Osteoporosis is an important disease of aging. The age-specific incidence of the disease is stable or increasing, and when this is coupled with the greater number of older Americans in the at risk population, it is clear that the prevalence of this disease will rise for the foreseeable future. Already nearly one million fractures occur annually in persons over the age of 65 and the vast majority of these are due to osteoporosis. Osteoporosis is due to the permanent loss of otherwise normal bone from the skeleton. Of the various subtypes of this disease, postmenopausal osteoporosis is by far the most common. Increased bone resorption is the principal mechanism for bone loss in postmenopausal osteoporosis, and recent evidence indicates that rates of bone resorption are important predictors of bone mass in older individuals. Parathyroid hormone (PTH) is the principal regulator of bone resorption on a day-to-day basis and increased sensitivity to PTH may underlie the increased bone resorption seen in osteoporosis. The applicant group has demonstrated that the pro-resorptive cytokine, IL-6, is regulated by PTH in vitro and in vivo, and plays a crucial role in mediating the resorptive actions of PTH. Thus, they have recently shown that circulating levels of IL-6 are elevated in states of parathyroid excess, are low in hypoparathyroidism, and correlate strongly with markers of bone resorption in patients with primary hyperparathyroidism. In experimental animals, they have demonstrated that PTH infusions cause serum IL-6 levels to rise, and neutralizing antisera to IL-6 block PTH-induced increases in bone resorption. They hypothesize that IL-6 is an important mediator of PTH's resorptive actions in bone and that, in the estrogen-deficient state, PTH-dependent IL-6 production increases. To test these hypotheses the investigators will: (1) conduct a prospective clinical trial in patients with primary hyperparathyroidism to determine if serum IL-6 levels correlate with rates of bone loss, as determined by dual energy x-ray densitometry; (2) examine the response of postmenopausal women to an infusion of PTH, before and after estrogen replacement, to determine if estrogen affects PTH-induced changes in IL-6; (3) determine whether neutralizing IL-6, in vivo, blocks PTH-induced bone loss in mice, and whether IL-6 knock-out mice do not lose bone in response to PTH; (4) explore the effect of ovariectomy on PTH-induced increases in circulating IL-6 in mice; and (5) use the isolated perfused rat liver system to begin to examine the role of the liver in the PTH-induced increases in circulating levels of IL-6.
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