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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 3 1246-1254
Copyright © 2004 by The Endocrine Society

Changes in the Serum Growth Factors and Osteoprotegerin after Bone Marrow Transplantation: Impact on Bone and Mineral Metabolism

Ki Hyun Baek, Won Young Lee, Ki Won Oh, Hye Soo Kim, Je Ho Han, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang and Choon Choo Kim

Department of Internal Medicine (K.H.B., H.S.K., J.H.H., M.I.K., B.Y.C., K.W.L., H.Y.S., S.K.K.) and Hematopoietic Stem Cell Transplantation Center (C.C.K.), The Catholic University of Korea, College of Medicine, and Sungkyunkwan University School of Medicine (W.Y.L.), Mizmedi Hospital (K.W.O.), Seoul 150-010, Korea

Address all correspondence and requests for reprints to: Moo-Il Kang, M.D., Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Mary’s Hospital, The Catholic University of Korea, No. 62 Yoido-dong Youngdeungpo-Gu, Seoul 150-010, Korea. E-mail: mikang{at}catholic.ac.kr.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The loss of bone mass often occurs after bone marrow transplantation (BMT), particularly during the early posttransplant period. There are few reports on the role of growth factors and osteoprotegerin (OPG) in the post-BMT bone loss.

This study prospectively investigated 110 patients undergoing BMT and analyzed 36 patients who had dual-energy x-ray absorptiometry performed before BMT and 1 yr after BMT. The biochemical markers of bone formation and resorption were measured at the short-term intervals during the year-long follow-up. The serum IGF-I, IGF binding protein (IGFBP)-3, fibroblast growth factor-2, macrophage-colony stimulating factor (M-CSF), and OPG levels were measured before and 1 wk, 3 wk, and 3 months after BMT.

The mean bone loss in the lumbar spine and the total proximal femur, which was calculated as the percent change from the baseline to the level at 1 yr, was 5.2% (P < 0.05) and 11.6% (P < 0.01), respectively. During the immediate post-BMT period, bone formation decreased, whereas bone resorption increased, which was indicated by the biochemical markers of bone turnover. The serum IGF-I levels also decreased progressively until 3 wk and then increased to the basal values at 3 months. The serum IGFBP-3 levels decreased progressively until 3 months. The serum fibroblast growth factor-2 levels decreased to the nadir at 1 wk and gradually recovered to the basal values at 3 months. The serum M-CSF levels increased immediately after BMT, which declined to its baseline level by 3 months. The serum OPG levels increased progressively, reached a peak at 3 weeks, and declined thereafter. There were significant correlations between the IGF-I and osteocalcin levels before BMT and at 3 wk after BMT (r = 0.45, P < 0.01; r = 0.54, P < 0.01). During the observation period, the serum IGFBP-3 and M-CSF levels showed positive correlations with the osteocalcin and serum collagen I carboxyl-terminal telopeptide levels, respectively. Although statistically not significant, the OPG levels tended to be positively associated with the serum collagen I carboxyl-terminal telopeptide levels. Significant correlations were observed between the percent changes from the baseline to 1 yr in the bone mineral density at the proximal femur and the serum IGF-I levels at 3 wk and 3 months after BMT (r = 0.52, P < 0.01; r = 0.41, P < 0.05).


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
BONE MARROW TRANSPLANTATION (BMT) is the treatment of choice for many hematological diseases, and the number of long-term survivors has increased remarkably over recent decades. BMT is frequently complicated by endocrine abnormalities (diabetes mellitus, thyroid dysfunction, hypogonadism, hypopituitarism, growth retardation, adrenal insufficiency, etc.), and a loss of bone mass has also been well documented as a sequel to BMT. Previous studies have reported a 5–15% loss in the bone mineral density (BMD) at the lumbar spine and the femoral neck within 1 yr after BMT (1, 2, 3, 4). The pathogenesis of transplantation-related bone loss is multifactorial and is not completely understood. The underlying disease itself, primary hypogonadism, and posttransplant immunosuppressants may all contribute to this posttransplant bone loss (5, 6), and the osteogenic potential of the bone marrow stromal cells from the recipient is lower after BMT (7).

After BMT, the major part of bone loss occurs during the first 6 months (2, 8), which is the period when the bone turnover markers show an increase in bone resorption and suppressed bone formation, namely, biochemical uncoupling (2, 9). It was suggested that the progressive increase in bone resorption during the immediate post-BMT period is related to both the steroid dose and the increase in the bone marrow IL-6 levels (10). In addition, damage to the osteoprogenitor cells by myeloablative therapy suppresses bone formation after BMT (7). Graft-vs.-host disease (GVHD), immunosuppressants, cytokine changes, changes in the growth factor levels, and changes in the status of receptor activator of NF{kappa}B ligand (RANKL)/osteoprotegrin (OPG) may cause this paradoxical uncoupling, but there are few data on the detailed mechanisms.

The growth factors produced by osteoblasts, including IGF, fibroblast growth factor (FGF), bone morphonegenetic protein, and TGF-ß play an important role in bone growth and osteogenesis (11). They are capable of stimulating both osteoblast cell proliferation and differentiation. The IGF binding proteins (IGFBPs) modulate biological actions of IGF indirectly by their binding to IGF (12). In addition, IGFBPs by itself may directly affect bone metabolism (13). The macrophage-colony stimulating factor (M-CSF) is one of a family of growth factors for the cells of the mononuclear phagocyte system and plays a crucial role in osteoclast formation and bone resorption (14). In addition, OPG is a secreted soluble member of the TNF receptor family, which has been found to be a potent inhibitor of osteoclast differentiation and function (15). This study investigated the changes in the levels of bone growth factors (IGF-I, FGF-2, and M-CSF) and IGFBP-3 during the post-BMT period and also assessed whether or not the changes in growth factor levels actually influence bone turnover and post-BMT bone loss. This study also observed the change in OPG and its influence on post-BMT bone metabolism. This study is the first prospective investigation of changes in the levels of bone growth factors and OPG after BMT.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects and sample collection

One hundred and ten patients who had received allogenic BMTs were enrolled in this study. Those who died, were lost during follow-up, and relapsed were excluded from this group. Therefore, a total of 36 patients (32.4 ± 7.5 yr, 17 men and 19 women) whose BMD could be measured before and 1 yr after BMT were analyzed. The underlying hematological diseases of the 36 patients were 33 cases of leukemia, two of severe aplastic anemia, and one of myelodysplastic syndrome. This study was approved by the Institutional Review Board of St. Mary’s Hospital (Seoul, Korea), and informed consent was obtained from all patients.

The preparative regimens consisted of several combinations of chemotherapeutics (high-dose cyclophosphamide, procarbazine, busulfan, melphalan, and antilymphocyte globulin). Twenty patients received an additional total body irradiation (TBI) (10–13.2 Gy) as a conditioning regimen. To prevent GVHD in the recipients, iv cyclosporin A (5 mg/kg·d 1 d before BMT and 3 mg/kg·d until the 20th day after BMT) was administered. Thereafter, oral cyclosporin A at 6 mg/kg·d was begun and continued in a tapering dose for 6–12 months. Established GVHD was treated using a combination of iv methylprednisolone or oral prednisolone and cyclosporin A. The doses were tapered when the clinical control of GVHD was achieved. After the completion of the study, hormone replacement therapy was started for women who showed hypogonadism after BMT.

In all patients, the blood was sampled to determine the serum calcium, phosphorus, creatinine, and bone turnover marker levels [osteocalcin and collagen I carboxyl-terminal telopeptide (ICTP)] before BMT and at 1, 2, 3, and 4 wk, 3 and 6 months, and 1 yr after BMT. The serum IGF-I, IGFBP-3, FGF-2, M-CSF, and OPG levels were determined before and 1 wk, 3 wk, and 3 months after BMT. The correlations between the serum levels of the bone turnover markers (osteocalcin and ICTP) and either the growth factors (IGF-I, IGFBP3, FGF-2, and M-CSF) or OPG were examined.

Assays

The serum calcium, phosphorus, and creatinine levels were determined using an autoanalyzer (747 automatic analyzer, Hitachi, Tokyo, Japan). The serum osteocalcin (N-tact Osteo SP, INCSTAR, Stillwater, MN) and ICTP (Telopeptide ICTP, Orion Diagnostica, Espoo, Finland) concentrations were determined in duplicate using a RIA. The maximum inter- and intraassay coefficients of variation (CV) for the range of concentrations evaluated were 7.7 and 5.4% for osteocalcin and 10.7 and 3.6% for ICTP, respectively. The FGF-2 and M-CSF (ELISA kit, R&D Systems, Inc., Minneapolis, MN) concentrations were measured in duplicate by an ELISA with detection limits of 0.22 and 15 pg/ml, respectively. The maximum inter- and intraassay CV for the range of concentrations evaluated were 13.4 and 8.7% for FGF-2 and 5.2 and 4.5% for M-CSF, respectively. The IGF-I concentrations were measured using an immunoradiometric assay (Biosource IGF-1-D RIA CT kit, Biosource Europe S.A., Nivelles, Belgium) with an interassay CV of 13.4%. The serum IGFBP-3 concentrations were determined by an immunoradiometric assay (IGFBP-3 IRMA, Immunotech, Marseilles, France). The maximum inter- and intraassay CV were 9.5 and 6.0%, respectively. OPG was detected by an ELISA kit (Oscotec, Seoul, Korea) using a mouse monoclonal antibody and a rabbit polyclonal antibody for detection and recombinant human OPG as the standard. The assay detects both monomeric and dimeric forms of OPG, including the OPG bound to its ligand. The sensitivity of the assay was 30 pg/ml, and the maximum inter- and intraassay CV were 9.0 and 6.9%, respectively.

Bone densitometry

The BMD of the lumbar spine (lumbar vertebrae L2–L4) and the proximal femur (femoral neck, trochanter, and Ward’s triangle) was measured by dual-energy x-ray absorptiometry using a Lunar Expert (Lunar Corp., Madison, WI) before BMT and 1 yr after BMT. The precision of the method (CV) was 1.0% at both locations.

Statistical analysis

All the values are reported as a mean ± SEM. Statistical analysis was performed using SPSS software. Comparisons between the pre-BMT and post-BMT biochemical characteristics were made using a Student’s t test for the paired data. The Pearson’s correlation coefficients were used to examine the bivariate correlations between two variables. A P value < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Changes in bone turnover markers after BMT

After BMT, the level of bone resorption marker ICTP progressively increased and reached a peak at 3 and 6 months (13.8 ± 1.6 ng/ml and 14.0 ± 1.7 ng/ml; P < 0.001 vs. baseline). Thereafter, it declined to the baseline by 12 months. The level of the bone formation marker osteocalcin decreased until 3 wk after BMT (1.8 ± 0.3 ng/ml; P < 0.001 vs. baseline). The levels then increased transiently at 3 and 6 months and returned to the basal level after 1 yr (Fig. 1Go). The serum creatinine levels were within the normal range throughout the entire observation period.



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  		FIG. 1. The changes in the serum bone turnover markers before and after allogenic BMT. The data are reported as a mean value ± SEM. Immediately after BMT, the level of ICTP, which is a marker of bone resorption, progressively increased, reaching a peak at 3 and 6 months. Thereafter, it declined to the baseline by 12 months. The level of osteocalcin, which is a marker of bone formation, decreased and reached its nadir at 3 wk. The levels then increased transiently at 3 and 6 months, and thereafter, it recovered to the baseline level by 1 yr. The serum creatinine levels were within the normal range throughout the entire observation period. *, P < 0.05; {dagger}, P < 0.01 vs. the basal value.

 
Changes in BMD after BMT

The mean bone loss in the lumbar spine, which was calculated as the percent change from the baseline (1.156 ± 0.031 g/cm2) to the level 12 months after BMT (1.097 ± 0.035 g/cm2), was 5.2% (P < 0.05). In the proximal femur, the amount of bone loss was calculated to be 11.6% from the baseline (1.077 ± 0.027 g/cm2) to the level 12 months after BMT (0.952 ± 0.025 g/cm2; P < 0.01).

Changes in IGF-I, IGFBP-3, FGF-2, M-CSF, and OPG after BMT

The serum levels of IGF-I, IGFBP-3, FGF-2, M-CSF, and OPG were determined before BMT and at 1 and 3 wk and 3 months after BMT. After BMT, the IGF-I levels progressively decreased and reached the nadir at 3 wk (213.0 ± 19.1 ng/ml; P < 0.01 vs. baseline), which then increased until 3 months (Fig. 2AGo). The IGFBP-3 level progressively decreased until 3 months after BMT (2854.8 ± 339.9 ng/ml; P < 0.01 vs. baseline) (Fig. 2BGo). The FGF-2 levels also decreased and reached the nadir at 1 wk (2.6 ± 0.4 pg/ml; P < 0.01 vs. baseline), which then recovered thereafter (Fig. 2AGo). The M-CSF levels increased immediately after BMT, reached its maximum at 1 wk (487.6 ± 92.0 pg/ml, P < 0.01 vs. baseline), and then declined to its baseline level by 3 months (Fig. 3AGo). The OPG levels increased until 3 wk after BMT (2207.5 ± 155.3 pg/ml; P < 0.01 vs. baseline) and declined thereafter (Fig. 3BGo).



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  		FIG. 2. The changes in the serum IGF-I, FGF-2, and IGFBP-3 levels in the peripheral blood before and after BMT. The data are reported as a mean value ± SEM. *, P < 0.05; {dagger}, P < 0.01 vs. the basal value. After BMT, the IGF-I level progressively decreased and reached its nadir at 3 wk. Thereafter, it recovered to its initial level by 3 months. A, The FGF-2 level also decreased, reaching its nadir at 1 wk, and increased thereafter. B, IGFBP-3 level progressively decreased until 3 months after BMT.

 


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  		FIG. 3. The changes in the M-CSF and OPG levels in the peripheral blood before and after BMT. The data are reported as a mean value ± SEM. *, P < 0.05; {dagger}, P < 0.01 vs. the basal value. A, Immediately after BMT, the M-CSF level increased, reaching its maximum at 1 wk, which declined thereafter. B, The serum OPG level increased, reaching a peak at 3 wk, which declined thereafter.

 
During the observation period, there were no significant differences between males and females in the FGF-2, M-CSF, and OPG levels. However, the IGF-I levels were generally lower in women than in men, and this was significant at 1 and 3 wk after BMT (1 wk, 306.1 ± 88.7 ng/ml vs. 185.5 ± 29.5 ng/ml; P < 0.01; 3 wk, 244.4 ng/ml ± 63.5 ng/ml vs. 164.9 ± 48.7 ng/ml; P < 0.05) (Fig. 4AGo). In addition, the IGFBP-3 levels were lower in women, which was significant 3 wk after BMT (3525.6 ± 1348.0 ng/ml vs. 2780.6 ± 725.7 ng/ml; P < 0.05) (Fig. 4BGo).



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  		FIG. 4. A, The differences in the serum IGF-I levels between males (n = 17) and females (n = 19) before and after BMT. At 1 and 3 wk after BMT, there were significant differences between the two groups. *, P < 0.05; {dagger}, P < 0.01 between two groups. B, The IGFBP-3 levels were lower in women, which was significant 3 wk after BMT.

 
There were no significant differences in the levels of the growth factors and OPG between the patients treated with TBI and those patients who were not (data are not shown).

Correlation between the bone turnover markers and either the growth factors or the OPG after BMT

This study examined the correlations between the levels of the bone turnover markers (osteocalcin and ICTP) and the levels of the growth factors (IGF-I, IGFBP-3, FGF-2, and M-CSF) before BMT and at 1 and 3 wk and 3 months after BMT, respectively. This study also examined the relationship between the bone turnover markers and the OPG levels at the same time points. There were statistically significant correlations between the IGF-I and osteocalcin levels before BMT and at 3 wk after BMT (r = 0.45 and P < 0.01; r = 0.54 and P < 0.01) (Table 1Go). The IGFBP-3 levels correlated well with the osteocalcin levels 3 weeks after BMT (r = 0.59 and P < 0.01). A significant correlation was also found between the M-CSF and ICTP levels 3 weeks after BMT (r = 0.54 and P < 0.05). Although not significant, the M-CSF levels also showed a positive correlation with the ICTP levels at the other time points (Table 1Go). No association was found between the serum FGF-2 levels and the bone turnover markers during the entire period. No significant correlation was observed between the osteocalcin and OPG levels during the observation period. However, there was a trend for a correlation between the ICTP and OPG levels 3 wk after BMT (r = 0.29 and P = 0.07), and the relationship moved in a similar direction during the follow-up period (Table 1Go).


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  		TABLE 1. The correlations between the bone turnover markers and either the serum growth factors or OPG after BMT

 
Correlation between the changes of BMD and growth factors or OPG after BMT

The correlations between the growth factors or the OPG levels and the percentage changes from the baseline to 1 yr in the BMD at the lumbar spine and proximal femur were examined. Statistically, significant correlations were found between the percentage changes in the BMD at the proximal femur from the baseline to 1 yr and at the serum IGF-I levels 3 wk and 3 months after BMT. The correlation coefficients were 0.52 and 0.41, respectively (P < 0.01 and P < 0.05, respectively) (Fig. 5Go). Albeit not significant, the M-CSF levels tended to be negatively associated with the percentage changes in the BMD of the proximal femur from the baseline to 1 yr (Table 2Go). No significant correlation was found between the percentage changes in the BMD at the lumbar spine and any of the parameters measured from the baseline to 1 yr after BMT (Table 2Go). Bone loss at the lumbar spine and proximal femur was not clearly influenced by the OPG levels during the observation period (Table 2Go).



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  		FIG. 5. A, Relationship between the percent changes in the BMD at the proximal femur from the baseline to 1 yr after BMT and the serum IGF-I levels at 3 wk after BMT (r = 0.52; P < 0.01); B, relationship between the percent changes in the BMD at the proximal femur from the baseline to 1 yr after the BMT and the serum IGF-I levels at 3 months after BMT (r = 0.41; P < 0.05).

 

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  		TABLE 2. The correlations between the percentage changes from the baseline to 1 yr in the BMD at the lumbar spine and proximal femur and either the serum growth factors or OPG

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
BMT is now an established treatment for several hematological malignancies. More attention needs to be paid to the long-term side effects in these unique patients because the number of long-term survivors continues to increase. Bone loss is one of the long-term adverse effects of this procedure. The underlying pathophysiology is believed to be multifactorial. Post-BMT bone loss is associated with hypogonadism induced by TBI and/or high-dose chemotherapy, reduced bone formation by glucocorticoids, cyclosporine for the prevention/treatment of GVHD, and reduced physical activity.

In this prospective study on the amount of post-BMT bone loss, the cumulative bone loss in the transplant recipients was 11.6% in the proximal femur and 5.2% in the lumbar spine compared with the basal level. Previous studies have demonstrated that depending on the measurement site, the amount of bone loss in the recipients can vary from 5–15% in 1 yr (1, 2, 3, 4).

The data on the change in the bone turnover markers showed that bone resorption increased progressively and bone formation decreased during the early post-BMT period. These results are also consistent with previous reports (2, 3, 7, 9, 10). Such paradoxical uncoupling of the bone metabolism suggests that post-BMT bone loss is a consequence of an imbalance between bone formation and bone resorption. Indeed, bone loss occurs mainly during the first 6 months after the graft (2, 8), and a remodeling imbalance primarily appears to be responsible for the early post-BMT bone loss. After a period of biochemical uncoupling, bone resorption and bone formation increased in concert above the baseline level, as reflected by the ICTP and osteocalcin levels. This high bone turnover state appears to result from a deprivation of the sex hormone and the use of cyclosporine. Sex hormone deprivation due to primary hypogonadism increases the amount of bone turnover in a similar way as observed with natural menopause, and it is well recognized that cyclosporine activates the osteoblasts as well as the osteoclasts (16). In this study, the prevalence of hypogonadism was not examined. However, according to a previous study, 86% of female recipients developed ovarian failure within 6 months after their BMT (3).

The fact that the serum osteocalcin level decreased means that osteoblast function was inhibited during the early post-BMT period, and there may be several possible causes for this. The use of glucocorticoids, which inhibits osteocalcin formation, might be the first possible explanation for the decreased osteoblast activity (17, 18). In our previous experiments, a lower serum osteocalcin level was found in the high-dose steroid group than in the low-dose steroid group (10). A second possibility is that a dysregulation of cytokine production after BMT might inhibit osteoblast and osteocalcin production. IL-1 and TNF-{alpha} not only stimulate bone resorption but also inhibit bone formation (19, 20). Changes in these proinflammatory cytokines are well documented and have been reported to increase immediately after BMT (21, 22). A third explanation is that a substantial number of osteoprogenitor cells are damaged by the myeloablative therapy. The pretreatment including TBI and high-dose chemotherapy cause direct damage to the osteoprogenitor cells (23), and the differentiation of the bone marrow stromal cells into osteoblasts is impaired after BMT (7).

In addition, this study showed that serum IGF-I levels decreased for up to 3 wk after BMT, which correlated with the serum osteocalcin levels at 3 wk after BMT. IGF-I represents the most abundant growth factor produced by the osteoblasts and is stored in the bone. It has been shown to stimulate osteoblast proliferation and differentiation (11). Although the liver contributes the majority of circulating IGF-I, changes in the skeletal and circulating IGF-I levels are similar in several model systems (13), and the serum concentrations of this peptide may indeed reflect the bone status. TBI-induced hypothalamic pituitary injury actually decreases GH secretion (24), and it appears to contribute to the low IGF-I and osteocalcin level. However, in this study, the IGF-I levels in the TBI(+) and TBI(–) groups were similar. Besides, a gonadal dysfunction, myeloablation-related osteogenitor cell injury, and a poor nutritional status after transplant might result in the low IGF-I levels in the bony microenvironment.

The IGFBP-3 level also showed a positive correlation with the serum osteocalcin levels, and this correlation was obvious 3 wk after BMT. In an in vivo animal study, IGFBP-3 potentiates the anabolic actions of IGF-I on the bone when administered in combination (25), and the serum IGFBP-3 levels showed a positive correlation with the BMD in women with osteoporosis (26). Therefore, it is possible that IGFBP-3 may either directly or along with IGF-I influence the bone metabolism during the early post-BMT period.

After BMT, the IGF-I and IGFBP3 levels were generally (significantly at some time points) lower in the serum from females than from male recipients. This gender difference may result from hypogonadism, which almost always develops in female patients after BMT. In contrast, the gonadotropin levels and testosterone levels do not change significantly in male patients after BMT (3). It is believed that the circulating levels of IGF-I correlate with the decrease in plasma estradiol levels, which occurs during menopause (27). These sexual differences in the IGF system explain, at least partly, the greater susceptibility of women to bone loss after BMT than men (3).

The serum ICTP levels increased immediately after BMT and continued to increase for up to 6 months. This active osteoclastic activity might make a large contribution to the post-BMT bone loss. This study confirmed that the M-CSF levels increased during the early post-BMT period. In addition, the increase in bone resorption was significantly associated with M-CSF levels 3 wk after BMT. Although statistically significant at only one time point, there was a trend of positive correlation with the ICTP level at the other time points. Moreover, the correlation analyses revealed that bone loss at the proximal femur appeared to be affected by the increased M-CSF level. Indeed, M-CSF is one of a family of growth factors for the cells of the mononuclear phagocyte system (28) and is essential for osteoclast formation from the circulating mononuclear precursors (14).

The TNF family molecule RANKL and its receptor, RANK, are the key regulators of bone remodeling and are essential for the development and activation of osteoclasts (29). RANKL from the osteoblasts mediates osteoclastogenesis in the presence of M-CSF produced by the osteoblasts and stromal cells. In contrast, OPG is a decoy receptor that acts by binding to and neutralizing both the soluble and cell-bound form of RANKL. OPG inhibits the differentiation, survival, and fusion of the osteoclastic precursor cells and blocks the activation of mature osteoclasts (15).

In this study, the serum OPG levels increased initially and then decreased to the baseline, paralleling changes in the ICTP levels after BMT. Furthermore, the OPG levels tended to be positively associated with the ICTP levels. However, no correlations were found between the serum OPG levels and the amount of bone loss during the first year after BMT. This result on the change in the OPG level after BMT is not the same as those after cardiac and renal transplantation (30, 31). The serum OPG levels decreased significantly in cardiac and renal transplantation recipients with the initiation of immunosuppressive therapy. Steroids and cyclosporine are known to down-regulate OPG (32, 33). It is difficult to discern why this discrepancy between solid organ transplant and BMT exists. In this study, the mean daily dose of prednisolone administered during the first 3 months was 11.1 mg, which is much smaller than used for cardiac and renal transplantation. Although steroids are known to reduce the serum OPG levels, no correlation between the mean daily steroid dose and OPG was found (data are not shown). Because similar doses of cyclosporine were administered to all the recipients according to a predetermined schedule, we did not confirm the effect of cyclosporine on the changes in the OPG levels after BMT. In addition, the OPG levels in the TBI(–) and TBI(+) groups were similar. It is possible that an increase in the serum OPG levels during the early post-BMT period could possibly compensate for an increase in bone resorption. However, because serum OPG originates from many tissues (34), the circulating OPG levels may not reflect the local milieu of the bone metabolism within the bone microenvironment. Additional studies on the source of the circulating OPG after BMT as well as the effect of BMT on the changes in the RANKL, actually the OPG/RANKL ratio, will be needed. This may provide more information on the high bone resorption state during the post-BMT period.

A positive correlation between the serum ICTP level and the mean daily steroid dose after BMT was previously reported (10). A correlation between the bone marrow IL-6 level and the bone resorption marker was also observed (10). In addition to the aforementioned factors, cyclosporine use and hypogonadism would be other possible causes of the increased bone resorption after BMT.

From the viewpoint of the BMD, positive correlations were found between the percent changes in the BMD at the proximal femur from baseline to 1 yr after BMT and the serum IGF-I levels at 3 wk and 3 months after BMT. This suggests that patients who had lower IGF-I levels during the early post-BMT period lost more bone at the proximal femur during the first year after the BMT. The serum IGF-I levels are lower in elderly individuals, postmenopausal women, and men with idiopathic osteoporosis (11). In addition, the IGF-I content of cortical bone decreases with age (35). Based on these findings, it is conceivable that the BMT-related bone loss may be due, at least in part, to the underproduction of IGF-I. However, there were no significant correlations between the BMD loss of the lumbar spine and the IGF-I changes. The exact mechanism for this site-selective difference is unclear. However, according to a previous report, IGF-I plays a more important role in the endocrine regulation of cortical bone metabolism compared with that of trabecular bone metabolism (26).

The serum FGF-2 level showed an abrupt decline immediately after the transplant but returned to its basal level 3 months after BMT. Okunieff et al. (36) also reported a significant decrease in the serum FGF-2 level during and after TBI. It is conceivable that myeloablation-induced tissue injury, including the bone, caused the suppressed FGF-2 level. However, the exact mechanism will be determined in future studies. Although FGF-2 is known to play many important physiological roles in bone growth, remodeling, and repair, no correlation between the FGF-2 level and either the bone turnover markers or the BMD changes were found.

The data in this study provide evidence that bone growth factors such as IGF-I, IGFBP-3, FGF-2, M-CSF, and OPG dynamically change after BMT. The results also suggest that a progressive increase in bone resorption during the post-BMT period is related to an increase in the serum M-CSF level, and the decreased bone formation is associated with a low IGF-I level. Indeed, the IGF-I level during the post-BMT period exerts an influence on the post-BMT BMD. Despite the immunosuppressive therapy, the serum OPG level increases initially after BMT, paralleling the changes in the level of bone resorption. This may compensate for the high bone resorption state during the early post-BMT period.


   Footnotes
 
This work was supported by a grant from the Korean Ministry of Health and Welfare (01-PJ1-PG1-01CH08-0001).

K.H.B. and W.Y.L. contributed equally to the work reported.

A section of these results was presented in abstract form at the 24th Annual Meeting of the ASBMR, San Antonio, TX, 2002.

Abbreviations: BMD, Bone mineral density; BMT, bone marrow transplantation; CV, coefficient(s) of variation; FGF, fibroblast growth factor; GVHD, graft-vs.-host disease; ICTP, collagen I carboxyl-terminal telopeptide; IGFBP, IGF binding protein; M-CSF, macrophage-colony stimulating factor; OPG, osteoprotegerin; RANKL, receptor activator of NF{kappa}B ligand; TBI, total body irradiation.

Received July 11, 2003.

Accepted December 1, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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