Long-term implications of COVID-19 on bone health: pathophysiology and therapeutics

Abstract

Background: SARS-CoV-2 is a highly infectious respiratory virus associated with coronavirus disease (COVID-19). Discoveries in the field revealed that inflammatory conditions exert a negative impact on bone metabolism; however, only limited studies reported the consequences of SARS-CoV-2 infection on skeletal homeostasis. Inflammatory immune cells (T helper-Th17 cells and macrophages) and their signature cytokines such as interleukin (IL)-6, IL-17, and tumor necrosis factor-alpha (TNF-α) are the major contributors to the cytokine storm observed in COVID-19 disease. Our group along with others has proven that an enhanced population of both inflammatory innate (Dendritic cells-DCs, macrophages, etc.) and adaptive (Th1, Th17, etc.) immune cells, along with their signature cytokines (IL-17, TNF-α, IFN-γ, IL-6, etc.), are associated with various inflammatory bone loss conditions. Moreover, several pieces of evidence suggest that SARS-CoV-2 infects various organs of the body via angiotensin-converting enzyme 2 (ACE2) receptors including bone cells (osteoblasts-OBs and osteoclasts-OCs). This evidence thus clearly highlights both the direct and indirect impact of SARS-CoV-2 on the physiological bone remodeling process. Moreover, data from the previous SARS-CoV outbreak in 2002-2004 revealed the long-term negative impact (decreased bone mineral density-BMDs) of these infections on bone health.

Methodology: We used the keywords "immunopathogenesis of SARS-CoV-2," "SARS-CoV-2 and bone cells," "factors influencing bone health and COVID-19," "GUT microbiota," and "COVID-19 and Bone health" to integrate the topics for making this review article by searching the following electronic databases: PubMed, Google Scholar, and Scopus.

Conclusion: Current evidence and reports indicate the direct relation between SARS-CoV-2 infection and bone health and thus warrant future research in this field. It would be imperative to assess the post-COVID-19 fracture risk of SARS-CoV-2-infected individuals by simultaneously monitoring them for bone metabolism/biochemical markers. Importantly, several emerging research suggest that dysbiosis of the gut microbiota-GM (established role in inflammatory bone loss conditions) is further involved in the severity of COVID-19 disease. In the present review, we thus also highlight the importance of dietary interventions including probiotics (modulating dysbiotic GM) as an adjunct therapeutic alternative in the treatment and management of long-term consequences of COVID-19 on bone health.

Keywords: Bone health; COVID-19; Gut microbiota; Inflammation; Probiotics; SARS-CoV-2.

Fig. 1

SARS-CoV-2 infection induce bone loss: In physiological conditions, the homeostatic balance between osteoblasts and osteoclasts maintains the bone health, whereas upon SARS-CoV-2 infection enhanced production of inflammatory cytokines shifts balance towards the bone-resorbing osteoclasts that further augments bone loss

Fig. 2

Factors influencing COVID-19 disease severity and bone loss: various factors such as dysbiosis of gut microbiota (GM), cytokine storm, administration of steroidal therapies, deficiency of vitamin D, gender and, hormonal factors influence COVID-19 and bone health

Fig. 3

SARS-CoV-2 affects bone health either directly or via cytokine storm: A Various organs of the body including skeleton system express angiotensin convertase enzyme 2 (ACE2) receptor that aids the entry of SARS-CoV-2 inside host cells. (1): Internalization of COVID-19 into target cells, (2): after pyroptosis waning cells generate death-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), (3): virus-derived DAMPs and PAMPs engulfed by macrophages in turn produce pro-inflammatory cytokines, (4) interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, chemokine (CC) ligand-2, CCL-3 and CXCL10, (5): recruitment of neutrophils and CD8⁺ T cells to the site of infection that further causes tissue injury in lung parenchyma, (6): “Cytokine Storm Syndrome”, i.e., flooding of cytokines into circulation that leads to multiorgan failure including skeleton system. B Inside the skeleton system, SARS-CoV-2 binds to ACE2 receptor on osteoclasts and induces its differentiation. Moreover, inflammatory cytokines further augment bone loss by binding to cytokine receptors. In addition, by inducing production of micro-RNA-4485, SARS-CoV-2 inhibits osteogenic ability of osteoblasts.

Fig. 4

Dysbiosis of Gut microbiota (GM) enhances COVID-19 disease severity and bone loss: healthy GM maintains the intestinal barrier that further generates the effective immune response resulting in clearance of virus and no bone loss. On the other hand, dysbiosis of GM results in loss of intestinal barrier integrity which further enhances cytokine storm and thus bone loss

Fig. 5

Probiotics and management of bone health post-SARS-CoV-2 infection: A Probiotics prevent COVID-19-induced dysbiosis by restoring gut microbiota composition. B Probiotics maintains Gut integrity and thus inhibit inflammation induced bone loss. C Probiotics can directly promote osteoblasts differentiation and suppress osteoclastogenesis. D Probiotics modulate bone health via modulating immune system. E Probiotics resolve inflammation by reducing inflammatory cytokines

Fig. 6

Modulation of dietary interventions reduces the COVID-19 disease severity and maintains bone health: intake of a ketogenic diet by remodeling the GM enhances the Tregs and reduces Th17 cells that further reduce COVID-19 disease severity and maintains bone health by producing IL-10 and reducing IL-17 cytokine. On the other hand, production of ketone bodies such as 3β-Hydroxybutyrate reduces the NLR family pyrin domain containing 3 (NLRP3) inflammasomes mediated production of IL-1β and IL-18 cytokines and thus maintains bone health. A perusal of intermittent fasting conserves energy and reduces macrophage (NLRP3 inflammasomes) and maintains bone health

Fig. 7

Correlation between Covid-19 and Bone Health: List of factors affecting the severity of COVID-19 disease and Bone loss