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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Jose Carreras BMT Unit, Department of
Haematology and Department of Clinical Chemistry, Royal Liverpool
University Hospital, Liverpool, England, and the Department of
Haematology, Southport District General Hospital, Southport, England.
The effect of high-dose chemotherapy and autografting on bone
turnover in myeloma is not known. A study of 32 myeloma patients undergoing blood or marrow transplant (BMT), conditioned with high-dose melphalan, was done. Bone resorption was assessed by urinary
free pyridinoline (fPyr) and deoxypyridinoline (fDPyr), expressed as a
ratio of the urinary creatinine concentration. Bone formation was
assessed by serum concentration of procollagen 1 extension peptide
(P1CP) and bone-specific alkaline phosphatase (BSAP). Eighteen cases
had normal fPyr and fDPyr at transplant, and in all but one of these
cases the level remained normal throughout subsequent follow-up. In
contrast, in 14 cases urinary fPyr and fDPyr levels were increased at
transplant. In these cases, both fPyr and fDPyr fell to normal levels
over the next few months (P = .0009 and .0019, respectively). fPyr and fDPyr levels at transplant and their trends
post-BMT were unrelated to the use of pre-BMT or post-BMT
bisphosphonate or post-BMT interferon. Nine cases had elevated P1CP or
BSAP at transplant, which rapidly normalized. In most patients there
was an increase in P1CP and/or BSAP several months post-transplant. In
conclusion, increased osteoclast activity may be present even in
apparent plateau phase of myeloma. High-dose chemotherapy with
autografting may normalize abnormal bone resorption, although the
effect may take several weeks to emerge and may be paralleled by
increased osteoblast activity. The findings provide biochemical
evidence that autografting may help normalize the abnormal bone
turnover characteristic of myeloma.
(Blood. 2000;96:2697-2702) Bone lesions are an important cause of morbidity in
myeloma. The typical lytic lesions arise because of a local imbalance between bone resorption and formation. This imbalance may be due to
both a low activity of bone-forming cells and an excess of osteoclast-mediated bone resorption.1-4 Excessive bone
resorption may be present even in cases with early disease and may be a
poor prognostic sign.2 Factors produced locally by myeloma
cells are responsible for osteoclast activation, especially
interleukin-6 and interleukin-1 A recent report15 suggests that autologous blood/marrow
stem cell transplantation (ABMT) in myeloma may delay disease
progression and prolong survival, and further randomized studies
addressing the role of ABMT are in progress. However, the effect of
transplantation on the outcome of bony disease in myeloma has not been
well studied. In a retrospective study by the European Blood and Marrow
Transplant Group,16 12 of 76 patients showed radiological
improvement of bone lesions following allografting. Lytic lesions
assessed by plain radiographs may progress following ABMT,
without evidence of hematological or immunological
progression.17
Type I collagen constitutes 90% of bone protein, and the resorption of
bone by osteoclasts results in the production of collagen peptides,
cross-linked peptides, cross-linking molecules, and amino acids.
Hydroxyproline released from the breakdown of collagen can be measured
in the urine as an estimate of osteoclast activity. However, this
molecule lacks specificity for bone, is present in the diet, may be
reused in new collagen formation, and is secreted during complement activation.
Newer assays have been developed that are more specific for Type I
collagen breakdown and formation and that accurately reflect osteoclast
or osteoblast function. Pyridinoline and deoxypyridinoline are
mature covalent crosslinks of collagen that are excreted in urine, and
their measurement in urine correlates well with bone collagen
resorption. Deoxypyridinoline measurement is believed to be most
specific for Type I collagen.18 Amino and carboxy terminal
propeptides of Type I collagen (P1NP, P1CP) can be measured in plasma
as indices of osteoblast collagen formation.19,20 Simultaneous measurements of these biochemical markers of bone turnover
can provide information on the likelihood of bone loss or accumulation
and on the coupling of bone cell activity.21 The use
of biochemical markers of bone turnover has been reported in untreated
myeloma and monoclonal gammopathies of undetermined significance22 and in a cross-sectional study of recipients of allogeneic bone marrow transplant (BMT) for diseases other than
myeloma.23
To investigate the effect of high-dose chemotherapy on bone turnover in
myeloma, the present study was designed to serially study markers of
bone turnover following BMT. Such a study, to our knowledge, has not
been previously reported.
Study population
All patients underwent peripheral blood stem cell (PBSC) harvesting
following mobilization with cyclophosphamide 1.5 gm/m2 and
granulocyte colony-stimulating factor (G-CSF). At least
3 × 106 CD34+ cells/kg recipient weight were
obtained from 17 cases, and CD34+ cells were positively
selected from these cases, using an Isolex 300 (Baxter, Newbury,
Berkshire, UK), in accordance with the manufacturer's instructions.
Five cases (numbers 11, 15, 25, 26, and 31) were transplanted with
autologous marrow as well as PBSC, because of a poor yield of the
latter; the remaining cases received PBSC alone. Conditioning was with
melphalan on day The post-transplant course is given in Table
2. For most of the duration of the study,
post-transplant G-CSF was only given routinely to recipients of marrow,
commencing on day +7 at a dose of 5 µg/kg per day until the
neutrophil count reached 1 × 109/L. Toward the end of
the study, this policy was extended to PBSC recipients, and a further
case (number 12) received G-CSF at the same dose from days 10-29 because of slow engraftment. On recovery from BMT, patients were
discharged to the care of their local physician, with the
recommendation to commence maintenance interferon at a dose of 3 megaunits three times weekly as soon as the neutrophil and platelet
counts were adequate and to commence/resume either pamidronate 90 mg
intravenously every 4 weeks or clodronate 800 mg twice daily orally,
depending on local hospital policy. Details are given in Table 2.
Five patients without bony disease undergoing autologous
transplantation for lymphomas were included as controls. Conditioning for each case was with BEAM (BCNU, etoposide, cytosine, and melphalan) from days Investigations of bone mineral turnover Clinical samples were taken immediately before starting conditioning therapy, daily until day 7, weekly until discharge from hospital, and every 1-2 months thereafter. Routine biochemistry analysis of serum and urine was performed on a Hitachi 747 analyser (Boehringer Mannheim, Lewes, UK). Urea, creatinine, calcium, and phosphate were all estimated by standard methodologies.Bone resorption was assessed by urinary levels of free pyridinoline (fPyr) and deoxypyridinoline (fDPyr) crosslinks, using high-performance liquid chromatography (HPLC), modified from the method described by Black et al.24 Acidified urine is applied to microgranular cellulose (CC31) in butanol 1:4, and washed before elution with heptafluorobutyric acid (0.1%). The eluate is then analyzed by ion pair reverse-phase HPLC by using fluorescence detection. Acetylated Pyr (Metra Biosystems, Oxford, UK) is used as an internal standard.25 Results are expressed as a ratio of the urinary creatinine (Creat) concentration (upper limit of normal = 21.8 nmol/mmol for fPyr/Creat and 6.4 nmol/mmol for fDPyr/Creat). The interassay coefficient of variation (CV) is less than 5.5% across the working range of the assay. Collagen formation and osteoblast function were assessed by serum levels of procollagen 1 extension peptide (P1CP) and by bone-specific alkaline phosphatase (BSAP). P1CP was measured in serum by radioimmunoassay supplied by Orion Diagnostica (Espoo, Finland), with a sensitivity of 1.2 µmol/L and a CV of 4.0%-6.6% at concentrations of 54-451 µmol/L. The upper limit of the reference range was 202 µmol/L in males aged 20-60 years; 170 µmol/L in other situations. BSAP was measured by using a commercial assay (Metra Biosystems, Oxford, UK), with a sensitivity of 0.7 U/L, a CV of less than 8% across the range 12-100 U/L, and an upper limit of the reference range of 20 U/L.
No control patient had abnormal levels of fPyr, fDPyr, P1CP, or BSAP, either on admission for BMT or during subsequent follow-up (data not shown). Bone resorption measurements Eighteen of the 32 myeloma patients had normal urinary fPyr and fDPyr levels on admission for BMT. In all but one of these cases, fPyr and fDPyr levels did not become significantly elevated at any subsequent follow-up point. The remaining case (case 13) showed a modest transient increase in both fPyr and fDPyr 21-89 days post-BMT, although all subsequent follow-up measurements to day 650 have been in the reference range (data not shown).Fourteen patients had significantly elevated fPyr and fDPyr on
admission for BMT (median = 31.2 and 8.2, respectively; mean = 41.0
and 9.2, respectively). Figure 1 shows
the variation in mean fPyr and fDPyr in these 14 cases over the first
30 days from transplantation. There was a temporary decrease in both
parameters for about 15 days after BMT; both fPyr and fDPyr were
significantly less on day +5 than pre-BMT values (P = .005
and .007, respectively; Mann-Whitney test). Both fPyr and fDPyr rapidly
returned to abnormally high pretransplant levels by day 30; there was
no significant difference between fPyr and DPyr on day 30 compared with
pre-BMT values.
Figure 2 shows how the fPyr and fDPyr
levels in these cases evolved over the 2 years following ABMT. The
trend was for a gradual decrease of both fPyr and fDPyr into the normal
range, and this decrease achieved statistical significance
(P = .0009 for day 100 versus day 300 fPyr, and
P = .0019 for day 100 versus day 300 fDPyr; Mann-Whitney
test).
Effect of pre-BMT bisphosphonate and post-BMT therapy No relationship was found between whether patients had received pre-BMT bisphosphonate and the presence of increased bone resorption at BMT. There was also no relationship between the pre-BMT use of bisphosphonate and the post-BMT trends of bone turnover markers. For the post-BMT trends in bone resorption markers described above, no difference was seen between patients who did or did not receive post-BMT bisphosphonate nor between those who did or did not receive post-BMT interferon.Measurements of bone deposition Figure 3 shows the results of P1CP and BSAP in all 32 cases. Results on case 3 are removed after day 302 post-ABMT because of deterioration in renal function and a rising parathormone level, because P1CP and BSAP levels are altered in the presence of renal osteodystrophy.26
Six patients (cases 2, 11, 12, 14, 24, and 27) had an elevated P1CP level at transplant, ranging from 188 to 268 µmol/L, 4 of whom also had elevated fPyr and fDPyr levels. In all 6 patients, P1CP levels returned to the reference range within 5 days of commencing conditioning therapy. Three different cases (16, 19, and 22) had elevated levels of BSAP; these levels also returned to within the reference range within 5 days of commencing conditioning. Seventeen of 22 assessable cases had an increase of P1CP 50-150 days following BMT (an increase was defined as at least 50% of the P1CP values at 50-150 days were at least 20 µmol/L above the pre-BMT value). These data are shown in Figure 3A. P1CP levels at day 100 are significantly higher than pre-BMT levels (P = .03). Similarly, several patients showed a posttransplant increase in BSAP levels (Figure 3B), beginning about 50 days from BMT; in some cases this increase persists into the second year of follow-up. In many cases, an increase in P1CP was associated with a rise in BSAP. In each case, this P1CP/BSAP elevation occurred at a time when fPyr and fDPyr were within the reference range, suggesting that at 50-150 days post-BMT, bone formation may exceed bone resorption. No relationship was seen between the post-BMT rise in P1CP and the use of post-BMT bisphosphonates. As will be seen from the data of Table 2 and Figure 3A, the rise in P1CP is at days 50-150, whereas only 6 cases have commenced bisphosphonate by day 147. In all cases, P1CP had returned to within the reference range by day 250 and remained within it thereafter. This rise cannot be explained by a gradual increase in bone remodeling following cessation of bisphosphonate treatment, for 2 reasons. First, such an increase would take 6-8 months to occur, whereas the present rise is already occurring well before day 100-150. Second, 8 cases received bisphosphonate pre-BMT but had not restarted it at the time of analysis, but 5 of these cases were followed for 105 days or less at the time of analysis, and none showed a rise in either P1CP or BSAP post-BMT. These 8 cases therefore hardly contribute to the rises shown in Figure 3. Disease progression Disease progression occurred in 11 patients (see Table 2), of which 9 were serological relapses without new bony lesions. One case developed an isolated soft tissue plasmacytoma in the pleura without alteration in the appearance of the adjacent ribs on plain radiographs, and one patient (case 2) developed a histologically confirmed new lytic lesion. Although increases in both fPyr and fDPyr levels were seen in case 2 at the time of progression (Figures 2A and 2B), insufficient data were available to test whether an upward trend in markers of bone resorption was predictive of disease progression.
Previous reports have established that osteopenia may arise following BMT,23,27-29 However, these studies focused on recipients of allografts, in whom contributing factors might include prolonged glucocorticoid therapy, hormonal deficiency (because of total body irradiation), and cyclosporin A therapy,23,30 Moreover, the patients in these series suffered from diseases that do not significantly affect bone metabolism. To our knowledge, no previous study has serially examined the effect of high-dose chemotherapy and autografting on bone turnover in myeloma. In the present study, we report 2 principal findings. First, increased bone turnover may be present in about half of patients in serological plateau or remission. No statistically significant relationship was found between the use of pre-BMT bisphosphonate and the presence of raised fPyr or fDPyr levels at BMT. However, the absence of a statistically significant difference in the present data does not mean that pre-BMT bisphosphonate has no relevance, merely that we cannot detect a difference in the present data. A much larger study designed to explore this association will be of considerable interest. All patients in this study received G-CSF before transplant for PBSC mobilization. G-CSF induces rapid bone remodeling and may increase osteoclast progenitor numbers31,32 and urinary fDPyr and serum alkaline phosphatase, peaking approximately 5 days after G-CSF commencement and returning to baseline about 7 days after cessation.33 Little is known of the long-term effects of G-CSF on the skeleton. Although prolonged G-CSF treatment may produce osteopenia in children, this condition might be due to their underlying marrow disorder.34 However, G-CSF treatment is unlikely to be the explanation of the increased fPyr and fDPyr levels seen on admission for BMT in 14 of the present cases, because G-CSF treatment was stopped at least 23 days before baseline measurements of bone turnover and also because no correlation was seen between fPyr and fDPyr levels and either the interval since stopping G-CSF or the total cumulative dose of G-CSF. The present data therefore suggest that the myeloma clone may continue to disturb bone turnover, independently of paraprotein production. This finding is in line with earlier histological evidence of persistent excessive osteoclast activity at plateau.4 A consistent observation was the temporary decrease in fPyr and fDPyr levels immediately following BMT, even in patients with normal fPyr and fDPyr levels on admission for BMT. This decrease was seen even in patients who received post-transplant G-CSF, which might be expected to produce an increase rather than a decrease in bone resorption. A possible explanation for this decrease is the cytotoxic effect of the conditioning chemotherapy. Second, high-dose chemotherapy and autografting may normalize abnormal bone resorption. This effect may take several weeks to emerge. In many cases, this normalization is accompanied by an increase in markers of bone deposition, indicating increased osteoblast activity. These changes were not related to the posttransplant use of either bisphosphonates or interferon. There was also no relationship between the pre-BMT use of bisphosphonate and the post-BMT trends of bone turnover markers. In subgroup analysis, the post-BMT trends in bone resorption markers are apparent both in patients who received post-BMT bisphosphonate and in those who did not, although we acknowledge that the association between bisphosphonate therapy and bone turnover markers requires testing in a much larger study. Our findings suggest that a delayed effect of high-dose chemotherapy/autografting may be to uncouple bone resorption and deposition, in favor of promoting bone deposition. These data are therefore in line with the view that high-dose therapy and autografting can improve skeletal morbidity in myeloma. Dual energy X-ray absorptiometry (DEXA) was not carried out in the present study, although a recent serial study35 of DEXA suggests that recovery of bone density does occur following high-dose therapy in myeloma, in agreement with the present data. In the present study, disease progression is defined in accordance with recent internationally agreed criteria.36 We cannot say from the present data whether increased bone resorption at BMT predicts a worse outcome (either in terms of time to progression or for the skeletal prognosis) or whether normalization of abnormal bone turnover following BMT improves the outlook. A much larger study will be needed to examine these roles for biochemical markers of bone metabolism. In summary, we provide evidence that high-dose therapy and autografting may improve abnormal bone resorption in myeloma and also may lead to increased osteoblast activity. Skeletal endpoints have not been examined in clinical trials of high-dose therapy reported so far. It is possible that the skeletal benefit of high-dose therapy may occur independently of any beneficial effect on time to progression and overall survival and, therefore, that high-dose therapy might benefit the patient's quality of life even without improving survival. Future studies to test this possibility are required.
Submitted August 3, 1999; accepted June 12, 2000.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Richard E. Clark, Department of Haematology at the Royal Liverpool University Hospital, Prescot St, Liverpool L7 8XP, United Kingdom.
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© 2000 by The American Society of Hematology.
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  B. Fohr, C. R. Dunstan, and M. J. Seibel Markers of Bone Remodeling in Metastatic Bone Disease J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5059 - 5075. [Abstract] [Full Text] [PDF]
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 J. R. Berenson, B. E. Hillner, R. A. Kyle, K. Anderson, A. Lipton, G. C. Yee, and J. S. Biermann American Society of Clinical Oncology Clinical Practice Guidelines: The Role of Bisphosphonates in Multiple Myeloma J. Clin. Oncol., September 1, 2002; 20(17): 3719 - 3736. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
.
1 at a dose of 200 mg/m2 in all except 3 cases, who received 70 mg/m2 because of either general
frailty (cases 8 and 11) or impaired renal function (case 3). This
patient had a serum creatinine level consistently less than 300 µmol/L (upper limit of reference range = 120 µmol/L) and a
parathormone level within the reference range until day +302 post-BMT,
beyond which she was removed from the study because of overt renal
deterioration. All patients received methylprednisolone 1.5 gm daily
from day 0 (the day of PBSC/marrow reinfusion) to +3 inclusive; no
patient received any corticosteroids subsequent to this.
