Cyrille B. Confavreux

Higher Serum Osteocalcin Is Associated With Lower Abdominal Aortic Calcification Progression and Longer 10-Year Survival in Elderly Men of the MINOS Cohort

CONTEXTnAbdominal aortic calcification (AAC) is an indicator of cardiovascular risk, especially in the diseases characterized by insulin resistance such as type 2 diabetes. Osteocalcin is a bone-secreted hormone that favors insulin sensitivity and insulin secretion.nnnOBJECTIVESnWe investigated whether total serum osteocalcin level at baseline is associated with AAC progression and 10-year all-cause mortality in elderly men.nnnDESIGN AND PARTICIPANTSnWe assessed 774 men aged 51-85 years from the MINOS cohort who had osteocalcin measurement and lumbar spine radiographs at baseline. They were followed-up prospectively for 10 years. Among them, 615 patients had a follow-up radiograph at 3.5 or 7 years.nnnMAIN OUTCOME MEASURESnSerum total osteocalcin was measured with an immunoradiometric assay on morning fasting serum collected at baseline. Kauppilas AAC score was assessed from lumbar spine radiographs. AAC progression rate was calculated as the difference between AAC on the last available radiograph and AAC at baseline divided by the follow-up time. Death status was collected over 10 years.nnnRESULTSnIn multivariate analysis, higher baseline total osteocalcin was associated with lower AAC progression rate (odds ratio = 0.74 [0.57-0.97] per 10 ng/mL variation; P = 0.029). At the 10-year follow-up, there were 599 men alive (77%), 181 dead (23%), and 2 lost to follow-up. Higher osteocalcin was associated with lower 10-year all-cause mortality (hazard ratio = 0.62 [0.44-0.86] per 10 ng/mL variation; P = 0.005).nnnCONCLUSIONnHigher baseline total osteocalcin concentrations were associated with lower AAC progression rate and lower mortality. These data suggest that osteocalcin level might be an independent indicator of cardiovascular risk and global health in elderly Caucasian men.

Persistence at 1 year of oral antiosteoporotic drugs: a prospective study in a comprehensive health insurance database

OBJECTIVEnTreatments against osteoporosis have demonstrated fracture risk reduction but persistence to therapy remains a major issue. Intermittent regimens have been developed to improve persistence. The aim of this 1-year prospective study was to compare, in the general population, the persistence of various oral regimens of antiosteoporotic treatment.nnnMETHODSnWe conducted this prospective study in the French comprehensive public health insurance database of the Rhône-Alpes region. Women aged 45 years or older who had a first reimbursement of an oral antiosteoporotic treatment during February 2007 composed the study cohort. Persistence was defined by the proportion of patients refilling a prescription in the pharmacist delivery register (ERASME). Using statistical analyses like Kaplan-Meier survival curves and log-rank tests, we compared the treatment persistence of strontium ranelate, raloxifene, and daily-, weekly-, and monthly bisphosphonates.nnnRESULTSnTwo thousand four hundred and nineteen patients were included over a period of 1 month and followed up for 12 months. Two hundred and eighty-nine (11.9%) patients were treated with monthly bisphosphonates, 1298 (53.7%) with weekly bisphosphonates, and 832 (34.4%) with daily treatments (526 strontium ranelate (21.7%), 296 raloxifene (12.2%), and 10 bisphosphonates (0.4%)). At 1 year, overall persistence was 34%. Fifty percent of patients on monthly bisphosphonates were still persistent while only 37% of patients on weekly bisphosphonates, 34% on raloxifene, and 16% on strontium ranelate were persistent. Therapy monitoring with biochemical markers or bone mineral density was associated with improved persistence.nnnCONCLUSIONnOverall persistence at 1 year was low, but intermittent regimens were associated with higher persistence rates, along with women who had therapy monitoring.

Serum sclerostin: the missing link in the bone-vessel cross-talk in hemodialysis patients?

SummaryWe found for the first time that in maintenance hemodialysis patients, higher sclerostin serum level was associated with severe abdominal aortic calcification (AAC). In addition, cortical bone microarchitecture (density and thickness) assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) at tibia was also independently associated with severe AAC. These results suggest that sclerostin may be involved in the association of mineral and bone disorder with vascular calcification in hemodialysis patients.IntroductionSevere abdominal aortic calcifications are predictive of high cardiovascular mortality in maintenance hemodialysis (MHD) patients. In patients with end-stage renal disease, a high aortic calcification score was associated with lower bone turnover on bone biopsies. Thus, we hypothesized that sclerostin, a Wnt pathway inhibitor mainly secreted by osteocytes and acting on osteoblasts to reduce bone formation, may be associated with vascular calcifications in MHD patients.MethodsFifty-three MHD patients, aged 53xa0years [35–63] (median [Q1–Q3]) were included. Serum was sampled before the MHD session to assay sclerostin. Framingham score was computed and the abdominal aortic calcification (AAC) score was assessed according to Kauppila method on lateral spine imaging using DEXA. Tibia bone status was evaluated by high-resolution peripheral quantitative computed tomography (HR-pQCT). Patients were distributed into two groups according to their AAC score: patients with mild or without AAC (score below 6) versus patients with severe AAC (score of 6 and above).ResultsIn multivariate analysis, after adjustment on age, dialysis duration and diabetes, serum sclerostin and cortical thickness were independently associated with severe AAC (odds ratio (OR)u2009=u20091.43 for each 0.1xa0ng/mL increase [95xa0% confidence interval (CI) 1.10–1.83]; pu2009=u20090.006 and 0.16 for 1 SD increase [0.03–0.73]; pu2009=u20090.018, respectively). A second cardiovascular model adjusted on Framingham score and the above mentioned confounders showed similar results.ConclusionsElevated sclerostin serum level and poorer tibia cortical bone structure by HR-pQCT were positively and independently associated with higher odds of severe AAC in MHD patients. Serum sclerostin may become a biomarker of mineral and bone disorder and vascular risk in MHD patients.

Combination of anti-angiogenic therapies reduces osteolysis and tumor burden in experimental breast cancer bone metastasis

The clinical efficacy of anti‐angiogenic monotherapies in metastatic breast cancer is less than originally anticipated, and it is not clear what the response of bone metastasis to anti‐angiogenic therapies is. Here, we examined the impact of neutralizing tumor‐derived vascular endothelial growth factor (VEGF) in animal models of subcutaneous tumor growth and bone metastasis formation. Silencing of VEGF expression (Sh‐VEGF) in osteotropic human MDA‐MB‐231/B02 breast cancer cells led to a substantial growth inhibition of subcutaneous Sh‐VEGF B02 tumor xenografts, as a result of reduced angiogenesis, when compared to that observed with animals bearing mock‐transfected (Sc‐VEGF) B02 tumors. However, there was scant evidence that either the silencing of tumor‐derived VEGF or the use of a VEGF‐neutralizing antibody (bevacizumab) affected B02 breast cancer bone metastasis progression in animals. We also examined the effect of vatalanib (a VEGF receptor tyrosine kinase inhibitor) in this mouse model of bone metastasis. However, vatalanib failed to inhibit bone metastasis caused by B02 breast cancer cells. In sharp contrast, vatalanib in combination with bevacizumab reduced not only bone destruction but also skeletal tumor growth in animals bearing breast cancer bone metastases, when compared with either agent alone. Thus, our study highlights the importance of targeting both the tumor compartment and the host tissue (i.e., skeleton) to efficiently block the development of bone metastasis. We believe this is a crucially important observation as the clinical benefit of anti‐angiogenic monotherapies in metastatic breast cancer is relatively modest.

Serum Sclerostin Increases After Acute Physical Activity

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 120xa0min 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 5xa0min 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 (meanu2009±u2009SD age: 22.9u2009±u20091.5 years) for the exercise test and 9 participants for the resting test (26.1u2009±u20093.1 years). There was no difference in body mass index between the two groups. Sclerostin increased after exercise in comparison to baseline (meanu2009±u2009SEM: 410u2009±u200927 vs. 290u2009±u200919xa0pg/mL; pu2009<u20090.001) corresponding to an increase of +44.3 ±5.5%. In the resting test, sclerostin remained stable (303u2009±u200920 vs. 294u2009±u200920xa0pg/mL, pu2009=u20090.76). 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.

Has sclerostin a true endocrine metabolic action complementary to osteocalcin in older men

SummaryThe reported association between sclerostin and diabetes mellitus or abdominal fat may be biased by body size and bone mass. In older men, the association between serum sclerostin levels and metabolic syndrome lost significance after adjustment for bone mass. The association between sclerostin and energy metabolism needs further clarification.IntroductionSclerostin is associated with abdominal fat, but this relationship may be biased since both are associated with body size and bone mass. Osteocalcin is a bone-derived hormone regulating energy metabolism. We assessed the association between serum sclerostin and metabolic syndrome (MetS) accounting for whole body mineral content (BMC) and osteocalcin.MethodsWe studied 694 men aged 51–85 who had serum osteocalcin and sclerostin measurements.ResultsSclerostin was higher in 216 men with MetS compared with those without MetS (pu2009<u20090.005). Average sclerostin level increased significantly across the increasing number of MetS components. In multivariable models, higher sclerostin was associated with higher odds of MetS (odds ratio (OR)u2009=u20091.24/1 standard deviation (SD) increase [95xa0% confidence interval (95xa0% CI), 1.01–1.51]; pu2009<u20090.05). After further adjustment for BMC, the association of MetS with sclerostin lost significance, whereas that with osteocalcin remained significant. Men who were simultaneously in the highest sclerostin quartile and the lowest osteocalcin quartile had higher odds of MetS (ORu2009=u20092.14 [95xa0% CI, 1.15–4.18]; pu2009<u20090.05) vs. men being in the three lower sclerostin quartiles and three upper osteocalcin quartiles. After adjustment for whole body BMC, the association lost significance.ConclusionsHigher sclerostin level is associated with MetS severity; however, this association may be related to higher whole body BMC. The adjustment for BMC had no impact on the association between MetS and osteocalcin. Clinical cross-sectional studies do not elucidate the potential role of sclerostin in the regulation of energy metabolism and direct experimental approach is necessary.

The Relationship Between Body Composition and Bone Quality Measured with HR-pQCT in Peritoneal Dialysis Patients

Background: Bone is known to be impaired in chronic kidney disease and dialysis patients. Recent studies have shown that body composition (fat mass and lean mass) may impact bone health. Some of these effects may be related to mediators that are secreted by adipose tissue. Methods: The aim of this study was to evaluate the association between body composition (dual x-ray absorptiometry [DEXA]) and adipokines (leptin, adiponectin), with bone density and microarchitecture assessed with high-resolution peripheral quantitative computed tomography (HR-pQCT) in chronic peritoneal dialysis (PD) patients in a single-center prospective study. Results: Twenty-three patients with a median age of 61 years and body mass index (BMI) of 27 kg/m2 were recruited. On univariate analysis, age was negatively associated with total volumetric bone mineral density (vBMD) (r = -0.75, p < 0.01), cortical vBMD (r = -0.85, p < 0.01), and cortical thickness (r = -0.71, p < 0.01). There was a negative association between leptin and cortical thickness (r = -0.48, p = 0.021). Fat mass (FM) was negatively correlated with cortical thickness (r = -0.52, p = 0.012). No association was found between bone parameters and dialysis duration, serum insulin, intact parathyroid hormone, osteocalcin, and adiponectin. The short dialysis vintage could in part explain the lack of correlation with bone parameters. In multivariate analysis, FM was significantly and negatively correlated with total vBMD, cortical and trabecular thickness. Conclusions: These data suggest that FM is negatively associated with bone quality in PD patients, supporting a relation between body composition and bone that is independent from other dialysis-associated complications. The relative contribution of the different fat deposits (visceral versus subcutaneous) needs to be assessed in future studies.