Low turnover osteoporosis in sheep induced by hypothalamic‐pituitary disconnection

Abstract

The hypothalamus is of critical importance in regulating bone remodeling. This is underscored by the fact that intracerebroventricular-application of leptin in ewe leads to osteopenia. As a large animal model of osteoporosis, this approach has some limitations, such as high technical expenditure and running costs. Therefore we asked if a surgical ablation of the leptin signaling axis would have the same effects and would thereby be a more useful model. We analyzed the bone phenotype of ewe after surgical hypothalamopituitary disconnection (HPD þ OVX) as compared to control ewe (OVX) after 3 and 12 months. Analyses included histomorphometric characterization, micro-CT and measurement of bone turnover parameters. Already 3 months after HPD we found osteopenic ewe with a significantly decreased bone formation (69%) and osteoclast activity (49%). After a period of 12 months the HPD group additionally developed an (preclinical) osteoporosis with significant reduction (33%) of femoral cortical thickness, as compared to controls (OVX). Taken together, HPD leads after 12 month to osteoporosis with a reduction in both trabecular and cortical bone caused by a low bone turnover situation, with reduced osteoblast and osteoclast activity, as compared to controls (OVX). The HPD-sheep is a suitable large animal model of osteoporosis. Furthermore our results indicate that an intact hypothalamo-pituitary axis is required for activation of bone turnover. ß

High fluoride and low calcium levels in drinking water is associated with low bone mass, reduced bone quality and fragility fractures in sheep

“…For the assessment and 3D visualization of the cortical thickness, porosity, bone volume per tissue volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N) and trabecular spacing (Tb.Sp), iliac crest biopsies were scanned (40 kV/114 mA) using a micro-computer tomography (μCT) 40 (Scanco Medical AG, Bruettisellen, Switzerland). The scanning process and analysis were executed as previously described [23]. Measurements of femora cortex were performed at midshaft.…”

Lower circulating preptin levels in male patients with osteoporosis are correlated with bone mineral density and bone formation

“…Recent advances and increased knowledge in the regulation of osteoblastic bone development and bone mass maintenance have enhanced the current understanding on why variations in normal osteoblastogenesis regulation induces bone diseases [5,6]. Further studies on the regulatory factors promote the discovery of therapeutic targets for stimulating bone formation, and when combined with other therapies, provide the ultimate treatment for osteoporosis [7-10].…”

Preclinical testing of drug delivery systems to bone

“…Therefore, alternatives were sought. When the ovariectomy is combined with a disconnection of the hypothalamus-pituitary axis, osteoporosis occurs within a year with a lower bone mineral density also in the femoral trabecular and cortical bone [249]. This osteoporotic phenotype is sustained for at least two years [250].…”

“…On the other hand, this model is also suitable for maxillofacial surgeons as the mandibular bone shows bone loss similar as seen in osteoporotic patients [252]. A drawback of this model is the fact that the pituitary insufficiency leads to many endocrine disturbances such as diabetes insipidus, abolition of gonadotropin secretion with undetectable LH and FSH levels, and no secretion of thyroid hormones [249].…”