Bone Metabolism in SARS-CoV-2 Disease: Possible Osteoimmunology and Gender Implications

Abstract

Even though inflammatory conditions are known to exert adverse effects on bone metabolism, there are no published data regarding SARS-CoV-2 infection and subsequent fracture risk. We present a brief review of the molecular mechanisms linking inflammatory diseases to increased fracture risk/osteoporosis and of the therapeutic strategies that can prevent bone resorption in patients with inflammatory disease, focusing on the RANK-RANKL system. We also make some considerations on gender differences in infection response and on their implications for survival and for the consequences of COVID-19. Several inflammatory cytokines, especially IL-1, IL-6, and TNF-α, stimulate osteoclast activity, favoring bone resorption through the RANK-RANKL system. Data from the previous SARS-CoV outbreak suggest that the present disease also has the potential to act directly on bone resorption units, although confirmation is clearly needed. Even though the available data are limited, the RANK-RANKL system may provide the best therapeutic target to prevent bone resorption after COVID-19 disease. Vitamin D supplementation in case of deficiency could definitely be beneficial for bone metabolism, as well as for the immune system. Supplementation of vitamin D in case of deficiency could be further advantageous. In COVID-19 patients, it would be useful to measure the bone metabolism markers and vitamin D. Targeting the RANK-RANKL system should be a priority, and denosumab could represent a safe and effective choice. In the near future, every effort should be made to investigate the fracture risk after SARS-CoV-2 infection.

Keywords: COVID-19; Denosumab; Fracture risk; Osteoporosis; SARS-CoV-2.

Fig. 1

The RANK-RANKL-OPG system. Bone metabolism is the result of the balance between bone resorption by osteoclasts and bone formation by osteoblasts. RANK is a transmembrane protein expressed by osteoclast precursors that derive from the colony-forming unit for macrophages (CFU-M). The binding of RANKL, expressed by osteoblasts, stimulates the formation and the activity of the osteoclasts, favoring bone resorption. OPG, an additional soluble protein produced by osteoblasts, prevents the binding between RANK and RANKL, counterbalancing bone resorption. Immune cells such as activated T cells and inflammatory cytokines act synergistically promoting the RANK-RANKL pathway. SARS-Cov-2 could have an additive effect promoting the cytokine storm which promotes bone resorption, but a direct effect of the virus on osteoclastic activation cannot be excluded. From a pharmacological point of view, estrogens and tocilizumab can reduce inflammatory cytokine levels (specially IL-6), whereas denosumab directly inhibits the RANK-RANKL interaction and they all represent potential protective agents against bone resorption

Fig. 2

Proposed mechanism of alarmins. Modified from Fig. 1 in De Martinis et al. [22]