Postmenopausal women with normal BMD who have fractures have deteriorated bone microarchitecture: A prospective analysis from The OFELY study.

Most postmenopausal women who sustain fragility fracture (Fx) have their areal bone mineral density (BMD) above the osteoporosis threshold. A sizeable proportion of them have normal aBMD. This study aimed to prospectively investigate the association of fragility Fx with bone microarchitecture (MA) assessed by high-resolution peripheral computed tomography (HR-pQCT) in postmenopausal women without low BMD. At the 14th annual follow-up of the OFELY study, we measured bone MA at the distal radius and tibia with HR-pQCT in addition to areal BMD with DXA, in 586 postmenopausal women. Among them, 166 (29 %) women, mean (SD) age 65 (8) yr, had normal BMD defined as a T score ≥ -1 at the lumbar spine, femoral neck, and total hip. During a median [IQR] 15 [14-15] yr of follow-up, 46 of those women sustained incident fragility Fx, including 19 women with a major osteoporotic Fx (clinical spine, forearm, proximal humerus, hip). Women who sustained Fx did not differ for age, BMI, tobacco and alcohol use, diabetes, falls, FRAX®, aBMD, and TBS compared with women without incident Fx. In contrast, they had significant impairment of volumetric densities, cortical area (Ct. Ar) and thickness (Ct. Th), stiffness (K), and estimated failure load (FL) at the radius compared with women without incident Fx. At the radius, each SD decrease of volumetric densities, Ct.Ar, Ct.Th, K, and estimated FL were significantly associated with an increased risk of all fragility fractures with hazard ratios (HR) from 1.44 to 1.56 and of major osteoporotic fractures (HR from 1.66 to 2.57). Lesser impairment of bone MA was seen at the tibia. We conclude that even in women with normal areal BMD fragility fractures are associated with deterioration of bone microarchitecture.

Klinefelter Bone Microarchitecture Evolution with Testosterone Replacement Therapy.

Klinefelter Syndrome (KS) patients, defined by a 47 XXY karyotype, have increased risk of fragility fractures. We have assessed bone microarchitecture by high resolution peripheral quantitative CT (HR-pQCT) at the radius and tibia in young KS patients, naïve from testosterone replacement therapy (TRT). Areal bone mineral density (BMD) and body composition were assessed by dual X-ray absorptiometry (DXA). Total testosterone (tT) was measured at baseline. Bone measurements have been repeated after 30 months of TRT. We enrolled 24 KS patients and 72 age-matched controls. KS patients were (mean ± SD) 23.7 ± 7.8 year-old. KS patients had significantly lower relative appendicular lean mass index (RALM) and lower aBMD at spine and hip than controls. Ten patients (42%) had low tT level (≤ 10.4 nmol/L). At baseline, we observed at radius a marked cortical (Ct) impairment reflected by lower Ct.area, Ct.perimeter, and Ct.vBMD than controls. At tibia, in addition to cortical fragility, we also found significant alterations of trabecular (Tb) compartment with lower trabecular bone volume (BV/TV) and Tb.vBMD as compared to controls. After 30 months of TRT, 18 (75%) KS patients were reassessed. Spine aBMD and RALM significantly increased. At radius, both cortical (Ct.Pm, Ct.Ar, Ct.vBMD, Ct.Th) and trabecular (Tb.vBMD) parameters significantly improved. At tibia, the improvement was found only in the cortical compartment. Young TRT naïve KS patients have inadequate bone microarchitecture at both the radius and tibia, which can improve on TRT.

Cost-effectiveness of treatment of women aged 70 years and older with both osteopenia and microstructural deterioration.

OBJECTIVE: Treatment is usually withheld from women with osteopenia even though they are the source of over 70% of all women having fragility fractures. As microstructural deterioration increases fracture risk and zoledronate reduces it, we aimed to determine whether identifying and treating women with osteopenia and severe microstructural deterioration is cost-effective. We also compared the health economic outcomes of 'global' versus 'targeted' treatment using SFS of women aged ≥70 years with osteopenia. DESIGN: We assessed the cost-effectiveness from using a Markov model that simulated 10-year follow up of women with osteopenia. Decision analysis compared measurement of distal radial microstructure using high resolution peripheral computed tomography (at a cost of USD $210) to target women with severe microstructural deterioration for zoledronate treatment, compared to standard care defined as measurement of bone mineral density (BMD) with treatment recommended when femoral neck BMD T score is ≤-2.5 SD with or without a prevalent fracture. In the 'global' treatment approach, high resolution peripheral quantitative tomography (HRpQCT) was not undertaken. SETTING: US healthcare system. PARTICIPANTS: A hypothetical cohort of 1000 women aged ≥70 years with osteopenia and no previous fractures was studied. MEASURES: Fractures, deaths, years of life lived, quality-adjusted life years (QALYs) lived and costs. Data inputs were obtained from published sources. A 3% annual discount rate was applied to future health benefits and costs. RESULTS: Women in the standard care group incurred 327 fractures during 7341.0 years and 4914.2 QALYs lived. Women in the intervention group incurred 300 fractures (number needed to treat 37) during 7359.2 years and 4928.8 QALYs lived. Net costs were USD $4,862,669 and $4,952,004, respectively, equating to 18.1 years of life saved and 14.6 QALYs saved, and incremental cost-effectiveness ratios of $4992 per year of life saved and $6135 per QALY saved. These ratios are well within the threshold considered to be cost-effective. Sensitivity analyses indicated the results were robust. Relative to standard of care, 'global' and 'targeted' treatment respectively resulted in 0.0364 vs. 0.0181 years of life (YoLS) saved per person, and 0.0292 and 0.0146 QALYs saved per person. The net costs per person for the respective approaches were $US 359 and $US 89. The incremental cost-effectiveness ratios were $9864 per YoLS and $12,290 per QALY saved for the 'global' approach and $4992 per YoLS and $6135 per QALY saved for the 'targeted' approach. CONCLUSION: Identifying and treating women ≥70 years of age with osteopenia and microstructural deterioration with zoledronate cost-effectively reduces the morbidity and mortality imposed by fragility fractures. This 'targeted' approach is more cost-effective than a 'global' approach and incurs only 25% of total costs. IMPLICATION: Women with osteopenia with bone fragility due to microstructural deterioration should be identified and targeted for treatment. SUMMARY: Women with osteopenia have 70% of fractures. Treating those with microstructural deterioration conferred an incremental cost-effectiveness ratio of $4992/year of life saved and $6135 per QALY saved.

Muscle mass is associated with incident fracture in postmenopausal women: The OFELY study.

The relationships between body composition and bone mineral density are well established but the contribution of body composition to the risk of fracture (Fx) has rarely been evaluated prospectively. We analyzed the risk of Fx by body composition in 595 postmenopausal women (mean age 66±8years) from a longitudinal cohort study (Os des Femmes de Lyon). We assessed the risk of the first incident fragility Fx according to body composition obtained from whole-body DXA: abdominal visceral (VFAT) and subcutaneous fat mass (SFAT), total body fat mass (FM), lean mass index (LMI) and appendicular skeletal muscle mass index (ASMI). During a median [IQ] follow-up of 13.1years [1.9], 138 women sustained a first incident Fx, including 85 women with a major osteoporotic Fx (MOP Fx: hip, clinical spine, humerus or wrist). After adjustment for age, women who sustained Fx had lower BMI (-4%, p=0.01), LMI (-6%, p=0.002) and ASMI (-3%, p=0.003), compared with women without Fx. After adjustment for age, prevalent Fx, physical activity, incident falls and FN BMD, each SD increase of baseline values of LMI and ASMI was associated with decreased Fx risk with adjusted hazard ratios of 0.76 for both of p≤0.02. Those associations were similar after accounting for the competing risk of death. VFAT and SFAT were associated with Fx risk in the multivariate model only for MOP Fx and the association did not persist after consideration of competing mortality. We conclude that lean mass and appendicular muscle mass indexes are associated with the risk of fracture in postmenopausal women independently of BMD and clinical risk factors.

Has sclerostin a true endocrine metabolic action complementary to osteocalcin in older men?

UNLABELLED: The reported association between sclerostin and diabetes mellitus or abdominal fat may be biased by body size and bone mass. In older men, the association between serum sclerostin levels and metabolic syndrome lost significance after adjustment for bone mass. The association between sclerostin and energy metabolism needs further clarification. INTRODUCTION: Sclerostin is associated with abdominal fat, but this relationship may be biased since both are associated with body size and bone mass. Osteocalcin is a bone-derived hormone regulating energy metabolism. We assessed the association between serum sclerostin and metabolic syndrome (MetS) accounting for whole body mineral content (BMC) and osteocalcin. METHODS: We studied 694 men aged 51-85 who had serum osteocalcin and sclerostin measurements. RESULTS: Sclerostin was higher in 216 men with MetS compared with those without MetS (p < 0.005). Average sclerostin level increased significantly across the increasing number of MetS components. In multivariable models, higher sclerostin was associated with higher odds of MetS (odds ratio (OR) = 1.24/1 standard deviation (SD) increase [95 % confidence interval (95 % CI), 1.01-1.51]; p < 0.05). After further adjustment for BMC, the association of MetS with sclerostin lost significance, whereas that with osteocalcin remained significant. Men who were simultaneously in the highest sclerostin quartile and the lowest osteocalcin quartile had higher odds of MetS (OR = 2.14 [95 % CI, 1.15-4.18]; p < 0.05) vs. men being in the three lower sclerostin quartiles and three upper osteocalcin quartiles. After adjustment for whole body BMC, the association lost significance. CONCLUSIONS: Higher sclerostin level is associated with MetS severity; however, this association may be related to higher whole body BMC. The adjustment for BMC had no impact on the association between MetS and osteocalcin. Clinical cross-sectional studies do not elucidate the potential role of sclerostin in the regulation of energy metabolism and direct experimental approach is necessary.

How to predict fragility fracture beyond 10 years? The OFELY study.

CONTEXT: Low bone mineral density (BMD) is a major determinant of fragility fractures (Fx), but its very long-term prediction is poorly documented. OBJECTIVE: We analyzed the risk of Fx beyond 10 years in women. DESIGN: In a longitudinal cohort study (Os des Femmes de Lyon), we studied 867 women aged 40 years and older (mean age 59 ± 10 y) over 20 years. MAIN OUTCOME: We assessed the risk of the first incident Fx according to the baseline BMD obtained by dual-energy X-ray absorptiometry, clinical risk factors, and the Fracture Risk Assessment Tool (FRAX). RESULTS: During a median (interquartile range) follow-up of 20 years (3), 245 women sustained one or more incident fragility Fx. Women who sustained a first Fx beyond 10 years (Fx 10-20, n = 109) were younger and had lower values of FRAX compared with those in the first 10 years (Fx 0-10, n = 136). After adjustment for age, they still had greater grip strength and BMD. Parental hip Fx was associated with an increased risk of Fx 10-20 but contrasting with Fx 0-10, the risk of Fx 10-20 was not associated with age, previous Fx, and FRAX except in women younger than 70 years. Each SD decrease of BMD at the spine, femoral neck, total hip, and ultradistal radius was associated with an increased risk of Fx 10-20 with adjusted odds ratios [95% confidence interval (CI)] of 1.43 (95% CI 1.12-1.82), 1.39 (95% CI 1.08-1.82), 1.47 (95% CI 1.14-1.89), and 2.00 (95% CI 1.47-2.7). Women with osteoporosis had an increased risk of both Fx 0-10 and Fx 10-20 compared with women with normal BMD, whereas osteopenia was not associated with a higher risk of Fx beyond 10 years. CONCLUSIONS: Low BMD in women is significantly associated with an increased risk of Fx over 20 years. Beyond 10 years, the prediction conferred by baseline BMD was better than that from clinical risk factors.

Association of serum sclerostin with bone mineral density, bone turnover, steroid and parathyroid hormones, and fracture risk in postmenopausal women: the OFELY study.

SUMMARY: Sclerostin is a key regulator of bone formation. In a population of 572 postmenopausal women (mean age, 67 years) followed prospectively for a median of 6 years, there was no significant association between baseline levels of serum sclerostin and incidence of all fractures which occurred in 64 subjects. INTRODUCTION: Sclerostin, an osteocyte soluble factor, is a major negative regulator of osteoblastic activity. Circulating sclerostin levels were reported to increase with age and to be modestly associated with bone mineral density (BMD) and bone turnover, but there are no data on the association with fracture risk. METHODS: We investigated 572 postmenopausal women (mean age, 67 ± 8.5 years) from the OFELY population-based cohort. The associations of serum sclerostin measured with a new two-site ELISA and spine and hip BMD by DXA, serum ß-isomerized C-terminal crosslinking of type I collagen (CTX), intact N-terminal propeptide of type I collagen (PINP), intact PTH, 25-hydroxyvitamin D [25(OH)D], estradiol, testosterone, and fracture risk were analyzed. At the time of sclerostin measurements, 98 postmenopausal women had prevalent fractures. After a median of 6 years (interquartile range, 5-7 years) follow-up, 64 postmenopausal sustained an incident fracture. RESULTS: Serum sclerostin correlated positively with spine (r = 0.35, p < 0.0001) and total hip (r = 0.25, <0.0001) BMD. Conversely, serum sclerostin was weakly negatively associated with the bone markers PINP (r = -0.10, p = 0.014) and CTX (r = -0.13, p = 0.0026) and with intact PTH (r = -0.13, p = 0.0064). There was no significant association of serum sclerostin with 25(OH)D, estradiol, free estradiol index, or testosterone. Serum sclerostin considered as a continuous variable or in quartiles was not significantly associated with the risk of prevalent or incident fracture. CONCLUSION: Serum sclerostin is weakly correlated with BMD, bone turnover, and PTH in postmenopausal women. It was not significantly associated with the risk of all fractures, although the number of incident fractures recorded may not allow detecting a modest association.

Non-hip, non-spine fractures drive healthcare utilization following a fracture: the Global Longitudinal Study of Osteoporosis in Women (GLOW).

UNLABELLED: We evaluated healthcare utilization associated with treating fracture types in >51,000 women aged ≥55 years. Over the course of 1 year, there were five times more non-hip, non-spine fractures than hip or spine fractures, resulting in twice as many days of hospitalization and rehabilitation/nursing home care for non-hip, non-spine fractures. INTRODUCTION: The purpose of this study is to evaluate medical healthcare utilization associated with treating several types of fractures in women ≥55 years from various geographic regions. METHODS: Information from the Global Longitudinal Study of Osteoporosis in Women (GLOW) was collected via self-administered patient questionnaires at baseline and year 1 (n = 51,491). Self-reported clinically recognized low-trauma fractures at year 1 were classified as incident spine, hip, wrist/hand, arm/shoulder, pelvis, rib, leg, and other fractures. Healthcare utilization data were self-reported and included whether the fracture was treated at a doctor's office/clinic or at a hospital. Patients were asked if they had undergone surgery or been treated at a rehabilitation center or nursing home. RESULTS: During 1-year follow-up, there were 195 spine, 134 hip, and 1,654 non-hip, non-spine fractures. Clinical vertebral fractures resulted in 617 days of hospitalization and 512 days of rehabilitation/nursing home care; hip fractures accounted for 1,306 days of hospitalization and 1,650 days of rehabilitation/nursing home care. Non-hip, non-spine fractures resulted in 3,805 days in hospital and 5,186 days of rehabilitation/nursing home care. CONCLUSIONS: While hip and vertebral fractures are well recognized for their associated increase in health resource utilization, non-hip, non-spine fractures, by virtue of their 5-fold greater number, require significantly more healthcare resources.

Effect of oral monthly ibandronate on bone microarchitecture in women with osteopenia-a randomized placebo-controlled trial.

UNLABELLED: We have examined the effect of oral monthly ibandronate on distal radius and tibia microarchitecture with high-resolution peripheral quantitative tomography compared with placebo, in women with osteopenia, and found that ibandronate did not significantly affect trabecular bone but improved cortical density and thickness at the tibia. METHODS: We have examined the effect of ibandronate on bone microarchitecture with peripheral high-resolution quantitative computed tomography (HR-pQCT) in a randomized placebo-controlled trial among 148 women with osteopenia. Patients received either oral 150 mg monthly ibandronate or placebo over 24 months. Bone microarchitecture was assessed at baseline, 6, 12, and 24 months, using HR-pQCT at the distal radius and tibia; areal bone mineral density (aBMD) was measured with DXA at the spine, hip, and radius. RESULTS: At 12 months, there was no significant difference in trabecular bone volume at the radius (the primary end point) between women on ibandronate (10.8 ± 2.5%) and placebo (10.5 ± 2.9%), p = 0.25. There was no significant difference in other radius trabecular and cortical microarchitecture parameters at 12 and 24 months. In contrast, at the tibia, cortical vBMD in the ibandronate group was significantly greater than in the placebo group at 6, 12, and 24 months, with better cortical thickness at 6, 12, and 24 months. With ibandronate, aBMD was significantly increased at the hip and spine at 12 and 24 months but at the radius was significantly superior to placebo only at 24 months. Most of the adverse events related to ibandronate were expected with bisphosphonate use, and none of them were serious. CONCLUSION: We conclude that 12 months of treatment with ibandronate in women with osteopenia did not affect trabecular bone microarchitecture, but improved cortical vBMD at the tibia at 12 and 24 months, and preserved cortical thickness at the tibia.

Early effects of zoledronic acid and teriparatide on bone microarchitecture, remodeling and collagen crosslinks: comparison between iliac crest and lumbar vertebra in ewes.

Iliac crest bone biopsies are used to assess the mechanism of action of drug treatments, yet there are little data comparing this site to sites prone to fracture. The purpose of this study was to compare the delay and the amplitude of responses to treatment in two different bone sites. The short-term effects of zoledronic acid and teriparatide on microarchitecture, collagen crosslinks and bone remodeling were evaluated in iliac crest and lumbar vertebrae. Aged ewes (n=8/gr) received either vehicle (CTRL) or a single injection of zoledronic acid (ZOL, 10mg) or daily injections of teriparatide (TPTD, 20 µg/d) for 3 months. Blood samples were collected monthly for assessing bone turnover markers. At the end of the study, a transiliac bone biopsy (IC) and L1 lumbar vertebrae (LV1) were collected to assess bone microarchitecture; pyridinoline (PYD), deoxypyridinoline (DPD), pentosidine (PEN) content, static and dynamic parameters of bone remodeling. In CTRL, Tb-BV/TV was significantly higher in LV1 than IC (p<0.0001). This was associated with a trend of higher Tb.N, Tb.Th, DA, an inferior Conn.D and a lower bone turnover as shown by the decreases of osteoid parameters, MS/BS, Ac.f in LV1 when compared to IC. In addition, the ratio PYD/DPD was 4 times higher in LV1 than IC. After 3 months, significant decreases of sALP (p<0.001) and sCTX (p<0.001) were observed in the ZOL-group whereas in TPTD-group, after transient increases, they returned to baseline values. When compared to their respective CTRL, ZOL induced significant increases in Tb.BV/TV, Conn.D, Tb.N and Tb.Sp, in IC but not in LV1. Regardless of the site, ZOL markedly depressed the bone turnover: The static parameters of bone formation significantly decreased and the diminution of MS/BS, BFR/BS and Ac.f varied from -94 to -98% vs CTRL (p<0.01 to 0.001). It was associated with a diminution of the DPD content and the PYD/DPD ratio mainly in IC cortices. In contrast, after 3 months, TPTD did not modify the 3D structure and microarchitecture in IC and LV1, except a trend of higher Conn.D in IC, compared to IC-CTRL. TPTD treatment induced a significant increase in cortical porosity in LV1 (p<0.05) when compared to LV1-CTRL. Static parameters of bone formation and resorption were augmented in both sites, significantly only in LV1 (p<0.05) with a trend of increases in MS/BS and BFR/BS, compared to LV1-CTRL. In conclusion, in adult ewes, the bone mass, microarchitecture, remodeling and collagen crosslink content differ according to the bone site (iliac crest and vertebra). Furthermore, after 3 months, the responses to ZOL and TPTD were of different magnitude and delay between the two bone sites. The distinction of bone sites to study the early effects of anti-osteoporotic therapies appears meaningful in order to approach their site-specific anti-fracture efficacy.

Burden of non-hip, non-vertebral fractures on quality of life in postmenopausal women: the Global Longitudinal study of Osteoporosis in Women (GLOW).

UNLABELLED: Among 50,461 postmenopausal women, 1,822 fractures occurred (57% minor non-hip, non-vertebral [NHNV], 26% major NHNV, 10% spine, 7% hip) over 1 year. Spine fractures had the greatest detrimental effect on EQ-5D, followed by major NHNV and hip fractures. Decreases in physical function and health status were greatest for spine or hip fractures. INTRODUCTION: There is growing evidence that NHNV fractures result in substantial morbidity and healthcare costs. The aim of this prospective study was to assess the effect of these NHNV fractures on quality of life. METHODS: We analyzed the 1-year incidences of hip, spine, major NHNV (pelvis/leg, shoulder/arm) and minor NHNV (wrist/hand, ankle/foot, rib/clavicle) fractures among women from the Global Longitudinal study of Osteoporosis in Women (GLOW). Health-related quality of life (HRQL) was analyzed using the EuroQol EQ-5D tool and the SF-36 health survey. RESULTS: Among 50,461 women analyzed, there were 1,822 fractures (57% minor NHNV, 26% major NHNV, 10% spine, 7% hip) over 1 year. Spine fractures had the greatest detrimental effect on EQ-5D summary scores, followed by major NHNV and hip fractures. The number of women with mobility problems increased most for those with major NHNV and spine fractures (both +8%); spine fractures were associated with the largest increases in problems with self care (+11%), activities (+14%), and pain/discomfort (+12%). Decreases in physical function and health status were greatest for those with spine or hip fractures. Multivariable modeling found that EQ-5D reduction was greatest for spine fractures, followed by hip and major/minor NHNV. Statistically significant reductions in SF-36 physical function were found for spine fractures, and were borderline significant for major NHNV fractures. CONCLUSION: This prospective study shows that NHNV fractures have a detrimental effect on HRQL. Efforts to optimize the care of osteoporosis patients should include the prevention of NHNV fractures.

Effects of strontium ranelate and alendronate on bone microstructure in women with osteoporosis. Results of a 2-year study.

UNLABELLED: Strontium ranelate appears to influence more than alendronate distal tibia bone microstructure as assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), and biomechanically relevant parameters as assessed by micro-finite element analysis (µFEA), over 2 years, in postmenopausal osteoporotic women. INTRODUCTION: Bone microstructure changes are a target in osteoporosis treatment to increase bone strength and reduce fracture risk. METHODS: Using HR-pQCT, we investigated the effects on distal tibia and radius microstructure of strontium ranelate (SrRan; 2 g/day) or alendronate (70 mg/week) for 2 years in postmenopausal osteoporotic women. This exploratory randomized, double-blind trial evaluated HR-pQCT and FEA parameters, areal bone mineral density (BMD), and bone turnover markers. RESULTS: In the intention-to-treat population (n = 83, age: 64 ± 8 years; lumbar T-score: -2.8 ± 0.8 [DXA]), distal tibia Cortical Thickness (CTh) and Density (DCort), and cancellous BV/TV increased by 6.3%, 1.4%, and 2.5%, respectively (all P < 0.005), with SrRan, but not with alendronate (0.9%, 0.4%, and 0.8%, NS) (P < 0.05 for all above between-group differences). Difference for CTh evaluated with a distance transformation method was close to significance (P = 0.06). The estimated failure load increased with SrRan (+2.1%, P < 0.005), not with alendronate (-0.6%, NS) (between-group difference, P < 0.01). Cortical stress was lower with SrRan (P < 0.05); both treatments decreased trabecular stress. At distal radius, there was no between-group difference other than DCort (P < 0.05). Bone turnover markers decreased with alendronate; bALP increased (+21%) and serum-CTX-I decreased (-1%) after 2 years of SrRan (between-group difference at each time point for both markers, P < 0.0001). Both treatments were well tolerated. CONCLUSIONS: Within the constraints of HR-pQCT method, and while a possible artefactual contribution of strontium cannot be quantified, SrRan appeared to influence distal tibia bone microstructure and FEA-determined biomechanical parameters more than alendronate. However, the magnitude of the differences is unclear and requires confirmation with another method.

FRAX® probabilities and risk of major osteoporotic fracture in France.

UNLABELLED: The incidence of hip fracture, death and the estimated incidence of major osteoporotic fracture in France were used to determine the lifetime and 10-year probability of fracture and incorporated into a probability model (FRAX®) calibrated to the French population. INTRODUCTION: Fracture probabilities in the French population have not been determined. Our aim was to determine the incidence of hip fracture in France and the estimated 10-year probabilities of hip and major osteoporotic fractures. METHODS: The study population included adults over 50 years living in France in 2004. Incident hip fracture cases were identified from the French PMSI database. Incidence of the other major osteoporotic fractures was imputed from the relationship between hip fracture incidence and other major fracture in Sweden. These data were used to calculate population-based fracture probabilities according to age and BMD using cutoff values for femoral neck T-scores from the NHANES III data in Caucasian women. The probability model (FRAX®) calibrated to the French population was used to compute individual fracture probabilities according to specific clinical risk factors. RESULTS: We identified 15,434 men and 51,469 women with an incident hip fracture. The remaining lifetime probability of hip fracture at 50 years was approximately 10 and 30% respectively. With a femoral neck T-score of -2 SD, one in two women and one in five men would sustain a major osteoporotic fracture in their lifetime. The 10-year probability of other major osteoporotic fractures increased with declining T-score and increasing age. Low body mass index and other clinical risk factors had an independent effect on fracture probability whether or not BMD was included in the FRAX® model. CONCLUSION: This analysis provides detailed estimation on the risk of fracture in the French population and may help to define therapeutic guidelines.

Staining procedure for the detection of microcracks: application to ewe bone.

Microcracks are one of the determinants of the bone strength and their accumulation may contribute to increased fracture risk. They are detected after bulk staining with various dyes, including basic fuschin, calcein and xylenol orange. The duration of staining usually varies across types of bone and species. The ewe is a large animal with a bone remodeling similar to humans, used as an animal model in bone histomorphometry studies. The aim of the present study was to determine the optimal conditions for bulk staining with xylenol orange of ewe bone. Xylenol orange 5mM in 70% ethanol was applied to iliac crest and vertebral biopsies for 2 or 15 days or 1, 2 or 3 months. After embedding, sections of 40, 50 and 80 µm thick were cut with either a precision diamond wire saw or a microtome. The staining was not visible after 2 or 15 days and was heterogeneous after 1 or 2 months. The quality of 40 and 50 µm thick sections was not preserved compared with those of 80 µm. Microcracks were suitably observed on ewe bone after bulk staining with xylenol orange for 3 months, in 80 µm thick sections. We conclude that the staining procedures should differ when examining ewe or human bone. This may be due to differences in bone matrix composition.

Systemic bone effects of biologic therapies in rheumatoid arthritis and ankylosing spondylitis.

Inflammatory joint diseases are responsible of chronic systemic inflammation, joint degradations, deformities, and altered quality of life. Patients suffering from chronic rheumatic diseases also present increased bone fragility and increased fracture risk. Registration of biologic therapies has deeply modified care in rheumatic diseases, especially in rheumatoid arthritis and ankylosing spondylitis. The available biologics are the anti proinflammatory cytokine therapies (TNFα blockers, anakinra and tocilizumab) and the biologics active on T cell activation (abatacept and rituximab). These drugs succeeded in blocking disease activity and joint degradation. They are also able to stop systemic bone loss among patients with inflammatory rheumatic diseases. In this review, we present the current understanding of the inflammatory-induced bone loss and the skeletal effects of biologic therapies in inflammatory joint diseases.

Oral bisphosphonates and risk of ischemic stroke: a case-control study.

UNLABELLED: Bisphosphonates have been associated with an increased risk of atrial fibrillation and may thus be associated with an increased risk of ischemic stroke. This would have substantial clinical and public health implications. We found no evidence of an association between bisphosphonate use and risk of ischemic stroke. INTRODUCTION: Bisphosphonates have been associated with an increased risk of atrial fibrillation in some studies and may be associated with an increased risk of ischemic stroke. However, data regarding these possibilities are limited. METHODS: We conducted a population-based case-control study of 6,257 female cases of ischemic stroke and 31,285 age- and gender-matched population controls. Data on bisphosphonate use, other medication use, comorbidity, and ischemic stroke were obtained from medical databases. Current bisphosphonate use was defined as at least one redeemed prescription within 90 days before diagnosis/index date. We estimated the odds ratio (OR) of ischemic stroke among users and nonusers of bisphosphonates using conditional logistic regression, controlling for potential confounding factors. RESULTS: One hundred eighty-two (2.9%) cases and 901 (2.9%) controls were current users of bisphosphonates. Etidronate and alendronate were prescribed with similar frequency among cases and controls. The adjusted OR of ischemic stroke for bisphosphonate users compared with nonusers was 0.97 (95% confidence interval [CI], 0.82-1.15). New and continuing bisphosphonate users had adjusted ORs for ischemic stroke of 1.16 (95% CI, 0.69-1.96) and 0.97 (95% CI, 0.81-1.16), respectively. Excluding patients with known atrial fibrillation/flutter yielded an OR of 1.00 (95% CI, 0.85-1.19). The OR for ischemic stroke was 0.59 (95% CI, 0.32-1.09) among patients with a history of previous hospitalization for cardiovascular disease and 1.07 (95% CI, 0.88-1.18) among those without (P < 0.001). The OR for former users was 1.23 (95% CI, 1.01-1.49). CONCLUSION: We found no evidence of an association of oral bisphosphonate use with the risk of ischemic stroke.

Failure to perceive increased risk of fracture in women 55 years and older: the Global Longitudinal Study of Osteoporosis in Women (GLOW).

UNLABELLED: We compared self-perception of fracture risk with actual risk among 60,393 postmenopausal women aged ≥55 years, using data from the Global Longitudinal Study of Osteoporosis in Women (GLOW). Most postmenopausal women with risk factors failed to appreciate their actual risk for fracture. Improved education about osteoporosis risk factors is needed. INTRODUCTION: This study seeks to compare self-perception of fracture risk with actual risk among postmenopausal women using data from GLOW. METHODS: GLOW is an international, observational, cohort study involving 723 physician practices in 17 sites in ten countries in Europe, North America, and Australia. Participants included 60,393 women ≥55 years attended by their physician during the previous 24 months. The sample was enriched so that two thirds were ≥65 years. Baseline surveys were mailed October 2006 to February 2008. Main outcome measures were self-perception of fracture risk in women with elevated risk vs women of the same age and frequency of risk factors for fragility fracture. RESULTS: In the overall study population, 19% (10,951/58,434) of women rated their risk of fracture as a little/much higher than that of women of the same age; 46% (27,138/58,434) said it was similar; 35% (20,345/58,434) believed it to be a little/much lower. Among women whose actual risk was increased based on the presence of any one of seven risk factors for fracture, the proportion who recognized their increased risk ranged from 19% for smokers to 39% for current users of glucocorticoid medication. Only 33% (4,185/12,612) of those with ≥2 risk factors perceived themselves as being at higher risk. Among women reporting a diagnosis of osteopenia or osteoporosis, only 25% and 43%, respectively, thought their risk was increased. CONCLUSION: In this international, observational study, most postmenopausal women with risk factors failed to appreciate their actual risk for fracture.

Bone microdamage: a clinical perspective.

INTRODUCTION: Microdamage accumulation due to fatigue loading may lead to fracture. In addition, several studies using animal models have suggested in recent years that bisphosphonates might increase microdamage accumulation. METHODS: We have reviewed the literature after a PubMed search, to examine the techniques to look for microcracks, the relationship between microdamage and bone strength, and the influence of anti-osteoporosis agents. RESULTS: Currently, the search for microcracks relies on bulk staining of bone samples, which are then examined on optic microscopy and fluorescence or confocal microscopy. The accumulation of microdamage is associated with fatigue loading and is likely to trigger targeted bone remodeling, especially in cortical bone. Several studies examining beagle dogs receiving bisphosphonates have shown a dose-dependent accumulation of microdamage in bone, with conflicting results regarding the consequences on bone mechanical properties. In living humans, obtaining data is limited to the iliac crest bone. The potential association between long-term bisphosphonate use and microcrack accumulation at the iliac crest bone has not been established unequivocally. CONCLUSIONS: Bone microdamage is critical in the understanding of bone quality. Assessment of microdamage is technically difficult, especially in humans. The clinical impact of microdamage potentially induced by bone drugs has not been established in humans.

Effectiveness of instant vertebral assessment to detect prevalent vertebral fracture.

INTRODUCTION: Vertebral fracture is currently underdiagnosed, despite its common severity and its value to predict further osteoporotic fracture. Morphometry using dual X-ray absorptiometry (DXA) [vertebral fracture assessment (VFA)] is a new technique that may facilitate detection of many vertebral fractures, as images are obtained at the same time as bone mineral density (BMD) measurement, and would also allow avoiding spine radiographs. METHODS: We conducted a cross-sectional study to assess the diagnostic value of Instant Vertebral Assessment (IVA), which is a morphometry scan using the Hologic Delphi densitometer, to detect prevalent vertebral fracture in postmenopausal women. Interobserver precision was assessed, then IVA scans were compared with lateral spine radiographs, considered the gold standard, to test diagnostic agreement between the two techniques. Sensitivity, specificity and predictive values were calculated, as well as the likelihood ratio of the positive test, using sensitivity and specificity at each vertebral level. RESULTS: Among 85 patients of whom 50% had at least one vertebral fracture identified with radiographs, we found that interobserver precision was moderate, with frequent difficulties in discerning upper thoracic vertebrae. On a per-vertebra basis, sensitivity was around 70% from L4 to T11 and lower above T11 whereas specificity was above 90% for all vertebrae, and the negative predictive value remained above 80% from L4 to T7 and decreased above T7. On a per-patient basis, sensitivity was 0.69, specificity 0.74, positive predictive value equalled 0.72 and negative predictive value 0.71. When only grades 2 and 3 fractures were considered, results were comparable, with slightly improved specificity. Then, with the likelihood ratios calculated in our sample, we obtained posttest probabilities using the prevalence of vertebral fracture at lumbar and thoracic levels in a large sample of postmenopausal women with osteopenia and osteoporosis with and without vertebral fracture [baseline data in women of the Multiple Outcomes on Raloxifene Evaluation (MORE) trial]. At levels where fractures were most common, likelihood ratios of the positive test were good or excellent, associated with sizeable posttest probabilities. CONCLUSION: IVA allowed diagnosis of vertebral fracture at levels where vertebral fracture were most common, i.e., the lumbar and mid and lower thoracic levels, but its value was weaker at the upper thoracic levels.