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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Assessment of vertebral fracture using densitometric morphometry.

Diagnosis of vertebral fracture is critical for management of osteoporosis, as existence of such deformities substantially increases the risk of subsequent fracture. Thus, accurate and precise techniques allowing detection of such deformities are essential to clinicians. So far, this detection has been performed by spinal lateral X-rays. More advanced techniques have recently been developed, based on dual energy X-ray absorptiometry (DXA). This review describes these different techniques and discusses the effectiveness of the DXA technique to assess vertebral deformities compared to X-ray. The use of DXA detection of vertebral fracture for clinical practice and clinical trials is discussed. Specifically, vertebral morphometry using DXA provides an excellent specificity, with moderate sensitivity. The major limitation of the DXA vertebral assessment is the poor quality of images of thoracic vertebrae. The clinical utility of vertebral morphometry using densitometry may help screening patients with vertebral fracture, but technological improvements are necessary to improve image quality.

Long-term effects of intravenous pamidronate in fibrous dysplasia of bone.

Fibrous dysplasia of bone (FD) is a rare disorder characterized by proliferation of fibrous tissue in bone marrow leading to osteolytic lesions. It causes bone pain and fractures. To date the only treatment is orthopedic. Histological and biochemical similarities between FD and Paget's bone disease related to increased osteoclastic resorption led us to propose treatment with the bisphosphonate pamidronate. The aim of the study was to assess the long-term effects of intravenous pamidronate in FD. In this open label phase III study, 20 patients with FD (11 males and 9 females; mean age 31 years) received courses of 180 mg of intravenous pamidronate every 6 months (60 mg/day during 3 days by infusion). The mean duration of follow-up was 39 months (range 18-64). Severity of bone pain, number of painful skeletal sites per patient, X-rays of all involved areas, serum alkaline phosphatase, fasting urinary hydroxyproline, and urinary type I collagen C-telopeptide were assessed every 6 months. The severity of bone pain and the number of painful sites appeared to be significantly reduced. All biochemical markers of bone remodeling were substantially lowered. We observed a radiographic response in nine patients with refilling of osteolytic lesions. A mineralization defect proven by bone biopsy was observed in one case. Four patients sustained bone stress lines, but no fracture occurred. We suggest that intravenous pamidronate alleviates bone pain, reduces the rate of bone turnover assessed by biochemical markers, and improves radiological lesions of FD. Few side effects were observed.

Serum estradiol and sex hormone-binding globulin and the risk of hip fracture in elderly women: the EPIDOS study.

It has been suggested that low serum 17beta-estradiol (E2) and sex hormone-binding globulin (SHBG) may predict hip fracture in postmenopausal women. We have investigated the predictive value of serum E2 and SHBG concentrations and urinary deoxypyridinoline (D-Pyr) and type I collagen breakdown products (CTX) in a large prospective cohort of 7,598 healthy elderly ambulatory women (EPIDOS study), aged 75 years or more. We performed a nested case control study, by matching 212 patients with incident hip fracture with 636 controls. Mean follow-up was 3.3 years (maximum, 4.9 years). Women having serum E2 below the limit of detection (3 pg/ml), that is, 2% of the population, were not at higher risk, with a relative hazard (RH) of 1.59 (95% CI = 0.45-5.55). Women having serum E2 below 5, 6, 7, or 8 pg/ml, in the lowest quartile, or below the median had no increased risk of hip fracture. In contrast, women having serum E2 in the highest quartile (i.e., > or = 10 pg/ml) were protected, with an RH of 0.66 (0.44-0.98) that did not remain significant after adjustment for weight (RH = 0.71 [0.47-1.06]). High serum SHBG values with different cut-offs tended to be associated with an increased risk of hip fracture. Women in the highest quartile had an RH of 2.5 (1.37-4.61), compared with those in the lowest quartile, that decreased markedly after adjustment for body weight (1.61 [0.99 -2.62]). The highest quartile of the ratio E2/SHBG, which is an index of free E2, was associated with a lower hip fracture risk (RH = 0.6 [0.4-0.91]) that was no longer significant after adjustment for weight. In contrast, urinary D-Pyr and CTX, when elevated above the upper limit of premenopausal values, were predictive of hip fracture, with an RH of 2.07 (1.49-2.9) and 1.67 (1.19-2.32), respectively, even after adjustment for body weight, serum E2, and SHBG. We conclude that in healthy elderly French women over 75 years of age, serum E2 and E2/SHBG in the highest quartile are associated with a lower risk of hip fracture and that this association is explained by a higher body weight. In addition, serum levels of E2 and SHBG do not account for the increased risk of hip fracture associated with high levels of bone resorption markers.

Influence of smoking on the antiosteoporotic efficacy of raloxifene.

The efficacy of estrogen therapy may be modified in women who smoke because of increased catabolism of estrogen and the interaction of tobacco products with the estradiol receptor. We examined whether the efficacy of raloxifene differed in smoking vs. nonsmoking women. We compared change in bone mineral density and biochemical markers of bone turnover, and incidence of new vertebral fracture in postmenopausal women of the Multiple Outcomes on Raloxifene Efficacy trial, who were randomized to either raloxifene (60 or 120 mg/d) or placebo. In the 17% of women who were current smokers, we found, compared with nonsmokers, lowered baseline trochanter bone mineral density (0.540 vs. 0.557 g/cm(2); P < 0.001) and serum osteocalcin (24.8 vs. 26.6 ng/liter; P < 0.001). Baseline urinary type I collagen breakdown products was increased among smokers (291.8 vs. 276.9 micromol/liter; P = 0.04). Body mass index was also lower in smokers (24.3 vs. 25.4; P < 0.001). After 6 months of treatment, there was no significant difference in reduction of bone turnover between smokers and nonsmokers. After 4 yr of treatment, the smoking-treatment interaction was not significant between smokers and nonsmokers for the percent increase in femoral neck bone mineral density (P = 0.25), trochanter bone mineral density (P = 0.24), and spine bone mineral density (P = 0.37). The smoking-treatment interaction for reduction in vertebral fracture risk was not significant either [odds ratio for fracture, 0.67 (0.45-0.98) for smokers and 0.56 (0.47-0.68) for nonsmokers; P = 0.44]. These results were not modified after stratification by tertiles of body mass index or when comparing heavy smokers vs. light smokers. We conclude that smoking does not influence the antiosteoporotic effect of raloxifene. This may represent an advantage over estrogen replacement therapy.

Treatment of fibrous dysplasia of bone with intravenous pamidronate: long-term effectiveness and evaluation of predictors of response to treatment.

Fibrous dysplasia (FD) of bone is a rare but potentially severe bone disease that often entails fractures, deformities, and bone pain. An activating mutation of the alpha subunit of Gs proteins leads to differentiation abnormalities of the osteoblastic lineage, which are responsible for development of fibrous tissue in the medulla and increased osteoclastic activity. This increased bone resorption has been the rationale to use bisphosphonates in our center since 1988. So, we have analyzed the largest series, so far, of patients treated with the bisphosphonate pamidronate and sought predictors of response to treatment. We have treated 58 patients (41 adults and 17 under 18 years of age) with FD in an open study, using intravenous (IV) pamidronate 180 mg every 6 months and calcium and vitamin D supplements, in combination with oral phosphate and calcitriol in patients with FD who also had renal phosphate wasting. Patients were followed up with biannual visits, for an average 50 months, with pain assessment, annual radiographs of affected bones, measurement of biochemical markers of bone turnover, and annual bone mineral density measurements in the case of affected hips. We found that pain intensity significantly decreased with treatment in the 44 patients who had bone pain at baseline, biochemical markers of bone turnover were significantly reduced, and about 50% of patients had improvement of bone lesions on radiographs, evidenced by filling of osteolytic lesions and/or cortex thickening. Bone mineral density was substantially increased in the 12 patients who had hip FD. There was no significant clinical or biological predictor of positive radiographic response to pamidronate treatment. Long-term treatment with pamidronate was safe, in particular among the 12 patients who were followed up for more than 8 years. Despite the lack of a control group, our results suggest that intravenous pamidronate improves radiological aspect in half of the patients with FD, decreases bone turnover, and may decrease pain intensity.