Commentaryon "Restoration of Bone Mass in the Severely Osteopenic Senescent Rat'

I the past several years the pharmaceutical industry has developed several new drugs, including bisphosphonates, that have been shown to be effective in the prevention and treatment of osteoporosis (1). All agents act by decreasing the bone destruction rate. Such drugs are particularly useful in the prevention of osteoporosis, because antiresorptive drugs, when applied early during the course of the disease, are very effective in preventing further bone loss, thereby stabilizing the skeleton. These drugs are also very effective in reducing the fracture rate in patients with established osteoporosis. In addition to these therapeutic advances, new diagnostic procedures have been developed to detect osteoporosis early (before fractures occur), such that it is now potentially possible to prevent fractures in patients with high bone turnover (1). These new diagnostic and therapeutic advances allow practitioners to perform admirably in the prevention and treatment of osteoporosis. However, there remains a serious deficiency in the armamentarium for the treatment of osteoporosis. The single most important deficiency in osteoporosis management is the inability to regenerate the skeleton in patients with severe established osteoporosis (1). Bone antiresorptive therapies cause only modest increases in bone density, such that patients with severe skeletal deficits remain at risk for osteoporotic fractures, even after a course of antiresorptive therapy. Consequently, in patients with severe osteoporosis, osteoporotic fractures may continue, although at a lower rate, despite antiresorptive therapy. Past research in animals and humans has demonstrated that pharmacological intervention can lead to large increases in bone formation and in bone density by means of agents that stimulate bone formation (1,2). Thus, the skeleton is inherently responsive to bone stimulatory agents. Based on the above rationale, the publication by Sibonga and colleagues is very timely in focusing on the current major need for the successful management of osteoporosis (3). These investigators applied a unique model to study the skeletal effect of the anabolic agent prostaglandin E2 (PGE2). The rats were ovariectomized at 3 months of age and then allowed to lose bone as a consequence of the ovariectomy up until the age of 23 months, at which time they received daily injections of PGEj for 2 months. In this model, the treated animals were aged (the life span of the rat is approximately 36 months), and me animals had very severe osteoporosis. Other workers have shown that PGE2 increases bone formation, but the experimental animal model used is not as severely osteoporotic and not as aged as the animals used in the present study (4). This model is analogous to the situation that is seen in some osteoporotic patients (i.e., severe osteoporosis with a loss of much of the trabecular supporting structure). It has been claimed in the past that losses of such supporting structure cannot provide the architectural framework to reestablish a new normal skeletal architecture with bone stimulatory agents. It was therefore interesting to note that there was evidence of de novo bone formation in the medullary space. Apparently this led to the creation of new trabeculae, which in turn led to a partial reestablishment of trabecular connections with other trabeculae, an architectural feature of trabecular bone that is important to mechanical performance. The foregoing observations illustrate that the study by Sibonga and colleagues (3) has advanced our understanding of the potential application of bone anabolic agents to the osteoporotic skeleton. In addition, this study has raised several questions as well. The investigators imply that there is no reduction in the response of old animals to the osteogenic agent PGEj compared with that of younger animals. Although there was an exuberant bone formation response in the old animals, to make such a conclusion would require a study design in which young and old animals were studied simultaneously. In addition, such a comparison would require a dose response in both young and old animals. In the present study, there was only one experimental group and only one dose of test agent. All of the conclusions in the study are based on the sampling of one site, namely, the tibial metaphysis. It would be important in future studies to examine other skeletal sites to establish that this effect is universal throughout the skeleton. The authors seem to attribute any potential deficiency in anabolic response to a bone-forming agent in the aged animal to be a consequence of a decrease in osteoprogenitor cells. However, there are several other potential mechanisms whereby older animals might not show as great an anabolic response as a younger animal: (i) higher rate of apoptosis, (ii) impairment in differentiation of osteoprogenitor cells into osteoblasts, (iii) impairment in responsiveness of osteoblasts to local and systemic cues, (iv) impairment in growth factor production by stromal cells and osteoblasts from older animals compared with that of younger animals. That apoptosis can influence cell number is