A comprehensive longitudinal study quantifying the systemic effects associated with ovariectomy and high-dose...

The sheep is a common preclinical model for osteoporosis in humans and allows for robust longitudinal studies. Appropriate characterization of large animal models is necessary prior to selection for preclinical studies. We sought to comprehensively characterize the process of bone loss in a 12-month sheep model of osteoporosis, and report on the sheep clinical pathologies throughout osteoporosis model development.

We induced osteoporotic bone loss in 10 sheep via ovariectomy and corticosteroid administration. Over a 12-month period, we performed serial bone density scanning, bone biopsy for microarchitecture and histomorphometry assessment, clinical assessments, and evaluated systemic levels of steroid hormones, as well as hematological and biochemical values. Statistical analysis was performed to compare the outcomes of osteoporotic sheep to healthy age-matched control sheep over time.

We successfully induced osteoporotic-like bone loss in the experimental group by observing decreased bone density in the lumbar spine and tibia by 6 months, including changes to bone microarchitecture (i.e., trabecular thinning, decreasing bone volume) and histomorphometry (i.e., decreased trabecular bone ratio) indicative of bone remodeling disruption. We also reported comprehensive systemic changes in the same animals over time. Compared to control animals, we observed a significant disruption to clinical pathology parameters and steroid hormone production in osteoporotic sheep. Osteoporotic model development induced hematological and serological disruptions at 3 months, including neutrophilia, immune cell suppression, electrolyte and protein imbalances, hyperphosphatemia, and elevated liver enzymes. Additionally, administration of corticosteroids appeared to suppress cortisol production over the course of model development, followed by a surge of endogenous cortisol following cessation of corticosteroid treatment. Estradiol surprisingly did not drop to significantly lower levels than controls for the duration of the experiment, suggesting that there are extragonadal sources of estradiol production or dietary sources of phytoestrogens in the sheep differing from humans.

Bone loss was induced in sheep within 3-6 months, and the most significant systemic disruptions appear to correlate with timing of high-dose corticosteroids. These findings offer a detailed characterization of the sheep model of osteoporosis, enabling investigators to distinguish the effects of treatment administration from those arising solely from model development.