Material and Method: Three hundred and thirteen patients were analyzed retrospectively. Bone mineral density loss was investigated by comparing dualenergy X-ray absorptiometry (DEXA) lumbar spine or femur neck T scores. The patients were examined in two main groups as newly diagnosed (n =104) and known osteoporosis (n =145) patients. Patients diagnosed with osteoporosis at the time of application constituted the newly diagnosed patient group. After the exclusion criteria, patients with known osteoporosis were subdivided according to their status of having COVID-19 infection (n =61), as well as worsening or healing in T scores. Initial and final T scores were compared in each group.

Results: In the newly diagnosed osteoporosis patient group, 22.9% of the patients (n =57) had been infected with COVID-19. In the patient group with known osteoporosis, this rate was 24.5% (n =61). While there was no significant difference between previous T-score values in the group with known osteoporosis with COVID-19, there was a statistical difference in final T-scores (p <0.001). When the group of patients with known osteoporosis were classified according to worsening or healing T-scores, those with COVID-19 infection had a worse final T-score (p <0.001). In the group with healing in the T score, the final DEXA values were better in the group without COVID-19 (p =0.004).

Conclusion: COVID-19 infection may affect bone metabolism, leading to progression of bone mineral density loss.

OP is common in the elderly, increases with age, and is characterized by a progressive alteration of bone mass with increased fracture risk often without trauma^14,15. OP affects about 0.5 million men and 1.2 million women worldwide and is the third most common chronic complication behind hypertension and arthritis^16,17. Studies have shown suggest that there are changes to bone metabolism following COVID-19 infection and during the recovery period^18,19. Additionally, others have shown that there is a higher risk of fracture associated with COVID-19^20,21. Interestingly as well, those with some type of low bone mineral density (BMD) fractures may have higher susceptibility to SARS-CoV2 infection²². Others observed an increase in severe clinical incidence in COVID-19 patients with lower BMD compared to those with higher BMD suggesting that scoring BMD levels may be a strong prognosticator of COVID-19 severity²³.

One potential consequence of COVID-19 is cytokine release syndrome, which contributes to acute inflammatory complications^24,25. Reports have also shown that increased cytokines release not only causes ARDS, but also chronic inflammatory diseases including chronic pulmonary inflammation and arthritis, which contribute to ‘long’ COVID-19 complications^26-30. Additionally, the complications may be linked to accelerated bone loss, systemic OP, and increased fractures^31,32. Previous reports have determined that chronic lung diseases like chronic obstructive pulmonary disease (COPD) and asthma have been linked to bone loss^33,34. Despite evidence for long-term complications of COVID-19, there is still a lack of investigations on OP, COVID-19 and lung involvement. In this report, the main goals were to determine whether the hyper-inflammation caused by COVID-19 infection negatively effects bone health. Therefore, we investigated BMD loss, by comparing DEXA values and lung involvement, in patients with and without COVID-19 who were previously diagnosed with OP and followed up for 15 months in our polyclinic.

Exclusion criteria were as follows: 1- those with disease affecting the musculoskeletal system (pituitary gland disease, thyroid gland diseases, parathyroid gland disease, rheumatic disease history, and/or malignancy); 2- Those with a history of drug use that would affect the musculoskeletal system; and 3- those with OP who received medical treatment and had previous DEXA values that could not be determined. After exclusion criteria were considered, the study was completed with 249 female patients with postmenopausal OP and the absence or presence of COVID-19 infection. The current study was conducted according to the Helsinki Declaration, and approved by Ethical Committee of Firat University (approval code: 16.03.2022-357). The minimum number of patients to be included in the study was determined to be 313 to achieve 80% power at the significance level of α=0.5 with a medium effect size.

Patients were stratified into groups. The first group consisted of patients with new diagnosis of OP and COVID-19 positive (nDOP/COVID+) and new diagnosis OP and COVID-19 negative (nDOP/COVID-). The second group consisted of patients with known OP who were COVID-19 positive (kOP/COVID+) or COVID-19 negative (kOP/COVID-). Patients were followed up for 15 months after receiving medical treatment with biphosphonate or denosumab and previous (initial) DEXA values were compared to the final DEXA value T-Scores. For the kOP/COVID+ group, patients were categorized based on worsening DEXA value T-Scores (kOP/COVID+ W) or healing DEXA value T-Scores (kOP/COVID+ H). The kOP/COVID- cohort consisted of patients grouped based on worsening DEXA value T-Scores (kOP/COVID- W) or healing DEXA value T-Scores (kOP/COVID- H) (Table 1).

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Table 1: Descriptive statistics.

COVID-19 testing and lung involvement (CT):
For determination of COVID-19 infection, the date that patients were PCR positive was recorded via the public health management system. In the same system, the follow-up CT scans from individuals with COVID-19 infection were analyzed for lung involvement. CT examination was evaluated according to thorax CT reports obtained through the HIMS hospital system and clinical data information through the Public Health Management System.

BMD scoring and diagnosis of OP:
Diagnosis of OP was determined in accordance to the International Society for Clinical Densitometry guidelines (35, 36). DEXA was used to calculate bone mineral density. A scoring system using the lowest BMD T-score was used and included the total lumbar spine (LS) L1-L4 or femur neck as recommended by the guidelines above. A T-score between +1 and -1 was considered normal, while a T-score within -1 and -2.5 was an indicator of low BMD; however, not enough to diagnose as OP. A DEXA value of -2.5 or lower was considered T-score indicative of OP and higher fracture risk (a greater negative value is directly proportional to OP severity).

Statistics
Data were analyzed with IBM SPSS version 23. Conformity to normal distribution was evaluated by Shapi-ro Wilk and Kolmogorov-Smirnov tests. The Mann-Wihney U Test was used to compare the data that were not normally distributed according to the paired groups. Kruskall-Wallis H Test was used to compare the data that were not normally distributed according to groups of three or more, and multiple comparisons were examined with Dunn's test. Wilcoxon test was used to compare the before and after L1-L4 T-Scores that were not normally distributed within the groups. Analysis results were presented as mean ± standard deviation (SD) and median (minimum (MIN)-maximum (MAX)) for quantitative data, and as frequency and percentage for categorical variables. A p-value of less than 0.05 was considered statistically significant.

In table 2, patients with a known diagnosis of OP and receiving medical treatment were compared based on COVID-19 infection.

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Table 2: Comparison of COVID-19 infection status and DEXA L1-4/L2-4 T-score values in patients with known OP.

There were no statistical differences observed between the medians of the previous T-Scores in kOP/COVID+ and kOP/COVID- (p=0.364). However, a comparison between the medians of the final DEXA T-Scores in kOP/COVID+ and kOP/COVID- was statistically different compared (p <0.001).

In table 3, patients with a known diagnosis of OP and receiving medical treatment were grouped according to fixed/decreasing or worsening of their final DEXA values. A worsening of DEXA value T-scores was detected in 82 of the 249 total patient cohort (56.5%).

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Table 3: Comparison of DEXA values of patients with known OP whose DEXA values were found to worsen based on COVID-19 infection.

For kOP/COVID+ W, 38 of the 82 patients (46.3%) were COVID-19 positive and had worsened DEXA values, while 44 of the 82 patients (53.6%) in kOP/COVID- W group had worse DEXA values. No significant difference was found between the previous DEXA values for both groups. However, there was as significantly worse (higher) final T-Score for those patients who had COVID-19 infection (kOP/COVID+ W) (p <0.001).

Table 4 shows a comparison between patients with known OP, healing DEXA value T-scores and COVID-19 infection status.

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Table 4: Comparison of patients with known osteoporosis and healing DEXA values based on COVID-19 infection.

There were 63 total patients between the kOP/COVID+ H and kOP/COVID- H groups. The kOP/COVID+ H group made up 36.5% (n =23) of the total patients, while kOP/COVID- H made up 63.5% (n =40). There were no significant differences for previous DEXA T-Scores in either group. However, the final DEXA T score was found to be significantly lower in the group that did not have COVID-19 infection.

Low BMD has been shown to associate with poor survival in patients with pulmonary complications or respiratory infection (37, 38). Others have shown that patients with COVID-19 may be able to use low BMD as a predictor of severity or mortality^18,21. Conversely, patients with low BMD fractures may have increased susceptibility to COVID-19^19,22. People with low BMD, like that of postmenopausal OP patients, should be aware of the potential increased risk of infection or even sepsis. Our data suggests that BMD worsens in postmenopausal women following COVID-19 infection. These studies combined suggests that the low BMD is not only a potential prognostic factor in patients with COVID-19 but also a possible indicator of previous COVID-19 infection or ‘long’ COVID complications.

In our study, 118 (47.4%) of the 249 patients tested positive for COVID-19. CT determined lung involvement was observed in 71 (28.5%) of the total 249 patients enrolled in the study. When all patients who were positive for COVID-19 were considered, 60.17% had lung involvement. COVID-19 has been shown to contribute to lung complications (i.e., pneumonia or bronchitis) and the potential for severe complications like ARDS³⁹. Those with chronic lung diseases have a higher risk of severe complications resulting from COVID-19⁴⁰. Interestingly, several reports have demonstrated a link between OP or osteopenia in patients with interstitial lung disease suggesting lung involvement can contribute to the risk of bone resorption complications^41,42. Others have shown that OP may represent a common comorbidity of COPD^43,44.

While our study has some strengths, there are several limitations that must be considered. Our study was a retrospective study design with follow-up data for only one year. Even though we enrolled 249 postmenopausal woman with and without COVID-19, our sample size was relatively small. In addition, lung involvement was confined to a broad category and did not include the specifics on the type of involvement (i.e., pneumonia, bronchitis, fluid retention etc). Also, we did not include any controls who were positive/negative for COVID-19 with no history of OP (or low BMD). Therefore, future studies are needed to investigate the findings of COVID-19 on worsening of BMD in OP patients in a larger population. Nevertheless, our study shows that COVID-19 infection results in the progression of BMD loss in patients with a known history OP. More research is needed to identify possible treatment options for improving bone health and preventing COVID-19 infection-related bone complications in the elderly.

1) Aslan A, Aslan C, Zolbanin NM, Jafari R. Acute respiratory distress syndrome in COVID-19: possible mechanisms and therapeutic management. Pneumonia 2021; 13: 14.

2) Tzotzos SJ, Fischer B, Fischer H, Zeitlinger M. Incidence of ARDS and outcomes in hospitalized patients with COVID-19: a global literature survey. Critical Care 2020; 24: 516

3) Attaway AH, Scheraga RG, Bhimraj A, Biehl M, Hatipoğlu U. Severe covid-19 pneumonia: pathogenesis and clinical management. BMJ 2021; 372: 436.

4) Mousavizadeh L, Ghasemi S. Genotype and phenotype of COVID-19: Their roles in pathogenesis. J Microbiol Immunol Infect 2021; 54: 159-63.

5) Elicker BM. What Are the Long-term Pulmonary Sequelae of COVID-19 Infection? Radiology 2022; 304: 193-4.

6) Ragab D, Salah Eldin H, Taeimah M, Khattab R, Salem R. The COVID-19 Cytokine Storm; What We Know So Far. Front Immunol 2020; 11: 1446.

7) Meyer NJ, Gattinoni L, Calfee CS. Acute respiratory distress syndrome. Lancet 2021; 398: 622-37. 8. Gallo Marin B, Aghagoli G, Lavine K, et al. Predictors of COVID-19 severity: A literature review. Rev Med Virol 2021; 31: 1-10.

9) Caranci N, Di Girolamo C, Bartolini L et al. General and COVID-19-Related Mortality by Pre-Existing Chronic Conditions and Care Setting during 2020 in Emilia-Romagna Region, Italy. Int J Environ Res Public Health 2021; 18: 13224.

10) Elezkurtaj S, Greuel S, Ihlow J et al. Causes of death and comorbidities in hospitalized patients with COVID-19. Sci Rep 2021; 11: 4263.

11) Chen Y, Klein SL, Garibaldi BT et al. Aging in COVID-19: Vulnerability, immunity and intervention. Ageing Res Rev 2021; 65: 101205.

12) Salimi S, Hamlyn JM. COVID-19 and Crosstalk With the Hallmarks of Aging. J Gerontol A Biol Sci Med Sci 2020; 75: 34-41.

13) Perrotta F, Corbi G, Mazzeo G et al. COVID-19 and the elderly: insights into pathogenesis and clinical decision-making. Aging Clin Exp Res 2020; 32: 1599-608

14) Miller PD. Management of severe osteoporosis. Expert Opinion on Pharmacotherapy 2016; 17: 473-88.

15) Management of osteoporosis in postmenopausal women: the 2021 position statement of The North American Menopause Society. Menopause 2021; 28: 973-97

16) Salvio G, Gianfelice C, Firmani F et al. Remote management of osteoporosis in the first wave of the COVID-19 pandemic. Arc Osteoporos 2022; 17: 37.

17) Clynes MA, Harvey NC, Curtis EM, Fuggle NR, Dennison EM, Cooper C. The epidemiology of osteoporosis. Br Med Bull 2020; 133: 105-17. 18. Qiao W, Lau HE, Xie H et al. SARS-CoV-2 infection induces inflammatory bone loss in golden Syrian hamsters. Nat Commun 2022; 13: 2539.

19) Salvio G, Gianfelice C, Firmani F, Lunetti S, Balercia G, Giacchetti G. Bone Metabolism in SARS-CoV-2 Disease: Possible Osteoimmunology and Gender Implications. Clin Rev Bone Miner Metab 2020; 18: 51-7.

20) Battisti S, Napoli N, Pedone C et al. Vertebral fractures and mortality risk in hospitalised patients during the COVID-19 pandemic emergency. Endocrine 2021; 74: 461-9.

21) Kumar A, Haider Y, Passey J, Khan R, Gaba S, Kumar M. Mortality Predictors in Covid-19 Positive Patients with Fractures: A Systematic Review. Bull Emerg Trauma 2021; 9: 51-9.

22) Ran S, Zhang S, Chen H, Zhao M, Liu B. Total body bone mineral density and severe COVID-19: A Mendelian randomization analysis in five age strata. Bone 2022; 155: 116281.

23) Tahtabasi M, Kilicaslan N, Akin Y et al. The Prognostic Value of Vertebral Bone Density on Chest CT in Hospitalized COVID-19 Patients. J Clin Densitom 2021; 24: 506-15.

24) Que Y, Hu C, Wan K et al. Cytokine release syndrome in COVID-19: a major mechanism of morbidity and mortality. Int Rev Immunol 2022; 41: 217-30.

25) Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science 2020; 368: 473-4.

26) Ragab D, Salah Eldin H, Taeimah M, Khattab R, Salem R. The COVID-19 Cytokine Storm; What We Know So Far. Front Immunol 2020; 11: 1446.

27) Szabo PA, Dogra P, Gray JI et al. Longitudinal profiling of respiratory and systemic immune responses reveals myeloid celldriven lung inflammation in severe COVID-19. Immunity 2020; 54: 797-814.

28) Wang L-X, Chen X, Jia M, Wang S, Shen J. Arthritis of large joints shown as a rare clinical feature of cytokine release syndrome after chimeric antigen receptor T cell therapy: A case report. Medicine 2018; 97: 4-55.

29) Queiroz MAF, Neves PFMD, Lima SS, et al. Cytokine Profiles Associated With Acute COVID-19 and Long COVID-19 Syndrome. Front Cell Infect Microbiol 2022; 12: 922422.

30) Buonsenso D, Piazza M, Boner AL, Bellanti JA. Long COVID: A proposed hypothesis-driven model of viral persistence for the pathophysiology of the syndrome. Allergy Asthma Proc 2022; 43: 187-93.

31) Sapra L, Saini C, Garg B et al. Long-term implications of COVID-19 on bone health: pathophysiology and therapeutics. Inflamm Res 2022; 71: 1025-40.

32) Tang J. Aging and disease 2022; 13: 960-9.

33) Inoue D, Watanabe R, Okazaki R. COPD and osteoporosis: links, risks, and treatment challenges. Int J Chron Obstruct Pulmon Dis 2016; 11: 637-48.

34) Sarkar M, Bhardwaj R, Madabhavi I, Khatana J. Osteoporosis in chronic obstructive pulmonary disease. Clin Med Insights Circ Respir Pulm Med 2015; 9: 5-21.

35) Lewiecki EM, Watts NB, McClung MR et al. Official Positions of the International Society for Clinical Densitometry. J Clin Endocrinol&Metabol 2004; 89: 3651-5.

36) Schousboe JT, Shepherd JA, Bilezikian JP, Baim S. Executive summary of the 2013 International Society for Clinical Densitometry Position Development Conference on bone densitometry. J Clin Densitom 2013; 16: 455-66.

37) Schulze-Hagen MF, Roderburg C, Wirtz TH et al. Decreased Bone Mineral Density Is a Predictor of Poor Survival in Critically Ill Patients. J Clin Med 2021; 10: 3741.

38) Zhang X, Man K-W, Li GH-Y, Tan KCB, Kung AW-C, Cheung C-L. Osteoporosis is a novel risk factor of infections and sepsis: A cohort study. eClinicalMedicine 2022; 49: 101488.

39) Estenssoro E, Loudet CI, Dubin A et al. Clinical characteristics, respiratory management, and determinants of oxygenation in COVID-19 ARDS: A prospective cohort study. J Crit Care 2022; 71: 15402.

40) Beltramo G, Cottenet J, Mariet A-S et al. Chronic respiratory diseases are predictors of severe outcome in COVID-19 hospitalised patients: a nationwide study. Eur Respir J 2021; 58: 2004474.

41) Xie Z, He Y, Sun Y et al. Association between pulmonary fibrosis and osteoporosis in the elderly people: A case-control study. Medicine (Baltimore) 2016; 95: 5239.

42) Alhamad EH, Nadama R. Bone mineral density in patients with interstitial lung disease. Sarcoidosis Vasc Diffuse Lung Dis 2015; 32: 151-9.

43) Majid H, Kanbar-Agha F, Sharafkhaneh A. COPD: osteoporosis and sarcopenia. COPD Research and Practice 2016; 2: 3.

44) Bhattacharyya P, Paul R, Ghosh M et al. Prevalence of osteoporosis and osteopenia in advanced chronic obstructive pulmonary disease patients. Lung India 2011; 28: 184-6.