Abstract: We aimed to establish a murine model to investigate the potential therapeutic role of human mesenchymal stem cells (MSCs) in skeletal disorders in vivo. Therefore, we specifically focused on 2 experimental models: the bisphosphonate-related osteonecrosis of the jaw (ONJ) and ovariectomy (OVX)-induced bone loss to simulate postmenopausal osteoporosis. Utilizing NOD.CB17-Prkdcscid/J (NOD-SCID) mice, known for their compromised immune systems, we examined the development of ONJ following varying dosages and routes of administration of zoledronic acid, with and without adjunctive dexamethasone treatment. Surprisingly, we found a very low incidence of ONJ compared to the results reported in immunocompetent mice, suggesting that factors intrinsic to the NOD-SCID mice, such as immune deficiency and possibly altered microbiota due to sterile housing conditions, may influence the development of this condition. On the other hand, these mice did not show the anticipated bone loss following bilateral OVX, challenging conventional wisdom and emphasizing the multifaceted nature of osteoporosis involving both the immune system and microbiota. This study reveals the limitations of immunodeficient mice as experimental models in bone research. On the other hand, it is consistent with experimental data suggesting a role of osteoimmunology and osteomicrobiology mechanisms in the pathogenesis of some skeletal disorders.

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