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.

Lycopene treatment against loss of bone mass, microarchitecture and strength in relation to regulatory mechanisms in a postmenopausal osteoporosis model.

Lycopene supplementation decreases oxidative stress and exhibits beneficial effects on bone health, but the mechanisms through which it alters bone metabolism in vivo remain unclear. The present study aims to evaluate the effects of lycopene treatment on postmenopausal osteoporosis. Six-month-old female Wistar rats (n=264) were sham-operated (SHAM) or ovariectomized (OVX). The SHAM group received oral vehicle only and the OVX rats were randomized into five groups receiving oral daily lycopene treatment (mg/kg body weight per day): 0 OVX (control), 15 OVX, 30 OVX, and 45 OVX, and one group receiving alendronate (ALN) (2µg/kg body weight per day), for 12weeks. Bone densitometry measurements, bone turnover markers, biomechanical testing, and histomorphometric analysis were conducted. Micro computed tomography was also used to evaluate changes in microarchitecture. Lycopene treatment suppressed the OVX-induced increase in bone turnover, as indicated by changes in biomarkers of bone metabolism: serum osteocalcin (s-OC), serum N-terminal propeptide of type 1 collagen (s-PINP), serum crosslinked carboxyterminal telopeptides (s-CTX-1), and urinary deoxypyridinoline (u-DPD). Significant improvement in OVX-induced loss of bone mass, bone strength, and microarchitectural deterioration was observed in lycopene-treated OVX animals. These effects were observed mainly at sites rich in trabecular bone, with less effect in cortical bone. Lycopene treatment down-regulated osteoclast differentiation concurrent with up-regulating osteoblast together with glutathione peroxidase (GPx) catalase (CAT) and superoxide dismutase (SOD) activities. These findings demonstrate that lycopene treatment in OVX rats primarily suppressed bone turnover to restore bone strength and microarchitecture.

Risk factors for falls in a longitudinal cohort study of Saudi postmenopausal women: the Center of Excellence for Osteoporosis Research Study.

OBJECTIVE: This study aims to identify possible risk factors for falls among Saudi postmenopausal women in a population-based study. METHODS: Seven hundred seven postmenopausal women aged 50 years or older were followed in a prospective cohort study. Participant demographic characteristics, medical history, lifestyle factors, past-year history of falls, and physical activity (PA) scores were assessed. We recorded single and multiple falls, anthropometric parameters, five special physical performance tests, hormone levels, and bone mineral density measurements. Data on knee osteoarthritis (OA), lumbar spondylosis, and osteopenia were collected. Knee and lower back pain were assessed by interview, and cognition was assessed with Mini-Mental State Examination. RESULTS: During the mean (SD) follow-up of 5.2 (1.3) years, 164 women (23.2%) reported at least one fall, of whom 73 women (10.3%) reported multiple falls. Six independent predictors of all falls were identified: PA score of 12.61 or lower (lowest quartile; odds ratio [OR], 4.10; 95% CI, 1.82-8.90); past-year history of falls (OR, 2.44; 95% CI, 2.30-2.90); age 65 years or older (OR, 2.16; 95% CI,1.30-3.12); presence of knee OA (OR, 1.56; 95% CI,1.03-2.34); handgrip strength of 13.88 kg or lower (lowest quartile; OR, 1.33; 95% CI,1.09-1.64); and 8-ft walk test of 3.94 s or longer (highest quartile; OR, 1.18; 95% CI, 1.07-1.35). CONCLUSIONS: Poor PA score, past-year history of falls, age 65 years or older, presence of knee OA, poor handgrip strength, and prolonged time on the 8-ft walk test are risk factors for all falls among Saudi postmenopausal women.

Increased serum sclerostin and decreased serum IGF-1 are associated with vertebral fractures among postmenopausal women with type-2 diabetes.

Insulin-like growth factor 1 (IGF-1) is a determinant of bone mass and is inversely associated with vertebral fractures (VFs). Sclerostin regulates bone formation by inhibiting Wnt/ß-catenin signaling. Currently, there is little information on circulating sclerostin levels among postmenopausal women with type-2 diabetes mellitus (T2DM) with VFs in relation to serum IGF-1 (s-IGF-1). We investigated the relationships between serum sclerostin, s-IGF-1, and VFs in postmenopausal women with T2DM. We assessed cross-sectionally 482 postmenopausal women with T2DM and 482 age-matched postmenopausal women without T2DM who were recruited at diabetic clinics and primary health care centers for inclusion in a bone health survey. The main outcome measures were serum sclerostin, s-IGF-1, bone mineral density (BMD), and bone turnover markers. Lateral X-rays of the thoracic and lumbar spine were taken to diagnose VFs. Serum sclerostin levels were increased, whereas s-IGF-1 levels were decreased when T2DM women were stratified by the number of VFs (P<0.0001). Multiple logistic regression analysis showed that serum sclerostin levels were positively associated with 1 VF (odds ratio [OR]=1.27, (95% CI:1.01-2.03), P=0.016), 2 VFs (OR=1.41, (95% CI:1.03-2.36), P=0.006), and ≥3 VFs (OR=1.54, (95% CI:1.12-2.44) P=0.005). s-IGF-1 levels were inversely associated with 1 VF (OR=0.58, (95% CI:0.39-0.88), P=0.041), 2 VFs (OR=0.42, (95% CI:0.21-0.90), P=0.012), and ≥3 VFs (OR=0.19, (95% CI: 0.14-0.27), P<0.001). Increased serum sclerostin and decreased s-IGF-1 were associated with VFs among postmenopausal women with T2DM, suggesting that sclerostin and/or IGF-1 may be involved in increased bone fragility in T2DM and could be potential markers of VF severity.

Physical activity in relation to serum sclerostin, insulin-like growth factor-1, and bone turnover markers in healthy premenopausal women: a cross-sectional and a longitudinal study.

CONTEXT: There is limited information on the effects of mechanical loading caused by physical activity (PA) on sclerostin, IGF-I, and bone turnover markers (BTM). OBJECTIVE: The objective of the investigation was to study the relationships between serum sclerostin, serum-IGF-I (s-IGF-I), BTM, and the PA level in premenopausal women and to discern how 8 wk of PA training (PAT) affects the serum levels of sclerostin, IGF-I, and BTM. DESIGN: This was a cross-sectional study with a subgroup followed up longitudinally. SETTINGS AND SUBJECTS: A total of 1235 randomly selected premenopausal women were cross-sectionally studied. We also followed up 58 of these women longitudinally during an 8-wk course of PAT (4 d/wk) and compared them with 62 controls. All women were medically examined, and bone mineral density (BMD) and serum levels of sclerostin, s-IGF-I, and BTM were determined. RESULTS: Women with PA of greater than 120 min/wk showed significantly lower serum sclerostin (by 36.8%) but higher s-IGF-I (by 107%) levels than sedentary controls. Bone formation markers were also higher in the PA greater than 120 min/wk group compared with the sedentary controls. In the longitudinal study, the 8-wk PAT program led to a decrease in serum sclerostin (by 33.9%, P<0.0001) but increases in the serum levels of the bone-formation markers and IGF-I (s-IGF-I by 74.2%, P<0.0001). CONCLUSIONS: This study demonstrates that even minor changes in PA are associated with effects on serum levels of sclerostin, IGF-I, and BTM and suggests that sclerostin could be a link between mechanical loading and disuse osteoporosis in humans.

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.

Determinants of serum sclerostin in healthy pre- and postmenopausal women.

Sclerostin is a secreted Wnt antagonist produced almost exclusively by osteocytes that regulates bone mass. However, there is currently limited information on the determinants of sclerostin in a large population-based study. The main objectives of the present study were to: (1) establish reference normative interval values for serum sclerostin in randomly selected healthy premenopausal women; (2) study the changes in serum sclerostin in relation to age in premenopausal and postmenopausal women and the factors that may influence bone turnover; and (3) determine the effect of menopausal status on serum sclerostin. A total of 1803 women were studied (including [n = 1235] premenopausal, and [n = 568] postmenopausal women, respectively, aged 20 to 79 years). A total of 443 healthy premenopausal women (aged 35 to 45 years) were used to establish reference normative intervals for serum sclerostin. All women studied were medically examined and had their bone mineral density values obtained for the lumbar spine (L(1) -L(4) ) and femoral neck according to a detailed inclusion criteria. In all women, values of serum sclerostin increased with increasing age up to the age of 45 years, and remained increased in postmenopausal women. Significant increases were evident in serum sclerostin in postmenopausal women with increasing years since menopause. Using stepwise multiple linear regression analysis, several variables were identified as determinants of serum sclerostin, including age, parathyroid hormone, estradiol (E(2)), and follicle-stimulating hormone (FSH) for premenopausal women; age, FSH, and E(2) for postmenopausal women; and age, serum osteocalcin, FSH, and E(2) in the entire sample studied. Further studies are needed to establish the potential role of this increase in mediating the known age-related impairment in bone formation.

Reference intervals of biochemical bone turnover markers for Saudi Arabian women: a cross-sectional study.

Biochemical bone turnover markers (BTMs) provide important information on the diagnosis, therapy and monitoring of metabolic bone diseases including osteoporosis. One goal of antiresorptive therapy in women is to decrease biochemical BTMs to the lower half of reference intervals for healthy pre-menopausal counterparts, using newly developed automated assays of such markers. The main objectives of the present study were to: (1) establish reference interval values for the following biochemical BTMs: serum osteocalcine (s-OC), bone alkaline phosphatase (s-bone ALP), procollagen type 1 N-terminal propeptide (s-PINP), crosslinked C-terminal telopeptide of Type 1 collagen (s-CTX), tartarate-resistant acid phosphatase isoform 5b (s-TRACP-5b) and urinary: CTX (u-CTX), N-telopeptides of type 1 collagen (u-NTX), pyridinoline (u-PYD) and deoxypyridinoline (u-DPD) in randomly selected Saudi healthy pre-menopausal women; (2) study the changes in biochemical BTMs in relation to age in pre- and post-menopausal women and the factors reported to influence bone turnover and (3) determine the effect of menopausal status on BTMs. A total of 2125 women were studied [including (n=1557) pre-, and (n=568) post-menopausal women, respectively, aged 20-79 years]. A total of 765 healthy pre-menopausal women (aged 35-45 years) were used to establish reference intervals for biochemical BTMs. All women studied were medically examined and had their bone mineral density (BMD) values obtained for the lumbar spine (L(1)-L(4)) and femoral neck according to detailed inclusion criteria. In all women, values of biochemical BTMs, decreased with increasing age up to the age of 45 years, increased steeply among women in their 50s and remained increased in post-menopausal women. Significant increases were evident in all biochemical BTMs in post-menopausal women with >5 years since menopause with the exception of s-OC, u-DPD, and u-PYD. Using stepwise multiple linear regression analysis, several variables were identified (depending on the BTM) as determinants of BTMs including age, BMI, parity, FSH, LH, PTH, s-Ca, s-Mg, s-PO(4) and 25(OH)D. In the reference intervals group, there are no significant correlations between any of the biochemical BTMs and age of menarche, day of menstrual cycle, physical activity, total daily dietary calcium and caffeine intakes and parity. It is recommended that the age range 35-45 years should be used when establishing biochemical BTMs reference intervals in Saudi Arabian pre-menopausal women.

Maternal serum free-beta-chorionic gonadotrophin, pregnancy-associated plasma protein-A and fetal nuchal translucency thickness at 10-13(+6) weeks in relation to co-variables in pregnant Saudi women.

OBJECTIVE: To establish normative values and distribution parameters of first-trimester screening markers, namely, fetal nuchal translucency (NT), maternal serum free beta-human chorionic gonadotrophin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A), at 10 to 13(+6) weeks of gestation in Saudi women and to evaluate the effect of co-variables including maternal body weight, gravidity, parity, fetal gender, twin pregnancy, smoking and ethnicity on these markers. METHODS: A cohort of Saudi women (first cohort n = 1616) with singleton pregnancies prospectively participated in the present study, and fetal NT together with maternal serum free beta-hCG and PAPP-A were determined at 10 to 13(+6) weeks of gestation. The distribution of gestational age-independent multiples of the median (MoM) of the parameters was defined and normative values were established, and correction for maternal body weight was made accordingly. The influence of various co-variables was examined using the data collected from the first and the second (n = 1849) cohorts of women and 62 twin pregnancies, and compared with other studies. RESULTS: All markers exhibited log-normally distributed MoMs. Gestational age-independent normative values were established. Maternal body weight was corrected, particularly for maternal free beta-hCG and PAPP-A using standard methods. Fetal NT showed a negative relationship with increasing gravidity (r = -0.296) or parity (r = -0.311), whereas both free beta-hCG and PAPP-A exhibited a significant positive relationship. There was a significant increase in the MoM of free beta-hCG in female fetuses. Smoking decreased MoM values of free beta-hCG (by 14.6%; P < 0.01) and PAPP-A (by 18.8%; P < 0.001). Twin pregnancy showed significant increases in MoM values of free beta-hCG (by 1.87-fold) and PAPP-A (by 2.24-fold), with no significant changes in fetal NT MoM values. Fetal NT MoM values were lower in Africans and Asians but higher in Orientals, as compared to Saudi women (P < 0.05; in each case). MoM values (body weight-corrected) of free beta-hCG were 25.2% higher in Africans and 19.4% higher in Orientals but 6.8% lower in other Arabian and Asian (by 5.8%) women as compared to Saudi women (P < 0.05; in each case). CONCLUSIONS: The normative values and distribution parameters for fetal NT, maternal serum free beta-hCG and PAPP-A were established in Saudi singleton pregnancies, the maternal body weight together with smoking, twin pregnancy and ethnicity being important first-trimester screening co-variables. Gravidity, parity and fetal gender are also considered to influence one or more of the first-trimester markers examined.

Influence of age, sex, folate and vitamin B12 status on plasma homocysteine in Saudis.

OBJECTIVE: To evaluate the reference intervals for fasting total plasma homocysteine concentrations in Saudi healthy males and females in relation to age, sex and the nutritional status of folate and vitamin B12. METHODS: A prospective study was conducted on randomly selected Saudi healthy males (n=642) and females (n=784) living in the Jeddah area, Kingdom of Saudi Arabia. Plasma homocysteine together with serum folate and plasma vitamin B12 concentrations were determined. Analysis of variance was used to examine differences among various groups according to age, sex or folate, or both or vitamin B12 status for different variables. Correlations were carried out using multiple linear regression analysis. RESULTS: Reference intervals for plasma homocysteine concentrations in Saudi healthy males and females (age 20 -69 years) was documented. The age-adjusted geometric mean of plasma homocysteine concentration was significantly greater in males (9.91 micromol/L) than in females (8.08 micromol/L) (P<0.0001). In both males and females, values for serum folate and plasma vitamin B12 concentrations significantly and negatively correlated with plasma homocysteine concentrations (P<0.000). Serum total cholesterol showed significant positive correlations with plasma homocysteine in both males (r=0.448, P<0.000) and females (r=0.313; P < 0.000). Diastolic (r= 0.182; P<0.001) and systolic (r=0.309; P < 0.000) blood pressure values showed significant positive correlations with plasma homocysteine concentrations in females only. Stepwise multiple linear regression analysis showed that in both males and females, age, sex, serum folate, and waist-to-hip ratio and plasma vitamin B12 were significant determinants of plasma homocysteine concentrations. CONCLUSION: The first data on plasma homocysteine concentrations in Saudi healthy males and females are reported. Age and sex differences were confirmed and a significant inverse relationship between plasma homocysteine concentrations and that of serum folate and plasma vitamin B12 was observed. Various independent variables including age, sex, serum folate, waist-to-hip ratio and plasma vitamin B12 contributed to the changes in plasma homocysteine. Plasma homocysteine concentrations should be evaluated in patients at risk for cardiovascular and other related diseases in the Saudi population.