In search of an animal model for postmenopausal diseases.

Abstract

The purpose of this review is to discuss the use of the aged ovariectomized ewe as a cost-effective large animal model to study coronary artery disease (CAD), osteoporosis, osteoarthritis (OA), and oral bone loss--conditions seen after menopause. Earlier studies from our laboratory showed a significant decline in the bone mineral density (BMD) of the iliac crest following ovariectomy in sheep, while subsequent studies demonstrated decreased bone loss (measured by dual energy X-ray absorptiometry (DXA)) in the lumbar vertebrae following ovariectomy. We examined the effects of estrogen deficiency and estrogen therapy on the terminal aorta of the aged ovariectomized (OVX) ewes and demonstrated subintimal thickening in the distal aorta of animals that were estrogen deficient when compared to the control groups. A popular model to study OA is the knee joint of sheep following medial or lateral meniscus removal combined with exercise, but there is a need for an estrogen-deficient large animal model of OA to study articular cartilage changes occurring after menopause. We saw an effect of ovariectomy on the biomechanical properties (aggregate modulus and shear modulus) of articular cartilage. Estrogen deficiency had a detrimental effect on the articular cartilage of the knee even though the cartilage of the OVX animals appeared grossly normal. In another study, 13.5 months following ovariectomy, we found an increase in estrogen receptor binding capacity of the articular cartilage suggesting that articular cartilage is a sex-hormone sensitive tissue. There is intense interest in the correlation between systemic osteoporosis and bone loss of the mandible and maxilla. We studied mandibular bone loss in OVX sheep using DXA. The mean BMD of the OVX group versus sham and estradiol-treated animals was lower, indicating that systemic bone loss in OVX ewes may be accompanied by oral bone loss. Coronary artery disease, osteoporosis, osteoarthritis (OA) and oral bone loss all have a major impact on women's heath after menopause and we found that certain characteristics of these conditions can be reproduced in the skeletally mature or aged estrogen-deficient sheep. It is premature to promote the sheep as the only model to study estrogen deficiency and the many differences from small animal omnivores and non-human primates need to be overcome and a search for more economical models must continue. This model, however, may offer the opportunity to study postmenopausal conditions and the safety and efficacy of new therapeutic agents.