Biology of Blood and Marrow Transplantation
Volume 13, Issue 5 , Pages 517-520, May 2007

Increased Risk of Bone Loss without Fracture Risk in Long-Term Survivors after Allogeneic Stem Cell Transplantation

Stem Cell Allogeneic Transplantation Section, Hematology Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland

Received 20 December 2006; accepted 29 January 2007.

Article Outline

Abstract 

We studied bone mineral density (BMD) in 79 long-term survivors of allogeneic stem cell transplantation (SCT) (median follow-up: 78 months; range: 38-160). Seventy patients received a total body irradiation (TBI)-based myeloablative SCT and 9 patients received a non-TBI, reduced-intensity SCT. Fourteen (18%) patients were receiving immunosuppressive therapy (IST) for chronic graft-versus-host disease (cGVHD) beyond 3 years from SCT. Fifty-eight (73.4%) of patients had bone loss (BL): 33 (41.8%) with osteopenia and 25 (31.6%) with osteoporosis. Factors associated with a significantly increased risk of osteoporosis were age and prolonged IST and for overall BL prolonged IST. However, BL was not associated with an increased fracture risk, despite the fact that most patients had not received prophylactic biphosphonates. Our data shows that BL is a long-term posttransplant complication, and emphasize the importance of serial BMD scans, and the treatment of BL with biphosphonates reserved for worsening BL or additional risk factors.

Key Words: Bone loss, Myeloablative, Nonmyeloablative, Stem cell transplantation

 

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Introduction 

As stem cell transplantation (SCT) becomes safer, nearly 90% of patients alive 2 years after allo-SCT will become long-term survivors [1]. As patients age after transplant, the focus of care moves from cure of the original disease to the identification and treatment of delayed and long-term complications that can affect quality of life. Chronic graft-versus-host disease (cGVHD) has attracted the most attention, but large database analyses identify significant frequencies of other problems such as hypothyroidism, secondary cancer, and pulmonary complications in long-term survivors. Consecutive follow-up of long-term survivors after allo-SCT is, however, lacking. In 2005, we therefore initiated a follow-up study for long-term survivors of allo-SCT. Patients were enrolled at the third annual visit after transplantation. Annual screening includes evaluation for cGVHD, major organ dysfunction, secondary malignancies, hormonal profile, fertility, and quality of life.

In this analysis we evaluated bone mineral density (BMD) in long-term survivors. Bone loss (BL) after SCT has been described but mainly at earlier time points [2, 3, 4]. Here, we describe site-specific BL and risk factors in a patient cohort with a median survival posttransplant exceeding 5 years.

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Study Design 

Patients and Methods 

Four hundred seventeen patients with hematologic disorder received SCT from an HLA identical sibling in our institute between 1993 and 2003. We carried out a cross-sectional study on a group of patients enrolled at a minimum of 3 years posttransplantation between April 2005 and October 2006, in an institutional review board-approved long-term evaluation protocol (05-H-0130). Of 111 patients surviving 3 or more years at the initiation of study in 2005, 84 (76%) patients gave written informed consent according to principles outlined in the Declaration of Helsinki, and 79 underwent dual energy X-ray absorptiometry (DEXA) scanning to determine BMD. Diagnoses were chronic myelogenous leukemia (CML) (46), myelodysplastic syndrome (MDS) (13), acute myelogenous leukemia (AML) (12), acute lymphoblastic leukemia (ALL) (3), chronic lymphocytic leukemia (CLL) (2), severe aplastic anemia (1), mastocytosis (1), and multiple myeloma (1). Seventy (median age 35 years) received a myeloablative stem cell transplantation (MST). Conditioning consisting of total-body irridiation (TBI) 12-13.6 Gy and cyclophosphamide (±fludarabine) with a T cell-depleted bone marrow transplantation (BMT) (14) or peripheral blood stem cell transplantation (PBSCT) (56) and cyclosporine as GVHD prophylaxis. Nine received a non-TBI reduced intensity regimen (RIC) (median age: 37 years) of fludarabine 125 mg/m2 and cyclophosphamide 60 mg/kg, followed by a PBSCT with cyclosporine as GVHD prophylaxis.

Bone mineral density was measured by DEXA at 7 anatomic sites (Table 1). Both T- and Z-scores were measured in adult patients and the Z-score in children (5). Patients were advised to take vitamin D and calcium supplements after SCT. All but 1 female and no male patients were taking hormonal replacement therapy. Two patients (aged 61 and 65 years) continued taking biphosphonates given before SCT for osteoporosis. Radiologic evaluations for fractures were performed when clinically indicated only in symptomatic individuals.

Table 1. Site-Specific Incidence of Bone Loss
SiteOsteopeniaOsteoporosis
AP spine18(23%)14(18%)
Femoral neck36(46%)6(8%)
Femur (T)26(33%)3(4%)
Femur (IT)26(33%)2(3%)
Femur (W)28(35%)7(9%)
Total hip28(35%)3(4%)
Forearm19(24%)11(14%)

AP indicates anterior–posterior; T, trochanteric; IT, intertrochanteric; W, ward.

Definitions 

Bone mineral density results were expressed as the number of standard deviations from normal values of young, healthy, gender-matched controls (T-score) and from normal values of age- and gender-matched controls (Z-score). World Health Organization criteria for BMD were used. We classified patients as normal (T-score ≥ −1), osteopenia (T-score < −1 and > −2.5), and osteoporosis (T-score ≤ −2.5). Taking the broad age range of the study population, for children and adolescents, the Z-score was used to define the BL (osteopenia—Z-scores between 1 and 2, SD below the mean; osteoporosis—Z-score >2 SD below the mean) to avoid the underestimation. Another reason for selecting the T-score in adults over the Z-score is that the T-score has been shown to be the most relevant indicator of fracture risk in adults or older individuals [5, 6, 7].

Statistical Analysis 

Analysis was performed in November 2006. The risk factors influencing BL were determined by univariate and multivariate analyses of various clinical and transplant factors of patients with and without BL. In univariate analyses, chi-squared tests or Fisher’s exact tests were used for categoric variables where appropriate, and the Mann-Whitney U-test was used for continuous variables. Logistic regression was used for multivariate analysis, which included factors found to be significant in univariate analyses. Statistical significance was accepted at P < .05. The following variables were analyzed to identify factors associated with BL in long-term survivors: age (as a continuous or discontinuous variable); gender; diagnosis; BMT versus PBSCT, TBI versus no TBI, TBI dose 12 versus 13.6 Gy; disease risk (standard or high); follow-up (continuous, < versus ≥ median; 10 versus <10 years follow-up); acute GVHD (aGVHD), cGVHD, prolonged immunosuppressive therapy (IST) (beyond 3 years posttransplant). Analysis was performed separately for factors associated with overall BL (development of osteoporosis or osteopenia) and osteoporosis.

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Results 

Age of patients at transplantation ranged from 6-66 years (median: 35). Thirty-three patients were female and 46 were male. Seventy-seven (97%) are alive after median follow-up 78 months (range: 38-160) post-SCT. Two patients died from nonrelapse causes or progressive leukemia at 39 and 59 month’s post-SCT, respectively. aGVHD grades II-IV occurred in 15 (19%) patients and chronic GVHD in 63 (79.7%) (limited—47 [59.5%]; extensive—16 [20.2%]). Fourteen (18%) were on immunosuppression at the time of DEXA scanning at a median follow-up 42 months (range: 38-108).

BL 

Bone loss occurred in 58 (73.4%) patients; 33 (41.8%) with osteopenia and 25 (31.6%) with osteoporosis. However, no patient suffered fractures related to BL. The mean T-score of adult patients was −1.8 ± 0.18 (male: −1.9 ± 0.2; female: −1.6 ± 0.5); whereas the mean Z-score of 5 children (age: <18) was −1.6 ± 0.45. Site-specific BL is described in Table 1. There was a preponderance of osteopenia and osteoporosis in typical sites such as AP spine (23% and 18%), femoral neck (46% and 8%), femur (Ward’s area) (35% and 9%), and total hip (35% and 4%), but also in the forearm (24% and 14%).

Factors Associated with BL 

On univariate analysis significant factors for overall BL was prolonged IST, whereas for development of osteoporosis they were age and prolonged IST (P = .01) (Figure 1B). The oldest quartile suffered most with 11 of 19 (median age: 46 years, range: 44-66; mean T-score −2.3 ± 0.5) developing osteoporosis versus 14 of 60 in the younger 3 quartiles (P = .01). A similar higher incidence of osteoporosis was noted when age was grouped as < versus ≥ median (P = .03). All 14 patients, >3 years from transplant on immunosuppression (steroids 6; calcineurin inhibitors 7, sirolimus 1) at the time of study had BL compared with 44 of 65 not on IST (P = .01). Similarly, 9 of 14 on IST versus 16 of 65 not on IST had osteoporosis (P = .008). There was no impact of gender, diagnosis, BMT versus PBSCT, TBI versus no TBI, TBI dose 12 versus 13.6 Gy, disease risk (standard or high), follow-up (continuous, short versus long; 10 versus < 10 years follow-up), aGVHD, cGVHD on development of overall BL or osteoporosis in long-term survivors.

Again, multivariate logistic regression analysis age (oldest quartile versus first 3 quartiles odds ratio [OR] 3.5, P = .03; age < versus ≥ median OR 2.7, P = .45) and prolonged IST (OR 5.3, P = .01) were independently associated with increased risk of osteoporosis (Table 2).

Table 2. Significant Factors Associated with Osteoporosis after Allogeneic Stem Cell Transplantation—Logistic Regression Analysis
FactorOdd Ratio (OR)95% Confidence IntervalP
Age
First three quartile1.0
Oldest quartile3.51.1-11.4.03
Prolonged IST
No1.00
Yes5.31.3-21.2.01

IST indiciates immunosuppressive therapy.

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Discussion 

Bone loss is a well-recognized complication of SCT, but there is a wide variations in reported incidence (3%-52%) [2, 3, 5, 8, 9, 10, 11, 12, 13]. However. most previous studies report bone density within the first 2 years post-SCT [2, 9, 10, 11, 12]. Some studies address bone density beyond 2 years, but very few beyond 5 years post-SCT [3, 8, 14]. The longest follow-up at 10 years only reports osteoporosis-related findings from a questionnaire [3]. Our series is important because it is a detailed site-specific analysis of BL at 7 anatomic sites and risk factor analysis of long term-survivors after SCT at a median follow-up beyond 5 years, describing a 540 patient/year experience. The finding of a high rate of BL in SCT patients who are cured of their underlying disease and who mostly have no other comorbidities is of concern. As expected, older patients and those on prolonged IST for cGVHD suffered severe BL irrespective of type of IST. However even in younger patients more than half had BL. Despite a high prevalence of BL, no patient in our series experienced fractures; however, it is possible that we might have missed asymptomatic fractures because radiologic evaluation was performed only when clinically indicated. Similar to the study of Kerschan-Schind et al [14], we found no increase in BL after TBI-based MST compared to non-TBI based SCT.

The optimal management of BL after SCT is not known. Earlier studies have shown that BL occurs immediately after SCT [2, 4, 12] and recovery on longer follow-up has been reported [2, 3, 13]. Treatment of BL within 1-2 years after SCT with biphosphonates appears promising with improvement in bone mass index at certain sites but without correction in the hips [10, 12] and femoral neck [12, 13]. However, the benefit of treatment was lost when biphosphonates were stopped [12]. Furthermore, biphosphonates are associated with increased risk of osteonecrosis of the jaw and safety data for prolonged biphosphonates after SCT is not available.

Our study draws attention to BL as a prevalent and persisting complication of SCT that outlasts cGVHD. It, therefore, appears important to continue to monitor BL patterns life-long after SCT. Whether prevention and treatment of BL is useful with either calcium/vitamin-D or addition of biphosphonates should be determined by prospective studies. In the absence of other data we have chosen conservative management with calcium/vitamin-D, reserving biphosphonates for BL worsening on serial follow-up or for additional risk factors.

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References 

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 The first two authors contributed equally to this work.

PII: S1083-8791(07)00144-9

doi:10.1016/j.bbmt.2007.01.085

Biology of Blood and Marrow Transplantation
Volume 13, Issue 5 , Pages 517-520, May 2007

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