Technetium-99 Conjugated with Methylene Diphosphonate Ameliorates Glucocorticoid Induced Osteoporosis by Inhibiting...

Technetium-99 conjugated with methylene diphosphonate (⁹⁹Tc-MDP) is an effective anti-inflammatory drug in treating rheumatoid arthritis (RA) for over 15 years in China. However, as a special form of bisphosphonate, the antiosteoporotic effect of ⁹⁹Tc-MDP is unclear. We systematically investigated the effects of ⁹⁹Tc-MDP on cancellous and cortical bone, respectively, in glucocorticoid induced osteoporosis (GIO) animal models. Forty-eight Sprague-Dawley rats were randomly divided into six groups: blank, negative control, high dose, medium dose, low dose, and positive control groups. After dexamethasone was given to all groups except the blank group to induce osteoporosis, the rats in different groups were treated with saline, MDP, or different doses of ⁹⁹Tc-MDP. After treatment, all rats were sacrificed, and their tibiae and femora were analyzed with microcomputed tomography (micro-CT), histology and biomechanics. Micro-CT analyses showed that (1) ⁹⁹Tc-MDP reversed glucocorticoid induced bone microarchitecture destruction by increasing BV/TV, Tb.Th, and Tb.N and decreasing BS/BV, Tb.Sp, and TBPf; (2) effect of ⁹⁹Tc-MDP increased as its dosage increased; and (3) ⁹⁹Tc-MDP could improve cortical bone thickness while MDP failed to do so. Micro-CT spatial structure analysis and histology also yielded consistent results, indicating that ⁹⁹Tc-MDP increased trabecular number and connectivity morphologically. Secondly, biomechanics revealed that ⁹⁹Tc-MDP can enhance the extrinsic stiffness of bone by changing bone geometry. Finally, ⁹⁹Tc-MDP could inhibit osteoclastogenesis in PBMCs in human. In conclusion, ⁹⁹Tc-MDP exerted antiosteoporotic effect by improving both cancellous and cortical bone, as well as increasing extrinsic bone stiffness which might be attributed to the its inhibition of osteoclast differentiation. The antiosteoporotic effect of ⁹⁹Tc-MDP may suggest a potential clinical application for patients with GIO.