Rebeca Reyes-García

Circulating Levels of Sclerostin Are Increased in Patients with Type 2 Diabetes Mellitus

CONTEXT Diabetes mellitus is a risk factor for osteoporotic fractures. Sclerostin is an inhibitor of bone formation. However, there are no data about sclerostin levels in type 2 diabetes mellitus (T2DM). OBJECTIVES The aims were to evaluate serum sclerostin in T2DM patients and to analyze its relationship with bone metabolism. DESIGN, SETTING, AND PATIENTS This was a cross-sectional study. We compared serum sclerostin in the T2DM group (n = 74) and control group (n = 50), and we analyzed its relationship with calciotropic hormones, bone turnover markers, bone mineral density (BMD), and morphometric vertebral fractures. RESULTS Sclerostin levels were significantly higher in T2DM patients than control subjects (P < 0.001) and in T2DM males than in T2DM females (P < 0.001). Serum sclerostin was positively correlated with age in males T2DM (P = 0.031). In linear regression analysis, gender, study group, and age were predictive of sclerostin levels (P < 0.05). Sclerostin concentrations were positively associated with duration of T2DM (P = 0.064) and glycated hemoglobin (P = 0.074) independently of age in T2DM patients. Sclerostin was inversely related to bone turnover markers (P < 0.05) and positively related to lumbar spine, femoral neck, and total hip BMD (P < 0.05) in the T2DM group. Sclerostin was significantly lower in osteoporotic than nonosteoporotic patients with T2DM (P = 0.048). CONCLUSIONS Circulating sclerostin is increased in T2DM independently of gender and age. Serum sclerostin is also correlated with duration of T2DM, glycated hemoglobin, bone turnover markers, and BMD in T2DM patients. Additional studies are needed to evaluate the role of sclerostin on bone metabolism in this population.

Atherosclerotic Disease in Type 2 Diabetes Is Associated With an Increase in Sclerostin Levels

OBJECTIVE Wnt/β-catenin signaling is related to the pathogenesis of several diseases. Sclerostin is an inhibitor of Wnt/β-catenin signaling. However, there are few data regarding the sclerostin levels and vascular disease. Our aim was to examine the relationship between serum sclerostin and atherosclerotic disease (AD) in type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS We performed a cross-sectional study including 78 T2DM patients (45.3% females, mean age 59 ± 5.7 years; 54.7% males, 57.4 ± 6.7 years). RESULTS Serum sclerostin concentrations of T2DM patients in the AD group were significantly higher than in the non-AD group (P = 0.006). For each increase of 1 pmol/L in sclerostin level, there was a 4% increase of the risk of AD in T2DM patients. A concentration of ≥42.3 pmol/L showed a sensitivity of 69% and a specificity of 54.8% to detect an increased risk of AD. In males, sclerostin levels were higher in those with AD (P = 0.04), abnormal intima-media thickness (IMT) (P = 0.004), carotid plaques (P < 0.001), and aortic calcification (P < 0.001). In females, higher levels of sclerostin were related to abnormal IMT (P = 0.03) and aortic calcifications (P = 0.004). Homocysteine (β = 0.319 [95% CI 0.561–2.586], P = 0.003) and IMT (β = 0.330 [14.237–67.693], P = 0.003) were positively correlated with sclerostin. CONCLUSIONS Circulating sclerostin is increased in T2DM patients with atherosclerotic lesions. Although the sample size of our study was small, these data suggest that sclerostin levels could be a major modulator of Wnt signaling in AD with implications in T2DM patients.

Normocalcemic primary hyperparathyroidism: one-year follow-up in one hundred postmenopausal women

Routine measurement of parathormone (PTH) has lead to the identification of high PTH levels without hypercalcemia. This situation, which is known as normocalcemic hyperparathyroidism [1], was defined by Wills in 1962 and is established after ruling out the main causes of secondary hyperparathyroidism. There are conflicting data about its bone effects and clinical course. The aims of our study was to evaluate the frequency of normocalcemic hyperparathyroidism in postmenopausal, to analyse parameters related to bone metabolism, and to assess changes after one-year follow-up. We conducted a prospective study conducted in a cohort of 100 healthy postmenopausal women. Clinical and biochemical data and bone mass by quantitative ultrasound (QUS) were determined at baseline and after 1 year. The study protocol was approved by the ethical review board of our hospital and was done conformed to the ethics guidelines for research in humans. All the participants in the study provided written informed consent. Baseline characteristics of the study groups are shown in Table 1. 16 patients had high PTH levels, one woman with criteria of primary hyperparathyroidism (PTH 109 pg/ml and calcium 11.2 mg/dl) who was excluded from the study and 15 of them with normal calcium serum levels (PTH 78 ± 13 pg/ml and serum calcium 9.3 ± 0.3 mg/dl). In this group, six patients had high PTH with 25-OH vitamin D [30 ng/ml and were classified as normocalcemic primary hyperparathyroidism. There were no differences in biochemical and clinical variables between women with secondary hyperparathyroidism and normocalcemic hyperparathyroidism except for 25-OH vitamin D: 17.4 ± 10 versus 33.2 ± 2.6 ng/ml, p \ 0.001 (Table 1). There was a high percentage of women in both groups with low 25-OH vitamin levels: 72.6 % (61/84) in normal PTH group versus 57.2 % in women with secondary hyperparathyroidism (9/15) (p = 0.32). Women with secondary hyperparathyroidism and normocalcemic hyperparathyroidism have normal values of renal function, bone turnover markers and bone mass measured by QUS. In the group consisting of secondary and normocalcemic hyperparathyroidism, PTH showed a negative correlation with QUS parameters: QUI: r = -0.621, p = 0.013; BMD r = -0.554, p = 0.032; Tscore r = -0.571, p = 0.026. No correlation was observed between PTH and bone mass in the group with normal PTH levels. After one-year of follow-up, PTH remained high in 86.7 % (13/15) of women and in 13.3 % (2/15) PTH has dropped to normal values. In women with secondary hyperparathyroidism there were no significant changes in biochemical and clinical variables (Table 1). The six women with baseline criteria of normocalcemic hyperparathyroidism remained in this category after 1 year. No episodes of hypercalcemia or other relevant clinical events were observed in this group. To our knowledge, no previous studies have evaluated the frequency of normocalcemic hyperparathyroidism in postmenopausal Spanish women. In the Canadian Multicentre Osteoporosis normocalcemic hyperparathyroidism was diagnosed in 16.7 % of subjects, but they considered 25-OH vitamin D \20 ng/ml as vitamin D deficiency which may have contributed to the higher prevalence observed. The evaluation of well known causes of secondary hyperparathyroidism in our sample (low vitamin D, renal disease, malnutrition) allowed us to exclude women A. Garcia-Martin (&) R. Reyes-Garcia M. Munoz-Torres Bone Metabolic Unit, Endocrinology Division, University Hospital San Cecilio, Avenida Doctor Oloriz 16, 18012 Granada, Spain e-mail: garciamartin_t@hotmail.com

Serum cathepsin K as a marker of bone metabolism in postmenopausal women treated with alendronate

CONTEXT Cathepsin K is a member of the cysteine protease family that cleaves both helical and telopeptide regions of collagen I, the major type of collagen in bone. Measurement of circulating levels of cathepsin K may be useful to assay the number or function of osteoclasts. OBJECTIVE The aim of the study was to evaluate the role of serum cathepsin K as a biochemical marker of bone metabolism in patients with postmenopausal osteoporosis before and after treatment with alendronate. DESIGN, SETTING AND PARTICIPANTS The study was a case-control and prospective study with postmenopausal osteoporotic women including a total number of 86 subjects. Serum cathepsin K was determined in 46 women with postmenopausal osteoporosis before and after 3, 6 and 12 months of treatment with alendronate. Basal serum cathepsin K levels were also compared between premenopausal healthy women (n=20), postmenopausal women without osteoporosis (n=20) and osteoporotic women. In addition, serum carboxyterminal cross-linked telopeptide of type I collagen (CTX), osteocalcin (OC) and bone-specific alkaline phosphatase (bALP) were measured. MAIN OUTCOME MEASURE Changes in cathepsin K serum levels after alendronate treatment. RESULTS Serum cathepsin K levels were higher in postmenopausal women with osteoporosis (9.4+/-11pmol/L) compared with healthy postmenopausal women (6.8+/-8.1pmol/L; p<0.01) and premenopausal women (6.3+/-5.0pmol/L, p<0.01). Serum cathepsin K decreases gradually after alendronate treatment (17% at 3 months, 22% at 6 months and 41% at 12 months, p<0.01). In contrast, the treatment resulted in early and sustained reductions in serum CTX. CONCLUSION We conclude that serum cathepsin K seems to provide additional information on bone metabolism in postmenopausal women treated with alendronate.

Effects of raloxifene therapy on circulating osteoprotegerin and RANK ligand levels in post-menopausal osteoporosis

Previous in vitro studies suggest that the anti-resorptive effect of raloxifene might be mediated by changes in several cytokines involved in the bone remodeling process. In this context, the osteoprotegerin (OPG)-receptor activator of NFκB ligand (RANKL) system is considered a key component in the osteoclastogenesis regulation. The aim of this study was to determine the effects of raloxifene treatment on serum concentrations of OPG, receptor RANKL and its relationship with biochemica markers of bone turnover and bone mineral density (BMD) in previously untreated women with post-menopausal osteoporosis. We selected 47 post-menopausal women (mean age 63±7 yr) with densitometric criteria of osteoporosis. We determined at baseline, 3, 6, and 12 months anthropometric parameters, biochemical markers of bone turnover, serum levels of 25(OH) D, serum levels of OPG and RANKL. BMD (dual-energy x-ray absorptiometry) in lumbar spine (LS) femoral neck and total hip was measured at baseline and 12 months after raloxifene (60 mg/day) treatment. Serum levels of OPG decreased in the 3rd and 6th month of treatment (p<0.001) and returned to basal levels in the 12th month. There was a significant decrease of RANKL levels and OPG/RANKL ratio after 1 yr of raloxifene treatment. In addition, BMD in LS increased significantly (2.5%) in the 12th month of treatment (p=0.031). Finally, the biochemical markers of bone turnover (total alkaline phosphatase, bone alkaline phosphatase, osteocalcin, tartrate-resistant acid phosphatase, urine cross-linked carboxi-terminal telopeptide of type I collagen) decreased significantly from the 3rd month of treatment. In conclusion, our results support the hypothesis that raloxifene may inhibit osteoclast activity, at least partly modulating the OPG-RANKL system.

FGF23 in type 2 diabetic patients: relationship with bone metabolism and vascular disease.

The relationship between fibroblast growth factor (FGF) 23 and vascular disease is well established in chronic kidney disease (CKD). Regarding serum FGF23 and bone fragility, there is contradictory data. Type 2 diabetes (T2D) is associated with higher rates of cardiovascular disease and fractures despite high bone mineral density (BMD), so the evaluation of FGF23 and its relationship with bone and cardiovascular disease in T2D is of interest. Our hypothesis was that serum FGF23 may be related to cardiovascular disease and bone metabolism (BMD, osteoporosis, and fractures) in T2D. We performed a cross-sectional study including 68 T2D subjects and 45 subjects without diabetes. We analyzed the relationship between circulating FGF23, bone metabolism, cardiovascular events, and intima-media thickness (IMT). There were no differences in FGF23 according to group. In the …

Daily Intake of Milk Enriched with n-3 Fatty Acids, Oleic Acid, and Calcium Improves Metabolic and Bone Biomarkers in Postmenopausal Women

Objective: Nutritional strategies can be effective for the prevention of menopause-related diseases, such as osteoporosis and cardiovascular disease. Our aim was to evaluate the effects of a dairy product enriched in polyunsaturated fatty acids, calcium, oleic acid, and vitamins on cardiovascular markers and bone metabolism in postmenopausal women with moderate cardiovascular risk. Methods: One hundred seventeen healthy postmenopausal women (aged 45 ± 7.7 years) were allocated to 2 groups: the intervention group (IG; n = 63), who consumed 0.5 L/day of a low-lactose skimmed milk enriched with 40 mg/100 mL of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), 0.54 g/100 mL oleic acid, and vitamins, and the control group (CG; n = 54), who consumed 0.5 L/day of semiskimmed milk 0.5 L/day enriched with vitamins A and D. Results: After 12 months, in the IG there was an improvement in lipid profile: a −5.78% decrease in total cholesterol (p = 0.010), −9.79% (p = 0.004) in low-density lipoprotein (LDL) cholesterol, −9.56% (p < 0.001) in total cholesterol (TC)/high-density lipoprotein (HDL) ratio, and −3.38% in LDL/HDL ratio (p < 0.001). No changes were observed in the CG. In the IG we observed a decrease of −28.20% in high-sensitivity C-reactive protein (hs-CRP; p = 0.012). There was no effect on bone turnover markers or serum osteoprotegerin (OPG) in either of the study groups. In the IG, receptor activator of nuclear factor κB ligand (RANKL) was reduced −17.64% (p = 0.003), with no effect in the CG. Conclusion: In postmenopausal women with moderate cardiovascular risk, dietary supplementation with a dairy drink enriched with fatty acids (EPA+DHA), oleic acid, minerals, and vitamins induces a positive effect on cardiovascular risk and parameters of bone metabolism. Its regular consumption may be a useful nutritional support for postmenopausal women.

Relationship of Dickkopf1 (DKK1) with Cardiovascular Disease and Bone Metabolism in Caucasian Type 2 Diabetes Mellitus

Objectives Dickkopf-1 (DKK1) is a potent inhibitor of Wnt signalling, which exerts anabolic effects on bone and also takes part in the regulation of vascular cells. Our aims were to evaluate serum DKK1 in type 2 diabetes (T2DM) patients and to analyze its relationships with cardiovascular disease (CVD). We also evaluated the relationship between DKK1 and bone metabolism. Design We conducted a cross-sectional study in which we measured serum DKK1 (ELISA, Biomedica) in 126 subjects: 72 patients with T2DM and 54 non-diabetic subjects. We analysed its relationship with clinical CVD, preclinical CVD expressed as carotid intima media thickness (IMT), and bone metabolism. Results T2DM patients with CVD (P = 0,026) and abnormal carotid IMT (P = 0,038) had higher DKK1 concentrations. DKK1 was related to the presence of CVD in T2DM, independently of the presence of risk factors for atherosclerosis. Therefore, for each increase of 28 pg/ml of serum DKK1 there was a 6,2% increase in the risk of CVD in T2DM patients. The ROC curve analysis to evaluate the usefulness of DKK1 as a marker for high risk of CVD showed an area under the curve of 0,667 (95% CI: 0,538–0,795; P = 0,016). In addition, there was a positive correlation between serum DKK1 and spine bone mineral density in the total sample (r = 0,183; P = 0,048). Conclusion In summary, circulating DKK1 levels are higher in T2DM with CVD and are associated with an abnormal carotid IMT in this cross-sectional study. DKK1 may be involved in vascular disease of T2DM patients.

Effects of alendronate treatment on serum levels of osteoprotegerin and total receptor activator of nuclear factor κB in women with postmenopausal osteoporosis

Objective: Bisphosphonates are potent inhibitors of bone resorption that are used as effective therapeutic agents for the management of osteoporosis and other bone diseases. The osteoprotegerin (OPG)-receptor activator of nuclear factor &kgr;B (RANKL) system plays an important role in the regulation of bone metabolism and vascular biology. The effects of bisphosphonate treatment in OPG-RANKL system have not been fully elucidated. The aims of the study were to evaluate the effects of alendronate treatment (70 mg once/wk) on serum concentrations of OPG, total RANKL, and biochemical markers of bone turnover in untreated women with postmenopausal osteoporosis and to determine the correlation between changes in bone mineral density and changes in serum OPG, total RANKL, and bone turnover markers. Methods: The study was a single group pretest/posttest design including a total number of 46 participants. Serum OPG and total RANKL serum levels were determined before and after 3, 6, and 12 months of treatment with alendronate. We also measured serum carboxyterminal cross-linked telopeptide of type I collagen, osteocalcin, and bone-specific alkaline phosphatase. The main outcome measures are the changes in OPG and total RANKL serum levels after alendronate treatment. Results: Serum OPG changes were not significant at 3 and 6 months (−1.6% and −1%), but at 12 months, there was a significant reduction of 6.5% (P < 0.01). Total RANKL serum levels increased during treatment: 23% at 3 months, 25% at 6 months, and 52% at 12 months (P < 0.001 for all comparisons). Basal levels of OPG, total RANKL, and bone turnover markers were not correlated, and we did not find correlations between changes in these parameters after treatment. Conclusions: We conclude that the determination of total RANKL integrates the free RANKL and the fraction bound to OPG. The apparent decrease in the serum levels of OPG might reflect an increase in OPG binding to RANKL, which results in a beneficial effect on bone.

Relationship between Proinflammatory and Antioxidant Proteins with the Severity of Cardiovascular Disease in Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus patients are at significant risk of cardiovascular disease, however, the pathophysiology of these complications is complex and incompletely known in this population. The aim of this study was to compare the serum proteome of patients with type 2 diabetes mellitus presenting or not presenting cardiovascular disease with non-diabetic subjects to find essential proteins related to these cardiovascular complications. This cross-sectional study compares the serum proteome by a combination of protein depletion with 2D-DIGE (2-dimension Difference Gel Electrophoresis) methodology. The proteins differentially expressed were identified by MALDI TOF/TOF (Matrix-assisted laser desorption/ionization and Time-Of-Flight ion detector) or LC-MS/MS (Liquid Chromatography coupled to Mass-Mass Spectrometry). Type 2 diabetes mellitus patients with cardiovascular disease showed higher expression of plasma retinol binding protein and glutathione peroxidase-3 compared to those without cardiovascular disease and non-diabetic controls. These results show that proteins related to the inflammatory and redox state appear to play an important role in the pathogenesis of the cardiovascular disease in the type 2 diabetes mellitus patients.