The etiology of osteonecrosis of the hip may have a genetic basis. The interaction between certain risk factors and a genetic predisposition may determine whether this disease will develop in a particular individual.The rationale for use of joint-sparing procedures in the treatment of this disease i

Nontraumatic osteonecrosis of the femoral head: ten years later.

In the context of additional characterization of the pathoetiologic associations of heritable hypofibrinolysis and thrombophilia with osteonecrosis of the hip, the authors assessed 15 women and 21 men at entry to a 12-week treatment study of the amelioration of Ficat Stages I or II osteonecrosis by low molecular weight heparin (Enoxaparin). All 36 patients had osteonecrosis of the hip; four patients had unifocal osteonecrosis, 25 patients had two joints affected, five had three affected joints, and two had four affected joints. In 11 of 15 women (73%), hyperestrogenemia of pregnancy (20%) or exogenous estrogen supplementation (53%) were associated with the development of osteonecrosis. Five gene mutations affecting coagulation and nine serologic coagulation tests were studied. Compared with control subjects, patients were more likely to have heterozygosity and homozygosity for the hypofibrinolytic 4G polymorphism of the plasminogen activator inhibitor-1 gene. Moreover, the plasminogen activator inhibitor-1 gene product, plasminogen activator inhibitor activity, the major determinant of hypofibrinolysis, was 10 times more likely to be high (> 21.1 U/mL) in patients than in control subjects (31% versus 3%), with a median of 15.7 versus 6.3 U/mL. Compared with controls, patients were more likely to have the thrombophilic methylenetetrahydrofolate reductase gene mutation. In addition, the thrombophilic methylenetetrahydrofolate reductase gene product, homocysteine, was four times more likely to be high (>13.5 umol/L) in patients than in control subjects (20% versus 5%), with a median of 9.1 versus 7 umol/L. Twenty-three percent of patients had low levels (< 65%) of the thrombophilic free protein S versus 3% of control subjects. Patients were more likely than control subjects to have hypofibrinolytic high lipoprotein (a) (≥ 35 mg/dL), 33% versus 13%. Median lipoprotein (a) was higher in patients than in control subjects, 15 versus 5 mg/dL. Heritable hypofibrinolysis and thrombophilia, often augmented in women by hyperestrogenemia, seem to be major pathoetiologies of osteonecrosis. If the association between coagulation disorders and osteonecrosis reflects cause and effect, as postulated, then anticoagulation with Enoxaparin should be a promising therapy for patients with osteonecrosis.

Hypofibrinolysis, thrombophilia, osteonecrosis.

The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis.

https://www.chem.purdue.edu/lecture/docs/538_AJCN_Vitamin%20K.pdf

Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging?

Basic and clinical research have shown the efficacy of various cellular mediators (bone morphogenetic proteins, interleukins, angiogenic growth factors) in healing bone defects. The potential application of these growth and differentiation factors to other musculoskeletal conditions, including osteonecrosis of the femoral head, only recently has been explored. Osteonecrosis is a disease of unknown pathogenesis that usually progresses to hip joint destruction necessitating total hip arthroplasty. The pathology involves ischemic events followed by death of bone and marrow elements. A process of repair then is initiated, but unless the lesion is small (less than 15% of the femoral head involved), this repair process is usually ineffective. The net result is weakening of subchondral bone with subsequent collapse of the articular surface. Because the results of hip arthroplasty in patients with osteonecrosis are relatively poor, much focus has been on modalities aimed at femoral head preservation. The surgical alternatives may include core decompression, osteotomy, nonvascularized, and vascularized bone grafting, which might be enhanced with the use of growth and differentiation factors. At least three of these factors are potential candidates as therapeutic modalities: cytokines (such as interleukins, tumor necrosis factors, and signaling molecules such as fibroblast growth factors, platelet derived growth factors, insulinlike growth factors, and transforming growth factor betas), bone morphogenetic proteins, and angiogenic factors. Despite considerable effort, evaluation of these growth and differentiation factors has been hampered by the lack of an animal model that adequately simulates the pathology of osteonecrosis in humans. Therefore, investigators have attempted to model certain aspects of the disease process. Recently, several investigators have attempted to mimic osteonecrosis in the femoral head of large mammals by combinations of devascularization, freezing, osteotomy of the femoral neck, or creation of a head defect. Results from some of these studies have confirmed the potential for growth and differentiation factors to effect more rapid healing and filling of defects with biomechanically competent and viable bone. The application of this therapy shows promise, and clinical studies on efficacy and safety are ongoing.

Osteonecrosis of the femoral head : potential treatment with growth and differentiation factors

Osteonecrosis that is associated with the use of drugs such as corticosteroids14,24,32,35,39 or with underlying disease processes36,45,48,49 such as alcohol abuse39 has been characterized as secondary. Despite extensive investigations of the demographic characteristics of patients who have osteonecrosis32,35,39, as many as 39.5 per cent of these patients (934 of 2364 in one study39) have had no known risk factors, and the osteonecrosis has been characterized as idiopathic. However, as one of us (C. J. G.) and colleagues16-19,21-24,27 as well as others5,28,37,46 have shown, many instances of osteonecrosis that previously would have been regarded as idiopathic actually were associated with heritable thrombophilia (an increased tendency for intravascular thrombosis) and hypofibrinolysis (a reduced ability to lyse thrombi).

The association between coagulation abnormalities and osteonecrosis has been recognized for more than thirty-five years2,28,37,41, but it has not been studied extensively, to our knowledge. Recent studies by one of us (C. J. G.) and colleagues16-24,27 and by others5,28,37,46 have redirected attention to this area. This association has major implications not only for the diagnosis and treatment of osteonecrosis but also for the screening of the relatives of affected individuals and the possible prevention of this and other thrombotic and thromboembolic disorders in those who are found to be at increased risk because of inherited thrombophilia or hypofibrinolysis17,18,21,22,24.

We report the case of a patient in whom multifocal osteonecrosis was found to be associated with …

Henri Pierre-Jacques

Papers

Familial Heterozygous Protein-S Deficiency in a Patient Who Had Multifocal Osteonecrosis. A Case Report*