Bone Abstracts

Introduction: Cathepsin K is necessary for bone matrix resorption. Excessive resorption associated with osteoporosis and osteoarthritis can be reduced by cathepsin K inhibition. MIV-711, a highly selective cathepsin K inhibitor, successfully attenuates both bone resorption and cartilage degradation in non-clinical studies.Aim: To determine safety, tolerability, pharmacokinetics and pharmacodynamics of MIV-711 during multiple oral dosing to postmenopausal...

Aim: To determine the safety, tolerability, pharmacokinetics and pharmacodynamics of the cathepsin K inhibitor MIV-711.Methods: A double-blind, placebo-controlled, randomized study in 27 healthy subjects of both genders. Single ascending doses 20–600 mg were investigated for adverse events, clinical chemistry, vital signs, ECG parameters, pharmacokinetics, and serum levels of CTX-I.Results: MIV-711 was well tolerated with no a...

Osteoclasts are highly specialized cell types, responsible for the resorption of bone matrix. Coordinated with osteoblasts they contribute to a proper bone turnover. An impaired or reduced function of the osteoclast leads to a pathogenic increase of the bone mass and finally osteopetrosis. Lysosomal hydrolases, as exemplied by CTSK and Acp5 (TRAP), are known to play an important role in the function of osteoclasts, and knockout mouse models of these proteins develop a bone res...

Antenatal glucocorticoid (GC) injections are not only used to enhance fetal lung maturation in preterm children but also for the treatment of maternal conditions such as autoimmune diseases or infections. Animal models and clinical studies suggest that the regulation of the hypothalamic–pituitary–adrenal axis is altered in the offspring of GC-treated mothers with increased sensitivity to stress.Objective: The aim of this study is i) to define t...

Owing to their anti-inflammatory effects, steroid therapy using glucocorticoids (GCs) is still part of the treatment of rheumatoid arthritis (RA), despite several severe side effects like glucocorticoid-induced osteoporosis (GIO). Until now the molecular mechanisms underlying the beneficial and side effects of GC therapy are poorly understood. GCs exert their actions via the glucocorticoid receptor (GR) that alters gene expression by either binding as a dimer to GC response el...

Chronic stress and depression are associated with alterations in the hypothalamic–pituitary–adrenal signalling cascade and considered a risk factor for bone loss and fractures. However, the mechanisms underlying the association between stress and poor bone health are unclear. Utilising a transgenic (tg) mouse model in which glucocorticoid signalling is selectively disrupted in mature osteoblasts and osteocytes (HSD2OB-tg mice), the current study examines t...

FDA guidelines recommend the sheep as large animal model for osteoporosis. Studies of osteoporosis induction use dual energy x-ray absorptiometry (DEXA) to evaluate bone status. Experimentally, the T-score is calculated based on reference bone mineral density (BMD) values of animals before treatment (0 M). Whereas clinically the reference BMD represents values of an independent group of patients around 30 years old. The study hypothesize that the use of additional ind...

Chronic stress and depression are associated with alterations in the hypothalamic-pituitary-adrenal signalling cascade and considered a risk factor for bone loss and fractures. However, the mechanisms underlying the association between stress and poor bone health are unclear. Utilising a transgenic (tg) mouse model in which glucocorticoid signalling is selectively disrupted in mature osteoblasts and osteocytes (HSD2OB-tg mice), the current study examines the impact ...

Objectives: Osteocytes play a major role in bone metabolism as mechanosensors, key regulators of osteoblast and osteoclast activity and of the mineral homeostasis. Therefore the assessment of osteocytes characteristics is important to understand bone pathology. We propose to study indirectly the osteocytes by performing quantitative backscattered electron imaging to quantify the sectioned osteocyte lacunae density and size in 2D on bone samples.Methods: ...

Objectives: Mice with a non-functioning vitamin D receptor (VDR mutants) develop severe secondary hyperparathyroidism, which can be rescued by a diet enriched with calcium, phosphate and lactose. In this work, we studied the effects of a low calcium challenge (CD), normal calcium (ND) and a calcium enriched rescue diet (RD) on the bone mineralization density distribution (BMDD) and osteocyte lacunae sections (OLS) in these mice.Methods: BMDD and OLS were...