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In the large community-based SCOOP trial, systematic fracture risk screening using FRAX ® led to greater use of AOM and greater adherence, in women at high fracture risk, compared with usual care., Introduction: In the SCreening of Older wOmen for Prevention of fracture (SCOOP) trial, we investigated the effect of the screening intervention on subsequent long-term self-reported adherence to anti-osteoporosis medications (AOM)., Methods: SCOOP was a primary care-based UK multicentre trial of screening for fracture risk. A total of 12,483 women (70-85 years) were randomised to either usual NHS care, or assessment using the FRAX ® tool ± dual-energy X-ray absorptiometry (DXA), with medication recommended for those found to be at high risk of hip fracture. Self-reported AOM use was obtained by postal questionnaires at 6, 12, 24, 36, 48 and 60 months. Analysis was limited to those who initiated AOM during follow-up. Logistic regression was used to explore baseline determinants of adherence (good ≥ 80%; poor < 80%)., Results: The mean (SD) age of participants was 75.6 (4.2) years, with 6233 randomised to screening and 6250 to the control group. Of those participants identified at high fracture risk in the screening group, 38.2% of those on treatment at 6 months were still treated at 60 months, whereas the corresponding figure for the control group was 21.6%. Older age was associated with poorer adherence (OR per year increase in age 0.96 [95% CI 0.93, 0.99], p = 0.01), whereas history of parental hip fracture was associated with greater rate adherence (OR 1.67 [95% CI 1.23, 2.26], p < 0.01)., Conclusions: Systematic fracture risk screening using FRAX ® leads to greater use of AOM and greater adherence, in women at high fracture risk, compared with usual care.

Introduction: Increased biochemical bone turnover markers (BTMs) measured in serum are associated with bone loss, increased fracture risk and poor treatment adherence, but their role in clinical practice is presently unclear. The aim of this consensus group report is to provide guidance to clinicians on how to use BTMs in patient evaluation in postmenopausal osteoporosis, in fracture risk prediction and in the monitoring of treatment efficacy and adherence to osteoporosis medication., Methods: A working group with clinical scientists and osteoporosis specialists was invited by the Scientific Advisory Board of European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO)., Results: Serum bone formation marker PINP and resorption marker βCTX-I are the preferred markers for evaluating bone turnover in the clinical setting due to their specificity to bone, performance in clinical studies, wide use and relatively low analytical variability. BTMs cannot be used to diagnose osteoporosis because of low sensitivity and specificity, but can be of value in patient evaluation where high values may indicate the need to investigate some causes of secondary osteoporosis. Assessing serum levels of βCTX-I and PINP can improve fracture prediction slightly, with a gradient of risk of about 1.2 per SD increase in the bone marker in addition to clinical risk factors and bone mineral density. For an individual patient, BTMs are not useful in projecting bone loss or treatment efficacy, but it is recommended that serum PINP and βCTX-I be used to monitor adherence to oral bisphosphonate treatment. Suppression of the BTMs greater than the least significant change or to levels in the lower half of the reference interval in young and healthy premenopausal women is closely related to treatment adherence., Conclusion: In conclusion, the currently available evidence indicates that the principal clinical utility of BTMs is for monitoring oral bisphosphonate therapy.

We evaluated the efficacy of abaloparatide in women who were at increased risk for fracture, based on CHMP recommended risk thresholds, at the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE) study baseline. Among patients at high risk based on FRAX probabilities, 18 months of abaloparatide significantly decreased risk for all fracture endpoints compared with placebo., Purpose: Abaloparatide, a novel anabolic agent for the treatment of postmenopausal osteoporosis, significantly reduced the risk of vertebral and nonvertebral fractures in the ACTIVE study compared with placebo. In this post hoc analysis, we evaluated abaloparatide's efficacy in a subset of women in the study at an increased risk of fracture at baseline, based on the Committee for Medicinal Products for Human Use (CHMP) recommended risk thresholds for inclusion in clinical trials., Methods: Women with a baseline 10-year risk of major osteoporotic fracture ≥ 10% or hip fracture ≥ 5%, assessed using the FRAX® tool (including femoral neck bone mineral density), were included in the analysis. The proportion with one or more events of new morphometric vertebral fractures was calculated. Event rates for nonvertebral, major osteoporotic, and all clinical fractures were estimated using Kaplan-Meier analysis., Results: Following 18 months of treatment, abaloparatide significantly reduced incident vertebral fractures compared with placebo (relative risk reduction = 91%; 0.5% versus 5.6%; p < 0.001). Abaloparatide treatment was also associated with significantly fewer nonvertebral, major osteoporotic, and clinical fractures compared with placebo: 2.7% versus 5.8%, p = 0.036; 1.3% versus 6.0%, p < 0.001; and 3.5% versus 8.2%, p = 0.006, respectively. The effect of abaloparatide on major osteoporotic fractures (78% reduction) was significantly greater than that seen with teriparatide (23% reduction, p = 0.007)., Conclusion: In a subset of postmenopausal women at increased risk of fracture as judged by CHMP guidance, abaloparatide significantly decreased the risk of all fracture endpoints compared with placebo.

This study investigated the relationship between muscle and bone status in elderly individuals. Our results suggested links between sarcopenia and osteoporosis; impairment in muscle status (i.e., muscle mass, muscle strength, and physical performance) is associated with deterioration in bone mass and texture subsequently leading to an increased risk of fracture., Introduction: Accumulating evidence has shown associations between sarcopenia and osteoporosis, but existing studies face inconsistencies in the clinical definition of both conditions. Thus, we sought to investigate bone health among older individuals with or without muscle health impairment., Methods: We conducted an analysis of cross-sectional data available from the Sarcopenia and Physical Impairment with Advancing Age (SarcoPhAge) study. Sarcopenia was diagnosed according to the European Working Group on Sarcopenia in Older People (EWGSOP) (i.e., a low muscle mass plus either low muscle strength or low physical performance). Muscle mass and areal bone mineral density (aBMD) were determined using dual-energy X-ray absorptiometry (DEXA). Muscle strength was assessed using a hand dynamometer, and physical performance was assessed with the Short Physical Performance Battery test. Using the cutoff limits proposed by the EWGSOP, we have classified women in the "low SMI group" when its value was < 5.50 kg/m 2 , in the "low muscle strength group" when strength was < 20 kg, and in the "low physical performance group" when SPPB < 8 points. The thresholds of < 7.26 kg/m 2 (for SMI), < 30 kg (for muscle strength), and SPPB < 8 points were used for men. The 10-year fracture risk was obtained using the FRAX® tool. Moreover, bone texture was determined using the trabecular bone score (TBS) method., Results: The study sample consisted of 288 older subjects aged 74.7 ± 5.7 years, and 59.0% of the subjects were women. Sarcopenia was diagnosed in 43 individuals (14.9%), and osteoporosis was diagnosed in 36 subjects (12.5%). Moreover, aBMD values were, most of the time, lower in older men and women with muscle impairment (i.e., low muscle mass, low muscle strength, and low physical performance). For these subjects, we also noted a higher probability of fracture. When comparing bone quality, there were no significant differences in the TBS values between sarcopenic and non-sarcopenic older men and women or between those with low and high muscle mass. However, when controlling for confounders (i.e., age, BMI, number of co-morbidities, smoking status, and nutritional status), TBS values were lower in older women with low muscle strength (p = 0.04) and in older men with low physical performance (p = 0.01)., Conclusions: Our study showed interrelationships between components of sarcopenia and osteoporosis, with older subjects with muscle impairment having poorer bone health.

Unlabelled: FRAX(R) incrementally improved prediction of incident major osteoporotic fractures compared with the simplified Canadian Association of Radiologists and Osteoporosis Canada (CAROC) tool., Introduction: There is debate over the value of seemingly more complex fracture prediction tools over simpler fracture prediction tools. FRAX(R) and the simplified CAROC tool are both widely used in Canada for estimating 10-year probability of major osteoporotic fractures. We compared the performance of these tools for predicting fracture outcomes., Methods: Using a bone densitometry registry for Manitoba, Canada, we identified 34,060 individuals age ≥50 years not receiving anti-osteoporosis therapy. Fracture Risk Assessment (FRAX) and CAROC were used to classify 10-year fracture risk as low (<10 %), moderate (10-20 %) and high (>20 %). Net reclassification improvement (NRI) was used to quantify the performance of FRAX versus CAROC., Results: During mean 9.8 years of follow-up, 3905 individuals sustained fractures. There were 10 (of 35 total) situations where observed fracture risk fell outside of the predicted range, and all 10 discordances favoured FRAX. NRI among incident fracture cases was not significantly changed, but there was a significant improvement in risk categorization for those who remained fracture-free (+1.7 %, P < 0.001) resulting in overall improvement (NRI overall +0.028, P < 0.001). Within nine pre-specified subgroups, there was no case of significant worsening in NRI when using FRAX instead of CAROC. In absolute terms, only 36 individuals would need to be assessed using FRAX instead of CAROC to yield an improvement in prediction (8 among individuals with prior fracture and 4 among those with prolonged glucocorticoid use)., Conclusions: FRAX provides improvement in fracture risk prediction compared with the simplified CAROC tool in individuals referred for osteoporosis screening, supporting the use of FRAX as the international reference tool for fracture risk assessment.

There are occasional marked discordances in BMD T-scores at the lumbar spine (LS) and femoral neck (FN). We investigated whether such discordances could contribute independently to fracture prediction using FRAX. We studied 21,158 women, average age 63 years, from 10 prospective cohorts with baseline FRAX variables as well as FN and LS BMD. Incident fractures were collected by self-report and/or radiographic reports. Extended Poisson regression examined the relationship between differences in LS and FN T-scores (ΔLS-FN) and fracture risk, adjusted for age, time since baseline and other factors including FRAX 10-year probability for major osteoporotic fracture calculated using FN BMD. To examine the effect of an adjustment for ΔLS-FN on reclassification, women were separated into risk categories by their FRAX major fracture probability. High risk was classified using two approaches: being above the National Osteoporosis Guideline Group intervention threshold or, separately, being in the highest third of each cohort. The absolute ΔLS-FN was greater than 2 SD for 2.5% of women and between 1 and 2 SD for 21%. ΔLS-FN was associated with a significant risk of fracture adjusted for baseline FRAX (HR per SD change = 1.09; 95% CI = 1.04-1.15). In reclassification analyses, only 2.3-3.2% of the women moved to a higher or lower risk category when using FRAX with ΔLS-FN compared with FN-derived FRAX alone. Adjustment of estimated fracture risk for a large LS/FN discrepancy (>2SD) impacts to a large extent on only a relatively small number of individuals. More moderate (1-2SD) discordances in FN and LS T-scores have a small impact on FRAX probabilities. This might still improve clinical decision-making, particularly in women with probabilities close to an intervention threshold.

Unlabelled: Use of lumbar spine T-score or minimum T-score as a bone mineral density (BMD) input to the FRAX® algorithm led to miscalibration compared with the recommended femoral neck input. Use of a weighted mean between the lumbar spine and femoral neck T-scores was found to provide an arithmetically equivalent result to a previously described offset adjustment., Introduction: FRAX assumes that the BMD input, when used in the calculation, is from the femoral neck. Use of other BMD inputs is not recommended, but there are no studies describing how this affects the performance of FRAX., Methods: Ten-year probabilities of a major osteoporotic fracture were calculated with different BMD inputs for 20,477 women and men aged 50 years and older from Manitoba, Canada. FRAX probability calculated with femoral neck BMD was designated the reference method. We also derived FRAX probabilities where the BMD input was based upon the lumbar spine T-score, minimum T-score (lumbar spine or femoral neck), weighted mean T-score (lumbar spine or femoral neck), or used an adjustment for the spine-hip T-score difference (offset). Fracture outcomes were assessed using a population-based administrative data repository., Results: All FRAX models showed good risk stratification with minimal differences. There was no consistent improvement in FRAX performance when lumbar spine or minimum T-score were used as inputs, but calibration was adversely affected due to higher mean fracture probabilities compared with the femoral neck. The weighted mean T-score was found to be equivalent to the spine-hip T-score offset adjustment, and both slightly improved risk classification without a change in calibration., Conclusions: The choice of BMD input to the FRAX model has a large effect on performance. The lumbar spine T-score or minimum T-score should not be used as inputs to the FRAX algorithm. Use of a weighted mean between the lumbar spine and femoral neck T-scores slightly improves risk classification.

Unlabelled: The consensus views on osteoporosis in men are reported., Introduction: A workshop was convened within a meeting on osteoporosis in men to identify areas of consensus amongst the panel (the authors) and the participants of the meeting., Methods: A public debate with an expert panel on preselected topics was conducted., Results and Conclusions: Consensus views were reached on diagnostic criteria and several aspects on the pathophysiology and treatment of osteoporosis in men.

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., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

Unlabelled: This study estimated the 10-year probability of osteoporotic fracture in Hong Kong Southern Chinese based on a simplified model of the recently developed WHO fracture risk prediction tool (FRAX). Thus, the data provides further insights into potential development of a population-specific FRAX model for Hong Kong in the future., Introduction: The purpose of this paper was to estimate the 10-year probability of osteoporotic fracture in Hong Kong (HK) Southern Chinese according to age and bone mineral density (BMD) T-score at the femoral neck based on the methodology of the FRAX risk assessment tool calibrated to the epidemiology of HK., Methods: Hip fracture data was obtained from the Clinical Data Analysis Reporting System (CDAS) of the Hospital Authority of HK and population size and death rates were taken from the HK Government Census and Statistics Department. Fracture probability was calculated using the cut-off values for T-scores derived from the NHANES III data for Caucasian women aged 20-29 years for BMD at the femoral neck., Results: In this study, the 10-year probability of osteoporotic fracture in HK Southern Chinese increased markedly with increasing age and decreasing femoral neck BMD T-scores in both women and men. Interestingly, at low T-scores, the increase in 10-year probability of osteoporotic fracture in women with age was greater than in men. Fracture probabilities were substantially higher than those from mainland China., Conclusions: Based on this evidence, and until we have HK Southern Chinese population-specific information, we recommend the application of the Caucasian risk profile to calculate the absolute fracture risk for HK Southern Chinese subjects.

Summary: This study examined the effects of the use of clinical risk factors (CRFs) alone, BMD alone or the combination using the FRAX tool for the detection of women at risk of hip fracture. BMD tests alone selected women at higher risk and a greater number of hip fracture cases were identified compared to the use of CRFs alone. The combined use of CRFs and BMD identified fewer women above a threshold risk than the use of BMD alone, but with a higher hip fracture risk and thus had the more favourable positive predictive value (PPV) and number needed to treat (NNT)., Introduction: Algorithms have recently become available for the calculation of hip fracture probability from CRFs with and without information on femoral neck BMD. The aim of this study was to examine the effects of the use of CRFs alone, BMD alone or their combination using the FRAX tool for the detection of women at risk of hip fracture., Methods: Data from 10 prospective population based cohorts, in which BMD and CRFs were documented, were used to compute the 10-year probabilities of hip fracture calibrated to the fracture and death hazards of the UK. The effects of the use of BMD tests were examined in simulations where BMD tests were used alone, CRFs alone or their combined use. The base case examined the effects in women at the age of 65 years. The principal outcome measures were the number of women identified above an intervention threshold, the number of hip fracture cases that would be identified, the positive predicted value and the NNT to prevent a hip fracture during a hypothetical treatment with an effectiveness of 35% targeted to those above the threshold fracture risk. We also examined BMD values in women selected for treatment. Sensitivity analysis examined the effect of age and limited use of BMD resources., Results: BMD tests alone selected women at higher risk of hip fracture than the use of CRFs alone (6.1% versus 5.3%). BMD tests alone also identified a greater number of hip fracture cases (219/1,000) compared to the use of CRFs alone (140/1,000). The combined use of CRFs and BMD identified fewer women above a threshold risk than the use of BMD alone (168/1,000 versus 219/1,000, respectively), but with a higher hip fracture risk (PPV, 8.6% versus 6.1%), and consequently a lower number needed to treat (NNT) (33 versus 47). In sensitivity analyses, the PPV and NNT were always better for the combination than either BMD or CRFs alone across all ages studied (50-70 years)., Conclusions: The use of FRAX in combination with BMD increases the performance characteristics of fracture risk assessment.

Unlabelled: Guidance is provided in a European setting on the assessment and treatment of postmenopausal women with or at risk from osteoporosis., Introduction: The European Foundation for Osteoporosis and Bone disease (subsequently the International Osteoporosis Foundation) published guidelines for the diagnosis and management of osteoporosis in 1997. This manuscript updates these in a European setting., Methods: The following areas are reviewed: the role of bone mineral density measurement for the diagnosis of osteoporosis and assessment of fracture risk; general and pharmacological management of osteoporosis; monitoring of treatment; assessment of fracture risk; case finding strategies; investigation of patients; health economics of treatment., Results and Conclusions: A platform is provided on which specific guidelines can be developed for national use.

Unlabelled: BMD and clinical risk factors predict hip and other osteoporotic fractures. The combination of clinical risk factors and BMD provide higher specificity and sensitivity than either alone. INTRODUCTION AND HYPOTHESES: To develop a risk assessment tool based on clinical risk factors (CRFs) with and without BMD., Methods: Nine population-based studies were studied in which BMD and CRFs were documented at baseline. Poisson regression models were developed for hip fracture and other osteoporotic fractures, with and without hip BMD. Fracture risk was expressed as gradient of risk (GR, risk ratio/SD change in risk score)., Results: CRFs alone predicted hip fracture with a GR of 2.1/SD at the age of 50 years and decreased with age. The use of BMD alone provided a higher GR (3.7/SD), and was improved further with the combined use of CRFs and BMD (4.2/SD). For other osteoporotic fractures, the GRs were lower than for hip fracture. The GR with CRFs alone was 1.4/SD at the age of 50 years, similar to that provided by BMD (GR = 1.4/SD) and was not markedly increased by the combination (GR = 1.4/SD). The performance characteristics of clinical risk factors with and without BMD were validated in eleven independent population-based cohorts., Conclusions: The models developed provide the basis for the integrated use of validated clinical risk factors in men and women to aid in fracture risk prediction.

Low body mass index (BMI) is a well-documented risk factor for future fracture. The aim of this study was to quantify this effect and to explore the association of BMI with fracture risk in relation to age, gender and bone mineral density (BMD) from an international perspective using worldwide data. We studied individual participant data from almost 60,000 men and women from 12 prospective population-based cohorts comprising Rotterdam, EVOS/EPOS, CaMos, Rochester, Sheffield, Dubbo, EPIDOS, OFELY, Kuopio, Hiroshima, and two cohorts from Gothenburg, with a total follow-up of over 250,000 person years. The effects of BMI, BMD, age and gender on the risk of any fracture, any osteoporotic fracture, and hip fracture alone was examined using a Poisson regression model in each cohort separately. The results of the different studies were then merged. Without information on BMD, the age-adjusted risk for any type of fracture increased significantly with lower BMI. Overall, the risk ratio (RR) per unit higher BMI was 0.98 (95% confidence interval [CI], 0.97-0.99) for any fracture, 0.97 (95% CI, 0.96-0.98) for osteoporotic fracture and 0.93 (95% CI, 0.91-0.94) for hip fracture (all p <0.001). The RR per unit change in BMI was very similar in men and women ( p >0.30). After adjusting for BMD, these RR became 1 for any fracture or osteoporotic fracture and 0.98 for hip fracture (significant in women). The gradient of fracture risk without adjustment for BMD was not linearly distributed across values for BMI. Instead, the contribution to fracture risk was much more marked at low values of BMI than at values above the median. This nonlinear relation of risk with BMI was most evident for hip fracture risk. When compared with a BMI of 25 kg/m(2), a BMI of 20 kg/m(2) was associated with a nearly twofold increase in risk ratio (RR=1.95; 95% CI, 1.71-2.22) for hip fracture. In contrast, a BMI of 30 kg/m(2), when compared with a BMI of 25 kg/m(2), was associated with only a 17% reduction in hip fracture risk (RR=0.83; 95% CI, 0.69-0.99). We conclude that low BMI confers a risk of substantial importance for all fractures that is largely independent of age and sex, but dependent on BMD. The significance of BMI as a risk factor varies according to the level of BMI. Its validation on an international basis permits the use of this risk factor in case-finding strategies.

Background: A case finding strategy based on a number of established risk factors has been suggested by Royal College of Physicians' (RCP) guidelines to optimise bone densitometry referrals for assessment of osteoporosis., Objective: The performance of clinical referral criteria was examined in women and men aged <65 years referred for bone mineral density (BMD) assessment., Study Design: Cross sectional observational study over six months., Results: Though BMD tended to be lower in patients with multiple criteria for referral, differences from those referred with a single criterion were not statistically significant. The overall prevalence of osteoporosis was higher than expected in both sexes, 11.6% in women and 27.5% in men (expected prevalences were 8% and <1% respectively). BMD was significantly lower in patients referred with a single criterion compatible with the RCP guidelines than in age matched controls or in those patients referred with non-RCP criteria (mean (SD) Z score -0.47(1.38) v 0.35(1.41), p<0.001). Low body mass index was also significantly associated with a lower than expected BMD. In contrast, spine BMD was higher than expected in those with self reported back pain, loss of height, or spinal curvature (p = NS)., Conclusion: Most of the criteria recommended by the RCP performed well in identifying relatively younger patients with low BMD and osteoporosis. However, prior fractures and corticosteroid use did not reach statistical significance probably due to inclusion of all energy fractures, and current or past steroid use of unspecified dose or duration. Criteria like loss of height and/or spine curvature perform relatively poorly, reflecting the need for further investigation to better identify those needing BMD assessment.

The objectives of the present study were to estimate 10 year probabilities of osteoporotic fractures in men and women according to age and bone mineral density (BMD) at the femoral neck. Risks were computed from the incidence of a first hip, distal forearm, proximal humerus and symptomatic vertebral fracture from patient records in Malmö, Sweden and future mortality rates for each year of age from Poisson models using the Swedish patient register and statistical year book. Fracture probability was computed using the Swedish population and cut-off values for T-scores based on the NHANES III female population. We assumed that the risk of fracture increased with decreasing BMD as assessed by meta-analysis in independent studies. The 10-year probability of any fracture was determined from the proportion of individuals fracture-free from the age of 45 years. With the exception of forearm fractures in men, 10 year probabilities increased with age and T-score. In the case of hip and spine fractures, fracture probabilities for any age with low BMD were similar between men and women. The effect of age on risk independently of BMD suggests that intervention thresholds should not be at a fixed T-score but vary according to absolute probabilities. Intervention thresholds based on hip BMD T-scores are similar between sexes.

Previous studies have demonstrated that an Sp1 binding site polymorphism in the collagen type I gene (COLIA1) is related to reduced bone mineral density (BMD) and osteoporotic fractures in certain populations, particularly in the elderly. We have examined the relationship among these COLIA1 Sp1 alleles, BMD, quantitative ultrasound properties of bone, and fractures in a population-based cohort of elderly women from the UK. The study group comprised 314 women aged 75 years and over who agreed to participate in a clinical study of bisphosphonate therapy in preventing bone loss at the hip. Women were enrolled regardless of the presence or absence of osteoporosis, but those with other diseases that might affect skeletal metabolism were excluded. The genotype distribution for the Sp1 polymorphism was in Hardy-Weinberg equilibrium (SS - 78%; Ss - 20%; ss - 2%) but the proportion of individuals who carried the "s" allele (22%) was significantly lower than previously observed in another study of the UK population (37.1%) (P < 0.001). There were no significant associations between COLIA1 genotypes and metacarpal cortical index, BMD of the forearm, tibial SOS, calcaneal SOS, or calcaneal BUA. While there was a trend towards lower BMD values at the hip in patients with Ss and ss genotypes, this was not statistically significant (SS = 0.721 +/- 0.14; Ss = 0.704 +/- 0.13; ss = 0.683 +/- 0.20 P = 0.6). Prevalent vertebral fractures occurred in 22% of subjects and prior fractures of the wrist, ankle, and hip were reported by 20%, but there was no significant difference in COLIA1 genotype distribution between fracture patients and controls. We conclude that COLIA1 Sp1 alleles are not significantly associated with BMD, ultrasound properties of bone, or fractures in this population-based sample of elderly women.

Fractures and subsequent morbidity determine the impact of established postmenopausal osteoporosis. Health-related quality of life (HRQOL) has become an important outcome criterion in the assessment and follow-up of osteoporotic patients. As part of the baseline measurements of the Multiple Outcomes of Raloxifene Evaluation (MORE) study, HRQOL was assessed in 751 osteoporotic (bone mineral density [BMD] T score > or = -2.5) women from Europe with or without vertebral fractures (VFX). This was done using the quality of life questionnaire of the European Foundation for Osteoporosis (QUALEFFO), Nottingham Health Profile (NHP) and the EQ-5D (former EuroQol). QUALEFFO contains questions in five domains: pain, physical function, social function, general health perception, and mental function. Each domain score and QUALEFFO total scores are expressed on a 100-point scale, with 0 corresponding to the best HRQOL. In comparison with patients without VFX, those with VFX were older (66.2 +/- 5.9 years vs. 68.8 +/- 6.3 years; p < 0.001), had higher prevalence of nonvertebral fractures (25% vs. 36%; p = 0.002), and higher QUALEFFO scores (worse HRQOL; total score, 26 +/- 14 vs. 36 +/- 17; p < 0.001). QUALEFFO scores increased progressively with increasing number of VFX, especially lumbar fractures (p < 0.001). Patients with a single VFX already had a significant increase in QUALEFFO scores (p < 0.05). Similar, though weaker, associations were seen for NHP and EQ-5D scores. This study confirms decreased HRQOL for patients with prevalent VFX. In osteoporotic patients, QUALEFFO scores change in relation to the number of VFX. QUALEFFO is suitable for clinical studies in patients with postmenopausal osteoporosis.

There is a well-established relationship between bone mineral density (BMD) and fracture risk. Estimates of the relative risk of fracture from BMD have been derived mainly from short-term studies in which the correlation between BMD at assessment and BMD in later life ranged from 0.8 to 0.9. Because individuals lose bone mineral at different rates throughout later life, the long-term predictive value of low BMD is likely to decrease progressively with time. This article examines and formalizes the relationship between current BMD, correlation coefficients, and long-term risk. The loss of predictive value has important implications for early assessment and supports the view that measurements should be optimally targeted at the time interventions are contemplated and, when necessary, repeated in later life.

The diagnosis of osteoporosis is based on bone mass measurement. To avoid the errors associated with the measurement of spinal bone density the total hip has been accepted as the standard measurement site. This information is not available for many early measurements. We have assessed whether it is possible to derive clinically useful information about total hip bone mineral density (BMD) from measurements at other hip sites. The bone mass measurements of 46 patients participating in a current trial of therapy for osteoporosis were reviewed. The total hip BMD as directly measured was compared with that obtained from the formula: Total hip BMD = 0.48 x Neck BMD + 0.62 x Trochanteric BMD + 0.03. In 30 patients with follow-up data the rate of change in hip BMD over a year was also determined by both methods. In the pretreatment state there was good agreement between the two measures (r2 = 0.96, SEE 0.012 g/cm2). If the formula was used to compute a change in total hip BMD, the agreement between both methods remained good. However, the standard error of the estimate of the change represented 59% of the observed change. This indicates that the error associated with this estimate is too great to allow clinically meaningful conclusions to be drawn from calculated total hip BMD. We conclude that, whilst it may be possible to obtain reasonable point estimates of total hip BMD from other measures in the hip, these estimates are too imprecise to allow conclusions about change in BMD to be made.

Metacarpal morphometry represents a potentially cheap and widely available non-invasive assessment of skeletal status. In two cross-sectional studies, we compared the performance characteristics of a semiautomated technique (the Teijin Bonalyzer) with an in-house manual measurement, and with measures of skeletal strength at other sites. The metacarpal cortical index (mCI) was measured on hand radiographs of 178 osteoporotic women using both the Teijin Bonalyzer and a digitizing tablet. Measurements on the latter were consistently lower than with the Bonalyzer except for mCI (0.443+/-0.080 vs 0.364+/-0.060, p<0.001), although correlation coefficients between these two methods were highly significant (r = 0.62-0.83, p<0.001). The reproducibility errors of metacarpal bone mineral density (mBMD) were constant (1.1-1.2%) whilst those for mCI showed a marked operator-dependency (2.0-7.9%). In 379 elderly community-dwelling women, Bonalyzer mCI and mBMD showed a significant decline with age (r = -0.30 and -0.27 respectively, p<0.05). Both mCI and mBMD correlated significantly with forearm BMD (r = 0.50 and 0.57 respectively, p<0.001) and hip BMD (r = 0.48 and 0.53 respectively, p<0.001). After adjustment for age and weight, hip BMD demonstrated the best discrimination for prevalent vertebral fractures as judged by the gradient of risk for a 1 SD decrease in measurement (odds ratio (OR) 2.17, 95% CI 1.56-3.01). Similar but smaller gradients of risk were shown by Bonalyzer mCI (OR 1.32, 95% CI 1.00-1.75), mBMD (OR 1.35, 95% CI 1.02-1.78) and forearm BMD (OR 1.39, 95% CI 1.08-1.80). MCI, and in particular mBMD, may be useful assessments of bone mass and fracture risk. In our study, it is comparable to peripheral assessment of skeletal status by forearm densitometry.

In 1994 the WHO proposed guidelines for the diagnosis of osteoporosis based on measurement of bone mineral density. They have been widely used for epidemiological studies, clinical research and for treatment strategies. Despite the widespread acceptance of the diagnostic criteria, several problems remain with their use. Uncertainties concern the optimal site for assessment, thresholds for men and diagnostic inaccuracies at different sites. In addition, the development of many new technologies to assess the amount or quality of bone poses problems in placing these new tools within a diagnostic and assessment setting. This review considers the recent literature that has highlighted the strengths and weaknesses of diagnostic thresholds and their use in the assessment of fracture risk, and makes recommendations for actions to resolve these difficulties.

Osteoporosis is caused by a reduction in bone mass, but the cause of osteoporotic fractures is multifactorial because fractures arise following various degrees of trauma. There are therefore several different categories of risk factors for osteoporotic fracture. They may be related to the determinants of bone mineral density, capture the risk of falls, be related to skeletal fragility independently of bone mineral density or a combination of these. The identification of strong risk factors permits the identification of patients in whom further assessment and treatment can be offered in case finding strategies.

Densitometric measurements are prone to imprecision in elderly subjects and the present study was primarily designed to dissect out the effects of age and bone mineral density on proximal femur dual energy x-ray absorptiometry (DXA) reproducibility. The study comprised 17 elderly women (mean age 74.6 years, range 65-84 years), 13 early postmenopausal women with osteopenia (mean age 56.2 years, range 50-63 years), and 17 elderly men (mean age 73.8 years, range 65-86 years). Each subject was given triplicate proximal femur scans by a QDR 2000 Densitometer (Hologic Inc., Waltham, MA) with repositioning between scans. Because of subject selection in the early postmenopausal women there were no significant differences in bone mineral density (BMD) at any site among the three groups. Despite this, reproducibility errors expressed as either coefficient of variation (CV) % or mean standard deviation (SD) were greater in the elderly subjects, regardless of gender, when compared with the younger female subjects. The variability in measurement errors with age were least marked for the total hip and trochanteric sites. Within the elderly subjects, BMD appeared to exert little influence on measurement errors. We conclude that short-term proximal femur reproducibility is dependent on age-related factors other than BMD. There is no influence of gender on the measurement errors. It is likely that local factors (e.g., hip osteoarthritis) or general frailty may influence repositioning but this needs further exploration. In the meantime, the total hip and trochanteric sites should be used as they provide the most reproducible measurements in the elderly.

Background: Women with primary breast cancer who receive systemic therapy may experience ovarian failure or early menopause, leading to a loss of bone mineral density (BMD). Loss of BMD may be reduced by use of bisphosphonates, compounds that inhibit the action of osteoclasts (cells that absorb or remove bone tissue). We have conducted a double-blind, randomized, two-center trial to evaluate BMD in women with primary breast cancer who were given the bisphosphonate clodronate (1600 mg/day orally) or placebo for 2 years., Methods: From August 31, 1990, through March 31, 1996, more than 300 eligible patients had been accrued, randomly assigned to study treatment, given the appropriate primary surgical care and systemic (chemotherapy and/or tamoxifen) therapy, and had completed follow-up for at least 1 year. BMD in the lumbar spine and in the hip, including the trochanteric area, was measured by use of dual-energy x-ray absorptiometry at the beginning of treatment and after 1 and 2 years of treatment. Changes in BMD were calculated as percent changes from the initial readings. Treatment effects for clodronate versus placebo (i.e., mean percent changes in BMD with clodronate minus mean percent changes in BMD with placebo) at 1 and 2 years for individual sites were calculated., Results: After 1 year, the treatment effects for clodronate versus placebo in the lumbar spine, the total hip, and the trochanter, respectively, were as follows: +2.38% (95% confidence interval [CI] = 1.36-3.41), +0.74% (95% CI = -0.13 - 1.60), and +1.29% (95% CI = 0.24-2.34). After 2 years, the corresponding treatment effects were +1.72% (95% CI = 0.12-3.34), +1.85% (95% CI = 0.51-3.20), and +2.30% (95% CI = 0.66-3.94), respectively., Conclusions: Oral clodronate appears to reduce the loss of BMD in patients who receive treatment for primary breast cancer.

In Europe there is a 3-fold variation, according to geographical center, in risk of vertebral deformity in men and women over the age of 50. We investigated the relationship between bone density, as assessed by dual-energy X-ray absorptiometry (DEXA) of the spine and hip and prevalent vertebral deformities in 13 of the 36 centers participating in the European Vertebral Osteoporosis Study (EVOS). Each center recruited an age-stratified sample of men and women aged 50 years and over, and of those who agreed to densitometry, 288/2088 women and 233/1908 men were found to have one or more deformities of the vertebrae between T4 and L4 as assessed by the McCloskey algorithm. DEXA was in each case performed on L2-L4, the proximal femur, or both. Bone densitometry results were cross-calibrated between centers using the European Spine Phantom prototype and results expressed as bone mineral density (BMD, g/cm2). In both genders, subjects with deformities involving loss of anterior vertebral body height alone comprised over 20% of the total with deformities and these related poorly to BMD. Other classes of deformity were found by logistic regression to relate significantly to BMD in one or both genders, with odds ratios for the risk of any of these ranging from 1.67 to 2.11 for a 1 SD reduction in bone density at spine, femoral neck, or trochanter (p < 0.001). Adjusting for anthropometric variables and BMD did not remove the effect of age on risk which rose 1.67- to 1.78-fold per decade according to gender. The greater unadjusted rate of increase in deformity risk with age in women was attributable to their faster rate of bone loss with age; after adjusting for age, body mass index (BMI), and BMD at the trochanter in grams per square centimeter, men had a 2-fold higher risk of deformity than women. Analysis of the relationship between mean bone density and the prevalence of deformity in each center demonstrated no significant differences between centers in either gender, after adjusting for BMD, age, and BMI together with an a posteriori statistical adjustment for imperfect cross-calibration of densitometers. It is concluded that BMD is an important determinant of deformity risk in both genders. Together with age, BMD explains much of the differences in risk both between the sexes and between individual geographical centers in Europe.

Hip fracture is the most serious complication of osteoporosis and the incidence is rising worldwide. Bone mineral density measurements can be used not only to diagnose osteoporosis at the hip, but also to give prognostic information on the lifetime risk of hip fracture. A number of additional risk factors enhance the ability of density measurements to assess risk. Candidates include markers of bone resorption, prior fragility fractures, hip axis length, and estimates of postural integrity, each of which improve prognostic value independently of bone mineral assessments. Their use in the stratification of risk will help define intervention thresholds for treatments and improve the design of population screening policies, particularly in elderly women in whom the burden of hip fracture is greatest.

Bone mineral assessments provide a tool for the diagnosis, assessment and monitoring of individuals with osteoporosis. The correct application of this methodology and the interpretation of assessment will improve the direction of treatments to those most at need.

Purpose: Tamoxifen is an effective treatment for metastatic and primary breast cancer and is now being evaluated as a chemoprevention agent in healthy women. Any long-term effects on estrogen-sensitive tissues such as bone may have important therapeutic implications., Methods: We measured bone mineral density (BMD) in the lumbar spine and hip using dual-energy x-ray absorptiometry (DXA) in premenopausal and postmenopausal healthy women who participated in our placebo-controlled tamoxifen chemoprevention of breast cancer trial., Results: BMD data are now available from 179 women for this analysis. In premenopausal women, BMD decreased progressively in the lumbar spine (P < .001) and in the hip (P < .05) for women on tamoxifen, but not those on placebo. The mean annual loss in lumbar BMD per year over the 3-year study period in tamoxifen-treated compliant women who remained premenopausal throughout the study period was 1.44% (1.88% calculated on an intent-to-treat basis) compared with a small gain of 0.24% per annum for women on placebo (P < .001). Tamoxifen had the opposite effect in postmenopausal women. The mean annual increase in BMD for women on tamoxifen was 1.17% in the spine (P < .005) and 1.71% in the hip (P < .001) compared with a noninsignificant loss for women on placebo., Conclusion: These results indicate that tamoxifen treatment is associated with a significant loss of BMD in premenopausal women, whereas it prevents bone loss in postmenopausal women. These adverse and beneficial effects of tamoxifen should be considered in the assessment of the therapeutic benefits for both the adjuvant treatment and the chemoprevention of breast cancer.

We evaluated changes in bone mineral density (BMD) after tibial fractures, both at the site of fracture and at adjacent sites, using dual-energy X-ray absorptiometry. Five patients were studied prospectively for six months after fractures of the midshaft treated by intramedullary nailing or the application of an external fixator. We also reviewed 21 adult and 10 children who had sustained fractures of the tibia at least five years previously, comparing BMD in the injured limb with that in the non-injured limb and in a control group of 10 normal subjects. We found a significant fall in BMD distal to a tibial fracture; this was evident at one month, fell to approximately 50% of normal at three months and persisted at six months. We found no significant improvement with weight-bearing. Review at 5 to 11 years after adult midshaft fractures showed persistent bone loss in the distal tibia (46.5 +/- 9.8% of control values), but persisting sclerosis at old fracture sites (172 +/- 38% of control values). In contrast, we found no significant differences in BMD between the injured and control limb after fractures sustained in childhood either at the fracture site or in the distal segment. We conclude that, in adults, tibial fractures are associated with definite and persistent post-traumatic loss of distal BMD.

A population survey was performed to estimate the prevalence of vertebral fractures in women aged 45-69 and to determine their relationship to bone density and symptoms. Subjects were 1035 women aged 45-69 (mean 55.4 years, response rate 77%) from the age-sex register of a large 11,000-person general practice in Chingford, London. Thoracic and lumbar spine x-rays were read by a semiautomated quantitative method. Vertebral fractures were diagnosed using a variety of morphometric methods, including a new method we recently developed and the published methods of Melton and Eastell. These methods all detect abnormal ratios between anterior, central, or posterior vertebral height and between observed posterior vertebral height and values predicted from the posterior height of adjacent vertebrae. Bone mineral density (BMD) of lumbar spine L1-4 and neck of femur was measured by dual-energy x-ray absorptiometry (DXA). Using our method, 147, 14.2% (95% CI 12.0-16.2%) of the 1035 women, had minor fractures (at least two vertebral ratios 2-2.99 SD below the mean) and 20, 1.9% (95% CI 1.2-3.0%) of the total, had severe fractures (at least two ratios more than 3 SD below the mean). In the 147 women with minor fractures, bone density of the spine was not significantly lower than in the other 868 women, and reported back pain or loss of height was no more common. Women with multiple minor fractures did have lower bone density, by 0.4 SD. In the 20 women with severe fracture, bone density was significantly lower, by 0.6 SD.(ABSTRACT TRUNCATED AT 250 WORDS)

This is increasing evidence that interventions with drugs affecting bone metabolism decrease the risk of hip fracture. The use of such agents is increasing in Europe, and there is a need to develop the strategies for optimum means of intervention. This paper assesses the impact of the increasing use of such agents on hip fracture outcome using several sets of assumptions. Since hip fractures occur largely after the age of 70 years, intervention directed at this age has a significant impact on hip fractures prevented. Indeed, the gains are greater if the effects of a 5-year treatment wear off once treatment has stopped. The targeting of intervention to those with the lowest values of bone mineral density increases the efficiency of intervention on hip fracture outcome by 70-140%, depending on the gradient of risk associated with decreasing bone mineral density.

The effect of sodium fluoride therapy on iliac trabecular bone has been studied in 15 patients with primary osteoporosis by comparing bone biopsies taken before and after two years of treatment. A marked increase in bone volume (43%) was observed, which was attributable to an increase in trabecular thickness (46%) rather than their number. Because the trabecular bone surface, the trabecular number, the bone volume/trabecular width ratio, and the trabecular terminus number do not change significantly after fluoride treatment, we conclude that fluoride does not induce the de novo generation of trabeculae, nor does it restore trabecular connectivity despite the restoration of bone mass. These data suggest that the restoration of skeletal mass with fluoride may not lead to a comparable decrease in the risk of future fracture.

1. We have examined the relationship between broadband ultrasound attenuation in the os calcis and measurements of bone mineral in the distal forearm and lumbar spine of normal and postmenopausal osteoporotic women. 2. Values of broadband ultrasound attenuation in postmenopausal women with vertebral osteoporotic fractures were significantly lower (35%) than in normal pre- and peri-menopausal women (55.4 +/- 3.8 and 79.6 +/- 0.8 dB/MHz, respectively). 3. Broadband ultrasound attenuation correlated significantly with bone mineral content measured in the distal forearm by single-photon absorptiometry (r = 0.77, P less than 0.0001) and with bone mineral content (r = 0.66, P less than 0.0001) and bone mineral density (r = 0.72, P less than 0.0001) measured in the lumbar spine by dual-photon absorptiometry. 4. Although significant, these correlations are not sufficiently close to be predictive. However, the accuracy of broadband ultrasound attenuation in discriminating between normal subjects and patients with vertebral fracture compared very favourably with direct measurements in the spine by dual-photon absorptiometry. 5. Broadband ultrasound attenuation, but not the other measurements, correlated significantly with age in the osteoporotic patients (r = 0.50, P less than 0.05). 6. These findings may reflect the partial dependence of broadband ultrasound attenuation on the intrinsic trabecular architecture of cancellous bone, the disruption of which contributes to an increase in fracture risk.

1. We have examined the relationship between the attenuation of broadband ultrasound in the os calcis in vitro and its bone mineral density measured by quantitative computed tomography and by physical density. 2. Broadband ultrasound attenuation was found to correlate closely with physical density (r = 0.85, P less than 0.0001), but the correlation was less than that observed between quantitative computed tomography and physical density (r = 0.92, P less than 0.0001). Measurements of broadband ultrasound attenuation and quantitative computed tomography were significantly correlated (r = 0.80, P less than 0.0001). 3. Partial correlation analysis showed a significant relationship between broadband ultrasound attenuation and bone density, but when the effect of physical density was taken into account no significant correlation was found between broadband ultrasound attenuation and quantitative computed tomography (r = 0.08, not significant). 4. Broadband ultrasound attenuation in three prospective amputees showed a high degree of concordance between measurements in vivo and in vitro, with no interference by surrounding soft tissues. 5. The correlation between physical density and broadband ultrasound attenuation was independent of quantitative computed tomography, suggesting that the technique measures aspects of density which differ from its mineral density. Broadband ultrasound attenuation holds promise as a reproducible, rapid, radiation-free assessment of skeletal status.

Summary: Vertebral fracture (VF) is a strong predictor of subsequent fracture. In this study of older women, VF, identified by dual-energy X-ray absorptiometry (DXA) vertebral fracture assessment (VFA), were associated with an increased risk of incident fractures and had a substantial impact on fracture probability, supporting the utility of VFA in clinical practice. Purpose: Clinical and occult VF can be identified using VFA with dual-energy X-ray absorptiometry (DXA). The aim of this study was to investigate to what extent VFA-identified VF improve fracture risk prediction, independently of bone mineral density (BMD) and clinical risk factors used in FRAX. Methods: A total of 2852 women, 75–80 years old, from the prospective population-based study SUPERB cohort, were included in this study. At baseline, BMD was measured by DXA, VF diagnosed by VFA, and questionnaires used to collect data on risk factors for fractures. Incident fractures were captured by X-ray records or by diagnosis codes. An extension of Poisson regression was used to estimate the association between VFA-identified VF and the risk of fracture and the 5- and 10-year probability of major osteoporotic fracture (MOF) was calculated from the hazard functions for fracture and death. Results: During a median follow-up of 5.15 years (IQR 4.3–5.9 years), the number of women who died or suffered a MOF, clinical VF, or hip fracture was 229, 422, 160, and 124, respectively. A VFA-identified VF was associated with an increased risk of incident MOF (hazard ratio [HR] = 1.78; 95% confidence interval [CI] 1.46–2.18), clinical VF (HR = 2.88; 95% [CI] 2.11–3.93), and hip fracture (HR = 1.67; 95% [CI] 1.15–2.42), adjusted for age, height, and weight. For women at age 75 years, a VFA-identified VF was associated with 1.2–1.4-fold greater 10-year MOF probability compared with not taking VFA into account, depending on BMD. Conclusion: Identifying an occult VF using VFA has a substantial impact on fracture probability, indicating that VFA is an efficient method to improve fracture prediction in older women. [ABSTRACT FROM AUTHOR]

Osteoporosis is a disease characterized by impaired bone microarchitecture and reduced bone mineral density (BMD) resulting in bone fragility and increased risk of fracture. In western societies, one in three women and one in five men will sustain an osteoporotic fracture in their remaining lifetime from the age of 50 years. Fragility fractures, especially of the spine and hip, commonly give rise to increased morbidity and mortality. In the five largest European countries and Sweden, fragility fractures were the cause of 2.6 million disability-adjusted life years in 2016 and the fracture-related costs increased from €29.6 billion in 2010 to €37.5 billion in 2017. In the European Union and the USA, only a small proportion of women eligible for pharmacological treatment are being prescribed osteoporosis medication. Secondary fracture prevention, using Fracture Liaison Services, can be used to increase the rates of fracture risk assessment, BMD testing and use of osteoporosis medication in order to reduce fracture numbers. Additionally, established primary prevention strategies, based on case-finding methods utilizing fracture prediction tools, such as FRAX, to identify women without fracture but with elevated risk, are recommended in order to further reduce fracture numbers. [ABSTRACT FROM AUTHOR]

The introduction of the 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 bone mineral density. Since age-specific rates of fracture and death differ across the world, FRAX models are calibrated with regard to the epidemiology of hip fracture (preferably from national sources) and mortality (usually United Nations sources). Models are currently available for 73 nations or territories covering more than 80% of the world population. FRAX has been incorporated into more than 80 guidelines worldwide, although the nature of this application has been heterogeneous. The limitations of FRAX have been extensively reviewed. Arithmetic procedures have been proposed in order to address some of these limitations, which can be applied to conventional FRAX estimates to accommodate knowledge of dose exposure to glucocorticoids, concurrent data on lumbar spine bone mineral density, information on trabecular bone score, hip axis length, falls history, type 2 diabetes, immigration status and recency of prior fracture. [ABSTRACT FROM AUTHOR]