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Summary The use of areal bone mineral density (aBMD) for fracture prediction may be enhanced by considering bone microarchitectural deterioration. Trabecular bone score (TBS) helped in redefining a significant subset of non-osteoporotic women as a higher risk group. Introduction TBS is an index of bone microarchitecture. Our goal was to assess the ability of TBS to predict incident fracture. Methods TBS was assessed in 560 postmenopausal women from the Os des Femmes de Lyon cohort, who had a lumbar spine (LS) DXA scan (QDR 4500A, Hologic) between years 2000 and 2001. During a mean follow-up of 7.8 ± 1.3 years, 94 women sustained 112 fragility fractures. Results At the time of baseline DXA scan, women with incident fracture were significantly older (70 ± 9 vs. 65 ± 8 years) and had a lower LS_aBMD and LS_TBS (both −0.4SD, p  < 0.001) than women without fracture. The magnitude of fracture prediction was similar for LS_aBMD and LS_TBS (odds ratio [95 % confidence interval] = 1.4 [1.2;1.7] and 1.6 [1.2;2.0]). After adjustment for age and prevalent fracture, LS_TBS remained predictive of an increased risk of fracture. Yet, its addition to age, prevalent fracture, and LS_aBMD did not reach the level of significance to improve the fracture prediction. When using the WHO classification, 39 % of fractures occurred in osteoporotic women, 46 % in osteopenic women, and 15 % in women with T-score > −1. Thirty-seven percent of fractures occurred in the lowest quartile of LS_TBS, regardless of BMD. Moreover, 35 % of fractures that occurred in osteopenic women were classified below this LS_TBS threshold. Conclusion In conclusion, LS_aBMD and LS_TBS predicted fractures equally well. In our cohort, the addition of LS_TBS to age and LS_aBMD added only limited information on fracture risk prediction. However, using the lowest quartile of LS_TBS helped in redefining a significant subset of non-osteoporotic women as a higher risk group which is important for patient management.

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 β-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.

Summary We studied bone turnover markers (BTM) and bone microarchitecture (using high-resolution peripheral quantitative computed tomography (HR-pQCT)) in 171 postmenopausal women and their 210 premenopausal daughters. BTM levels correlated positively between mothers and daughters. The mother-daughter pairs with high BTM levels had lower cortical density than those with low BTM levels. Introduction We assessed the correlation of serum bone turnover markers (BTM) between postmenopausal mothers and their premenopausal daughters as well as possible determinants of this association and its impact on resemblance of bone microarchitecture between mothers and their daughters. Methods Cross-sectional analysis was performed in 171 untreated postmenopausal mothers (54 sustained fragility fractures) and their 210 premenopausal daughters. Intact N-terminal propeptide of type I collagen (PINP) and β-isomerized C-terminal crosslinking telopeptide of type I collagen (CTX-I) were measured in the fasting status. Bone microarchitecture was assessed using HR-pQCT. Results After adjustment for age, weight, lifestyle factors, hormones, and mother’s fracture status, BTM levels correlated positively between mothers and daughters (Intraclass Correlation Coefficient = 0.22–0.27, p <0.005). Average BTM levels were ∼0.6 SD higher among daughters of mothers in the highest BTM quartile vs. the ones in the lowest BTM quartile. The variability of BTM levels explained ≤10 and ≤14 % of variability of bone microarchitecture in the daughters and mothers, respectively. Cortical density was lower by 2.3–2.9 % (0.6 SD, p <0.05 to <0.005) in the daughters from the mother-daughter pairs with high BTM levels (defined by generation-specific quartiles) than in the daughters from the pairs with low BTM levels. Corresponding differences for the mothers were 4.5–4.8 % (0.5 SD, p <0.05 to <0.01). Conclusion BTM levels correlated between postmenopausal mothers and their premenopausal daughters after adjustment for age, weight, mother’s fracture status, lifestyle, and hormonal factors. Family resemblance of BTM levels may contribute to family resemblance of some bone microarchitectural parameters, especially of cortical density.

Physical activity has a major impact on bone density and on osteoporosis prevention. Sclerostin is produced by osteocytes and inhibits bone formation. The impact of exercise on sclerostin secretion has not been studied so far. This pilot study aimed to explore circulating sclerostin levels immediately after acute exercise. Healthy young women practicing physical activity less than 120 min per week were enrolled. The exercise was a 45-min, low-speed, treadmill running test. Blood samples were taken at rest before exercise and within 5 min after the end of exercise. We assessed serum creatinine, 25-OH vitamin D, alkaline phosphatase, C-telopeptide of type I collagen, bone-specific alkaline phosphatase, and sclerostin. Sclerostin stability at rest was also validated over the same period of time among women fulfilling the same inclusion criteria. The study included 23 participants (mean ± SD age: 22.9 ± 1.5 years) for the exercise test and 9 participants for the resting test (26.1 ± 3.1 years). There was no difference in body mass index between the two groups. Sclerostin increased after exercise in comparison to baseline (mean ± SEM: 410 ± 27 vs. 290 ± 19 pg/mL; p  < 0.001) corresponding to an increase of +44.3 ±5.5%. In the resting test, sclerostin remained stable (303 ± 20 vs. 294 ± 20 pg/mL, p  = 0.76). There was a substantial increase in serum sclerostin in untrained healthy young women immediately after physical activity. These results suggest the existence of an acute release of systemic sclerostin in response to physical activity.

Summary In older men, severe abdominal aortic calcification and vertebral fracture (both assessed using dual-energy X-ray absorptiometry) were positively associated after adjustment for confounders including bone mineral density. Introduction Abdominal aortic calcification (AAC) is associated with higher fracture risk, independently of low bone mineral density (BMD). Dual-energy X-ray absorptiometry (DXA) can be used to assess both vertebral fracture and AAC and requires less time, cost, and radiation exposure. Methods We conducted a cross-sectional study of the association between AAC and prevalent vertebral fractures in 901 men ≥50 years old. We used DXA (vertebral fracture assessment) to evaluate BMD, vertebral fracture, and AAC. Results Prevalence of vertebral fracture was 11 %. Median AAC score was 1 and 12 % of men had AAC score >6. After adjustment for age, weight, femoral neck BMD, smoking, ischemic heart disease, diabetes, and hypertension, AAC score >6 (vs ≤6) was associated with 2.5 (95 % CI, 1.4–4.5) higher odds of vertebral fracture. Odds of vertebral fracture for AAC score >6 increased with vertebral fracture severity (grade 1, OR  = 1.8; grade 2, OR  = 2.4; grade 3, OR  = 4.4; trend p  < 0.01) and with the number of vertebral fractures (1 fracture, OR  = 2.0, >1 fracture, OR = 3.5). Prevalence of vertebral fracture was twice as high in men having both a T-score < −2.0 and an AAC score > 6 compared with men having only one of these characteristics. Conclusions Men with greater severity AAC had greater severity and greater number of vertebral fractures, independently of BMD and co-morbidities. DXA can be used to assess vertebral fracture and AAC. It can provide a rapid, safe, and less expensive alternative to radiography. DXA may be an important clinical tool to identify men at high risk of adverse outcomes from osteoporosis and cardiovascular disease.

Bone loss before and around the time of menopause is not well characterized by longitudinal studies. We measured bone mineral density at various skeletal sites--total body, femoral neck, trochanter, anteroposterior (AP) and lateral spine, and forearm--with dual-energy X-ray absorptiometry in a large prospective cohort of 272 untreated pre- and perimenopausal women aged 31-59 years, at 1 year intervals for 3 years. Sex steroids and the following markers of bone remodeling were measured: serum osteocalcin (OC), procollagen I carboxyterminal extension peptide, bone alkaline phosphatase (BAP) and urinary crosslinks (CTX and NTX). Seventy-six women were classified as perimenopausal and 196 as premenopausal. Over the 3 years, premenopausal women had no significant bone loss at any site and a small but significant increase in bone mineral density at the trochanter, total hip, AP spine and radius. Perimenopausal women significantly lost bone from cancellous and cortical sites, i.e., the femoral neck, trochanter and lumbar spine. In perimenopausal women with increased follicle stimulating hormone, the rate of bone loss at the femoral neck correlated negatively with OC and BAP. In perimenopausal women, serum estradiol levels decreased during the 3 years of follow-up and bone loss from the trochanter and the AP spine was correlated with serum estradiol after 3 years. In conclusion, among premenopausal women there is no bone loss. In contrast, there is a rapid and diffuse bone loss in perimenopausal women, related to decreased estrogen secretion. Bone markers may be useful to identify these women losing bone.

BackgroundMicroRNAs (miRs) have emerged as pivotal epigenetic key actors of gene regulation and several miRs have been shown to be at the crossroads of angiogenesis and of bone turnover, taking part in the calcification process by acting on osteoblasts and osteoclasts.1 Calcification of the aortic media is highly regulated and involves numerous factors, including calcium deposal and other bone remodelling factors.2 ObjectivesThe objective of this study was to find a signature of miRs linked both to osteoporotic fracture risk and abdominal aortic calcification (AAC).The first outcome was the link between miRs levels at baseline and incident osteoporotic fractures (IOF) during 20 years; the second outcome was the link between miRs levels at baseline and the increase in AAC during 17 years.MethodsPost-menopausal women older than 50 years from the OFELY cohort (Os des FEmmes de LYon) were selected if they had available serums at inclusion, and available data for each outcome.3 miRs selected after literature review because of their impact on vascular calcification and bone turnover (miRs 26a-5p, 34a-5p, and 223–5 p) were measured at baseline. Bioassays of miRs was conducted with miRCURY Biofluids (Exiqon) extraction kit, TaqMan Life Technologies protocol, and QuantStudio 7 flex (Applied Biosystems) for RNA quantification. Results are expressed by relative quantification of Cycle threshold (Ct).ResultsA sample of 434 age-matched women (63 [57–72] years old), 50% with incident osteoporotic fracture during the 20 years of follow-up, was included. 183 women had available data to explore AAC; 93 had an increase in Kauppila score in 17 years (58 [55–61] years old), 90 did not (55 [53–58] years old).No significant link was underlined between miRs and IOF (miR-26: 1.06 [0.85–1.27] vs 0.99 [0.85–1.17], p=0.07; miR-34: 1.15 [0.53–1.87] vs 1.26 [0.60–2.07], p=0.35; miR-223: 1.01 [0.68–1.43] vs 1 0.05 [0.72–1.56], p=0.32).No miR was significantly linked to an increase in AAC (miR-26: 1.09 [0.94–1.28] vs 1.10 [0.89–1.30], p=0.95; miR-34: 0.78 [0.46–1.21] vs 0.73 [0.38–1.50], p=0.90; miR-223: 0.97 [0.69–1.22] vs 0.78 [0.56–1.22], p=0.11).ConclusionsNo association was observed between the 3 tested miRs and IOF or increase in AAC. Larger studies are necessary to select interesting epigenetic pathways reproductible on wider population.References[1] Krzeszinskia JY, Wei W, Huynh H, Jin Z, Wang X, Chang T-C, et al. miR-34a Blocks Osteoporosis and Bone Metastasis by Inhibiting Osteoclastogenesis and Tgif2. Nature2014Aug 28;512(7515):431.[2] Szulc P. Abdominal aortic calcification: A reappraisal of epidemiological and pathophysiological data. Bone2016Mar;84:25–37.Disclosure of InterestNone declared

BackgroundSystemic sclerosis (SSc) is a rare autoimmune disorder characterised by a vascular and fibrosing involvement of the skin and internal organs. Data about the association between systemic sclerosis (SSc) and osteoporosis (OP) are controversial and scarce about the risk factors of OP in SSc.1,2 ObjectivesThe aim of the study was to determine the OP frequency in SSc and assess its risk factors.MethodsIn a prospective cohort of SSc patients, usual risk factors of OP were assessed, as well as SSc organ involvements: pulmonary, cardiac, skin and renal involvements and SSc treatments. All patients underwent dual energy X-ray absorptiometry: bone mineral density (BMD) was measured at the lumbar spine (LS), femoral neck (FN) and total hip (TH). Osteoporosis was defined as having a T-score inferior to −2.5.ResultsForty-eight patients were included with a median age of 60 years,27–81 41 women (85.4%), with a diffuse cutaneous subtype in 13 cases (27.1%) and illness duration of 12.6 years (0.3–41.1). Average BMD was 0.98±0.21 in LS, 0.84±0.13 in FN and 0.86±0.15 in TH. OP was found in 19 patients (40%). Among patients with OP, an associated auto-immune disorder was found in 13 patients (68.4%) versus 10 (34.5%) in the non-OP group (p=0.04), digestive sub-occlusion in 4 patients (21% versus 0 patients, p=0.02), and chronic liver disease in 6 patients (31.6%) versus 2 (6.9%, p=0.04). Respiratory explorations found a DLCO of 12.7 (6.8–17.2) versus 15.6 (9.6–32.2) (p=0.007), a CVF of 2.47 (1.1–4) versus 3 (1.7–5.9) (p=0.03). DAS28-CRP was significantly higher (2.29 (1,53–4.46) in the OP group versus 1.86 (0–3.8) in the non-OP group, p=0.02); with a higher frequency of hand X-ray erosions (6 OP patients (31.6%) versus 2 (6.9%), p=0.04). No difference was found in Rodnan score, SSc subtype, illness duration, malnutrition, treatments (proton pump inhibitors, cyclophosphamide, steroids), autoantibodies profile; nor with the usual OP risk factors: age, smoking, personal or family history of OP fractures, alcohol consumption, weight, BMI, long term steroid treatment, early menopause and thyroid disease. No difference in serum vitamin D, calcium, thyroid hormones and C-reactive protein levels was found between OP and non-OP groups.ConclusionsOsteoporosis was associated with SSc-related factors such as: articular, digestive and respiratory involvements, and associated auto-immune diseases. Usual OP risk factors where not significantly different between osteoporotic SSc patients and non-osteoporotic patients.References[1] Caimmi C, Caramaschi P, Barausse G, Orsolini G, Idolazzi L, Gatti D, et al. Bone Metabolism in a Large Cohort of Patients with Systemic Sclerosis. Calcif Tissue Int. 2016Jul 1;99(1):23–9.[2] Omair MA, Pagnoux C, McDonald-Blumer H, Johnson SR. Low bone density in systemic sclerosis. A systematic review. J Rheumatol. 2013Nov;40(11):1881–90.Disclosure of InterestNone declared

Summary We investigated the familial resemblance of bone microarchitecture parameters between postmenopausal mothers with fragility fracture and their premenopausal daughters using high-resolution peripheral quantitative computed tomography (HR-pQCT). We found that daughters of women with fracture have lower total volumetric bone mineral density (vBMD), thinner cortices, and impaired trabecular microarchitecture at the distal radius and tibia, compared to controls. Introduction Familial resemblance of areal bone mineral density (aBMD) in mothers and daughters has been widely studied, but not its morphological basis, including microarchitecture. Methods We compared aBMD, vBMD, bone size, and bone microarchitecture at the distal radius and tibia assessed by HR-pQCT in mothers and their premenopausal daughters. We included 115 women aged 43 ± 8 years whose mothers had sustained a fragility fracture and 206 women aged 39 ± 9 years whose mothers had never sustained a fragility fracture. Results Women whose mothers had fracture had significantly ( p  < 0.05) lower aBMD at the lumbar spine, total hip, femoral neck, mid-distal radius, and ultradistal radius compared to controls. In similar multivariable models, women whose mothers had a fracture had lower total vBMD at the distal radius (−5 %, 0.3 standard deviation [SD]; p  < 0.005) and distal tibia (−7 %, 0.4 SD; p  < 0.005). They also had lower cortical thickness and area at the distal radius (−5 %, 0.3 SD and −4 %, 0.2 SD, respectively; p  < 0.005) and at the distal tibia (−6 %, 0.3 SD and −4 %, 0.3SD, respectively; p  < 0.005). Trabecular vBMD was lower at the distal radius (−5 %, 0.3 SD; p  < 0.05) and tibia (−8 %, 0.4 SD; p  < 0.005), with a more spaced and heterogeneous trabecular network (4 and 7 % at the radius and 5 and 9 %, at the tibia, p  < 0.05, for Tb.Sp and Tb.Sp.SD, respectively). Conclusion Premenopausal daughters of women who had sustained fragility fracture have lower total and trabecular vBMD, thinner cortices, as well as impaired trabecular microarchitecture at the distal radius and tibia, compared with premenopausal daughters of women without fracture.

Summary The aim of the study was to investigate prospectively whether the levels of urinary pentosidine could predict fractures in postmenopausal women from the OFELY cohort. The results of the study suggest that urine pentosidine concentration is not an independent risk factor for fractures in postmenopausal women from a French cohort. Introduction Pentosidine has been described as an independent risk factor for hip and vertebral fracture in postmenopausal Japanese women. We investigated the prediction of urinary pentosidine on all fragility fracture risk in healthy untreated postmenopausal women from the OFELY cohort. Methods Urinary pentosidine was assessed at baseline in 396 healthy untreated postmenopausal women aged 63.3 ± 8.4 years from the OFELY cohort using high-performance liquid chromatography method. Incident clinical fractures were recorded during annual follow-up and confirmed by radiographs, and vertebral fractures were assessed on radiographs performed every 4 years. Multivariate Cox’s regression analysis was used to calculate the risk of urinary pentosidine levels after adjustment for age, prevalent fractures, and total hip bone mineral density (BMD). Results During a mean follow-up of 10 years, 88 of the 396 postmenopausal women have undergone incident vertebral ( n  = 28) and peripheral ( n  = 60) fractures. Fracture risk was higher in postmenopausal women with pentosidine in the highest quartile ( p  = 0.02), but it did not remain significant after adjustment for age, BMD, and prevalent fracture. Conclusions Urine pentosidine concentration is not an independent risk factor of osteoporotic fracture in healthy postmenopausal women from the OFELY cohort.