Effects of reciprocal treatment with estrogen and estrogen plus parathyroid hormone on bone structure and strength in ovariectomized rats.

Abstract

Intermittent administration of PTH has been found to be an effective anabolic agent in cancellous bone. We have reported previously that combined treatment with PTH and estrogen in estrogen-deficient rats was beneficial in correcting established osteopenia. To determine if the beneficial effects of PTH therapy can be preserved by estrogen alone and whether PTH therapy can be effective in treating osteopenic subjects stabilized with estrogen, we have undertaken a "crossover" study in the rat model of estrogendeficiency induced osteopenia. Six-month-old female rats were ovariectomized and after 5 wk treated for 8 wk with vehicle, 30 rig/kg per day of rPTH(1-34) plus 15 ,.g/kg per day of 17fi-estradiol or 17f3-estradiol alone. One group from each treatment regimen was then sacrificed and for an additional 8 weeks the remaining rats were (a) maintained on their previous treatment; (b) "crossed over" to their reciprocal treatment; or (c) administered vehicle only. At the end of this second 8-wk treatment period all rats were sacrificed. Bone mineral density of the distal femur, histomorphometric measurements of the proximal tibia and mechanical testing of the distal femur and selected vertebral bodies were performed. Our results demonstrated that (a) the gains in bone mass, trabecular connectivity and mechanical strength induced by PTH can be maintained by estrogen alone, but are reversed when both agents are withdrawn; and (b) rats with established osteopenia, maintained on estrogen treatment alone, can derive the full beneficial effects from the addition of PTH to the treatment at a later date. These data indicate that combined and/or sequential use of antiresorptive and anabolic agents may be a promising approach to the treatment of osteoporosis. (J. Clin. Invest. 1995. 96:2331-2338

Pharmacological treatment of osteopenia induced by gastrectomy or ovariectomy in young female rats

“…Our results with OVX rats confirm previous reports that PTH restores trabecular bone, while estrogen does not (Abe et al 1993, Shen et al 1995. This is the first study in which alendronate, estrogen and PTH have been used in an attempt to reverse GXevoked osteopenia.…”

“…At the end of the study (16 weeks after surgery and 8 weeks after starting the drug treatment), we found no statistically significant difference between the serum osteocalcin concentrations in OVX, GX and SHAM-operated rats. Some authors have reported reduced serum osteocalcin levels after treatment with alendronate and estrogen in rats (Shen et al 1995, Frolik et al 1996. In this study, alendronate had no effect on serum osteocalcin.…”

“…On the other hand, PTH increased the serum osteocalcin concentration in GX (65 (11)%, p = 0.007) and OVX rats (159 (17)%, p = 0.001), but not in SHAM-operated rats (16 (15)%, p = 0.91). PTH has previously been reported to increase serum osteocalcin levels in OVX rats (Shen et al 1995).…”

“…10 mM citrate buffered saline, pH 5.5, was used as vehicle for PTH, saline as vehicle for alendronate, and sesame oil (Apoteksbolaget, Gothenburg, Sweden) for estrogen. The doses chosen are effective for preventing OVX-induced osteopenia (Wronski et al 1988, Seedor et al 1991, Shen et al 1995.…”

Parathyroid hormone induces formation of new cancellous bone with substantial mechanical strength at a site where it had disappeared in old rats

“…In tests of the distal femoral metaphysis another test method has been used that certainly tests only cancellous bone. That is the indentation test, where an indentor, 1.6 mm thick, compresses and penetrates to a depth of 2.0 mm the cancellous bone of a 4.0-mm-high transverse specimen placed on a flat surface (13,14). The cancellous bone of the distal metaphysis is not, however, uniform.…”