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ObjectiveCirculating osteoglycin may facilitate the crosstalk between bone and pancreas to empower adaptation of bone mass to whole body energy balance. We aimed to examine whether osteoglycin is associated with bone and metabolic parameters and if osteoglycin levels differ between patients with type 1 and 2 diabetes (T1D and T2D).Design and methodsA cross-sectional study of 190 patients with diabetes mellitus and stable hemoglobin A1c (HbA1c) (97 T1D and 93 T2D) was conducted. S-osteoglycin was analyzed by ELISA. Unpaired t-tests were performed to test differences between patients with T1D and T2D and linear regression analyses were performed to investigate associations between osteoglycin, glycemic markers, bone turnover markers and characteristics.ResultsS-osteoglycin did not differ between patients with T1D and T2D (p=0.10). No associations were present between osteoglycin and age, gender, microvascular complications, HbA1c, or plasma glucose in T1D or T2D patients (p>0.05 for all). S-osteoglycin was not associated with levels of bone turnover markers (C-terminal cross-linked telopeptide of type-I collagen (CTX), P-procollagen type 1 amino terminal propeptide (P1NP), P-osteocalcin (OC), P-sclerostin, S-osteoprotegerin (OPG) or S-Receptor Activator of Nuclear factor Kappa beta Ligand (RANKL)) in neither T1D or T2D patients (p>0.05 for all).ConclusionOsteoglycin levels were similar in T1D and T2D patients. Osteoglycin did not correlate with glucose, HbA1c or any other biochemical marker of bone turnover. Thus, we did not find evidence supporting the existence of an osteoglycin-bone-pancreas axis.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT01870557.

Background: Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis. Methods: The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between −2·5 and −4·0 if no previous radiographic vertebral fracture, or between −1·5 and −4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than −4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66). Findings: Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43–40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45–60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40–0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39–0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68–0·87; all p

Background: The increased fracture risk in persons with diabetes is underestimated by conventional fracture predictors. The aims of this study were to conduct a systematic review and a meta-analysis to compare the levels of bone turnover markers (BTM) in persons with diabetes with and without fractures. Methods: We conducted a systematic literature search. Eligibility criteria were studies investigating BTMs in persons with diabetes with/without fractures. For the meta-analysis, we used the standardised mean difference (SMD) of the markers investigated. Results: We included eight observational studies. Levels of osteocalcin, procollagen type 1 amino terminal propeptide (P1NP), and Insulin-like growth factor-1 (IGF-1) were significantly lower in persons with fracture than in persons without fracture (-0.36 (-0.46, -0.26)) (SMD (95% confidence interval), (-0.57 (-0.75, -0.40)), and (-0.50 (-0.61, -0.39)) respectively. Levels of N-terminal cross-linked telopeptide of type 1 collagen (NTX), sclerostin, and bone-specific alkaline phosphatase (BAP) were significantly higher in persons with fracture (0.24 (0.13, 0.35), (0.47 (0.29, 0.65)), and (0.14 (0.01, 0.27)), respectively, whereas C-terminal cross-linked telopeptide (CTX) showed no difference between the groups. In sensitivity analysis removing one larger study, results were insignificant for osteocalcin, P1NP, NTX, and sclerostin. Conclusions: The results suggest that BTMs may be associated with fracture status in persons with diabetes. Persons with diabetes and fracture have lower levels of formative BTMs and IGF-1, and higher levels of NTX, sclerostin, and BAP compared with no fracture, however, some results were dependent on one larger study.

ObjectiveVisceral adipose tissue (VAT) is associated with an increased risk of metabolic syndrome (MetS). Recent studies have suggested that VAT negatively affects bone. However, MetS has also been associated with higher estradiol (E2) levels, which is bone protective. We therefore investigated the impact of VAT and E2levels on bone density, structural parameters, and strength estimates.DesignA cross-sectional study was conducted in 72 obese men with MetS to investigate the impact of VAT and E2levels on bone.MethodsBone parameters were assessed by dual-energy X-ray absorptiometry (DXA), quantitative computed tomography (QCT), and high-resolution peripheral QCT (HRpQCT) at lumbar spine, proximal femur, radius, and tibia. VAT volume was measured by magnetic resonance imaging (MRI) and sexual hormones were measured in blood samples.ResultsMen with high VAT had a lower bone density at the hip (PP=0.008 andP=0.02), compared with men with low VAT, despite a similar body weight and BMI. Generally, E2levels were low (median 43 pmol/l), and men with E2levels below median had reduced bone density at lumbar spine (P=0.04), and impaired structural parameters at radius and tibia, compared with men with E2levels above median. At the hip, VAT volume and E2levels affected bone density independently and additively, and 50% of men with high VAT and low E2levels had osteopenia with significantly lowerT-score at FN (P=0.004).ConclusionsHigh VAT and low E2negatively affect bone in obese men with MetS. VAT and E2affect bone density at the hip independently and additively, revealing an unexpected high prevalence of osteopenia in middle-aged men with MetS.

Bone mineral density and biochemical markers of bone turnover in patients with predialysis chronic renal failure.BackgroundMetabolic bone disease might commence early in the course of renal failure. This study therefore examined the frequency and severity of the skeletal changes in predialysis chronic renal failure by measurements of bone mineral density (BMD), biochemical markers of bone turnover (osteocalcin, bone-specific alkaline phosphatase, carboxy terminal propeptide of type I collagen, and carboxy-terminal telopeptide of type I collagen), parathyroid hormone (PTH), ionized calcium (Ca++), phosphate (P), and vitamin D metabolites.MethodsThe study was performed in 113 patients (male/female: 82/31) with chronic renal diseases [mean glomerular filtration rate (GFR) of 37 ml/min] and in 89 matched, normal control subjects.ResultsThe patients had significantly (P < 0.05) reduced BMD in the spine (-6.3%), the femur (-12.1%), the forearm (-5.7%), and the total body (-4.2%) as compared with the control subjects. Dividing the patients into quartiles according to GFR revealed that BMD decreased with the gradual decline in renal function at all the measured skeletal sites, but was most pronounced in the femur: 0.63 ± 0.03, 0.74 ± 0.02, 0.77 ± 0.02, and 0.82 ± 0.03 g/cm2 in each quartile from lowest to highest GFR compared with 0.82 ± 0.02 g/cm2 in the control group (P < 0.0001). All of the measured bone markers showed increasing plasma levels with the more advanced stages of renal failure. Serum PTH and serum P levels increased, whereas serum Ca++ and 1,25-dihydroxyvitamin D decreased. BMD Z-scores of the femur and of the forearm correlated to the biochemical markers and to PTH (P < 0.05 to P < 0.0001). The biochemical markers all showed strong correlations to PTH, also when corrected for the effect of the decline in GFR (r = 0.40 to 0.92, P < 0.01 to P < 0.0001).ConclusionSkeletal changes are initiated at an early stage of chronic renal failure, as estimated from reduced BMD and elevated levels of PTH and from the biochemical markers of both bone formation and bone resorption.

Serum N-terminal-pro-B-type natriuretic peptide (NT-proBNP) is elevated in systolic heart failure due to volume expansion and pressure overload. Recent data suggest a direct stimulatory effect of thyroid hormones on NT-proBNP synthesis. We examined the influence of acutely induced hyperthyroidism on serum levels of NT-proBNP.Forty-three healthy women were evaluated before and after treatment with 60 mug triiodothyronine (T(3)) daily for 7 days in a noncontrolled study.Before treatment, NT-proBNP was independently and inversely associated with thyrotropin (TSH), (r = -0.34, p = 0.02). T(3) therapy induced an increase in free T(3) (3.3 times, p0.0001) and suppression of TSH ( p0.0001). Heart rate increased by 14% ( p0.0001); weight decreased 0.6 kg ( p0.0001). Median NT-proBNP increased from 53 to 66 pg/mL ( p0.0001). The increase in NT-proBNP levels was independently associated with increase in free T(3) ( p = 0.05) and with reduction in TSH ( p = 0.04), without any association to the changes in cardiac workload.NT-proBNP is influenced by thyroid function among healthy women, as demonstrated by an inverse association between TSH and NT-proBNP. Induction of an acute hyperthyroid state resulted in an increase in NT-proBNP, which seems to reflect a direct action of T(3) on the NT-proBNP secretion rather than an effect of increased cardiac workload.