Elisabeth Sornay-Rendu

Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study.

The mechanisms leading to increased bone loss and skeletal fragility in women with postmenopausal osteoporosis are still poorly understood. Increased bone resorption, low serum estradiol and high serum sex‐hormone‐binding globulin (SHBG) recently have been reported as predictors of vertebral and hip fractures in elderly women. In a cohort of healthy untreated younger postmenopausal women aged 50–89 years (mean, 64 years), we compared baseline levels of bone markers and endogenous hormones in 55 women who subsequently had a fracture (20 vertebral and 35 peripheral fractures) with levels in the 380 women who did not fracture during a mean 5 years of follow‐up. Women with levels in the highest quartile of four bone resorption markers including urinary‐free deoxypyridinoline (D‐Pyr), urinary type I collagen N‐telopeptides (NTX), and urinary and serum type I collagen C‐telopeptides (CTX) had about a 2‐fold increased risk of fractures compared with women with levels in the three lowest quartiles with relative risk (RR) and 95% CI of 1.8 (1.0‐3.4) for free D‐Pyr, 1.7 (0.9‐3.2) for urinary NTX, 2.3 (1.3‐4.1) for urinary CTX, and 2.1 (1.2‐3.8) for serum CTX. Serum levels of bone alkaline phosphatase (BAP) in the highest quartile were associated with an RR of fracture of 2.4 (1.3‐4.2). Women with serum levels of estradiol and dehydroepiandrosterone (DHEA) sulfate in the lowest quartile had an RR of fracture of 2.2 (1.2‐4.0) and 2.1 (1.2‐3.8), respectively. Increased levels of SHBG and intact parathyroid hormone (PTH) were moderately associated with an increased risk of fracture. Similar results were obtained when the analysis was restricted to symptomatic vertebral and nonvertebral fractures. Adjustment of biochemical markers by hormone levels did not significantly alter the results. Women with both high bone resorption markers and low estradiol (or low DHEA sulfate) had a higher risk of fracture with RRs of 3.0‐3.3 (p < 0.001). After adjustment for bone mineral density (BMD) of the hip, spine, radius, or total body, bone markers and hormones were still predictive of fracture risk with similar RRs. We conclude that high levels of some biochemical markers of bone turnover, low serum estradiol, low DHEA sulfate, high SHBG, and high PTH are associated with increased risk of osteoporotic fracture in postmenopausal women, independently of each other and of BMD. The mechanism by which some postmenopausal women have an increased rate of bone turnover leading to an increased risk of fracture remains to be elucidated.

Alterations of Cortical and Trabecular Architecture Are Associated With Fractures in Postmenopausal Women, Partially Independent of Decreased BMD Measured by DXA: The OFELY Study

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.

Finite Element Analysis Based on In Vivo HR-pQCT Images of the Distal Radius Is Associated With Wrist Fracture in Postmenopausal Women

BMD, bone microarchitecture, and bone mechanical properties assessed in vivo by finite element analysis were associated with wrist fracture in postmenopausal women.

Identification of Osteopenic Women at High Risk of Fracture: The OFELY Study†

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.

Apparent Pre- and Postmenopausal Bone Loss Evaluated by DXA at Different Skeletal Sites in Women: The OFELY Cohort

We measured the bone mineral density (BMD) at various skeletal sites (total body, hip, anteroposterior [AP] and lateral [lat] spine, and forearm) in a large population‐based cohort of women aged 31–89 years (the OFELY cohort), and results were analyzed according to age and postmenopausal years. A significant apparent bone loss was found before the menopause in cancellous bone, i.e., at the lat spine and Wards triangle (−10%; p < 0.05–0.001). Cross‐sectional analysis indicated that, after the menopause, apparent bone loss was accelerated within the 10 years following menopause, continued thereafter at all sites except the AP spine, and was again accelerated in elderly menopausal for more than 25 years. Between 30 and 80 years, BMD decreased by 15 to 44% (T score −1.6 to −3.4) according to the site. The amount of apparent bone loss was highest at the Wards triangle when expressed in percentage (44%) and at the mid‐ and distal radius when expressed in number of standard deviations from the peak bone mass (−3.4). As a result, the percentage of women classified as osteoporotic according to the World Heath Organization, i.e., with a T score ≤−2.5, varied substantially from site to site and was highest at the radius (37% and 46%) and lateral spine (25–31%), intermediate at the Wards triangle, AP spine, and whole body BMD, and lowest at the whole body bone mineral content, femoral neck, and trochanter (10–12%). In conclusion, this cross‐sectional but large study suggests that there is a moderate apparent premenopausal bone loss that occurs only at cancellous bone sites and that apparent bone loss is accelerated at most skeletal sites after the age of 75 years. Because of the highly variable coefficient of variation of the peak bone mass at various skeletal sites, the percentage of postmenopausal women identified as being osteoporotic varies widely according to the site of measurement.

Markers of Bone Turnover Predict Postmenopausal Forearm Bone Loss Over 4 Years: The OFELY Study

The ability of biochemical markers to predict the rate of postmenopausal bone loss is still controversial. To investigate this issue further, baseline levels of a panel of specific and sensitive biochemical bone markers were correlated to the rate of change of forearm bone mineral density (BMD) assessed by four measurements over a 4‐year period using dual‐energy X‐ray absorptiometry in a large population‐based prospective cohort of 305 women aged 50–88 years (mean 64 years), 1–38 years postmenopausal. In the whole population, higher baseline levels of bone formation (serum osteocalcin and serum type I collagen N‐terminal propeptide) and bone resorption markers (urinary N‐telopeptides; urinary and serum C‐telopeptides) were significantly associated with faster BMD loss (r = −0.19 to −0.30, p < 0.001), independently of age. In women within 5 years of menopause that have the highest rate of bone loss, the predictive value of bone markers was increased with correlation coefficients reaching 0.53. Women with an abnormally high bone turnover, i.e., with levels of bone markers at baseline 2 SD above the mean of premenopausal women, had a rate of bone loss that was 2‐ to 6‐fold higher than women with a low turnover (p = 0.01–0.0001) according to the marker. When the population was categorized according to quartiles of bone markers at baseline, a similar relationship between increased levels of bone markers and faster rate of bone loss was found (p = 0.008–0.0001). In the logistic regression model, the odds‐ratio of fast bone loss, defined as the rate of bone loss in the upper tertile of the population, was increased by 1.8‐ to 3.2‐fold for levels of biochemical markers in the high turnover group compared with levels within the premenopausal range, with, however, a limited value for identifying individual fast bone losers. We conclude that increased levels of some of the new biochemical markers of bone turnover are associated with greater radial bone loss. Because increased bone loss is associated with an increased risk of fracture, bone turnover markers may be useful to improve the prediction of the risk of osteoporosis in postmenopausal women.

Low serum IGF-1 and occurrence of osteoporotic fractures in postmenopausal women

The link between serum insulin-like growth factor 1 (IGF-1) and postmenopausal osteoporosis remains controversial. In this study of healthy postmenopausal women, decreased serum concentrations of IGF-1 were strongly associated with an increased risk of osteoporotic fractures independently of bone-mineral density.

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.

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 individuals 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 ≤ –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.