Wandering histiocytes, foreign body giant cells, and inflammatory connective-tissue cells are stimulated by degradation products of dead matrix to grow in and repopulate the area of an implant of decalcified bone. Histiocytes are more numerous than any other cell form and may transfer collagenolytic activity to the substrate to cause dissolution of the matrix. The process is followed immediately by new-bone formation by autoinduction in which both the inductor cells and the induced cells are derived from ingrowing cells of the host bed. The inductor cell is a descendant of a wandering histiocyte; the induced cell is a fixed histiocyte or perivascular young connective-tissue cell. Differentiation of the osteoprogenitor cell is elicited by local alterations in cell metabolic cycles that are as yet uncharacterized.

https://science.sciencemag.org/content/sci/150/3698/893.full.pdf

Bone: Formation by Autoinduction

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140673607604577.pdf

The operation of the century: total hip replacement

Non-traumatic avascular necrosis of the femoral head

Advancing biomaterials of human origin for tissue engineering

Pathogenesis and natural history of osteonecrosis.

Extensive localized bone resorption within the femur was observed after four total hip replacements. The amount and location of the resorption suggested the presence of infection or tumor, but there was no evidence of either condition and the roentgenographic appearance differed from that associated with a loose uncemented endoprosthesis or a grossly loose femoral component of a total hip replacement. At reoperation the femoral components were not rigidly fixed but were only slightly loose. Histologically there were sheets of macrophages, a few giant cells, and multiple small fragments of a birefringent material, but no inflammatory cells. While the exact mechanism of this serious complication is unclear, the findings suggest that a benign, non-inflammatory, adverse tissue response can occur in relation to the femoral components of total hip replacements that are not rigidly fixed. In all four hips, reimplantation of a new total hip replacement was successful after follow-up of thirteen to eighteen months.

Extensive localized bone resorption in the femur following total hip replacement.

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.

In 31 patients with osteonecrosis (primarily of the hip), 74% had 1 or more primary coagulation disorders. In 18 patients, 15 (83%) who had coagulation disorders, the osteonecrosis was initially identified as idiopathic and was not associated with known underlying drugs (glucocorticoids) or diseases (alcoholism, sickle cell disease, Gaucher's disease). In 13 patients, 8 (62 %) who had coagulation disorders, the osteonecrosis was initially identified as secondary, and was associated with glucocorticoids in 12 patients, and with alcoholism in 1. The coagulation disorders included thrombhophilia (increased tendency to intravascular thrombosis) and hypofibrinolysis (reduced ability to lyse thrombi). Of the 18 patients initially thought to have idiopathic osteonecrosis, thrombophilia alone was found in 12% (resistance to activated protein C in 6%, low protein C in 6%), hypofibrinolysis alone was found in 50% (high lipoprotein(a) in 44%, low stimulated tissue plasminogen activator activity was found in 6%), and mixed thrombophilia hypofibrinolysis was found in 22%. Resistance to activated protein C was more common in these 18 patients than in healthy controls (11% versus 0%), as was high lipoprotein(a) (67% versus 20%). Of the 13 patients with secondary osteonecrosis, thrombophilia alone was found in 8% (low protein C), hypofibrinolysis alone was found in 30% (high Lp(a) in 15%, low tissue plasminogen activator activity in 15%), and mixed thrombophilia hypofibrinolysis was found in 23%. Low tissue plasminogen activator activity was more common in the 13 patients with secondary osteonecrosis than in controls (27% versus 7%), as was low protein C (23% versus 0%). In aggregate, these findings lead us to the speculation that primary, heritable thrombophilia or hypofibrinolysis causes thrombotic venous occlusion in the head of the femur, leading to venous hypertension and hypoxic death of bone (osteonecrosis).

Thrombophilia and hypofibrinolysis: pathophysiologies of osteonecrosis.

UNLABELLED In a prospective pilot study, we hypothesized that enoxaparin (60 mg/day for 12 weeks) would prevent progression of Stages I and II osteonecrosis of the hip associated with thrombophilia or hypofibrinolysis or both over > or = 108 weeks of followup versus untreated historic controls, with different treatment responses in primary versus corticosteroid-associated secondary osteonecrosis. Patients with one or more thrombophilic-hypofibrinolytic disorder and Ficat Stages I or II osteonecrosis of at least one hip were included. A blinded committee interpreted anteroposterior and frog-leg lateral radiographs at entry in the study and every 36 weeks to > or = 108 weeks. Maintenance of the disease at Stages I and II versus progression of the osteonecrosis to Stages III and IV requiring total hip replacement was the major end point. Sixteen patients had primary osteonecrosis (25 hips; 13 Stage I, 12 Stage II), and 12 had secondary osteonecrosis (15 hips; five Stage I, 10 Stage II). With no Enoxaparin-related complications, 19 of 20 hips (95%) with primary osteonecrosis were unchanged from Stages I and II osteonecrosis at > or = 108 weeks; 12 of 15 hips (80%) with secondary osteonecrosis progressed to Stages III and IV osteonecrosis. In primary osteonecrosis at > or = 108 weeks, survival of 95% hips, or 76% (19/25 hips, based on intent to treat), compared favorably with untreated historical controls (approximately 20% 2-year survival), comparable to 20% survival in secondary hip osteonecrosis. Enoxaparin may prevent progression of primary hip osteonecrosis, decreasing the incidence of total hip replacement. LEVEL OF EVIDENCE Therapeutic study, II-1 (prospective cohort study).

Enoxaparin prevents progression of stages I and II osteonecrosis of the hip.

Thirty-three (75 per cent) of forty-four unselected children who had Legg-Perthes disease were found to have coagulation abnormalities. Twenty-three children had thrombophilia (a deficiency in antithrombotic factor C or S, with an increased tendency toward thrombosis); nineteen of the twenty-three children had protein-C deficiency and four had protein-S deficiency. Seven children had a high level (0.25 gram per liter or more) of lipoprotein(a), a thrombogenic, atherogenic lipoprotein associated with osteonecrosis in adults. Three children had hypofibrinolysis (a reduced ability to lyse clots). The mean age of the children when the Legg-Perthes disease was first diagnosed was 5.8 ± 2.7 years, and the mean age at the time of the present study was 10.1 ± 4.4 years. At least one of the first-degree relatives of eleven of the nineteen probands who had a low protein-C level had a low protein-C level as well; all of these low levels represented previously undiagnosed familial protein-C deficiency. The eleven probands who had familial protein-C deficiency were more likely to have early onset of Legg-Perthes disease (at or before the age of five years) than the eleven children who had normal levels of protein C, protein S, and lipoprotein(a) as well as normal fibrinolytic activity (chi-square = 6.6; p = 0.01). At least one first-degree relative of one of the four probands who had a low protein-S level had a low protein-S level and previously undiagnosed familial protein-S deficiency. At least one first-degree relative of six of the seven probands who had a high level of lipoprotein(a) had a familial high level of lipoprotein(a). Six of the seven children who had a high level of lipoprotein(a) also had a low level of stimulated tissue-plasminogen activator activity, the major initiator of fibrinolysis. At least one first-degree relative of one of the three probands who had normal levels of protein C, protein S, and lipoprotein(a) but low stimulated tissue-plasminogen activator activity also had low stimulated tissue-plasminogen activator activity (familial hypofibrinolysis). Legg-Perthes disease, thrombophlebitis, premature myocardial infarction, and stroke, which are ramifications of the familial thrombophilic-hypofibrinolytic disorders, were common in the first and second-degree relatives of the thirty-three children with Legg-Perthes disease who also had thrombophilic-hypofibrinolytic disorders. CLINICAL RELEVANCE: Protein-C or S deficiency, hypofibrinolysis, or a high level of lipoprotein(a) may result in thrombotic venous occlusion of the femur, which leads to the venous hypertension and osteonecrosis of the femoral head characteristic of Legg-Perthes disease. When Legg-Perthes disease develops in a child, the levels of proteins C and S, lipoprotein(a), and stimulated fibrinolysis should be measured. Early diagnosis of protein-C or S deficiency, hypofibrinolysis, or a high level of lipoprotein(a) in such children may open avenues for pharmacological preventive therapy to reduce thrombophilia, stimulate fibrinolysis, or lower the level of lipoprotein(a), potentially ameliorating the Legg-Perthes disease process.

Richard A. Freiberg

Papers

Extensive localized bone resorption in the femur following total hip replacement.

Hypofibrinolysis, thrombophilia, osteonecrosis.

Thrombophilia and hypofibrinolysis: pathophysiologies of osteonecrosis.

Enoxaparin prevents progression of stages I and II osteonecrosis of the hip.

Association of antithrombotic factor deficiencies and hypofibrinolysis with Legg-Perthes disease.