Double Trouble-COVID-19 and the widespread use of Corticosteroids: Are We Staring at an Osteonecrosis Epidemic?

A combination of immune-mediated vascular damage and routine use of systemic corticosteroid (CS) therapy in COVID-19 may significantly increase the risk and burden of osteonecrosis (ON) after COVID-19.This narrative review by Dr Gautam M. Shetty explores the pathogenesis, risk factors, and possible preventive and early treatment measures for ON in COVID-19.

Currently, with subsequent waves of pandemic occurring in several countries, COVID-19 may become endemic around the globe due to virus mutation and "immune escape", variations in immunity among populations, and uneven vaccine distribution. Clinical presentations of COVID-19 have been attributed to an immune-mediated vascular disease causing micro- and microvascular endothelial damage and hypercoagulability.

Systemic corticosteroid (CS) therapy is frequently administered to hospitalized patients with severe or critical COVID-19 and has been reported to improve survival and shorten the duration of hospitalization. Despite lack of clinical benefits and potential harmful effects when used in the early phase of COVID-19, CS therapy has also been widely used in non-critically ill patients with mild or moderate COVID-19.

Steroid-induced osteonecrosis of the femoral head (ONFH) is responsible for up to 47.4% of all patients diagnosed with non-traumatic ONFH. The risk of steroid-induced ON (SION) depends on the cumulative and maximum dose and the underlying disease state, and may occur even with low doses, especially in the presence of co-morbidities such as diabetes.

Furthermore, there is an urgent need to identify preventive and early diagnostic and treatment measures in COVID-19 patients to avert a possible epidemic of ON which may occur in the coming years.

An extensive literature search was performed using the PubMed, Medline, and Science Direct databases from January 2000 to August 2021 for relevant articles on etiopathogenesis, epidemiology, clinical manifestations, and treatment of severe acute respiratory syndrome coronavirus (SARS-CoV) infection and steroid-induced ON (SION).

"Angiocentric" Pathogenesis of COVID‑19

The SARS-CoV-2 can directly infect endothelial cells using the angiotensin converting enzyme 2 (ACE2) receptor causing immune-mediated endothelial damage.

The combination of a hyperinflammatory and hypercoagulable state leads to widespread breakdown of vascular function in COVID-19.

The ACE2 receptor is locally expressed in skeletal muscles and bone marrow-derived stem/progenitor cells (BMSPCs) and their targeting by SARS-CoV-2, may lead to sarcopenia, reduced muscle strength, altered skeletal repair, and anaphasic bone loss.

The pathogenesis and progression of non-traumatic ON is multifactorial and involves a combination of various mechanisms such as hypercoagulability, suppression of angiogenesis, hyperadipogenesis, altered bone remodelling and genetic predisposition.

Corticosteroids in COVID‑19 Treatment

Systemic CS such as dexamethasone (DX) and methylprednisolone (MPS) are frequently used in the treatment of hospitalized and critically ill COVID-19 patients to alleviate "cytokine storm" and to reduce the need for mechanical ventilation, duration of hospitalization and mortality.

Corticosteroids diminish local perfusion by inducing microvascular thrombosis and increasing intraosseous pressure by promoting intramedullary adipogenesis which causes arterial obstruction and venous stasis. Corticosteroids also cause an imbalance in bone resorption and repair by decreasing osteoblast production, increasing osteocyte apoptosis, and prolonging osteoclast lifespan.

Potential risk factors for osteonecrosis after COVID infection

 COVID-related factors

• Cumulative dose of>5000 mg MPS or equivalent corticosteroid

• Treatment duration with corticosteroids>10 days

• Severe COVID-19 pneumonia

• Moderate and severe ARDS

• ICU admission

• Mechanical ventilation support

• Elevated serum markers—IL-6≥40 pg/ml, Ferritin≥300 ng/ml, Triglycerides≥300 mg/L,

• D-dimer≥1000 ng/ml

 Pre-existing factors

• Excessive alcohol consumption

• Smoking

• Cardiovascular or cerebrovascular disease

• Rheumatoid or autoimmune disorders being treated with

• steroids

• Blood disorders—hemoglobinopathy, sickle-cell anemia, coagulopathy, myeloproliferative

• diseases, leukemia

• Tumors treated with chemotherapy or ionizing irradiation

• Metabolic or endocrine disorders—hypercholesterolemia, hypertriglyceridemia, Gaucher disease,

• hyperparathyroidism, Cushing's disease

• Chronic renal disease

• Pregnancy

Prevention, Early Diagnosis and Treatment of ON in COVID‑19.

A cumulative MPS-equivalent dose of<5000 mg and course duration <10 days may lower the risk of ON.

Intermittent rather than continuous CS treatment with a "steroid holiday", and addition of lipid-lowering statins and anti-coagulants with or without a vasodilator may help reduce the risk of ON.

Despite encouraging results in animal models, the efficacy of lipid lowering statins in preventing SION in human subjects is unclear.

Although anticoagulants such as low-molecular weight heparin (LMWH) or enoxaparin are frequently administered in severe COVID-19 to prevent or treat thromboembolic complications, there may be a need to continue standard thromboprophylaxis in high-risk patients to prevent ON.

Clinical symptoms appear much later than radiological changes in ONFH and are often misdiagnosed as originating from the lumbar spine or the knee joint. Hence, regular hip monitoring using MRI should be carried out in high-risk patients, at 3, 6, and 12 months after initiation of CS treatment for COVID-19.

Early treatment of SION may help delay disease progression, reduce morbidity, and the risk for joint replacement surgery in such patients. Intervention depends on the stage of disease and includes bisphosphonates (oral alendronate 70 mg weekly along with IV zoledronic acid 5 mg annually) or anticoagulants (low-molecular weight heparin 5000LXU subcutaneously, once daily for 2 weeks every 6 months) with limited weight-bearing for stage I disease, and simple core decompression for stage II disease.

A combination of physical therapy and pharmacotherapy (bisphosphonates, anticoagulants, and vasodilators) can be used to delay progression of early stage ON.

Further reading:

Double Trouble—COVID‑19 and the widespread use of Corticosteroids: Are We Staring at an Osteonecrosis Epidemic?

Gautam M. Shetty

Indian Journal of Orthopedics (2022) 56:226–236

https://doi.org/10.1007/s43465-021-00546-8