We employed skeletally matured rats to study changes in
biochemical markers of bone turnover, bone mineral density (BMD), and bone biomechanics produced by continuous elevation of
parathyroid hormone (PTH) in
estrogen-deplete and -replete rodents. Ninety-six 7-month-old virgin female rats were divided randomly into 12 groups (n = 8) and treated as follows. One group was killed on the day of surgery. The remaining groups were either bilaterally ovariectomized (Ovx) or
sham-operated and left untreated for 8 weeks, at which 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 received subcutaneous implants of Alzet miniosmotic pumps with vehicle for PTH. Two Ovx groups were given pumps with vehicle as well as a subcutaneous implant of 17beta-estradiol, which delivered 10 microg/kg per day. Two Ovx groups were implanted with rat
PTH(1-34) in Alzet miniosmotic pumps, which delivered 30 microg PTH/kg per day. Two Ovx groups were implanted with both
estradiol pellets and PTH-loaded pumps. One group of Ovx animals from each treatment was killed after 2 weeks and the other after 4 weeks.
Biochemical markers of bone turnover, serum
osteocalcin and urinary free
pyridinoline, BMD, and mechanical strength of excised bones were measured. As expected, there was a significant increase in
N-terminal PTH and serum
calcium levels in all PTH infusion groups. Both serum
osteocalcin and urinary
pyridinoline showed a rapid increase within the first 2 weeks of the PTH infusion and remained elevated at week 4. In
estrogen-replete groups,
osteocalcin increased by week 2 of PTH infusion but
pyridinoline did not increase until week 4. BMD of the distal and proximal femur showed the expected decrease 8 weeks after
ovariectomy but did not exhibit any further changes during the 4 weeks of treatment with vehicle. Four weeks of PTH infusion in Ovx animals resulted 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 rats.
Estrogen repletion in PTH-infused Ovx animals resulted in significant improvements of BMD comparable with
sham-operated animals at all three femoral regions. The indentation test at the cancellous bone of the distal femur, three-point bending test at the midshaft femur, and cantilever bending test at the femoral neck showed that the changes in mechanical strength in these sites were consistent to the changes found in BMD. Our results showed that (1) continuously elevated levels of PTH induced additional loss of BMD in
estrogen-deficient animals beyond the rapid bone loss phase associated with
ovariectomy, (2)
estrogen repletion, given by implant, to PTH-infused Ovx animals, reversed these BMD changes increasing BMD to levels comparable with
estrogen-sufficient rats, and (3) these changes were reflected in the mechanical strength determined at these sites. These results lend experimental support that
hormone replacement therapy may benefit bone health in postmenopausal women with
primary hyperparathyroidism (PHPT). In addition, it raises the possibility that a continuous elevation of PTH could exert
anabolic effects on skeletal tissue if its catabolic component can be minimized.