Osteoporosis Preclinical Research: A Systematic Review on Comparative Studies Using Ovariectomized Sheep

Abstract

Sheep ovariectomy (OVX) alone or associated to steroid therapy, deficient diet, or hypothalamic–pituitary disconnection has proven to be of critical importance for osteoporosis research in orthopedics. However, the impact of specific variables, such as breed, age, diet, time after OVX, and other variables, should be monitored. Thus, the design of comparative studies is mandatory to minimize the impact of these variables or to recognize the presence of unwanted variables as well as to better characterize bone remodeling in this model. Herein, we conducted a systematic review of the last 10 years on PubMed, Scopus, and Web of Knowledge considering only studies on OVX sheep where a control group was present. Of the 123 records screened, 18 studies were included and analyzed. Results showed that (i) Merino sheep are the most exploited breed; (ii) 5–6 years of age is the most used time for inducing OVX; (iii) ventral midline laparotomy is the most common approach to induce OVX; (iv) OVX associated to steroid therapy is the most widely used osteoporosis model; and (v) success of OVX was mostly verified 12 months after surgery. In detail, starting from 12 months after OVX a significant decline in bone mineral density and in microarchitectural bone parameters as well as in biochemical markers were detected in all studies in comparison to control groups. Bone alteration was also site-specific on a pattern as follows: lumbar vertebra, femoral neck, and ribs. Before 12 months from OVX and starting from 3–5 months, microarchitectural bone changes and biochemical marker alterations were present when osteoporosis was induced by OVX associated to steroid therapy. In conclusion, OVX in sheep influence bone metabolism causing pronounced systemic bone loss and structural deterioration comparable to the situation found in osteoporosis patients. Data for treating osteoporosis patients are based not only on good planning and study design but also on a correct animal use that, as suggested by 3Rs principles and by ARRIVE guidelines, includes the use of control groups to be directly contrasted with the experimental group.

Postmenopausal Hormone Replacement Therapy for Health Maintenance during Aging

“…A large body of literature in both animal models and humans has demonstrated that estrogen deficiency leads to accelerated bone loss, increased bone resorbing osteoclastic activity, and impaired bone formation [40]. Similar effects were observed in OVX mice [41] and sheep [42]. Also, in human observational studies, postmenopausal period results in accelerated bone loss in both trabecular and cortical bone, leading to an increased risk of fracture [43].…”

Animal Experimental Models in Bone Metabolic Disease

“…Although several mouse and rat models of bone loss have been developed, the mouse model of post-menopausal osteoporosis from ovariectomy is the most used [9]. Post-menopausal osteoporosis from ovariectomy was also studied in a sheep model [10]. Other mouse or rat models of bone loss are based on skeleton disuse, lactation-induced bone loss, glucocorticoid excess, bone loss associated with erythropoietin receptor signaling, or models of bone loss associated with a hypoxia environment [9,11].…”