Aseptic Osteonecrosis

Abstract

Aseptic osteonecrosis (ON) is defined as the death of bone tissue secondary to the compromise of the vasculature with consequent collapse of the bone structure with joint pain and loss of function. It has been associated with numerous conditions, including human immunodeficiency virus (HIV) infection and solid-organ transplantation. Nevertheless, data are scant in HIV-infected populations undergoing solid-organ transplantation. We describe three cases of ON diagnosed in patients coinfected with HIV-hepatitis B virus (HBV)/HIV-hepatitis C virus (HCV) undergoing liver transplantation (LT) at the Modena University Transplant Center, Italy. CASE REPORTS Case 1 A 39-year-old white man with alcohol and HCV-related cirrhosis underwent LT in March 2007. HIV infection was diagnosed in 1988, and the patient was categorized as C3 (1993 Centers for Disease Control and Prevention) with a nadir CD4+ cell count of 0.038×109/L (38/μL). The first antiretroviral therapy (ART) regimen was started in 1997 with a cumulative exposure of 83 months to protease inhibitors (PIs). He has a medical history of osteopenia, dyslipidemia, and cigarette smoking. On the 13th postoperative day (pod), unboosted atazanavir was resumed with emtricitabine and tenofovir as backbone. Immunosuppressive (IS) regimen was based on cyclosporine and methylprednisolone (cumulative dose of 1972 mg), which was tapered rapidly. During the 10 months, the patient developed progressive bilateral coxalgia. The magnetic resonance imaging (MRI) showed severe ON in the femoral heads (Fig. 1A), for which he underwent a total hip arthroplasty on both joints. Surgery was effective, and the patient went back to his regular job.FIGURE 1: Magnetic resonance imaging (MRI) showing aseptic osteonecrosis. A, Pelvis MRI of case 1. At both femoral heads, large areas of approximately 4 cm of subchondral bone alteration delimited by a peripheral rib are found. On the left side, it is associated with the presence of an extensive bone marrow signal alteration of the neck and the remaining femoral head attributable to edema. The findings described are compatible with necrosis of both femoral heads, more advanced on the left where it is associated with bone marrow edema and abundant joint effusion. B, Shoulder MRI case 2. Widespread alteration in the signal intensity of endospongious bone marrow of humeral head and neck. C, Pelvis MRI of case 2. At the head of the femur, bilaterally, it can be appreciated that the presence of abnormalities is consistent with aseptic osteonecrosis (left>right extension also at the femoral neck). D, Pelvis MRI of case 3. At the loading portion of the femoral head, it can be appreciated that the left wide area of the lunate morphology is characterized by the heterogeneous signal and that the rib is bounded by low signal, attributable to early stage avascular necrosis.Case 2 A 44-year-old white man experiencing HBV/HCV-related cirrhosis with multifocal hepatocellular carcinoma underwent LT in April 2007. Diagnosis of HIV infection was made in 1988, and nadir CD4+ cell count was 0.070×109/L (70/μL) (stage B3). He started ART in 2001 with a cumulative exposure of 17 months to PIs. The patient showed a history of smoking, hypertriglyceridemia, and osteoporosis. IS therapy included rapamycin and methylprednisolone (cumulative dose of 7060 mg). The same pretransplant ART regimen containing lamivudine, abacavir, and unboosted atazanavir was resumed on the 18th pod. In October 2008, for progressive pain in the left shoulder and left coxalgia, MRI was performed, revealing ON in both joints (Fig. 1B and C), which was confirmed by triphasic bone scan. To date, surgical indication was not yet given. Case 3 A 32-year-old white man underwent LT in January 2009 because of HCV-related cirrhosis. HIV infection was diagnosed in 2004, with a nadir CD4+ cell count of 0.347×109/L (347/μL) (stage A2). ART was started in 2005 with a cumulative exposure of 2 months to PIs. The patient was a smoker and is overweight. IS therapy was based on rapamycin and methylprednisolone (cumulative dose of 1880 mg). The same pretransplant ART regimen containing lamivudine, raltegravir, and unboosted atazanavir was resumed on the 10th pod. Two months after transplantation, rapamycin was switched to cyclosporine because of painful peripheral edemas. In April 2009, he reported an intense left coxalgia. MRI revealed bilateral ON in the femoral heads (Fig. 1D), which was then confirmed by positron emission tomography. For inefficacy of conservative treatment, in July 2009, total hip arthroplasty on the left side was performed. To date, indication for contralateral hip replacement has not yet been placed. DISCUSSION ON is an emerging complication in HIV-infected patients undergoing LT. In our series, the prevalence of ON in the femoral and humeral heads was 12.5% (3/24), apparently higher than the 4% historical control described in HIV population and the 2% to 8% reported after LT (1, 2). At our center, in the same time frame, only two cases of ON were diagnosed in 438 HIV-uninfected patients (0.46%). Our series showed some of the well-known risk factors for ON identified in the general population. Among them is age (3, 4). In fact, two patients were younger than 40 years. Our cases showed also some HIV-specific risk factors that have been independently associated with ON. Among them is exposure to ART (5). In our series, the duration of ART was 38.84, 45, and 2 months, respectively. The risk associated with PI exposure is still controversial (1, 6–9). All three patients underwent a PI-based ART regimen after LT. IS agents have also been investigated in relation to the risk of developing ON (10–13). IS therapy included cyclosporine in one patient and rapamycin in the other two (case 3 was switched early to cyclosporine). This case series underlines the importance of early diagnosis of ON and suggests prospective studies to investigate HIV-specific risk factors. The potential for a pathogenetic link between ON and both ART and IS drugs points out the need for future trials to explore properly designed regimens for HIV-infected patients after LT. Stefania Cocchi 1 Erica Franceschini1 Marianna Meschiari1 Mauro Codeluppi1 Gianluca Rompianesi2 Fabrizio Di Benedetto2 Giorgio Enrico Gerunda2 Cristina Mussini1 Giovanni Guaraldi1 1 Clinic of Infectious Diseases Department of Internal Medicine and Medical Specialties University of Modena and Reggio Emilia Modena, Italy 2 Liver and Multivisceral Transplant Centre Department of General Surgery University of Modena and Reggio Emilia Modena, Italy