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The Journal of Bone and Joint Surgery (American) 79:1726-30 (1997)
© 1997 The Journal of Bone and Joint Surgery, Inc.

Case Report

Bone-Marrow Transplantation in Sickle-Cell Disease. Effect on Osteonecrosis: A Case Report with a Four-Year Follow-up*

P. HERNIGOU, M.D.{dagger}, F. BERNAUDIN, M.D.{dagger}, P. REINERT, M.D.{dagger}, M. KUENTZ, M.D.{dagger} and J. P. VERNANT, M.D.{dagger}, CRETEIL, FRANCE

Investigation performed at Hôpital Henri Mondor, Creteil


   Introduction
Top
 Introduction
Case Report
 Discussion
 References
 
Sickle-cell disease involves both hematological and osseous abnormalities because it affects the two major functions of bone tissue: hematopoiesis and osteogenesis. Symptoms include dactylitis, painful vaso-occlusive crises, splenic reticuloendothelial dysfunction (also called functional asplenia), and multiple-organ damage and failure in children and adults. It is probably the most common cause of avascular necrosis worldwide5; in series of adult patients, the reported prevalence of involvement of the femoral head was 30 per cent (ninety-five of 320 hips)13 and that of the humeral head was 48 per cent (106 of 220 shoulders)11.

Osteopetrosis is another disease that is associated with both hematological and osseous abnormalities. Walker, in the mid-1970s, performed a series of experiments on osteopetrotic mice and found that it was possible to correct both types of abnormalities simultaneously with use of a bone-marrow allograft26-29.

The use of bone-marrow transplantation for the treatment of sickle-cell disease was reported in 1984 by Johnson et al., who described the case of an eight-year-old girl who had acute myeloblastic leukemia and sickle-cell anemia15. The hematopoietic system of the patient was converted to one showing sickle-cell trait, which was identical to that of the donor. Bone-marrow transplantation represents an approach for the treatment of severe sickle-cell disease and is the only curative therapy for this hemoglobinopathy to our knowledge. This new therapeutic approach should be considered for only a small proportion of patients because of its associated risks and because of uncertainty regarding the long-term outcome. From 1984 to 1993, at least forty-seven patients had a bone-marrow transplantation for the treatment of sickle-cell disease14,24. Correction of anemia and functional asplenia was observed6,7. It remains to be determined if such treatment reverses other abnormalities such as osteonecrosis, which frequently is associated with sickle-cell disease.

We report the case of a patient who had osteonecrosis of the humeral head secondary to sickle-cell disease. Treatment with a bone-marrow allograft led to a favorable outcome and a tendency toward normalization of the bone marrow after a follow-up of four years. This patient was previously described in a preliminary report10 that was published in 1994. The four-year follow-up of this patient confirms the initial findings of the preliminary report. However, there is still uncertainty regarding the long-term outcome of this procedure.


   Case Report
Top
 Introduction
 Case Report
Discussion
 References
 
A thirteen-year-old boy had severely symptomatic sickle-cell disease that was associated with severe hemolytic anemia as well as frequent (twice monthly) severe vaso-occlusive events that necessitated the use of morphine. The diagnosis of homozygous (SS) sickle-cell disease had been made on the basis of hemoglobin electrophoresis when the patient was one year old. Osteonecrosis of the left humeral head had been diagnosed when the patient was twelve years old (Fig. 1). At the time of presentation, the patient had impaired function and constant moderate pain that limited his participation in recreational and sports activities but did not interfere with sleep. The patient was able to raise the hand to the levels of the waist, the xiphoid process, and the neck but not to the top of the head. He had only 10 degrees of external rotation, 130 degrees of forward elevation, and 120 degrees of lateral abduction. The strength of forward elevation was limited to grade 4 (of 5) on manual muscle-testing. He had no other abnormalities of the bones or the joints. Magnetic resonance imaging of the left shoulder showed low signal intensity in the epiphysis (Fig. 2) instead of the high signal intensity that normally is observed as a result of the high fat content of the epiphyses of individuals of the same age who do not have sickle-cell disease. Because of the severity and frequency of the vaso-occlusive crises despite the use of transfusion therapy, and in view of the availability of an HLA-identical sibling, bone-marrow transplantation was proposed to the patient and his family.



Fig. 1 Radiograph made before the bone-marrow transplantation, showing osteonecrosis and evident collapse of the humeral head (arrow). (Reprinted, with permission, from: Hernigou, P., and Bernaudin, F.: Bone marrow transplantation [BMT] and correction of bone abnormalities associated with sickle cell disease [SCD]. Rev. chir. orthop., 80: 138–143, 1994.)

 


 Fig. 2 T1-weighted magnetic resonance imaging scan of the shoulder, showing low signal intensity in the entire epiphysis. In children and adolescents who have sickle-cell disease22, the volume of red hematopoietic marrow is expanded secondary to hemolytic anemia. Thus, fatty replacement of the marrow in the epiphysis does not occur. This explains why children and adults who have sickle-cell disease have abnormal bone marrow with exuberant hematopoiesis. Once the disease becomes severe, the medullary cavity and the epiphyses continue to have low signal intensity23 on T1-weighted magnetic resonance imaging scans—that is, they have a gray or black appearance rather than the usual white appearance that is due to high fat content. (Reprinted, with permission, from: Hernigou, P., and Bernaudin, F: Bone marrow transplantation [BMT] and correction of bone abnormalities associated with sickle cell disease [SCD]. Rev. chir.orthop., 80: 138–143, 1994.)

 
The transplantation was performed in February 1992 after administration of a conditioning regimen of busulfan (sixteen milligrams per kilogram of body weight), cyclophosphamide (200 milligrams per kilogram of body weight), and total lymphoid irradiation in order to suppress the immune response and to eliminate hematopoietic precursors. The bone-marrow donor was an HLA-identical sibling for whom a mixed-leukocyte culture was non-reactive; the donor was heterozygous for sickle-cell anemia. The marrow was infused intravenously for one-half hour, beginning forty-eight hours after the last infusion of cyclophosphamide. The dose of nucleated marrow cells that was infused was 2 x 108 per kilogram of body weight. After the transplantation, prophylaxis against graft-versus-host disease consisted of methotrexate (fifteen milligrams per square meter on the first day and ten milligrams per square meter on the third and sixth days). Administration of cyclosporin A had been initiated on the day before the transplantation and was continued for six months; the dose was adjusted to maintain an effective cyclosporinemia between 150 and 250 nanograms per milliliter during this period. The patient was isolated in a laminar airflow room for five weeks. He was maintained on a low-bacterial diet and was managed with oral administration of non-absorbable antibiotics, including nifuroxazide (800 milligrams per day), gentamicin (eighty milligrams per day), neomycin (one gram per day), and colistin sulfate (150 milligrams per day). Antiviral prophylaxis (acyclovir; five milligrams per kilogram of body weight every eight hours) and standard immunoglobulins were administered intravenously as described previously2. Blood products that were given before and after the transplantation of bone marrow were irradiated. In order to avoid vaso-occlusive crises during the first six weeks after the operation, care was taken to maintain the hemoglobin-S level at less than 30 per cent of the total hemoglobin with use of packed red blood cells from patients who had normal levels of hemoglobin.

Engraftment and chimerism were assessed with use of cytogenetic and enzymatic analysis and by determination of the hemoglobin pattern and the red blood cell phenotype. Engraftment was successful; graft-versus-host disease did not occur; and full, stable, total donor chimerism was observed, with the patient having the same hemoglobin-S level as the heterozygous donor.

Three months after the transplantation, radiographs showed rapid reconstruction of the left proximal humeral epiphysis (Fig. 3) and T1-weighted magnetic resonance images demonstrated a tendency toward normalization of the marrow signal in that region (Fig. 4). The reappearance of a high-intensity signal on T1-weighted images reflected the high fat content of the proximal humeral epiphysis. The pain in the shoulder had decreased and forward elevation had increased to 150 degrees, but there had been no improvement in external rotation, lateral abduction, or strength.



Fig. 3 Radiograph of the shoulder, made three months after the transplantation, showing the reconstruction of the proximal humeral epiphysis. (Reprinted, with permission, from: Hernigou, P., and Bernaudin, F.: Bone marrow transplantation [BMT] and correction of bone abnormalities associated with sickle cell disease [SCD]. Rev. chir. orthop., 80: 138–143, 1994.)

 


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  		Fig. 4 T1-weighted magnetic resonance imaging scan of the shoulder, made three months after the transplantation, showing high signal intensity in the proximal humeral epiphysis (arrow).

 
Four years later, the patient was well and was no longer receiving treatment. A magnetic resonance imaging scan confirmed the tendency toward normalization of the marrow signal in the proximal part of the humerus (Fig. 5). The patient was without pain most of the time and had only slight pain during recreational and sports activities. External rotation remained limited to 10 degrees, but forward elevation had increased to 170 degrees and lateral abduction had increased to 160 degrees. The strength of forward elevation was grade 5.



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  		Fig. 5 Coronal magnetic resonance imaging scan of the shoulder, made four years after the transplantation, showing regions of high signal intensity (arrows) that indicate the high fat content of the proximal humeral epiphysis.

 


   Discussion
Top
 Introduction
 Case Report
 Discussion
References
 
To the best of our knowledge, Johnson et al.15 were the first to show that hemolytic anemia secondary to sickle-cell disease could be corrected by transplantation of bone marrow. Transplantation of bone marrow leads to a regression of the hematological manifestations of sickle-cell disease, including hemolytic anemia25. This explains the tendency toward normalization of the marrow signal as seen on magnetic resonance imaging scans made after the transplantation. The decrease in low-intensity signal and the appearance of high-intensity signal corresponded to the fatty replacement of the normal hematopoietic tissue in the epiphysis, a phenomenon that begins several years earlier in normal children.

Since the report by Johnson et al.15, bone-marrow transplantation has proved to be successful for the treatment of sickle-cell disease because of the lifelong conversion of the bone marrow, which results in the correction of anemia and functional asplenia. Engraftment was successful in forty-one of the forty-seven patients who had a bone-marrow transplantation before 199314,24, and the effectiveness of this treatment has continued to be evaluated1,8,17,30. The possibility that bone-marrow transplantation may have an effect on osteonecrosis was reported by two of us (P. H. and F. B.) in a preliminary study of two patients10. One of the patients lived in Africa and was lost to follow-up after six months; the second patient is the basis of the present report.

A surprising finding in the present study was the very rapid reconstruction of the humeral head, which was observed three months after the bone-marrow transplantation. This finding was especially notable in view of the fact that no radiographic improvement had been observed during the entire year preceding the transplantation. It is possible that the effect of the bone-marrow transplantation may explain the rapidity of the reconstruction of the epiphysis. The underlying mechanisms are unclear, but several hypotheses have been proposed. A mechanistic concept recently has been suggested for the reversible functional asplenia in children7,21. This concept is based on the fact that blood that has a high viscosity because of the presence of sickled cells bypasses the reticuloendothelial tissue of the spleen through intrasplenic shunts31. This functional asplenia may reverse after a transfusion of packed red blood cells in young patients who have a palpable spleen or after a bone-marrow transplantation. As there is a structural and functional similarity between the circulation in the spleen9 and that in the bone marrow31, it is reasonable to suggest that the same mechanistic concept that is applied to the spleen can be applied to the bone marrow. Thus, it is possible that the effect of the bone-marrow transplantation resulted in the rapid reconstruction of the epiphysis. The normal hematopoietic marrow31 of the epiphysis has a rich sinusoidal system that is fed by several epiphyseal vessels. However, blood flow in the sinusoidal system is sluggish and the biochemical environment facilitates the sickling process. As blood that contains sickled cells has a high viscosity, this produces a relative obstruction to blood flow at the capillary level. Moreover, the arteriovenous anastomoses that are believed to be present in bone31 may divert the blood flow with a resultant bypassing of the blood flow, producing an apparent functional hypovascularization. However, when sickled red blood cells are replaced with normal red blood cells after the transplantation of bone marrow, the epiphyseal circulation may be restored. The restoration of circulation may allow rapid reconstruction of the bone marrow.

Another possible explanation is that, after transplantation of bone marrow, the increased blood flow that is due to the decrease in blood viscosity may lead to an increase in capillary filtration. This may increase the exposure of osteoblasts and their precursor cells to growth factor, which could lead to the formation of bone3,16 in patients who are known to have a high number of osteoprogenitor cells in the marrow.

In patients who have sickle-cell disease, the physiological balance between the two main functions of bone tissue (hematopoiesis and osteogenesis) is altered. Hematopoiesis is increased, and abnormalities of the microvascular blood supply in the areas of hematopoiesis may result in osteonecrosis. The case of our patient suggests that the transplantation of hematopoietic stem cells for the purpose of correcting hemolytic anemia also might normalize the bone marrow in patients who have sickle-cell disease. The risk of additional epiphyseal necrosis in such patients then is decreased because the cells do not sickle. This is important because avascular necrosis is a frequent, chronic complication of sickle-cell disease12,20 that can be debilitating when there is involvement of the femoral head13. The treatment of avascular necrosis in patients who have sickle-cell disease is difficult in view of the high rate of complications associated with joint replacement.

Kaplan et al.18, in 1988, described the case of a patient in whom hematopoietic and osteogenic function normalized after the treatment of infantile malignant osteopetrosis with bone-marrow transplantation. Our study seems to demonstrate that the presence of hematopoietic tissue in the epiphysis of a patient who has sickle-cell disease is reversible after bone-marrow transplantation. This finding is of critical importance in the establishment of a curative role for bone-marrow transplantation in the treatment of sickle-cell disease. Nevertheless, it should be remembered that bone-marrow transplantation rarely is indicated for patients who have this disease and is not currently offered to patients who have only osteonecrosis. As bone-marrow transplantation is associated with the risks of mortality and graft-versus-host disease, and as there is uncertainty regarding the long-term outcome of the procedure, we believe that this treatment should be offered only to children who have severe symptomatic sickle-cell anemia and who have an HLA-compatible sibling. This may represent as few as 1 to 2 per cent of the total population of children who have sickle-cell anemia19. Furthermore, four years represents a relatively short period of follow-up for such a treatment, and the long-term outcome of this procedure is still uncertain.


   Footnotes
 
*No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. No funds were received in support of this study.

{dagger}Hôpital Henri Mondor, 51, avenue du Mal de Lattre Tassigny, 94010 Creteil CEDEX, France.


   References
Top
 Introduction
 Case Report
 Discussion
 References
 

  1. Abboud, M. R.; Jackson, S. M.; Barredo, J.; Beatty, J.; and Laver, J.: Bone marrow transplantation for sickle cell anemia. Am. J. Pediat. Hematol./Oncol., 16: 86-89, 1994.[Medline]

  2. Bernaudin, F.; Souillet, G.; Vannier, J. P.; Plouvier, E.; Lemerle, S.; Michel, G.; Bordigoni, P.; Lutz, P.; and Kuentz, M.: Bone marrow transplantation (BMT) in 14 children with severe sickle cell disease (SCD): the French experience. Bone Marrow Transplant., 12 (Supplement 1): 118-121, 1993.

  3. Bronk, J. T.; Meadows, T. H.; and Kelly, P. J.: The relationship of increased capillary filtration and bone formation. Clin. Orthop., 293: 338-345, 1993.

  4. Charache, S.: Experimental therapy of sickle cell disease. Use of hydroxyurea. Am. J. Pediat. Hematol./Oncol., 16: 62-66, 1994.[Medline]

  5. David, H. G.; Bridgman, S. A.; Davies, S. C.; Hine, A. L.; and Emery, R. J. H.: The shoulder in sickle-cell disease. J. Bone and Joint Surg., 75-B(4): 538-545, 1993.

  6. Ferster, A.; De Valck, C.; Azzi, N.; Fondu, P.; Toppet, M.; and Sariban, E.: Bone marrow transplantation for severe sickle cell anaemia. British J. Haematol., 80: 102-105, 1992.[Medline]

  7. Ferster, A.; Bujan, W.; Corazza, F.; Devalck, C.; Fondu, P.; Toppet, M.; Verhas, M.; and Sariban, E.: Bone marrow transplantation corrects the splenic reticuloendothelial dysfunction in sickle cell anemia. Blood, 81: 1102-1105, 1993.[Abstract/Free Full Text]

  8. Ferster, A.; Corazza, F.; Vertongen, F.; Bujan, W.; Devalck, C.; Fondu, P.; Cochaux, P.; Lambermont, M.; Khaladji, Z.; and Sariban, E.: Transplanted sickle-cell disease patients with autologous bone marrow recovery after graft failure develop increased levels of fetal haemoglobin which corrects disease severity. British J. Haematol., 90: 804-808, 1995.[Medline]

  9. Garnett, E. S.; Goddard, B. A.; Markby, D.; and Webber, C. E.: The spleen as an arteriovenous shunt. Lancet, 1: 386-388, 1969.[Medline]

  10. Hernigou, P., and Bernaudin, F.: Bone marrow transplantation (BMT) and correction of bone abnormalities associated with sickle cell disease (SCD). Rev. chir. orthop., 80: 138-143, 1994.

  11. Hernigou, P.; Allain, J.; Bachir, D.; and Galacteros, F.: Osteonecrosis of the proximal humerus in sickle-cell disease [abstract]. Rev. rhumat. English Ed., 62: 693, 1995.

  12. Hernigou, P.; Galacteros, F.; Bachir, D.; and Goutallier, D.: Étude de 164 nécroses épiphysaires (hanches, épaules, genoux). Rev. rhumat., 56: 869-875, 1989.

  13. Hernigou, P.; Galacteros, F.; Bachir, D.; and Goutallier, D.: Deformities of the hip in adults who have sickle-cell disease and had avascular necrosis in childhood. A natural history of fifty-two patients. J. Bone and Joint Surg., 73-A: 81-92, Jan. 1991.[Abstract/Free Full Text]

  14. Johnson, F. L.; Mentzer, W. C.; Kalinyak, K. A.; Sullivan, K. M.; and Abboud, M. R.: Bone marrow transplantation for sickle cell disease. The United States experience. Am. J. Pediat. Hematol./Oncol., 16: 22-26, 1994.[Medline]

  15. Johnson, F. L.; Look, A. T.; Gockerman, J.; Ruggiero, M. R.; Dalla-Pozza, L.; and Billings, F. T. III: Bone marrow transplantation in a patient with sickle-cell anemia. New England J. Med., 311: 780-783, 1984.[Medline]

  16. Johnson, M. W.: Behavior of fluid in stressed bone and cellular stimulation. Calcif. Tissue Internat., 36 (Supplement 1): 572-576, 1984.

  17. Kalinyak, K. A.; Morris, C.; Ball, W. S.; Ris, M. D.; Harris, R.; and Rucknagel, D.: Bone marrow transplantation in a young child with sickle cell anemia. Am. J. Hematol., 48: 256-261, 1995.[Medline]

  18. Kaplan, F. S.; August, C. S.; Fallon, M. D.; Dalinka, M.; Axel, L.; and Haddad, J. G.: Successful treatment of infantile malignant osteopetrosis by bone-marrow transplantation. A case report. J. Bone and Joint Surg., 70-A: 617-623, April 1988.[Free Full Text]

  19. Mentzer, W. C.; Heller, S.; Pearle, P. R.; Hackney, E.; and Vichinsky, E.: Availability of related donors for bone marrow transplantation in sickle cell anemia. Am. J. Pediat. Hematol./Oncol., 16: 27-29, 1994.[Medline]

  20. Milner, P. F.; Kraus, A. P.; Sebes, J. I.; Sleeper, L. A.; Dukes, K. A.; Embury, S. H.; Bellevue, R.; Koshy, M.; Moohr, J. W.; and Smith, J.: Osteonecrosis of the humeral head in sickle cell disease. Clin. Orthop., 289: 136-143, 1993.

  21. Pearson, H. A.; Spencer, R. P.; and Cornelius, E. A.: Functional asplenia in sickle-cell anemia. New England J. Med., 281: 923-926, 1969.

  22. Rao, V. M.; Fishman, M.; Mitchell, D. G.; Steiner, R. M.; Ballas, S. K.; Axel, L.; Dalinka, M. K.; Gefter, W.; and Kressel, H. Y.: Painful sickle cell crisis: bone marrow patterns observed with MR imaging. Radiology, 161: 211-215, 1986.[Abstract/Free Full Text]

  23. Sebes, J. I.: Diagnostic imaging of bone and joint abnormalities associated with sickle cell hemoglobinopathies. Am. J. Radiol., 152: 1153-1159, 1989.[Free Full Text]

  24. Vermylen, C., and Cornu, G.: Bone marrow transplantation for sickle cell disease. The European experience. Am. J. Pediat. Hematol./Oncol., 16: 18-21, 1994.[Medline]

  25. Vermylen, C.; Cornu, G.; Ferster, A.; Ninane, J.; and Sariban, E.: Bone marrow transplantation in sickle cell disease: the Belgian experience. Bone Marrow Transplant., 12 (Supplement 1): 116-117, 1993.

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  30. Walters, M. C.; Patience, M.; Leisenring, W.; Eckman, J. R.; Scott, J. P.; Mentzer, W. C.; Davies, S. C.; Ohene-Frempong, K.; Bernaudin, F.; Matthews, D. C.; Storb, R.; and Sullivan, K. M.: Bone marrow transplantation for sickle cell disease. New England J. Med., 335: 369-376, 1996.[Abstract/Free Full Text]

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