Alterations of cortical and trabecular architecture are associated with fractures in postmenopausal women, partially independent of decreased BMD measured by DXA: the OFELY study.

UNLABELLED: We assessed the role of low aBMD and impaired architecture-assessed by an HR-pQCT system-in a case-control study of postmenopausal women with fractures. Vertebral and nonvertebral fractures are associated with low volumetric BMD and architectural alterations of trabecular and cortical bone, independent of aBMD assessed by DXA. INTRODUCTION: Alterations of bone architecture and low BMD both contribute to skeletal fragility, but the contribution of cortical and trabecular architecture, independently of areal BMD (aBMD), to the risk of fracture in postmenopausal women has not been thoroughly evaluated. We assessed the role of impaired architecture and low BMD in postmenopausal women with fractures. MATERIALS AND METHODS: A matched case-control study in women from the OFELY cohort was performed after 13 years of follow-up. One hundred one women (mean, 73.7+/-8 years) who sustained a fragility fracture during the follow-up of the study were age-matched with one control who never had a fracture. Density and architecture at the distal radius and tibia were measured with high-resolution pQCT (HR-pQCT) using an XTreme CT (Scanco Medical AG, Bassersdorf, Switzerland). aBMD at the total hip and ultradistal radius was measured by DXA. RESULTS: There were 80 peripheral fractures in 72 women, 44 vertebral fractures in 34 women, and both types of fractures in 5 women over the 14 years of follow-up. At the distal radius, women with fractures had lower volumetric total (D tot) and trabecular (D trab) BMDs, BV/TV, cortical thickness (Cort Th), trabecular number (TbN), and trabecular thickness (TbTh) and higher trabecular separation (TbSp) and distribution of trabecular separation (TbSpSd) than controls without fractures. In a logistic model, each SD decrease of volumetric total and trabecular densities was associated with a significantly increased risk of fracture at both sites (ORs ranged from 2.00 to 2.47). After adjusting for aBMD measured by DXA at the ultradistal radius, differences between cases and controls remained significant for D trab, and there was a similar trend for TbN, TbSp, and TbSpSd, with adjusted ORs ranging from 1.32 to 1.50. At the distal tibia, before and after adjusting for total hip aBMD, differences between cases and controls remained significant for D tot, D trab, Cort Th, and TbTh, with adjusted ORs ranging from 1.80 to 2.09. CONCLUSIONS: In postmenopausal women, vertebral and nonvertebral fractures are associated with low volumetric BMD and architectural alterations of trabecular and cortical bone that can be assessed noninvasively and that are partially independent of aBMD assessed by DXA.

Low width of tubular bones is associated with increased risk of fragility fracture in elderly men--the MINOS study.

The risk of fragility fractures in elderly men is only partly explained by areal bone mineral density (aBMD) measured by dual X-ray absorptiometry (DXA). Several studies suggest the importance of bone morphology for the risk of fracture. The aim of this study was to assess the value of bone size and estimated structural parameters for the prediction of incident fractures in a large cohort of men. This study was made in 759 men aged 50-85 from the MINOS cohort. During a 90-month follow-up, 74 men sustained incident vertebral and peripheral fractures. Areal BMD was measured by DXA at femoral neck, distal radius and distal ulna. Estimates of structural bone parameters and volumetric BMD (vBMD) were derived from aBMD measured by DXA. Given the limited number of fractures, the predictive value of investigated parameters was assessed for peripheral and vertebral fractures jointly by using logistic regression. Men who sustained the fractures had, at baseline, lower aBMD (3.5-6.5%), lower bone mineral content (BMC 5.4-8.7%) and lower cortical thickness (3.5-6.9%) compared with the men without fracture. At all the three skeletal sites, aBMD, BMC, width, cortical area and thickness, cross-sectional moment of inertia (CSMI), and section modulus predicted incident fractures (O.R. = 1.28-1.92 per 1 SD decrease, P < 0.05-0.0001). Fracture risk was weakly associated with vBMD for ulna (O.R. = 1.25 per 1 SD decrease, P < 0.05) but not for femoral neck or radius. After adjustment for aBMD, bone width remained a significant predictor of fractures (O.R. = 1.37-1.48 per 1 SD decrease, P < 0.02-0.01). Men with osteopenia (BMD T score < -1) and low bone width (T score < -1) had the fracture incidence similar to that observed in men with BMD T score < -2. Bone width and aBMD of the femoral neck and radius were predictive of fractures in 49 men with the incident peripheral fractures, whereas their O.R. did not attain the level of statistical significance in 25 men with the incident vertebral fractures. Men, who had both low aBMD and low CSMI ( both T scores < -1), had the fracture risk 3.8 to 4.2 higher than the reference group (both T scores >or= -1). Men, who had both low aBMD and low section modulus (both T scores < -1), had the fracture risk 2.1 to 4.1 higher than the reference group (both T scores >or= -1). In conclusion, men who sustained a fragility fracture during a 90-month follow-up had, at baseline, lower BMC because they had narrower bones but not necessarily less dense. In elderly men, small bone width, low BMC and poor resistance to bending may increase bone fragility. Low bone width seems to be associated with an increased fracture risk in elderly men regardless of aBMD.

Rate of forearm bone loss is associated with an increased risk of fracture independently of bone mass in postmenopausal women: the OFELY study.

UNLABELLED: BMD is a major determinant of the risk of fragility fractures, but the role of the rate of postmenopausal bone loss is still unclear. In 671 postmenopausal women from the OFELY cohort, we found that the rate of bone loss was significantly associated with fracture risk independently of other well-known predictors including BMD and previous fractures. INTRODUCTION: The level of BMD is a major determinant of the risk of fragility fractures, but the role of the rate of postmenopausal bone loss is still unclear. MATERIALS AND METHODS: In the OFELY study, we analyzed the risk of fracture in 671 postmenopausal women (mean age, 62.2 +/- 9 years), according to the rate of bone loss. BMD was measured annually by DXA at the forearm, with a mean number of measurements of 10.3 +/- 2.6. Peripheral fractures, all confirmed by radiographs, were prospectively registered, and vertebral fractures were evaluated with spine radiographs every 4 years. RESULTS: During a median (interquartile range [IQ]) of 11.2 years (11-12.3 years) of follow-up, 183 incident fragility fractures including 53 vertebral and 130 nonvertebral fractures were recorded in 134 women. The annual median +/- IQ rate of bone loss, calculated from the slope, was -0.30 +/- 0.76% at the mid-radius, -0.55 +/- 0.79% at the distal radius, and -0.40 +/- 0.96% at the ultradistal radius. Women with incident fracture had a rate of bone loss (before fracture) higher by 38-53% than those without fracture (p = 0.0003-0.016). Using multivariate Cox regression models, we found that bone loss in the highest tertile at the mid-radius, distal radius, and ultradistal radius was associated with a significant increased risk of all fractures with an hazard ratio from 1.45 to 1.70 (p = 0.02 to p = 0.009 after adjusting for age, previous fractures, maternal history of fracture, physical activity, grip strength, falls, and baseline BMD). CONCLUSIONS: The rate of bone loss in postmenopausal women is significantly associated with fracture risk independently of other well-known predictors such as BMD and history of fractures.

Identification of osteopenic women at high risk of fracture: the OFELY study.

UNLABELLED: About one-half of women with incident fractures have BMD above the WHO diagnostic threshold of osteoporosis. In the OFELY study, low BMD, increased markers of bone turnover, and prior fracture could be used to identify, within osteopenic women, those at high risk of fracture. INTRODUCTION: Recent data suggest that about one-half of women with incident fractures have BMD above the World Health Organization (WHO) diagnostic threshold of osteoporosis (T score

In vivo assessment of trabecular bone microarchitecture by high-resolution peripheral quantitative computed tomography.

CONTEXT: Assessment of trabecular microarchitecture may enhance the prediction of fracture risk and improve monitoring of treatment response. A new high-resolution peripheral quantitative computed tomography (HR-pQCT) system permits in vivo assessment of trabecular architecture and volumetric bone mineral density (BMD) at the distal radius and tibia with a voxel size of 82 microm3. OBJECTIVE AND PATIENTS: We determined the short-term reproducibility of this device by measuring 15 healthy volunteers three times each. We compared HR-pQCT measurements in 108 healthy premenopausal, 113 postmenopausal osteopenic, and 35 postmenopausal osteoporotic women. Furthermore, we compared values in postmenopausal osteopenic women with (n = 35) and without previous fracture history (n = 78). DESIGN AND SETTING: We conducted a cross-sectional study in a private clinical research center. INTERVENTION AND MAIN OUTCOME MEASURE: We took HR-pQCT measurements of the radius and tibia. Femoral neck and spine BMD were measured in postmenopausal women by dual-energy x-ray absorptiometry. RESULTS: Precision of HR-pQCT measurements was 0.7-1.5% for total, trabecular, and cortical densities and 2.5-4.4% for trabecular architecture. Postmenopausal women had lower density, trabecular number, and cortical thickness than premenopausal women (P < 0.001) at both radius and tibia. Osteoporotic women had lower density, cortical thickness, and increased trabecular separation than osteopenic women (P < 0.01) at both sites. Furthermore, although spine and hip BMD were similar, fractured osteopenic women had lower trabecular density and more heterogeneous trabecular distribution (P < 0.02) at the radius compared with unfractured osteopenic women. CONCLUSION: HR-pQCT appears promising to assess bone density and microarchitecture at peripheral sites in terms of reproducibility and ability to detect age- and disease-related changes.

Disc space narrowing is associated with an increased vertebral fracture risk in postmenopausal women: the OFELY Study.

UNLABELLED: We have analyzed the relationship between spine osteoarthritis and fractures in the OFELY cohort. Despite a higher BMD associated with spine OA, the risk of fragility fractures is not reduced. Disc space narrowing is associated with an increased risk of vertebral fracture. These data indicate that the risk of osteoporotic fracture should not be underestimated in women with spine OA. INTRODUCTION: Although osteoarthritis (OA) and osteoporosis both increase with age, their co-existence is uncommon. A higher BMD in OA is well documented, but a reduction of the fracture risk is still controversial. Our objective was to analyze the risk of fracture in postmenopausal women with spine OA. MATERIALS AND METHODS: In a cross-sectional study, spine OA was evaluated by lateral radiographs according to the method of Lane, and BMD was measured by DXA in 559 postmenopausal women from the OFELY cohort (mean age, 68 +/- 8 years; range, 58-94 years) 8 years after their inclusion into the study. Previous fragility fractures, all confirmed by radiographs, were prospectively registered during the annual follow-up for 8 years, and vertebral fractures were evaluated with spine radiographs. Severity of OA was assessed by scoring on osteophytes and disc narrowing on a four-point scale from 0 (normal) to 3 (severe) and graded as 0 (normal), 1 (mild osteophyte and/or narrowing), or 2 (moderate or severe osteophyte and/or narrowing). RESULTS: Osteophytes and disc narrowing were present in 75% and 64%, respectively, of women at the lumbar spine and in 88% and 51%, respectively, at the thoracic spine, increasing with age. BMD of the spine, hip, and whole body increased with the severity of osteophytosis, whereas severity of narrowing was associated with a higher BMD only at the spine. Ninety-six fractures, including 48 vertebral fractures, occurred before OA assessment. No significant association was found between spine OA and all fragility fractures. In contrast, disc narrowing was associated with an increased risk of vertebral fracture with an odds ratio (95% CI) of 3.2 (1.1-9.3) after adjusting for age, body mass index, and BMD. The risk of vertebral fracture increased with the severity of disc narrowing. In comparison with the score 0, the odds ratio increased from 2.8 (0.9-8.7) to 4.6 (1.2-16.9) in women with mild to severe disc narrowing score. CONCLUSIONS: Despite a higher BMD, women with spine OA do not have a reduced risk of fracture. Disc narrowing is associated with a significant increased vertebral fracture risk.

Long-term variability of markers of bone turnover in postmenopausal women and implications for their clinical use: the OFELY study.

UNLABELLED: Bone marker variability has raised concern for its use in individual patients. Serum osteocalcin (formation) and CTX (resorption) were measured every year for 4 years in 268 postmenopausal women. Seventy percent to 80% of women classified as having high bone turnover at baseline were similarly classified by the same methods 4 years later. INTRODUCTION: High bone marker levels are a risk factor for osteoporosis in postmenopausal women, but variability of measurements has raised doubts about their clinical use in an individual patient. METHODS: We studied 268 untreated postmenopausal women (50-81 years of age) belonging to a population-based prospective cohort. We collected fasting morning blood samples every year for 4 years to measure serum intact osteocalcin (OC) and serum C-terminal cross-linked telopeptide of type I collagen (CTX) as bone formation and resorption markers, respectively. RESULTS: Serum OC and CTX remained stable during follow-up (+ 1.2%/year, p = 0.003 and -0.13%/year, p = 0.70 for OC and S-CTX, respectively). At baseline, women were classified as having low (tertile 1), intermediate (tertile 2), or high (tertile 3) bone turnover. Agreement of classification between baseline and 4-year measurements was moderate (kappa [95% CI]: 0.51 [0.43-0.59] and 0.52 [0.44-0.60] for OC and S-CTX, respectively). Less than 10% of women in tertile 1 or 3 of either marker at baseline were found in the opposite tertile 4 years later. When the two markers were combined, only 2% of women at high turnover at baseline--defined as OC and/or S-CTX in tertile 3--were classified at low turnover 4 years later. Among women classified at high bone turnover at baseline (tertile 3), 70-80% were also found at high turnover 4 years later. Among women in tertile 2, only 51% and 43% for OC and CTX, respectively, remained in the same tertile at the second measurement. CONCLUSIONS: Serum levels of bone formation and resorption markers are stable over 4 years in postmenopausal women, on average. The majority of women classified as having high bone turnover were similarly classified by the same methods 4 years later. However, 20-30% of these women at risk for fracture would be incorrectly classified, suggesting that further investigation would be required to reduce the number of patients who would be treated unnecessarily if the decision was made on bone marker measurement. For women with intermediate levels, classification may be improved by a second measurement or by combining two markers.

Effect of withdrawal of hormone replacement therapy on bone mass and bone turnover: the OFELY study.

The beneficial effects of hormone replacement therapy (HRT) on bone mineral density (BMD) and bone turnover are well documented but whether HRT withdrawal is followed by an accelerated rate of bone loss is still controversial. We analyzed 26 women who have withdrawn HRT during a 6-year follow-up of the OFELY cohort. They were compared with three groups of women from the same cohort: one hundred four healthy postmenopausal women who continued HRT during the 6-year follow-up, 78 untreated postmenopausal women matched for age, and 31 untreated women within 5 years of menopause. Bone markers [serum osteocalcin (Intact OC), bone alkaline phosphatase (Bone ALP), and serum CTX] were performed annually during 4 years and bone mineral density (BMD) was measured at the forearm (DXA) during 6 years. Withdrawal of HRT was followed by a significant bone loss with an annual rate ranged from -0.7 to -1.6% at the radius according to the skeletal site and by a marked increase of bone markers after 6 months: +36 % for osteocalcin, +23% for bone alkaline phosphatase, and +120% for serum CTX (P < 0.05 to P < 0.001). In contrast, in the HRT continuing group, there was no bone loss and no substantial change of bone markers over 4 years. The rate of bone loss after withdrawal of HRT was significantly greater than in postmenopausal women matched for age who never received HRT (2.2 to 2.8 times higher according to the radius area) and not different as compared to the accelerated bone loss observed in untreated women within 5 years of menopause. We conclude that in postmenopausal women who have been on HRT for 6 years, cessation of treatment results in a rapid increase of bone turnover and a rate of bone loss similar to early postmenopausal women during the subsequent 4 years and greater than untreated women of the same age.

Age determines longitudinal changes in body composition better than menopausal and bone status: the OFELY study.

Long-term body composition (BC) changes and their determinants have been rarely explored. We aimed to evaluate BC changes in French women from the Os des Femmes de Lyon (OFELY) cohort and to explore several determinants of those changes. At baseline, premenopausal (PreM) women (n = 145) had lower fat body mass (FM) and greater lean body mass (LM), relative skeletal muscle mass index (RASM), and total body bone mineral content (TBBMC) compared with untreated postmenopausal (PostM) women (n = 412). During a 6-year follow-up, LM and RASM did not change, whereas a significant increase of FM and a decrease of TBBMC were observed in PreM (n = 88) and PeriM women (n = 44; women who became PostM during the follow-up). In untreated PostM women, FM increased, whereas LM, RASM, and TBBMC decreased (p < 0.0001). Age was a significant determinant of the changes in BC. After controlling for age, menopausal status was still a significant determinant only for changes in TBBMC. FM, LM, RASM, and TBBMC were higher in women with normal bone mineral density (BMD) compared with women with osteopenia or osteoporosis (p < 0.0001), but after adjusting for age, changes of BC were not significantly different according to the bone status. After controlling for age and menopausal status, levels of P1NP in the highest quartile were associated with a greater decrease of LM and RASM compared with lower levels. In conclusion, BC changes in French women over a 6-year follow-up showed a high interindividual variability. Aging may be the most important determinant of changes in body composition, rather than menopausal and bone status.

Finite element analysis performed on radius and tibia HR-pQCT images and fragility fractures at all sites in men.

Few studies have investigated bone microarchitecture and biomechanical properties in men. This study assessed in vivo both aspects in a population of 185 men (aged 71 ± 10 years) with prevalent fragility fractures, compared to 185 controls matched for age, height, and weight, from the Structure of the Aging Men's Bones (STRAMBO) cohort. In this case-control study, areal BMD (aBMD) was measured by DXA, bone microarchitecture was assessed by high resolution (HR)-pQCT, and finite element (µFE) analysis was based on HR-pQCT images of distal radius and tibia. A principal component (PC) analysis (PCA) was used to study the association of synthetic PCs with fracture by computing their odds ratio (OR [95%CI]) per SD change. Specific associations with vertebral fracture (n = 100), and nonvertebral fracture (n = 85) were also computed. At both sites, areal and volumetric BMD, cortical thickness and trabecular number, separation, and distribution were significantly worse in cases than in controls, with differences ranging from -6% to 15%. µFE-derived stiffness and failure load were 8% to 9% lower in fractures (p < .01). No difference in load distribution was found between the two groups. After adjustment for aBMD, only differences of µFE-derived stresses, stiffness, and failure load at the tibia remained significant (p < .05). PCA resulted in defining 4 independent PCs, explaining 83% of the total variability of bone characteristics. Nonvertebral fractures were associated with PC1, reflecting bone quantity and strength at the radius (tibia) with OR = 1.64 [1.27-2.12] (2.21 [1.60-3.04]), and with PC2, defined by trabecular microarchitecture, with OR = 1.27 [1.00-1.61]. Severe vertebral fractures were associated with PC1, with OR = 1.56 [1.16-2.09] (2.21 [1.59-3.07]), and with PC2, with OR = 1.55 [1.17-2.06] (1.45 [1.06-1.98]). In conclusion, microarchitecture and biomechanical properties derived from µFE were associated with all types of fractures in men, showing that radius and tibia mechanical properties were relatively representative of distant bone site properties.

Effects of preexisting microdamage, collagen cross-links, degree of mineralization, age, and architecture on compressive mechanical properties of elderly human vertebral trabecular bone.

Previous studies have shown that the mechanical properties of trabecular bone are determined by bone volume fraction (BV/TV) and microarchitecture. The purpose of this study was to explore other possible determinants of the mechanical properties of vertebral trabecular bone, namely collagen cross-link content, microdamage, and mineralization. Trabecular bone cores were collected from human L2 vertebrae (n = 49) from recently deceased donors 54-95 years of age (21 men and 27 women). Two trabecular cores were obtained from each vertebra, one for preexisting microdamage and mineralization measurements, and one for BV/TV and quasi-static compression tests. Collagen cross-link content (PYD, DPD, and PEN) was measured on surrounding trabecular bone. Advancing age was associated with impaired mechanical properties, and with increased microdamage, even after adjustment by BV/TV. BV/TV was the strongest determinant of elastic modulus and ultimate strength (r² = 0.44 and 0.55, respectively). Microdamage, mineralization parameters, and collagen cross-link content were not associated with mechanical properties. These data indicate that the compressive strength of human vertebral trabecular bone is primarily determined by the amount of trabecular bone, and notably unaffected by normal variation in other factors, such as cross-link profile, microdamage and mineralization.

The FRAX tool in French women: How well does it describe the real incidence of fracture in the OFELY cohort?

The FRAX tool estimates an individual's fracture probability over 10 years from clinical risk factors with or without bone mineral density (BMD) measurement. The aim of our study was to compare the predicted fracture probabilities and the observed incidence of fracture in French women during a 10-year follow-up. The probabilities of fracture at four major sites (hip, clinical spine, shoulder, or wrist) and at the hip were calculated with the FRAX tool in 867 women aged 40 years and over from the Os des Femmes de Lyon (OFELY) cohort.The incidence of fracture was observed over 10 years. Thus 82 women sustained 95 incident major osteoporotic (OP) fractures including 17 fractures at the hip. In women aged at least 65 years (n = 229), the 10-year predicted probabilities of fracture with BMD were 13% for major OP fractures and 5% for hip fractures, contrasting with 3.6% and 0.5% in women younger than 65 years (p < .0001). The predicted probabilities of both major OP and hip fractures were significantly higher in women with osteoporosis (n = 77, 18% and 10%) and osteopenia (n = 390, 6% and 2%) compared with women with normal BMD (n = 208, 3% and <1%; p < .0001. The predicted probabilities of fracture were two and five times higher in women who sustained an incident major OP fracture and a hip fracture compared with women who did not (p < .0001). Nevertheless, among women aged at least 65 years with low BMD values (T-score < or = -1; n = 199), the 10-year predicted probability of major OP fracture with BMD was 48% lower than the observed incidence of fractures (p < .01). A 10-year probability of major OP fracture higher than 12% identified more women with incident fractures than did BMD in the osteoporotic range (p < .05). In French women from the OFELY cohort, the observed incidence of fragility fractures over 10 years increased with age following a pattern similar to the predicted probabilities given by the FRAX tool. However, in women aged at least 65 years with low BMD, the observed incidence of fractures was substantially higher than the predicted probability.

Rapid loss of appendicular skeletal muscle mass is associated with higher all-cause mortality in older men: the prospective MINOS study.

BACKGROUND: Changes in body composition underlying the association between weight loss and higher mortality are not clear. OBJECTIVE: The objective was to investigate the association between changes in body composition of the appendicular (4 limbs) and central (trunk) compartments and all-cause mortality in men. DESIGN: In men aged > or = 50 y, body composition was assessed every 18 mo for 7.5 y with a whole-body dual-energy X-ray absorptiometry scan. Mortality was assessed for 10 y. Data were analyzed by logistic regression and Cox model and adjusted for age, body mass index (BMI), educational level, lifestyle, physical performance, comorbidities, body composition, and serum concentrations of 17beta-estradiol and 25-hydroxycholecalciferol. RESULTS: Of 715 men who were followed up, 137 (19.2%) died. Mortality was higher in men with the fastest weight loss [lowest compared with middle tertile odds ratio (OR): 2.31; 99% CI: 1.05, 5.09]. Faster loss of appendicular skeletal muscle mass (ASMM) was predictive of mortality (lowest compared with middle tertile OR: 3.60; 99% CI: 1.64, 7.89). Faster loss in ASMM remained a strong predictor of mortality after adjustment for weight loss (OR: 3.41; 99% CI: 1.51, 7.71). Faster loss in ASMM was the strongest predictor of death in the stepwise procedures when it was analyzed jointly with changes in the mass of other compartments. Loss in ASMM calculated over 36 mo was also a stronger predictor of death than were changes in the mass of other compartments (hazard ratio: 1.33 per 1-SD decrease; 95% CI: 1.06, 1.66). CONCLUSION: The accelerated loss of ASMM is predictive of all-cause mortality in older men regardless of age, BMI, lifestyle, physical performance, health status, body composition, and serum 17beta-estradiol and 25-hydroxycholecalciferol.

Association between bone turnover rate and bone microarchitecture in men: the STRAMBO study.

Few data concern the relationship between bone turnover and microarchitecture in men. We investigated the association between levels of biochemical markers of bone turnover (BTM) and bone microarchitecture in 1149 men aged 19 to 85 years. Bone microarchitecture was assessed by high-resolution peripheral quantitative computed tomography at the distal radius and tibia. Bone formation was assessed by serum osteocalcin, bone alkaline phosphatase, and N-terminal extension propeptide of type I collagen. Bone resorption was assessed by serum C-terminal telopeptide of type I collagen and urinary excretion of total deoxypyridinoline. BTM levels were high in young men and decreased until age 50 years. Urinary deoxypyridinoline (DPD) increased after age 70 years, whereas other BTMs remained stable. Before 50 years of age, only cortical volumetric bone mineral density (D(cort)) correlated negatively with BTM levels. Between 50 and 70 years of age, D(cort) and some microarchitectural parameters correlated significantly with BTM at the radius and tibia. After 70 years of age, higher BTM levels were associated with lower cortical thickness and D(cort) at both the skeletal sites. At the distal radius, men in the highest BTM quartile had lower trabecular density, number (Tb.N), and thickness (Tb.Th) and more heterogeneous trabecular distribution compared with men in the lower quartiles. At the distal tibia, higher BTM levels were associated with lower Tb.N and Tb.Th in the central but not subendocortical area. Thus, in men, bone microarchitecture depends weakly on the current bone turnover rate until age 70. Thereafter, bone turnover seems to be a significant determinant of bone microarchitecture.

Finite element analysis performed on radius and tibia HR-pQCT images and fragility fractures at all sites in postmenopausal women.

Assessment of bone strength at the radius by micro-finite element analysis (muFEA) has already been associated with wrist fractures. In this study, the analysis has been extended to the distal tibia, and to a larger group of subjects to examine the association with several types of fragility fractures. We have compared muFEA based on in vivo HR-pQCT measurements of BMD and microarchitecture at the radius and tibia, in a case-control study involving 101 women with prevalent fragility fracture and 101 age-matched controls, from the OFELY cohort. Areal BMD was measured by DXA at the radius and the hip. All parameters were analyzed in a principal component (PC) analysis (PCA), and associations between PCs and fractures were computed as odds ratios (OR [95% CI]) per SD change. Radius (tibia) PCA revealed three independent components explaining 76% (77%) of the total variability of bone characteristics. The first PC describing bone strength and quantity, explained 50% (46%) of variance with an OR=1.84 [1.27-2.67] (2.92 [1.73-4.93]). The second PC including trabecular microarchitecture, explained 16% (10%) of variance, with OR=1.29 [0.90-1.87] (1.11 [0.82-1.52]). The third PC related to load distribution explained 10% (20%) of variance, with OR=1.54 [1.06-2.24] (1.32 [0.89-1.96]). Moreover, at the radius, vertebral fractures were associated with trabecular microarchitecture PC with OR=1.86 [1.14-3.03], whereas nonvertebral fractures were associated with bone strength and quantity PC with OR=2.03 [1.36-3.02]. At the tibia, both vertebral (OR=2.92 [1.61-5.28]) and nonvertebral fracture (2.64 [1.63-4.27]) were associated to bone strength and quantity PC. In conclusion, muFEA parameters at the radius and tibia were associated with all types of fragility fractures. We have also shown that muFEA parameters obtained with distal tibia data were associated with prevalent fractures with a similar magnitude that with parameters obtained at the radius.

Severity of vertebral fractures is associated with alterations of cortical architecture in postmenopausal women.

Patients with vertebral fractures (VFx) have trabecular architectural disruption on iliac biopsies. Because cortical bone is an important determinant of bone strength, we assessed cortical and trabecular microarchitecture at peripheral sites in patients with VFx of varying number (N) and severity (S). Bone architecture and volumetric density (vBMD) were assessed at the distal radius and tibia with HR-pQCT (XTreme CT; Scanco Medical, Bassersdorf, Switzerland) in 100 women with VFx (age, 74 +/- 9 yr) of different S (GI, n = 23; GII, n = 35 ; GIII, n = 42) and in 362 women (age, 69 +/- 7 yr) without peripheral or VFx (G0) from the OFELY study. Spine areal BMD (aBMD) was assessed by DXA. Among all women, at the radius and after adjustment for age and aBMD, there were significant trends in lower vBMD, cortical thickness (Cort.Th), trabecular number (Tb.N) and thickness (Tb.Th), higher trabecular separation (Tb.Sp), and distribution of separation (Tb.Sp.SD) with greater VFx S and N. Among women with VFx, lower Cort.Th and cortical vBMD (D.Cort) were associated with severe (GIII) and multiple (n > 2) VFx (p < 0.05). The age-adjusted OR for each SD decrease of Cort.Th was 2.04 (95% CI, 1.02-4.00) after adjustment for aBMD. At the tibia, there were trends for lower vBMD, Tb.N, Tb.Th, and higher Tb.Sp and Tb.Sp.SD with greater VFx S and N (p < 0.001). Among women with VFx, lower Cort.Th and D.Cort were associated with severe and multiple (n > 3) VFx (p < 0.01). In postmenopausal women, VFx are associated with low vBMD and architectural decay of trabecular and cortical bone at the radius and tibia, independently of spine aBMD. Severe and multiple VFx are associated with even more alterations of cortical bone.

Effects of yearly zoledronic acid 5 mg on bone turnover markers and relation of PINP with fracture reduction in postmenopausal women with osteoporosis.

In patients with osteoporosis treated with antiresorptive agents, reduction in bone turnover explains much of the observed fracture risk reduction. Lower levels of bone turnover markers (BTMs) appear to be associated with a lower risk of fracture in bisphosphonate-treated patients. BTMs were measured in a subset of subjects in the HORIZON Pivotal Fracture Trial. Annual infusions of zoledronic acid 5 mg significantly reduced BTMs: median decrease of 50% for beta-C-terminal telopeptides of type 1 collagen (beta-CTX), 30% for bone alkaline phosphatase (ALP), and 56% for procollagen type 1 amino-terminal propeptide (PINP). The mean level of BTMs decreased in treated patients but remained within the premenopausal range before the next injection. The percentage of zoledronic acid-treated patients with values below the premenopausal reference range at all time points was 1.7%, 17.8%, and 19% for bone ALP, CTX, and PINP, respectively. The third injection of zoledronic acid resulted in 60% reduction of beta-CTX within 9-11 days, followed by a gradual increase, indicating the persistence of osteoclastic bone resorption. The association between changes in BTMs and fracture incidence was assessed in 1132 patients who had PINP measurements at baseline and 1 yr. There was no association between low PINP levels at 1 yr and increased fracture incidence. In summary, (1) annual injections of zoledronic acid reduced BTMs in the premenopausal range, with a significant response persisting after the third infusion; and (2) low levels of PINP were not associated with increased fracture risk.

Finite element analysis based on in vivo HR-pQCT images of the distal radius is associated with wrist fracture in postmenopausal women.

UNLABELLED: BMD, bone microarchitecture, and bone mechanical properties assessed in vivo by finite element analysis were associated with wrist fracture in postmenopausal women. INTRODUCTION: Many fractures occur in individuals with normal BMD. Assessment of bone mechanical properties by finite element analysis (FEA) may improve identification of those at high risk for fracture. MATERIALS AND METHODS: We used HR-pQCT to assess volumetric bone density, microarchitecture, and microFE-derived bone mechanical properties at the radius in 33 postmenopausal women with a prior history of fragility wrist fracture and 33 age-matched controls from the OFELY cohort. Radius areal BMD (aBMD) was also measured by DXA. Associations between density, microarchitecture, mechanical parameters and fracture status were evaluated by univariate logistic regression analysis and expressed as ORs (with 95% CIs) per SD change. We also conducted a principal components (PCs) analysis (PCA) to reduce the number of parameters and study their association (OR) with wrist fracture. RESULTS: Areal and volumetric densities, cortical thickness, trabecular number, and mechanical parameters such as estimated failure load, stiffness, and the proportion of load carried by the trabecular bone at the distal and proximal sites were associated with wrist fracture (p < 0.05). The PCA revealed five independent components that jointly explained 86.2% of the total variability of bone characteristics. The first PC included FE-estimated failure load, areal and volumetric BMD, and cortical thickness, explaining 51% of the variance with an OR for wrist fracture = 2.49 (95% CI, 1.32-4.72). Remaining PCs did not include any density parameters. The second PC included trabecular architecture, explaining 12% of the variance, with an OR = 1.82 (95% CI, 0.94-3.52). The third PC included the proportion of the load carried by cortical versus trabecular bone, assessed by FEA, explaining 9% of the variance, and had an OR = 1.61 (95% CI, 0.94-2.77). Thus, the proportion of load carried by cortical versus trabecular bone seems to be associated with wrist fracture independently of BMD and microarchitecture (included in the first and second PC, respectively). CONCLUSIONS: These results suggest that bone mechanical properties assessed by microFE may provide information about skeletal fragility and fracture risk not assessed by BMD or architecture measurements alone and are therefore likely to enhance the prediction of wrist fracture risk.

The fracture risk index and bone mineral density as predictors of vertebral structural failure.

Structural failure becomes increasingly likely as the load on bone approximates or exceeds the bone's ability to withstand it. The vertebral fracture risk index (FRI) expresses the risk for structural failure as a ratio of compressive stress (load per unit area) to estimated failure stress, and so should be a more sensitive and specific predictor of vertebral fracture than spine areal BMD (aBMD) or volumetric BMD (vBMD), surrogates of bone strength alone. To address this issue, we analyzed the results of a case-control study of 89 postmenopausal women with vertebral fractures and 306 controls in Melbourne, Australia, and a 10-year community-based prospective study in which 30 postmenopausal women who had incident vertebral fractures were compared with 150 controls in Lyon, France. The FRI and vBMD of the third lumbar vertebral body and spine aBMD were derived using dual X-ray absorptiometry. In the cross-sectional analysis, each SD increase in FRI was associated with 2.1-fold (95% confidence interval [CI], 1.55-2.73) increased vertebral fracture risk, while each SD decrease in aBMD or vBMD was associated with 4.0-fold (95% CI, 2.69-6.18 and 2.65-6.94, respectively) increase in risk. Using receiver operating characteristic (ROC) analysis, the FRI was less sensitive and specific than aBMD in discriminating cases and controls (area under ROC, 0.76 vs 0.84, p<0.01). The area under ROC curve did not differ between FRI and vBMD (0.76 vs 0.79, NS). In the prospective data set, the FRI was not predictive [hazard ratio, HR, 1.20 (95% CI, 0.9-1.7)] and was in contrast to aBMD [HR, 2.4 (95% CI, 1.5-3.8)] and vBMD [HR, 2.1 (95% CI, 1.39-3.17)]. There was also lower sensitivity using a cutoff value of FRI>or=1 compared with aBMD T-score of -2.5 SD in both studies. There was poor agreement (kappa=0.13-0.18) between FRI and aBMD T -scores in detecting fractures; each method only identified around 50% of fractured cases. Within the constraints of the sample size, we concluded that applying a biomechanical index such as FRI at the spine is no better in discriminating fracture cases and controls than conventional aBMD or vBMD. The FRI may not predict incident vertebral fractures.

Disc space narrowing as a new risk factor for vertebral fracture: the OFELY study.

OBJECTIVE: In a previous cross-sectional analysis, we found a positive association between disc space narrowing (DSN) and vertebral fracture. The aim of the present study was to analyze prospectively the risk of vertebral and nonvertebral fractures in women with spine osteoarthritis (OA). METHODS: Using radiographs, spine OA was evaluated in 634 postmenopausal women from the OFELY (Os des Femmes de Lyon) cohort (mean+/-SD age 61.2+/-9 years). Prevalence and severity of spine OA were assessed by scoring osteophytes and DSN. Incidental clinical fractures were prospectively registered during annual followup, and vertebral fractures were evaluated by radiography every 4 years. RESULTS: During an 11-year followup, fractures occurred in 121 women, including 42 with vertebral fractures. No association was found between osteophytes and the risk of fracture. In contrast, DSN was associated with an increased risk of vertebral fractures but not of nonvertebral fractures. After adjusting for confounding variables, the presence of DSN was associated with a marked increased risk of vertebral fractures, with an odds ratio of 6.59 (95% confidence interval 1.36-31.9). In addition, 95% of incident vertebral fractures were located above the disc with the most severe narrowing. CONCLUSION: This longitudinal study shows that, despite a higher bone mineral density (BMD), women with spine OA do not have a reduced risk of fracture and that DSN is significantly associated with vertebral fracture risk. The location of DSN and of incident vertebral fractures suggests that disc degeneration impairs the biomechanics of the above spine, which leads to the increased risk of vertebral fractures, independent of BMD. We suggest that DSN is a newly identified risk factor for vertebral fracture that should be taken into consideration when assessing vertebral fracture risk in postmenopausal women.