ANIMAL-MODELS OF CORTICAL POROSITY

Increased cortical porosity (Ct.Po) has been observed as a consequence of aging, disease (hyperparathyroidism, osteoporosis), and pharmacologic intervention (thyroid hormone, fluoride, parathyroid hormone, prostaglandins). Whether this is permanent or transient in humans has not been established nor has the impact of Ct.Po on bone strength or fracture incidence been determined. There is a need to understand the causes and consequences of increased Ct.Po and how it relates to disease states and osteoporosis therapies. The mechanism of increased Ct.Po is thought to be an increased activation of Haversian remodeling systems accompanied by increased Haversian canal diameter. Increased activation at the endocortical surface and subsequent trabecularization may also contribute to loss of cortical bone. Ct.Po has been observed in several animal models which can be used to further study the phenomenon. Ct.Po is seen in normal dogs and is increased by treatment with PTH and prostaglandins. In the dog it has also been shown that increased Ct.Po is reversible after anabolic therapy is discontinued. Furthermore, in dogs an antiresorptive agent (risedronate) will block PTH-induced increases in Ct.Po (control 1.6% +/- 0.7; PTH 3.0% +/- 1.1, PTH plus risedronate 1.8% +/- 1.2) without interfering with anabolic effects. In rats, increased Ct.Po occurs following treatment with anabolic agents such as PTH, prostaglandin, and insulin-like growth factor 1 (IGF-1). For instance, with IGF-1, Ct.Po increased from 0.4% +/- 0.4 to 5.4% +/- 1.8. Other species in which Ct.Po is observed include primates and ferrets. For now the dog is the species of choice to study Ct.Po because its remodeling characteristics are similar to those of humans and because it is well characterized. Rats are a less satisfactory species because they normally do not exhibit much Haversian remodeling. Primates closely resemble the remodeling of humans but are expensive and difficult to work with. Ferrets are a smaller species and provide advantages in ease of use and test material requirements. Key issues needing to be addressed in these animal models include: the relationship between Ct.Po and strength, the mechanism(s) whereby anabolic agents induce increased Ct.Po, and the mechanism responsible for the prevention of increased Ct.Po by use of antiresorptive agents. This information will be essential to the development of improved anabolic agents capable of stimulating bone formation without increasing Ct.Po.