Antonia García-Martín

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

Osteocalcin as a marker of metabolic risk in healthy postmenopausal women.

Objective: Several studies have reported the role of osteocalcin on glucose and fat metabolism. In this study, we analyzed the relationship between the concentration of osteocalcin and metabolic risk factors in healthy postmenopausal women. Methods: Cross-sectional analyses of 54 postmenopausal women aged 56 ± 3.5 years were conducted. We recorded clinical and biochemical data of metabolic risk including fasting plasma glucose (FPG) level and evaluated the relationship between serum osteocalcin and bone formation markers. Results: Serum osteocalcin concentration was negatively correlated with FPG (&bgr; = −0.328, P = 0.035). When osteocalcin levels were divided into tertiles, we found significant differences in FPG between the highest and the lowest tertiles (84 ± 11 vs 98 ± 30 mg/dL, respectively; P = 0.029). We found significantly lower osteocalcin levels in women with impaired fasting glucose levels than in those with normoglycemia (10.7 ± 6.1 vs 17.1 ± 7.4 ng/mL, respectively; P = 0.006). We also found lower concentrations of osteocalcin in obese women versus nonobese women (14.4 ± 8.8 vs 17.3 ± 6.2 ng/mL; P = 0.034) and women with increased low-density lipoprotein cholesterol levels versus those with low LDL-c levels (14.1 ± 5.4 vs 18.9 ± 9.1 ng/mL; P = 0.045). A concentration of 13.5 ng/ mL or lower showed a sensitivity of 85.7% and a specificity of 63.8% to detect increased risk for diabetes (FPG ≥100 mg/dL). In contrast, serum levels of bone alkaline phosphatase did not correlate with any variable. Conclusions: In this population, there is a consistent association between osteocalcin and markers of metabolic syndrome. We suggest potential usefulness of serum osteocalcin as a predictor for increased risk of diabetes in postmenopausal women.

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 …

Experience with cinacalcet in primary hyperparathyroidism: results after 1 year of treatment

Objectives: To assess the characteristics of patients with primary hyperparathyroidism (PHPT) treated with cinacalcet and to evaluate its efficacy in reducing serum calcium and parathyroid hormone (PTH) concentrations after 1 year of treatment. Methods: The study included 20 patients with PHPT who had completed at least 12 months of treatment with cinacalcet (eight patients for refusal of parathyroidectomy, three for surgery not possible due to comorbidities and nine for progressive hypercalcemia prior to surgery). We recorded clinical and biochemical data at baseline, and after 3, 6 and 12 months of treatment. We also monitored adverse events. Cinacalcet was administered in increasing doses until normal serum calcium was reached or side effects preventing a further increase occurred. Results: After 3 months of treatment, serum calcium significantly decreased (11.73 ± 0.85 versus 10.71 ± 1.63 mg/dl, p < 0.001) and serum phosphorus significantly increased (2.41 ± 0.48 versus 2.63 ± 0.70 mg/dl, p = 0.004) while no significant change occurred in PTH (181.91 ± 102.37 versus 195.47 ± 111.71 pg/ml, p = 0.695). No further variation was observed after 6 months compared with 3 months of follow up. However, after 12 months of treatment, there was a significant decrease in PTH concentrations compared with baseline (181.91 ± 102.37 versus 152.47± 70.16 pg/ml, p = 0.028) as well as serum calcium (11.73 ± 0.85 versus 10.20± 0.95 mg/dl, p < 0.001); serum phosphorus significantly increased (2.41 ± 0.48 versus 2.71 ± 0.43 mg/dl, p = 0.01). Normocalcemia (S-Ca < 10.2 mg/dl) was achieved in 55% of patients. The medication was usually well tolerated (83.4%). Most common adverse events were nausea and vomiting, especially at the beginning of therapy. Conclusion: Cinacalcet rapidly reduced serum calcium in patients with PHPT and this reduction remained stable after 1 year of treatment. We also observed a decrease in PTH. Cinacalcet is an effective alternative in nonsurgical treatment of PHPT and may be useful in the preoperative hypercalcemia management.

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.

Ischemic heart disease is associated with vertebral fractures in patients with type 2 diabetes mellitus

Discordant results about the relationship between diabetes complications and the risk of fragility fractures have been reported. Our aims were to analyze the factors related to morphometric vertebral fractures (VFs) in patients with type 2 diabetes mellitus, and to explore the association between the presence of VFs and the main cardiovascular risk factors.

Serum 25 OH vitamin D concentrations and calcium intake are low in patients with prostate cancer

OBJECTIVE To evaluate dietary calcium intake (DCI) and vitamin D serum concentrations in patients with prostate cancer. METHODS We conducted a cross-sectional study including 91 subjects with prostate cancer. We determined DCI by a questionnaire, 25 OH vitamin D levels and bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA). RESULTS According to current guidelines (1000 mg/day), calcium intake was low in patients with prostate cancer (394±201 mg/day). Twenty-two percent (20) of patients had adequate levels of vitamin D, whereas 29.7% (27) of patients were vitamin D deficient and 48.3% (44) were classified as vitamin D insufficiency. Vitamin D levels were not different in patients with or without androgen-deprivation therapy. There were no correlation between DCI, 25 OH vitamin and BMD. CONCLUSIONS In summary, in our group of prostate cancer patients DCI was low and vitamin D deficiency is highly prevalent. Although this is a common condition in other populations, in this group of patients especially prone to osteoporosis could have more relevance. Additional research is needed to establish the consequences of low calcium intake and vitamin D deficiency in prostate cancer patients.