Post-transplant complications Decreased bone mineral ... - Nature

Bone Marrow Transplantation (2001) 28, 387–391  2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt

Post-transplant complications Decreased bone mineral density is common after autologous blood or marrow transplantation AD Schimmer1, K Mah2, L Bordeleau3, A Cheung2, V Ali1, M Falconer1, M Trus2 and A Keating1 1

ABMT Long-term Follow-up Research Unit, University of Toronto ABMT Program; 2Princess Margaret Hospital; and 3Sunnybrook Regional Cancer Centre, University of Toronto, Toronto, Canada

Summary: Survivors of autologous blood or marrow transplantation (ABMT) are predisposed to decreased bone mineral density (BMD), but data are lacking on the incidence and risk factors for this condition. Therefore, we measured BMD in 64 of 68 consecutive ABMT survivors (35 men and 29 women) attending the University of Toronto ABMT long-term follow-up clinic. Patients were evaluated a median of 4.2 years (range: 4.9 months–11.4 years) after ABMT. Median age at evaluation was 49.6 years (range: 23.5–68.2 years). At the L1– L4 vertebrae, 17 (26%) patients (eight men and nine women) had osteopenia and one male (2%) had osteoporosis. Mean BMD at L1–L4 did not differ from healthy young adults or age and sex matched controls. At the femoral neck, 30 patients (46%) (18 men and 12 women) had osteopenia and five (8%) (two men and three women) had osteoporosis. Mean BMD at the femoral neck was significantly lower than in healthy young adults and age- and sex-matched controls. By regression analysis, patients with decreased BMD were older than those with normal BMD (P = 0.02). Gender, body mass index, time from BMT to evaluation and presence of hypogonadism were not associated with decreased BMD. Treatment of decreased bone density was instituted and follow-up data were obtained 1 year after treatment in 22 of 39 patients with reduced BMD. Nineteen (86%) patients had stabilization or improvement of their bone density at follow-up. We conclude that, after ABMT, over half of the patients have evidence of osteopenia or osteoporosis. Men and women were equally affected. In our study, only older age at evaluation was predictive for loss of BMD. We recommend the measurement of BMD as an integral component to the follow-up of ABMT patients. Bone Marrow Transplantation (2001) 28, 387–391. Keywords: ABMT; bone density; osteopenia; osteoporosis

Correspondence: Dr AD Schimmer, at his present address: The Burnham Institute, Building 6, Room 6308, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA Received 14 March 2001; accepted 11 June 2001

As the number of long-term survivors of autologous blood or marrow transplantation (ABMT) increases, greater attention is turning to the late complications of this procedure. One such complication is decreased bone mineral density – osteopenia and osteoporosis. Osteopenia is a systemic condition characterized by reduced bone mass and increased susceptibility to bone fracture. Osteoporosis is a more severe reduction in bone mass and a greater susceptibility to bone fracture. In the short term, osteoporosis seems trivial compared with a diagnosis of cancer, but for those cured of their disease, decreased bone mineral density contributes to chronic morbidity and mortality in the form of bone fractures. For example, 50% of patients who sustain an osteoporosisrelated hip fracture require assistance with activities of daily living1 and elderly patients who suffer an osteoporosis-related hip fracture have an increased 1-year mortality of 12–37%.2 ABMT predisposes to decreased BMD through early and late acting mechanisms. ABMT is associated with an acute increase in bone turnover due to the high-dose chemotherapy, marrow reinfusion and G-CSF administration, but effects on long-term bone density are unknown.3–5 The late effects of ABMT on BMD are primarily due to the hypogonadism induced by the alkylating agents and total body irradiation given pre-transplant.6–9 The patient’s underlying disease also contributes to reduced BMD. For example, chemotherapy, corticosteroids and retinoids received during induction and salvage therapy can decrease bone mineral density.10–13 Furthermore, multiple myeloma is associated with systemic osteoporosis as a result of increased osteoclastic activity.14 ABMT patients also may have general risk factors for osteoporosis that include older age,15 thin body habitus,16,17 a family history of osteoporosis,18 smoking,19,20 and physical inactivity.16 While survivors of ABMT have significant risks for decreased BMD, little is known about the incidence or predictive variables for osteopenia and osteoporosis in this population. Castelo-Braco et al21 reported a 70% incidence of decreased BMD among 13 women after either allo- or autotransplant. In contrast, Ebeling et al22 noted no decrease in BMD among 10 ABMT patients. These previous studies, however, involved small numbers of patients and often included results from both allo- and autotransplant patients. The results from studies in allotransplant

Decreased bone mineral density after ABMT AD Schimmer et al

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patients may not necessarily be applicable to ABMT patients. ABMT differs from allotransplant in that ABMT patients may be older, are more likely to have received prednisone in their induction and salvage chemotherapy regimens, and do not require immunosuppressive therapy including prednisone and cyclosporine after transplant. In view of these considerations, the rate of decreased BMD after ABMT may be different from the rate after allotransplant. Here, we report the incidence of decreased BMD among a cohort of consecutive long-term survivors of ABMT and identify factors predictive of bone loss after autotransplant.

breast cancer received mitoxantrone 63 mg/m2, vinblastine 12 mg/m2 and cyclophosphamide 6 g/m2. The patient with the desmoplastic round cell tumor received carboplatin 500 mg/m2 and thiotepa 250 mg/m2. Twenty-four patients also received total body irradiation (500–1200 cGy) prior to ABMT.

Patients and methods

Results

Patients

Patient characteristics

We evaluated BMD in 64 of 68 consecutive patients (35 men and 29 women) attending the University of Toronto ABMT long-term follow-up clinic between January 1999 and January 2000. Patients received their ABMT for nonHodgkin’s lymphoma (NHL) (n = 21), Hodgkin’s disease (HD) (n = 16), acute myeloid leukemia (AML) (n = 11), multiple myeloma (MM) (n = 11), breast cancer (Br ca) (n = 4), or desmoplastic round cell tumor (n = 1). Sixty-three of 64 patients were in remission at the time of evaluation. One patient had relapsed 3 years after ABMT for multiple myeloma, but had stable disease on prednisone (50 mg alternate days) for 15 months prior to evaluation. One patient developed myelodysplasia after ABMT for NHL and required red blood cell transfusions for 4 years prior to evaluation.

Table 1 lists the baseline characteristics of the 64 patients in the study. Patients were evaluated a median of 4.2 years (range 4.9 months–11.4 years) after ABMT. Median age at evaluation was 49.6 years (range: 23.5–68.2 years). At evaluation, patients were receiving prednisone for treatment of myeloma (n = 2) or adrenal insufficiency (n = 1), lthyroxine (n = 14), calcium (n = 7), and vitamin D (n = 4). Twenty-seven men were hypogonadal, defined as a decreased free or total serum testosterone levels, and not receiving testosterone supplementation at the time of evaluation. Eleven women were hypogonadal defined as an absence of cyclical menstrual cycles, reduced serum estradiol levels, and not receiving hormone supplementation at the time of evaluation. Four men and 12 women were on hormone replacement therapy at evaluation. Two women were receiving tamoxifen after ABMT for breast cancer. Three women had regained regular menses after ABMT. Ten of 11 patients with myeloma were receiving a bisphos-

Assessment of BMD BMD was evaluated at the L1–L4 vertebrae and the femoral neck by dual energy X-ray absorptiometry (DEXA). In serial evaluations, changes in bone density greater than 3% at L1–L4 and greater than 5% at the femoral neck were considered significant.23 Serial measurements were performed on the same DEXA scanner. All patients provided informed consent to participate in the study and undergo DEXA. Definitions Decreased BMD was defined according to WHO criteria.24 Osteopenia was defined as a T score between −1 and −2.5 and osteoporosis was defined as a T score less than −2.5; where a T score is the number of standard deviations from which a patient’s bone mass differs from the mean peak bone mass of healthy young adult. A Z score was also calculated and reflects the number of standard deviations from which a patient’s bone mass differs from the mean bone mass of age- and sex-matched controls. Intensive therapy prior to ABMT Most patients (n = 59) received VP-16 60 mg/kg and melphalan 160–180 mg/m2 as intensive therapy before transplantation as previously reported.9 The four patients with Bone Marrow Transplantation

Statistical analysis BMD scores between our cohort and matched controls were compared using Students’ t-tests. Predictive variables were determined by logistic regression analysis.

Table 1

Patient characteristics

n

64

Gender Male Female

35 29

Median time from ABMT to evaluation Median age at evaluation Underlying disease (n): NHL HD AML Multiple myeloma Breast cancer Desmoplastic round cell tumor Total body irradiation (n) Concurrent therapy (n) Prednisone l-thyroxine Bisphosphonates Calcium Vitamin D Hormone replacement

4.2 years (range 4.9 months–11.4 years) 49.6 years (range 23.5–68.2 years) 21 16 11 11 4 1 24 3 14 10 7 4 16


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phonate at evaluation (pamidronate (n = 9), alendronate (n = 1)). No patient had evidence for secondary osteoporosis from thyrotoxicosis or hyperparathyroidism. Two patients were smokers. None of the 64 patients reported bone fractures after ABMT. L1–L4 vertebrae BMD was measured at the L1–L4 vertebrae by DEXA. At the L1–L4 vertebrae, 17 of 64 patients (27%) had osteopenia (eight males and nine females) and one male (2%) had osteoporosis. Mean BMD at L1–L4 was 1.09 g/cm2 ± 0.17 g/cm2. Mean T and Z scores at L1–L4 were −0.3 ± 1.2 and 0.01 ± 1.2, respectively. The mean BMD at L1–L4 did not differ significantly from healthy young adults or age sex matched controls (P = 0.9 and 0.5 respectively by t-test). Of the ten patients with multiple myeloma, two had osteopenia at L1–L4. Femoral neck BMD was measured at the femoral neck by DEXA. At the femoral neck, 30 patients (47%) (18 males and 12 females) had osteopenia and five (8%) (two males and three females) had osteoporosis. Mean BMD at the femoral neck was 0.857 ± 0.161 g/cm2. The mean T and Z scores at the femoral neck were −0.9 ± 1.3 and −0.3 ± 1.1, respectively. Mean BMD at the femoral neck was significantly lower than in healthy young adults and age and sex matched controls (P = 0.0009 and 0.0007, respectively, by the t-test). Of the 10 patients with multiple myeloma, six had osteopenia at the femoral neck and two had osteoporosis. Variables predictive for decreased BMD after autotransplant By logistic regression analysis, patients with decreased BMD were older than those with normal BMD (P = 0.02). Gender, body mass index, time from BMT to evaluation, TBI, the presence of hypogonadism and underlying disease were not predictive for decreased BMD after autotransplant.

Normal 39% Osteopenia 53%

Osteoporosis 8% Figure 1 Bone mineral density at the femoral neck and L1–L4 vertebrae among survivors of ABMT. Osteopenia was defined as a T score between −1 and −2.5 and osteoporosis was defined as a T score less than −2.5; where a T score is the number of standard deviations from which a patient’s bone mass differs from the mean peak bone mass of healthy young adult. The lower T score between the femoral neck and the L1– L4 vertebrae was used to determine the presence of osteopenia or osteoporosis.

Although not a primary endpoint of the study, repeat DEXA studies were performed in 22 of the 39 patients with reduced BMD 1 year after their initial scans and the institution of therapy. Scans were not obtained in 17 patients due to the development of relapsed disease (n = 4), a second malignancy (n = 1), loss to follow-up (n = 2) or patient or physician preferences (n = 10). Of the 22 patients with repeat scans, 13 showed no change in their BMD, six had increased bone density at L1–L4 or the femoral neck and three had decreased BMD at L1–L4 or at the femoral neck. The details of the significant changes in BMD of the nine patients are shown in Table 2. Of the three patients with decreased BMD on follow-up, one received an ABMT for myeloma, one for NHL, and one for breast cancer. All patients with decreased BMD on follow-up were in remission between scans. Discussion

Follow-up of BMD Thirty-nine of 64 (61%) patients had osteopenia or osteoporosis in the lumbar spine and/or femoral neck (Figure 1). After DEXA scanning, these patients received treatment according to the Canadian consensus guidelines for the treatment of osteoporosis.25 Briefly, patients with osteopenia and osteoporosis at the lumbar spine or femur were provided lifestyle counseling by the clinic nurses that included advice on increasing physical activity and reducing osteoporosis-related risk factors, such as smoking and excess alcohol intake. Patients with decreased BMD were prescribed calcium and vitamin D. Those with hypogonadism were offered hormone replacement therapy if there were no contraindications. Patients with osteoporosis of the lumbar spine or femur were also prescribed bisphosphonates. Compliance with the prescribed treatment was not measured.

Decreased BMD can lead to significantly increased morbidity and mortality because of osteoporosis-related bone fractures.1,2 Survivors of ABMT have risk factors for decreased BMD that are greater than the general population. Yet, little is known about the incidence and risk factors for decreased BMD after ABMT. We studied the incidence of decreased bone mineral density among 64 consecutive survivors of ABMT attending our ABMT longterm follow-up clinic. In our cohort, we observed a 61% incidence of decreased BMD at the L1–L4 vertebrae or femoral neck. This value can be compared to a 31% incidence of osteoporosis or osteopenia among a general cohort of 5896 women aged 46–54 years.26 The incidence of decreased BMD that we observed is comparable to results of previous studies on osteoporosis after allo- or autotranplant. Valimaki et al27 studied 44 adults 1 year after allotransplantation. Osteopenia or osteoBone Marrow Transplantation


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Table 2

Characteristics of patients with significant changes in BMD after 1 year of treatment for osteopenia or osteoporosis

Patient No.

Underlying disease

T score at L1–L4 at evaluation

NHL MM Br Ca MM MM NHL NHL NHL MM

−1.5 1 −0.9 −2.1 −0.76 −1.63 0.9 −2.35 0.57

1 2 3 4 5 6 7 8 9

Change at L1–L4 after 1 year (%)

3.3 12 −4.2 −3.3 4.5 4.5 −17 NS NS

T score at femoral neck at evaluation

Change at femoral neck after 1 year (%)

−1.33 −3 −1.5 −2.2 −2.32 −2.43 −1.3 −2.16 −1.61

NS NS NS NS NS NS NS 9.5 6.5

NS = no significant change.

porosis was detected at the lumbar spine or femoral neck in 50% and 45% of patients. Comparable results were obtained by Sullivan et al28 who studied a similar population. Castelo-Braco et al21 reported on 13 females 13 months (mean) after transplant. Eight females underwent autotransplantation and five received an allotransplant. All 13 women were menopausal at evaluation and none were receiving hormone replacement therapy. In this group, 70% had evidence of osteopenia or osteoporosis in the lumbar spine. In contrast, Ebeling et al22 reported no osteopenia or osteoporosis in a group of 10 patients evaluated 1 year after ABMT. The lack of decreased BMD in these patients may be due, in part, to the early use of estrogen replacement therapy. Furthermore, a greater incidence of decreased BMD may become apparent with longer follow-up. All females received hormone replacement therapy starting 2 months after transplant. The authors did not comment on calcium and vitamin D supplemental intake by their patients. The incidence of bone fractures after allo- or autotransplant is not well characterized. We did not observe any bone fractures among our patients after ABMT. Others have reported an incidence of rib and vertebral fractures ranging from 1%–9%.22,28,29 The low incidence of bone fractures in this group may reflect the relatively young age of blood and marrow transplant survivors. As the number of older long-term transplant survivors increases, a greater appreciation of the incidence of osteoporosis-related bone fractures after transplantation is likely. In our study, older age was the only significant predictor for decreased bone density after ABMT by regression analysis. While multiple myeloma is a known risk factor for decreased bone mineral density,14 underlying disease was not predictive in our model. Eight of 10 patients (80%) with myeloma had decreased BMD after ABMT. Even if the patients with myeloma are excluded from the analysis, the incidence of decreased BMD is 31 of 54 patients (57%), which is still higher than a general cohort.26 It is noteworthy that gender was not predictive for decreased bone density. The similar incidence of decreased BMD among the males and females is likely related to the high rate of hypogonadism seen in both groups after ABMT.9,30 Ebling et al22 reported that bone loss correlated with cyclosporine use and Bone Marrow Transplantation

cumulative prednisone dose received after allotransplant, but the impact of other demographic and clinical variables was not reported. The other studies on bone density after blood or marrow transplant did not report predictive variables. In our study, 22 patients with osteopenia or osteoporosis had their bone mineral density evaluation repeated 1 year after treatment. While not a primary end-point of the study, 86% of these patients had stabilization or improvement in bone density. To our knowledge, no other group has documented the response to therapy for decreased bone density after allo- or autotransplant. BMD was not measured prior to ABMT in our patients, so we can not tell whether the abnormalities are due to the induction or salvage therapy the patients received or to the ABMT intensive therapy regimen. The lack of pretransplant BMD measurements are a limitation to the study and impair our ability to comment on the cause of the abnormality. However, osteopenia and osteoporosis are issues that pertain more to long-term survivors of bone marrow transplant than to patients battling relapsed disease, so it is the posttransplant scores that are clinically most important. In conclusion, after ABMT, most patients have evidence of osteopenia or osteoporosis. Men and women were equally affected. In our study, only older age at evaluation was predictive for loss of BMD. Since early recognition and aggressive treatment of bone loss can prevent bone fracture, we recommend that measurement of BMD and aggressive preventive therapy be an integral component to the followup of ABMT patients. Acknowledgements ADS was supported by fellowships from the Canadian Institute of Health Research and the Leukemia Research Fund of Canada. AK holds the Gloria Seymour Chair in Cell Therapy and Transplantation at the University of Toronto and University Health Network. We would like to thank MD Minden (Princess Margaret Hospital, Toronto, Canada) for his helpful advice and discussion.

References 1 Lindsay R, Cosman F. Primary osteoporosis. In: Coe F, Favus M (eds). Disorders of Bone and Mineral Metabolism. Raven Press: New York, NY, 1992, pp 831–888.


2 Lyons AR. Clinical outcomes and treatment of hip fractures. Am J Med 1997; 18 (Suppl.): 51S–63S. 3 Carlson K, Simonsson B, Ljunghall S. Acute effects of highdose chemotherapy followed by bone marrow transplantation on serum markers of bone metabolism. Calcif Tissue Int 1994; 55: 408–411. 4 Withold W, Wolf HH, Kollbach S et al. Monitoring of bone metabolism after bone marrow transplantation by measuring two different markers of bone turnover. Eur J Clin Chem Clin Biochem 1996; 34: 193–197. 5 Takamatsu Y, Simmons PJ, Moore RJ et al. Osteoclastmediated bone resorption is stimulated during short-term administration of granulocyte colony-stimulating factor but is not responsible for hematopoietic progenitor cell mobilization. Blood 1998; 92: 3465–3473. 6 Keilholz U, Korbling M, Fehrentz D et al. Long-term endocrine toxicity of myeloablative treatment followed by autologous bone marrow/blood derived stem cell transplantation in patients with malignant lymphohematopoietic disorders. Cancer 1989; 64: 641–645. 7 Mertens AC, Ramsay NK, Kouris S, Neglia JP. Patterns of gonadal dysfunction following bone marrow transplantation. Bone Marrow Transplant 1998; 22: 345–350. 8 Shalet SM, Didi M, Ogilvy-Stuart AL et al. Growth and endocrine function after bone marrow transplantation. Clin Endocrinol 1995; 42: 333–339. 9 Schimmer AD, Quatermain M, Imrie K et al. Ovarian function after autologous bone marrow transplantation. J Clin Oncol 1998; 16: 2359–2363. 10 Brennan BM, Rahim A, Adams JA et al. Reduced bone mineral denisty in young adults following cure of acute lymphoblastic leukaemia in childhood. Br J Cancer 1999; 79: 1859– 1863. 11 Leone J, Vilque JP, Jolly D et al. Effect of chlorambucil on bone mineral density in the course of chronic lymphoid leukemia. Eur J Haematol 1998; 61: 135–139. 12 Melhus H, Michaelsson K, Kindmark A et al. Excessive dietary intake of vitamin A is associated with reduced bone mineral density and increased risk of hip fracture. Ann Intern Med 1998; 129: 770–778. 13 Carlson K, Simonsson B, Ljunghall S. Acute effects of highdose chemotherapy followed by bone marrow transplantation on serum markers of bone metabolism. Calcif Tissue Int 1994; 55: 408–411. 14 Taube T, Beneton MN, McCloskey EV et al. Abnormal bone remodelling in patients with myelomatosis and normal biochemical indices of bone resorption. Eur J Haematol 1992; 49: 192–198. 15 Schott AM, Cormier C, Hans D et al. How hip and wholebody bone mineral density predict hip fracture in elderly women: the EPIDOS prospective study. Osteoporos Int 1998; 8: 247–254.

16 Turner LW, Fu Q, Taylor JE, Wang MQ. Osteoporotic fracture among older US women: risk factors quantified. J Aging Health 1998; 10: 372–391. 17 Rubin LA, Hawker GA, Peltekova VD et al. Determinants of peak bone mass: clinical and genetic analyses in a young female Canadian cohort. J Bone Miner Res 1999; 14: 633– 643. 18 Cohen-Solal ME, Baudoin C, Omouri M et al. Bone mass in middle-aged osteoporotic men and their relatives: familial effect. J Bone Miner Res 1998; 13: 1909–1914. 19 Cornuz J, Feskanich D, Willett WC, Colditz GA. Smoking, smoking cessation, and risk of hip fracture in women. Am J Med 1999; 106: 311–314. 20 Grainge MJ, Coupland CA, Cliffe SJ et al. Cigarette smoking, alcohol and caffeine consumption, and bone mineral density in postmenopausal women. The Nottingham EPIC Study Group. Osteoporos Int 1998; 8: 355–363. 21 Castelo-Braco C, Rovira M, Pons M et al. The effect of hormone replacement therapy on bone mass in patients with ovarian failure due to bone marrow transplantation. Maturitas 1996; 23: 307–312. 22 Ebeling PR, Thomas DM, Erbas B et al. Mechanisms of bone loss following allogeneic and autologous stem cell transplantation. J Bone Miner Res 1999; 14: 342–350. 23 Nguyen TV, Popock N, Eisman JA. Interpretation of bone mineral density and its changes. J Clin Densitom 2000; 3: 107–119. 24 Kanis JA, Gluer CC. An update on the diagnosis and assessment of osteoporosis with densitometry. Committee of Scientific Advisors, International Osteoporosis Foundation. Osteoporos Int 2000; 11: 36–42. 25 Hanley DA, Josse RG. Prevention and management of osteoporosis: consensus statements from the Scientific Advisory Board of the Osteoporosis Society of Canada. CMAJ 1996; 155 (Suppl.): 921–923. 26 Smeets-Goevaers GC, Lesusink GL, Papapoulos SE et al. The prevalence of low bone mineral density in Dutch perimenopausal women: Eindhoven perimenopausal osteoporosis study. Osteoporos Int 1998; 8: 404–409. 27 Valimaki MJ, Kinnunen K, Tahtela R et al. A prospective study of bone loss and turnover after allogeneic bone marrow transplantation: effect of calcium supplementation with or without calcitonin. Bone Marrow Transplant 1999; 23: 355– 361. 28 Sullivan KM, Stern JA, Seidel K et al. Bone density during the first year following allogeneic bone marrow transplantation. Blood 1998; 92: (Suppl. 1) 493a (Abstr. 2030). 29 Stern JM, Chesnut CH, Bruemmer B et al. Bone density loss during treatment of chronic GVHD. Bone Marrow Transplant 1996; 17: 395–400. 30 Schimmer AD, Ali V, Imrie K et al. Male sexual function after autologous blood or marrow transplantation. Blood 1997; 90 (Suppl. 1): 379a (Abstr. 1689).

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