The osteoprotegerin (OPG)/receptor activator of NF-kappa B ligand (RANKL) system has a major role in the pathogenesis of bone disease in myeloma (MM). The effect of autologous stem cell transplantation (ASCT) on bone turnover in MM was evaluated in 51 patients (35M/16F). Markers of bone resorption (NTX, TRACP-5b), bone formation (bone-alkaline phosphatase (bALP), osteocalcin), OPG and sRANKL were measured pre- and every month post-ASCT. The median follow-up period was 12 months. Four patients were transplanted in CR, 44 were transplanted in PR and three patients had progressive/resistant disease. All patients received bisphosphonates both pre- and post-ASCT. At baseline the majority of patients had increased NTX, TRACP-5b levels, and sRANKL/OPG ratio, while markers of bone formation were strongly suppressed. ASCT produced a significant reduction of sRANKL/OPG ratio, with a concomitant decrease of NTX, and TRACP-5b levels, starting the second month post-ASCT. Bone formation markers, osteocalcin and bALP, started to increase after the 9th and 11th month post-ASCT, respectively, while the increase of OPG preceded this. These results provide biochemical evidence that ASCT normalizes the abnormal bone resorption in MM patients possibly through the decrease of RANKL/OPG ratio, while bone formation requires a longer period to return to normal.
Bone disease in multiple myeloma (MM) mainly includes osteolytic lesions due to an increased osteoclastic activity, which is not accompanied by a comparable increase in bone formation.1 Excessive bone resorption may be present even in cases with early disease, while lytic lesions may progress following chemotherapy.2 Cytokines produced locally by stromal or myeloma cells, including interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), macrophage inflammatory protein-1 alpha (MIP-1α) are responsible for the osteoclast activation.3, 4 The receptor activator of nuclear factor-kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system has a major role in osteoclastogenesis, as RANKL directly induces osteoclast differentiation and proliferation by binding to its receptor RANK on the surface of osteoclast precursors.5 OPG is the soluble decoy receptor for RANKL and one of the most potent antiresorptive agents known. OPG-deficient mice have marked osteopenia and increased number of osteoclasts, while RANK-deficient mice develop severe osteopetrosis.6, 7 In MM the ratio of RANKL/OPG is increased due to an increase in RANKL production and a decrease in OPG production by stromal cells.8 In murine myeloma models RANKL expression correlates with the presence of lytic lesions, while the administration of RANK-Fc or recombinant OPG improves bone disease and decreases myeloma tumor burden.9, 10 Furthermore, the ratio of soluble RANKL (sRANKL)/OPG has recently been found to be elevated in the serum of patients with MM at diagnosis and correlates with the extent of bone disease as well as survival in these patients.11, 12 The possible presence and production of RANKL by myeloma cells may explain the major role of this pathway in the biology of myeloma bone disease as well as tumor growth and survival.13, 14, 15
High-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) is the treatment of choice for eligible patients with MM, conferring a survival advantage of around 15 months over conventional chemotherapy.16, 17 There is some evidence that ASCT may help in normalizing the abnormal bone remodeling in myeloma.18 However, there is no information about the effect of ASCT on the RANKL/OPG pathway, osteoclast activity, and the novel markers of bone remodeling. Furthermore, the observation that ASCT correlates with a significant and persistent loss of bone mineral density (BMD) in patients with leukemia or lymphoma reflects the complex effect of ASCT on the bone.19 The aim of this study was to evaluate the effect of ASCT on bone remodeling in patients with MM, and to investigate if there is any correlation between markers of bone turnover and response to treatment. We measured sRANKL, OPG, markers of bone resorption (N-telopeptide of collagen type I (NTX), and tartrate-resistant acid phosphatase isoform 5b (TRACP-5b)) and bone formation ((bone alkaline phosphatase (bALP), and osteocalcin (OC)), before and every month post-ASCT in an attempt to better understand the effect of ASCT on myeloma bone disease and myeloma biology.
Patients and methods
In all, 51 patients (35M/16F) with MM who received HDT and ASCT were studied. All patients had adequate stem cell collection (at least 2 × 106 CD34+ cells/kg) and met all the eligibility criteria of the ASCT protocol that included age ⩽70 years, acceptable cardiac (ejection fraction >40%), pulmonary (diffusion capacity for carbon monoxide >50% of normal) and hepatic (bilirubin and transaminases <2 × upper limit) function. Poor performance status due to MM was not an exclusion criterion. Informed consent was obtained from all patients.
Evidence of bone involvement at the time of transplant was documented using plain radiography (baseline date before transplant: within 1 month before transplantation). Patients were considered to have bone involvement if there were radiographic abnormalities consistent with MM bone disease, including osteoporosis, osteolytic lesions and fractures. Although bone pain was documented, the presence of bone pain alone was not considered to be indicative of bone disease in the absence of radiographic abnormalities. A grading of bone morbidity into three groups according to the radiographic evaluation of the skeleton was made. Group A included patients with no lytic lesions or osteoporosis alone; group B included patients with 1–3 osteolytic lesions, and group C included patients with more than three osteolytic lesions and/or a pathological fracture due to MM. We have used the <3/>3 as cutoff for bone lesions as advanced bone disease includes more than three lytic lesions in the Durie–Salmon staging system.
The following biochemical parameters were evaluated: sRANKL, OPG, bone resorption markers (TRACP-5b, NTX), bone formation markers (bALP, OC), paraprotein, CRP and β2-microglobulin. The above markers were measured at baseline, and then monthly post-ASCT.
In total, 35 healthy control donors with a similar age and gender distribution to the patients were also tested. The median age of these controls was 57 years (range: 35–71 years). The medical record of each control was reviewed to ensure that they had no evidence of bone disease, and that they were not taking any medication that could alter the normal bone turnover.
The study was conducted with Ethical Committee approval and under the guidelines of the Declaration of Helsinki.
Measurement of markers of bone turnover
Blood and urine samples were obtained at baseline and then monthly post-ASCT. After veinpuncture serum was separated within 4 h and stored at −70°C until the day of measurement. The levels of sRANKL in the serum were determined by an enzyme-linked immunosorbent assay (ELISA; No. BI-20422 H, Biomedica Medizinprodukte, Gesellschaft GmbH & Co. KG, Wien, Austria); levels of serum OPG were also evaluated by an ELISA method of the same company (Biomedica Medizinprodukte, Gesellschaft GmbH & Co KG, Wien, Austria). The intra- and interassay coefficients of variation (CV) are less than 10% for both tests, according to the manufacturer. The detection limit for sRANKL is 0.08 pmol/l, and for OPG is 0.14 pmol/l. Serum TRACP-5b was measured using a solid phase immunofixed-enzyme activity assay (BoneTRAP assay, SBA, Oulu, Finland). The sensitivity of this assay is 0.06 U/l; intra- and interassay CVs are less than 6 and 8%, respectively. Normal values ranged from 0.5 to 3.8 U/l for men and premenopausal women, and up to 4.8 U/l for postmenopausal women. Urinary NTX excretion was also quantified by an ELISA assay (OSTEOMARK NTX urine, Ostex International, Inc., Seattle, WA, USA) having intra- and interassay CV of 7.6 and 4%, respectively. Normal values ranged from 20 to 55 nM BCE (bone collagen equivalents)/mM creatinine (up to 75 nM BCE/mM creatinine for postmenopausal women). Serum bALP and OC were also determined using ELISA methods (Metra BAP, Quidel Corporation, San Diego, CA, USA; and N/MID Osteocalcin, Osteometer BioTech A/S, Herley, Denmark, respectively). Normal values ranged from 11.6 to 42.7 U/l for serum bALP, while normal values of OC were: 11–46 ng/ml in males and 25–48 ng/ml in postmenopausal females).
Differences between baseline and monthly values of the studied parameters, as well as between patients and controls, were evaluated using the Wilcoxon rank-sum test. Associations between bone disease status and biochemical markers were examined by the Kruskal–Wallis test, while the Spearman Rank correlation test was employed to examine relationships between various parameters and clinical patient characteristics. All P-values are two sided and confidence intervals refer to 95% boundaries.
Table 1 summarizes the characteristics of the 51 patients. The median age of patients was 58 years (range: 38–69 years) and the median follow-up was 12 months (range: 4–23 months). At diagnosis, two patients (4%) had stage I disease, nine (18%) had stage II disease and 40 (78%) had stage III disease. In total, 40 patients (78%) received ASCT for the first time, while 11 patients (21%) received their second ASCT. The median time from diagnosis to transplantation was 11 months (range: 6–52 months) for patients who received the first ASCT, while the median time from the first to the second transplantation was 41 months (range: 25–72 months) for 11 patients who received their second ASCT. Four patients (8%) were transplanted in CR, 44 (86%) were transplanted in first or second PR and three patients (6%) had progressive or resistant disease, according to EBMT criteria.20 In all, 40 patients (78%) received 200 mg/m2 melphalan as conditioning regimen, six patients received 140 mg/m2 melphalan, while four patients received 100 mg/m2 melphalan and one patient received 70 mg/m2 melphalan. No patient received total body irradiation.
Five patients (10%) had no evidence of lytic bone lesions (group A), while seven patients (13%) had 1–3 lytic lesions in the skeletal survey (group B), and 39 patients (76%) had multiple lytic lesions or fractures at the time of transplantation (group C). All patients had received bisphosphonates (clodronate, pamidronate or zoledronic acid) as part of their treatment. Before entering the trial and post-ASCT most patients (43/51, 84%) received zoledronic acid at a dose of 4 mg i.v., every 28 days.
Eight patients (15%) had increased levels of β2-microglobulin, while only three patients (6%) had increased levels of CRP at the time of transplantation. There are no data on cytogenetics in this cohort of patients.
Markers of bone remodeling and osteoclast function at the time of transplantation
Patients with myeloma before transplant had elevated median sRANKL, TRACP-5b and NTX values compared with controls (P<0.0001 for all markers), while serum levels of OPG and OC were lower than controls (P<0.001 and 0.0001, respectively) (Table 2). In particular, the majority of patients had elevated levels of NTX (35 patients, 68%) and TRACP-5b (27 patients, 53%) prior to ASCT, while 17 patients (33%) and three patients (6%) had reduced values of OC and bALP, respectively. Furthermore, 20 patients (39%) had higher values of sRANKL at the time of transplantation than the highest value observed in the control group (3.95 pmol/l), while 18 patients (35%) had lower values of OPG at the time of ASCT than the lowest value observed in the control group, which was 3.23 pmol/l. The ratio of sRANKL/OPG was also significantly higher in myeloma patients before transplant compared with the control group (P<0.0001). In total, 24 patients (47%) had higher sRANKL/OPG ratios at the time of ASCT compared with the highest value observed in the control group. There was no correlation between sRANKL/OPG ratio, and bone disease status at the time of ASCT or response to induction chemotherapy. However, there was a strong correlation between NTX levels and extent of bone disease at the time of transplantation (P<0.005; Figure 1). No other correlation was observed between the different markers of bone remodeling and osteoclast function with the extent of bone disease at the time of ASCT or the response to initial chemotherapy.
Effect of ASCT on markers of bone remodeling and osteoclast function
HDT and ASCT produced a significant reduction of NTX (Figure 2a), TRACP-5b (Figure 2b) and sRANKL (Figure 3a) compared with baseline levels, starting at 2 months post-ASCT that persisted during the 12-month follow-up period. There was an increase in median values of NTX, TRACP-5b and sRANKL 1 month post-transplant, which was not significant compared with baseline, followed by a significant reduction at 2 months post-ASCT. Bone formation markers, OC and bALP, started to increase after the 9th and 11th month post-ASCT, respectively (Figure 4), while the increase of OPG preceded this (5th month post-ASCT; Figure 3a). The ratio of sRANKL/OPG was reduced two months post-ASCT and this reduction persisted during the follow-up period (Figure 3b). The changes in the studied parameters are depicted in Table 3.
The univariate analysis showed no correlation between the above markers of bone remodeling and the response to transplantation. In all, 10 patients (19%) achieved a CR at 3 months post-ASCT, while 34 patients (66%) had a PR and three patients (6%) an MR post-transplant. Three patients showed no response to treatment and one patient had progressive disease.
During the follow-up period, nine patients relapsed. Of these, five patients had increased NTX levels, four had increased TRACP-5b levels and three had increased sRANKL/OPG ratio pre-ASCT. However, only one patient had an increase of NTX, TRACP-5b values, and sRANKL/OPG ratio 3 months before progression and one patient showed the same phenomenon at the time of progression.
Myeloma bone disease is a major cause of morbidity in MM patients. Over the last few years newly characterized molecules, which belong to the TNF superfamily, have been shown to play an important role in osteoclastogenesis in MM. RANKL is produced by myeloma and stromal cells, while its decoy receptor OPG is mainly produced by the osteoblasts and stromal cells.8, 9, 21 It has been shown that RANKL expression is upregulated and OPG expression is downregulated in MM.5, 6, 22 Our group has previously shown that serum sRANKL/OPG ratio is increased in MM and correlates with the extent of bone disease and markers of bone resorption (TRACP-5b, NTX).11
ASCT has been proven to be an effective treatment for MM offering a higher response rate and a significant survival benefit compared to conventional chemotherapy.16, 17 There is very limited available information regarding the effect of HDT followed by ASCT on skeletal disease in myeloma. In this study we have tried to investigate the effect of ASCT on RANKL/OPG pathway and on markers of bone resorption and formation in MM patients. It is the first time that the levels of NTX, TRACP-5b, sRANKL, OPG and OC were measured in patients with MM who underwent HDT and ASCT.
The majority of the patients (86%) were transplanted in PR. Both markers of bone resorption, NTX and TRACP-5b, along with the ratio RANKL/OPG were increased before transplantation, indicating that the reduction of the myeloma burden, achieved by conventional chemotherapy (as this was assessed by the paraprotein levels and the bone marrow infiltration by myeloma cells), is not always accompanied by a respective improvement of bone disease. This finding is in accordance with the observation of Clark et al18 that 44% of myeloma patients had increased urinary levels of free pyridinoline and deoxypyridinoline (older and not specific markers for collagen type-I degradation products) at the time of ASCT. These data also confirm that myeloma clone may disturb bone turnover independently of paraprotein production and are in consistence with evidence of persistent excessive osteoclast activity and increased bone resorption even in plateau phase of myeloma.23, 24 Furthermore, the increased levels of TRACP-5b in myeloma patients pre-ASCT, an enzyme that is produced only by activated osteoclasts,25 suggest that there is increased osteoclast activity in patients at partial remission. As the sRANKL/OPG ratio is also increased in this cohort of patients, we may assume that this abnormality in the RANKL/OPG pathway may be responsible for the osteoclast activation, which leads to increased bone resorption and increased collagen type-I degradation products (NTX). Bone formation was also disturbed in myeloma patients before ASCT, as reflected by the reduced levels of OC in our patients. Moreover, OPG levels were reduced in myeloma patients pretransplant. Both OPG and OC are produced mainly by osteoblasts. Osteoblasts in active myeloma are functionally exhausted and promptly undergo apoptosis in the presence of myeloma cells from patients with severe bone disease, suggesting that a cytotoxic effect on osteoblasts plays a pivotal role in the pathogenesis of bone disease in MM.26 Furthermore, it has been recently reported that myeloma cells inhibit the osteoblast function through the overproduction of an inhibitor of osteoblast differentiation, namely dickkopf1 (DKK1) protein; this is associated with the presence of lytic lesions in MM patients.27 Our results indicate that the osteoblast activity remains suppressed even in patients with low tumor burden, resulting in decreased bone formation and supporting the important role of osteoblasts in myeloma lytic bone disease.
Markers of bone resorption (NTX and TRACP-5b) have decreased in the second month compared with pre-ASCT values and normalized by the third month after transplantation. On the contrary, markers of bone formation had not normalized until the eighth month post-ASCT providing an indication that bone formation may delay in normalizing. The RANKL/OPG ratio was significantly decreased by the third month. However, serum levels of sRANKL remained higher than controls even in patients who achieved a PR post-ASCT. This result, as well as the notion that not all patients normalized NTX, also confirms the observation that increased bone resorption may be apparent even in patients with PR or in plateau phase of the disease.23 Conversely, the increase in OPG levels may compensate this increased bone resorption leading to no bone disease progression in most patients.
An increase of both markers of bone resorption, even if not significant, was marked at 1 month after transplantation. These results are in agreement with other findings from Carlson et al,28 who had analyzed 24 patients undergoing bone marrow transplantation (14 receiving autologous transplant). Their study showed that bone formation as reflected by serum osteocalcin and bALP was decreased with nadir levels at 2 and 3 week after marrow infusion while a simultaneous increase in bone resorption (increased ICTP) occurred.
Our findings are consistent with the sole study of the effect of ASCT on skeleton in MM patients, where the trend was for a temporary decrease in bone resorption immediately after the transplant, followed by a gradual normalization. In that study most of the patients showed a sustained increase of bone formation markers beginning about 50 days post-ASCT, suggesting that later on after transplant, bone formation may exceed bone resorption. Bone resorption was assessed by urinary levels of free pyridinoline and deoxypyridinoline crosslinks measured by HPLC, while collagen formation and osteoblast function were assessed by serum levels of PCIP and bALP.18 It is important to point out that in both studies osteoblast function normalized much later. It has been suggested that the failure of serum markers of bone formation to increase in a period of increased bone resorption may reflect a selective impairment of the osteoblastic compartment after HDT.29
In our study the majority of patients received zoledronic acid both pre- and post-ASCT. The antiresorptive activity of bisphosphonates, and especially of zoledronic acid in MM, has been well documented.30 Recently, it has been shown that in addition to its direct inhibiting effect on both osteoclast precursors and mature osteoclasts, zoledronic acid may inhibit the recruitment and differentiation of osteoclasts by cleavage of transmembrane RANKL in stromal and osteoblast-like cells.31 Furthermore, zoledronic acid seems to have an antimyeloma effect in murine models, which has not yet been demonstrated in humans.32 There is in vitro evidence that the combination of conventional chemotherapy with bisphosphonates may help to overcome chemotherapy resistance by myeloma cells.33 The decrease of markers of bone resorption in our study may also be the result of the combined effect of HDT plus ASCT with zoledronic acid, which has been shown to be a potent inhibitor of osteoclast function. The inhibition of RANKL production by zoledronic acid in vitro31 may also support the existence of a synergistic effect of ASCT with zoledronic acid on the reduction of serum levels of sRANKL post-ASCT. Furthermore, the increase in OPG, which has been observed in our study 4 months post-ASCT, supports the notion that the combination of ASCT with zoledronic acid may also have a synergistic action in reducing bone resorption through the increase of OPG production. Viereck et al34 have shown that both pamidronate and zoledronic acid can increase production of OPG from primary human osteoblasts, thus antagonizing the osteoclastogenic activity of RANKL. The normalization of the ratio sRANKL/OPG few months post-ASCT, which leads to the normalization of increased bone resorption may thus be the result of both ASCT and zoledronic acid administration. However, we have not found a causal relationship between improved sRANKL/OPG ratio and decreased bone resorption; therefore, we can only assume that RANKL/OPG pathway may have mediated the decrease of bone resorption. Possibly, a larger number of patients may be needed to assess a strong correlation between decreased bone resorption markers and reduced sRANKL/OPG ratio.
The fact that bone marrow transplantation may affect the skeleton was demonstrated by measuring BMD. Gandhi et al analyzed the effect of autologous transplantation on BMD in 38 patients, of whom only one had MM. At 3 months, there was a significant decline of BMD at the femoral neck and a nonsignificant trend towards reduction at the spine. The reduction in BMD persisted for up to 2 years at the femoral neck but values returned to baseline at the spine. Bone-specific ALP showed an initial decline at 1 month but had recovered to pretransplant levels by 3 months reflecting the rapid initial decline in BMD. No new fractures were detected at 1-year post-transplant.19 On the other hand, Ebeling et al35 have shown that in a group of autologous transplant recipients, there was no significant decrease either in femoral neck and spinal BMD or in total body bone mineral content when compared with the patients receiving an allergenic transplant. These studies reflect the complex mechanisms, which underlie bone remodeling in different disorders and the effect of ASCT on them. However, our study supports the beneficial effect of ASCT on bone remodeling in MM.
Nine patients relapsed during the observation period of this study. Some of these patients had increased values of NTX, TRACP-5b and sRANKL/OPG ratio at baseline (5, 4, and 3, respectively), but from the present data we cannot infer whether increased bone resorption or sRANKL/OPG ratio pre-ASCT predicts a worse outcome or whether the normalization of abnormal bone turnover following ASCT improves survival.
In conclusion, this study suggests that HDT and ASCT, possibly in combination with bisphosphonates, normalize abnormal bone resorption in myeloma. This may be due to the normalization of RANKL/OPG ratio, though this effect may take several weeks to emerge. This effect may occur independently of the beneficial role of ASCT in overall survival, while markers of bone resorption and/or osteoclast function may predict the disease progression. Further studies with larger number of patients and longer follow-up period may clarify these questions.
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The paper has been presented as a poster presentation in the American Society of Hematology Annual Meeting 2003 in San Diego: ‘Autologous Stem Cell Transplantation normalizes abnormal bone resorption through the reduction of sRANKL/osteoprotegerin ratio in multiple myeloma’ (Blood 2003; 102: abstract no. 3658).
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Terpos, E., Politou, M., Szydlo, R. et al. Autologous stem cell transplantation normalizes abnormal bone remodeling and sRANKL/osteoprotegerin ratio in patients with multiple myeloma. Leukemia 18, 1420–1426 (2004). https://doi.org/10.1038/sj.leu.2403423
- autologous transplantation
- multiple myeloma
- bone markers
- receptor activator of nuclear factor kappa-B ligand (RANKL)
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