Skeletal effects of parathyroid hormone infusion in ovariectomized rats with or without estrogen repletion

We employed skeletally matured rats to study changes in biochemical markers of bone turnover, bone mineral density (BMD), and bone biomechanics produc ed by continuous elevation of parathyroid hormone (PTH) in estrogen-deplete and -replete rodents. Ninety-six 7-month-old virgin female rats were divid ed randomly into 12 groups (n = 8) and treated as follows. One group was ki lled on the day of surgery. The remaining groups were either bilaterally ov ariectomized (Ovx) or sham-operated and left untreated for 8 weeks, at whic h point, two groups, one sham and one Ovx, were killed. The remaining nine groups were treated for 2 weeks or 4 weeks. One sham and two Ovx groups rec eived subcutaneous implants of Alzet miniosmotic pumps with vehicle for PTH . Two Ovx groups were given pumps with vehicle as well as a subcutaneous im plant of 17 beta-estradiol, which delivered 10 mu g/kg per day. Two Ovx gro ups were implanted with rat PTH(1-34) in Alzet miniosmotic pumps, which del ivered 30 mu g PTH/kg per day. Two Ovx groups were implanted with both estr adiol pellets and PTH-loaded pumps. One group of Ovx animals from each trea tment was killed after 2 weeks and the other after 4 weeks. Biochemical mar kers of bone turnover, serum osteocalcin and urinary free pyridinoline, BMD , and mechanical strength of excised bones were measured. As expected, ther e was a significant increase in N-terminal PTH and serum calcium levels in all PTH infusion groups. Both serum osteocalcin and urinary pyridinoline sh owed a rapid increase within the first 2 weeks of the PTH infusion and rema ined elevated at week 4. In estrogen-replete groups, osteocalcin increased by week 2 of PTH infusion but pyridinoline did not increase until week 4. B MD of the distal and proximal femur showed the expected decrease 8 weeks af ter ovariectomy but did not exhibit any further changes during the 4 weeks of treatment with vehicle. Four weeks of PTH infusion in Ovx animals result ed in BMD loss at the midshaft, distal, and proximal regions of the femur. Estrogen repletion by itself beginning 8 weeks after ovariectomy, produced no change in BMD at any site when compared with from Ovx vehicle-treated ra ts. Estrogen repletion in PTH-infused Ovx animals resulted in significant i mprovements of BMD comparable with sham-operated animals at all three femor al regions. The indentation test at the cancellous bone of the distal femur , three-point bending test at the midshaft femur, and cantilever bending te st at the femoral neck showed that the changes in mechanical strength in th ese sites were consistent to the changes found in BMD. Our results showed t hat (1) continuously elevated levels of PTH induced additional loss of BMD in estrogen-deficient animals beyond the rapid bone loss phase associated w ith ovariectomy, (2) estrogen repletion, given by implant, to PTH-infused O w animals, reversed these BMD changes increasing BMD to levels comparable w ith estrogen-sufficient rats, and (3) these changes were reflected in the m echanical strength, determined at these sites.. These results lend experime ntal support that hormone replacement therapy may benefit bone health in po stmenopausal women with primary hyperparathyroidism (PHPT). In addition, it raises the possibility that a continuous elevation of PTB could exert anab olic effects on skeletal tissue if its catabolic component can be minimized .