High Plasma Sphingosine 1-phosphate Levels Predict Osteoporotic Fractures in Postmenopausal Women: The Center of Excellence for Osteoporosis Research Study.

BACKGROUND: Higher sphingosine 1-phosphate (S1P) plasma levels are associated with decreased bone mineral density (BMD), and increased risk of prevalent vertebral fracture. So, we hypothesized that postmenopausal women with increased baseline plasma S1P levels have a greater risk for future incident fracture (osteoporosis-related fractures [ORFs]). METHODS: This study was conducted in a prospective longitudinal cohort of 707 women recruited in 2004 and followed up annually for a mean period of 5.2±1.3 years. They were postmenopausal (aged ≥50 years). The primary outcome measure was the time to the first confirmed ORF event using radiographs and/or a surgical report. RESULTS: The plasma S1P levels (µmol/L) were significantly higher in the women with incident fracture (7.23±0.79) than in those without ORFs (5.02±0.51; P<0.001). High S1P levels were strongly associated with increased fracture risk. After adjustment for age and other confounders, the hazard ratio (HR) was 6.12 (95% confidence interval [CI], 4.92-7.66) for each 1-standard deviation increase in plasma S1P levels. The women in the highest quartile of S1P levels had a significant increase in fracture risk (HR, 9.89; 95% CI, 2.83-34.44). Results were similar when we compared plasma S1P levels at the 1-year visit. CONCLUSIONS: The associations between plasma S1P levels and fracture risk were independent of BMD and other confounders. These findings demonstrate that high plasma S1P level at baseline and at years 1 to 5 is a strong and independent risk factor for future [ORFs] among postmenopausal women and could be a useful biomarker for fracture risk assessment in this population.

High serum sclerostin predicts the occurrence of osteoporotic fractures in postmenopausal women: the Center of Excellence for Osteoporosis Research Study.

Sclerostin regulates bone formation by inhibiting Wnt pathway signaling. Low circulating sclerostin levels cause high bone mass. We hypothesized that postmenopausal women with increased sclerostin levels have a greater risk for osteoporosis-related fractures. We examined the association between circulating sclerostin together with bone turnover markers and osteoporosis-related fracture risk in 707 postmenopausal women, in a population-based study with a mean follow-up period of 5.2 ± 1.3 years. Multivariate Cox proportional hazards regression models were used to analyze fracture risk, adjusted for age, body mass index, and other confounding risk factors. High sclerostin levels were strongly associated with increased fracture risk. After adjustment for age and other confounders, the relative fracture risk was more than sevenfold among postmenopausal women for each 1-SD increment increase in sclerostin level. Women in the highest quartile of sclerostin levels had about a 15-fold increase in fracture risk. Results were similar when we compared sclerostin at the 1-year visit to an average of two to three annual measurements. Fracture risk attributable to sclerostin levels was 56.6% in the highest quartile. Only high levels of bone resorption markers (plasma cross-linked C-terminal telopeptide of type 1 collagen [p-CTx], urinary CTx [u-CTx], and urinary N-telopeptide of type 1 collagen [u-NTx]) were predictive of osteoporosis-related fractures but at much lower hazard ratio (HR) values than that of serum sclerostin. Associations between sclerostin levels and fracture risk were independent of bone mineral density and other confounding risk factors. High sclerostin levels are a strong and independent risk factor for osteoporosis-related fractures among postmenopausal women. © 2012 American Society for Bone and Mineral Research.

Independent predictors of all osteoporosis-related fractures among healthy Saudi postmenopausal women: the CEOR Study.

This study was designed to identify independent predictors of all osteoporosis-related fractures (ORFs) among healthy Saudi postmenopausal women. We prospectively followed a cohort of 707 healthy postmenopausal women (mean age, 61.3±7.2 years) for 5.2±1.3 years. Data were collected on demographic characteristics, medical history, personal and family history of fractures, lifestyle factors, daily calcium intake, vitamin D supplementation, and physical activity score. Anthropometric parameters, total fractures (30.01 per 1000 women/year), special physical performance tests, bone turnover markers, hormone levels, and bone mineral density (BMD) measurements were performed. The final model consisted of seven independent predictors of ORFs: [lowest quartile (Q(1)) vs highest quartile (Q(4))] physical activity score (Q(1) vs Q(4): ≤12.61 vs ≥15.38); relative risk estimate [RR], 2.87; (95% confidence interval [CI]: 1.88-4.38); age≥60 years vs age<60 years (RR=2.43; 95% CI: 1.49-3.95); hand grip strength (Q(1) vs Q(4): ≤13.88 vs ≥17.28 kg) (RR=1.88; 95% CI: 1.15-3.05); BMD total hip (Q(1) vs Q(4): ≤0.784 vs 0.973 g/cm(2)) (RR=1.86; 95% CI: 1.26-2.75); dietary calcium intake (Q(1) vs Q(4): ≤391 vs ≥648 mg/day) (RR=1.66; 95% CI: 1.08-2.53); serum 25(OH)D (Q(1) vs Q(4): ≤17.9 vs ≥45.1 nmol/L) (RR=1.63; 95% CI: 1.06-2.51); and past year history of falls (RR=1.61; 95% CI: 1.06-2.48). Compared with having none (41.9% of women), having three or more clinical risk factors (4.8% of women) increased fracture risk by more than 4-fold, independent of BMD. Having three or more risk factors and being in the lowest tertile of T-score of [total hip/lumbar spine (L1-L4)] was associated with a 14.2-fold greater risk than having no risk factors and being in the highest T-score tertile. Several clinical risk factors were independently associated with all ORFs in healthy Saudi postmenopausal women. The combination of multiple clinical risk factors and low BMD is a very powerful indicator of fracture risk.