Restoring and maintaining bone in osteopenic female rat skeleton: I. Changes in bone mass and structure

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Abstract
This experiment contains the crucial data for the lose, restore, and maintain (LRM) concept, a practical approach for reversing existing osteoporosis. The LRM concept uses anabolic agents to restore bone mass and architecture (+ phase) and then switches to an agent with the established ability to maintain bone mass, to keep the new bone (± phase). The purpose of this study was to learn whether switching to an agent known chiefly for its ability to maintain existing bone mass preserves new bone induced by PGE2 in osteopenic, estrogen-depleted rats. The current study had three phases, the bone loss (-), restore (+), and maintain (±) phases. We ovariectomized (OX) or sham ovariectomized (sham-OX) 5.5-month-old female rats (- phase). The OX rats were treated 5 months postovariectomy with 1–6 mg PGE2 per kg/day for 75 days to restore lost cancellous bone mass (+ phase), and then PGE2 treatment was stopped and treatment began with 1 or 5 μg/kg of risedronate, a bisphosphonate, twice a week for 60 days (± phase). During the loss (-) phase, the cancellous bone volume of the proximal tibial metaphysis in the OX rat fell to 19% of initial and 30% of age-matched control levels. During the restore (+) phase, the cancellous bone volume in OX rats doubled. When PGE2 treatment was stopped, however, and no special maintenance efforts were made during the maintain (±) phase, the PGE2-induced cancellous bone disappeared. In contrast, the PGE2-induced cancellous bone persisted when the PGE2 treatment was followed by either a 1 or 5 μg treatment of risedronate per kg given twice a week for 60 days during the maintain (±) phase. The tibial shaft demonstrated very little cortical bone loss during the loss (-) phase in OX rats. The tibial shaft cortical bone fell some 8%. During the restore (+) phase, new cortical bone in OX rats increased by 22%. When PGE2 treatment was stopped and nothing was given during the maintain (±) phase, however, all but the PGE2-induced subperiosteal bone disappeared. In contrast, when PGE2 treatment was stopped and 1 μg risedronate per kg twice a week for 60 days was administered during the maintenance (±) phase, the PGE2-induced subperiosteal bone and some of the subendocortical bone and marrow trabeculae persisted. When 5 μg risedronate per kg was given twice a week, all the PGE2-induced bone persisted. The study shows that most of the new cancellous and cortical bone induced by PGE2 can be maintained for at least 60 days after discontinuing PGE2 by administering enough of the resorption inhibitor, risedronate. The lower dose of risedronate was not adequate to save most of the PGE2-induced endocortical bone.
Funding Information
  • National Institutes of Health ((AR-38346))
  • Department of Energy ((DE-FG02-89ER 60764 A 001))
  • National Aeronautics and Space Administration ((NAG-2-435))
  • Department of Energy ((DE-ACOl-76EV001 19))