Maintenance of cancellous bone in ovariectomized, human parathyroid hormone [hPTH(1-84)]-treated rats by estrogen, risedronate, or reduced hPTH

This study compares effects of maintenance doses of human parathyroid hormo ne [hPTH(1-84)], 17 beta -estradiol (E-2), and risedronate on distal femur bone mineral density and proximal tibia cancellous bone histomorphometry in ovariectomized (ovx), osteopenic rats previously administered a higher dos e of hPTH. Nine groups (n = 8) of 3.5-month-old ovx or intact Sprague-Dawle y rats were left untreated for 11 weeks to allow for the development of can cellous osteopenia in the ovx groups. Next, the ovx rats received subcutane ous injections of hPTH (75 mug/kg per day, three times per week) or vehicle for 12 weeks. Treatments were then changed to E-2 (10 mug/kg per day, two times per week), risedronate (Ris; 3 mug/kg per day, three times per week), low-dose hPTH(1-84) (LowPTH, 25 mug/kg per day, three times per week), or vehicle, and administered for 36 weeks. The intact control group remained u ntreated for the duration of study. Femora and tibiae were collected at wee ks -11 (baseline); 0 (ovx effect); 12 (hPTH effect), and 24, 36, and 48 (ma intenance effects). Endpoints evaluated included distal femur bone mineral density (BMD) and proximal tibia cancellous bone volume (BV/TV), osteoclast surface (Oc.S), mineralizing surface (MS), mineral apposition rate (MAR), and bone formation rate (BFR). Ovariectomy had a negative effect on distal femur BMD and proximal tibia BV/TV. Treatment of ovx rats with hPTH for 12 weeks resulted in higher BMD in comparison to intact controls, and higher c ancellous BV/TV in comparison to ovx controls. Discontinuation of hPTH resu lted in loss of gained BMD within 24 weeks and loss of gained BV/TV within 12 weeks. Treatment of ovx rats with hPTH for 12 weeks followed by E2 treat ment left BMD and BV/TV similar to vehicle-treated ovx rats by week 48 (36 weeks after commencement of the E2 maintenance treatment). Maintenance trea tment with risedronate resulted in BMD and BV/TV similar to that of intact controls. Maintenance treatment with low-dose hPTH resulted in greater BMD and similar BV/TV in comparison to intact controls. MS and BFR were highest after low-dose hPTH administration. MS and BFR were lowest after E2 or ris edronate, whereas Oc.S was lowest after risedronate administration. Thus, i n osteopenic rats, the increment in distal femur BMD and proximal tibia BV/ TV gained by 12 weeks of hPTH treatment was lost within 24 and 12 weeks of treatment termination, respectively. Low-dose hPTH maintained BMD and BV/TV after hPTH treatment by stimulating bone formation, whereas risedronate ma intained BMD and BV/TV by reducing bone resorption. E. in a maintenance dos e failed to maintain BMD and BV/TV after withdrawal of hPTH treatment. (C) 2001 by Elsevier Science Inc. All rights reserved.