase: 56 (2.0%) women in the clodronate group and 58 (2.1%) women in the placebo group (hazard ration [HR], 1.02; 95% CI, 0.71-1.47). Clodronate did, however, decrease the incidence of any clinical fracture by 20% (264 women [9.5%] versus 337 [12.1%] in the placebo group; HR, 0.80; 95% CI, 0.68-0.94). The incidence of osteoporosis-associated nonhip fractures was also significantly decreased by 29% (5.2% versus 7.4%; HR, 0.71; 95% CI, 0.57-0.87). The ability of clodronate to reduce the risk of osteoporotic fracture was independent of baseline BMD, but the number needed-to-treat was lower in the presence of osteoporosis. Oral daily clodronate can prevent fractures without significant adverse effects in elderly women living in the general community. The effect on hip fracture risk is not significant, but an effect similar to that at other nonvertebral sites cannot be excluded. This study suggests that antiresorptive therapies can reduce fracture incidence in high-risk individuals even in the presence of a normal or osteopenic BMD.

Guidelines for the treatment of glucocorticoid-induced osteoporosis and their future problems

Osteoporosis is the most frequent adverse effect of glucocorticoids. Management guidelines for glucocorticoid-induced osteoporosis have been established in the United States, the United Kingdom, and many other countries. The 2004 edition of the guidelines on the management and treatment of glucocorticoid-induced osteoporosis have been proposed by The Japanese Society for Bone and Mineral Research. The subjects were patients with using or planning to use oral glucocorticoids for 3 months or longer. The criterion for starting treatment was patients with prior fragility fracture and with new fractures during treatment, patients with less bone mineral density (BMD) than 80% of young adult mean, and patients with using as a dose of 5mg/day or higher (mean daily dose) as prednisolone equivalent. The bisphosphonates have been recommended as first-line drugs and active vitamin D(3) and vitamin K(2) have been recommended as second-line drugs.

Indications du raloxifène chez la femme ménopausée

Since the diffusion of the WHI's trial and MWS results, which reported a negative risk/benefit balance of hormone therapy, the management of postmenopausal women has deeply changed over the last 2-3 years. In particular, for the prevention of osteoporosis, the use of other efficient agents tends now to be more widely recommended rather than estrogens. The SERMs with raloxifene are new molecules that have estrogen agonist effects on bone and estrogen antagonist or neutral effects on endometrial and breast tissue. The efficacy of raloxifene to inhibit postmenopausal bone loss as well as to reduce the incidence of vertebral fractures has been demonstrated in women at high risk for osteoporosis through a large randomized placebo-controlled trial involving several thousands of postmenopausal women (MORE trial). Furthermore, the extraskeletal effects of raloxifene might represent an advantage for a global management approach of postmenopausal women, although to date, its exclusive indication is namely the prevention of osteoporosis. However, the estrogen antagonist effects of raloxifene on breast tissue as well as its good safety profile with regard to both the endometrium and the risk of heart diseases are likely to make raloxifene of particular interest for women around the age of 60 years old. Adverse events associated with raloxifene only included an increase in the absolute risk of venous thromboembolism in a comparable manner as with estrogen therapy. Also, its lack of efficacy in reducing hot flushes or preventing vaginal dryness may limit its use in young symptomatic postmenopausal women. Also, its lack of reimbursement in women with no prior fragility fracture must be taken into account.

Antiresorptive Therapy for the Prevention of Postmenopausal Osteoporosis

Osteoporosis is a condition associated with decreased bone strength and an increased fracture risk. It may be defined based on bone mineral density (BMD) with a T-score at the hip or spine of less than -2.5 standard deviations in young healthy individuals or from an osteoporotic fracture (i.e. a fracture occurring after low-energy trauma or no apparent trauma). Risk factors predisposing to fractures include: increasing age; female gender; low BMD; a prior fragility fracture; a family history of fragility fractures; low bodyweight; lack of estrogen in women (i.e. post menopause); corticosteroid use; smoking; a number of diseases; deficiency in calcium and vitamin D; an increased risk of falls (i.e. impaired vision); immobilization; and Caucasian race. The more risk factors that are present the higher the risk of fractures over the following 10 years. The need to initiate preventive therapy with anti-osteoporotic treatment increases steeply with the absolute fracture risk. Indications for referral for dual energy x-ray absorptiometry measurement of BMD include: age >65 years; age <65 years in postmenopausal women with any of the risk factors already mentioned; premature menopause (<45 years); prolonged amenorrhea (>1 year) in younger women; fragility fractures; and diseases or conditions known to lead to osteoporosis.Anti-resorptive therapies include calcium plus vitamin D, bisphosphonates (alendronate, etidronate, risedronate, ibandronate), selective estrogen receptor modulators (raloxifene), hormone replacement therapy, and calcitonin. Guidelines from several countries on when to initiate anti-resorptive therapy state that therapy may be started in patients with a prior fragility fracture (some guidelines state that in this situation no BMD measurements are necessary) or in patients with a T-score of less than -2.5 (some guidelines state that additional risk factors need to be present in this situation). Some guidelines state that anti-resorptive therapy may be initiated in patients with a T-score in the osteopenic range (from -1 to -2.5, i.e. not frank osteoporosis) in the presence of other risk factors. The cost effectiveness of anti-resorptive therapy increases with the absolute fracture risk. In some scenarios, treatment with bisphosphonates may be cost effective in a 50-year-old woman with an absolute hip fracture risk of >or=1.1% over the next 10 years.