Increased sclerostin serum levels associated with bone formation and resorption markers in patients with immobilization-induced bone loss.

CONTEXT: Sclerostin, a Wnt signaling antagonist on the osteoblasts produced by osteocytes, is regulated by mechanical strain and is implicated in the pathogenesis of disuse bone loss. There are no data on sclerostin in humans. OBJECTIVE: The aim of the study was to evaluate sclerostin in patients immobilized after stroke, compared with control subjects, and to analyze its relationship with markers of bone formation and resorption. DESIGN: This was a cross-sectional study. SETTING AND PATIENTS: We studied 40 postmenopausal women immobilized after a single episode of stroke 6 months or longer after onset, and 40 postmenopausal women from the general community. Bone status was assessed by quantitative ultrasound measurements at the calcaneus. Bone alkaline phosphatase (b-AP), carboxy-terminal telopeptide of type I collagen (CrossLaps), and sclerostin were evaluated by ELISA. We also used ELISA to measure serum levels of Dickkopf-1, another soluble inhibitor of Wnt/beta-catenin signaling, highly expressed by osteocytes. RESULTS: Immobilized patients had higher sclerostin serum levels (median 0.975 ng/ml; 25th to 75th percentiles 0.662-1.490) than controls (median 0.300 ng/ml; 25th to 75th percentiles 0.165-0.400: P < 0.0001) and an increased bone turnover with a more significant rise in bone resorption (CrossLaps) than formation (b-AP) markers. Sclerostin correlated negatively with b-AP (r = -0.911; P < 0.0001) and positively with CrossLaps (r = 0.391; P = 0.012). Dickkopf-1 did not significantly differ between the groups. Patients also had quantitative ultrasound measurements index lower than controls (P < 0.001). CONCLUSIONS: This study shows for the first time that long-term immobilized patients present hypersclerostinemia associated with reduced bone formation, and suggests that sclerostin could be a link between mechanical unloading and disuse osteoporosis in humans.

Therapeutic perspectives.

Osteoporosis and atherosclerosis are linked by biological association. This encourages the search for therapeutic strategies having both cardiovascular and skeletal beneficial effects. Among drugs that may concordantly enhance bone density and reduce the progression of atherosclerosis we can include bisphosphonates (BP), statins, ß -blockers, and possibly anti-RANKL antibodies. Available data come from experimental animals and human studies. All these treatments however lack controlled clinical studies designed to demonstrate dual-action effects.

Survival after parathyroidectomy in patients with end-stage renal disease and severe hyperparathyroidism.

BACKGROUND: Patients with end-stage renal disease (ESRD) and secondary hyperparathyroidism (SHPT) are at high risk of mortality. Whether an increased risk of death persists after a parathyroidectomy (PTX) is not clearly established. SUBJECTS AND METHODS: The survival of 40 patients with ESRD and SHPT who underwent PTX was compared with that of 664 ESRD patients. RESULTS: From first dialysis, a lower mortality rate was found in the group of patients who underwent PTX than in the nonoperated ESRD group (hazard ratio: 0.23; 95% CI: 0.14-0.37). The patients who underwent PTX were younger, had a longer time on dialysis, and had a higher prevalence of kidney transplantation. The mean number of comorbidities was lower (Charlson score 4.2 +/- 2.1 versus 6.4 +/- 2.9, p < 0.001). Then, we randomly selected two matched controls for each PTX case (80 controls, 40 PTX) who had at least an equivalent mean duration of dialysis between the first dialysis and PTX of the PTX group. In a univariate model, there was a trend for PTX being associated with prolonged survival. The mortality was higher both among those at an advanced age and those with a high Charlson score. Adjustments for these covariates made the effect of PTX no more significant. CONCLUSIONS: The risk of death of patients with severe SHPT leading to PTX differed from that of nonoperated subjects. The apparent differences in survival may be related to the number and severity of associated comorbidities. ESRD patients who undergo PTX may represent a subset of healthier subjects.

Pamidronate and osteoporosis prevention in liver transplant recipients.

Osteoporosis is a common complication in patients with end-stage liver disease and after orthotopic liver transplantation (LT), with resulting increasing fracture rate. In this study, we investigated the role of treatment with pamidronate in preventing further bone loss after LT. Eighty-five patients with end-stage liver disease were included in the study. Pamidronate 30 mg was given intravenously every 3 months after LT for the duration of 1 year to 43 patients with osteopenia or osteoporosis prior LT. The remainders served as controls. All patients received a supplementation of calcium and vitamin D. Bone mineral density (BMD) at the lumbar spine and the femoral neck, and markers of bone metabolism were measured before and 12 months after LT. Sixty-two BMD were available at 12 months; only paired BMD were evaluated. A significant increase in lumbar spine BMD was observed in pamidronate treated patients. No change was evident in controls. Femoral neck BMD decreased in both treated and untreated patients. Osteocalcin serum levels and deoxypyridinoline urinary excretion were significantly reduced by treatment. Our study suggests that pamidronate decreases bone turnover and is effective in preventing the course of bone loss after LT, however the efficacy, at the dosage regimen employed and in a follow-up of 12 months, appears to be limited to trabecular bone, with no effect on the cortical structure of the femur.

Association of high alpha2-Heremans-Schmid glycoprotein/fetuin concentration in serum and intima-media thickness in patients with atherosclerotic vascular disease and low bone mass.

OBJECTIVE: Alpha2-Heremans-Schmid glycoprotein (AHSG; fetuin), a member of the cystatin superfamily of cysteine protease inhibitors involved in vascular pathology and bone metabolism, has been reported to be reduced in patients with atherosclerosis and medial calcification related to end stage renal disease or dialysis. No data on fetuin in patients with peripheral artery disease associated with low bone mass and normal renal function are available in the literature. In the present study we evaluated serum fetuin concentrations, bone mass, and markers of bone turnover in patients with atherosclerosis of peripheral vessels and normal kidney function. PATIENTS AND METHODS: Ninety consecutive patients with evidence of atherosclerotic plaques at the common carotid or femoral artery were studied. Severity grade of disease was documented by ultrasound measurement of intima-media thickness (IMT). Fasting serum levels of fetuin were measured by sandwich enzyme immunoassay. MAIN RESULTS: The mean patient serum concentration of fetuin was 57.68+/-13.6 ng/ml, significantly higher than that of control subjects (41.6+/-7.6 ng/ml; p<0.001). The mean serum concentration of bone-specific alkaline phosphatase (BAP) were 8.4+/-2.3 microg/l, significantly lower than controls (13.6+/-1.6 microg/l; p<0.001). Fetuin was correlated with IMT (r=0.8530; p<0.0001) and inversely correlated with BAP (r=-0.5503; p<0.0001). Patients had a vertebral and femoral bone mass significantly lower than controls. CONCLUSION: This study documented for the first time that, in patients with atherosclerosis of peripheral vessels, serum fetuin levels were higher than in healthy subjects, and correlated with the severity of disease; further studies are required to analyse the role of AHSG as an independent predictor of atherosclerotic disease and low bone mass in patients with normal renal function.

Glucocorticoid-induced osteoporosis and its treatment.

UNLABELLED: Osteoporosis and fractures are frequent and important consequences of glucocorticoid therapy. Many factors contribute to bone loss during glucocorticoid therapy, such as underlying disease, malnutrition, vitamin D insufficiency, hypogonadism, and low body weight. Bone loss occurs particularly in the first few months of glucocorticoid treatment and affects more cancellous than cortical bone, with reduced bone formation and increased bone resorption. The risk of fracture increases rapidly in patients with glucocorticoid therapy. The existence of a threshold is not well defined but the risk of fracture is increased in patients with higher doses of glucocorticoids. Other effects include altered production of gonadal sex hormones, inhibition of intestinal calcium absorption, and enhancement of renal excretion of calcium. Prevention of glucocorticoid-induced osteoporosis is based on general measures such as calcium and vitamin D supplementation, adequate protein intake, regular physical exercise, and specific therapies. Bisphosphonates, which are potent bone resorption inhibitors, have been shown to increase bone mineral density and to decrease fracture risk, so that they represent the first choice in the prevention of glucocorticoid-induced osteoporosis. Glucocorticoid-induced osteoporosis is a major burden to those whom it affects. It can be prevented provided efficacious preventive measures are introduced early during glucocorticoid treatment. LEVEL OF EVIDENCE: Level V (expert opinion). See the Guidelines for Authors for a complete description of the levels of evidence.

Increased prevalence of peripheral arterial disease in osteoporotic postmenopausal women.

The aim of this study was to investigate the prevalence and correlates of peripheral arterial disease (PAD) in a population of osteoporotic postmenopausal women. The presence of PAD was assessed by ankle brachial index (ABI) in 345 ambulatory osteoporotic postmenopausal women, and in 360 community-based, age- and race-matched postmenopausal women with normal bone mineral density (BMD) (control group). PAD was detected in 63/345 (18.2%) osteoporotic women and in 14/360 (3.8%) control subjects (P < 0.0001). The mean ABI values were significantly lower in the osteoporosis group than in the control group (0.98 +/- 0.09 vs. 1.04 +/- 0.06, P < 0.0001). No difference in cardiovascular risk factors was observed between osteoporotic patients and controls, or between osteoporotic patients with and without PAD. Osteoporotic patients with PAD had lower femoral neck BMD T scores than those without PAD (-4.2 +/- 0.7 vs. -2.3 +/- 0.7, P < 0.0001). Only 4 PAD patients (5.1%) had intermittent claudication. In multivariate logistic regression analysis, factors independently associated with PAD within osteoporotic patients were lower femoral neck BMD T score (odds ratio (OR) = 0.20, 95% confidence interval (CI), 0.05-0.70, P = 0.01) and systolic blood pressure (OR = 1.02, 95% CI, 1.00-1.03, P = 0.01). This study shows for the first time an increased prevalence of PAD among osteoporotic postmenopausal women, with a lower femoral neck BMD T score being a significant independent predictor. The findings suggest that vascular status evaluation should be done in osteoporotic postmenopausal women in order to identify candidate patients for preventive and therapeutic cardiovascular interventions.

Supplementation of L-arginine prevents glucocorticoid-induced reduction of bone growth and bone turnover abnormalities in a growing rat model.

The present study was designed to evaluate the effects of glucocorticoid (GC) treatment on bone turnover and bone mineral density in the growing rat. Because of the recent evidence that nitric oxide (NO) can counteract prednisolone-induced bone loss in mature rats, we examined the effect on bone of the NO donor L: -arginine in young male rats, in which bone mass is increased by the same biological mechanism as in children and adolescents. Thirty-six 10-week-old Sprague-Dawley male rats were assigned to six groups of six animals each, and treated for 4 weeks with either vehicle (once a week subcutaneous injection of 100 microl of sesame oil); prednisolone sodium succinate, 5 mg/kg, 5 days per week by intramuscular injection (i.m.); L-arginine, 10 mg/kg intraperitoneally (i.p.) once a day; N(G)-nitro-L-arginine methylester (L-NAME), 50 mg/kg subcutaneously once a day; prednisolone sodium succinate 5 mg/kg, 5 days per week i.m. +L-arginine 10 mg/kg i.p. once a day; or prednisolone sodium succinate, 5 mg/kg, 5 days per week i.m. +L-NAME 50 mg/kg subcutaneously once a day. Serum calcium, alkaline phosphatase (ALP), osteocalcin, and the C-terminal telopeptides of type I collagen (RatLaps) were measured at baseline conditions and after 2 and 4 weeks. Prior to treatment, and after 2 and 4 weeks, the whole body, vertebral, pelvic, and femoral bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) scanning. Prednisolone and prednisolone+L-NAME treated rats had significantly lower ALP and osteocalcin levels than controls at 2 and 4 weeks, and significantly higher levels of Rat-Laps than controls at 4 weeks. Prednisolone, L-NAME, and prednisolone+L-NAME produced a significant inhibition of bone accumulation and bone growth at all sites measured. Supplementation with L-arginine appeared to prevent the inhibition of bone growth and increase in bone resorption induced by prednisolone. These data would suggest, for the first time, that supplementation with an NO donor could be considered as a treatment for steroid-induced osteoporosis in the developing skeleton.

[Corticosteroid-induced osteoporosis]. / Ostéoporose induite par les corticoïdes.

Osteoporosis and fractures are the frequent consequences of corticosteroid therapy. Cancellous bone is primarily affected with a decrease of bone formation and an increase of bone resorption. Prevention of corticosteroid-induced osteoporosis is based upon general measures such as calcium and vitamin D supplementation, adequate protein intake, regular physical exercise, and upon specific therapies like those used in primary osteoporosis. Biphosphonates, which are potent bone resorption inhibitors, have been shown to increase bone mineral density and to decrease vertebral fracture rate. Therefore, they appear to be a first choice in the prevention of corticosteroid-induced osteoporosis.

Quantitative ultrasound of bone and clodronate effects in thalassemia-induced osteoporosis.

Osteoporosis in beta-thalassemia major has emerged as a topic of interest since optimized transfusion regimens have increased life expectancy and quality in these patients. Although the pathogenesis of thalassemic osteopathy is multifactorial, the evidence of an increased resorption phase suggests that the use of antiresorptive drugs such as bisphosphonates can be considered a valuable therapeutic strategy to reduce bone turnover and the risk of fragility fractures. We compared the effects of long-term cyclical clodronate therapy (300 mg intravenous infusion every 3 weeks for 2 years) and of an active placebo (calcium 1 vitamin D) on bone mass and bone turnover in 30 male patients with beta-thalassemia major. We also tested the possibility of using quantitative ultrasound (QUS) for assessing bone involvement in thalassemic osteopenia and in monitoring the response to antiresorptive therapy. Broadband ultrasound attenuation (BUA) was significantly reduced in patients with beta-thalassemia major as compared to healthy controls. In calcium and vitamin D-treated patients, a significant decline in spine, femoral, and total body areal bone density was observed. In the patients given intravenous clodronate we measured a substantial stability of bone mass, which was not significantly changed at the end of the study. The urinary excretion of deoxypyridinoline (a marker of bone resorption) showed a progressive significant decline throughout the study period in clodronate-treated patients. No significant change was observed in BUA values in both groups of patients. These results indicate that intermittent intravenous clodronate administration was not able to increase areal bone density in our thalassemic patients. Moreover, this is the first study to have assessed the usefulness of broadband ultrasound measurements in beta-thalassemia major.

Bone ultrasonometry, bone density, and turnover markers in type 1 Gaucher disease.

In 12 patients (mean age, 33 +/- 13 years) with type 1 Gaucher disease (GD), we evaluated bone mass by broadband ultrasound attenuation (BUA) of the calcaneus and dual X-ray absorptiometry (DXA) of the total body, lumbar spine, and hip. In all patients, we measured serum levels of osteocalcin (OC) and bone-specific alkaline phosphatase (BAP) and urinary excretion of pyridinoline (Pyr/Cr) and deoxypyridinoline (D-Pyr/Cr) cross-links. Compared to age- and sex-matched healthy controls, patients with GD showed marked osteopenia at all measuring sites as expected. Values of BUA (67.25 +/- 15.83 dB/MHz) were also significantly reduced. OC and BAP concentrations were within the normal range. Pyr/Cr and D-Pyr/Cr were significantly higher than in controls. Calculating T- and Z scores, we found a significant correlation between the Bone Severity Score Index (BSSI) and both BUA and BMD measurements. A significant correlation was also found between pyridinoline urinary excretion and both BSSI and BUA at the calcaneus. Our data suggest that type 1 GD in adulthood is associated with increased bone resorption and that BUA at the calcaneus may be a relevant tool in the assessment of bone status in these patients.