Osteonecrose , Necrose Asseptica ou Avascular
MEU NOME É JOÃO CARLOS (www.grupos.com.br/grupos/osteonecrose), FIZ TRANSPLANTE RENAL EM ABRIL DE 1996 AOS 32 ANOS. ESTE ESPAÇO É PARA DIVULGAÇÃO E TROCA DE INFORMAÇÕES ENTRE PACIENTES COM PROBLEMAS ÓSSEOS, PRINCIPALMENTE OSTEONECROSE ( NECROSE ASSÉPTICA OU AVASCULAR ) E OSTEOPOROSE, DEVIDO À TERAPIA COM GLUCOCORTICÓIDES.
DEPOIS DE 2 ANOS, EM JULHO DE 1998, QUANDO BRINCAVA DE PULAR COM A MINHA FILHA, SENTI DORES NA COXA DIREITA, PRÓXIMO À VIRILHA. APÓS UMA NOITE DE SONO, VOLTEI A SENTI-LAS QUANDO FICAVA EM PÉ, EM QUALQUER LUGAR. TEMPOS DEPOIS FOI DIAGNOSTICADO NECROSE ASSÉPTICA DA CABEÇA DO FÊMUR ( OSTEONECROSE ). FOI REALIZADO ENTÃO UMA CIRURGIA DE DESCOMPRESSÃO COM ENXERTIA OSSEA EM AMBAS AS CABECAS FEMORAIS. UM ANO APOS A PRIMEIRA CIRURGIA FOI DIAGNOSTICADO TAMBÉM NO JOELHO ESQUERDO.
SAIBA MAIS SOBRE A OSTEONECROSE E A OSTEOPOROSE
OSTEONECROSE ( OSTEONECROSIS , AVASCULAR NECROSIS , AVN ) EM TRANSPLANTADOS RENAIS
Osteonecrose ( ON ) , também chamada de Necrose Asséptica Óssea, Necrose Avascular, Osteonecrose asséptica, etc., é um problema que acomete os vasos sangüíneos ósseos, mais comumente nas cabeças Femorais e Umerais, embora haja relatos de aparecimento em joelhos, maxilares, etc. Alguns autores relatam a ocorrência de pelo menos 5 % de incidência de Osteonecrose asseptica depois de transplante renal [1,2,3]. Embora a Osteonecrose asseptica possa ter causas diversas, as principais seriam Corticosteroideterapia ( para Asma, Artrite Reumática, Transplante de Órgãos, etc ) , Anemia Falciforme, Mergulhadores Profissionais ( Osteonecrose disbárica ), por radiação contra tratamento de câncer ( Osteoradionecrosis ), Alcoolismo e sem causa definida ( Idiopatica ). Tem havido relato de pacientes portadores de HIV tambem desenvolverem o problema, bem como traumatismos que afetem a circulação local também podem ocasionar Osteonecrose asseptica. Parece haver concordância entre muitos autores de que existe uma grande incidência de alguma anormalidade do sistema de coagulação sobreposta às causas mais conhecidas [4,6,7]. Tal fato tem levado alguns centros especializados em OSTEONECROSE a recomendarem exames para verificação de coagulação em portadores de OSTEONECROSE [9,10,11]. As causas não estão bem estabelecidas, mas acredita-se que haja a ocorrência de oclusão venosa ocasionada por algum "gatilho" , que leva aquela parte do osso à morte por isquemia [7]. Ocorrem cerca de 10.000 a 20.000 novos casos anuais de ON somente nos Estados Unidos, afetando a população em sua fase mais produtiva [5].
A Osteonecrose (em criancas e adolescentes tb pode ser chamada de doenca de Legg - Perthes)é devida a uma oclusão vascular, em locais cuja a vascularização é pobre. Começa devagar, com dores na articulação afetada ( principalmente sob esforço ), estalos e diminuição na amplitude de movimentos. Somente com Ressonância Magnética o diagnóstico pode ser feito precocemente [5].
Tratamentos:
Diversas técnicas têm sido apresentadas para o tratamento de Osteonecrose (ou Legg Perthes)das cabeças femorais ( ou umerais , ou ainda de joelho, cotovelo, calcanhar, etc ), a maioria delas cirúrgicas, tais como Descompressão , Enxerto Ósseo utilizando o osso ilíaco, Enxerto Ósseo de Fíbula ( com técnicas de microcirurgia ), Hemiartroplastia, "Trapdoor", etc., todas com graus variados de sucesso e técnicas operativas distintas [13,14,15,16,17,18,]. Evidentemente, caso nenhuma destas soluções tenha resultado satisfatório, é feita então a colocação de prótese total no quadril, mesmo esta tendo diversas técnicas, materiais e variadas taxas de revisão. Cabe ao médico informar as diversas alternativas existentes e, junto com o paciente, definir o melhor procedimento. É extremamente importante o diagnóstico precoce da osteonecrose, uma vez que os prognósticos são melhores quando a intervenção é feita antes do colapso total da área atingida, pois neste caso, resta apenas a solução de colocação de prótese. [47,48,49,50,51,52].
Outras técnicas menos invasivas para osteonecrose (ou Legg Perthes)em fase inicial estão sob pesquisa , sem ainda uma aceitação universal, tais como Terapia de Oxigenação Hiperbárica ( usado principalmente em Osteoradionecrose mandibular ) [19,20], Campos Eletromagnéticos Pulsáteis [21], Ultrasom, Lovastatina [53], etc. A utilização de Proteínas Osteogênicas Recombinantes Humanas, em conjunto com enxertos ósseos, parece ser extremamente promissora [39,40,41,42,43].
Outros Possíveis Fatores de Risco
Inúmeros estudos tem sido levado a cabo a fim de se determinar aqueles pacientes com maior risco de desenvolverem Osteonecrose (ou Legg Perthes). Uma vez que a ocorrência de Necrose Asseptica em transplantados renais é multifatorial [2], tem sido difícil para os estudiosos do assunto estabelecerem com precisão os fatores de risco, porém parece certo que a corticoterapia é fator gerador de uma série deles. Alguns estudos estão relacionados abaixo:
1- Aumento de gorduras no sangue / hipoplasia de medula óssea: Tem sido estudado a ocorrência de embolismo gorduroso em pacientes com Osteonecrose. É sabido também o papel da prednisona, ciclosporina e da Síndrome Nefrótica na hiperlipidemia [7,24,25,26,27,28,53,54] ;
2- Osteopenia / Osteoporose : A prednisona é a grande responsável pelo aparecimento de Osteoporose após transplante renal, principalmente nos primeiros 6 meses, mesmo com a diminuição da dose após o advento da ciclosporina. Hipóteses tem sido levantadas sobre a diminuição do estoque ósseo, que diminuiria também a medula e sua conseqüente vascularização nestas áreas, levando talvez à osteonecrose asseptica [1,23,25,31,32,33,53] ;
3- Distúrbios de coagulação : Parece ser o caminho mais presente na Osteonecrose asseptica, uma vez que a oclusão vascular está diretamente relacionada com a coagulação. Como já foi relatado antes, inúmeros estudos tem relacionado que uma grande porcentagem de pacientes com Osteonecrose asseptica possuem problemas de coagulação ( em até 75% ) , sejam hereditárias ou adquiridas. Tanto a ciclosporina quanto a prednisona parecem ter efeitos trombóticos ( formação de trombos ) e/ou hipofibrinolíticos ( dificuldade em dissolver trombos ), com anormalidades nas dosagens de Fibrinogênio, Proteínas C e S, Antitrombina III, Anticorpos Anticardiolipina, Homocisteína, Resistência à Proteína C Ativada, Anticorpo Lúpico, Inibidor do Ativador do Plasminogênio tipo 1, Lipoproteína (a), etc [4,6,7,22,28,29,35,36,37,44,45,46].
No Brasil não se tem notícia de um centro especializado em Osteonecrose (ou Legg Perthes), mas devido à grande especificidade da doença e da baixa incidência, é aconselhável a procura em centros ortopédicos especializados. O Hospital das Clínicas da USP, o Hospital das Clínicas da UFMG, o Hospital de Traumato Ortopedia no Rio de Janeiro, etc. Parece que a equipe de Bioengenharia e Ortopedia da Faculdade de Medicina de Ribeirão Preto desenvolveu um aparelho chamado de Artrodistrator para pacientes infantis com doenca de Legg-Calvé - Perthes. O projeto parece ser coordenado pelo Prof. José Volpon. O Dr. Cyrillo Cavalheiro Filho do INCOR / SP pesquisa associação entre ON e problemas de coagulação. Grande número de pacientes dele com ON possuem coagulopatias. O Dr. Ilidio Pinheiro, do Hospital São Vicente de Paulo, no Rio de Janeiro, me operou e após 5 anos sem muletas ou prótese, posso afirmar que a cirurgia foi um sucesso. Apesar da evolução radiológica das lesões, espero somente colocar prótese após 10 anos de cirurgias. Fator muito importante que considero é a abordagem multiprofissional. A fisioterpia fiz na ABBR (excelente) com acompanhamento do Dr. Leonardo Grandi (Fisiatria) e fisioterapeuta Francesco, da área de cinesioterapia. Ainda, o Dr. Cyrillo trata da anticoagulação.
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Osteonecrosis
Thrombophilia and Hypofibrinolysis: Reversible etiologies of osteonecrosis.
Thrombophilia (increased tendency to develop thrombosis) and hypofibrinolysis (reduced ability to lyse thrombi) may be pathogenetic for osteonecrosis of the head of the femur (1-5, 10, 12-16) and jaw (6, 7) in adults and with osteonecrosis of the femur in children (Legg-Perthes disease) (8, 9, 11). In adults and children, thrombophilia or hypofibrinolysis may predispose to thrombotic venous occlusion in bone which leads to intramedullary hypertension, anoxia, and ischemic bone death characteristic of osteonecrosis.
Thrombophilia and hypofibrinolysis are transmitted as autosomal dominant traits, although their effects can be amplified by diseases and drugs (3,4,14,15). The major heritable thrombophilic and hypofibrinolytic disorders pathogenetic for osteonecrosis are as follows(1-16):
Thrombophilic Disorders:
Resistance to activated protein C: Resistance to activated protein C is the most common currently recognized heritable thrombophilic factor, found in 3-7% of the general population and in 11% to 50% of patients with venous thrombosis (11). Heritable resistance to activated protein C is caused by a CGA-->CAA substitution at position 1691 of the Factor V Leiden gene which blocks binding of activated protein C to the prothrombotic Factor V, producing thrombophilia. Activated protein C resistance (APCR) can be amplified by exogenous estrogens (oral contraceptives, post-menopausal estrogen supplementation) (7).
Protein C deficiency: When protein C is deficient, factor Va is inadequately suppressed, leading to increased procoagulant activity and increased risk of venous thrombosis. The thrombotic tendency in protein C deficiency can be amplified by exogenous estrogens and by pregnancy.
Protein S deficiency: Protein S is a cofactor for protein C. When protein S is deficient, factor Va is not adequately suppressed, leading to increased procoagulant activity and increased risk of venous and arterial thrombosis.
Protein C and S deficiency have been found in 2-5% and 5-9% of patients with venous thrombosis. Protein C is activated by an endothelial cell surface thrombin-thrombomodulin complex, and along with its cofactor protein S inhibits the prothrombotic factors V and VIII; hence deficiency in protein C and/or S leads to thrombophilia.
Anticardiolipin Antibodies: Anticardiolipin antibodies (ACLA) belong to a family of antiphospholipid autoantibodies which are directed against negatively charged phospholipid antigens. Anticardiolipin antibodies are prothrombotic by a variety of mechanisms including inhibition of prostacyclin synthesis, impairment of the thrombomodulin-protein C-protein S anticoagulant system, acting as anti- endothelial cell antibodies, or interacting with platelet membrane phospholipids. ACLA are associated with both venous and arterial thrombi.
Hypofibrinolysis:
Low stimulated tissue plasminogen activator activity (tPA-Fx) often accompanied by high plasminogen activator inhibitor activity (PAI-Fx):
There is an excess of the major inhibitor of fibrinolysis, PAI-Fx, so that the major stimulator of fibrinolysis, tPA-Fx, cannot be activated; the process of lysis of thrombi cannot begin, or is slowed. High plasma triglycerides can increase PAI-Fx, causing a decrease in tPA-Fx.
High lipoprotein (a) [Lp(a)]: In the closed space of bone, we believe that high Lp(a) may reduce fibrinolysis. The apparent hypofibrinolytic action of Lp(a) in bone appears to be augmented by corticosteroid therapy.
Thrombophilia and/or hypofibrinolysis have been found in 76% of 289 patients with osteonecrosis (17). In studies of osteonecrosis of the hip, provided that therapy is begun prior to irreversible segmental collapse of the head of the femur (5, 17), treatment of thrombophilia and hypofibrinolysis can reverse or retard the progression of osteonecrosis. Two adults with early, potentially reversible osteonecrosis of the hip (Ficat stages I, II) had thrombophilia (resistance to activated protein C, protein C deficiency) and were treated respectively with Coumadin (targeted INR of 2-2.5) and with Winstrol (an anabolic-androgenic steroid) 6 mg/day (6,7,11). On therapy, thrombophilia was normalized, severe hip pain resolved, and the progression of their osteonecrosis was reversed/retarded, as shown by MRI/X-ray. Two adults with osteonecrosis of the hip (Ficat stages I, II) had hypofibrinolysis (high PAI-1, high Lp[a]). Winstrol (6 mg/day) normalized fibrinolytic activity, resolved their severe hip pain, and reversed/retarded their osteonecrosis, as shown by MRI and X-ray. In 4 hypofibrinolytic adults (high PAI-1, high Lp[a]) with more advanced osteonecrosis (segmental collapse of the head of the femur-Ficat stages III, IV), Winstrol (6 mg/day) normalized fibrinolysis but had no effect on hip pain, MRI, or X-ray.
DISCUSSION
Our studies in 289 adults and children with osteonecrosis of the hip, knee, or jaw have begun to illuminate the pathogenetics of osteonecrosis (1-17). The majority (about 80%) of patients with osteonecrosis have heritable thrombophilia (increased likelihood of thrombosis) and/or hypofibrinolysis (reduced ability to lyse thrombi).
References:
1. Glueck, CJ, Glueck HI, Mieczkowski L, Tracy T, Speirs J, Stroop D. Familial high plasminogen activator inhibitor with hypofibrinolysis, a new pathophysiologic cause of osteonecrosis? Thrombosis Haemostasis 1993;69:460-465.
2. Glueck CJ, Glueck HI, Welch M, Freiberg R, Stroop D, Hamer T, Tracy T. Familial idiopathic osteonecrosis mediated by familial hypofibrinolysis with high levels of plasminogen activator inhibitor. Thrombosis Haemostasis. 1994; 71:195-198.
3. Glueck CJ, Freiberg R, Glueck HI, et al: Hypofibrinolysis: A common, major cause of osteonecrosis. Am. J. Hematology 1994;45:156-166.
4. Glueck CJ, Freiberg R, Tracy T, Stroop D, Wang P: Thrombophilia, hypofibrinolysis, and osteonecrosis. Clinical Orthopedics, (ARCO Symposium Issue),1997;334:43-56.
5. Glueck CJ, Freiberg R, Glueck HI, Tracy T, Stroop D, Hamer T: Idiopathic osteonecrosis, hypofibrinolysis, high plasminogen activator inhibitor, high Lp(a), and therapy with Stanozolol. Am. J. Hematology 1995;48:213- 220.
6. Gruppo R, Glueck CJ, McMahon RE, Bouquot J, Becker A, Tracy T, Wang P: Anticardiolipin antibodies, thrombophilia, and hypofibrinolysis. Pathophysiology of osteonecrosis of the jaw. J Lab Clin. Med. 1996;127(5):481-488.
7. Glueck CJ, McMahon RE, Bouquot J, Stroop D, Tracy T, Wang P: Pathophysiology of osteonecrosis of the jaw: Thrombophilia and hypofibrinolysis. Oral Surgery, Oral Medicine, Oral Pathology 1996;81(5):557-566.
8. Glueck CJ, Glueck HI, Greenfield D, et al: Protein C and S deficiency, thrombophilia, and hypofibrinolysis: Pathophysiologic Causes of Legg- Perthes Disease. Pediatric Research 1994;35:383-388.
9. Glueck CJ, Crawford A, Roy D, Freiberg R, Glueck HI, Stroop D: Association of antithrombotic factor deficiency and hypofibrinolysis with Legg Perthes disease. Journal of Bone and Joint Surgery 1996;78-A: 3-13.
10. Glueck CJ, Glueck HI, Tracy T, Speirs J, McCray C, Stroop D: Relationships between lipoprotein (a), lipids, apolipoproteins, basal and stimulated fibrinolytic regulators, and D-Dimer. Metabolism 1993;42:236-246.
11. Glueck CJ, Brandt G, Gruppo R, Crawford A, et al. Resistance to activated protein C and Legg-Perthes disease. Clinical Orthopedics and Rel. Res. 1997; 338:139-52.
12. Glueck CJ, Fontaine RN, Gupta, A, Tracy T, Wang P. A major gene for plasminogen activator inhibitor activity.J. Invest. Med. 1997;314A.
13. Glueck CJ, Fontaine, RN, Gupta, A, Tracy T, Wang P. 4G/4G and 4G/5G polymorphisms in the plasminogen-activator inhibitor gene promotor: associations with plasminogen activator inhibitor activity, insulin, and triglycerides. J. Invest. Med. 1997; 330A.
14. Glueck CJ, Fontaine, RN, Gupta A, Tracy T, Wang P. Familial 4G/4G/ homozygosity in the plasminogen-activator inhibitor gene promotor, hyperinsulinemia, thrombosis, and osteonecrosis. J. Invest. Med. 1997; 331A
15. THROMBOPHILIA AND HYPOFIBRINOLYSIS: PATHOGENETIC ETIOLOGIES OF OSTEONECROSIS. CJ Glueck, R Freiberg, R Gruppo, A Crawford. Jewish Hosp, Cincinnati, Ohio., In Press, Thrombosis and Haemostasis, 1997
Thrombophilia and hypofibrinolysis may be pathogenetic for osteonecrosis (ON) of the femur in adults and children, causing thrombotic venous occlusion in bone, intramedullary hypertension, and ischemic bone death. Thrombophilia and hypofibrinolysis were assessed in 291 patients with ON, 103 adults in 3 cohorts with ON of the hip (n=30,31,42), 64children with ON of the hip, and 124 adults with ON of the jaw in 2 cohorts (n=49, n=55). Of the 291 patients, 75% had familial thrombophilia /hypofibrinolysis. Only 14 of 64 (22%) children with ON had normal coagulation measures. In 64 children with ON, the mutant Factor V gene was found in 13% vs 4% of healthy normal children (p=.02), low protein C in 28% vs 3% (p=.005), and low stimulated tissue plasminogen activator activity (tPA-Fx) in 36% vs 14% (p=.05). In 3 cohorts comprising 103 adults with ON of the hip, only 13%, 26%, and 33% respectively had normal coagulation measures. In these 103 patients, low tPA-Fx (usually with high plasminogen activator inhibitor activity [PAI-Fx]) was found in 28% vs 6% of normal controls (p=.02), and high Lp(a) in 40% vs 22% (p=.001). In the 42 patients where anticardiolipin antibodies (ACLA) were measured, 22% had high IgG vs 5% of controls (p=.02), 22% had high IgA vs 3% of controls (p=.008). Of 124 patients with ON of the jaw, only 27% had normal coagulation measures. The mutantFactor V gene was found in 22% of patients vs 0% of controls (p=.001), low protein C in 14% vs 0% (.02), and high PAI-Fx in 18% vs 8% (p=.03). Most (75%) children and adults with ON have heritable thrombophilia and/or hypofibrinolysis which, we postulate, facilitate thrombotic blockage of venous drainage of bone, subsequent increase in bone venous pressure, reduced arterial perfusion, anoxia, and subsequent ischemic bone death (osteonecrosis).
Abstract and Articles in press:
16. AMELIORATION OF OSTEONECROSIS BY TREATMENT OF THROMBOPHILIA AND HYPOFIBRINOLYSIS. R Freiberg, CJ Glueck. Jewish Hospital, Cincinnati, Ohio, USA. In Press. Thrombosis and Haemostasis, 1997.
Thrombophilia and hypofibrinolysis may be pathogenetic for osteonecrosis of the femur, causing thrombotic venous occlusion in bone, intramedullary hypertension, anoxia, and ischemic bone death (osteonecrosis [ON]). We assessed whether treatment of thrombophilia /hypofibrinolysis would ameliorate ON. Familial thrombophilia or hypofibrinolysis in 9 adults with osteonecrosis were treated with Coumadin (target INR 2.5) or Winstrol (6 mg/day) (anabolic-andro genicsteroid), with follow-up of thrombophilia/ hypofibrinolysis for about 1 year on therapy. Two adults with early ON of the hip (Ficat stages I, II) had familial thrombophilia (resistance to activated protein C, protein C deficiency). On Coumadin and Winstrol, respectively, thrombophilia was normalized, severe hip pain resolved with resumption of usual activities, and was reversed/retarded, as shown by MRI/X-ray. Three adults with early ON (Ficat stages I, II) had hypofibrinolysis (high plasminogen activator inhibitor activity [PAI-Fx], high Lp[a]). Winstrol normalized fibrinolytic activity, completely resolved severe hip pain with resumption of usual activity, and reversed/retarded ON, by MRI/X-ray. In 4 hypofibrinolytic adults (high PAI-Fx, high Lp[a]) with more advanced ON (segmental collapse of the head of the femur (Ficat III, IV), Winstrol normalized fibrinolysis without improving hip pain, activity restriction, or MRI/X-ray progression of ON. If therapy to normalize thrombophilia/ hypofibrinolysis is begun early in ON, before irreversible collapse of the head of the femur, progression of ON can be stopped and often reversed. Normalization of thrombophilia/hypofibrinolysis cannot improve ON, if started after collapse of the head of the femur. Most patients with osteonecrosis have thrombophilia and/or hypofibrinolysis as a major underlying pathoetiology. When assessing a patient with osteonecrosis one should measure the major determinants of thrombophilia: resistance to activated protein C (and, if abnormal, do the PCR assay for the Mutant Factor V Leiden gene), protein C, protein S, anticardiolipin antibodies IgG and IgM, and the lupus anticoagulant. Also, one should measure the major determinants of hypofibrinolysis: plasminogen activator inhibitor 1 and stimulated tissue plasminogen activator activity, and lp(a). With these measures in hand, the underlying coagulation defect can be treated and if the osteonecrosis is Ficat I or II, it can be reversed by treatment of the coagulation defect.
17. Glueck CJ, Freiberg R, Gruppo R et al. Thrombophilia and hypofibrinolysis: Reversible pathogenetic etiologies of osteonecrosis in adults and children. In Urbaniak JR, Jones, TP Jr(eds). Osteonecrosis: etiology, diagnosis, and treatment. Rosemony, IL. Amer. Acad. Orthopedic surgeons. 1997;pp105-110.
Recent progress in amelioration of osteonecrosis by treatment of thrombophilia and hypofibrinolysis.
AMELIORATION OF OSTEONECROSIS BY TREATMENT OF THROMBOPHILIA AND HYPOFIBRINOLYSIS. CJ Glueck, RA Freiberg, R Gruppo, P Kirk, RN Fontaine, A Gupta, T Tracy, P Wang. Cholesterol Center, Jewish Hospital, Cincinnati, Ohio. J Invest Med 1998;46:227A
Fifteen patients with Ficat stage I or II osteonecrosis (ON), 5 with thrombophilia, and 10 with hypofibrinolysis, were treated to determine the effect of therapy (Rx) on the symptomatic and radiographic progression of ON. To assess symptomatic relief, pain was rated daily by 5 numeric scores. MRI scans were done initially and at 6-8 months on Rx. Of the 5 thrombophilic patients, 2 had homocysteinemia, 1 was heterozygous for the mutant Factor V Leiden gene, 1 had high anticardiolipin antibody (IgG). They were treated for 26 weeks (range 6-42) with folic acid/B6 (n=2), or coumadin (n=2), or low molecular weight heparin (n=1). Twenty-two of 25 (88%) pain scores were improved on Rx (p<.001). On Rx, 4 of 5 patients became pain free. MRIs in 3 improved after 30, 38, and 39 weeks on Rx. Of the 10 hypofibrinolytic patients, 7 had high plasminogen activator inhibitor activity (PAI-Fx), 4 were homozygous and 3 heterozygous for the mutant PAI-1 gene, 4 had high Lp(a). They were treated with the anabolic-androgenic steroid, Winstrol (6 mg/day) for 11 weeks (range 3-31). Sixteen of 46 (35%) of pain scores were improved on Rx (p<.001), 23 (50%) were unchanged, and 7 (15%) worsened. On Rx, 1 of 10 patients became pain free; MRIs in 4 patients were unchanged after 4, 10, 12, and 31 weeks on Rx. Rx for thrombophilia was more successful than for hypofibrinolysis with 100% improvement in overall pain score vs 40%, p=.04, and 100% vs 33% improvement in mood score, p=.028. After covariance adjusting for severity of pain before Rx, pain relief in the thrombophilic group was greater than in the hypofibrinolytic group (p=.02). Rx of thrombophilia and hypofibrinolysis ON before segmental collapse of the head of the femur shows promise in amelioration of ON.
HERITABLE THROMBOPHILIA AND HYPOFIBRINOLYSIS: COMMON PATHOETIOLOGIES OF RETINAL VEIN THROMBOSIS. L Vadlamani, CJ Glueck, H Bell, A Gupta, RN Fontaine, P Wang, T Tracy, R Gruppo, D Stroop. Cholesterol Center, Jewish Hospital, Cincinnati, Ohio
In 17 patients, our specific aim was to determine whether heritable thrombophilias and hypofibrinolyses were pathoetiologic risk factors for retinal vein thrombosis (RVT). Coagulation measures in 17 patients with RVT were compared to those in healthy normal controls. Three of 17 patients (18%) were heterozygous for the thrombophilic Factor V Leiden G1691A mutation versus 7 of 233 controls (3%), p=.023. Two of 17 (12%) patients had normal alleles (5G/5G) for the plasminogen activator inhibitor (PAI) gene promoter; 88% were heterozygous or homozygous for the 4G polymorphism. Of 234 controls, 85 (36%) had 5G/5G; 149 (64%) were either heterozygous or homozygous for the 4G polymorphism, p=.03. Of 14 RVT patients with measures of dilute Russel's viper venom time, a thrombophilic antiphospholipid antibody, 6 (43%) were abnormal (>38.8 sec) vs 1/30 (3.3%) controls p=.002. Patients were more likely (8/16, 50%) to have high levels of hypofibrinolytic Lp(a) (>35 mg/dl) than controls (5/40, 13%), X2=9, p=.003. Patients were more likely to have high levels of the major determinant of hypofibrinolysis, plasminogen activator inhibitor activity (PAI-Fx). PAI-Fx was high (>22 U/L) in 6/16 patients (38%) vs 1/40 controls (2.5%), X2=12.8, p=.001. Hypofibrinolytic disorders often occurred in clusters. Median Lp(a) in patients with the 4G/4G genotype was 62 mg/dL vs 5.3 in 4G/4G controls (p=.048). Patients with retinal vein thrombosis commonly have both thrombophilia and hypofibrinolysis, opening avenues to protection of the contralateral eye by anticoagulant therapy, and to prevention of thrombosis in other venous and arterial beds.
E-mail: glueckch@healthall.com
For additional molecular diagnostic testing contact Molecular Diagnostics Laboratories (MDL)
Osteonecrosis of the Femoral Head,
at the Pre-prosthetic Stage
P. Hernigou
Hôpital Henri Mondor - Créteil - France
Osteonecrosis of the femoral head (ONFH) is a disabling condition that affects mainly younger subjects, in the midst of their working lives; to this day, it has remained a devastating disease. Its treatment stands at the borderline between Medicine and Surgery, and requires a thorough understanding of the pathogenesis, the natural history, and the treatment options as a function of the different disease stages, which are best assessed with further investigations.
Osteonecrosis (ON) may be defined as the death of the cell components of bone - both osteocytes and bone marrow cells. ONFH is not a specific entity, but the final common pathway of various conditions that impair the blood supply to the femoral head - hence the frequently used term avascular necrosis.
MECHANISM OF ONFH AS A FUNCTION OF AETIOLOGY
The chief causes of nontraumatic ONFH are treatment with corticosteroids, sickle cell disease (SCD), and chronic alcohol abuse.
In patients on long-term steroids, there is a notoriously high incidence of avascular necrosis. Even patients who are given high-dose steroids for short periods of time (e.g. for the management of cerebral oedema) are at increased risk of ON. Also, since the introduction, some years ago, of steroid therapy after the majority of organ transplants, ONFH has frequently been observed in kidney transplant recipients. Of course, the mechanism underlying the ON in patients treated with steroids is complex: it involves changes in the walls of capillaries within the bone, and an accumulation of fat in the reticular cells and the fat cells of the bone marrow.
In SCD, the main change in the blood which gives rise to ON is the diminished deformability of the red blood cells (RBCs) as the haemoglobin S (HbS) molecules polymerize into rigid aggregates. When the oxygen saturation of the haemoglobin falls, HbS polymers will be formed, and the originally disk-shaped RBCs will become less deformable. These stiff cells will obliterate the microcirculation. This mechanism of altered RBC deformability accounts for the epiphyseal ON in SCD; in other words, the ON observed is the manifestation of rheological disturbances.
Initially, all nontraumatic forms of ON were considered to be idiopathic; nowadays, many different causes are recognized: caisson disease, Gaucher’s disease, radiation, SLE, collagen disease, pregnancy, blood disorders, chemotherapy, organ transplants, pancreatitis, etc. In addition to these established causes, there are other risk factors that have not been universally accepted. Thus, chronic alcohol abuse is so common that some wonder whether it is a predisposing factor for ON. However, a daily intake of 150 mL of ethanol (the equivalent of 1.5 L of red wine with an alcohol content of 10%) appears to be the exposure threshold for alcohol-associated ON. Obviously, the amount of alcohol should be seen in relation to the subject’s body weight. Lipid disorders, which often occur in a context of occlusive vascular disease, diabetes, or atheromatosis, have frequently been suggested as causative factors or co-factors.
While, as a rule, the mechanisms leading to ON have two processes in common (bone ischaemia, and bone marrow disturbance), there are still several unanswered questions.
What is the mechanism of cell death in ONFH? Which cell population dies first - the osteocytes or the bone marrow cells?
There is no conclusive evidence that the death of the osteocytes or the bone marrow cells is due to ischaemia caused by alterations of the vessel walls, embolism, or thrombosis. Of course, the high rate of ON in some disorders (such as caisson disease), and the physiological and biochemical disturbances involved, point to a causal relationship between the disease and the ON, and suggest that local ischaemia is, at least, an important factor in this process of cell death. However, even in these cases, the actual mechanism responsible for the presumed reduction in blood flow is not known with any degree of certainty. There are no observations that would support the view that (fat or other) embolisms are the main and causative abnormality.
The bone cells may be affected by a metabolic disorder, and their nutrition may be compromised by a purely local reduction in blood supply to a level that is not, in itself, incompatible with cell survival. Under such circumstances, any additional adverse factors may be fatal to the bone cells. These factors may be cytotoxic agents such as ethanol; or substances such as cortisone, regardless of whether the hypercortisonism is exogenous or endogenous. The agents concerned may directly affect the cells or their precursors; equally, they may act through capillary endothelial lesions, to produce vascular insufficiency.
The roles played by these factors (and many others, which may also cause cell death) probably vary with the different disorders (alcohol abuse, diabetes, gout, kidney transplants, etc.), and in different patients.
What is the role of vascular pathology in the process of osteonecrosis?
The question is whether the first disturbances are localized in a wedge-shaped arterial micro-territory, or whether, even at this early stage, they are distributed throughout a larger part of the femoral head. If the underlying disorder is a vascular one, the question is whether the disorder is intraosseous, extraosseous, or both; whether it is in the arteries, in the capillaries, in the endothelium, or in the veins. The most recent investigations suggest that the mechanism is one of distal emboli which retrogradely affect the arterial circulation, or that the underlying disorder is on the venous side.
Is there an underlying abnormality?
Regardless of the underlying cause, most forms of ON (even those that are apparently idiopathic), have a number of pathogenetic features in common. Disorders of lipid metabolism are frequently seen. This would suggest that avascular necrosis stems, first and foremost, from an increase in the volume of the fat cells in the bone marrow. Since the marrow is confined in the inextensible space of the femoral head, this lipid overload will produce increased intraosseous pressure, which will lead to a bone compartment syndrome, and, eventually, to the death of the bone cells.
(SIGMA) The quality of the bone tissue: ON tends to be more severe, and to progress more rapidly, in the combined osteoporosis and osteomalacia that is seen in patients treated with steroids; in the osteoporosis associated with chronic alcohol abuse; in the renal osteodystrophy of kidney transplant recipients; and in other bone tissue pathologies.
What is the role of mechanical factors?
(SIGMA) Independently of the initiating biological factor that causes the necrotic phenomenon in a single event, there are mechanical factors involved in the production of ONFH. This is obvious from the fact that the necrotic zone is situated around the upper pole of the femoral head, and that the collapse of the head always occurs in the main weight-bearing region. The importance of mechanical factors is highlighted by a comparison of the strength of a trabecula of dead bone, and that of a living trabecula. Necrotic bone has a modulus of elasticity that is ca. 70% less than that of normal living cancellous bone; and the ultimate breaking load of necrotic bone is about half that of viable bone. Trabecular fractures have been described even in healthy femoral heads; their numbers are increased in porotic heads. If the bone is necrotic, there should be even more fractured trabeculae; worse, these fractures in dead bone cannot heal. Thus, the fracture burden will gradually increase, and in the maximally stressed zones of the femoral head, a subchondral fracture will occur. This fracture will show up on radiographs as a curved line, the so-called crescent sign. The influence of mechanical factors is also shown by the fact that the way in which the necrotic segment becomes demarcated matches the isobar pattern in a sphere that has been compressed at one site. The zone around the necrotic segment will be exposed to abnormally high loads, which will further worsen the pressure pattern and the ischaemic phenomena, causing yet more microfractures, and, thus, contributing to the spread of the necrotic lesions.
PATHOHISTOLOGICAL PROCESSES IN ONFH
The secondary cellular and tissular response pattern is marked by the apposition of new viable bone on the surface of the dead trabeculae. This creeping substitution may be such as to fill in all the spaces in the cancellous bone, to produce what is, to all intents and purposes, cortical bone tissue.
The extent and magnitude of this response will vary with the extent of the necrosis and with the zone affected by ON.
What happens at the junction between viable and dead bone
The repair of necrotic cancellous bone consists in two different processes, which appear to occur independently of each other: cell proliferation and invasion of the femoral head by reparative tissue; and the differentiation of mesenchymal cells into osteoblasts, which lay down new bone on the surface of the dead trabeculae. Later on, osteoclasts appear. These cells are derived either from mesenchymal precursors or from blood monocytes.
In the initial phase, there is intensive proliferation, and the osteoblasts rapidly lay down large amounts of new bone. However, after this reparative front has progressed several millimetres, the process soon comes to a halt. Osteoblast formation ceases or slows down considerably; as a result, the reparative front is made up of fibrous tissue and clusters of capillaries and mesenchymal cells.
What happens at the subchondral end plate
What happens in the repair of the cortical end plate below the cartilage differs markedly from the reparative processes in the cancellous bone of the femoral head. At the subchondral level, bone resorption far exceeds new bone formation, and the net result is loss of subchondral bone. The reparative process does not stop at the subchondral end plate: it continues into the articular cartilage, which may become ossified. This invasion by reparative tissue, and the local reactions set up by this invasion, pave the way for the osteoarthritic changes that will ultimately occur. The changes in the femoral head as an organ are not directly brought about by cell death: a dead femoral head may function for years without any apparent structural compromise. What causes a change in the mechanical properties of the femoral head as an organ, to make it deform and collapse, is the action of living cells involved in the reparative process. The starting point of the fracture is the zone of least resistance created on the lateral side of the femoral head, by the resorption of the subchondral bone and its overlying cartilage; this resorption is the result of the reparative process. In idiopathic ON, the fracture extends underneath the cartilage into the necrotic bone, as a result of stresses at the interface between the cancellous bone and the dense subchondral end plate. This process will lead to subchondral separation, producing the typical crescent sign seen on radiographs.
What happens in the articular cartilage
The articular cartilage remains viable for a long time (Fig. 1); it will go on functioning normally, despite the necrosis and subsequent reparative processes. The cartilage cells are nourished from the synovial fluid, which allows them to survive. In fact, later on the surviving cartilage cells appear to produce collagen faster than do healthy adult cartilage cells. Histochemical analysis has shown normal collagen and glycosaminoglycan levels early on; much later, with the onset of arthritic changes, there is first a relative, and eventually an absolute, loss of proteoglycans.
Figure 1 Gross photograph of a femoral head, with normal-looking cartilage over the necrotic segment
Development of OA
OA of the hip is the result of excessive pressure acting on the healthy parts of the femoral head; of the incongruency between the deformed head and the acetabulum; of the invasion of cartilage by reparative capillaries; and, later on, by pannus formation, which completes the destruction of the cartilage.
MRI IN FEMORAL HEAD OSTEONECROSIS
ONFH most commonly involves the anterosuperior portion of the femoral head. An MRI scan of a normal femoral head will show a uniformly high signal intensity on T1- and T2-weighting, throughout the femoral head. In the overwhelming majority of cases, the basic pattern of ON consists in a zone of decreased signal intensity on T1- and T2-weighted images. This low-intensity zone is at the site shown as a necrotic region on plain radiographs, in typical osteonecrosis with femoral head collapse. The low-intensity zone may be homogeneous or heterogeneous, with a speckling of high intensity against the low-intensity background, both on T1- and on T2-weighted images.
Early on, the most typical image is a thin low-intensity band on T1- and T2-weighting, which goes to the subchondral bone and is more or less concave towards the top of the femoral head.
With gadolinium, the contrast of the marrow spaces is enhanced, and the sensitivity of the technique for the detection of ON is improved. Gadolinium contrast enhancement may also be useful in screening for femoral head perfusion problems after hip fractures.
A variety of imaging protocols may be used for the visualization of the different features. MRI provides excellent soft tissue contrast, and allows images to be produced in virtually any plane. The standard protocol usually starts with a T1-weighted axial localizer (short TR, short TE). So-called T2-weighted spin-echo sequences enhance the specificity of the technique. In certain cases, these images may be replaced by fast T2 gradient-echo sequences, which save imaging time. So-called STIR (short T1 inversion recovery) sequences suppress the marrow fat signal. These sequences give a strong signal of tissues with long T1 and T2 relaxation times (granulation tissue and joint fluid), which improves the contrast between the bone marrow and the abnormal tissues. Also, chemical shift MR imaging to produce specific water or fat images may be used, to give better characterization of the different constituents.
MRI - HISTOLOGY CORRELATION
On the T1-weighted scans, MRI shows a curved low-intensity band with its concave side towards the top of the femoral head; this band defines an upper polar sector of varying size; the chief feature is the lack of homogeneity of the pattern in that sector.
The examination of surgical specimens, which is made easier by the use of surface coils, shows a marked decrease in signal intensity in the area of the subchondral end plate and in the zone between the dead and the viable bone that demarcates the necrotic segment. The in-between zone of the actual segment is heterogeneous, both in the surgical specimen and when imaged in vivo. Microradiographs of the bone sections show the well-known three zones of necrosis: the cartilage, with the subchondral end plate still attached to it, is separated from the necrotic segment; the necrotic segment consists of a delicate and regular openwork of bone, whose uniform appearance is at odds with the heterogeneous MRI signal pattern. The necrotic segment is separated from the living bone by a remodelling zone, which perfectly matches the low-intensity band seen on MRI scans. Since the changes in MRI signal intensity are fat-related, the histological workup also shows patterns related to the presence or absence of fat cells in the zones studied. In the zone of fibrosis and osteolysis that demarcates the necrotic segment (Fig. 2),
Figure 2 Histological pattern in ONFH. The peripheral portion of the necrotic segment is bordered below by a fibrovascular zone devoid of fat cells, which does not produce a signal on MRI.
the tissue newly formed by bone remodelling is chiefly fibrovascular, without any fat cells. This accounts for the peripheral low-intensity band seen in the femoral head. Within the necrotic segment, the mottled MRI pattern correlates well with what is shown by histology: in some areas, the fat cells are “mummified”, with intact cell walls. These zones give a normal-intensity signal on MR imaging, because the triglycerides are still intact inside the cells, and have not been broken down. By contrast, in areas where the fat cells have been destroyed, there will be decreased signal intensity. This is accounted for by the fact that once the fat cell wall has been disrupted, the triglycerides are released. In the environment containing sodium salts from the joint fluid (transudate), the triglycerides undergo saponification (breakdown), and produce a weak MR signal. Similarly, in the subchondral zone, with its trabecular fractures and resorptive processes, histology will show rupture of the fat cells, which will, once again, produce a low-intensity signal. Thus, a “histologically dead zone” may produce different MR signals, with the necrotic segment retaining a normal bone pattern for several months. This is why the subject of investigations at an early stage of ON, and the staging of ON, is somewhat more complex than might be assumed: in theory, ischaemic necrosis follows cell anoxia; the fat cells can survive this anoxia for between two and five days. Even after that time, it is not certain that MRI will be diagnostic at this very early stage, since the fat cells will remain “mummified”, with the triglycerides still inside the walls of the cells. A low signal intensity on the MRI scans is not due to cell death as such, but to the release and the breakdown of the triglycerides. However, this process can probably occur in the subchondral zone only if there has been trabecular fracture and resorption. Thus, the question is whether, early in the course of the disease, a weak MR signal in the subchondral zone is not, in fact, evidence of subchondral separation (Fig. 3), which, at that stage, would otherwise be revealed only by histology, since the lesion would not yet show up on radiographs. Subchondral separation is the radiological cut-off between Stages II and III in the Arlet & Ficat classification of ON; histologically, this separation may be present at an earlier stage.
Figure 3 Histological pattern in ONFH, with clearly visible subchondral fracture
Pathohistologically, bone marrow necrosis is the feature most readily detected. The only sign of osteocyte necrosis is the disappearance of these cells, leaving empty and often widened osteocyte lacunae. The actual pattern seen will depend upon the stage of the necrosis. At an advanced stage (in a femoral head that has collapsed and is being examined after its removal for THR), the conical sequestrum is made up of dead trabeculae, with empty osteocyte lacunae. The bone marrow is usually a magma, with loss of haematopoietic cells, and fat cells with absent nuclei and ruptured cell walls. Sometimes, the marrow is replaced by eosinophil debris, without any remaining identifiable cell structures. This necrotic zone, of varying size, is situated under the subchondral end plate. In the concave reparative zone, there is fibrovascular proliferation; dead trabeculae are completely or partially resorbed by osteoclasts, and replaced or covered with viable appositional bone, by osteoblasts.
AGE OF THE LESION - MRI AND RADIOGRAPHIC EVIDENCE
The prognosis of ONFH is governed by the collapse of the femoral head as a result of subchondral fracture; this lesion first produces a radiolucent crescent, and subsequently a loss of sphericity of the femoral head. The treatment to be given will often be a function of this loss of sphericity and the subchondral separation. MRI is an excellent modality that correlates well with the histological findings; it may also be used to establish the extent of the ON; however, it is not very suitable when it comes to detecting the collapse. The best imaging technique to provide evidence of subchondral separation or loss of sphericity is still conventional radiography.
The earliest radiographic sign is an increased density inside the femoral head; however, the main contribution of conventional radiography is the demonstration of subchondral separation. In fact, it is the most reliable modality for the detection of the crescent sign and the loss of femoral head sphericity. The crescent sign should be looked for on lateral views, which open up the hip joint and, consequently, show the crescent. Loss of sphericity is also seen earlier on the lateral films, because of the anterosuperior site of the lesion. The most reliable lateral incidence to show loss of sphericity is the frog lateral view.
These advantages of conventional radiography notwithstanding, MRI can, of course, furnish information to help establish the age of the osteonecrotic lesion. If the necrotic zone is still of high intensity on the MR images (Fig. 4), the patient will usually have an asymptomatic hip or one that has been causing pain for less than six months. If, on the other hand, the zone is of low signal intensity (Fig. 5), then three quarters of the patients will have hip pain, and the pain history will be longer than six months. Thus, low-intensity ON is, as a rule, of longer standing than is ON that is still giving a high-intensity signal on MRI scans.
Figure 4 MRI pattern of a small incipient ONFH lesion. A.p. and lateral views. The zone inside the necrotic segment is still of high intensity.
Figure 5 Long-standing necrosis. The necrotic zone is of low signal intensity.
Joint effusion shows up well on MR images, giving a high-intensity signal on T2-weighting; a large effusion may be taken as indirect evidence of ON with subchondral collapse: prior to collapse, there may be a small effusion; however, in general, massive effusion occurs only in cases of subchondral collapse.
MANAGEMENT
Many surgical treatments have been devised in ONFH. Of course, the large number of treatment modalities shows that the condition is difficult to treat, and that there are limits to what can be done.
The most important aspect of the management of ONFH is an early diagnosis of the condition.
Pre-collapse
Customarily, ONFH patients have been treated nonsurgically. However, purely medical treatment will allow only few patients to live with their condition for one or two years. Usually, the patients are kept off weight-bearing on the affected side; however, this treatment principle has several limitations: it does not abolish the muscle tone around the joint, even when the patient is lying down. The use of two elbow crutches (as a substitute for axillary crutches) does not provide the required complete weight relief; and even if crutches afford some protection, there is still the question of how long the patients should be kept off weight-bearing. Between the diagnosis of ONFH and the loss of femoral head sphericity, up to 4 or 5 years may elapse. Strictly speaking, the patients should be kept off weight-bearing for this entire period of time. Seeing that the patients are usually young and in the midst of their working lives, it would be futile to attempt such prolonged weight relief. It should also be borne in mind that if patients are kept on nonsurgical treatment for a long period of time, eventual surgery may come too late, since the lesions will, by then, have progressed to a stage where femoral head preserving surgery can no longer help.
Very early in the course of the disease, core decompression remains the most logical treatment modality, if one accepts that the condition is a compartment syndrome, with increased pressure inside the femoral head. Core decompression has been in use for a considerable time; the results reported by different authors vary, no doubt because of different patient populations and different ON stages treated with decompression. However, while fundamental research and clinical studies have shown that dead bone may be revascularized by living bone, the reparative osteogenic potential is slight in ONFH: the number of bone progenitor cells in the uninvolved part of the femoral head and in the trochanteric region is less than in healthy subjects. It would, therefore, make sense not only to core, but to introduce new cells. This can be done by placing a tibial graft, a vascularized graft or cancellous bone into the coring tract. The same result may be produced more readily by harvesting bone marrow from the anterior iliac crests, concentrating the marrow thus obtained, and reinjecting it into the necrotic zones.
Post-collapse
Once the femoral head has lost its sphericity, core decompression will still afford pain relief, but will not be able efficaciously and lastingly to halt the gradual collapse of the weight-bearing zone. The important goal to achieve at this stage is the immobilization of the necrotic segment. A mobile segment will produce increased pressure in the femoral head, and may contribute to the progression of the necrosis. To this end, attempts have been made to use early reconstruction, with debridement of the necrotic zone and replacement of the dead bone with autologous bone reinforced with a vascularized fibular graft, to support the subchondral bone at risk of collapse. This is an attractive approach, which does, however, require the patient to be kept off weight-bearing for a long period of time (3 - 6 months). The surgery involved is technically demanding; the postoperative management is quite cumbersome (3 - 6 months off weight-bearing); often, both hips are affected; and the treatment may not work. This is why only few patients have been managed in this way.
Since the survival of the cartilage cells is ensured by their nutrition from the synovial fluid, the femoral head may be restored to sphericity by elevating the necrotic segment and keeping it in this restored position, by the injection of cement. In this approach, acrylic cement is used to give the femoral head its correct shape, and to delay the progression to OA which follows the deformation of the head. Cement injection has several advantages: it allows immediate weight-bearing; it provides immediate pain relief; and it does not interfere with the patient’s work for an unduly long period of time. Also, conversion to a hip replacement is straightforward, should the pain recur. In such cases, femoral head resurfacing would undoubtedly be a suitable treatment option.
For femoral head preserving surgery, osteotomies of various kinds (valgus, varus, flexion, deflexion, rotational) have been used for a long time. These osteotomies are still difficult to perform. Also, they may require prolonged weight relief after surgery, and conversion to hip replacement in case of failure may be difficult.
Following the onset of arthritic changes
Once OA has developed, or the femoral head has suffered major collapse, joint replacement is the only viable option (Fig. 6). Surface replacement arthroplasties have given good results in some cases, but have come to be less frequently used, because of the rapid deterioration seen in some cases, which contrasts with the good results habitually seen following THR.
Figure 6 Gross and radiographic appearance of ONFH, showing the subchondral fracture
BONE MARROW AUTOGRAFTS IN THE TREATMENT OF ONFH
Very early in the course of the disease, core decompression remains the most logical treatment modality, if one accepts that the condition is a compartment syndrome, with increased pressure inside the femoral head. Core decompression has been in use for a considerable time; the results reported by different authors vary, no doubt because of different patient populations and different ON stages treated with decompression. However, while fundamental research and clinical studies have shown that dead bone may be revascularized by living bone, the reparative osteogenic potential is slight in ONFH: the number of bone progenitor cells in the uninvolved part of the femoral head and in the trochanteric region is less than in healthy subjects. It would, therefore, make sense not only to core, but to introduce new cells.
The treatment of ONFH with bone marrow autografts is based upon the view, now commonly held, that the osteogenic cells derive from a stem cell in the bone marrow stroma. It is thought that this stem cell gives rise to osteoblasts, chondroblasts, fibroblasts, etc.; and that the actual cell type obtained from that one precurseur will depend upon the culturing conditions used. The clonogenic potential of the different cells has been demonstrated; each cell colony is derived from a single stem cell is known as a CFU-F (fibroblast colony-forming unit).
When red bone marrow is transplanted, the graft will contain osteogenic precursors, which will repopulate the osteonecrotic bone. In the early stages of the disease, the femoral head will still be round (Fig. 7). By definition, the necrotic zone will be acellular, at least as far as osteocytes and bone marrow cells are concerned. However, before Stage III, the bone framework is still intact; in particular, it will have retained its strength, even though the cell population in the upper end of the femur is abnormally small. This is why it was thought that conventional core decompression should be supplemented by an autograft of cells harvested by bone marrow aspiration from the ipsilateral iliac crest. We have used this approach in the treatment of Stage I and Stage II ONFH.
Figure 7 Gross appearance of a femoral head with pre-Stage III ONFH. The affected zone is abnormally “white”, and bordered by a small red revascularization zone.
Figure 8 Technique of bone marrow harvesting and reinjection, in the treatment of ONFH by bone marrow autograft
The bone marrow is harvested under general anaesthesia (Fig. 8). The usual sites are the anterior iliac crests; the posterior crests are less frequently used. A bevelled metal trocar of 6 - 8 cm length and a bore of 1.5 mm is pushed deep into the cancellous bone. A 10 mL syringe that has been flushed with heparin is used to aspirate the marrow. Once the needle has been inserted to the desired depth, the tip is swept around a full circle in 45° steps, with the bevel pointing in different directions at each step. Bone marrow is withdrawn at each of these points. Once this 360° aspiration has been performed at one site, the needle is brought out and reinserted at a different site, where the 360° sweep in 45° steps is repeated. This procedure is continued until a sufficient quantity of bone marrow has been harvested. The cell content of the marrow thus obtained will be greater if the marrow has been aspirated in small (2 mL) fractions, since, under these conditions, the proportion of contaminating peripheral blood will be less. The same percutaneous tract may be used for multiple punctures of the iliac crest. All the marrow aspirated is discharged into a plastic collection bag containing ACD (acid citrate dextrose) anticoagulant solution. It is then filtered, to remove fat aggregates and clots.
Bone marrow harvesting is most conveniently done by two operators, each working on one iliac crest. An assistant places the aspirated material in the collection bag and flushes the syringes with heparin.
The aspirated material needs to be reduced in volume in order to increase its stem cell content. This is done by removing some of the RBCs (the non-nucleated cells) and the plasma, in such a way as to retain only the nucleated cells, i.e. the mononuclear stem cells as well as the monocytes, the lymphocytes, and some PMNs. This involves a considerable amount of bone marrow handling. Although the technique as such is suitable for large volumes of marrow, great care must be taken to ensure that everything is done with full sterile precautions, so as to obtain a product that is safe for reinjection. Two techniques are available: bone marrow may be harvested, concentrated, and reinjected under the same anaesthetic, in which case concentration must be performed sufficiently speedily so as not to exceed a time of ca. 30 minutes; or the harvested material may be frozen and reinjected at a later stage; in that case, there is no constraint on the time taken to concentrate the marrow.
For reinjection under the same anaesthetic, a COBE 2991 blood cell washer was used. With this technique, the bone marrow is centrifuged for 5 minutes at 400 g (g = gravity). Leucapheresis is performed during 40 to 50 seconds at a collection rate of 100 mL/min. This centrifuging technique yields a “concentrated myeloid suspension” of ca. 50 mL stem cells, from a 300 mL volume of aspirated bone marrow; the stem cell concentrate is placed in a syringe for reinjection.
The bone marrow is injected into the femoral head using a small (Mazabraud) trocar. The instrument is introduced through the greater trochanter, as in conventional core decompression. Its position in the femoral head and in the necrotic segment is monitored with biplane fluoroscopy. Since, at the time of treatment, the plain radiographs will show little if any evidence of necrosis, the preoperative MRI scans should be used together with the image intensifier views, to determine the site of the lesion. After the injection of the bone marrow, a few millilitres of contrast should be injected, in order to check the area in the femoral head through which the injected bone marrow will spread. It has been established that the contrast medium will not damage the bone progenitor cells.
Although the bore of the trocar is small compared with the trephines normally used for core decompression, femoral head and trochanteric region pressure measurements have shown that even a small hole will relieve the intraosseous pressure. If, during the bone marrow injection, the pressure in the femoral head is found to rise, a normal pressure pattern will be restored once the injection is finished, exactly as in intraosseous pressure measurements. In our patients, no complications were observed during anaesthesia; in particular, there was no reduction in oxygen saturation, and no change in the pulse rate or blood pressure.
There are still several theoretical and practical questions that remain unresolved. Thus, it is not known how many cells need to be injected, or what the optimum concentration is. The technique’s mechanism of action is, undoubtedly, complex. During the injection, the femoral head is flushed, and some of the fat is removed, as the 25 mL volume of bone marrow is injected. Also, the bone marrow contains not only stem cells but also bone morphogenetic proteins such as BMP-2, which are introduced into the femoral head and into the necrotic segment. The procedure, which may be used in other conditions as well, holds great promise because of its inherent advantages: it is straightforward; it involves autologous transplantation; and it is well tolerated, since both the marrow harvesting and the injection into the femoral head are done percutaneously. Obviously, its usefulness has to be weighed against that of other treatment modalities. The decision will be primarily a function of the stage of ON: once the femoral head has lost its sphericity, bone marrow autografts can no longer be used.
USE OF CEMENT FOR RESTORATION OF FEMORAL HEAD SPHERICITY IN ONFH
In ONFH, subchondral separation and the loss of sphericity of the femoral head constitute a point of no return in the course of the disease. It is generally accepted that once this stage has been reached, the condition will inexorably progress to OA, in the shorter or the longer term. This is why attempts have been made to restore the sphericity of the femoral head by elevating the necrotic segment and keeping it in its correct position, by the injection of cement. In this approach, the acrylic cement is used to restore the rounded femoral head pattern, relying on the fact that the cartilage cells will survive because the articular cartilage is nourished by the synovial fluid.
The technique has been used in the treatment of osteonecrotic femoral heads that had lost their sphericity but had not yet progressed to arthritic changes.
The surgical technique involves exposure of the hip by a Smith-Petersen approach and a T-shaped capsular incision to expose the anterosuperior aspect of the femoral head as well as the anterior part of the neck. The incision of the capsule must be limited inferiorly, so as not to damage the lateral circumflex femoral artery.
The necrotic segment is usually obvious: while the cartilage over the lesion is grossly indistinguishable from the cartilage over the healthy part of the femoral head, the necrotic zone is commonly surrounded by a groove or low ridge. Pressure with a dissector may also be used to detect the necrotic zone, which will spring back after having been depressed, rather like an indented table tennis ball (Fig. 9). This phenomenon is no doubt due to the elasticity of the overlying cartilage and the mobility of the necrotic segment, which is detached from the living bone and from the subchondral end plate.
Figure 9 Diagrammatic representation of loss of femoral head sphericity in ONFH. The cartilage is still grossly normal, but the head may be depressed like a table tennis ball.
Elevating the articular cartilage and restoring the sphericity of the femoral head can be readily achieved by the use of a pin inserted between the viable bone and the necrotic segment. Levering on the pin will, as a rule, allow the cartilage to be raised sufficiently to restore the rounded pattern of the femoral head; this restoration of the contour can be appreciated by direct vision. If need be, two or three pins may be used; these pins may be left in situ to steady the segment during the cement injection.
Low-viscosity cement is injected using a cement gun (Fig. 10); the cement is placed under the detached segment and, if necessary, in the subchondral zone. The object is to finish up with a spherical head and a necrotic segment that will neither move nor allow itself to be depressed (Fig. 11). After surgery, weight-bearing is allowed from Day 3, and a standard programme of hip physiotherapy is initiated.
Figure 10 Cement injection technique: The collapsed segment is lifted, and cement is injected into the subchondral zone and below the segment.
Reproduced with permission of the Journal of Bone and Joint Surgery (1993, 75B, 875-880)
Figure 11 Intraoperative view. Starting at the top: The necrotic segment is readily identified, and may be depressed with a dissector. - The segment is elevated with a pin; through this tract, cement is subsequently injected. - Postoperative view.
Reproduced with permission of the Journal of Bone and Joint Surgery (1993, 75B, 875-880)
This technique shows that it is possible, early in Stage III ONFH, to restore the sphericity of the femoral head (Fig. 12), and that the immobilization of the necrotic segment affords immediate pain relief. The technique is beneficial because of the straightforward postoperative management, and the fact that the patient is allowed to weight-bear immediately. Also (unlike certain rotational osteotomies), it does not jeopardize later conversion to THR. However, despite all these benefits, the technique is not a miracle treatment of ON that preserves the femoral head. On the other hand, considering the high rate of osteotomy failure necessitating conversion to THR, cement injection appears to be justified. It should probably be used only in cases where the ON is not very far advanced and not progressing very rapidly. In our study, the best results were obtained in adult patients with idiopathic ONFH, and in SCD cases. While the procedure cannot alter the natural history of ON, it probably allows the patient a more comfortable and painfree life until, eventually, he or she will have to undergo THR, between five and ten years after the collapse of the femoral head.
Figure 12 Femoral head with subchondral separation, before and after cement injection
AUTHOR’S PUBLICATIONS
Ph. HERNIGOU, F. GALACTEROS, D. GOUTALLIER : Nécrose de hanche drépanocytaire (fréquence, aspect morphologique, évolutif et thérapeutique). Revue de Chirurgie Orthopédique 1989, Suppl. 1, 75, 120-121.
Ph. HERNIGOU, M.C. VOISIN, E. DESPRES, D. GOUTALLIER : Confrontation de l’imagerie par résonnance magnétique nucléaire et de l’histologie dans les nécroses des têtes fémorales. Revue du Rhumatisme 1989, 56, (11), 741 -744.
Ph. HERNIGOU, F. GALACTEROS, D. BACHIR, D. GOUTALLIER : Etude de 164 nécroses épiphysaires (hanches, épaules, genoux) chez 55 patients drépanocytaires, caractéristiques, aspect épidémiologique et étio-pathogénique. Revue du Rhumatisme 1989, 56 (12), 869-875.
Ph. HERNIGOU, F. GALACTEROS, D. BACHIR, D. GOUTALLIER : Histoire naturelle de la nécrose de hanche dans le malade drépanocytaire. A propos de 104 nécroses. Revue de Chirurgie Orthopédique 1989, 75, 542-557.
Ph. HERNIGOU, D. GOUTALLIER : Reconstruction in avascular necrosis of the spheric geometrical shape of the femoral head with acrylic cement. Bone Circulation and Bone necrosis, Ed. J. Arlet, B. Mazieres, Springer Verlag 1990, 353-355.
Ph. HERNIGOU, F. GALACTEROS, D. BACHIR, D. GOUTALLIER : Deformities of the hip in adults who have Sickle-Cell disease and had avascular necrosis in childhood. : Journal of Bone and Joint Surgery 1991, 73 A, 1, 81-92.
Ph. HERNIGOU, F. GALACTEROS, D. BACHIR, D. GOUTALLIER : Séquelles des nécroses de hanche de l’enfant drépanocytaire. Revue du Rhumatisme 1991, 58 (10), 643.
Ph. HERNIGOU, B. COPIN, K. EZZAOUIA, D. GOUTALLIER : Dissection sous-chondrale dans les nécroses de hanche de l’adulte (confrontation entre l’aspect per-opératoire, les radiographies, le scanner, la résonnance magnétique nucléaire et l’histologie). Revue du Rhumatisme 1991, 58 (10), 695.
Ph. HERNIGOU, D. GOUTALLIER : Reconstruction de la sphéricité de la tête fémorale des nécroses par relèvement du séquestre et comblement par du ciment. Revue du Rhumatisme 1991, 58 (10), 696.
Ph. HERNIGOU, D. GOUTALLIER : Reconstruction de la sphéricité de la tête fémorale des nécroses par relèvement du séquestre et comblement par du ciment. Revue de Chirurgie Orthopédique 1992, Suppl. I, 213.
Ph. HERNIGOU, D. BACHIR, F. GALACTEROS : Avascular necrosis of the femoral head in sickle-cell disease. J. Bone and Joint Surg. (BR) 1993, 75 B, 875-880.
Ph. HERNIGOU, F. BEAUJEAN : Bone marrow activity in the upper femoral extremity in avascular osteonecrosis. Rhum. (Eng. Ed.) 1993, 60 (1), 610.
Ph. HERNIGOU : La nécrose de hanche. Revue Synoviale 1993, 17, 11-16.
Ph. HERNIGOU, F. BEAUJEAN : La moëlle osseuse, une clé dans la compréhension des nécroses de hanche idiopathiques. Revue du Rhumatisme et des Maladies Ostéoarticulaires 1993, 60, n° 10, 722.
Ph. HERNIGOU : Nécrose de hanche et cicatrice du cartilage de croissance. Revue du Rhumatisme 1994, 61 (n° 10), 704.
Ph. HERNIGOU, A. de LADOUCETTE : Ostéonécrose aseptique de la tête fémorale. Thérapeutique Rhumatologique Médecine-Sciences, Edit. Flammarion 1995, 357-359.
Ph. HERNIGOU : Ostéonécrose des épiphyses de l’adulte. Edition technique, Encyclopédie Médico-chirurgicale Appareil Locomoteur 1995, 14-028-A-10
Ph. HERNIGOU : Traitement des nécroses de hanche (aux stades I et II) par autogreffe de moelle osseuse. Revue du Rhumatisme 1995, n° 10, 194.
M.C. VOISIN, I. BROCHURIOU, M.H. SY, Ph. HERNIGOU : Aspect anatomo-pathologique de la tête fémorale dans les nécroses drépanocytaires au stade III. Revue du Rhumatisme 1995, 62 (n° 10), 742.
Ph. HERNIGOU : Autologous bone marrow grafting of avascular osteonecrosis before collapse. Rev. Rhum. (Engl. Ed.) 1995, 62, 10, 650.
Ph. HERNIGOU, F. BEAUJEAN : Abnormalities in bone marrow of the iliac crest in patients with osteonecrosis. Journal of Bone and Joint Surgery, 1997, 79A, 7, 1047-1053.
Ph. HERNIGOU, F. BEAUJEAN : Autologues bone morrow grafting of avascular necrosis before collapsus. Journal of Bone and Joint Surgery, 1997, 79B, Supp. II, 171.
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Copyright © 2001, BMJ
BMJ 2001;323:665 (22 September)
Premature osteonecrosis and sirolimus treatment in renal transplantation
Sunil Bhandari and Josette Eris
Department of Renal and Transplant Medicine, Statewide Renal Services, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia
Correspondence to: S Bhandari, Hull and East Yorkshire Hospitals NHS Trust, Hull Royal Infirmary, Hull HU3 2JZ
Introduction
The incidence of osteonecrosis or avascular necrosis has fallen as a result of new advances in immunosuppression and lower corticosteroid regimens.1 2 Mycophenolate mofetil and sirolimus are associated with an increase in surgical complications.3 4 Sirolimus may also be associated with avascular necrosis in patients after renal allograft transplantation. This could be attributed to sirolimus's adverse lipid profile, its potent bone marrow suppressive effect, or perhaps an idiosyncratic effect
A 39 year old man with IgA nephropathy received a cadaveric renal transplant. He was a non-smoker and non-drinker. Seven months after receiving the transplant he developed an acute painful left leg. He was taking prednisone 10 mg, cyclosporin 300 mg, and sirolimus 5 mg daily. His trough sirolimus concentration was 20.7 ng/ml (range 5-20). Hip x ray and magnetic resonance imaging confirmed avascular necrosis in both hips. Sirolimus was discontinued, and tacrolimus and mycophenolate mofetil were introduced. Disodium pamidronate treatment produced symptomatic improvement.
A 49 year old man with polycystic kidney disease received a cadaveric renal transplant. He was a non-smoker and non-drinker. Six months after the transplantation he developed hip pain. Investigations confirmed bilateral avascular necrosis. He was taking prednisone 10 mg, cyclosporin 200 mg, and sirolimus 5 mg daily. His trough sirolimus concentration was 5.8 ng/ml. Sirolimus was changed to mycophenolate mofetil, and elective bilateral hip replacements were arranged.
Avascular necrosis, a recognised complication of transplantation, is commonly associated with prolonged high doses of corticosteroid.1 2 Occurring 6-12 months after transplantation, it is less likely to result from corticosteroid treatment. In our transplant population the prevalence of avascular necrosis is 2% in patients on standard treatment, with less than 0.5% in the first year (unpublished data). In those patients receiving sirolimus the prevalence is 3.8% (2 from 52 cases). Data sheets suggest a frequency of 1-10% with corticosteroids. No other reports have been published. Although our data are compared with historical controls, we believe that sirolimus may be a cause of early post-transplant bone pain because of avascular necrosis.
Competing interests: Patients of JE were part of the sirolimus phase III multicentre study
References
Kubo, T., Fujioka, M., Yamazoe, S., Yoshimura, N., Oka, T., & Ushijima, Y. Relationship between steroid dosage and osteonecrosis of the femoral head after renal transplantation as measured by magnetic resonance imaging. Transplant Proc 1998; 30: 30393040. [PubMed]
Han, D., Kim, S., Chang, J., & Kim, S. Avascular necrosis following renal transplantation. Transplant Proc 1998; 30: 30343035. [PubMed]
Adams, J., Zeier, M., Mandelbaum, A., & Wiesel, M. Increased rate of surgical complications due to mycophenolate-mofetil following renal transplantation—possible implications [abstract]. J Am Soc Nephrol 1999; 752A: A3803.
Hricik, DE., Weigel, K., Knauss, TC., Seaman, D., & Schulak, JA. Increased incidence of wound healing complications in kidney transplant patients receiving sirolimus [abstract]. J Am Soc Nephrol 1999; 758A: A3835.
J Bone Joint Surg Br 2001 Jul;83(5):715-20 Related Articles, Books, LinkOut
Perthes' disease in the adolescent.
Joseph B, Mulpuri K, Varghese G.
Department of Orthopaedics, Kasturba Medical College, Manipal, Karnataka State, India.
We studied the natural history of Perthes' disease in 62 children in whom the onset of symptoms was in adolescence. Three patterns of disease were noted, namely, late-onset pattern, segmental collapse, or destructive with failure of revascularisation. In the late-onset pattern, the disease followed the sequence of healing seen in younger children, but adequate epiphyseal remodelling did not occur. Consequently, the femoral head was never spherical after revascularisation. With segmental collapse, early and irreversible collapse of part of the epiphysis occurred with gross deformation of the femoral head. The destructive pattern was characterised by a failure of revascularisation and repair of the avascular epiphysis. The radiological outcome was poor in all three patterns. The poorest clinical results were found in the destructive type which was frequently associated with incapacitating pain requiring arthrodesis or excision arthroplasty within three years of onset of the disease.
PMID: 11476312 [PubMed - indexed for MEDLINE]
Rheumatology International
ISSN: 0172-8172 (printed version)
ISSN: 1437-160X (electronic version)
Table of Contents
Abstract Volume 20 Issue 6 (2001) pp 243-245
case report: Arthritis and osteonecrosis in a patient with thrombophilia
Amira A. Shahin (1)(2)
(1) Department of Rheumatology and Rehabilitation, Faculty of Medicine, Cairo University, Cairo, Egypt
(2) 453 Al-Ahram Street, Al-Ahram, Giza, Egypt
Received: 6 January 2001 / Accepted: 4 March 2001 / Published Online: 30 May 2001
Abstract. This case report describes a very rare entity of thrombophilia manifesting as persistent arthritis and digital ulcers. A 9-year-old Egyptian girl presented with a 2-year history of persistent arthritis and digital ulcers. The case was followed up after 4 years. The clinical manifestations and laboratory investigations are recorded. Thrombophilia with partial protein C deficiency appeared to be responsible for the clinical manifestations with underlying ipsilateral osteonecrosis of patella and calcaneum and resorption of the terminal phalanges. Her older sister showed the same picture with additional pulmonary hypertension. In conclusion, arthritis and osteonecrosis appear as a rare presentation of thrombophilia and protein C deficiency, and ignorance of this may lead to misdiagnosis or confusion with other childhood rheumatic diseases.
Keywords. Arthritis · Osteonecrosis · Thrombophilia · Protein C deficiency
Cementless hip arthroplasty in the treatment of patients with femoral head necrosis.
Xenakis TA, Gelalis J, Koukoubis TA, Zaharis KC, Soucacos PN.
Department of Orthopaedic Surgery, University of Ioannina, School of Medicine, Greece.
Treatment of patients with osteonecrosis of the femoral head focuses on pain relief and improved function of the hip. Total hip arthroplasty remains an effective tool for the treatment of patients with end-stage osteonecrosis with collapse of the femoral head, although there is a greater risk for failure. The aim of the current study was to assess the long-term survival of cementless total hip arthroplasties in 28 patients (36 hips) with osteonecrosis of the femoral head (Steinberg Stage V and Stage VI) with an average followup of 11.2 years (range, 10-15 years). There were 19 women and nine men with an average age of 51.4 years (range, 28-65 years). A threaded titanium cup CST (Conical Screwed Titanium) was used in all patients and different cementless femoral components were used depending on the optimal fit in the femoral canal as assessed during preoperative templating. No serious complications were encountered postoperatively. The patients were evaluated preoperatively and postoperatively with the Merle d'Aubigne and Postel scale. After cementless total hip arthroplasty, the average pain score improved 3.6 points, walking ability improved 1.6 points, and range of motion improved 1 point. Two patients had thigh pain. Radiographic evaluation on anteroposterior and lateral radiographs of the proximal femur was excellent in 10 hips postoperatively. No heterotropic ossification was observed, although proximal femoral atrophy was seen in 15 hips. Clinical and radiologic findings did not correlate. There were two revisions of the acetabular implants in one patient with bilateral idiopathic osteonecroses and total hip replacement. Overall, survival of the prostheses was 93.4% at the average followup of 11.2 years.
Clin Orthop 2001 May;(386):85-92
Partial resurfacing arthroplasty of the femoral head in avascular necrosis. Methods, indications, and results.
Siguier T, Siguier M, Judet T, Charnley G, Brumpt B.
Clinique Jouvenet, Paris, France.
The current study reports results using a partial surface replacement for osteonecrosis of the femoral head. The surgical technique, implant design, and instrumentation cause minor soft tissue disruption and require little bony resection. Thirty-seven prostheses were placed in 33 patients during the past 7 years. The mean age of the patients was 43 years (range, 24-59 years), and the preoperative Ficat classification was Stage III in 26 hips, Stage IV in 10, and Stage II in one hip. For the surviving prostheses, the mean followup was 49 months (range, 24-89 months). Of the 28 surviving implants, 24 continue to function well and the patients have excellent or good hip scores according to the Merle d'Aubigne system. There were nine failures, mainly attributable to the extension of the osteonecrosis. In comparison with alternative techniques, the operative surgery for partial surface replacement is straightforward, requiring little preoperative planning and immediate weightbearing postoperatively. Should failure occur, little bone stock loss is incurred and revision to a total hip replacement is as simple as primary hip arthroplasty.
Clin Orthop 2001 May;(386):71-8
Core decompression with bone grafting for osteonecrosis of the femoral head.
Steinberg ME, Larcom PG, Strafford B, Hosick WB, Corces A, Bands RE, Hartman KE.
Department of Orthopaedic Surgery, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Although core decompression is one of the more popular procedures for treating avascular necrosis, considerable controversy exists concerning its safety and effectiveness. The current authors review the results of a prospective study of 406 hips in 285 patients treated by one surgeon with core decompression and bone grafting. Patients were followed up for 2 to 14 years. The outcome was determined by the change in the Harris hip score, quantitative radiographic measurements, and need for total hip replacement. These hips were compared with 55 hips in 39 patients treated non-operatively and with historic controls. Five complications occurred after 406 procedures including two fractures that resulted from falls during the first postoperative month. Of the 312 hips in 208 patients with a minimum 2-year followup, 36% of hips (113 hips in 90 patients) required hip replacement at a mean of 29 months: 18 of 65 hips (28%) with Stage I disease; 45 of 133 hips (34%) with Stage II disease; three of 13 hips (23%) with Stage III disease; and 45 of 92 hips (49%) with Stage IV disease. Before femoral head collapse (Stages I and II combined) hip replacement was performed in 10 of 77 hips (14%) with small lesions (A), 33 of 68 hips (48%) with intermediate lesions (B), and 20 of 48 hips (42%) with large lesions (C). Results as determined by changes in Harris hip scores and radiographic progression were similar. Patients who underwent core decompression and bone grafting have a very low complication rate. In patients treated before femoral head collapse, the outcome is significantly better than in patients who received symptomatic treatment. The results are correlated with the stage and the size of the necrotic lesion.
Clin Orthop 2001 May;(386):19-33
Hypofibrinolysis, thrombophilia, osteonecrosis.
Glueck CJ, Freiberg RA, Fontaine RN, Tracy T, Wang P.
Cholesterol Center, Jewish Hospital, Cincinnati, OH 45229, USA.
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) (> or = 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.
Clin Orthop 2001 May;(386):173-8
Statin therapy decreases the risk of osteonecrosis in patients receiving steroids.
Pritchett JW.
Department of Orthopaedic Surgery, University of Washington, Seattle 98104, USA.
Osteonecrosis is a devastating complication of systemic steroid use. Prolonged steroid use produces a hyperlipidemic state in most patients and puts them at risk for osteoporosis and osteonecrosis. The fat content within the femoral head increases, resulting in increased intracortical pressure that may lead to sinusoidal collapse and osteonecrosis. Statins are lipid-clearing agents that dramatically reduce lipid levels in blood and tissues. Statins are widely used to prevent cardiovascular disease and have been shown to reduce the adverse effects of steroids on lipid metabolism. The purpose of this study was to determine whether the use of statin drugs affects later development of osteonecrosis in patients receiving steroids. The records of 284 patients who were taking statin drugs at the time they were started on high dose steroids were examined to determine whether osteonecrosis had developed. The patients remained on statin drugs during the entire time of steroid exposure. Magnetic resonance imaging scans were used to verify the osteonecrosis unless it was visible by radiograph. After an average of 7.5 years (minimum followup, 5 years), only three patients (1%) from the group had osteonecrosis develop. This 1% incidence is much less than the 3% to 20% incidence usually reported for patients receiving high-dose steroids. Statins may offer some protection against having osteonecrosis develop when steroid treatment is necessary.
Clin Orthop 2001 May;(386):120-30
Treatment of avascular necrosis of the femoral head with vascularized fibular transplant.
Soucacos PN, Beris AE, Malizos K, Koropilias A, Zalavras H, Dailiana Z.
Department of Orthopaedic Surgery, University of Ioannina, School of Medicine, Greece.
Two hundred twenty-eight hips in 187 patients with avascular necrosis of the femoral head were treated with vascularized fibular transplant from March 1989 to March 2000. The etiologic factors associated with the disease included corticosteroids in 84 patients (44%; 101 hips, trauma in 25 patients (13%; 29 hips), alcohol abuse in 24 patients (12%; 28 hips), and 41 hips (18%) were classified as idiopathic. Systemic disorders, including systemic lupus erythematosus, sickle cell anemia, inflammatory bowel disease, pregnancy, and dysbaric disease were observed in 12, nine, four, three, and one hip(s), respectively. Of the 228 hips operated on, 184 hips (152 patients) were assessed postoperatively with followup ranging from 1 to 10 years (mean, 4.7 years). Using the Steinberg classification system, 39 hips (21%) were in Stage II; 45 hips (25%) were in Stage II; 77 hips (42%) were in Stage IV; and 23 hips (12%) were in Stage V. Of the 184 hips treated, 101 (54%) remained stable postoperatively, whereas 69 (38%) had progression, and 14 hips (8%) were converted to total hip arthroplasty. Of the 69 hips that had progression, 44 (64%) did not progress until 6 to 10 years after the procedure, whereas 25 (36%) progressed within the first 5 years postoperatively. The best results were obtained in patients with Stage II osteonecrosis in whom 95% of the hips did not progress postoperatively. In contrast, only 39% of the hips in patients with Stage V osteonecrosis remained stable. Preoperative and postoperative clinical evaluation using the Harris hip score showed an increase from 85 to 96 points in hips with Stage II disease; from 74 to 91 points in hips with Stage III disease; from 69 to 85 points in hips with Stage IV disease; and from 61 to 76 in hips with Stage V disease. The current results show that the vascularized fibular graft is an excellent procedure for the precollapse stages and a valuable alternative for patients with Stages III, IV, and V of the disease.
Clin Orthop 2001 May;(386):114-9
Long-term results of free vascularized fibular grafting for femoral head necrosis.
Judet H, Gilbert A.
Clinic Jouvenet, Institut de la Main, Paris, France.
The current authors report on the long-term results of free vascularized fibula transplantation for the treatment of idiopathic femoral head necrosis. Briefly, the technique introduced by the authors in 1978 involves the excision of the necrosed bone and its replacement by autologous cancellous bone taken from the iliac crest. The contralateral fibula with its nutrient vessels is introduced through the head and neck of the femur and the vessels are anastomosed microsurgically to the anterior circumflex artery and vein. The current study assesses 60 patients (68 hips) operated on from 1978 to 1985 with an average followup of 18 years (range, 15-22 years). The overall results were good in 52% of the patients. In relation to the stage of necrosis according to the classification system of Marcus et al, good results were achieved in 80% of the patients with Stages II and III disease. In relation to patient age, good results were obtained in 80% of the patients operated on before the age of 40 years. The long-term results indicate that the method of free vascularized fibula transplantation used by the authors is a valuable method for the treatment of idiopathic osteonecrosis of the femoral head for patients younger than 40 years of age with Stage II or III necrosis.
Clin Orthop 2001 May;(386):106-13
Treatment of osteonecrosis in the hip of pediatric patients by free vascularized fibular graft.
Dean GS, Kime RC, Fitch RD, Gunneson E, Urbaniak JR.
Duke University Medical Center, Division of Orthopaedic Surgery, Durham, NC 27710, USA.
The purpose of the current study was to review the demographics and etiologies of symptomatic femoral head osteonecrosis in the pediatric and adolescent population and to assess the results of treatment using free vascularized fibular grafting. A group of patients with femoral head osteonecrosis who were treated with free vascularized fibular grafting was reviewed. Patients who were studied were 18 years of age or younger at the time of surgery. Records were examined for demographic data, etiology of osteonecrosis, stage of the disease at time of surgery, and results of treatment including preoperative and postoperative Harris hip scores. Eighty-two pediatric and adolescent patients with osteonecrosis of the femoral head underwent 90 free vascularized fibular grafting procedures. Fifty patients (54 hips) who have been followed up at least 2 or more years (average, 4.3 years) constituted the study group. At the last followup, total hip arthroplasty was performed in seven hips (seven patients) and hip fusion was performed in one hip (one patient). The average Harris hip scores in patients who did not undergo total hip arthroplasty improved from a preoperative average of 55.3 points to 90.2 points at the latest followup. Treatment of patients with osteonecrosis with free vascularized fibular grafting resulted in a lower rate of conversion to total hip arthroplasty or fusion (16%) in pediatric and adolescent patients when compared with conversion to total hip arthroplasty in adults (25%). The quality of life as evidenced by the increased Harris hip scores was improved significantly in this group of pediatric and adolescent patients.
Osteoporose ( Osteoporosis ) em Transplantados Renais
Osteoporose é um achado comum em pacientes submetidos a transplante renal, devido, principalmente, ao uso de corticosteróides. Mesmo após o advento da ciclosporina, onde as doses de prednisona puderam ser diminuídas, a diminuição da densidade óssea é comum, com um decréscimo acentuado, principalmente, nos primeiros 6 meses após a cirurgia [1,2] . Tal fato também é relatado em outros transplantes [5,6]. Além disso, a própria patologia renal já se encarregara de afetar negativamente a saúde óssea, com acumulação de diversos elementos no tecido ósseo, o uso prévio corticosteróides, problemas nas concentrações de cálcio, fósforo, aumento da reabsorção/diminuição da formação óssea, etc. [2,3,4,7,8,9,10,44].
Alguns estudos tem relatado aumento na densidade óssea com drogas tradicionalmente utilizadas para hipercalcemia com insuficiência renal concomitante [27,37,40]. A utilização de Pamidronato e de Alendronato em pacientes em uso crônico de corticosteróides[26,28,31], e também em transplantados [5,29,32] tem sido estudada recentemente para osteoporose.
Recentes estudos relacionando um novo corticosteróide ( Deflazacort ) com menos efeitos colaterais tem sido desenvolvidos também para utilização em transplantes, principalmente em crianças [39,41,42,43]. Talvez em um futuro próximo ele possa vir a ser utilizado em larga escala .
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[18] - Deo S, Gibbons CL, Emerton M, Simpson A - "Total hip replacements in renal transplant patients" J Bone Joint Surg Br 1995 Mar 77 (2) : pp 299-302 ;
[19] - Devlin VJ, Einhorn TA, Gordon SL - "Total hip arthroplasty after renal transplantation. Long-term follow up study and assessment of metabolic bone status" J Arthroplasty 1988 ; 3 (3) : pp 205-13 ;
[20] - Rombouts JJ, Dirson Y, Squifflet JP - "Aseptic necrosis of the femoral head following renal transplantation : assessment of a 25-year experience " Acta Orthop Belg 1992 ; 58 (4) : pp 373-87 ;
[21] - Jacobs JJ, Skipor AK, Patterson LM "Metal release in patients who have had a primary total hip arthroplasty. A prospective, controlled, longitudinal study" J Bone Joint Surg Am 1998 Oct ; 80 (10) : pp 1447-58 ;
[22] - Betts F, Wright T, Salvati EA "Cobalt-alloy metal debris in periarticular from total hip revision arthroplasties. Metal contents and associated histologic findings" Clin Orthop 1992 Mar ; (276) : pp 75-82 ;
[23] - Watts NB - "Clinical utility of biochemical markers of bone remodeling" Clin Chem 1999 Aug ; 45 (8pt2) : pp 1359-68 ;
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[26] - Saag KG, Emkey R, Schnitzer TJ - "Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis" N Engl J Med 1998 July ; vol 339 No 5 : pp 292-99 ;
[27] - Machado CE, Flombaum C "Segurança no uso de pamidronato em pacientes com insuficiência renal e hipercalcemia " Oncologia Atual 1993 vol 3 No 6 : pp 254-62 ;
[28] - Gallagher SJ, Fenner JAK, Anderson K "Intravenous pamidronate in the treatment of osteoporosis associated with corticosteroid dependent lung disease : na open pilot study" Thorax 1992 ; 47 : pp 932-936 ;
[29] - Reeves HL, Francis RM, Manas DM - "Intravenous bisphosphonate prevents syntomatic osteoporotic vertebral collapse in patients after liver transplantation" Liver Transpl Surg 1998 Sep ; 4 (5) : pp 404-9 ;
[30] - Adami S, Zamberlan N "Adverse effects of bisphosphonates. A comparative review" Drug Saf 1996 Mar ; 14 (3) : pp 158-70 ;
[31] - Landman JO, Hamdy NA, Papadoulos SE "Skeletal metabolism in patients with osteoporosis after discontinuation of long-term treatment with oral pamidronate" J Clin Endocrinol Metabol 1995 Dec ; 80 (12) : 3465-8 ;
[32] - Moe SM "The treatment of steroid-induced bone loss in transplantation" Curr Opin Neprol hypertens 1997 Nov ; 6 (6) : pp 544-9 ;
[33] - Machado ACM, Hannon R, Fastell R "Monitoring Alendronate therapy for osteoporosis" J Bone Min Research 1999 Apr ; vol 14 No 4 : pp 602 ;
[34] - Cosman F, Nieves J, Wollfert L "Alendronate does not block the anabolic effect of PTH in postmenopausal osteoporotic women" J Bone Min Research 1998 vol 13 No 6 : pp 1051 ;
[35] - Kress BC, Mizrahi IA, Armour KW "Use of Bone Alkaline Phosphatase to monitor Alendronate therapy in individual postmenopausal osteoporotic women" Clin Chem 1999 ; 45 : pp 109-1017 ;
[36] - Lane NE, Sanches S, Modin GW "Parathyroid Hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial" J Clin Invest 1998 Oct 15 ; 102 (8) : pp 1627-33 ;
[37] - Davenport A, Goel S, Mackenzie JC "Treatment of hypercalcemia with pamidronate in patients with end stage renal failure" Scand J Urol Nephrol 1993 ; 27 (4) : pp 447-51 ;
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MAIS SITES INTERESSANTES:
http://www.reumatologia.cjb.net
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http://www.med.jhu.edu/avncenter
ESTE SITE É DO CENTER FOR OSTEONECROSIS RESEARCH AND EDUCATION, UNIVERSIDADE JOHN HOPKINS - USA;
http://members.aol.com/MarieS1520/2bkn.html
ESTE SITE É DA AVN INTERNATIONAL SUPPORT GROUP - USA. .SITE MARAVILHOSO, COMPREENDENDO VÁRIOS ASPECTOS DE INTERESSE AOS PORTADORES DE DOENCAS MÚSCULO-ESQUELÉTICAS;
http://www.totallyhip.org
ESTE SITE É DA TOTALLY HIP REPLACEMENT SUPPORT GROUP - USA, É DEDICADO ÀQUELAS PESSOAS QUE TIVERAM QUE COLOCAR PRÓTESE NOS QUADRIS;
http://www.kidney.org
ESTE SITE É DO NATIONAL KIDNEY FOUNDATION; Este site é dedicado a transplantes, o presidente honorário é o Larry Hagman, do seriado Dallas ( ele fez transplante hepático )
http://www.onelist.com/community/osteonecrosis
ESTE SITE É PARA AQUELAS PESSOAS QUE NECESSITAM DE INFORMACÕES SOBRE OSTEONECROSE ASSEPTICA, SUPORTE EMOCIONAL, ETC. EU MESMO PERTENCO A ELE.;
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