An unusual bilateral groin pain after COVID-19 infection in an 82-year-old man

Avascular necrosis (AVN), also called osteonecrosis, consists of a necrosis of epiphyseal bone, which induces mechanical failure and consequently joint pain, loss of function and poor quality of life [1]. AVN involves femoral head in more than 75% of cases and can be unifocal or multifocal. Its etiology has not been yet clarified; however, identified risk factors include corticosteroid treatment, alcohol abuse, trauma, sickle cell disease and coagulation abnormalities [1].

Coronavirus disease (COVID-19) is an emerging pandemic disease caused by the SARS-CoV-2 virus. The association between COVID-19 and the increased risk of venous and arterial thromboembolic events has been largely demonstrated. Recently, only few cases of AVN after steroid treatment for COVID-19 disease were described: the interval between corticosteroid intake and development of symptomatic AVN is shorter and a smaller cumulative dose of steroids seems to be required for the onset of AVN in patients with COVID-19 infection [2].

Below, we present a patient case of bilateral AVN of femoral head associated with SARS-CoV-2 infection and its favorable outcome after neridronate intravenous administration.

An 82-year-old man was admitted to the Internal Medicine Division due to acute respiratory distress syndrome (ARDS) 12 days after the diagnosis of SARS-CoV-2 infection. He was a former smoker, with a history of hypertension and prostate cancer, the latter previous treated with transurethral resection of the prostate (TURP) and external beam radiation therapy (RT). Laboratory data at admission time are reported in Table 1. Thoracic computed tomography (CT) showed bilateral ground glass opacities, with superimposed septal thickening, and consolidations. The progressive respiratory failure led to the need of respiratory support, with gradual decalage until the patient was weaned from ventilation at the 12th ICU Day. During hospitalization, the patient was administered intravenous methylprednisolone 40 mg per day for 3 days and then discharged with oral prednisolone in tapering dose for 20 days (total—462.5 mg). Total steroid received amounted to 612.5 mg of prednisolone equivalent. He also started long-term calcium (500 mg twice a day) and vitamin D (cholecalciferol 1000 IU daily) supplementation.

Table 1.

Biochemical parameters at admission time

Test	Result	Reference range
Red blood cell (RBC) × 10 million/μL	4.41	4.50–5.50
Hemoglobin (Hb) g/dl	13.8	14.4–18
White blood cell (WBC) × 103/μL	7.16	4.50–9.0
Platelets (PLT) × 103/μL	211	150–350
Calcium (mg/dl)	7.40*	8.2–10.4
Phosphorus (mg/dl)	4.30	2.5–4.6
Albumin (g/dl)	3.37*	4.02–4.76
Creatinine (mg/dl)	2.09*	0.5–1.2
Alkaline phosphatase (IU/L)	67	40–150
C-reactive protein (mg/L)	135.2*	0–0.50
Glucose (mg/dl)	162*	65–110
Sodium (mEq/L)	141	134–145
Potassium (mEq/L)	3.4*	3.5–5.2
Magnesium (mg/dl)	2.37	1.5–3.8
Chloride (mEq/L)	100	98–110
Glutamic-oxaloacetic transaminase (GOT) U/L	27	0–42
Glutamic-pyruvic transaminase (GPT) U/L	21	0–50
Lactic dehydrogenase (LDH) U/L	325*	135–225
Total bilirubin (mg/dl)	0.42	0–1.2
Direct bilirubin (mg/dl)	0.19	0–0.30
Prothrombin time (PT) %	73	70–120
International normalized ratio (INR)	1.25*	0.80–1.20

*Value out of range

4 weeks after the hospital discharge, the patient experienced worsening bilateral groin pain more evident on the left side: he developed inability to maintain a prolonged upright position and locomotor deficit with progressive need for unilateral walking stick. He started oral and subsequent intramuscular analgesic administration with temporary benefit. At a clinical evaluation decreased range of motion (ROM) of both the lumbar spine and the bilateral hip, and pain during passive hip intrarotation and extrarotation emerged. Rating of patient pain was achieved through the unidimensional Visual Analog Scale (VAS), which provides a range of scores from 0 to 10 (0 = no pain; 10 = worst pain possible), showing a VAS score of 8.

An anteroposterior hip radiograph was performed, excluding lesions attributable to fractures. Then, a magnetic resonance imaging (MRI) showed a bilateral bone marrow edema (BME) in the head and neck of the femur and an osteonecrotic focus without any trabecular collapse: those findings were consistent with the diagnosis of bilateral avascular necrosis (AVN) of the femoral head [Ficat–Arlet stage IIB—Association Research Circulation Osseous (ARCO) stage II] (Fig. 1a).

Fig. 1.

Instrumental assessment of patient’ bilateral femur. Panel a: Baseline MRI—MR STIR sequence showing bilateral bone marrow edema in the head and neck of the femur and mild joint effusion on the left side (arrow heads—panel a). Panel b: 1 year later, a STIR-weighted MRI scan showed within the superior aspect of the left femoral head a high-signal serpiginous rim delineating an area of low signal, which consists of necrosis. On the left side, a small focus of avascular necrosis was seen within the left femoral head with “the double-line sign”, highly specific for AVN (red arrows—panel b). Bone marrow edema was also noted in the right iliac bone (green arrow—panel b). Imaging features compatible with bilateral stage II femoral head AVN

Given the severity of symptoms, the instrumental picture, and the risk of progression to irreversible bone lesions, the patient started treatment with bisphosphonate neridronate: in detail, it was administered intravenously at 100 mg in 250 ml of saline solution in 2 h, every 3 days, for a total number of four administrations. Patient continued oral supplementation of calcium and vitamin D.

After 2 months, a significative regression of pain with a reduction of functional impairment were reported, leading to a progressive discontinuation of analgesic treatment: VAS score reduced to 3 and hip ROM increased, particularly range of internal rotation, flexion of hip joint, and abduction. Furthermore, patient gradually stopped to use stick for walking.

After 12 months, a new MRI was performed, revealing a “double-line” sign at the right femoral head, which occurs later in the AVN process, after the beginning of osseous repair (Fig. 1b).

Our patient used a cumulative dose of slightly more than 600 mg of prednisolone, which is in line with previous reports: a recent cases series of AVN of the femoral head after glucocorticoid treatment for COVID-19 infection documented a mean dose of prednisolone about 758 mg (from 400 to 1250 mg) [3]. It seems that patients with COVID-19 infection are more susceptible to manifest AVN at lower threshold dose of steroid, despite the higher cumulative dose of 2000 mg prednisolone (or its equivalent) required for AVN development in general population [3].

Moreover, in our case, patient reported first symptoms of AVN 1 month after hospital discharge for COVID-19: the usual interval between corticosteroid intake and development of symptomatic AVN is from 6 months to 1 year, instead the shorter range of 58 days (45–67 days) indicated for the development of AVN post COVID-19 diagnosis in the recent case series, suggesting an earlier onset of presentation of AVN in SARS-CoV-2 infection [3]. All of this suggests a fascinating etiopathogenetic hypothesis of AVN in our case, which goes beyond steroid therapy and involves the patient’s procoagulative state, due to SARS-CoV-2 infection, but also advanced age, history of previous neoplasia and hyperglycemia. As known, apart from steroids, SARS-CoV-2 infection in itself can induce a hypercoagulable state, in which endothelial dysfunction is the major player: endothelial cell activation can intensely activate platelets and the coagulation system, in addition to endothelium damage due to the dysregulation of the renin–angiotensin system SARS-CoV-2-related. In combination with the hypoxia, this prothrombotic state increases blood viscosity and activates the hypoxia-induced transcription factor-dependent signaling, finally leading to the risk of thrombosis and osteonecrosis [2].

Early stages of AVN (stage I or II of the Ficat–Arlet classification), when joint surface is still preserved, can be managed with conservative treatment and bisphosphonates (Bps) use is widely suggested to slow the progression of osteonecrosis and to avoid surgical interventions such as core decompression or joint arthroplasty. Our patient was approached with a conservative treatment administrating bisphosphonate neridronate, accordingly to previous experiences in the literature [4]. Neridronate is an amino-BP characterized by a unique safety and efficacy profile which is used to treat osteogenesis imperfecta, Paget’s disease of bone, algodystrophy and osteoporosis: this drug is able to inhibit bone resorption and possibly influence metabolic activity of osteoblasts, with good results in terms of reduction of musculoskeletal pain [5]. Available data about pharmacological management of AVN of the femoral head in COVID-19 in terms of Bps are only about the administration of oral alendronate and intravenous zoledronate [3].

Further studies are needed to better clarify the determinants of AVN in COVID-19 and the protective role of Bps to delay the progression of osteonecrosis.

Author contributions

FB, AG and AC designed the study and prepared the first draft of the paper. IGB and AS performed the literature search and participated in the images acquisition and interpretation. All authors revised the paper critically for intellectual content and approved the final version. All authors agree to be accountable for the work and to ensure that any questions relating to the accuracy and integrity of the paper are investigated and properly resolved.

Funding

No funds, grants, or other support was received.

Data availability

Availability of data and materials can be requested by email.

Declarations

Conflict of interest

Federica Bellone, Agostino Gaudio, Italo Giuseppe Bellone, Alberto Stagno and Antonino Catalano declare that they have no conflict of interest.

Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments.

Informed consent

A freely given, informed consent to participate in the study has been obtained from participant.