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Originally published as JCO Early Release 10.1200/JCO.2005.11.676 on June 13 2005 © 2005 American Society of Clinical Oncology. Avascular Necrosis of Femoral and/or Humeral Heads in Multiple Myeloma: Results of a Prospective Study of Patients Treated With Dexamethasone-Based Regimens and High-Dose ChemotherapyFrom the Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR Address reprint requests to Elias Anaissie, MD, Division of Supportive Care, The Myeloma Institute for Research and Therapy, The University of Arkansas for Medical Sciences, 4301 W Markham St, Slot 776, Little Rock, AR 72205; e-mail: anaissieelias{at}uams.edu
PURPOSE: To assess the prevalence, time of onset, risk factors, and outcome of avascular necrosis (AVN) of bone in patients with multiple myeloma undergoing antineoplastic therapy. PATIENTS AND METHODS: A total of 553 consecutive assessable patients were enrolled onto a treatment protocol consisting of dexamethasone-containing induction chemotherapy, autologous stem-cell transplantation, consolidation chemotherapy, and maintenance with interferon alfa. Patients were randomly assigned to receive thalidomide (269 patients) or no thalidomide (284 patients) throughout the study period. RESULTS: With a median follow-up of 33 months (range, 5 to 114 months), AVN of the femoral head(s) developed in 49 patients (9%). Median time to onset of AVN was 12 months (range, 2 to 41 months). Three risk factors for AVN were identified by multivariate analysis: cumulative dexamethasone dose (odds ratio [OR], 1.028; 95% CI, 1.012 to 1.044; P = .0006 [per 40 mg dexamethasone]), male sex (OR, 0.390; 95% CI, 0.192 to 0.790; P = .009), and younger age (OR, 0.961; 95% CI, 0.934 to 0.991 per year; P = .0122). Thalidomide-treated patients had a prevalence of AVN similar to that of the control group (8% v 10%, respectively; P = .58). AVN-related pain and limited range of motion of the affected joint were present in only nine and four patients, respectively, and four patients underwent hip replacement because of AVN. Fluorine-18 fluorodeoxyglucose positron emission tomography failed to detect abnormal uptake in the AVN-affected bones. CONCLUSION: AVN is a rare and usually asymptomatic complication during myeloma therapy. Cumulative dexamethasone dose, male sex, and younger age, but not thalidomide, increase the risk of AVN.
Avascular necrosis (AVN) of bone, also called ischemic or aseptic necrosis, is thought to be caused by a compromised blood supply. Most occurrences are secondary to trauma (fractures and dislocations), but may also result from glucocorticoid therapy, radiation therapy, alcoholism, connective tissue diseases, or sickle cell anemia.1,2 The condition may be debilitating because of severe pain and limited range of motion of the affected joint, requiring joint replacement in some patients. The diagnosis is primarily based on the findings of magnetic resonance imaging (MRI).3 In cancer patients, corticosteroid therapy is considered the most important predisposing factor for AVN, when given for the treatment of the underlying disease4-11 or for control of graft-versus-host disease (GVHD),4-8 nausea and vomiting,12 or retinoic acid syndrome.13 Corticosteroids reduce blood flow to the affected bone14 and induce apoptosis of osteoblasts and osteocytes in experimental models of AVN.15-17 The prevalence, time to onset, risk factors, and outcome of AVN in cancer patients undergoing intensive antineoplastic therapy, including dexamethasone-containing chemotherapy and autologous stem-cell transplantation (ASCT) are not well defined. The aim of this study was to assess these variables in myeloma patients undergoing intensive therapy including ASCT. Secondary aims included the evaluation of the role of thalidomide in the development of AVN (given the antiangiogenic properties of this agent) and the diagnostic role of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) in this complication.
Patients and Treatment A total of 561 patients with previously untreated myeloma participated in study UARK 98-026 (Total Therapy II)18 started in 1998 at the University of Arkansas for Medical Sciences (Little Rock, AR). The treatment protocol consisted of four phases. In the first phase, induction was performed with four cycles of chemotherapy: vincristine 0.5 mg/d on days 1 through 4, doxorubicin 10 mg/m2/d on days 1 to 4, dexamethasone 40 mg orally (PO) days 1 to 4, 9 to 12, 17 to 20; dexamethasone 40 mg PO daily on days 1 through 4, cyclophosphamide 400 mg/m2/d on days 1 to 4, etoposide 40 mg/m2/d on days 1 to 4, and cisplatin 15 mg/m2/d on days 1 to 4 (DCEP); cyclophosphamide 750 mg/m2/d on days 1 through 4, doxorubicin 15 mg/m2/d on days 1 to 4, and dexamethasone 40 mg PO daily on days 1 to 4, and DCEP. All intravenous chemotherapy agents were administered by 24-hour continuous infusion.
In the second phase, tandem ASCT was performed using high-dose melphalan (200 mg/m2, reduced to 140 mg/m2 in patients In the third phase, 1-year consolidation chemotherapy was administered with four cycles of dexamethasone 40 mg PO daily on days 1 through 4, cisplatin 7.5 mg/m2/d on days 1 to 4, doxorubicin 7.5 mg/m2/d on days 1 to 4, cyclophosphamide 300 mg/m2/d on days 1 to 4, and etoposide 30 mg/m2/d on days 1 to 4. All intravenous chemotherapeutic agents were administered by 24-hour continuous infusion. Cycles were repeated every 3 months. In the fourth phase, maintenance therapy was administered with dexamethasone pulsing every month and interferon alfa 3 million units subcutaneously three times a week, indefinitely, if tolerated. At study entry, patients were randomly assigned to receive thalidomide or no thalidomide throughout the study period. The daily dose of thalidomide was 400 mg during the induction phase, 100 mg between transplantations, and 200 mg during the post-transplant consolidation. Thalidomide was given at a dose of 100 mg every other day during the first year of maintenance, and decreased to 50 mg every other day thereafter. Patients were also given intravenous bisphosphonates (pamidronate or zoledronate) at monthly intervals throughout the observation period.
Imaging Studies
Statistical Analysis
Prevalence and Risk Factors Eight of 561 myeloma patients were excluded from analysis because they had AVN before study enrollment. Risk factors for AVN in these eight patients included previous use of corticosteroids (either as treatment for myeloma in the month preceding study enrollment [three patients] or symptomatic therapy for various conditions [five patients]); thus, a total of 553 patients were assessable. The median follow-up was 33 months (range, 5 to 114 months). A diagnosis of AVN was made in 49 (9%) patients, none of whom had received radiation therapy to the AVN-affected bone. AVN developed throughout the phases of the treatment regimen without clustering of occurrences (data not shown). The median time to develop AVN was 12 months (range, 2 to 41 months) after study enrollment. A total of 91 joints were involved, including the femoral head (bilateral in 34 patients [68 joints] and unilateral in 15 patients) and the humeral head in four patients (eight joints). All four patients who had humeral head involvement had concomitant femoral head AVN. Among the 34 patients with bilateral femoral head involvement, AVN was detected simultaneously in both femora in 27 patients (79%), whereas involvement of the contralateral bone was diagnosed 8 months later (range, 3 to 19 months) in the remaining seven patients. Table 1 lists the characteristics of the 49 patients with AVN compared with those of 504 control patients. Most patients with AVN were male, with a male-to-female ratio of 2.7. Three risk factors for AVN were identified by univariate (Table 1) and multivariate analysis (Table 2): higher cumulative dexamethasone dose (odds ratio [OR], 1.028; 95% CI, 1.012 to 1.044; P = .0006 [per 40 mg of dexamethasone]), male sex (OR, 0.390; 95% CI, 0.192 to 0.790; P = .009), and younger age (OR, 0.961; 95% CI, 0.931 to 0.991 per year; P = .0122).
The cumulative dexamethasone dose ranged from 800 to 2,880 mg, with a median cumulative dose to onset of AVN of 1,120 mg. Figure 1 displays the relationship between the actual dexamethasone dose and the predicted probability of AVN. A logistic regression equation predicted that a patient receiving a cumulative dexamethasone dose of 2,880 mg had a 20% chance of developing AVN, a probability that was 4.2-fold higher than that of a patient treated with a cumulative dexamethasone dose of 800 mg. When adjusted for body weight in kilograms, the cumulative dexamethasone dose remained significantly associated with an increased probability of AVN (OR, 1.030; 95% CI, 1.005 to 1.055; P = .0201; Table 1).
A logistic regression equation predicted that a 25-year-old patient had a 24% chance of developing AVN—a probability six-fold higher that that of a 77-year-old patient. Thalidomide therapy, stage of multiple myeloma, body weight, tumor cytogenetics, and BMD were not significantly associated with AVN. Twenty-two of 269 patients (8%) randomly assigned to thalidomide developed AVN, compared with 27 of 284 control patients (10%; P = .58; Table 1).
Clinical Features and Imaging Studies
FDG-PET scan was performed after documentation of AVN in 21 of 49 AVN patients and failed to detect abnormal uptake in the AVN-affected bones (Fig 2). Plain x-rays were diagnostic of AVN in only three of 26 AVN patients who underwent this examination at the time of AVN diagnosis and all four had severe collapse of the femoral head(s) (Fig 2). After the diagnosis of AVN, 39 patients underwent serial follow-up MRI studies, with a median follow-up of 13 months (range, 3 to 45 months). The AVN lesions remained stable in 30 patients (77%), improved in one patient (3%), and worsened in eight patients (20%).
Our study evaluated the prevalence, risk factors, and outcome of AVN in a homogeneous population of 553 adult myeloma patients uniformly treated with dexamethasone-containing chemotherapy regimens and ASCT. Our results indicate that AVN is uncommon in this setting. When present, AVN is usually detected at a median of 12 months after treatment initiation, can be multifocal, most commonly affects the bilateral femoral heads, and remains asymptomatic in most patients. Three risk factors for AVN were identified: larger cumulative dexamethasone dose, male sex, and younger age; osteopenia and thalidomide did not predispose our patients to this complication. That thalidomide was not a risk for AVN is an important and novel finding that stands in contrast to the theoretical concerns raised regarding the potential of thalidomide to increase AVN risk because of its antiangiogenic properties.19 Our findings of a significant association between AVN and younger age is in agreement with the finding of Torii et al,20 who postulated that this relationship may be due to the age-related decrease in the number of glucocorticoid receptors in humans.21,22 Our findings of a lack of association between AVN and osteopenia support those of a previous study in allogeneic bone marrow transplant recipients.4 Our data also confirm the increased incidence of AVN among males, but with a lower male-to-female ratio (2.7:1) than in the general population (8:1).23,24 Whether a pulse corticosteroid schedule, such as the one employed in our study, increases the risk for AVN compared with continuous administration of lower doses remains to be determined. This is unlikely, however, in view of the fact that depot (continuous release) corticosteroid treatment for hay fever has been reported to induce bilateral hip AVN.25 Six major studies evaluated AVN among patients with hematologic cancers (mostly leukemias, lymphomas, and aplastic anemia), but focused almost exclusively on allogeneic bone marrow transplant (BMT) recipients,4-7,20,26 and except for one,4 were retrospective in nature. In contrast, our study was conducted in a homogeneous population with the same underlying disease and therapy, and included the largest number of patients treated with ASCT. The type of transplant (autologous or allogeneic) is relevant to the pathogenesis of AVN. Because of the strong association between AVN and allogeneic BMT, GVHD was thought to be an important risk factor for AVN.4-7,20,26 However, the 9% rate of AVN among our patients treated with corticosteroids and ASCT is comparable to the 2% to 19% described among allogeneic BMT recipients, suggesting that corticosteroid therapy (widely used to suppress GVHD) is the likely risk factor for AVN in the allogeneic setting. Our study has a follow-up of 33 months. It is possible but unlikely that a longer follow-up would have revealed a significantly higher prevalence of AVN. Indeed, AVN is usually diagnosed within 2 years of initiation of steroid treatment in patients with hematologic cancer5,6,20,26 and may even develop after a short course of corticosteroids.27,28 Similar to reports by others,29 most patients with AVN did not develop progressive joint destruction despite continued exposure to corticosteroids. By preventing bone resorption, monthly bisphosphonate prophylaxis could have contributed to the low rate of symptomatic AVN in our series, as suggested by experimental30 and clinical studies.31 However, and in contrast to this protective effect on hip AVN, bisphosphonates recently have been associated with an increasing risk of osteonecrosis of the jaw.32 As previously shown,33 MRI was the most sensitive imaging modality for the early diagnosis of AVN, whereas FDG-PET scan was noncontributory. These imaging studies have been performed as part of our investigational study but are not necessary in practice, unless clinically indicated. Our results suggest that lowering the cumulative dose of corticosteroids should be considered in myeloma patients undergoing intensive dexamethasone-containing antineoplastic therapy and who are at a higher risk for AVN, namely younger males. In addition, patients who develop hip pain should undergo MRI evaluation of the affected joint to rule out bone osteonecrosis. Finally, thalidomide can be added safely to dexamethasone without concerns about increasing the risk for AVN. In conclusion, AVN is a rare and usually asymptomatic complication in patients with multiple myeloma receiving dexamethasone-containing antineoplastic regimens. Cumulative dexamethasone dose, male sex, and younger age, but not thalidomide, increase the risk of AVN.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Assouline-Dayan Y, Chang C, Greenspan A, et al: Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 32:94-124, 2002[Medline] 2. Tektonidou MG, Malagari K, Vlachoyi-annopoulos PG, et al: Asymptomatic avascular necrosis in patients with primary antiphospholipid syndrome in the absence of corticosteroid use: A prospective study by magnetic resonance imaging. Arthritis Rheum 48:732-736, 2003[CrossRef][Medline] 3. Gillespy T III, Genant HK, Helms CA: Magnetic resonance imaging of osteonecrosis. Radiol Clin North Am 24:193-208, 1986[Medline] 4. Tauchmanova L, De Rosa G, Serio B, et al: Avascular necrosis in long-term survivors after allogeneic or autologous stem cell transplantation: A single center experience and a review. Cancer 97:2453-2461, 2003[CrossRef][Medline] 5. Socie G, Cahn JY, Carmelo J, et al: Avascular necrosis of bone after allogeneic bone marrow transplantation: Analysis of risk factors for 4388 patients by the Societe Francaise de Greffe de Moelle (SFGM). Br J Haematol 97:865-870, 1997[CrossRef][Medline] 6. Wiesmann A, Pereira P, Bohm P, et al: Avascular necrosis of bone following allogeneic stem cell transplantation: MR screening and therapeutic options. Bone Marrow Transplant 22:565-569, 1998[CrossRef][Medline] 7. Fink JC, Leisenring WM, Sullivan KM, et al: Avascular necrosis following bone marrow transplantation: A case-control study. Bone 22:67-71, 1998[Medline] 8. Mascarin M, Giavitto M, Zanazzo GA, et al: Avascular necrosis of bone in children undergoing allogeneic bone marrow transplantation. Cancer 68:655-659, 1991[CrossRef][Medline] 9. Thornton MJ, O'Sullivan G, Williams MP, et al: Avascular necrosis of bone following an intensified chemotherapy regimen including high dose steroids. Clin Radiol 52:607-612, 1997[CrossRef][Medline] 10. Hui L, Wiernik PH: Avascular necrosis of bone after adult acute lymphocytic leukemia treatment with methotrexate, vincristine, L-asparaginase, and dexamethasone (MOAD). Am J Hematol 52:184-188, 1996[CrossRef][Medline] 11. Marymont JV, Kaufman EE: Osteonecrosis of bone associated with combination chemotherapy without corticosteroids. Clin Orthop Relat Res 204:150-153, 1986 12. Virik K, Karapetis C, Droufakou S, et al: Avascular necrosis of bone: The hidden risk of glucocorticoids used as antiemetics in cancer chemotherapy. Int J Clin Pract 55:344-345, 2001[Medline] 13. al-Bahar S, Pandita R, Hoffbrand AV: Bilateral osteonecrosis of the head of the femur complicating acute promyelocytic leukemia: A sequel to treatment of retinoic acid syndrome with dexamethasone. Acta Haematol 96:88-91, 1996[Medline]
14. Boss JH, Misselevich I: Osteonecrosis of the femoral head of laboratory animals: The lessons learned from a comparative study of osteonecrosis in man and experimental animals. Vet Pathol 40:345-354, 2003
15. Eberhardt AW, Yeager-Jones A, Blair HC: Regional trabecular bone matrix degeneration and osteocyte death in femora of glucocorticoid- treated rabbits. Endocrinology 142:1333-1340, 2001 16. Weinstein RS, Jilka RL, Parfitt AM, et al: Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids: Potential mechanisms of their deleterious effects on bone. J Clin Invest 102:274-282, 1998[Medline]
17. Weinstein RS, Nicholas RW, Manolagas SC: Apoptosis of osteocytes in glucocorticoid-induced osteonecrosis of the hip. J Clin Endocrinol Metab 85:2907-2912, 2000 18. Barlogie B Jr, Shaughnessy JD: Early results of total therapy II in multiple myeloma: Implications of cytogenetics and FISH. Int J Hematol 76:337-339, 2002 (suppl 1) 19. Smith DW: Is avascular necrosis of the femoral head the result of inhibition of angiogenesis? Med Hypotheses 49:497-500, 1997[CrossRef][Medline] 20. Torii Y, Hasegawa Y, Kubo T, et al: Osteonecrosis of the femoral head after allogeneic bone marrow transplantation. Clin Orthop Relat Res 382:124-132, 2001 21. Grasso G, Lodi L, Lupo C, et al: Glucocorticoid receptors in human peripheral blood mononuclear cells in relation to age and to sport activity. Life Sci 61:301-308, 1997[CrossRef][Medline] 22. Armanini D, Scali M, Vittadello G, et al: Corticosteroid receptors and aging. J Steroid Biochem Mol Biol 45:191-194, 1993[CrossRef][Medline] 23. Mazieres B: Osteonecrosis, in Klippel J, Dieppe P (eds): Rheumatology. London, United Kingdom, Mosby, 1998, pp1-47 24. Calandriello B, Grassi G: Idiopathic osteonecrosis of the femoral head: Epidemiological and aetiological factors. Ital J Orthop Traumatol 8:9-18, 1982
25. Nasser SM, Ewan PW: Lesson of the week: Depot corticosteroid treatment for hay fever causing avascular necrosis of both hips. BMJ 322:1589-1591, 2001 26. Enright H, Haake R, Weisdorf D: Avascular necrosis of bone: A common serious complication of allogeneic bone marrow transplantation. Am J Med 89:733-738, 1990[CrossRef][Medline] 27. O'Brien TJ, Mack GR: Multifocal osteonecrosis after short-term high-dose corticosteroid therapy: A case report. Clin Orthop Relat Res 176-179, 1992 28. Taylor LJ: Multifocal avascular necrosis after short-term high-dose steroid therapy: A report of three cases. J Bone Joint Surg Br 66:431-433, 1984 29. Ribeiro RC, Fletcher BD, Kennedy W, et al: Magnetic resonance imaging detection of avascular necrosis of the bone in children receiving intensive prednisone therapy for acute lymphoblastic leukemia or non-Hodgkin lymphoma. Leukemia 15:891-897, 2001[CrossRef][Medline] 30. Little DG, Peat RA, McEvoy A, et al: Zoledronic acid treatment results in retention of femoral head structure after traumatic osteonecrosis in young Wistar rats. J Bone Miner Res 18:2016-2022, 2003[CrossRef][Medline] 31. Agarwala S, Sule A, Pai BU, et al: Alendronate in the treatment of avascular necrosis of the hip. Rheumatology (Oxford) 41:346-347, 2002
32. Migliorati CA: Bisphosphonates and oral cavity avascular bone necrosis. J Clin Oncol 21:4253-4254, 2003
33. Mitchell MD, Kundel HL, Steinberg ME, et al: Avascular necrosis of the hip: Comparison of MR, CT, and scintigraphy. AJR Am J Roentgenol 147:67-71, 1986 Submitted January 10, 2005; accepted March 24, 2005. This article has been cited by other articles:
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
70 years of age or with a creatinine level > 3.0 mg/dL) as a conditioning regimen. 
). (B) Coronal T1-weighted magnetic resonance image shows decreased signal within LFH (
