TIME-DEPENDENT CHANGES IN BIOCHEMICAL BONE MARKERS AND SERUM-CHOLESTEROL IN OVARIECTOMIZED RATS - EFFECTS OF RALOXIFENE HCL, TAMOXIFEN, ESTROGEN, AND ALENDRONATE

Bone loss associated with postmenopausal osteoporosis can be reduced b y treatment with antiresorptive agents such as estrogen or bisphosphon ates. Whereas bisphosphonates primarily affect bone loss, estrogens ha ve an advantage of also lowering serum cholesterol levels, although th ey have a detrimental effect in the uterus. Recently, raloxifene HCl, a selective estrogen receptor modulator (SERM), has been shown to decr ease both bone loss and cholesterol levels without the negative uterin e effects. These antiresorptive agents reduce bone turnover, which can be evaluated by measuring bone turnover markers. To compare the effec ts of estrogen, two SERMs (raloxifene HCl and tamoxifen), and alendron ate, a bisphosphonate that inhibits bone loss by an estrogen-independe nt pathway, on metabolic bone markers and cholesterol levels, rats wer e ovariectomized 2 weeks prior to 3 weeks of daily oral treatment with raloxifene HCl (3 mg/kg), ethynyl estradiol (0.1 mg/kg), tamoxifen (3 mg/kg), or alendronate (3 mg/kg). Raloxifene HCl, tamoxifen, and ethy nyl estradiol reduced serum cholesterol to levels below control values within 4 days after initiation of treatment, whereas alendronate had no effect. After 3 weeks of treatment, serum cholesterol values in eth ynyl estradiol treated animals, although still below the control value , had risen 6.4-fold; raloxifene HCl and tamoxifen values rose by only 1.4-1.5-fold. Therefore, compared with estrogen, SERMs may have a lon ger-term suppressive effect on serum cholesterol. At 4 days of treatme nt, ovariectomized rats had a 1.4-fold increase in serum osteocalcin l evel compared with controls. Ethynyl estradiol lowered this level with in 1 week of treatment by 18%, with a more pronounced reduction of 34% at 3 weeks. In contrast, raloxifene HCl, tamoxifen, or alendronate ha d very little effect after the first week (6% to 13% reduction), altho ugh there was an 18% to 25% reduction by 3 weeks. Urinary pyridinoline levels, elevated 1.4-fold in the ovariectomized rat compared with con trols 2 weeks after surgery, were reduced to control values after 2 we eks of treatment with raloxifene HCl, ethynyl estradiol, tamoxifen, or alendronate. These data support the concept that estrogen, raloxifene HCl, tamoxifen, and alendronate inhibit bone loss in the ovariectomiz ed animal by reducing bone resorption. The results also indicate that for treatment of postmenopausal osteoporosis, raloxifene HCl may have an advantage over the other antiresorptives studied in having both non -uterotrophic and hypocholesterolemic effects in addition to its abili ty to inhibit bone resorption.