Serum 25-hydroxyvitamin D status, quantitative ultrasound parameters, and their determinants in Greek population.

Vitamin D deficiency and quantitative ultrasound measurements are associated with bone fragility. We assessed these parameters and their correlates. 87.7% of the population has vitamin D inadequacy and this correlated with lifestyle factors. These results contribute to epidemiological data needed for population guidelines for bone health. PURPOSE: Vitamin D deficiency and quantitative ultrasound (QUS) parameters are among the most important clinical risk factors of bone fragility. Few data are available for Greek population. The aim of the study was to evaluate the serum 25-hydroxyvitamin D [25(OH)D] level and their determinants, as well as QUS parameters in Greek population. METHODS: OSTEOS is an observational cross-sectional study conducted from June 2010 to July 2012. Nine hundred seventy adults were recruited from rural and urban areas throughout Greece and completed the appropriate questionnaire. Serum 25(OH)D measured by enzyme immunoassay, QUS parameters, broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (SI), was assessed with an Achilles device. Univariate Analysis of Variance was used for the assessment of serum 25(OH)D determinants. RESULTS: Mean serum 25(OH)D of the total population was 20,00 ± 8,00 ng/mL. Females had lower levels than males. The negative determinants of serum 25(OH)D in the total population were the female sex and the winter-spring season of sampling while age proved negative association solely in obese subjects. Positive determinants of vitamin D status were summer sun exposure and organized physical activity as expected. Urban had lower SOS and SI than rural residents. Individuals with 25(OH)D ≥ 20 ng/mL had higher SOS than those with 25(OH)D < 20 ng/mL. BUA, SOS, and SI are positively correlated with organized physical activity and negatively with PTH. CONCLUSIONS: This study reports that vitamin D deficiency is highly prevalent among healthy Greek men and women, demonstrates the multifactorial causation of 25(OH)D levels, and points out that further research is required to determine more factors related to vitamin D status and bone health.

Periostin and sclerostin levels in juvenile Paget's disease.

Juvenile Paget's disease (JPD) is a rare, autosomal recessive disorder featuring markedly increased serum alkaline phosphatase activity, indicative of greatly accelerated bone turnover throughout the skeleton. The main aim of this study was to evaluate circulating periostin and sclerostin levels in two adult patients with mild JPD (due to "Balkan" mutation). We measured periostin and sclerostin levels in a previously described woman and a newly diagnosed man with JPD, and 10 apparently healthy individuals, matched (1:5) to JPD patients for gender, age and body mass index. Sclerostin levels were similar between JPD patients and controls. Periostin levels were about 2.5 times higher in JPD patients. Periostin and sclerostin levels were negatively correlated (rs= -0.63; p=0.03). In conclusion, a trend towards higher periostin levels was observed in JPD patients, whereas sclerostin levels were similar to controls.

Low periostin levels in adult patients with Langerhans cell histiocytosis are independently associated with the disease activity.

PURPOSE: Langerhans cell histiocytosis (LCH) is a rare proliferative disease of cells of the CD1a+/CD207+ myeloid dendritic cell lineage that may infiltrate one or more organs or systems at all ages. We aimed to evaluate periostin and sclerostin serum levels in adult patients with LCH. PROCEDURES: This was a cross-sectional study comparing 38 adult patients with LCH with 38 age- and sex-matched healthy controls. Serum periostin and sclerostin levels were measured to compare between LCH patients and controls as well as between patients with active and non-active disease. RESULTS: Serum periostin levels were significantly lower in LCH patients than controls (457±72ng/ml vs. 721±79ng/ml, p=0.014) but this was not the case for sclerostin levels which did not differ between patients and controls, respectively (29.0±1.8pmol/L vs. 39.5±3.8pmol/L, p=0.12). Patients with active disease had significantly lower periostin levels than those with inactive disease (240±78ng/ml vs. 558±94ng/ml, p=0.008). No effect of specific site involvement, extend of disease, or treatment administered was found on any of the above parameters measured. CONCLUSIONS: Lower serum periostin levels were observed in adult LCH patients with active disease. The finding warrants further investigation to define whether periostin could serve as a serum biomarker for LCH activity.

Circulating sclerostin and Dickkopf-1 levels in patients with nonalcoholic fatty liver disease.

There is increasing evidence for bone-liver interplay. The main aim of this study was to determine serum sclerostin and Dickkopf (DKK)-1 levels in patients with nonalcoholic fatty liver disease (NAFLD) and their association with the disease severity. Patients with biopsy-proven NAFLD, 13 with nonalcoholic simple steatosis (SS) and 14 with steatohepatitis (NASH), and 20 gender-, age-, body mass index- and waist circumference-matched controls were enrolled. Serum sclerostin, DKK-1, bone turnover markers, vitamin D, insulin and standard biochemical and hematologic parameters were measured; lumbar spinal dual-energy X-ray absorptiometry was performed. We observed that there was a progressive decline in serum sclerostin levels from the controls (76.1 ± 6.8) to SS (53.5 ± 6.4) and NASH (46.0 ± 8.1 pmol/l) patients (p = 0.009); in adjusted pairwise comparisons, sclerostin was significantly higher in the controls than in NASH patients (p = 0.012). Although serum DKK-1 did not differ between groups (p = 0.135), there was a trend toward U-shaped distribution (controls 35.8 ± 2.8; SS 27.3 ± 2.9; NASH 36.8 ± 4.4 pmol/l). Higher DKK-1 levels were independently associated with NASH. Regarding specific histological lesions, DKK-1 levels were marginally lower in NAFLD patients with lower (≤33 %) than higher (>33 %) steatosis grade (27.7 ± 3.1 and 38.8 ± 4.7 pmol/l, respectively; p = 0.049). No other significant difference was observed within histological lesions. In conclusion, serum sclerostin levels were lower in NASH patients than in controls. DKK-1 levels were independently associated with NASH in NAFLD patients. The potential importance of these findings indicates a possible bone-liver interaction and warrants further investigation.

Denosumab in treatment-naïve and pre-treated with zoledronic acid postmenopausal women with low bone mass: Effect on bone mineral density and bone turnover markers.

PURPOSE: To compare denosumab-induced changes in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD), bone markers and free soluble receptor activator of nuclear factor kappaB ligand (sRANKL) between treatment naïve postmenopausal women with low bone mass (naïve group) and those who were previously treated with a single zoledronic acid infusion (post-Zol group). PROCEDURES: Procollagen type 1N-terminal propeptide (P1NP), C-terminal cross-linking telopeptide of type 1 collagen (CTx) and sRANKL levels were measured in serum samples obtained at baseline and 3, 6 and 12months after denosumab initiation. LS and FN BMD were measured at baseline and 12months. RESULTS: LS and FN BMD increased significantly in both naïve and post-Zol group (p<0.001 and p=0.025 vs. p<0.001 and p=0.017, respectively). Despite the higher P1NP and CTx levels in naïve patients at baseline (both p<0.001), denosumab caused comparable decreases in both groups at month 3, which returned to post-Zol group baseline levels at month 6 and 12 in all patients. Similarly, sRANKL levels decreased significantly at month 3 in both groups and returned to baseline levels at months 6 and 12. CONCLUSIONS: In patients previously treated with zoledronic acid, sequential denosumab treatment is effective in terms of BMD increases and bone turnover suppression. Despite the lower baseline levels in patients pre-treated with zoledronic acid, bone markers are similarly decreased in both groups following denosumab administration and maintain their reversibility. Denosumab reversibly suppresses endogenous free sRANKL levels in both naïve and zoledronic acid pre-treated patients.

Circulating semaphorin-4D and plexin-B1 levels in postmenopausal women with low bone mass: the 3-month effect of zoledronic acid, denosumab or teriparatide treatment.

OBJECTIVE: The evaluation of circulating semaphorin-4D (sema4D) and plexin-B1 in postmenopausal women with low bone mass and the effect of antiresorptive or osteoanabolic treatment. METHODS: Serum samples were obtained from postmenopausal women with low bone mass at baseline and 3 months after zoledronic acid infusion (n = 30), denosumab injection (n = 30) or teriparatide initiation (n = 28) and from controls matched for age, age at menopause and body mass index (n = 30) at the same time points. MAIN OUTCOME MEASURES: Circulating sema4D and plexin-B1. RESULTS: Circulating sema4D increased following denosumab (p = 0.026), whereas decreased following teriparatide (p = 0.013). Sema4D/plexin-B1 ratio increased following denosumab (p = 0.004). At baseline, sema4D and plexin-B1 levels were higher in patients pre-treated with bisphosphonates compared to naïve ones (p < 0.001 and p = 0.001, respectively). In bivariate correlations sema4D was inversely correlated with serum carboxyterminal telopeptide of type 1 collagen (rs -0.282, p = 0.002), intact parathyroid hormone (rs -0.388, p < 0.001) and 25(OH)D (rs -0.316, p < 0.001), whereas there was a trend towards correlation with lumbar spine bone mineral density (rs -0.191, p = 0.053). CONCLUSIONS: Sema4D levels are independently associated with previous bisphosphonate treatment, intact parathyroid hormone and 25(OH)D levels. Denosumab and teriparatide seem to exert an opposite effect on circulating sema4D levels. Further studies are needed to evaluate whether sema4D mediates the coupling effect that occurs following both antiresorptive and osteoanabolic treatment.

The AGT and the GNB3 polymorphisms and insulin resistance in prehypertension.

OBJECTIVE: This study surveyed the frequencies of single nucleotide polymorphisms (SNPs) M235T AGT and C825T GNB3, and their association with insulin resistance, other biochemical markers and qualitative variables in subjects with high normal blood pressure and/or prehypertension in the Greek population. DESIGN: 330 men and women of Greek origin were divided into 3 groups: a) hypertensive, b) prehypertensive and c) control group. These groups were genetically tested for these polymorphisms and insulin resistance with the HOMA index. RESULTS: No statistically significant differences were found among the polymorphisms of the compared groups. However, the ? allele carriers (CT/TT vs. CC) of the C825T polymorphism were associated with an increased BMI in all 3 groups (p=0.004). The HOMA index was higher in the hypertensive (p=0.006) and prehypertensive (p=0.016) versus the control group, and similar results were found for insulin (hypertensive vs. control p=0.012, prehypertensive vs. control p=0.001) without statistical significance between the first 2 groups (p=0.522). Additionally, there was a statistically significant difference between the control group and the hypertensive and prehypertensive groups regarding cholesterol (control vs. hypertensive p=0.001, control vs. prehypertension p=0.018) and triglycerides (control vs. hypertensive p=0.0001, control vs. prehypertension p=0.007). Differences were also noted between the control and the hypertensive group regarding the value of HDL (p=0.005) and LDL (p=0.013). CONCLUSION: This study failed to demonstrate a correlation between specific SNPs, blood pressure and insulin resistance in the 3 groups. However, T allele carriers of the polymorphism C825T were found to have an increased BMI. Similarly, increased insulin resistance and lipidemia were more common in the hypertensive and prehypertensive populations.

Parathyroid hormone changes following denosumab treatment in postmenopausal osteoporosis.

OBJECTIVE: Denosumab is a new potent antiresorptive treatment of osteoporosis that can potentially induce a compensatory increase in parathyroid hormone (PTH) levels. We aimed to evaluate the alteration of PTH 1 and 6 months after denosumab's administration with different regimens of calcium and vitamin D (Ca/D) supplementation. DESIGN: Prospective, multicenter, study in a relatively small, heterogeneous sample of postmenopausal women followed for 6 months. PATIENTS: Forty seven postmenopausal women followed in 2 outpatient clinics, requiring onset or continuation of osteoporosis treatment. We administered 1 g calcium carbonate and 800 IU cholecalciferol daily for 6 months (Group A) or the double dose for the first month followed by the 1 g/800 IU Ca/D regimen for the next 5 months (Group B). MEASUREMENTS: Parathyroid hormone (PTH) alterations between and within groups, and their associations with serum Ca and bone markers. RESULTS: Parathyroid hormone (PTH) levels were significantly higher at month 1 and 6 only in Group A; Ca levels were significantly decreased at month 1 and returned to baseline values at month 6 within the same Group. The mean per cent change between month 1 and baseline for PTH [Δ(PTH1-0 )] was significantly higher in Group A than B (63·5% ± 28·2% vs -3·0% ± 4·7%, P = 0·029). Δ(PTH1-0 ) was correlated with the reciprocal Δ-changes of Ca (rs  = -0·610; P = 0·002) and collagen type I C-terminal telopeptide (rs  = -0·697; P = 0·003) only in Group A. CONCLUSIONS: An increase in PTH should be expected, at least following the first administration of denosumab in common clinical practice. The effect of this compensatory onsequence in bone metabolism warrants further investigation.

Reduced bone mineral density in adult patients with Langerhans cell histiocytosis.

This retrospective study evaluated bone mineral density (BMD) and bone turnover in adults with LCH. Twenty-five adult patients and 25 matched controls were evaluated with BMD measurement and indices of bone metabolism. A BMD value below the expected range for age (Z-score ≤ - 2.0) was found in 20% of patients; in particular, all postmenopausal women and men over 50-years had either osteoporosis or osteopenia. Patients with active disease had significantly lower Z-scores compared to patients with inactive disease and controls. Reduced bone turnover was found in all 14 patients treated with chemotherapy. No fractures due to osteoporosis were identified during 305.15 patient-years of follow-up.

Obesity and endocrine disease.

Several endocrine abnormalities are reported in obesity. Some of these abnormalities are considered as causative factors for the development of obesity, whereas others are considered to be secondary effects of obesity and usually are restored after weight loss. Thyroid hormones usually are normal in obesity, with the exception of T3 which is elevated. Prolactin is normal but prolactin response to different stimuli is blunted. GH is low and GH response to stimuli is blunted. IGF-I levels are normal or elevated. Cortisol, ACTH, and urine free cortisol levels are usually normal; however, a hyperresponsiveness of the HPA axis with increased cortisol and ACTH response to stimulatory tests is observed in centrally obese individuals. Total testosterone and SHBG levels are low, but free testosterone levels are usually normal in obese men. LH and FSH levels usually are normal and estrogens are elevated. Norepinephrine levels are elevated, whereas epinephrine levels are low or normal. Aldosterone levels are elevated but renin activity is usually normal. Parathyroid hormone levels are elevated with normal serum calcium levels and increased urine calcium levels. Monogenic mutations that result in severe obesity have been described in several individuals. Also, several endocrine diseases have obesity as one their clinical manifestations. Hypothyroidism, Cushing's syndrome, GH and testosterone deficiency, polycystic ovarian syndrome, insulinoma, hypothalamic lesions, and genetic syndromes often present with obesity. In most of these conditions, appropriate treatment of the primary disease results in weight loss. In addition, the fat cell has been found to be an endocrine organ that produces several peptides that are bioactive and participate in the regulation of adipocyte function.