Osteoporotic fractures are a major source of morbidity and mortality in older women. The incidence of hip fractures in women doubles every five to sex years after age 40; 25-30% of women with hip fracture lose their independence as a result of fracture. Vertebral crush fractures also increase with age and may result in substantial pain and functional decline. Although women over 70 years are at the highest risk for osteoporotic hip and spine fractures, most research has focused on prevention of fractures in more recently menopausal women. We propose a three- part intervention development study (IDS) to closely examine the effect of estrogen on local factors in bone, bone turnover, and bone loss at the hip. Part A of IDS#1 will examine skeletal dose response, as measured by biochemical markers of bone turnover, to randomized, sequential 6-week courses of micronized 17beta-estradiol (0.25mg, 0.5 mg, 1.0 mg.). Sixty women, stratified by age (55-69 years or 70-85 years), will then be randomized to a treatment regimen (order of estrogen does). Serum and urine will be collected for measurement of biochemical markers at baseline, 6 weeks on treatment and 6 weeks post-treatment for each dose of estrogen. There will be a 6-week wash-out period between each dose; all woman will receive each dose of estrogen. We will also determine the lowest dose of estrogen to decrease bone turnover in the older age group; this dose will be used in Part b of IDS#1. Part B is a 2-year study to compare the effect of estrogen, calcium, the combination of estrogen and calcium and a control group on bone density at the hip in women over 70-85 years. One-hundred and sixty women will be randomized to the above treatment groups for 2 years. Part C of IDS#1 is a pilot study to quantitate gene expression of local regulatory factors and constitutive proteins in of women who undergo estrogen withdrawal or estrogen replacement. We will recruit 12 women over 70 years -6 who have not received estrogen in the past 10 years (group 1) and 6 who have been on estrogen for at least 2 years (group 2). Group 1 will be placed on 1.0 mg/d 17beta-estradiol and Group 2 will be withdrawn from estrogen. cDNA will be prepared by reverse transcribing mRNA from small needle iliac crest biopsy obtained at baseline and 3 months after estrogen withdrawal or replacement. If bone in older women is more sensitive to ERT than younger women, then a lower dose might reduce bone turnover and prevent bone loss at the hip without producing adverse effects, such as breast tenderness and fluid retention, two very common complaints of women taking ERT. Thus, older women may be more willing to accept ERT. Further, if these studies demonstrate substantial differences in local regulators associated with estrogen deficiency and replacement, the results could lead to new approaches to the prevention and therapy of bone loss in older adults.
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