NDT Advance Access originally published online on April 18, 2007
Nephrology Dialysis Transplantation 2007 22(8):2412; doi:10.1093/ndt/gfm198
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Why does post-transplant osteonecrosis develop?
Correspondence and offprint requests to: Email: alpersoy{at}uludag.edu.trSir,
We read with interest the article by Ekmekci et al. [1], on the association of thrombophilia and osteonecrosis (ON) of the femoral head in renal transplant recipients. We previously reported a case with diffuse ON and severe osteoporosis which was unusual in its presentation in the early post-transplant period, focusing on pre-transplant hormonal changes [2]. Following our report, Dr Weinstein drew our attention to their research supporting glucocorticoid (GC)-induced ON involved in osteocyte apoptosis, by personal communication. They demonstrated that osteoblasts and osteocytes were the direct targets of GC action in vivo, and that excess levels of steroid hormone directly induced apoptosis of these cell types.
Ekmekci et al. [1] reported that factor V Leiden and prothrombin gene mutations might be an important risk factor for the development of ON of the femoral head. They observed no difference in the cumulative doses of GCs and ciclosporin A between the ON and control groups, whereas Celik et al. [3] found that the 3, 6 and 12 month treatments with cumulative GC doses were significantly higher in the ON group and that there was no correlation between ON and genetic mutations of factor V Leiden, prothrombin and 5,10-methylenetetrahydrofolate reductase (MTHFR). Our case had MTHFR C677T heterozygous mutation but not factor V Leiden G1691A and prothrombin G2021A mutations. In the non-transplant population, there are different reports on the relation of genetic mutations predisposing to coagulation and ON [3,4].
A recent hypothesis emphasizes the fact that vascular thrombosis is the major pathogenetic event leading to osteocyte necrosis and eventual collapse of the femoral head in ON [5]. Exogenous and endogenous factors lead to endothelial dysfunction, thrombus formation and ischaemia, finally inducing apoptosis in osteocytes and osteoblasts. Thrombophilia, particularly impaired fibrinolysis, can play a potential role in thrombus formation. Decreased fibrinolytic activity through elevated plasminogen activator inhibitor (PAI)-1 levels can be associated with the subsequent development of ON and transient osteoporosis of the hip [6]. Glueck et al. [7] first ascribed a role to the PAI-1 genotype in association with ON. Ferrari et al. [6] demonstrated a strong association between the 4G/4G genotype of PAI-1 and ON in GC-treated renal transplant recipients. However, a significant correlation of the incidence of ON with PAI-14G/5G or MTHFR C677T polymorphisms was not observed in Japanese renal transplant recipients [8]. Osteocyte apoptosis may be an important mechanism in the GC-induced loss of bone mineral density and microarchitectural deterioration predisposing to fractures. It has been found that bisphosphonates inhibit osteoblast and osteocyte apoptosis induced by GC [9]. Furthermore, impaired osteoblastogenesis and early osteoblast apoptosis may play important roles in the pathogenesis of post-transplant osteoporosis by possible mechanisms such as post-transplant hypophosphataemia, GC usage and pre-existing bone disease [10]. Ekmekci et al. [1] did not report osteoporosis status in their study. Perhaps they could evaluate whether the pre-existing osteoporosis was related to the development of ON and whether biphosphonate or statin usage, if present, affected the outcome in patients with osteoporosis, especially in those with thrombophilia.
ON can be the end result of a process that starts as osteoporosis [2]. Although the aetiologies of post-transplant osteoporosis and ON are multifactorial, there can be a complex pathogenic relationship between both processes. The state of bones in the pre-transplant period, the effect of uraemic milieu, post-transplant medications and other cofactors on haemostatic alterations, and individual genetic differences can determine the outcome. More evidence is needed to better comprehend the role of these parameters for future prevention and treatment of ON.
Conflict of interest statement. None declared.
1Departments of Nephrology, and
2Endocrinology and Metabolism
Uludag University Medical School
Gorukle
Bursa 16059
Turkey
References
- Ekmekci Y, Keven K, Akar N, et al. Thrombophilia and avascular necrosis of femoral head in kidney allograft recipients. Nephrol Dial Transplant (2006) 21:3555–3558.
[Abstract/Free Full Text] - Ersoy A, Kahvecioglu S, Ersoy C, Akdag I, Yurtsever I, Dilek K. Is glucocorticoid-induced osteonecrosis after kidney transplantation related to osteoporosis? Nephrol Dial Transplant (2006) 21:1452–1453.
[Free Full Text] - Celik A, Tekis D, Saglam F, et al. Association of corticosteroids and factor V, prothrombin, and MTHFR gene mutations with avascular osteonecrosis in renal allograft recipients. Transplant Proc (2006) 38:512–516.[CrossRef][Web of Science][Medline]
- Bjorkman A, Svensson PJ, Hillarp A, Burtscher IM, Runow A, Benoni G. Factor V leiden and prothrombin gene mutation: risk factors for osteonecrosis of the femoral head in adults. Clin Orthop Relat Res (2004) 425:168–172.[CrossRef][Medline]
- Kerachian MA, Harvey EJ, Cournoyer D, Chow TY, Seguin C. Avascular necrosis of the femoral head: vascular hypotheses. Endothelium (2006) 13:237–244.[CrossRef][Web of Science][Medline]
- Ferrari P, Schroeder V, Anderson S, et al. Association of plasminogen activator inhibitor-1 genotype with avascular osteonecrosis in steroid-treated renal allograft recipients. Transplantation (2002) 74:1147–1152.[CrossRef][Web of Science][Medline]
- Glueck CJ, Fontaine RN, Gruppo R, et al. The plasminogen activator inhibitor-1 gene, hypofibrinolysis, and osteonecrosis. Clin Orthop Relat Res (1999) 366:133–146.[CrossRef][Medline]
- Asano T, Takahashi KA, Fujioka M, et al. Relationship between postrenal transplant osteonecrosis of the femoral head and gene polymorphisms related to the coagulation and fibrinolytic systems in Japanese subjects. Transplantation (2004) 77:220–225.[Web of Science][Medline]
- Van Staa TP. The pathogenesis, epidemiology and management of glucocorticoid-induced osteoporosis. Calcif Tissue Int (2006) 79:129–137.[CrossRef][Web of Science][Medline]
- Rojas E, Carlini RG, Clesca P, et al. The pathogenesis of osteodystrophy after renal transplantation as detected by early alterations in bone remodeling. Kidney Int (2003) 63:1915–1923.[CrossRef][Web of Science][Medline]
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