Corticosteroid Dose as a Risk Factor for Avascular Necrosis of the Bone after Hematopoietic Cell Transplantation

Article Outline

• Abstract
• Introduction
• Methods
  • Patients
  • Controls
  • Risk Factors
  • Statistical Analysis
• Results
  • Patients
  • Avascular Necrosis
  • Risk Factors
• Discussion
• Acknowledgments
• References
• Copyright

Exposure to corticosteroids increases the risks of avascular necrosis (AVN) of the bone after hematopoietic cell transplantation (HCT). However, whether this effect is dependent on the dose of corticosteroids is not well known. We conducted a case-controlled study, which included 74 recipients of autologous or allogeneic HCT with AVN and 147 controls without AVN that were matched by age, sex, and year of HCT to cases. Cases with AVN included 8 autologous HCT recipients, 58 myeloablative allogeneic HCT recipients, and 8 recipients of nonmyeloabalative allogeneic HCT. Corticosteroid exposure was expressed as cumulative doses of prednisone. Cases received higher cumulative doses of prednisone than controls, and among allogeneic HCT recipients, cases were more likely to have developed acute and chronic graft-versus-host disease (aGVHD, cGVHD). Cumulative dose of prednisone was an independent risk factor for AVN. Compared to no corticosteroid exposure, exposure to <3870 mg cumulative dose of prednisone was associated with 4.0 (95% confidence intervals, 1.5-11.2) times higher risk, 3870-9735 mg with 5.6 (2.1-15.2) times higher risk and >9735 with 8.6 (3.2-23.5) times higher risk of AVN. Exposure to higher doses of corticosteroids increases the risk of AVN in HCT recipients.

Key Words: Allogeneic hematopoietic cell transplantation, Autologous hematopoietic-cell transplantation, Avascular necrosis of bone, Late complications

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Introduction 

Improvements in transplantation techniques and supportive care have led to an increasing number of hematopoietic cell transplant (HCT) survivors. These survivors are at risk of late complications because of HCT-related exposures including conditioning-regimen chemotherapy and irradiation, immunosuppressive drugs, and graft-versus-host disease (GVHD) 1, 2, 3, 4, 5, 6. Avascular necrosis (AVN) of the bone is 1 such late complication that occurs because of disruption of blood supply to the bone with resultant death of the bone and collapse of bone structure. AVN has been described in 4% to 19% of HCT survivors and can lead to joint pain, bone destruction, and loss of function with significant impairment in quality of life 7, 8, 9, 10, 11, 12, 13, 14. Up to 48% of affected patients require joint replacement surgery 8, 9, 11.

Putative risk factors for posttransplant AVN include female sex, older age, allogeneic donor source, acute and chronic GVHD (aGVHD, cGVHD), corticosteroid therapy, and total body irradiation (TBI) 7, 8, 9, 11, 13, 15, 16, 17. Recently, exposure to calcineurin inhibitors and mycophenolate mofetil have been implicated as risk factors for development of AVN [13]. The effect of corticosteroid dose on AVN risk has not been previously described. We conducted a single institution case-controlled study to determine the association between cumulative doses of corticosteroids and risk of AVN. We also describe the clinical presentation of AVN in our patient cohort and examine other important risk factors for post-HCT AVN.

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Methods 

Patients 

The University of Minnesota Blood and Marrow Transplant program's database, which prospectively collects transplant and disease-related data and tracks post-HCT outcomes, was queried for AVN of the bone as a post-HCT complication. Patients were eligible for our study if they had received an allogeneic or autologous HCT between 1990 and 2007. All age groups, diagnoses, and donor sources were considered for our study. Medical charts of patients with AVN were reviewed to obtain more information about AVN diagnosis, risk factors, and treatment. To be classified as an AVN case, patients were required to have computed tomography (CT) or magnetic resonance imaging (MRI) evidence of AVN or had undergone joint arthroplasty or another surgical procedure for AVN.

Eighty-four cases of AVN were reported among 3786 patients (autologous = 1157, allogeneic = 2629). From these, 10 patients were excluded; 6 patients did not meet our case definition for AVN (lack of radiological evidence of AVN) and the diagnosis of AVN preceded HCT in 4 patients. Hence, our final cohort of cases consisted of 74 patients (Table 1).

Table 1. Characteristics of Cases and Controls

Characteristic	Cases	Controls	P-Value
N	74	147
Age, years			—∗
Median (range)	28 (4-60)	28 (4-60)
Sex			—∗
Male	46 (62%)	95 (64%)
Female	28 (38%)	52 (36%)
Diagnosis			.12
Acute leukemia	36 (49%)	49 (33%)
Chronic myelogenous leukemia	15 (20%)	30 (20%)
Lymphoma	12 (16%)	32 (22%)
Nonmalignant disorder	8 (11%)	18 (12%)
Other	3 (4%)	18 (12%)
Previous transplant	0	11 (8%)	.02
Transplant type			.04
Allogeneic myeloablative	58 (78%)	93 (63%)
Allogeneic nonmyeloablative	8 (11%)	17 (12%)
Autologous	8 (11%)	37 (25%)
Total-body irradiation dose			.62
No total-body irradiation	15 (20%)	38 (26%)
200 cGy	8 (11%)	17 (12%)
1320 cGy	51 (69%)	92 (62%)
Acute GVHD (allogeneic HCT only)			<.01
No	14 (21%)	49 (44%)
Yes	52 (79%)	61 (56%)
Chronic GVHD (allogeneic HCT only)			<.01
No	17 (26%)	73 (66%)
Yes	49 (74%)	37 (34%)
Prednisone cumulative dose, mg†			.05
Median (interquartile range)	7043 (2352-12,755)	1800 (0-7895)
Prednisone cumulative dose, mg†,‡			<.01
No prednisone exposure	6 (8%)	50 (34%)
<3,870	18 (24%)	37 (25%)
3,870-9,735	22 (30%)	33 (23%)
>9,735	28 (38%)	27 (18%)

GVHD indicates graft-versus-host disease; HCT, hematopoietic cell transplantation.

Controls 

Two controls were randomly selected for each case from the same cohort of 3786 patients and were matched to cases by age (±5 years), sex, and year of transplantation (±1 year). We did not match cases and controls by transplant type because we wanted to evaluate this variable as a risk factor for AVN. Medical records of controls were reviewed to ascertain absence of AVN or other bone complications. In addition, controls with any documented history of bone and joint related symptoms were excluded.

Risk Factors 

The primary objective of this study was to evaluate cumulative dose of corticosteroids as a risk factor for AVN. The following additional risk factors for AVN were also considered a priori: (1) diagnosis (acute leukemia versus chronic myelogenous leukemia versus lymphoma versus nonmalignant disorders), (2) transplant type (autologous versus allogeneic), (3) TBI use (yes versus no), and (4) history of previous transplantation.

Corticosteroid dose was abstracted from a detailed review of medical charts for both cases and controls. For the purposes of this study, corticosteroid dose is presented as prednisone dose in “mg.” Dose of other corticosteroids, if used, was converted to an equivalent dose of prednisone. Data on corticosteroid exposure was obtained from the date of diagnosis of hematologic disorder to the date of onset of AVN. Hence, these included use of corticosteroids as part of initial or salvage therapy for the underlying hematologic disorder (eg, prednisone in CHOP chemotherapy regimen for non-Hodgkin lymphomas). For controls, similar data was collected from the time of diagnosis. However, the duration of corticosteroid exposure for controls was considered from the date of transplantation to the date of onset of AVN in its corresponding matched case. Because data on dose of corticosteroids was recorded retrospectively, assumptions about dose were made where there were gaps between reports of corticosteroid use (eg, in between follow-up visits). If the dose on follow-up visit was unchanged, then the dose during the gap was assumed to be the same. If the dose on follow-up visit was lower or higher than previous reported dose, medical records were reviewed for information about a dose taper or increase schedule, which was then used to estimate the corticosteroid dose during that time period.

We could not evaluate duration of corticosteroid exposure as a risk factor for AVN because this was highly correlated with cumulative corticosteroid dose. Similarly, aGVHD and cGVHD were closely correlated with corticosteroid exposure, and only the latter was considered in the risk factor analysis. Exposure to calcineurin inhibitors also could not be evaluated as a risk factor because all allogeneic HCT recipients received cyclosporine as part of GVHD prophylaxis regimen.

Statistical Analysis 

Cases and controls were compared using either chi-square or Fisher's tests, as appropriate, for categoric variables and Wilcoxon rank sum test for continuous variables. Multivariable conditional logistic regression was used to identify risk factors that were significantly and independently associated with AVN of bone after HCT. Because our main objective was to explore the effect of corticosteroid dose on the risk of AVN, we compiled data from both cases and controls to categorize cumulative corticosteroid dose (as mg of prednisone) into tertiles. Hence, 4 categories for corticosteroid exposure were considered in multivariate analysis if sample size permitted: no exposure, cumulative prednisone dose in the lower third (<3870 mg), cumulative prednisone dose in the middle third (3870-9735 mg), and cumulative prednisone dose in the upper third (>9735 mg). Statistical analyses were performed using SAS 9.1 (SAS Institute, Cary, NC).

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Results 

Patients 

Seventy-four cases and 147 controls were included in our study (Table 1). A greater proportion of controls had received an autologous transplant and had undergone previous transplantation. Cases received higher cumulative doses of corticosteroids than controls, and among allogeneic HCT recipients, cases were more likely to have developed aGVHD and cGVHD. Figure 1 describes the distribution of autologous and allogeneic HCT recipients by corticosteroid exposure. Compared to cases, a greater proportion of controls had no exposure to corticosteroids. Also, a larger proportion of cases received higher cumulative doses of corticosteroids compared to controls (cumulative prednisone dose in the highest tertile: 39% versus 23% for allogeneic HCT recipients and 25% versus 5% for autologous HCT recipients). However, corticosteroid exposure did not differ by age at transplantation, and the cumulative doses of prednisone among cases and controls were comparable across age groups. For cases, median prednisone dose was 6831 mg among patients <18 years, 6575 mg among patients 18 to 45 years and 7875 mg for patients >45 years of age at HCT. The median prednisone dose for controls in the 3 age groups was 1050 mg, 2460 mg, and 1061 mg, respectively.

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• Figure 1 

  Corticosteroid exposure of cases and controls by transplant type. The height of the columns represents proportion of patients within each category. Corticosteroid exposure is presented as cumulative dose of prednisone.

Avascular Necrosis 

Table 2 describes the characteristics of cases with AVN of the bone. The overall cumulative incidence of AVN at 5-years post-HCT was 3% (95% confidence intervals [CI], 2%-4%) and included 8 autologous HCT recipients, 58 recipients of myeloabalative allogeneic HCT, and 8 recipients of nonmyeloabalative allogeneic HCT. The median age at onset of AVN was 28 (range: 4-60) years and 23% of cases occurred in children (aged <18 years). AVN occurred at a median of 16 (range: 2-80) months after HCT, and it occurred within 2 years of transplantation in 64% of cases. AVN involved a total of 156 joints in these 74 patients (median number of joints involved 2 [range: 1-6]). Proximal femur (54%) and distal femur (36%) were the most common sites of involvement. Association Research Circulation Osseous stage [18], which classifies progressively worsening radiologic abnormalities and amount of bone involvement from stage 0 to 4, could be assigned for 52 cases; of these, stage 3 or 4 (that requires surgical intervention) was present in 60%. Thirty-five (48%) required surgical treatment for AVN, among which joint replacement was performed in 31 patients.

Table 2. Characteristics of Patients with Avascular Necrosis of Bone by Transplant Type

Characteristic	Autologous HCT	Myeloablative Allogeneic HCT	Nonmyeloablative Allogeneic HCT
N	8	58	8
Time from HCT to AVN, months
Median (range)	21 (1-80)	17 (2-76)	15 (4-41)
Age, years
Median (range)	26 (14-57)	25 (4-54)	55 (29-60)
Year of HCT
1990-1999	4 (50%)	42 (72%)	1 (13%)
2000-2007	4 (50%)	16 (28%)	7 (87%)
Diagnosis
Acute leukemia	2 (25%)	30 (52%)	4 (50%)
Chronic myeloid leukemia	0	15 (26%)	0
Lymphoma	4 (50%)	4 (7%)	4 (50%)
Nonmalignant disorder	0	8 (14%)	0
Other	2 (25%)	1 (2%)	0
Previous transplant	0	0	0
Donor type
Related	—	28 (48%)	2 (25%)
Unrelated	—	22 (38%)	0
Umbilical cord blood	—	8 (14%)	6 (75%)
Conditioning regimen
Cy + TBI (1320 cGy)	6 (75%)	46 (79%)	0
Cy + Flu + TBI (200 cGy)	0	0	7 (87%)
Other	2 (25%)	12 (21%)	1 (13%)
Total-body irradiation∗
No	6 (75%)	9 (16%)	0
Yes	2 (25%)	49 (84%)	8 (100%)
Acute GVHD
No	—	12 (21%)	2 (25%)
Yes	—	46 (79%)	6 (75%)
Chronic GVHD
No	—	16 (28%)	3 (38%)
Yes	—	42 (72%)	5 (62%)
Corticosteroid exposure
No	3 (38%)	3 (5%)	0
Yes	5 (62%)	55 (95%)	8 (100%)
Prednisone cumulative dose, mg†
Median (interquartile range)	1266 (0-0-6953)	7,460 (3398-13,883)	7,350 (2854-9322)

HCT indicates hematopoietic cell transplantation; AVN, avascular necrosis of bone; Cy, cyclophosphamide; Flu, fludarabine; TBI, total body irradiation; GVHD, graft-versus-host disease.

We also compared the characteristics of patients who developed AVN within 1 year of HCT (N = 28) with those who developed it at 1 year or later (N = 48). The age at diagnosis, sex, year of HCT, diagnosis, transplant type, TBI dose, prevalence of aGVHD and cGVHD and exposure to corticosteroids were comparable between the 2 groups.

Six patients with no previous corticosteroid exposure developed AVN. These included 2 patients each with chronic myelogenous leukemia, acute myelogenous leukemia, and Hodgkin lymphoma. Three patients had received a myeloabalative allogeneic HCT and the other 3 received an autologous HCT. Four patients had received TBI-based conditioning regimens.

Risk Factors 

On multivariate analysis, corticosteroid exposure was independently associated with the risk of developing AVN after both autologous and allogeneic HCT (Table 3). Increasing cumulative dose of corticosteroids incrementally increased the risks of AVN in all patients and in allogeneic HCT patients. An adequate number of events were not available to investigate the effect of corticosteroid dose in the subgroup of autologous HCT recipients. For the whole cohort, 51% of patients with prednisone dose in the highest tertile developed AVN, compared to 40% in patients with prednisone dose in the intermediate tertile, 33% in patients with prednisone dose in the lowest tertile, and 11% among patients who had no exposure to prednisone.

Table 3. Multivariate Analysis for Corticosteroid Exposure as a Risk Factor for Avascular Necrosis of Bone after Hematopoietic Cell Transplantation

Variable∗	Odds Ratio (95% CI)	P-Value
All patients (N = 221)
Prednisone cumulative dose, mg†		<.01
No prednisone exposure	1.0
<3870	4.0 (1.5-11.2)
3870-9735	5.6 (2.1-15.2)
>9735	8.6 (3.2-23.5)
Allogeneic HCT (N = 176)
Prednisone cumulative dose, mg†		<.01
No prednisone exposure	1.0
<3870	3.4 (0.9-13.1)
3870-9735	4.7 (1.3-17.9)
>9735	7.3 (2.0-27.5)
Autologous HCT (N = 45)‡
Exposure to prednisone		.03
No	1.0
Yes (any dose)	6.0 (1.2-30.9)

HCT indicates hematopoietic cell transplantation; CI, confidence interval.

In addition to corticosteroid exposure, the only other independent risk factor for AVN was allogeneic HCT (relative risk 2.5, 95% CI: 1.2-5.8, P = .01). Diagnosis, use of TBI in conditioning, or prior transplantation did not increase the risks of AVN.

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Discussion 

Our study highlights the importance of corticosteroid dose as a risk factor for AVN of the bone among HCT recipients. AVN is a debilitating complication of HCT, and early detection and treatment of AVN can alleviate its morbidity. However, screening for AVN would require periodic radiologic imaging studies such as CT or MRI scans, and such an approach may not be feasible or cost effective for application among all HCT recipients or among all HCT recipients on corticosteroid therapy. Our findings indicate that a subgroup of patients who receive very high doses of corticosteroids have the highest risk for developing AVN, and may be candidates for further investigations, including screening and early treatment strategies.

Systemic corticosteroids have been implicated in the development of AVN, but the etiology is not well defined. Animal studies have provided some crucial insights. Weinstein et al. [19] demonstrated that mice given high doses of prensisolone have increased osteoblast apoptosis as well as osteoclast apoptosis leading to decreased bone density. Wang et al. [20] showed that steroids in rabbits produce fat degeneration, necrosis of osteocytes, and fat embolism in the microvasculature of the femoral head. In other studies, rabbits treated with methylprednisolone for 6 weeks had decreased blood flow to the femoral head based on perfusion studies [21].

In HCT survivors, exposure to corticosteroids is a well-established risk factor for the development of AVN 8, 11, 13, 15, 16. However, corticosteroid dose has not been well investigated as a risk factor. In 1977, Cruess [22] described detailed clinical and pathological characteristics of AVN in 95 patients who had received corticosteroids for indications other than HCT and underwent a surgical procedure for AVN. Their cohort included 68 solid organ transplant recipients. In an analysis limited to solid-organ transplant recipients, the mean total dose (± standard error) of prednisone was 27.3 ± 11.2 g in patients without AVN, 32.6 ± 9.1 g in patients with AVN but without subchondral collapse, and 42.3 ± 14.5 g in patients with AVN and subchondral collapse. Fink et al. [12] have described a case-controlled study among autologous and allogeneic HCT recipients, which included 87 cases of AVN and their age, sex, and transplant year matched controls. After adjusting for TBI, aGVHD or cGVHD and type of transplant, exposure to corticosteroids was associated with a 14-fold increase in risk of AVN. This risk was somewhat higher among current users than in past users. Any duration of corticosteroid use increased the risk of AVN, although longer duration of exposure (<26 weeks versus 26 weeks to 1 year versus >1 year) did not cause an incremental increase in this risk. They did not evaluate the effect of corticosteroid dose in their study. In a more contemporary prospective cohort study of 207 autologous and allogeneic HCT recipients reported by Tauchmanova et al. [15], AVN occurred in 12 patients. In univariate analyses that were not adjusted for other important risk factors, AVN developed in a significantly greater proportion of patients who received higher cumulative doses of corticosteroids (≥6 g) and had a longer duration of exposure to corticosteroids (>216 days). In summary, these previous studies and our present analysis suggest that the risk associated with corticosteroid exposure is cumulative, and is related to both the dose and duration of treatment.

From the perspective of investigating screening strategies for AVN, the definition of “high-dose corticosteroids” needs to be explored further. The categories used in our study were based on tertiles of the prednisone dose observed in our cohort (<3870 mg, 3870-9735 mg, and >9735 mg). Prednisone dose (or equivalent dose of another corticosteroid) of 0.5 mg/kg/day for 1 year in an adult weighing 60 kg (cumulative dose ∼11,000 mg) corresponds to the highest tertile dose of corticosteroids in our cohort. However, patients who had received a lower dose of corticosteroids were also at increased risk of AVN. In addition to dose, the duration of exposure to corticosteroids may also be important. Studies need to explore whether risks of AVN with a higher dose but short duration, or conversely, lower dose but longer duration of corticosteroid exposure are any different. Because dose highly correlated with duration of exposure in our study, we could not consider duration of corticosteroid exposure as a risk factor in our analysis.

Our study does have some limitations. Although we accounted for corticosteroid exposure as part of initial or salvage therapy, we did not include corticosteroid use as part of the antiemetic regimens in estimating cumulative corticosteroid exposure. However, antiemetic regimens typically contain relatively small doses and use short duration of corticosteroids. Very long-term HCT survivors without GVHD may not be followed by our transplant program, and we were not able to include patients without GVHD who may have developed AVN since discharge from our program. The characteristics of patients identified retrospectively versus on prospective monitoring may differ. Furthermore, although we did use control patients who did not have any documented joint symptoms, they did undergo imaging studies to definitely rule out AVN. Finally, given the characteristics of our cohort, we could not account for other recognized risk factors for AVN such as use of calcineurin inhibitors and duration of corticosteroid exposure.

In conclusion, AVN is a debilitating complication of HCT, and often requires surgical intervention for management of symptoms. Exposure to higher doses of corticosteroids increases its risk. As more information becomes available on risk factors and the pathogenesis of this disease, we may be able to target HCT recipients at higher risk for developing AVN for close monitoring and early and timely interventions.

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Acknowledgments 

Financial disclosure: This research was partially supported by the American Society of Hematology Trainee Award to Sarah McAvoy.

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