Sheep model for osteoporosis: Sustainability and biomechanical relevance of low turnover osteoporosis induced by hypothalamic–pituitary disconnection

Abstract

Hypothalamo-pituitary disconnection (HPD) leads to low bone turnover and osteoporosis in sheep. To determine the sustainability of bone loss and its biomechanical relevance, we studied HPD-sheep 24 months after surgery (HPD þ OVX-24) in comparison to untreated control (Control), ovariectomized sheep (OVX), and sheep 12 months after HPD (HPD þ OVX-12). We performed histomorphometric, HR-pQCT, and qBEI analyses, as well as biomechanical testing of all ewes studied. Twenty-four months after HPD, histomorphometric analyses of the iliac crest showed a significant reduction of BV/TV by 60% in comparison to Control. Cortical thickness of the femora measured by HR-pQCT did not change between 12 and 24 months after HPD but remained decreased by 30%. These structural changes were caused by a persisting depression of osteoblast and osteoclast cellular activity. Biomechanical testing of the femora showed a significant reduction of bending strength, whereas calcium content and distribution was found to be unchanged. In conclusion, HPD surgery leads to a persisting low turnover status with negative turnover balance in sheep followed by dramatic cortical and trabecular bone loss with consequent biomechanical impairment. #

Metaphyseal fracture healing in a sheep model of low turnover osteoporosis induced by hypothalamic–pituitary disconnection (HPD)

“…Our previous studies demonstrated that HPD induced a remarkable bone loss syndrome. The osteoporotic phenotype was caused by a profoundly low bone turnover, similar to senile osteoporotic patients . Trabecular bone loss was already evident 3 months after HPD and became increasingly prominent after 12 months.…”

“…Trabecular bone loss was already evident 3 months after HPD and became increasingly prominent after 12 months. Cortical thickness was diminished only after 12 months indicating that HPD might first affect the highly metabolically active trabecular bone . In the present study we analyzed the bone 8 months after HPD.…”

“…HPD ablates the central leptin signaling axis, which is known to regulate bone homeostasis, and leads to an insufficiency of the anterior and posterior pituitary. This model emphasizes the importance of central regulation of bone homeostasis and mimics the low turnover state in senile osteoporotic patients …”

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

“…Consequently, the apparent Young’s modulus E app and the bending strength σ max of each specimen were calculated using the equations and . The outer radius in the lateral direction α of the diaphyseal cortex and the second moment of area with reference to the anterior–posterior axis I y were defined from HR-pQCT slices as described previously [29]. …”

Preclinical testing of drug delivery systems to bone

“…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]. Indeed, long bone defects can be investigated in this model [251].…”