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G. R. MUNDY, Endocrinology & Metabolism, University of Texas, Health Science Center at San Antonio, San Antonio, TX 78284-7877

Osteoporosis is a major public health problem in the Western world affecting approximately 100 million people. It occurs predominantly in postmenopausal women and represents an imbalance between the coupled processes of bone resorption and bone formation, so that bone is progressively lost after mid-life. Important etiologic factors are estrogen deficiency after the menopause, calcium deficiency and the aging process, which impairs bone formation. Current pharmacologic approaches to osteoporosis are to ensure adequate calcium and vitamin D intake and inhibit bone resorption by drugs that decrease osteoclast activity such as hormone replacement therapy, bisphosphonates and calcitonin. However, patients with osteoporosis have lost more than 50% of bone at critical sites in the skeleton, and have associated disruption of trabecular bone microarchitecture. They need therapeutic approaches to restore or rebuild the bone that has been lost by enhancing osteoblast differentiation and subsequent bone formation. Recently, we have described an important connection between the pathway of cholesterol synthesis and bone. We have found that drugs that inhibit the enzyme HMG-Co-A reductase, the rate limiting step in cholesterol biosynthesis, also increase osteoblast differentiation both in vitro and in vivo. These drugs are taken by more than 3 million people daily to lower serum cholesterol and reduce the risk of heart attack. However, this recent data indicates that in addition to this effect, they enhance the expression of the bone growth regulatory factor, BMP-2, and thereby increase new bone formation by enhancing osteoblast differentiation. They also suggest that the pathway of cholesterol biosynthesis provides a number of potential molecular targets that may be important in future drug discovery efforts to increase bone formation.