The Laboratory Rat as an Animal Model for Osteoporosis Research

Osteoporosis is an important systemic disorder, affecting mainly Caucasian women, with a diverse and multifactorial etiology. A large variety of animal species, including rodents, rabbits, dogs, and primates, have been used as animal models in osteoporosis research. Among these, the laboratory rat is the preferred animal for most researchers. Its skeleton has been studied extensively, and although there are several limitations to its similarity to the human condition, these can be overcome through detailed knowledge of its specific traits or with certain techniques. The rat has been used in many experimental protocols leading to bone loss, including hormonal interventions (ovariectomy, orchidectomy, hypophysectomy, parathyroidectomy), immobilization, and dietary manipulations. The aim of the current review is not only to present the ovariectomized rat and its advantages as an appropriate model for the research of osteoporosis, but also to provide information about the most relevant age and bone site selection according to the goals of each experimental protocol. In addition, several methods of bone mass evaluation are assessed, such as biochemical markers, densitometry, histomorphometry, and bone mechanical testing, that are used for monitoring and evaluation of this animal model in preventive or therapeutic strategies for osteoporosis.Abbreviations: BMD, bone mineral density; DEXA, dual-energy X-ray absorptiometry; μCT, microcomputerized tomography; pQCT, peripheral quantitative computerized tomographyOsteoporosis is a multifactorial skeletal disease, characterized by reduction in bone mass and disruption of the microarchitectural structure of bone tissue, resulting in loss of mechanical strength and increased risk of fracture.² The disorder can be localized or involve the entire skeleton. Generalized osteoporosis can be primary (postmenopausal and senile) or secondary. In the European Union, osteoporosis is a leading cause of mortality and morbidity in the elderly and a key factor in the high cost of medical care.³⁴Although osteoporosis usually makes its appearance late in life, and age is a major risk factor, its roots can be tracked back into adolescence. Particularly during periods of rapid bone growth, dietary calcium levels are of high importance.³⁴ Other factors that contribute to the pathogenesis of osteoporosis are lifestyle and genetic and hormonal attributes.^13,71 Reduced physical activity increases the rate of bone loss, and muscle contraction is the prevailing source of skeletal loading. Regarding hormonal factors, women, especially in the decade after menopause, can show a severe reduction of bone mass, thus explaining the high incidence of osteoporotic fractures in women compared with men.³⁴The multiple factors implicated in osteoporosis, its obscure pathogenesis, the dramatic decline in quality of life, high incidence of the disorder (especially in postmenopausal women), financial cost, and high mortality, make the need for further experimentation in animal models imperative. Experimental research can improve our understanding of pathogenesis and of the activity of pharmaceutical agents in the prevention or treatment of the disease. Although many aspects of the disorder have been revealed, others remain unclear, including the mechanisms involved in calcium homeostasis in the extracellular space and its effect on bone physiology and disease⁶⁵ and the cell and molecular pathways triggered after mechanical loading to orchestrate bone renewal.⁵³ Current research is focused on new therapeutic possibilities targeting the osteolytic enzymes of the osteoclast and the mechanisms activating bone progenitor cells and those controlling apoptosis as new potential treatments.^63,64Many therapeutic advances in the management of osteoporosis were studied first in diverse animal models and then entered clinical practice.^31,67,69 All of these models should fulfill similar basic criteria: they must comply with national and local ethical and legislative considerations, be accessible to experimental centers, be easy and safe to handle, have a low cost of acquisition, require little maintenance, reliably reproduce the disease and the biological material to be examined should be readily available. Laboratory rats meet most of these criteria. In addition, the availability of detailed knowledge of the rat skeleton and protocols for rapid induction of osteopenia, have increased this model''s popularity. Here we review the advantages and limitations of the use of the laboratory rat in osteoporosis research.