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Corticosteroids-induced osteonecrosis in patients with COVID-19: a call for caution

Authors:
Bin Zhang at The First Affiliated Hospital of Jinan University
Bin Zhang
  • The First Affiliated Hospital of Jinan University
Shuixing Zhang at Guangdong Academy of Medical Sciences/Guangdong General Hospital,Guangzhou,China
Shuixing Zhang
  • Guangdong Academy of Medical Sciences/Guangdong General Hospital,Guangzhou,China
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LETTER TO THE EDITOR
Corticosteroid-Induced Osteonecrosis in COVID-19: A Call
For Caution
Bin Zhang and Shuixing Zhang
Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, China
To the Editors:
We read with great interest the article by Yu and colleagues
(1)
in
the Journal of Bone Mineral Research entitled “Osteoporosis Man-
agement in the Era of COVID-19.”The authors provide excellent
guidance on treatment of osteoporosis patients during the
corona virus 2019 (COVID-19) pandemic. In addition to previous
osteoporosis, we should also pay close attention to other muscu-
loskeletal complications caused by COVID-19. As of June
30, 2020, there were more than 10.39 million confirmed COVID-
19 cases worldwide, with 5,07,416 deaths. Until now, no specific
treatments have been recommended for COVID-19 except for
meticulous supportive care. To fight against the cytokine storm
caused by COVID-19 infection, some patients have received
treatment with systemic corticosteroids, especially severe and
critically ill patients.
(2)
In China, low-dose (<1 to 2 mg/kg),
short-term (3–5 days) methylprednisolone is recommended as
adjuvant treatment for COVID-19,
(3)
which was derived from
the lesson of the severe acute respiratory syndrome (SARS) epi-
demic in 2003. However, improper use of systemic corticoste-
roids can increase the risk of osteonecrosis of the femoral
head (ONFH).
Many recovered patients with SARS suffered from avascular
osteonecrosis as a consequence of corticosteroid usage during
their infection. Higher cumulative doses and longer treatment
durations of steroids are more likely to lead to the development
of osteonecrosis in SARS patients.
(4)
In a retrospective study of
539 patients with SARS who were treated with steroids, the inci-
dence of steroid-induced ONFH was 24.1%.
(5)
This study sug-
gested that male gender, younger age, total dose of steroids,
and the use of more than one type of steroid were associated
with an increased incidence of ONFH.
(5)
During long-term
follow-up of SARS patients 7 years after steroid administration,
Zhao and colleagues
(6)
found that larger lesions and less viable
lateral column were the crucial risk factors for progression of
ONFH, and small ONFH lesions seldom collapsed.
Corticosteroids should be administered with caution, including
minimizing dose andduration, avoiding the use of multiple types.
New drugs, such as tocilizumab, may be an alternative to control
the cytokine storm instead of corticosteroids.
(7)
We should
develop a risk stratification system of ONFH for COVID-19
patients
(8)
: (i) low-risk patients would receive no corticosteroids;
(ii) moderate-risk patients would receive corticosteroids with
duration <1 week and cumulative dose <2000 mg; and
(iii) high-risk patients would receive corticosteroids with duration
≥1 week and cumulative dose ≥2000 mg or intravenous pulse
≥80 mg/day lasting for at least 3 days. Different follow-up plans
should be made in COVID-19 patients after discharge according
to various risks, with MRI as the preferred imaging tool for early
detection of ONFH. During corticosteroid treatment, bisphospho-
nates and vitamin E should be prescribed to patients; anticoagu-
lants, vasodilators, and traditional Chinese medicine couldalso be
alternatives.
(9)
Physical therapy and combined pharmacotherapy
can be used to delay or prevent collapse of steroid-induced ONFH
in early stages.
(10)
Disclosures
The authors declare no competing interests.
Author Contributions
BZ: Conceptualization; investigation; writing-original draft. SZ:
Conceptualization; writing-review and editing.
References
1. Yu EW, Tsourdi E, Clarke BL, Bauer DC, Drake MT. Osteoporosis man-
agement in the era of COVID-19. J Bone Miner Res. 2020;35:1009–13.
https://doi.org/10.1002/jbmr.4049.
2. Li S, Hu Z, Song X. High-dose but not low-dose corticosteroids poten-
tially delay viral shedding of patients with COVID-19. Clin Infect Dis
Forthcoming. Epub 2020 Jun 26. doi: https://doi.org/10.1093/cid/
ciaa829.
3. National Health Commission of the People’s Republic of China.
Guidelines for the diagnosis and treatment of novel coronavirus
(2019-nCoV) infection (trial version 7) (in Chinese). National Health
Commission of the People’s Republic of China. 2020. doi: https://
doi.org/10.7661/j.cjim.20200202.064.
4. Zhao R, Wang H, Wang X, Feng F. Steroid therapy and the risk of
osteonecrosis in SARS patients: a dose-response meta-analysis.
Osteoporos Int. 2017;28:1027–34.
Received in original form June 30, 2020; accepted July 11, 2020. Accepted manuscript online July 22, 2020.
Address correspondence to: Shuixing Zhang, MD, PhD, The First Affiliated Hospital of Jinan University, No. 613 Huangpu West Road, Tianhe District, Guangzhou,
Guangdong 510627, China. E-mail: shui7515@126.com
Journal of Bone and Mineral Research, Vol. 00, No. 00, Month 2020, pp 1–2.
DOI: 10.1002/jbmr.4136
© 2020 American Society for Bone and Mineral Research
1n
5. Guo KJ, Zhao FC, Guo Y, Li FL, Zhu L, Zheng W. The influence of age,
gender and treatment with steroids on the incidence of osteonecro-
sis of the femoral head during the management of severe acute
respiratory syndrome: a retrospective study. Bone Joint J. 2014;
96-B:259–62.
6. Zhao FC, Guo KJ, Li ZR. Osteonecrosis of the femoral head in SARS
patients: seven years later. Eur J Orthop Surg Traumatol. 2013;23:671–7.
7. Deng F, Gao D, Ma X, et al. Corticosteroids in diabetes patients
infected with COVID-19. Ir J Med Sci Forthcoming. Epub 2020 Jun
25. doi: https://doi.org/10.1007/s11845-020-02287-3.
8. Weiheng C. Expert consensus on prevention and treatment of osteo-
necrosis of the femoral head (ONFH) after COVID-19 with traditional
Chinese medicine. J Trad Clin Orthop Trauma. 2020;32:4–6.
9. Tang C, Wang Y, Lv H, et al. Caution against corticosteroid-based
COVID-19 treatment. Lancet. 2020;395:1759–60.
10. Wang W, Zhang N, Guo W, Gao F, et al. Combined pharmacotherapy
for osteonecrosis of the femoral head after severe acute respiratory
syndrome and interstitial pneumonia: two and a half to fourteen year
follow-up. Int Orthop. 2018;42:1551–6.
Journal of Bone and Mineral Research
n2ZHANG AND ZHANG

Supplementary resource (1)

jbmr.4136.pdf
Data
August 2020
Bin Zhang · Shuixing Zhang
... Zhang and Zhang suggested applying a risk stratification strategy for patients who had COVID-19 infection for the early detection of FHAVN, which was based on the recommendations by the ARCO committee China branch; they suggested dividing the patients into three main categories: 1-low-risk, if the patients did not receive corticosteroids, 2-moderate-risk, if less than 2000 mg corticosteroids were administered and for less than a week, and 3-high-risk, if more than 2000 mg corticosteroids were received for more than one week or if the patient received IV pulse more than 80 mg per day for at least three days [10,62,63]. ...
... They recommended tailoring the follow up plan according to the risk category, where patients recovering from COVID-19 should be followed for at least 24 months, with MRI being the diagnostic modality of choice for screening and early detection; furthermore, the high-risk group should attend regular clinic follow up at two to six months intervals after being exposed to corticosteroids, while the frequency is less for the low and moderate risk groups [62,63]. From the articles included in the current review, some authors recommended performing early MRI for patients recovering from COVID-19 infection if they started feeling hip joint discomfort [18,22,28]. ...
... Various modalities were suggested for non-surgical intervention management options for early detected FHAVN, including protected weight bearing, physical therapy, vasodilators, oral anticoagulants, traditional Chinese therapy, and bisphosphonates [12,62,63]. Furthermore, reports on FHAVN post-SARS showed that the osteonecrotic lesions tend to reduce in size and stabilize over time, unlike AVN developed after steroid usage in other conditions such as autoimmune diseases [45,64]. ...
Rheumatology Femoral head avascular necrosis in COVID-19 survivors: a systematic review
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The current systematic review aimed to document published cases of femoral head avascular necrosis (FHAVN) post-COVID-19, to report the COVID-19 disease characteristics and management patients received, and to evaluate how the FHAVN were diagnosed and treated among various reports. A systematic literature review was performed per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines through a comprehensive English literature search on January 2023 through four databases (Embase, PubMed, Cochrane Library, and Scopus), including studies reporting on FHAVN post-COVID-19. Fourteen articles were included, ten (71.4%) were case reports, and four (28.6%) case series reported on 104 patients having a mean age of 42.2 ± 11.7 (14:74) years, in which 182 hip joints were affected. In 13 reports, corticosteroids were used during the COVID-19 management plan for a mean of 24.8 ± 11 (7:42) days, with a mean prednisolone equivalent dose of 1238.5 ± 492.8 (100:3520) mg. A mean of 142.1 ± 107.6 (7:459) days passed between COVID-19 diagnosis and FHAVN detection, and most of the hips were stage II (70.1%), and concomitant septic arthritis was present in eight (4.4%) hips. Most hips (147, 80.8%) were treated non-surgically, of which 143 (78.6%) hips received medical treatment, while 35 (19.2%) hips were surgically managed, 16 (8.8%) core decompression, 13 (7.1%) primary THA, five (2.7%) staged THA and three (1.6%) had first stage THA (debridement and application of antibiotic-loaded cement spacer). The outcomes were acceptable as regards hip function and pain relief. Femoral head avascular necrosis post-COVID-19 infection is a real concern, primarily attributed to corticosteroid usage, besides other factors. Early suspicion and detection are mandatory, as conservative management lines are effective during early stages with acceptable outcomes. However, surgical intervention was required for progressive collapse or patients presented in the late stage.
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... Unfortunately, however, their inappropriate and excessive use leads to an increase in cases of osteonecrosis [25][26][27] . There is clear evidence that prolonged use and cumulative doses of corticosteroids are associated with changes in bone homeostasis 26,28,29 . Glucocorticoids significantly alter the function of osteoblasts and osteoclasts in addition to mineral metabolism, drastically altering bone density and leading to changes such as osteonecrosis and osteoporosis 10,13,26,28 . ...
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... The first is the thrombosis associated with the disease itself, which may compromise the vascular supply of bones [41]. The other might be the use of drugs used in the treatment of COVID-19, such as steroids and tocilizumab [42,43]. ...
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... Это заболевание сопровождается васкулитом, может осложняться тромбозами сосудов различного калибра и требует терапии ГК у большинства пациентов, переносящих болезнь в среднетяжелой и тяжелой форме [86][87][88][89][90][91]. В мировой литературе только начинают появляться публикации о развитии АН во время или после перенесенного COVID-19 [92][93][94][95][96], однако уже сейчас описаны факторы риска (соответствуют характеристикам среднетяжелого и тяжелого течения болезни) развития АН после COVID-19 [97] и разработан протокол скрининга данного осложнения, основанный на определении кумулятивной дозы ГК [98,99], что напрямую подтверждает актуальность данной проблемы и косвенно предупреждает о росте числа АН в мире [100]. ...
Avascular necrosis of bone tissue: Definition, epidemiology, types, risk factors, pathogenesis of the disease. Analytical review of the literature
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Avascular necrosis (AN) of bone tissue is a common pathology that affects people of any age, more often young and able-bodied. The disease leads to rapid destruction of the subchondral bone and collapse, followed by the development of secondary osteoarthritis (OA) of the affected joint. The purpose of this review article is to present the accumulated knowledge about the prevalence of AN, the most commonly affected joints, risk factors and pathogenesis of the disease. Since most of the world’s literature sources present knowledge about the individual parts and facts that make up the pathogenesis of AN, this article analyzes all known paths of the development of the disease from the onset of ischemia to collapse and the development of secondary OA and the pathogenesis is presented in chronological order. Based on the results of the article, a definition of the term AN was proposed, and the stages of the disease within the pathogenesis, the most promising for conservative methods of treatment, were identified.
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Is COVID-19 an independent risk factor for the development of avascular necrosis of the hip? A retrospective study to evaluate the factors associated with avascular necrosis of the hip in patients who had COVID-19 infection
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The cumulative effect of hyper-coagulative COVID-19 disease and using steroids leads to increased avascular necrosis (AVN) hip incidence. This study aims to correlate the various factors of COVID-19 infection with the occurrence of AVN hip. It is a retrospective cross-sectional study of non-traumatic AVN hip patients with a history of COVID-19 infection. A total number of 50 patients satisfied the inclusion criteria. The following details were obtained: (a) patient’s demographics, (b) COVID-19: interval of infection and groin pain, duration of symptoms, severity, steroid intake, (c) AVN hip: involved side, Ficat-Arlet staging. The mean age was 36.3 years (range: 20–60), and body mass index (BMI) was 25.13 kg/m2 (range: 18.50–31.50). There were 45 males and five females. Sixty percent (30) of patients managed at home, 24% (12) required admission into the ward, 2% (1) were in ICU only, and 14% (7) admitted to both ICU and ward. The mean interval of COVID-19 infection and onset of hip pain was 359.02 days (range: 10–822 days). Thirty-eight percent (19) patients required steroids (injection and oral), 46% (23) took steroids (oral only), whereas 16% (8) recovered without steroids. The stage of AVN correlated with the severity of COVID-19 infection (p-value −0.038) and significant improvement in VAS and HHS after treatment in each stage. The mean follow-up was 9.79 months (6–19 months). A low-dose steroid intake with moderate to severe COVID-19 infection produces an additive effect on the development of AVN hip. Most affected individuals were adult males, and stage II AVN was the most common, managed with bisphosphonates and core decompression for short intervals.
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Knee Osteonecrosis After SARS-CoV-2 Virus Infection
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Osteonecrosis after COVID-19 infection is a complex pathology with multifactorial origin. Factors such as infection itself with associated coagulopathy, as well as genetic mechanisms, and medications used for its treatment such as corticosteroids, may also be involved. The variability in the presentation makes diagnosis difficult, which, if done soon, can help delay progression and reduce morbidity and the need for surgery. This report presents a case of knee osteonecrosis in a female patient who did not have previous knee pathology on imaging tests. She was diagnosed by magnetic resonance imaging months after hospital admission for SARS-COV 2 pneumonia, which required high-dose corticosteroid treatment.
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Avascular necrosis of femoral head following COVID-19 infection
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Introduction: It is crucial to be aware of post-COVID-19 non-pulmonary complications. Avascular necrosis (AVN) is one of these complications. It should be noted that the risk of AVN persists in individuals who have recovered from the COVID-19 infection. The current study aims to report several cases of AVN after being infected with SARS-CoV-2. Materials and methods: This is a single-centre retrospective case series conducted over a 2-year period (January 2021-December 2022) involving individuals who developed AVN after being infected with COVID-19. Result: The study included a total of 17 patients. The mean age of patients was 38.65±6.1 years. Twelve of them were male (70.6%) and five were female (29.4%), with a ratio of 3:1. The mean BMI of the patients was 28.3±2.4 kg/m2. Eleven (64.7%) patients reported administering steroid injections throughout the infection course. The mean interval between COVID-19 infection and presentation to the clinic was 6.53 months. The majority of patients (82.3%) complained of bilateral hip pain. Limping was observed in 47% of the cases. MRI showed AVN in all cases. Bilateral core decompression was performed in five cases (29.4%), total hip replacement in three cases (17.6%), and conservative treatment in nine cases (53%). Conclusion: The ongoing pandemic may have many long-term sequelae. There is a risk of developing AVN after COVID-19.
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Pediatri ve COVID-19
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Full-text available
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Combined pharmacotherapy for osteonecrosis of the femoral head after severe acute respiratory syndrome and interstitial pneumonia: two and a half to fourteen year follow-up
Article
Full-text available
  • Mar 2018
Purpose: The purpose of this study was to retrospectively analyze the clinical, functional, and radiological outcomes of combined pharmacotherapy to ONFH after high-dose corticosteroid therapy. Method: From August 2003 to June 2015, five patients (ten hips) of ONFH in ARCO stage I, after SARS and Interstitial pneumonia, were treated by combined pharmacotherapy. Lipo-prostaglandin E110 μg iv Bid × 28 days, enoxaparin 6000 iu H QD × 12 weeks, alendronate sodium tablet 10 mg QD × 1 year. The patients were fully weight-bearing following completion of the follow-up. Result: For these five patients (ten hips), Harris score was 100 from the diagnosis to final follow-up time. Radiologic findings show no signs of collapse, necrotic focus was repaired, and ARCO stages were changed from ICinto IIB. Conclusion: This combined pharmacotherapy has promising treatment results for delaying or preventing collapse of ONFH in ARCO stage I.
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Osteoporosis Management in the Era of COVID‐19
Article
  • May 2020
Osteoporosis is a chronic condition which reflects reduced bone strength and an associated increased risk for fracture. As a chronic condition, osteoporosis generally requires sustained medical intervention(s) to limit the risks for additional bone loss, compromise of skeletal integrity, and fracture occurrence. Further complicating this issue is the fact that the abrupt cessation of some therapies can be associated with an increased risk for harm. It is in this context that the COVID‐19 pandemic has brought unprecedented disruption to the provision of healthcare globally, including near universal requirements for social distancing. In this Perspective, we provide evidence, where available, regarding the general care of patients with osteoporosis in the COVID‐19 era, and provide clinical recommendations based primarily on expert opinion when data is absent. Particular emphasis is placed on the transition from parenteral osteoporosis therapies. It is hoped that these recommendations can be used to safely guide care for patients with osteoporosis until a return to routine clinical care standards is available.
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Steroid therapy and the risk of osteonecrosis in SARS patients: a dose-response meta-analysis
Article
  • Nov 2016
  • OSTEOPOROSIS INT
Introduction: The link between steroid treatment and the risk of osteonecrosis in SARS patients remains unknown. The present meta-analysis aimed to examine the dose-response association between steroid therapy and osteonecrosis incidence in SARS patients. The sex differences in the development of steroid-induced osteonecrosis were also examined. Methods: We searched PubMed, Web of Science, CNKI, and WANFANG for studies that involved steroid therapy and reported osteonecrosis data in SARS patients. Two authors independently extracted the data from the individual studies, and the rate ratio (RR) of osteonecrosis was calculated using random-effect models. Results: Ten studies with 1137 recovered SARS patients met the inclusion criteria. Close relationships between osteonecrosis incidence and both the cumulative dose and treatment duration of steroids were observed. The summary RR of osteonecrosis was 1.57 (95% confidence interval (CI) 1.30-1.89, p < 0.001) per 5.0 g increase in the cumulative dose of steroids and was 1.29 (95% CI 1.09-1.53, p = 0.003) for each 10-day increment of increase in treatment duration. The relationship was non-linear (p non-linear < 0.001 and p non-linear = 0.022). There were no significant differences in the risk of developing osteonecrosis between the male and female patients (RR 0.01, 95% CI -0.03 to 0.06, p = 0.582). Conclusions: SARS patients who received higher cumulative doses and longer treatment durations of steroids were more likely to develop osteonecrosis, and there were no sex differences in this dose-dependent side effect. Our findings suggest that it is important to reduce osteonecrosis risk by modifying the cumulative dose and the treatment duration of steroids in SARS patients.
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The influence of age, gender and treatment with steroids on the incidence of osteonecrosis of the femoral head during the management of severe acute respiratory syndrome: A retrospective study
Article
  • Feb 2014
Corticosteroid use has been implicated in the development of osteonecrosis of the femoral head (ONFH). The exact mechanism and predisposing factors such as age, gender, dosage, type and combination of steroid treatment remain controversial. Between March and July 2003, a total of 539 patients with severe acute respiratory syndrome (SARS) were treated with five different types of steroid. There were 129 men (24%) and 410 women (76%) with a mean age of 33.7 years (21 to 59). Routine screening was undertaken with radiographs, MRI and/or CT to determine the incidence of ONFH. Of the 129 male patients with SARS, 51 (39.5%) were diagnosed as suffering from ONFH, compared with only 79 of 410 female patients (19.3%). The incidence of ONFH in the patients aged between 20 and 49 years was much higher than that of the group aged between 50 and 59 years (25.9% (127 of 491) versus 6.3% (3 of 48); p = 0.018). The incidence of ONFH in patients receiving one type of steroid was 12.5% (21 of 168), which was much lower than patients receiving two different types (28.6%; 96 of 336) or three different types of steroid (37.1%; 13 of 35). Cite this article: Bone Joint J 2014;96-B:259–62.
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Osteonecrosis of the femoral head in SARS patients: Seven years later
Article
  • Jul 2012
This study is aimed to explore the progression of osteonecrosis of the femoral head (OFNH) in severe acute respiratory syndrome patients 7 years after steroid administration and to analyze factors affecting the prognosis. One-hundred and ninety hips in 117 patients with more than 7 years of follow-up were studied. The prevalence of progression to symptoms and collapse was determined. The total dose of steroid, gender, age, stage, lesion location, volume of necrosis, viable lateral column and bone marrow edema were analyzed and correlated with progression. During the 7 years of follow-up, 66 hips progressed to symptoms, 50 hips collapsed and 10 hips showed complete regression. Fifty-seven hips (86.36 %) caused pain and 32 (64.00 %) collapsed within 3 years of steroid administration. The lesion was relatively larger, and there was relatively less viable lateral column in hips that exhibited symptoms or collapsed. Mechanical failure of the necrotic segment of bone principally occurred within 3 years after the administration of steroids. Larger lesions and less viable lateral column were the main risk factors for progression. Small ONFH lesions seldom collapsed.
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National Health Commission of the People's Republic of China. Guidelines for the diagnosis and treatment of novel coronavirus (2019‐nCoV) infection (trial version 7) (in Chinese). National Health Commission of the People's Republic of China. 2020. doi: <https://doi.org/10.7661/j.cjim.20200202.064>
  • Jan 2020
National Health Commission of the People's Republic of China. Guidelines for the diagnosis and treatment of novel coronavirus (2019-nCoV) infection (trial version 7) (in Chinese). National Health Commission of the People's Republic of China. 2020. doi: https:// doi.org/10.7661/j.cjim.20200202.064.
Expert consensus on prevention and treatment of osteonecrosis of the femoral head (ONFH) after COVID-19 with traditional Chinese medicine
  • Jan 2020
  • 4
  • Weiheng
Weiheng C. Expert consensus on prevention and treatment of osteonecrosis of the femoral head (ONFH) after COVID-19 with traditional Chinese medicine. J Trad Clin Orthop Trauma. 2020;32:4-6.