The proposed program will facilitate the development of Neil Binkley as an academic geriatrician and gerontologist at the University of Wisconsin, an institution with a long history of gerontologic research. It will provide the opportunity to further develop and apply basic science and clinical skills to his focused area of interest, osteoporosis, by protecting his time and allowing the acquisition of skills and experience needed to mature as an independent researcher. Skeletal fragility becomes common with advancing age with up to 40 percent of females sustaining an osteoporotic fracture. As at least three vitamin K dependent skeletal proteins exist, it is plausible that vitamin K plays a role in the maintenance of skeletal health. While vitamin K insufficiency has classically been defined in terms of coagulation abnormalities (prolongation of the prothrombin time), it has recently become appreciated that measurement of undercarboxylation of other proteins, notably osteocalcin, is a much more sensitive measure of adequacy. If defined as elevated serum levels of undercarboxylated osteocalcin, some reports find the majority of postmenopausal women to be vitamin K insufficient. Thus it is plausible that vitamin K insufficiency is common and contributes to the development of osteoporosis. However, prior studies of the effect of vitamin K upon the skeleton have yielded contradictory results. Some reports find that vitamin K insufficiency is associated with low bone mass or skeletal fragility, while others find no effect, or even an increase in bone mass. These data have lead to diametrically opposed suggestions, i.e., that vitamin K insufficiency may cause osteoporosis and conversely, that vitamin K antagonists may be useful to treat osteoporosis. To address these divergent hypotheses, the overall goal of the proposed research is to determine if vitamin K or the vitamin K antagonist warfarin have a role in determining skeletal health. In this regard, we hypothesize that: 1. Vitamin K insufficiency produced by therapeutic anticoagulation leads to bone loss. 2. The disparate animal studies may be the result of unrecognized toxic effects of warfarin on the skeleton. 3. Vitamin K insufficiency and resultant reduced bone osteocalcin content may contribute to skeletal fragility by reducing bone strength. 4. Vitamin K insufficiency accentuates estrogen depletion bone loss. To test these hypotheses, we will utilize the rhesus monkey as a model in which to assess the effect of therapeutic warfarin treatment upon the skeleton. In addition, utilizing adult rats, we will evaluate the effect of long-term dietary vitamin K insufficiency and warfarin regimens on serum and bone osteocalcin, markers of skeletal turnover and calcium homeostasis, bone density and biochemical strength. Subsequently, we will assess the effect of pre-existing and ongoing vitamin K insufficiency upon ovariectomy induced bone loss in female rats. Delineation of the role(s) of vitamin K in skeletal health may have implications for osteoporosis prevention and treatment.
| Colman, R J; Kemnitz, J W; Lane, M A et al. (1999) Skeletal effects of aging and menopausal status in female rhesus macaques. J Clin Endocrinol Metab 84:4144-8 |
