Plasma Sclerostin Levels Research Articles

#3205 A 2-YEAR STUDY FOR CHANGE OF PLASMA BIOMARKERS INCLUDING LARGER MIDDLE MOLECULES IN DIALYTIC PATIENTS USING DIALYZERS WITH MEDIUM CUT-OFF MEMBRANES

Abstract Background and Aims Uremic toxins with middle molecular weight usually develop uremic symptoms. The larger middle molecules are regarded as causative molecules of uremic symptoms. Medium cut-off (MCO) membrane newly developed can remove larger middle molecules which can be not removed through high flux membrane and hemodiafiltration. Larger middle molecules are mainly related to cardiovascular complications. Therefore, long-term use of MCO membrane may have beneficial effects in dialytic patients, in terms of lowering concentrations of larger middle molecules associated with cardiovascular complications. Now, we report interesting 2-year results of long-term use of MCO membrane in dialytic patients. Method Thirty-four patients undergoing hemodialysis were prospectively analyzed during 24 months. We randomly divided enrolled patients into two groups: control and MCO group. Patients in the control group used dialyzer with high flux membrane and patients in MCO group used MCO membrane. We measured plasma levels of biomarkers with 3 or 6-month to investigate efficacy of the MCO membrane for small (3-month interval) to larger middle molecules (6-month interval). Particularly, we performed comparative analysis with larger middle molecules in both groups. We calculated reduction ratio of biomarkers per one session at 24-month. Results The levels of larger middle molecules at baseline did not show significant difference between two groups. However, compared with the control group, plasma sclerostin levels at 6-month and 12-month in MCO group did not increased significantly compared to baseline levels. Plasma sclerostin were lower in MCO group throughout 2 year, but the significant difference of plasma sclerostin levels between two groups unfortunately disappeared after 12 months. The levels of other biomarkers including FGF23, leptin and GDF15, also did not show significant difference between two groups. However, β2MG levels in MCO group compared to control group decreased significantly throughout 2 years (MCO group: 18-month, p = 0.01 and 24-month, p <0.001, respectively; control group: 18-month, p = 0.003 and 24-month, p <0.067, respectively). Interestingly, even in MCO group, there was no statically significant decrease in total protein and albumin levels after 24 months (p = 0.429 and p = 0.101, respectively) (Figure 1). The reduction ratio of larger middle molecules compared to small molecules per one session prominently increased in MCO group (sclerostin, p < 0.001; GDF15, p <0.001; FGF23, p <0.01; RBP4, p <0.01; phosphate, p = 0.821; calcium, p = 0.827; CRP, p = 0.729 and β2MG, p = 0.286, respectively) (Figure 2). Conclusion Conclusively, in MCO group, the significant change of plasma sclerostin associated with cardiovascular complications after 12 months disappeared. However, in MCO group compared to control group, there was a continuous decrease of β2MG and RBP4 throughout study period. In addition, the clearance of larger middle molecules is also prominently high in MCO group. Interestingly, there were also no significant differences of albumin between 24-month and baseline in MCO group. Therefore, the MCO membrane can be a good tool for controlling uremic symptoms or sings without protein loss even when used for a relatively long time in dialytic patients.

Etelcalcetide controls secondary hyperparathyroidism and raises sclerostin levels in hemodialysis patients previously uncontrolled with cinacalcet

IntroductionThere is scarce clinical experience with etelcalcetide in patients with secondary hyperparathyroidism uncontrolled with cinacalcet. The effect of etelcalcetide on serum sclerostin levels remains to be clarified. Materials and methodsProspective cohort study in prevalent hemodialysis patients with uncontrolled sHPT under cinacalcet for at least 3 months, mean parathyroid hormone (PTH)>800pg/mL and calcium (Ca)>8.3mg/dL. Etelcalcetide 5mg IV/HD was initiated after cinacalcet washout. Levels of PTH, Ca, and phosphorus (Pi) followed monthly for 6 months. Plasma sclerostin levels measured before etelcalcetide treatment and after 6 months. ResultsThirty-four patients were enrolled, 19 (55.9%) male gender. Mean age 60.7 (± 12.3) years; median time on HD 82.5 (7–296) months and median cinacalcet dose was 180mg/week (Interquartile Range: 180–270).Serum Ca, Pi and PTH levels showed a significant reduction after etelcalcetide treatment from 8.8mg/dL, 5.4mg/dL and 1005pg/mL to 8.1mg/dL (p=0.08), 4.9mg/dL (p=0.01) and 702pg/mL (p<0.001), respectively. Median etelcalcetide dose remained at 5mg/HD. Plasma sclerostin concentration increased from 35.66pmol/L (IQR11.94–54.58) to 71.05pmol/L (IQR54.43–84.91) (p<0.0001). ConclusionEtelcalcetide improved sHPT control in this group of patients, previously under cinacalcet treatment, and significantly increased plasma sclerostin concentration. The impact of etelcalcetide treatment on sclerostin levels is a novel finding.

Subcutaneous adipose tissue sclerostin is reduced and Wnt signaling is enhanced following 4-weeks of sprint interval training in young men with obesity.

Sclerostin is a Wnt/β‐catenin antagonist, mainly secreted by osteocytes, and most known for its role in reducing bone formation. Studies in rodents suggest sclerostin can also regulate adipose tissue mass and metabolism, representing bone–adipose tissue crosstalk. Exercise training has been shown to reduce plasma sclerostin levels; but the effects of exercise on sclerostin and Wnt/β‐catenin signaling specifically within adipose tissue has yet to be examined. The purpose of this study was to examine subcutaneous WAT (scWAT) sclerostin content and Wnt signaling in response to exercise training in young men with obesity. To this end, 7 male participants (BMI = 35 ± 4; 25 ± 4 years) underwent 4 weeks of sprint interval training (SIT) involving 4 weekly sessions consisting of a 5‐min warmup, followed by 8 × 20 s intervals at 170% of work rate at VO2peak, separated by 10 s of rest. Serum and scWAT were sampled at rest both pre‐ and post‐SIT. Despite no changes in serum sclerostin levels, we found a significant decrease in adipose sclerostin content (−37%, p = 0.04), an increase in total β‐catenin (+52%, p = 0.03), and no changes in GSK3β serine 9 phosphorylation. There were also concomitant reductions in serum TNF‐α (−0.36 pg/ml, p = 0.03) and IL‐6 (−1.44 pg/ml, p = 0.05) as well as an increase in VO2peak (+5%, p = 0.03) and scWAT COXIV protein content (+95%, p = 0.04). In conclusion, scWAT sclerostin content was reduced and β‐catenin content was increased following SIT in young men with excess adiposity, suggesting a role of sclerostin in regulating human adipose tissue in response to exercise training.

Etelcalcetide controls secondary hyperparathyroidism and raises sclerostin levels in hemodialysis patients previously uncontrolled with cinacalcet

IntroductionThere is scarce clinical experience with etelcalcetide in patients with secondary hyperparathyroidism uncontrolled with cinacalcet. The effect of etelcalcetide on serum sclerostin levels remains to be clarified. Materials and methodsProspective cohort study in prevalent hemodialysis patients with uncontrolled sHPT under cinacalcet for at least 3 months, mean parathyroid hormone (PTH)>800pg/mL and calcium (Ca)>8.3mg/dL. Etelcalcetide 5mg IV/HD was initiated after cinacalcet washout. Levels of PTH, Ca, and phosphorus (Pi) followed monthly for 6 months. Plasma sclerostin levels measured before etelcalcetide treatment and after 6 months. ResultsThirty-four patients were enrolled, 19 (55.9%) male gender. Mean age 60.7 (± 12.3) years; median time on HD 82.5 (7–296) months and median cinacalcet dose was 180mg/week (Interquartile Range: 180–270).Serum Ca, Pi and PTH levels showed a significant reduction after etelcalcetide treatment from 8.8mg/dL, 5.4mg/dL and 1005pg/mL to 8.1mg/dL (p=0.08), 4.9mg/dL (p=0.01) and 702pg/mL (p<0.001), respectively. Median etelcalcetide dose remained at 5mg/HD. Plasma sclerostin concentration increased from 35.66pmol/L (IQR11.94–54.58) to 71.05pmol/L (IQR54.43–84.91) (p<0.0001). ConclusionEtelcalcetide improved sHPT control in this group of patients, previously under cinacalcet treatment, and significantly increased plasma sclerostin concentration. The impact of etelcalcetide treatment on sclerostin levels is a novel finding.

Low sclerostin levels after long-term remission of acromegaly

PurposeBone health is compromised in acromegaly resulting in vertebral fractures (VFs), regardless of biochemical remission. Sclerostin is a negative inhibitor of bone formation and is associated with increased fracture risk in the general population. Therefore, we compared sclerostin concentrations between well-controlled acromegaly patients and healthy controls, and assessed its relationship with bone mineral density (BMD), and VFs in acromegaly.MethodsSeventy-nine patients (mean age 58.9 ± 11.4 years, 49% women) with controlled acromegaly, and 91 healthy controls (mean age 51.1 ± 16.9 years, 59% women) were included. Plasma sclerostin levels (pg/mL) in patients were measured with an ELISA assay, whereas in controls, serum levels were converted to plasma levels by multiplication with 3.6. In patients, VFs were radiographically assessed, and BMD was assessed using dual X-ray absorptiometry.ResultsMedian sclerostin concentration in controlled acromegaly patients was significantly lower than in healthy controls (104.5 pg/mL (range 45.7–234.7 pg/mL) vs 140.0 pg/mL (range 44.8–401.6 pg/mL), p < 0.001). Plasma sclerostin levels were not related to age, current growth hormone (GH) or insulin-like factor-1 (IGF-1) levels, gonadal state, treatment modality, remission duration, or BMD, VF presence, severity or progression.ConclusionPatients with long-term controlled acromegaly have lower plasma sclerostin levels than healthy controls, as a reflection of decreased osteocyte activity. Further longitudinal studies are needed to establish the course of sclerostin during different phases of disease and its exact effects in acromegalic osteopathy.

Sclerostin is an independent risk factor for all-cause mortality in kidney transplant recipients

BackgroundSclerostin is a hormone contributing to the bone-vascular wall cross talk and has been implicated in cardiovascular events and mortality in patients with chronic kidney disease (CKD). We analyzed the relationship between sclerostin and mortality in renal transplant recipients.Methods600 stable renal transplant recipients (367men, 233 women) were followed for all-cause mortality for 3 years. Blood and urine samples for analysis and clinical data were collected at study entry. We performed Kaplan–Meier survival analysis and Cox regression models considering confounding factors such as age, eGFR, cold ischemia time, HbA1c, phosphate, calcium, and albumin. Optimal cut-off values for the Cox regression model were calculated based on ROC analysis.ResultsSixty-five patients died during the observation period. Nonsurvivors (n = 65; sclerostin 57.31 ± 30.28 pmol/L) had higher plasma sclerostin levels than survivors (n = 535; sclerostin 47.52 ± 24.87 pmol/L) (p = 0.0036). Kaplan–Meier curve showed that baseline plasma sclerostin concentrations were associated with all-cause mortality in stable kidney transplant recipients (p = 0.0085, log-rank test). After multiple Cox regression analysis, plasma levels of sclerostin remained an independent predictor of all-cause mortality (hazard ratio, 1.011; 95% CI 1.002–1.020; p = 0.0137).ConclusionsBaseline plasma sclerostin is an independent risk factor for all-cause mortality in patients after kidney transplantation.

Factors associated with sclerostin levels – A calcification inhibitor – In individuals with type 2 diabetes mellitus; Is autonomic neuropathy the missing link?

BackgroundSclerostin inhibits bone formation and its expression is upregulated in the vasculature during the arterial calcification process as a counterregulatory mechanism preventing further calcification. Lower extremity arterial calcification (LEAC) is common in neuropathic patients with type 2 diabetes (T2DM). Herein, we investigated for associations between plasma sclerostin levels and diabetic neuropathy as well as LEAC in subjects with T2DM. MethodsA total of 74 individuals with and 76 without T2DMwere recruited. Plasma sclerostin levels were measured by ELISA. Diagnosis of cardiac autonomic neuropathy (CAN) was based on the battery of the four autonomic tests, while of somatosensory peripheral neuropathy (DPN) on neuropathy symptom score and neuropathy disability score. LEAC was assessed with conventional ankle and foot x-rays. ResultsPlasma sclerostin levels were higher in participants with LEAC vs. those without LEAC in both diabetes and non-diabetes cohorts (p = 0.035 and p = 0.003, respectively). In the diabetes cohort, patients with CAN, but not with DPN, had higher sclerostin levels when compared with those without CAN (p < 0.001). Multivariate analysis in the diabetes cohort demonstrated that sclerostin levels were associated positively with CAN and LEAC, while in the non-diabetes cohort there was a trend for a positive association with male gender and presence of LEAC. ConclusionPlasma sclerostin levels are increased in individuals with LEAC irrespectively of diabetes status. In addition, plasma sclerostin concentrations are associated independently with LEAC and CAN in people with T2DM.

Plasma sclerostin levels are associated with nutritional status and insulin resistance but not hormonal disturbances in women with polycystic ovary syndrome

ObjectiveThe aim of this study was to evaluate the circulating sclerostin levels with nutritional status, insulin resistance and hormonal disturbances in women with polycystic ovary syndrome (PCOS).Patients and methodsThe cross-sectional study involved 98 PCOS inpatients (20 normal weight, 17 overweight and 61 obese) with stable body mass. Body composition was assessed by bioimpedance method in addition to anthropometric measurements (body mass and height). Serum/plasma concentrations of glucose, insulin (with the calculation of homeostatic model assessment insulin resistance—HOMA-IR), estradiol, total testosterone, sex hormone-binding globulin (SHBG) and sclerostin were measured. Free androgen index (FAI) and estradiol/testosterone index were calculated.ResultsPlasma sclerostin levels were significantly higher in obese [0.61 (interquartile range 0.53–0.77) ng/mL] than in overweight [0.53 (0.49–0.57) ng/mL] and normal weight [0.49 (0.42–0.54) ng/mL] groups. Plasma sclerostin levels were significantly higher in the subgroup with insulin resistance [0.65 (interquartile range 0.53–0.77) vs. 0.52 (0.46–0.58) ng/mL; p < 0.001], while similar concentrations were observed in subgroups with FAI below and above median. Plasma sclerostin levels variability were explained by BMI (r = 0.40), the percentage of body fat (r = 0.40) and HOMA-IR values (r = 0.34) in multivariable models.ConclusionsCirculating sclerostin levels in women with PCOS are related to nutritional status and insulin resistance, but not to sex hormone disturbances.

P1098THE CHANGE OF PLASMA SCLEROSTIN AND OTHER BIOMARKERS IN HEMODIALYTIC PATIENTS USING DIALYZER WITH MEDIUM CUT-OFF MEMBRANE

Abstract Background and Aims Protein-bound toxins and uremic toxins with middle molecular weight usually develop uremic symptoms in patients with advanced chronic kidney disease (CKD) or end-stage renal disease (ESRD). Although the effect on uremic toxicity of the molecules is not proven yet, middle molecules or larger middle molecules is regarded with important substance concerning of development of uremic symptoms and cardiovascular complication, particularly in CKD patients. Hemodialysis (HD) or hemodiafiltration (HDF) using dialyzer with high flux membrane provided improved clearance for uremic toxins with middle molecular weights. However, uremic toxins with larger middle molecular weight could not be easily removed through above methods. Medium cut-off (MCO) membrane can remove larger middle molecules which can be not removed through high flux membrane and HDF. From this perspective, chronic use of MCO membrane lowering the plasma concentration of larger middle molecules associated with cardiovascular complications including vascular calcification may give beneficial effect, particularly in patients with ESRD. Method Twenty-five patients undergoing chronic hemodialysis were prospectively analyzed for 6 months. We randomly divided enrolled patients into two groups: control group and MCO group. Patients in the control group used dialyzer with high flux membrane and patients in MCO group used dialyzer with MCO membrane. The enrolled patients performed hemodialysis thrice a week during 6 months. We measured plasma levels of several biomarkers at baseline and 3-month and 6-month through the multiplexing using Luminex® technology. In this prospective study, we performed comparative analysis with larger middle molecules, such as CXCL16, sclerostin, and FGF-23, in both groups. Results The plasma levels of all biomarkers at baseline did not show significant difference between two groups (CXCL16: p =0.904, Sclerostin: p =0.322, FGF-23: p =0.065, respectively). However, plasma sclerostin levels at 3-month and 6-month were significantly lower in MCO group (p = 0.060, p &amp;lt;0.005, respectively). In addition, even after analysis of covariance through ANCOVA analysis, plasma sclerostin levels at 3-month and 6-month were significantly lower in MCO group compared with the control group (p = 0.042, p =0.001, respectively). But, there was no a significant decrease of plasma sclerostin levels according to time, particularly in MCO group (p = 0.157, p =0.412, respectively) (Figure 1). Conclusion This study showed the 6-month outcome for changes of the plasma levels of larger middle molecules, including CXCL16, sclerostin, and FGF-23, particularly in dialytic patients using dialyzer with MCO membrane. Plasma sclerostin associated with vascular calcification showed decreasing tendency during 6 months after application of MCO membrane, but, there was no statistical significance. However, plasma levels of sclerostin were significantly lower in dialytic patients using MCO membrane than those using high flux membrane at 3 and 6 months, respectively. Therefore, hemodialysis using dialyzer with MCO membrane may be an option to attenuate cardiovascular complications in ESRD patients.

Circulating sclerostin levels in relation to nutritional status, sex hormones and selected bone turnover biochemical markers levels in peri- and postmenopausal women

Hormonal changes during the peri- and postmenopausal age, especially decreasing estradiol levels as the result of the expired ovarian function, are an established link of the pathogenesis of postmenopausal osteoporosis. The objective of the study was to examine the association between the circulating sclerostin levels and nutritional status, sex hormones and selected bone markers turnover levels in peri- and postmenopausal women. The study enrolled 84 stable-body mass women (31 perimenopausal and 54 postmenopausal). Anthropometric measurements and serum estrone, testosterone, androstenedione, DHEA-S, osteocalcin, β-CTx, 25-OHVitamin D and sclerostin levels were obtained. There were not any differences between body mass, BMI, body fat and waist circumference between the study groups. The serum androstenedione and DHEA-S levels were similar in both study groups. However, estrone and total testosterone levels were observed to be notably higher in the perimenopausal group, unlike in the postmenopausal group (124.1 pg/mL vs. 98.3 pg/mL, p < 0.01 and 0.3 pg/mL vs. 0.22 pg/mL, p < 0.01, respectively). Higher plasma osteocalcin and β-CTx levels were shown in the postmenopausal rather than in the perimenopausal group (19.8 ng/mL vs. 16.8 ng/mL, p < 0.001 and 0.35 ng/mL vs. 0.29 ng/mL, p < 0.05, respectively). Plasma sclerostin and 25-OH-Vitamin D levels were similar. There was not any correlation between plasma sclerostin levels and the other studied parameters. In the multivariate regression analyses, sclerostin levels were proportional to the androstenedione ones (b = 0.06; p < 0.05) but inversely related to the log10(testosterone) levels (b = -0.18; p < 0.05). Circulating sclerostin levels are similar in peri- and postmenopausal women and are related to the androstenedione and testosterone levels regardless of the nutritional status.

Patients with non-ambulatory cerebral palsy have higher sclerostin levels and lower bone mineral density than patients with ambulatory cerebral palsy

Bone loss is a serious clinical issue in patients with cerebral palsy (CP). Sclerostin has garnered interest as a key mechanosensor in osteocytes, leading to considerations of the therapeutic utilization of anti-sclerostin medications. This study was undertaken to determine associations among mechanical unloading, sclerostin levels, and bone imbalance in patients with CP. A total of 28 patients with CP participated in this cross-sectional study. The following measurements were taken: anthropometrics, clinical diagnosis of CP subtype and ambulatory status, bone mineral density (BMD) z-scores at the lumbar spine and hip, and blood biochemical markers, including sclerostin, parathyroid hormone (PTH), osteocalcin, C-terminal telopeptide, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, creatinine, calcium, and phosphorus. In analysis according to CP subtype, patients with spastic CP showed significantly lower BMD z-scores at the lumbar spine and femur neck regions than patients with dyskinetic CP. In analysis according to ambulatory status, patients with non-ambulatory CP showed significantly lower BMD z-scores at all lumbar spine and femoral sites, lower PTH and creatinine levels, and higher plasma sclerostin levels than patients with ambulatory CP. In regression analysis, ambulatory status was a significant determinant of plasma sclerostin levels. This study is the first to report on sclerostin levels and BMD in patients with CP, based on the hypothesis that patients who lack sufficient weight-bearing activities would show increased sclerostin levels and decreased BMD scores, compared with patients who sustain relatively sufficient physical activity. Therefore, this report may provide clinical insights for clinicians considering ambulatory status, sclerostin levels, and bone loss in patients with CP.

A Randomized Trial on the Effect of Bone Tissue on Vibration-induced Muscle Strength Gain and Vibration-induced Reflex Muscle Activity.

Whole-body vibration (WBV) induces reflex muscle activity and leads to increased muscle strength. However, little is known about the physiological mechanisms underlying the effects of whole-body vibration on muscular performance. Tonic vibration reflex is the most commonly cited mechanism to explain the effects of whole-body vibration on muscular performance, although there is no conclusive evidence that tonic vibration reflex occurs. The bone myoregulation reflex is another neurological mechanism used to explain the effects of vibration on muscular performance. Bone myoregulation reflex is defined as a reflex mechanism in which osteocytes exposed to cyclic mechanical loading induce muscle activity. The aim of this study was to assess whether bone tissue affected vibration-induced reflex muscle activity and vibration-induced muscle strength gain. A prospective, randomised, controlled, double-blind, parallel-group clinical trial. Thirty-four participants were randomised into two groups. High-magnitude whole-body vibration was applied in the exercise group, whereas low-magnitude whole-body vibration exercises were applied in the control group throughout 20 sessions. Hip bone mineral density, isokinetic muscle strength, and plasma sclerostin levels were measured. The surface electromyography data were processed to obtain the Root Mean Squares, which were normalised by maximal voluntarily contraction. In the exercise group, muscle strength increased in the right and left knee flexors (23.9%, p=0.004 and 27.5%, p<0.0001, respectively). However, no significant change was observed in the knee extensor muscle strength. There was no significant change in the knee muscle strength in the control group. The vibration-induced corrected Root Mean Squares of the semitendinosus muscle was decreased by 2.8 times (p=0.005) in the exercise group, whereas there was no change in the control group. Sclerostin index was decreased by 15.2% (p=0.031) in the exercise group and increased by 20.8% (p=0.028) in the control group. A change in the sclerostin index was an important predictor of a change in the vibration-induced normalised Root Mean Square of the semitendinosus muscle (R2=0.7, p=0.0001). Femoral neck bone mineral density was an important predictor of muscle strength gain (R2=0.26, p=0.035). This study indicates that bone tissue may have an effect on vibration-induced muscle strength gain and vibration-induced reflex muscle activity. ClinicalTrials.gov: NCT01310348.

Effects of whole-body vibration on plasma sclerostin level in healthy women.

To determine whether plasma sclerostin levels are affected by applying whole-body vibration treatments. Following a pilot study, the pretsent prospective, randomized, controlled single-blind study was performed on 16 healthy volunteer women (ages 20 to 40 years). Subjects were randomly divided into 2 groups, and whole-body vibration was applied to the treatment group but not to the controls. The plasma sclerostin levels were measured before the treatment and at the 10th minute after whole-body vibration on the 1st, 2nd, and 5th days of application. The plasma sclerostin level measured at 10 min after the whole-body vibration treatment increased 91% (P = 0.024) on the 1st day and decreased 31.5% (P = 0.03) on the 5th day in the whole-body vibration group. In the control group, there was no change in the plasma sclerostin level at any time. A progressive increase in baseline plasma sclerostin levels during the 5 days of vibration sessions was also found. Our study demonstrated that whole-body vibration can change plasma sclerostin levels, and that this change is detectable 10 min after whole-body vibration treatments.

Effects of osteocytes on vibration-induced reflex muscle activity in postmenopausal women

To assess whether osteocytes have an effect on reflex myoelectrical activity during whole-body vibration (WBV) in postmenopausal women. Participants were classified into 2 groups: the low bone mineral density (BMD) group (n = 37) and normal BMD group (n = 43). Hip BMD was measured using dual-energy X-ray absorptiometry. Surface electromyography data recorded from the adductor longus muscle were processed to obtain vibration-induced reflex myoelectrical activity. Changes in plasma sclerostin (SOST) levels with WBV were expressed as a standardized vibration-induced SOST index. The standardized vibration-induced SOST index was 1.03 ± 0.24 in the low BMD group and 0.99 ± 0.33 in the normal BMD group. For plasma SOST levels, no group-by-time interaction was found. The resting myoelectrical activities of adductor muscles increased significantly during WBV in both groups. However, there was no significant difference in the main effects of WBV on resting myoelectrical activity between the groups. The standardized vibration-induced plasma SOST index was found to be a significant independent predictor of the standardized vibration-induced reflex myoelectrical activity of the adductor muscle in both groups. This study suggests that osteocytes serve as mechanoreceptors of reflex electromyography during WBV.

Sclerostin Is Positively Associated With Bone Mineral Density in Men and Women and Negatively Associated With Carotid Calcified Atherosclerotic Plaque in Men From the African American-Diabetes Heart Study

Bone mineral density (BMD) and calcified atherosclerotic plaque (CP) demonstrate inverse relationships. Sclerostin, an endogenous regulator of the Wnt pathway and bone formation, has been associated with impaired osteoblast activation and may play a role in vascular calcification. Our objective was to assess the relationships between sclerostin, BMD, and CP. Generalized linear models were fitted to test for associations between sclerostin, volumetric BMD (vBMD), and CP. A targeted population of 450 unrelated African Americans (AAs) with type 2 diabetes (T2D) was 56% female with mean/SD/median age of 55.4/9.5/55.0 years and a diabetes duration of 10.3/8.2/8.0 years. Plasma sclerostin, computed tomography-derived thoracic and lumbar vertebrae trabecular vBMD, coronary artery, carotid artery, and aortoiliac CP were measured. Plasma sclerostin was 1119/401/1040 pg/mL, thoracic vBMD was 206.3/52.4/204.8 mg/cm3, lumbar vBMD was 180.7/47.0/179.0 mg/cm3, coronary artery CP score was 284/648/13, carotid artery CP score was 46/132/0, and aortoiliac CP score was 1613/2910/282. Sclerostin levels were higher in men than women (P<.0001). Before and after adjusting for age, sex, body mass index, blood pressure, smoking, hemoglobin A1c, and low-density lipoprotein-cholesterol, plasma sclerostin levels were positively associated with thoracic and lumbar vertebrae vBMD (P<.0001). Sex-stratified analyses verified significant relationships in both men and women (both P<.001). Sclerostin was not associated with CP except for an inverse relationship with carotid CP in men (fully adjusted model, P=.03). In this cross-sectional study of AA men and women with T2D, circulating sclerostin was positively associated with vBMD in the spine in both sexes and inversely associated with carotid artery CP in men. Sclerostin may play a role in skeletal mineral metabolism in AA but fails to explain inverse relationships between BMD and CP.

Bone mineral density reduction and alterations in bone metabolism after chemotherapy in young bone sarcoma survivors

Bone mineral density reduction and alterations in bone metabolism after chemotherapy in young bone sarcoma survivors

Circulating Sclerostin Levels Are Decreased in Patients with Endogenous Hypercortisolism and Increase after Treatment

Increased bone fragility is a frequent complication of hypercortisolism due predominantly to suppression of bone formation. Sclerostin is an osteocyte-produced negative regulator of bone formation, which is up-regulated by glucocorticoids in mice. Our objective was to assess the effect of endogenous hypercortisolism on circulating sclerostin and bone turnover in humans. We measured sclerostin, β-C-terminal telopeptide, amino-terminal propeptide of type 1 procollagen, and fibroblast growth factor 23 in blood samples of 21 patients with endogenous hypercortisolism and 21 age- and gender-matched controls. In 12 patients, measurements were repeated at various time intervals after successful surgical treatment (transsphenoidal surgery or adrenalectomy). Plasma sclerostin levels were significantly decreased in patients compared with controls (112±49 vs. 207±48 pg/ml, P<0.001). In the 12 patients who were evaluated after surgical treatment, sclerostin levels increased from 121.4±46.5 to 175.8±78.5 pg/ml (P=0.003). These changes in plasma sclerostin levels were accompanied by significant increases in levels of fibroblast growth factor 23 (from 44.2±12.2 to 84.0±58.8 pg/ml, P=0.017) and of the bone turnover markers amino-terminal propeptide of type 1 procollagen (from 31.7±18.2 to 94.2±92.2 ng/ml, P=0.037) and β-C-terminal telopeptide (from 134.2±44 to 409.2±285 pg/ml, P=0.005). Contrary to the findings in mice, circulating sclerostin is decreased in patients with chronic endogenous hypercortisolism and increases after treatment. These findings suggest that in humans, chronic exposure to glucocorticoids affects the number or function of osteocytes rather than the production of sclerostin.

Long-term treatment with raloxifene, but not bisphosphonates, reduces circulating sclerostin levels in postmenopausal women

We determined whether suppression of sclerostin levels by estrogen treatment was mediated by anti-resorptive effect. Raloxifene, but not bisphosphonates, suppressed circulating sclerostin concentration, suggesting that sclerostin may mediate the action of estrogen on bone metabolism, independently of their anti-resorptive effects. Circulating sclerostin concentrations are higher in postmenopausal than in premenopausal women, and estrogen treatment suppresses sclerostin levels in both men and women. We determined whether anti-resorptives may suppress the circulating sclerostin levels. We conducted a retrospective observational study. Eighty postmenopausal women were treated with raloxifene for 19.4 ± 7.7 months (n = 16), bisphosphonates for 19.2 ± 6.7 months (n = 32), or were untreated (n = 32) for 17.1 ± 4.6 months. Plasma sclerostin concentrations were measured before and after treatment. Plasma sclerostin levels after treatment were significantly lower in the raloxifene than in the control group (55.8 ± 23.4 pmol/l vs. 92.1 ± 50.4 pmol/l, p = 0.046), but were similar between the bisphosphonate and control groups. Relative to baseline, raloxifene treatment markedly reduced plasma sclerostin concentration (-40.7 ± 22.8%, p < 0.001), with respect to both control (-7.5 ± 29.1%) and bisphosphonate (-3.1 ± 35.2%) groups. Changes in bone-specific alkaline phosphatase and osteocalcin levels showed reverse associations with sclerostin concentration changes in the raloxifene (γ = -0.505, p = 0.017) and control (γ = -0.410, p = 0.020) groups. Raloxifene, but not bisphosphonates, significantly suppressed circulating sclerostin concentration, suggesting that sclerostin may mediate the action of estrogen on bone metabolism, independently of their anti-resorptive effects.

Effects of Parathyroid Hormone Treatment on Circulating Sclerostin Levels in Postmenopausal Women

Intermittent PTH treatment stimulates bone formation, but the mechanism(s) of this effect remain unclear. Sclerostin is an inhibitor of Wnt signaling, and animal studies have demonstrated that PTH suppresses sclerostin production. The objective of the study was to test whether intermittent PTH treatment of postmenopausal women alters circulating sclerostin levels. Prospective study. The study was conducted at a clinical research unit. Participants included 27 postmenopausal women treated with PTH (1-34) for 14 d and 28 control women. Serum sclerostin levels were measured. Circulating sclerostin levels decreased significantly in the PTH-treated subjects, from (mean ± SEM) 551 ± 32 to 482 ± 31 pg/ml (-12.7%, P < 0.0001) but did not change in the control women (baseline, 559 ± 34 pg/ml; end point, 537 ± 40 pg/ml, P = 0.207; P = 0.017 for difference in changes between groups). Bone marrow plasma was obtained in a subset of the control and PTH-treated subjects (n = 19 each) at the end of the treatment period, and marrow plasma and peripheral serum sclerostin levels were significantly correlated (R = 0.64, P < 0.0001). Marrow plasma sclerostin levels were 24% lower in PTH-treated compared with control women, but perhaps due to the smaller sample size, this difference was not statistically significant (P = 0.173). Circulating sclerostin levels correlate with bone marrow plasma levels and are reduced by intermittent PTH therapy in postmenopausal women. Further studies are needed to assess the extent to which decreases in sclerostin production contribute to the anabolic skeletal response to PTH.