In Vivo Mechanical Assessment of Cortical Bone Rigidity Enhances Fracture Discrimination Beyond DXA in Postmenopausal Women

Some have questioned the usefulness of distinguishing high-trauma fractures from low-trauma fractures. The aim of this study is to compare BMD measurements and risk of subsequent low-trauma fracture in patients with prior high- or low-trauma fractures. Using a clinical BMD registry for the province of Manitoba, Canada, we identified women and men age 40years or older with fracture records from linked population-based healthcare data. Age- and sex-adjusted BMD Z-scores and covariate-adjusted hazard ratios (HR) with 95% confidence intervals (CI) for incident fracture were studied in relation to prior fracture status, categorized as high-trauma if associated with external injury codes and low-trauma otherwise. The study population consisted of 64,428 women and men with no prior fracture (mean age 63.7years), 858 with prior high-trauma fractures (mean age 65.1years), and 14,758 with prior low-trauma fractures (mean age 67.2years). Mean Z-scores for those with any prior high-trauma fracture were significantly lower than in those without prior fracture (P < 0.001) and similar to those with prior low-trauma fracture. Median observation time for incident fractures was 8.8years (total 729,069 person-years). Any prior high-trauma fracture was significantly associated with increased risk for incident major osteoporotic fracture (MOF) (adjusted HR 1.31, 95% CI 1.08-1.59) as was prior low-trauma fracture (adjusted HR 1.55, 95% CI 1.47-1.63), and there was no significant difference between the two groups (prior trauma versus low-trauma fracture P = 0.093). A similar pattern was seen when incident MOF was studied in relation to prior hip fracture or prior MOF, or when the outcome was incident hip fracture or any incident fracture. High-trauma and low-trauma fractures showed similar relationships with low BMD and future fracture risk. This supports the inclusion of high-trauma fractures in clinical assessment for underlying osteoporosis and in the evaluation for intervention to reduce future fracture risk.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of denosumab (Amgen Inc., UK) to submit evidence for the clinical and cost effectiveness of denosumab for the prevention of fragility fractures in post-menopausal women, as part of the Institute's single technology appraisal (STA) process. The University of Aberdeen Health Technology Assessment Group were commissioned to act as the Evidence Review Group (ERG); the role of the ERG being to appraise the manufacturer's submission and to produce an independent report. This article provides a description of the company submission, the ERG review and NICE's subsequent decisions. The manufacturer considered that denosumab would be appropriate for patients unable to take, comply with or tolerate oral bisphosphonates. Comparator treatments selected for the submission were, therefore, 'no treatment', raloxifene, strontium ranelate, intravenous zoledronic acid, intravenous ibandronate and teriparatide. The main effectiveness evidence for denosumab was derived from a large randomized controlled trial comparing denosumab with placebo. Given by subcutaneous injection at 6-monthly intervals for 3 years, denosumab reduced the incidence of hip fracture by 40%, and reduced the incidence of clinical vertebral fracture by 69%. An indirect treatment comparison was used to derive adjusted relative risk (RR) estimates for different types of fracture for each comparator versus placebo. The RRs (95% CI) applied for denosumab were 0.316 (0.208, 0.478) for clinical vertebral fracture, 0.605 (0.373, 0.983) for hip fracture and 0.842 (0.638, 1.110) for wrist fracture. Despite a number of concerns surrounding the methodology of the indirect comparison, the ERG was satisfied with the robustness of the effect estimates. The RR estimates were applied in a good-quality Markov model that took account of drug costs, administration and monitoring costs, costs associated with fractures, and long-term nursing home costs. Utility weights were used to adjust time spent in fracture states, allowing QALYs to be estimated. The base-case analysis was conducted for women aged 70 years with a T-score of -2.5 or less and no prior fracture, and women aged 70 years with a T-score of -2.5 or less with a prior fragility fracture. Subgroup analyses based on T-score and independent clinical risk factors were also undertaken. Applying a willingness-to-pay (WTP) threshold of £30 000 per QALY, the manufacturer's results suggested that denosumab would offer a cost-effective alternative to all treatment comparators for the primary and secondary prevention of fractures. The ERG was concerned about an assumption that denosumab would be administered in general practice at the average cost of two standard GP visits a year. As a result, the ERG requested some further sensitivity analysis and undertook some further modelling, applying an assumption that denosumab would be provided primarily in secondary care. This modification altered the cost effectiveness of denosumab versus 'no treatment' (in women with no prior fragility fracture) and zoledronic acid. The NICE Appraisal Committee concluded that, as a treatment option for the prevention of osteoporotic fractures, denosumab should be recommended only in post-menopausal women at increased risk of fracture who cannot comply with the special instructions for administering oral bisphosphonates, or have an intolerance of, or contraindication to, those treatments. For primary prevention, the Appraisal Committee also stipulated specific levels of fracture risk at which denosumab is recommended.

In a cross-sectional analysis in postmenopausal women, prior ankle fractures were associated with lower areal bone mineral density (BMD) and trabecular bone alterations compared to no fracture history. Compared to women with forearm fractures, microstructure alterations were of lower magnitude. These data suggest that ankle fractures are another manifestation of bone fragility. Whether ankle fractures represent fragility fractures associated with low areal bone mineral density (aBMD) and volumetric bone mineral density (vBMD) and/or bone microstructure alterations remains unclear, in contrast to the well-recognised association between forearm fractures and osteoporosis. The objective of this study was to investigate aBMD, vBMD and bone microstructure in postmenopausal women with prior ankle fracture in adulthood, compared with women without prior fracture or with women with prior forearm fractures, considered as typically of osteoporotic origin. In a cross-sectional analysis in the Geneva Retirees Cohort study, 63 women with ankle fracture and 59 with forearm fracture were compared to 433 women without fracture (mean age, 65 ± 1 years). aBMD was measured by dual-energy X-ray absorptiometry; distal radius and tibia vBMD and bone microstructure were measured by high-resolution peripheral quantitative computed tomography. Compared with women without fracture, those with ankle fractures had lower aBMD, radius vBMD (-7.9%), trabecular density (-10.7%), number (-7.3%) and thickness (-4.6%) and higher trabecular spacing (+14.5%) (P < 0.05 for all). Tibia trabecular variables were also altered. For 1 standard deviation decrease in total hip aBMD or radius trabecular density, odds ratios for ankle fractures were 2.2 and 1.6, respectively, vs 2.2 and 2.7 for forearm fracture, respectively (P ≤ 0.001 for all). Compared to women with forearm fractures, those with ankle fractures had similar spine and hip aBMD, but microstructure alterations of lower magnitude. Women with ankle fractures have lower aBMD and vBMD and trabecular bone alterations, suggesting that ankle fractures are another manifestation of bone fragility.

Pre-screening young postmenopausal women for BMD testing.

To estimate the clinical effectiveness and cost-effectiveness of strontium ranelate for the prevention of osteoporotic fractures in postmenopausal women, at different levels of absolute fracture risk. This considers secondary prevention in women who have sustained a previous fracture and primary prevention in those women without a previous fracture, as women with osteoporosis are asymptomatic until a fracture is sustained. Major electronic bibliographic databases were searched in September 2004 and updated in March 2005. A systematic review was carried out to determine clinical effectiveness using the major electronic bibliographic databases and handsearching reference lists of relevant articles and sponsor submissions. Data from selected studies were assessed and included in the meta-analyses, if appropriate. The model used to calculate cost-effectiveness ratios was an updated version of Sheffield Health Economic Model for Osteoporosis that was populated with absolute risk of fractures using an algorithm being developed for the World Health Organization and supplied in confidence to the authors. The model calculated the number of fractures that occur and provided as output data the costs associated with osteoporotic fractures, and the quality adjusted life-years (QALYs) accrued by a cohort of 100 osteoporotic women, with each fracture being detrimental to health and incurring a cost. When the costs of the intervention were included, the incremental cost compared with no treatment was calculated and divided by the gain in QALYs to calculate cost-effectiveness measures. Treatment with strontium ranelate was calculated against a no-treatment option to evaluate whether it could be given cost-effectively. An incremental analysis against alendronate was also conducted to estimate the cost-effectiveness of strontium ranelate relative to a current standard treatment. The cost-effectiveness of strategies for identifying and treating women without a prior fracture used the risk of fracture as an input to the cost-effectiveness model. Three trials were identified. Pooled data from two studies indicate that strontium ranelate therapy is associated with a reduction in the risk of vertebral fracture [relative risk (RR) compared with placebo 0.60, 95% confidence interval (CI) 0.53 to 0.69, p < 0.001] and non-vertebral fracture (RR 0.84, 95% CI 0.73 to 0.97, p = 0.01). In general, strontium ranelate therapy did not seem to be associated with an increased risk of adverse events. However, the risk of one rare but serious adverse event, venous thromboembolism (including pulmonary embolism), was found to be significantly higher in patients receiving strontium ranelate compared with placebo (RR 1.42, 95% CI 1.02 to 1.98, p = 0.036). Some nervous system disorders, including mental impairment, disturbed consciousness, memory loss and seizures, were also more common in patients randomised to strontium ranelate. Strontium ranelate provided gains in QALYs compared with no treatment in women with sufficient calcium and vitamin D intakes. The size of the QALY gain for each intervention was strongly related to the absolute risk of fracture. From the algorithm used, it is seen that strontium ranelate can be used cost-effectively in women at relatively high risk of osteoporotic fracture. However, the results of the probabilistic sensitivity analysis, using efficacy data from randomised controlled trials, suggest that it is not as cost-effective as alendronate, a comparator intervention from the bisphosphonate class. The use of strontium ranelate in women without a prior fracture will be dependent on identification algorithms being produced in conjunction with the National Institute for Health and Clinical Excellence Osteoporosis Guidelines Development Group. Strontium ranelate was shown to be clinically effective in the prevention of osteoporotic fractures. Scenarios have been found where strontium ranelate can be used cost-effectively, however given the probabilistic sensitivity analyses conducted, this intervention appears to be less cost-effective than the bisphosphonate alendronate. The evidence base for the efficacy of fracture prevention for strontium ranelate needs to be strengthened, particularly for hip fractures, where there is currently a non-significant reduction. If it were believed that the efficacy of strontium ranelate is dependent on either age or absolute risk, this would need to be proven. The evidence base on the T-score by age of the general female population needs to be strengthened, particularly in women over the age of 80 years. The prevalence of risk factors associated with fracture rates, over and above that provided by bone mineral density, also needs to be significantly strengthened to ensure that the estimated number of women that could be cost-effectively treated is accurate.

Evaluation of Bone Mineral Density in Children with Sickle Cell Anemia.

Geographic variation of bone mineral density and selected risk factors for prediction of incident fracture among Canadians 50 and older

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.

To determine the relationship of the bone mass attained in young adults with anthropometric and genetic factors. Cross-sectional study of normal individuals. We studied 341 healthy subjects between 22 and 45 years of age. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) and correlated with body weight, height and nine polymorphisms in six genes involved in sex steroid metabolism (17-hydroxylase, aromatase and 5-reductase) and activity (oestrogen receptors (ER)-alpha and -beta, and androgen receptor). The BMD was higher in men than in women (spine: 1.048 +/- 0.120 vs. 1.034 +/- 0.112; hip: 0.907 +/- 0.131 vs. 0.822 +/- 0.104 g cm(-2), P < 0.001). However, the difference was due, at least in part, to the larger body size in men and diminished markedly after height adjustment. There was a negative correlation between age and hip BMD. Body weight was the single most influential factor on spine and hip BMD in both sexes, explaining 8-9% of BMD variance. Amongst the genetic factors studied, a common CA repeat polymorphism in ER-beta showed a significant association with BMD in women (P = 0.03 at the spine, and 0.008 at the hip). The relationship between ER-beta genotype and BMD persisted after adjustment by body weight and age, explaining a further 2-3% of BMD variance. Allelic variants of other genes studied were not related with BMD. Body weight and allelic variants of ER-beta are associated with BMD in young adults.

Peak volumetric bone mineral density (BMD) is determined by the growth in bone size relative to the mineral accrued within its periosteal envelope. Thus, reduced peak volumetric BMD may be the result of reduced mineral accrual relative to growth in bone size. Because sex steroids and growth hormone (GH) influence bone size and mass we asked: What are the effects of gonadectomy (Gx) on bone size, bone mineral content (BMC), areal and volumetric BMD in growing male and female rats? Does GH deficiency (GH-) reduce the amount of bone in the (smaller) bone, i.e., reduce volumetric BMD? Does GH- alter the effect of Gx on bone size and mineral accrual? Gx or sham surgery was performed at 6 weeks in GH- and GH replete (GH+) Fisher 344 male and female rats. Changes in bone size, volume, BMC, areal and volumetric BMD, measured using dual X-ray absorptiometry (DPX-L), were expressed as percentage of controls at 8 months (mean +/- SEM). All results shown were significant (p < 0.05 level) unless otherwise stated. In GH+ and GH- males, respectively, Gx was associated with: lower femur volume (24%, 25%), BMC (43%, 45%), areal BMD (21%, 14%), and volumetric BMD (30%, 28%); lower spine (L1-L3) volume (26%, 28%), BMC (26%, 30%), and areal BMD (28%, 12%), but not volumetric BMD. Following Gx, GH+ females had increased femur volume (11%), no effect on BMC, decreased areal BMD (6%) and decreased volumetric BMD (17%); GH- females had no change in femur volume, but decreased femur BMC (24%), areal BMD (10%), and volumetric BMD (25%). In GH+ and GH- females, respectively, Gx was associated with a decrease in spine (L1-L3) BMC (12%, 15%), areal BMD (16%, 15%), and volumetric BMD (10%, 16%) with no change in volume. Deficits in non-Gx GH- relative to non-Gx GH+ (males, females, respectively) were: femur BMC (49%, 37%), areal BMD (23%, 8%), volume (19%, 19%) and volumetric BMD (37%, 22%); spine (L1-L3) BMC (46%, 42%), areal BMD (37%, 43%), volume (10%, 15%), and volumetric BMD (40%, 33%). Testosterone and GH are growth promoting in growing male rats, producing independent effects on bone size and mass; deficiency produced smaller appendicular bones with reduced volumetric BMD because deficits in mass were greater than deficits in size. At the spine, the reduction in size and accrual were proportional, resulting in a smaller bone with normal volumetric BMD. In growing female rats, estrogen was growth limiting at appendicular sites; deficiency resulted in a GH-dependent increase in appendicular size, relatively reduced accrual, and so, reduced volumetric BMD in a bigger bone. At the spine, accrual was reduced while growth in size was normal, thus volumetric BMD was reduced in the normal sized bone. Understanding the pathogenesis of low volumetric BMD requires the study of the differing relative growth in size and mass of the axial and appendicular skeleton in the male and female and the regulators of the growth of these traits.

Clinical risk factor status in patients with vertebral fracture but normal bone mineral density

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.

The validity of the bone mineral density (BMD) measurement depends on its accuracy as a predictor of the breaking strength of bone. As the breaking strength is proportional to the square of the apparent density, a small error in the calculation of BMD may result in a larger error in the predicted bone strength. The aims of this study were (i) to determine whether inaccuracies in the measurement of the dimensions, projected area, and volume of the vertebral body (used to derive the areal and volumetric BMD) result in errors in the predicted breaking strength and (ii) to compare the accuracy, sensitivity, and specificity of bone mineral content (BMC), areal BMD, volumetric BMD, and volumetric bone mineral apparent density (BMAD) as surrogates of bone strength. We measured the BMC (by densitometry), dimensions and volume (using calipers, densitometry, the Carter et al. and Peel and Eastell methods), and breaking strength (using the Instron 1114 apparatus, Newtons, N) of 22 vertebral body specimens. All methods resulted in errors in height, width, and depth between -11.3 +/- 1.0 and 30.4 +/- 1.8% relative to the "gold" standard caliper method. The vertebral body volume (of 38.0 +/- 1.2 cm3) measured by submersion was used as the gold standard to derive the volumetric BMD gold standard (of 0.162 +/- 0.01 g/cm3). All methods, except the Peel and Eastell method, resulted in errors ranging between -10.7 +/- 1.5 and 56.9 +/- 3.4% in vertebral body volume and -35.6 +/- 1.5 to 12.6 +/- 1.8% in volumetric BMD (all p < 0.0005). The same absolute value for volumetric BMD predicted a breaking strength that differed according to the method used to derive BMD. For example, a volumetric BMD of 0.162 g/cm3 predicted a breaking strength of 6208 N (submersion method), 5473 N (caliper method), 6095 N (Peel and Eastell method), 7697 N (DXA method), and 9470 N (Carter et al. method). The mean volumetric BMD derived by each method differed (0.181, 0.165, 0.133, and 0.104 g/cm3, respectively). However, all were accurate; each predicted a similar breaking strength (6177, 6217, 6209, and 6221 N respectively). Likewise, breaking strengths predicted by the mean BMC, areal BMD by calipers, and areal BMD by dual-energy X-ray absorptiometry (DXA) were 6267, 6214, and 6244 N, respectively. The methods were equally sensitive; a 1 standard deviation (SD) decrease in volumetric BMD resulted in a similar decrease in the breaking strength of 1818 (caliper), 2080 (Peel and Eastell), 2001 (DXA), and 1625 N (BMAD by Carter et al). A 1 SD decrease in BMC, areal BMD (using calipers) and areal BMD (using DXA) predicted a decrease in the breaking strength of 2019, 1738, and 1825 N, respectively. All methods were equally specific; the variance in bone strength explained by bone mass did not differ for volumetric BMD (38-61% depending on the method), BMC (58%), or areal BMD (48%). In conclusion, despite errors in the measurement of the dimensions of the vertebral body, bone mass, areal, and volumetric bone density are equally accurate, sensitive, and specific surrogates of the breaking strength of bone in vitro.

Areal and volumetric bone mineral density and risk of multiple types of fracture in older men

Osteoporosis is a major cause of morbidity and death in older persons. For women who are 50 years of age, the estimated lifetime risk for osteoporotic fracture is 54%, and studies suggest that the ...