Partial maintenance of extra cancellous bone mass by antiresorptive agents after discontinuation of human parathyroid hormone (1–38) in right hindlimb immobilized rats
Authors: Ma Yanfei , Dr. Jee Webster S.S. , Chen Yongyong , Gasser Jürg , Zhu Ke Hua , Jian Li Xiao , Kimmel Donald B. 
Published: February 2010

Abstract
The current study employs the immobilization (IM) rat model to induce osteopenia, parathyroid hormone (PTH) as the anabolic agent to restore bone mass, and 17β-estradiol, calcitonin, or risedronate as the maintenance agents to answer the following questions: How much cancellous bone loss occurs when PTH is withdrawn? Which antiresorptive or antiactivation agent maintains bone best? Ideally, what tissue-level histomorphometric conditions maintain added bone? Six-month-old female rats were treated with 200 μg PTH/kg/day subcutaneously at 30 days post-IM for 75 days. Then PTH treatment was stopped and switched to a vehicle (no treatment), 10 μg calcitonin/kg/day, 10 μg 17β-estradiol/kg/day, or 5 μg risedronate twice weekly for another 15 days (early response) or 60 days (late response). The rats had their right hindlimb immobilized throughout the study. The current report deals only with the maintenance phase involving 92 animals. Bone histomorphometry was performed on the secondary spongiosa of the right proximal tibial metaphysis (PTM). Cessation of PTH treatment followed by vehicle administration for 15 days resulted in partial loss of trabecular bone area and thickness from stimulated bone resorption and the fall of all formation indices. By contrast, all three antiresorptive agents maintained the cancellous bone mass during the same period. However, after prolonged withdrawal of PTH for 60 days, we found that 17β-estradiol and calcitonin maintained the cancellous bone slightly better than no treatment, while risedronate partially protected it from the mechanostat-induced bone loss. The risedronate treatment retained 71% of the PTH-added bone while calcitonin retained 48%, estrogen 42%, and no treatment 32%. The favorable histomorphometry profile for maintenance was the sustained reduction in bone resorption and turnover and normal age-related bone balance. We concluded that 1) cessation of PTH treatment will result in the loss of two-thirds of the added bone in 60 days; 2) currently, risedronate at the dose level employed as a maintenance agent is far superior to 17β-estradiol or calcitonin because of its long retention in bone; however, a longer observation period might result in less difference; and 3) the ideal tissue-level histomorphometry continues depressing bone resorption and turnover and maintains a normal age-related bone balance. Furthermore, we found the “lose, restore plus add, and maintain (LRAM)” concept was successful in maintaining most of the PTH-induced extra bone by risedronate for 60 days. It was far superior to 17β-estradiol or calcitonin. Possibly the last two agents would be effective in maintaining a normal amount of bone but not in preserving an excessive amount of bone. Nevertheless, the current study further emphasizes that clinicians should consider using the LRM treatment strategy when they plan to treat osteoporosis with bone anabolic agents.