**2. Etiology**

In studying FHN, the absence of a bipedal mammalian model limits our knowledge among risk factors and pathogenesis of the disease. Additionally, completing longitudinal studies is difficult for researchers and clinicians. However, scientific community agrees that ischemia plays a main role in the pathogenesis. As aforementioned, FHN is a multifactorial disease in which both genetic and daily-living factors lead to the pathology. When evaluating patients with osteonecrosis, physicians should first differentiate between primary ("idiopathic") osteonecrosis and secondary osteonecrosis [16]. Although the etiology of secondary osteonecrosis has not been clearly delineated, risk factors include both traumatic and nontraumatic conditions (i.e., corticosteroid use, alcohol consumption, smoking, coagulation abnormalities, etc.) [17].

Traumatic events may lead to bone fracture or at worst to femoral head displacement; since the trauma occurs, it directly results in disruption of the femoral head blood supply [18]. Malizos et al. distinguished different pathogeneses in patients with subcapital fracture and patients with hip dislocation. In the first case, the 10–20% of the vascularization of femoral head is preserved from ligamentum teres. Conversely, as the hip dislocation occurs, blood supply is interrupted, and perfusion depends on the integrity of retinacular vessels [2].

Otherwise, nontraumatic osteonecrosis is frequently associated with pathologies where corticosteroid treatment is required (i.e., systemic lupus erythematosus, organ transplant, lymphoma, etc.). A report described the case of a female patient who was just under 18 years old when she underwent surgery due to bilateral osteonecrosis of the femoral condyles that developed in the course of treatment of a hematological malignancy [19]. Even though, scientific literature does not know the exact dose of steroids necessary to induce osteonecrosis, the higher the dose the greater the risk. Indeed, daily mean or peak dose taken seems to be more implicated than cumulative or duration of therapy [3]. Furthermore, an addiction to alcohol and long drinking period were reported as risk factors for FHN. In comparing gender difference, studies indicated for males a greater frequency of alcohol-induced FHN with respect to females [20, 21]. Indeed, Shimizu et al. showed a bigger susceptibility of males in developing FHN in response to alcohol consumption. Specifically, females did not develop osteonecrosis for alcohol consumption for both short-time and long-time periods. However, further investigations are needed among sex-related factors responsible for this evidence [20].

Further risk factors of FHN can be identified in bone marrow transplantation, as well as metastatic malignancies, and pregnancy. Additionally, it may be associated with pathologies as hyperuricemia, pancreatitis, and leukemia or lymphoma [9, 14].
