Bone loss is recognized as one of the most frequent complications in long-term survivors after allogeneic stem cell transplantation [
Prospective studies of bone loss in patients after allo-HSCT are sparse, and cross-sectional studies revealed conflicting data. A positive correlation of bone loss was found for corticosteroid and CSA use, baseline BMD, and loss of muscle mass [
Oral bisphosphonates are widely used for treating osteoporosis and have been shown to improve BMD and decrease the rate of fractures in various patient populations [
The present study aimed at investigating the 12- and 24-month effect of ZA administration on lumbar and femoral BMD and bone turnover markers. Moreover, these data were correlated to clinical features. Finally, we identified risk factors which were associated with significant bone loss in this setting.
The study protocol was approved by the institutional ethics committee. Informed consent was given by the patient prior to study entry.
Forty patients after allo-HSCT were recruited on this prospective, monocentric phase II study between 2001 and 2006 at the Ludwig-Maximilians University Hospital of Munich.
The general aim of the study was to evaluate efficacy and tolerance of a 24-month interval therapy with ZA in patients with osteopenia/osteoporosis after allo-HSCT.
Eligibility criteria were as follows: signed informed consent, allogeneic HSCT within 4 years until inclusion, age ≥18 years, osteoporosis (T-score ≤−2.5 SD) or osteopenia (T-score −1.0 to −2.4), KPS ≥70%.
Exclusion criteria were relapsed underlying malignancy, and serum creatinine >1.5 mg/dL, history of tooth extraction or surgery of the jaw during the last six months, prior bisphosphonate treatment, or women with hypogonadism without adequate hormone replacement therapy.
The main variable was the mean percentage change of BMD of the lumbar spine (L1–L4) compared to baseline. Patients were screened for BMD by dual energy X-ray absorptiometry (DXA-Lunar prodigy). Secondary endpoints included BMD of total femur hip, parameters of bone modulation in serum and urine, for example, deoxypyridinoline (Dpd), and calcium excretion in urine by longitudinal measurements.
ZA was given at a dose of 4 mg IV every 3 months for 2 years (yrs) in combination with calcium (>500 mg/d), vitamin D3 (>400 IE/d), and, in case of hypogonadism, hormone-replacement therapy.
According to recent trials in patients with reduced BMD after allo-HSCT, the mean percentage annual bone increment will be estimated at 7.2% by a SEM of 0.49% and a standard deviation of 2.7%, respectively. To detect these changes by means of a paired
Forty patients fulfilled the inclusion criteria. Baseline examination was median 15.6 months after allo-HSCT. 36 patients (24 male, 12 female; median age 43.8 yrs) who had received at least 3 doses of ZA were evaluable. None of them had fractures. 26 out of those patients had at least two BMD measurements since baseline (BMD group) (Figure
Study design and flowchart. *BMD and Dpd measurements = BMD group (by DXA).
Detailed information of baseline characteristics and type of allo-HSCT is given in Table
Patient characteristics prior to study entry.
All patients ( | BMD group ( | |
---|---|---|
Median age (yrs) at HSCT (range) | 43.8 (18–64) | 43.9 (18–64) |
Gender (male/female) | 24/12 | 18/8 |
Underlying disease | ||
AML | 15 | 11 |
CML | 11 | 8 |
ALL | 5 | 4 |
NHL | 3 | 1 |
MDS | 2 | 2 |
Type of HSCT (BM/PBSCT/both) | 16/16/4 | 12/10/4 |
HLA (identical/different) | 28/8 | 19/7 |
Donor (related/unrelated) | 19/17 | 15/11 |
Donor sex (male/female) | 18/18 | 12/14 |
Cytoreduction prior to conditioning | 11 | 9 |
TBI ( | 9/12/15 | 7/9/10 |
Busulphan | 9 | 7 |
Cyclophosphamide | 35 | 26 |
ATG | 32 | 23 |
Immunosuppression | ||
CSA-MTX | 24 | 18 |
CSA-MMF | 12 | 8 |
Acute/chronic GvHD | 28/26 | 20/17 |
Corticosteroids prior to study | 29 | 20 |
Duration (days) ± SD | 152 ± 173 | 159 ± 198 |
Cumulative dose (g) ± SD | 11.1 ± 8.6 | 11.1 ± 9.1 |
Corticosteroids during the study | 29 | 20 |
Duration (days) ± SD | 628 ± 209 | 625 ± 121 |
Cumulative dose (g) ± SD | 5.4 ± 2.4 | 5.2 ± 1.6 |
The baseline examination of BMD was median 15.6 months after allo-HSCT. 26 out of 36 patients had at least two BMD measurements since baseline (BMD group). Among these patients, BMD (mean ± SD) of the lumbar spine significantly increased from
BMD (mean ± SD; g/m²) of lumbar spine (a) and femur hip (b) after treatment with zoledronic acid.
Lumbar spine: baseline 0.97 (±0.15), 1 year 1.04 (±0.18), 2 years 1.10 (±0.18)
Femur hip: baseline 0.82 (±0.10), 1 year 0.87 (±0.11), 2 years 0.91 (±0.10)
T-scores (mean ± SD) of lumbar spine and femur hip increased significantly compared to baseline (
T-score (mean ± SD) of lumbar spine (a) and femur hip (b) after treatment with zoledronic acid.
Lumbar spine: baseline −1.99 (±1.20), 1 year −1.41 (±1.49), 2 years −0.85 (±1.48)
Femur hip: baseline −1.88 (±0.83), 1 year −1.53 (±0.86), 2 years −1.18 (±0.70)
The increase of BMD (mean ± SD) was significantly pronounced in younger patients (<45 yrs) than in older patients (BMD FH:
Other analyzed factors as corticosteroid therapy prior to or during the study, baseline BMD, and underlying malignancy prior to allo-HSCT were not significantly associated with changes of BMD.
Detailed information is given in Table
Percentual BMD increase (%) of femur hip-significant and nonsignificant parameters (BMD group
1 year | 2 years | |||||
---|---|---|---|---|---|---|
1 year | 2 years | |||||
Age | <45 years | 16 | 8.9 | 12.0 | 0.007 | 0.02 |
≥45 years | 10 | 2.9 | 3.4 | |||
Donor gender | Female | 14 | 7.6 | 10.2 | 0.04 | 0.05 |
Male | 12 | 2.9 | 4.4 | |||
Immunosuppression | CSA/MTX | 18 | 7.1 | 9.3 | 0.01 | 0.02 |
CSA/MMF | 8 | 2.2 | 3.9 | |||
Gender | Male | 18 | 6.5 | 8.6 | — | — |
Female | 8 | 3.5 | 5.4 | — | — | |
BMD | Osteopenia | 13 | 5.5 | 7.8 | — | — |
Osteoporosis | 13 | 9.6 | 7.8 | — | — | |
Prior steroids | Yes | 20 | 5.9 | 8.2 | — | — |
No | 6 | 4.3 | 5.5 | — | — | |
Steroids during study | Yes | 20 | 5.3 | 8.8 | — | — |
No | 6 | 5.6 | 7.2 | — | — | |
Diagnosis | CML | 8 | 5.5 | 6.7 | — | — |
AML | 11 | 4.7 | 6.6 | — | — |
(—) Not significant.
36 patients had received at least 3 doses of ZA according to the study protocol (median 5 doses, range 3–8). Deoxypyridinoline (Dpd, nmol/nmol creatinine) decreased from
Metabolic parameters (mean values),
Baseline | 1 year | 2 years | ||
---|---|---|---|---|
Serum | Calcium (mmol/L) | |||
Phosphate (mg/dL) | ||||
Creatinine (mg/dL) | ||||
Albumin (g/dL) | ||||
Urine | Ca (mmol/24 h) | |||
Dpd* (nmol/nmol creatinine) | ||||
Estradiol (pg/mL) | ||||
FSH (IU/L) | ||||
LH (lU/L) | ||||
Vitamin D3 | OH (ng/mL) | |||
1,25 di-OH (pg/mL) |
± SD: standard deviation; Dpd: deoxypyridinoline, *
In general, ZA was well tolerated. One out of 40 patients was excluded after the first dose due to severe myalgia. Mild flu-like syndromes, bone pain, chest pain, or headache have been observed in 6 patients. None of the patients developed hypocalcaemia or increased creatinine serum levels (Table
Transplantation of hematopoietic stem cells is a widely accepted treatment option for various hematologic diseases. Despite constantly increasing survival rates, allo-HSCT is still associated with a considerably high morbidity and mortality. Therefore, long-term survivors after allo-HSCT are confronted with new problems if they develop chronic osteopenia or osteoporosis [
Factors which are associated with bone loss are age, hypogonadism, presence of GvHD and subsequent use of corticosteroids, and other immunosuppressants [
Data from prospective studies of bone loss in patients after allo-HSCT are sparse. Moreover, these studies revealed conflicting data. Studies with an observational period of 3, respectively, 4 years, demonstrate a rapid bone loss within the first 6 months [
Bisphosphonates are widely accepted for the treatment of osteoporosis and osteopenia. They have proven to be effective to increase BMD and to decrease the rate of skeletal complications in a variety of patient populations [
The increase in BMD was evident throughout the whole study population and during the whole study period. Nevertheless, there were some striking differences in BMD increase within subgroups. The percentual increase in BMD was significantly higher in patients at a younger age, in patients whose donor was a female and who had received immunosuppression with CSA/MTX. The latter may be speculatively explained by the finding that MMF is associated with hypocalcaemia and hypomagnesaemia in approximately 30%. But this had never been evaluated in a study.
In contrast to previous studies of Chae et al., and Schulte and Beelen, our data have not confirmed an influence of corticosteroid treatment on BMD increment [
Certainly, there are limitations of the present study consisting of a low study number, loss of patients who had undergone BMD measurements according to the study protocol (26 out of 36 patients), inclusion of patients with osteopenia and osteoporosis, and, moreover, limitations consisting of the heterogeneity of an allotransplant patient population (e.g., underlying disease, conditioning protocol, TBI). All these transplantation-associated factors certainly contribute to the presented results.
Multiple factors contribute to bone loss after allo-HSCT. Long-term survivors are confronted with severe problems, if they develop osteopenia- or osteoporosis-related complications as chronic pain and/or fractures. In summary, ZA was found to be effective not only to prevent but also to treat evident bone loss in the femoral hip and spine of patients after allo-HSCT. Thus, patients who are at a high risk for bone loss should be monitored carefully and should be considered to use ZA to prevent and to treat bone loss and skeletal events. However, the optimal time of initiation and duration requires further studies.
The authors declare that there is no conflict of interests.
The study was supported by Novartis Pharma GmbH, Germany.