Post-Transplant Complications Bone Mineral Density and Osteonecrosis in Survivors of Childhood Allogeneic Bone Marrow Transplantation

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Post-transplant complications Bone mineral density and osteonecrosis in survivors of childhood allogeneic bone marrow transplantation

SC Kaste1,2, TJ Shidler1, X Tong3, DK Srivastava3, R Rochester4, MM Hudson4,5, PD Shearer4,5 and GA Hale4,5

1Department of Diagnostic Imaging, St Jude Children’s Research Hospital, Memphis, TN, USA; 2Department of Radiology, University of Tennessee College of Medicine, Memphis, TN, USA; 3Biostatistics, St Jude Children’s Research Hospital, Memphis, TN, USA; 4Department of Hematology-Oncology (Division of Stem Cell Transplantation), St Jude Children’s Research Hospital, Memphis, TN, USA; and 5Department of Pediatrics, University of Tennessee College of Medicine, Memphis, TN, USA

Summary: are alive after undergoing allogeneic bone marrow transplantation (alloBMT) between 1968 and 2002 (M Our purpose was to evaluate frequency and severity of bone Horowitz, personal communication). Owing to the growing mineral decrements and frequency of osteonecrosis in success of pediatric alloBMT, an increasing number of long- survivors of pediatric allogeneic bone marrow transplanta- term survivors are at risk of disease- and therapy-induced tion (alloBMT). We retrospectively reviewed demographic adverse late effects, including diminished bone mineral density information, treatment, magnetic resonance (MR)imaging (BMD) and osteonecrosis. Limited guidelines are available studies (hips and knees), and bone mineral density (BMD) to direct management of survivors of pediatric alloBMT,1–3 studies of 48 patients as measured by quantitative computed of which few address potential skeletal complications.4 tomography (QCT). In all, 24 patients were male; 37 To assess the frequency and severity of bone mineral were Caucasian. Median age at alloBMT was 10.3 years deficits and of osteonecrosis in survivors of childhood (1.6–20.4 years). Of the 48 patients, 43 underwent QCT. alloBMT, we retrospectively reviewed the records of routine Median time between alloBMT and imaging was 5.1 years annual follow-up evaluations of survivors of pediatric (1.0–10.2 years). Median BMD Z-score was À0.89 (À4.06 alloBMT treated at a single pediatric transplant center. to 3.05). BMD Z-score tended to be associated with female sex (P ¼ 0.0559)but not with age at BMT, race, primary diagnosis, time from alloBMT, T-cell depletion of graft, Patients and methods total-body irradiation, or acute/chronic graft-versus-host disease (GVHD). MR showed osteonecrosis in 19 of 43 All patients who had follow-up evaluations for alloBMT (44%). We found no associations between osteonecrosis between March 1, 2001 and November 8, 2001, and who and sex, race, diagnosis, age at BMT, history of GVHD, underwent BMD assessment, and/or magnetic resonance time from BMT, or T-cell depletion. Seven patients (15%) (MR) of the hips and/or knees were eligible for inclusion. had MR changes of osteonecrosis and BMD Z-scores of Routine evaluation of BMD screening for osteonecrosis less than –1 s.d. We conclude that pediatric alloBMT using MR was initiated in March 2001. The reported survivors have decreased BMD and are at risk of patient cohort comprises a consecutive group of patients osteonecrosis. They should be monitored to assure early who returned for their annual post-BMT evaluation for intervention that may ameliorate adverse outcomes. whom these studies were part of routine evaluation. Bone Marrow Transplantation (2004) 33, 435–441. Information abstracted from medical records review doi:10.1038/sj.bmt.1704360 included demographic information, the date and type of Published online 12 January 2004 primary diagnosis, the alloBMT conditioning regimen Keywords: osteoporosis; childhood bone marrow trans- (including use of total body irradiation), T-cell depletion plantation; osteonecrosis of the graft, donor type, date of transplantation, and history of acute or chronic graft-versus-host disease (GVHD). We also retrospectively reviewed all quantitative computed tomography (QCT) and MR imaging studies The International Bone Marrow Transplant Registry performed during the annual evaluation of those patients. reports that 14 309 persons less than 21 years of age This study was approved by the St Jude Children’s Research Hospital Institutional Review Board (IRB); informed consent was waived for this retrospective study. Correspondence: Dr SC Kaste, Department of Diagnostic Imaging, St Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, Transplantation TN 38105-2794, USA; E-mail: [email protected] Received 11 August 2003; accepted 24 September 2003 All patients underwent alloBMT on IRB-approved Published online 12 January 2004 protocols. In all, 26 patients received bone marrow from BMD and AVN after childhood allogeneic BMT SC Kaste et al 436 HLA-matched siblings, 25 from matched unrelated donors Hip and knee radiographs (matched at five or six HLA loci), and eight from We no longer routinely perform radiographic evaluation of mismatched family members. All patients who had the hips or knees for assessment of osteonecrosis until such hematologic malignancies (n ¼ 50) were conditioned with time as orthopedic surgery is contemplated. Thus, from cytarabine (3 g/m2/dose, six doses) and cyclophosphamide radiographic reports, we captured whether or not patients (45 mg/kg/dose, two doses), with mesna uroprotection with MR findings of osteonecrosis underwent radiographic (45 mg/kg divided into five doses) and received total-body evaluation during the study period and whether or not the irradiation (TBI) in eight fractions over 4 days in doses of radiographs identified the presence of osteonecrosis. 150 or 175 cGy per fraction. Recipients of matched sibling grafts received 12 Gy and recipients of unrelated or mismatched family member grafts received 14 Gy. Definitions Patients with nonmalignant diseases (n ¼ 9) received a The Z-score (number of s.d.’s from the mean for age- and preparatory regimen of busulfan (1 mg/kg/dose, 16 doses) gender-matched control subjects) was used as an end point and cyclophosphamide (50 mg/kg/dose, four doses) with to allow analysis of the results obtained. BMD values with mesna uroprotection (50 mg/kg, administered as described a Z-score above –1 were considered to be normal. We above). considered osteopenia as a Z-score between –1 and –2 s.d. Recipients of unrelated donor or mismatched family and osteoporosis as a Z-score more than 2 s.d. below the member grafts received antithymocyte globulin to enhance mean (as modified from the World Health Organization immunosuppression. Marrow from mismatched family and National Osteoporosis Foundation criterion for members and from unrelated donors was depleted of osteopenia).10–12 At our institution, we initiate nutritional T lymphocytes by a factor of approximately 1.5 logs using counseling and suggest calcium and vitamin D supplemen- anti-T-cell monoclonal antibodies CD6 and CD8 plus tation for all patients with a BMD Z-score below –1 s.d.; all 5 rabbit complement. All recipients began receiving cyclo- patients with a BMD Z-score below –2 s.d. are also sporin A 2 days before transplantation, at a dosage referred for endocrinologic consultation for more rigorous adjusted to maintain plasma levels of 200–350 ng/ml. evaluation of risk factors that may contribute to BMD Patients given matched sibling marrow received additional deficits. Patients who have undergone BMT are evaluated GVHD prophylaxis with pentoxifylline or methotrexate annually in the Endocrine Clinic. (15 mg/m2 at day þ 1 followed by 10 mg/m2 at days þ 3, þ 6, and þ 11). Statistical analysis Acute and chronic GVHD were graded according to standard criteria.6 Patients with mild/moderate GVHD We used univariate analysis and logistic regression to assess (grade 1 or 2) were treated with methylprednisolone (1– if the following factors: age at BMT, age at BMT by group 2 mg/kg daily). If GVHD remained at grade 2 for more (o10 year vs 410 years), time from completion of therapy, than 7 days or progressed, the steroid dosage was increased gender, race (black vs white vs others), diagnosis (malignant to 5–10 mg/kg daily. vs nonmalignant), T-cell depletion (yes vs no), TBI (yes vs no), BMT type (matched sibling vs matched unrelated vs QCT technique donor mismatched family donor), acute GVHD (grade 2–4 vs others), chronic GVHD (yes vs no), hypothyroidism Vertebral trabecular BMD was determined by QCT (yes vs no), hypogonadism (yes vs no), adrenal insufficiency imaging using a Siemens Somatom-Plus spiral CT (yes vs no), and growth hormone deficiency (yes vs no) were scanner (Siemens, Iselin, NY, USA) and Mindwaves associated with osteopenia/osteoporosis. QCT Calibration Phantoms and software (Mindwaves The generalized linear model (GLM) was used to further Software, Inc., South San Francisco, CA, USA). Bone investigate if the following factors were correlated with mineral content was determined through direct axial images QCT Z-scores, while ignoring the definition of osteopenia of the centers of the bodies of the first and second and osteoporosis: age at BMT, age at BMT by group (o10

lumbar vertebrae (L1 and L2, respectively), as determined year vs 410 years), time from completion of therapy, from a sagittal or coronal scout image as described gender, race (black vs white vs others), diagnosis (malignant previously.6–9 If either or both bodies showed evidence vs nonmalignant), T-cell depletion (yes vs no), TBI (yes vs of fracture or deformity, the affected vertebral bodies no), BMT type (matched sibling vs matched unrelated were excluded from analysis and an alternate verte- donor vs mismatched family donor), acute GVHD (grade

bral body between T11 and L4 was chosen. BMD was 2–4 vs others), chronic GVHD (yes vs no), hypothyroidism calculated as the mean mg/cm3 value of the two vertebral (yes vs no), hypogonadism (yes vs no), adrenal insufficiency bodies. (yes vs no), growth hormone deficiency (yes vs no). Univariate analysis was performed. MR technique Osteonecrosis was defined by characteristic findings on MR imaging of either knees or hips.13–19 Patients who did

We performed coronal noncontrast T1-weighted and short not undergo MR imaging were excluded from the analysis tau inversion recovery imaging of the hips and knees and of osteonecrosis. Logistic regression was used to assess the sagittal FLASH 2-D imaging of the articular surfaces, association between osteonecrosis and age at BMT, gender, using a Siemens 1.5 T. Symphony or Vision MR unit race (black vs white vs others), diagnosis (malignant vs (Siemens, Inc., Erlangen, Germany). nonmalignant disease), time from completion of therapy,

Bone Marrow Transplantation BMD and AVN after childhood allogeneic BMT SC Kaste et al 437 T-cell depletion (yes vs no), TBI (yes vs no), acute GVHD (50%) patients were male, and 37 (77%) were Caucasian. (grade 2–4 vs others), and chronic GvHD (yes vs no). The median age was 10.3 years (range, 1.6–20.4 years) at All statistical analyses used SAS release 8.1 (SAS the time of alloBMT and 15.8 years (range, 4.4–27.2 years) Institute, Cary, NC, USA). at the time of the follow-up study. The median time elapsed between alloBMT and QCT was 5.1 years (range, 1.0–10.2 years). The most common primary diagnosis was acute Results myeloid leukemia (AML) (12 patients; 25%); the most common type of donor was a matched sibling (23 patients; Between March 1, 2001 and November 8, 2001, 65 48%). A total of 33 patients (69% studied of the cohort) survivors of alloBMT returned for their yearly anniversary had endocrinopathies: 28 (58%) hypothyroidism, 15 (31%) evaluation. In all, 55 patients (77%) underwent QCT and/ hypogonadism, and four (8%) with hypocortisolism, four or MR studies. Two patients had undergone two bone (8%) with precocious puberty, and four (8%) with growth marrow transplantations and were excluded from this hormone deﬁciency. All patients with an endocrinopathy study. Thus, the study cohort comprises 48 patients. Table 1 were receiving hormone replacement at the time of BMD lists selected characteristics of the 48 cases. Of these, 24 determination.

Table 1 Patient characteristics (total n ¼ 48) Characteristic n (%) Characteristic n (%)

Age at BMT (years) Sex Median 10.3 Female 24 (50.0) Range 1.6–20.4 Male 24 (50.0)

Race BMT donor White 37 (77.1) Matched sibling 18 (37.5) Black 6 (12.5) Matched unrelated donor 23 (47.9) Hispanic 5 (10.4) Mismatched family donor 7 (14.6)

Diagnosis Hematologic malignancy Endocrinopathya ALL 10 (20.8) Hypothyroidism 28 (58.3) AML 12 (25.0) Hypogonadism 15 (31.3) MDS 9 (18.8) Hypocorticalism 4 (8.3) CML 9 (18.8) Growth hormone deﬁciency 4 (8.3) Other leukemia 1 (2.1) Precocious puberty 1 (2.1) Nonmalignant disease Completion oftherapy to QCT (years) IERY 2 (4.2) N 43 Metabolic 1 (2.1) Median 5.1 SAA 2 (4.2) Range 1.0–10.2 SCID 1 (2.1) SLL 1 (2.1)

Acute GVHD Chronic GVHD None 20 (41.7) None 36 (75.0) Grade I 23 (47.9) Limited 12 (25.0) Grade II 4 (8.3) Grade IV 1 (2.1)

T-cell depletion TBI Yes 28 (58.3) Yes 45 (93.8) No 20 (41.7) No 3 (6.2)

Knee Hip Negative 28 (58.3) Negative 34 (70.8) Positive 15 (31.2) Positive 9 (18.8) No MR 1 (2.1) No MR 1 (2.1) None 4 (8.3) None 4 (8.3)

QCT Z-score (n ¼ 43) QCT Z-score oÀ2 9 (20.9) N 43 À2tooÀ1 11 (25.6) Median À0.88 XÀ1 23 (53.5) Range À3.3–2.33

BMT ¼ bone marrow transplant; ALL ¼ acute lymphoblastic leukemia; AML ¼ acute myeloid leukemia; CML ¼ chronic myeloid leukemia; HBSS ¼ sickle cell disease; MDS ¼ myelodysplastic syndrome; Metab ¼ metabolic disorders; Oleuk ¼ other leukemias, not classiﬁed as AML or ALL; AA ¼ severe aplastic anemia; SCID ¼ severe combined immunodeﬁciency; GVHD ¼ graft-versus-host disease; TBI ¼ total body irradiation. aSome patients had more than one endocrinopathy.

Bone Marrow Transplantation BMD and AVN after childhood allogeneic BMT SC Kaste et al 438 Bone mineral density and treatment are becoming progressively more important. Previous studies of childhood cancer patients indicating QCT studies were recorded for 43 patients (Table 1). The bone mineral deficits have prompted screening of this at median time between BMT and measurement of BMD was risk population in an effort to reduce the morbidity and 5.1 years (range, 1.0–10.2 years). The QCT Z-scores mortality associated with osteonecrosis and early-onset (n 43) showed that approximately 21% of the study ¼ osteoporosis. Most of our patients undergo QCT assess- population has osteoporosis (Z-score less than 2); 26% À ment of BMD and MR of the hips and knees as part of of patients had osteopenia with BMD Z-scores between their annual post-BMT examination. However, routine 1 and 2 s.d. À À imaging examination is costly in terms of resource Logistic regression analysis showed no significant asso- utilization, patient and staff time, and financial resources, ciation between osteopenia/osteoporosis (a QCT Z-score and it exposes patients to small amounts of ionizing 1) and age at the time of BMT, race, sex, time elapsed oÀ radiation. We therefore sought to estimate the frequency of since BMT, T-cell depletion, TBI, acute/chronic GVHD, osteopenia/osteoporosis and osteonecrosis in survivors of and diagnosis. However, when the GLM was used to test alloBMT returning for long-term follow-up. the association between these variables and the Z-scores without reference to the threshold defining osteopenia/ osteoporosis, sex and hypogonadism had P-values of Bone mineral decrements 0.0559 and 0.0637, respectively, suggesting trends toward Bone mineral loss as an adverse effect of childhood significances with BMD below the mean for age- and oncotherapy is the subject of intense interest. The develop- gender-matched controls. Male patients had higher QCT ment of this sequela is complex and multifactorial.1–4,20–22 Z-scores than did females (P 0.0559). The estimated mean ¼ Malignant disease, its therapy, altered nutrition during Z-score (s.d.) was 0.33 (1.42) for male and 1.18 (1.42) À À therapy, physical inactivity, and GVHD and its therapy for female patients, respectively. compound any innate deficits that may be present at the Patients with hypogonadism had lower QCT Z-scores time of alloBMT.4 Osteoporosis has been reported follow- than patients without hypogonadism (P 0.0637). The ¼ ing allogeneic BMT for a variety of diagnoses in adults.4,23–25 estimated mean Z-score (s.d.) for patients with hypogonad- However, studies of osteoporosis in children following ism and without hypogonadism were 1.39 (1.32) and À autologous or allogeneic BMT are limited.1,4,25 0.47 (1.46), respectively. Age at time of BMT, type of À Bhatia et al 25 reported that the DXA-determined BMD BMT, time from BMT, type of BMT, T-cell depletion, TBI, of 10 pediatric patients aged 3 to18 years, most of whom acute/chronic GVHD, race, and diagnosis did not correlate underwent allogeneic BMT for AML, was significantly with BMD Z-score. We found no correlation with decreased (median Z-score of À0.5) and lower than that of endocrinopathy other than hypogonadism. 13 adults in the same study (median Z-score of 0.0, P ¼ 0.03). Our study corroborates the finding of BMD MR imaging evidence of osteonecrosis deficits in a larger cohort of pediatric alloBMT survivors. We found an even greater BMD deficit (median Z-score, Of the 48 evaluable patients, 43 had undergone MR À0.88) than previously reported, possibly in part be due imaging of the hips and and/or knees; 19 had evidence of to a difference in technologic assessment (ie DXA vs QCT). osteonecrosis. In all, 12 (63%) were female and seven Our longer median follow-up period of nearly 5 years (as (37%) were male. Female sex was significantly associated opposed to the 2 years median follow-up in Bhatia’s study) with osteonecrosis. No associations were observed between permitted more time for any natural recovery of BMD, osteonecrosis and sex, race, diagnosis, age at BMT, history were it to occur. The presence of osteopenia (26%) or of acute/chronic GVHD, time from BMT, or T-cell osteoporosis (21%) in 47% of our cohort suggests depletion. Of patients with positive MR findings, eight that survivors of alloBMT during childhood will carry (42%) were clinically significant (one of whom had under- excess risks of fractures and other skeletal complications as gone hip arthroplasty and one underwent core decompres- they age. sion of the hip). Two patients also had involvement of the Several groups have evaluated clinical and treatment ankles and one patient had involvement of the elbows. Of factors predictive of BMD deficits. Glucocorticoid26–35 and the 19 patients with MR evidence of osteoncrosis, 12 methotrexate36–39 treatment and cranial irradiation40–42 underwent radiographic evaluation of the hips (two have been inconsistently associated with the risk of positive) and two of the knees (one positive). osteopenia. However, findings of these studies have been Seven patients (15%) had both MR changes suggestive limited by the generally small and heterogeneously treated of osteonecrosis involving the hips (n ¼ 2), knees (n ¼ 4) or patient cohorts. Among the few studies reporting BMD both (n ¼ 1), and BMD Z-scores less than À1 s.d. The after BMT, Stern et al 24 at the University of Washington BMD Z-scores obtained by QCT for these patients ranged Fred Hutchinson Cancer Research Center found a positive from À1.35 to À3.30. correlation between treatment for chronic GVHD with cyclosporin A and prednisone and BMD deficits, as determined by DXA in six of nine adult patients during 6 Discussion months of immunosuppression. Males with greater post transplant complications had greater loss of BMD.24 As As the surviving cohort of pediatric patients treated with also reported by Bhatia et al,25 we found no such alloBMT grows, skeletal complications related to disease correlation in our pediatric cohort.

Bone Marrow Transplantation BMD and AVN after childhood allogeneic BMT SC Kaste et al 439 Bone mineral accretion is most active during puberty would have had less exposure to bone-toxic immunosup- because of the intimate association between bone mineral pressive drugs. accretion and pubertal development.3,22,43 A balance Enright et al 23 used standard radiography, technetium- between gonadal, thyroid, adrenal, and growth hormones 99m MDPbone scintigraphy, and MR imaging to identify is necessary for maximum bone mineral accretion and osteonecrosis of bone in eight of 353 pediatric recipients skeletal development. Gonadal failure related to transplant (2%) of allogeneic transplants aged 0–19 years. They therapy is well known and multifactorial.1,44–46 Primary identified GVHD (acute or chronic) and increasing age ovarian failure is expected in adult women who have as significant independent risk factors for the develop- undergone bone marrow transplantation with less than ment of osteonecrosis. Patients aged 10–19 years had a 10% reportedly regaining ovarian function between 3 risk of AVN 2.4 times that of patients aged less than and 7 years after total body irradiation.1,44,45 Most 10 years.23 children who received total body irradiation when younger We found a much greater frequency of osteonecrosis in than 10 years progress through puberty normally. our study than reported in previous studies that utilized However, those who were at least 10 years of age at the radiographs.23,47 Half of the patients we examined, most of time of total body irradiation developed primary gonadal whom were female, had MR evidence of osteonecrosis. This failure.45 In about 75% of men who have received increased frequency reflects the greater sensitivity of MR irradiation, elevation of follicle-stimulating hormone imaging. Our post transplant population underwent screen- persisted even in the presence of normal or recovered ing due to an anticipated increased risk of therapy-related luteinizing hormone and normal testosterone.1 Thus, the osteonecrosis. Nearly half of those identified with osteone- trend we found between hypogonadism and bone mineral crosis were asymptomatic or had limited symptoms. It is deficits is not surprising and underscores the need to possible that early conservative intervention might amelio- prospectively monitor alloBMT patients for gonadal rate the more severe latent sequelae seen in the sympto- function. matic patients; this has yet to be proven in asymptomatic patients. Further, the median age of patients in our cohort Osteonecrosis was about 10 years at the time of alloBMT, which historically should place them at greater risk of osteo- Identification of osteonecrosis at an early stage allows necrosis than younger patients.23 However, we found no intervention that may arrest progression of pain and association between patient age at the time of alloBMT and functional impairment. Previous studies have utilized the development of osteonecrosis. Interestingly, the fre- radiography of the hips to detect osteonecrosis,23,47 but quency of involvement of the knees exceeded that of the current MR imaging technology provides earlier, more hips; a finding that, to our knowledge, has not been sensitive, and specific detection.13,15–18,48 We perform MR reported previously. imaging to identify osteonecrosis involving the hips or knees annually or when indicated by clinical symptoms Summary such as chronic joint pain. Orthopedic management of osteonecrosis is based on Osteopenia and osteoporosis typically remain asympto- symptoms and joint function. In the early stages, patients matic until fractures occur. Patients who are at risk should are treated with nonweight-bearing activities such as be screened and treated for conditions that adversely affect swimming to maintain joint function and to control body bone mineralization, such as hypogonadism and hypothy- weight.14,49 At more advanced stages, surgical intervention roidism.20,21,24,25 Prevention of osteoporosis by optimizing (ie core decompression, arthroplasty, or total joint replace- behaviors to improve and maintain bone health should be ment) may be necessary to ameliorate symptoms and an important aim of education in follow-up clinics. preserve joint function.14,49 Therapy for osteopenia/osteoporosis can undermine Using multivariate analysis, investigators at the Uni- therapy for osteonecrosis. Approximately, 15% of our versity of Minnesota identified increasing age at the time of studied cohort had evidence of both decreased BMD and BMT (P ¼ 0.002), acute or chronic GVHD requiring osteonecrosis. However, weight-bearing exercise such as steroid therapy (P ¼ 0.003) as significant and independent walking, gardening, running, team sports, etc, which have risk factors for developing osteonecrosis after allogeneic been shown to improve BMD, may exacerbate the transplantation in 28 (4%) of 642 consecutive patients symptoms and progression of osteonecrosis. For this ranging in age from 1.5 to 47 years (median, 26 years) at the patient cohort, weight-bearing exercise should be adjusted time of BMT. Symptoms developed a median of 12 months to the level of tolerance. after transplantation, but in 17 cases diagnosis was delayed Until proven otherwise, diagnosis and management of (range 0.5–24 months).23 We failed to find a correlation osteonecrosis should be symptom based and should con- between GVHD and the development of osteonecrosis, form to orthopedic practice. However, we recommend possibly because our cohort was relatively small and of routine screening of BMD for all alloBMT patients. younger age than the comparison group reported above. In Patients should be advised to evaluate all behaviors addition, few of our patients developed either acute or adversely affecting bone health. We specifically counsel chronic GVHD as reported previously.50 As we routinely our patients to avoid smoking, limit intake of caffeine and T-cell deplete all unrelated donor and mismatched family carbonated beverages, establish a weight-bearing exercise member grafts, our incidence of acute and chronic GVHD regimen after orthopedic consultation, and assure adequate is low for the entire alloBMT population.51 Thus, they dietary intake of calcium and vitamin D. Patients should

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