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.

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-1β.5-8 By the time that a lytic lesion is evident on a conventional bone radiograph, more than 50% of bone loss has occurred. Magnetic resonance imaging reveals abnormal appearances in 50% of patients with apparently normal skeletal surveys, using plain radiographs.9 Significant bone destruction may, therefore, have taken place in the presence of normal plain radiographs.10 Conventional chemotherapy may slow down or halt the progression of bony disease and may also relieve the associated pain, but even chemotherapy responders may have progression of skeletal disease.11 Bisphosphonates inhibit osteoclast-mediated bone resorption and may improve the skeletal prognosis in myeloma, in addition to their effects on myeloma-associated hypercalcemia.12-14 

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.19,20Simultaneous 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

Ethical approval was granted by the Liverpool Research Ethics Committee, and all patients gave written informed consent prior to entry. Thirty-four consecutive myeloma patients were enrolled in the study, although 2 were later excluded, one because of technical problems with the pre-BMT samples, and one because of the post-BMT diagnosis of celiac disease, which might have confounded the interpretation of bone mineral turnover. Thirty-two patients undergoing autografting were therefore available for analysis. Their median age was 54 years (range 40-68). Pre-BMT clinical details are given in Table1. All but 4 cases had secretory disease at original diagnosis, and all but 3 were transplanted in first plateau or first remission. Eight cases had no evidence of bony disease on skeletal survey at original diagnosis. Seventeen cases had received pretransplant bisphosphonate.

Table 1.

Characteristics of the study population

CaseAge (yr)/sexBony disease at diagnosisSerologyStatus at BMTBisphosphonate pre-BMT
54/M Yes Urinary kappa light chains 1st CR Yes 
52/F Yes Serum IgA lambda 1st plateau No 
63/F Yes Urinary lambda light chains 1st plateau Yes  
57/M Yes Serum IgA kappa 1st plateau No  
40/F Yes Serum IgG kappa 1st plateau No  
48/M Yes Serum IgA kappa (also small IgG) 1st CR Yes  
58/F Yes Serum IgA kappa 1st CR Yes  
68/F Yes Serum IgG lambda 1st plateau Yes  
44/M No Serum IgG kappa 2nd response No  
10 58/F Yes Urinary lambda light chains 1st CR Yes  
11 61/F Yes Nonsecretory 1st CR No  
12 52/F Yes Serum IgG kappa 1st plateau Yes 
13 60/F Yes Serum IgG lambda 1st plateau Yes 
14 40/M Yes Nonsecretory 1st CR No 
15 63/F Yes Nonsecretory 1st CR No 
16 64/M Yes Serum IgG kappa 1st plateau Yes 
17 59/M Yes Nonsecretory 1st CR Yes 
18 53/M No Urinary lambda light chains 2nd response No  
19 44/M No Serum IgG lambda 1st plateau No  
20 50/M No Serum IgG kappa 1st plateau Yes  
21 51/M Yes Urinary kappa light chains 1st plateau Yes  
22 56/M No Serum IgA lambda 1st CR No  
23 61/M No Serum IgA kappa 1st CR No  
24 52/M Yes Serum IgG 1st plateau No 
25 52/F No Serum IgG lambda 1st plateau No 
26 53/F Yes Urinary lambda light chains 1st CR No 
27 52/M Yes Serum IgG kappa 1st plateau Yes 
28 41/M Yes Serum IgG kappa 1st plateau No 
29 55/M Yes Serum IgA kappa 2nd CR Yes 
30 51/F Yes Serum IgG kappa 1st CR Yes 
31 61/M Yes Serum IgA lambda 1st plateau Yes 
32 46/M No Serum IgG lambda 1st CR Yes 
CaseAge (yr)/sexBony disease at diagnosisSerologyStatus at BMTBisphosphonate pre-BMT
54/M Yes Urinary kappa light chains 1st CR Yes 
52/F Yes Serum IgA lambda 1st plateau No 
63/F Yes Urinary lambda light chains 1st plateau Yes  
57/M Yes Serum IgA kappa 1st plateau No  
40/F Yes Serum IgG kappa 1st plateau No  
48/M Yes Serum IgA kappa (also small IgG) 1st CR Yes  
58/F Yes Serum IgA kappa 1st CR Yes  
68/F Yes Serum IgG lambda 1st plateau Yes  
44/M No Serum IgG kappa 2nd response No  
10 58/F Yes Urinary lambda light chains 1st CR Yes  
11 61/F Yes Nonsecretory 1st CR No  
12 52/F Yes Serum IgG kappa 1st plateau Yes 
13 60/F Yes Serum IgG lambda 1st plateau Yes 
14 40/M Yes Nonsecretory 1st CR No 
15 63/F Yes Nonsecretory 1st CR No 
16 64/M Yes Serum IgG kappa 1st plateau Yes 
17 59/M Yes Nonsecretory 1st CR Yes 
18 53/M No Urinary lambda light chains 2nd response No  
19 44/M No Serum IgG lambda 1st plateau No  
20 50/M No Serum IgG kappa 1st plateau Yes  
21 51/M Yes Urinary kappa light chains 1st plateau Yes  
22 56/M No Serum IgA lambda 1st CR No  
23 61/M No Serum IgA kappa 1st CR No  
24 52/M Yes Serum IgG 1st plateau No 
25 52/F No Serum IgG lambda 1st plateau No 
26 53/F Yes Urinary lambda light chains 1st CR No 
27 52/M Yes Serum IgG kappa 1st plateau Yes 
28 41/M Yes Serum IgG kappa 1st plateau No 
29 55/M Yes Serum IgA kappa 2nd CR Yes 
30 51/F Yes Serum IgG kappa 1st CR Yes 
31 61/M Yes Serum IgA lambda 1st plateau Yes 
32 46/M No Serum IgG lambda 1st CR Yes 

BMT, bone marrow transplant; CR, complete response; Ig, immunoglobulin.

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 −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.

The post-transplant course is given in Table2. 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.

Table 2.

Post-BMT outcome

CaseCD34 selectedPost-BMTOutcome
G-CSFIFNBisphosphonate
Yes No No From day 358 Well day 1363 
No No No No Progression day 501 
No No No No Renal failure day 353; progression day 491  
Yes No From day 115 No Progression day 640 
Yes No From day 814 From day 546 Well day 1206 
No No Days 181-467 From day 181 Progression day 658  
Yes No Days 106-730 From day 54 Well day 1104 
Yes No Days 93-397 From day 429 Progression day 597  
Yes No Days 62-206 No Progression day 225 
10 Yes No Days 260-376 Days 30-376 Progression day 390  
11 No* Yes No No Progression and consent withdrawn day 33  
12 No Yes No From day 545 Progression day 102  
13 No No Days 253-620 From day 30 Well day 783  
14 No No No No Well day 333; lost to follow-up since  
15 No* Yes Days 72-309 From day 72 Well day 693  
16 No No From day 42 From day 42 Well day 665  
17 Yes No Days 49-124 From day 94 Well day 648  
18 No Yes Days 167-451 No Progression day 451 
19 No Yes No No Well day 494 
20 Yes Yes No No Well day 404 
21 Yes Yes No No Well day 105; lost to follow-up since  
22 Yes Yes No No Well day 384 
23 Yes Yes From day 119 From day 147 Well day 370 
24 No Yes Days 129-312 No Well day 341 
25 No* Yes Days 105-231 No Progression day 272 
26 No* Yes No From day 282 Well day 309 
27 Yes Yes No No Well day 246 
28 Yes Yes No No Well day 237 
29 Yes Yes No No Well day 236 
30 Yes Yes Days 89-117 No Well day 214 
31 No* Yes No No Well day 111 
32 Yes Yes No No Well day 66 
CaseCD34 selectedPost-BMTOutcome
G-CSFIFNBisphosphonate
Yes No No From day 358 Well day 1363 
No No No No Progression day 501 
No No No No Renal failure day 353; progression day 491  
Yes No From day 115 No Progression day 640 
Yes No From day 814 From day 546 Well day 1206 
No No Days 181-467 From day 181 Progression day 658  
Yes No Days 106-730 From day 54 Well day 1104 
Yes No Days 93-397 From day 429 Progression day 597  
Yes No Days 62-206 No Progression day 225 
10 Yes No Days 260-376 Days 30-376 Progression day 390  
11 No* Yes No No Progression and consent withdrawn day 33  
12 No Yes No From day 545 Progression day 102  
13 No No Days 253-620 From day 30 Well day 783  
14 No No No No Well day 333; lost to follow-up since  
15 No* Yes Days 72-309 From day 72 Well day 693  
16 No No From day 42 From day 42 Well day 665  
17 Yes No Days 49-124 From day 94 Well day 648  
18 No Yes Days 167-451 No Progression day 451 
19 No Yes No No Well day 494 
20 Yes Yes No No Well day 404 
21 Yes Yes No No Well day 105; lost to follow-up since  
22 Yes Yes No No Well day 384 
23 Yes Yes From day 119 From day 147 Well day 370 
24 No Yes Days 129-312 No Well day 341 
25 No* Yes Days 105-231 No Progression day 272 
26 No* Yes No From day 282 Well day 309 
27 Yes Yes No No Well day 246 
28 Yes Yes No No Well day 237 
29 Yes Yes No No Well day 236 
30 Yes Yes Days 89-117 No Well day 214 
31 No* Yes No No Well day 111 
32 Yes Yes No No Well day 66 

BMT, bone marrow transplant; BM, bone marrow; PBSC, peripheral blood stem cell; G-CSF, granulocyte colony-stimulating factor; IFN, interferon.

*

Transplanted with BM and PBSC.

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 −6 to −1. Follow-up was limited to 30 days in the control cases.

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.

Fig. 1.

Trends in mean fPyr (A) and mean fDPyr (B) concentrations in the first 30 days following BMT, for the 14 cases with elevated levels at transplant.

Error bars represent 95% confidence limits. Dotted line = upper limit of the reference range.

Fig. 1.

Trends in mean fPyr (A) and mean fDPyr (B) concentrations in the first 30 days following BMT, for the 14 cases with elevated levels at transplant.

Error bars represent 95% confidence limits. Dotted line = upper limit of the reference range.

Close modal

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, andP = .0019 for day 100 versus day 300 fDPyr; Mann-Whitney test).

Fig. 2.

Long-term trends in mean fPyr (A) and mean fDPyr (B) concentrations for the 14 cases with elevated levels at transplant.

Error bars represent 95% confidence limits. Dotted line = upper limit of the reference range.

Fig. 2.

Long-term trends in mean fPyr (A) and mean fDPyr (B) concentrations for the 14 cases with elevated levels at transplant.

Error bars represent 95% confidence limits. Dotted line = upper limit of the reference range.

Close modal

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 

Fig. 3.

Changes in P1CP (A) and BSAP (B) concentrations following BMT.

Error bars represent 95% confidence limits.

Fig. 3.

Changes in P1CP (A) and BSAP (B) concentrations following BMT.

Error bars represent 95% confidence limits.

Close modal

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 2and 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,23,30Moreover, 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.

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.

1
Bataille
R
Chappard
D
Marcelli
C
et al
Mechanisms of bone destruction in multiple myeloma: the importance of an unbalanced process in determining the severity of lytic bone disease.
J Clin Oncol.
7
1989
1909
1914
2
Bataille
R
Chappard
D
Basle
M-F
Quantifiable excess of bone resorption in monoclonal gammopathy is an early symptom of malignancy: a prospective study of 87 bone biopsies.
Blood.
87
1996
4762
4769
3
Mundy
GR
Raisz
LG
Cooper
RA
Schlechter
GP
Salmon
SE
Evidence for the secretion of an osteoclast stimulating factor in myeloma.
N Engl J Med.
291
1974
1041
1046
4
Taube
T
Beneton
MNC
McCloskey
EV
Rogers
S
Greaves
M
Kanis
JA
Abnormal bone remodelling in patients with myelomatosis and normal biochemical indices of bone resorption.
Eur J Haematol.
49
1992
192198
5
Garrett
IR
Durie
BGM
Nedwin
GE
et al
Production of lymphotoxin, a bone resorbing cytokine, by cultured human myeloma cells.
N Engl J Med.
317
1987
526
532
6
Kawano
M
Tanaka
H
Ishikawa
H
et al
Interleukin-1 accelerates autocrine growth of myeloma cells through interleukin-6 in human myeloma.
Blood.
73
1989
2145
2148
7
Roodman
GD
Interleukin-6: an osteotropic factor?
J Bone Miner Res.
7
1992
475
478
8
Carter
A
Merchav
S
Silvian-Draxler
I
Tatarsky
I
The role of interleukin-1 and tumour necrosis factor-Ó in human multiple myeloma.
Br J Haematol
74
1990
424
431
9
Moulopoulos
LA
Dimopoulos
MA
Smith
TL
et al
Prognostic significance of magnetic resonance imaging in patients with asymptomatic multiple myeloma.
J Clin Oncol.
13
1995
251
256
10
Moulopoulos
LA
Dimopoulos
MA
Magnetic resonance imaging of the bone marrow in hematologic malignancies.
Blood.
90
1997
2127
2147
11
Belch
AR
Bergsagel
DE
Wilson
K
et al
Effect of daily etidronate on the osteolysis of multiple myeloma.
J Clin Oncol.
9
1991
1397
1402
12
Berenson
JR
Lichenstein
A
Porter
L
et al
Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma.
N Engl J Med.
334
1996
488
493
13
Lahtinen
R
Laakso
M
Palva
I
Virkkunen
P
Elomaa
I
Randomised placebo-controlled multicentre trial of clodronate in multiple myeloma.
Lancet.
340
1992
1049
1052
14
McCloskey
EV
MacLennan
ICM
Drayson
MT
Chapman
C
Dunn
J
Kanis
JA
A randomised trial of the effect of clodronate on skeletal morbidity in multiple myeloma.
Br J Haematol.
100
1998
317
325
15
Attal
M
Harousseau
JL
Stoppa
AM
et al
A prospective randomised trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma.
N Engl J Med.
335
1996
91
97
16
Gahrton
G
Tura
S
Ljungman
P
et al
Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma.
J Clin Oncol.
13
1995
1312
1322
17
Thornton
CO
Ballester
O
Greenfield
GB
Progression of bone disease in multiple myeloma patients treated with high dose therapy and autologous stem cell transplantation.
Blood.
88(suppl 1)
1996
481a
18
Fraser
WD
The collagen crosslinks pyridinoline and deoxypyridinoline: a review of their biochemistry, physiology, measurement and clinical applications.
J Clin Ligand Assay.
21
1998
102
110
19
Parfitt
AM
Simon
LS
Villanueva
AR
Krane
SM
Procollagen type 1 carboxy-terminal extension peptide in serum as a marker of collagen biosynthesis in bone. Correlation with iliac bone formation rates and comparison with total alkaline phosphatase.
J Bone Miner Res.
2
1987
427
436
20
Abildgaard
N
Bendix-Hansen
K
Kristensen
JE
et al
Bone marrow fibrosis and disease activity in multiple myeloma monitored by the aminoterminal propeptide of procollagen III in serum.
Br J Haematol.
99
1997
641
648
21
Eyre
DR
New markers of bone resorption.
J Clin Endocrinol Metab.
74
1992
470A
470B
22
Pecherstorfer
M
Seibel
MJ
Woitge
HW
et al
Bone resorption in multiple myeloma and in monoclonal gammopathy of undetermined significance: quantification by urinary pyridinium cross-links of collagen.
Blood.
90
1997
3743
3750
23
Withold
W
Wolf
H-H
Kolbach
S
Heyll
A
Schneider
W
Reinauer
H
Monitoring of bone metabolism after bone marrow transplantation by measuring two different markers of bone turnover.
Eur J Clin Chem Clin Biochem.
34
1996
193
197
24
Black
D
Duncan
A
Robins
P
Quantitative analysis of the pyridinium crosslinks of collagen in urine using ionpaired reverse-phase high performance liquid chromatography.
Anal Biochem.
169
1988
197
203
25
MacDonald
AG
Birkenshaw
G
Durham
B
Bucknall
RC
Fraser
WD
Biochemical markers of bone turnover in sero-negative spondylarthropathy: relationship to disease activity.
Br J Rheumatol.
36
1997
50
53
26
Joffe
P
Heaf
JG
Jensen
LT
Type I procollagen propeptide in patients on CAPD: its relationships with bone histology, osteocalcin, and parathyroid hormone.
Nephrol Dial Transplant.
10
1995
1912
1917
27
Bhatia
S
Ramsay
NKC
Weisdorf
D
Griffiths
H
Robison
LL
Bone mineral density in patients undergoing bone marrow transplantation for myeloid malignancies.
Bone Marrow Transplant.
22
1998
87
90
28
Sullivan
KM
Stern
JM
Seidel
K
et al
Bone density during the first year following allogeneic blood and marrow transplantation.
Blood.
92(suppl 1)
1998
493a
29
Kashyap
A
Yamauchi
D
Williams
C
et al
Bone marrow transplantation from matched sibling and unrelated donors significantly decreases recipient bone mineral density.
Blood.
92(suppl 1)
1998
458a
30
Carlson
K
Simonsson
B
Ljunghall
S
Acute effects of high dose chemotherapy followed by bone marrow transplantation on serum markers of bone metabolism.
Calcif Tissue Int
55
1994
408
411
31
Lee
MY
Fevold
KL
Muguruma
Y
Lottsfeldt
JL
Conditions that support long-term production of osteoclast progenitors in vitro.
Stem Cells.
15
1997
340
346
32
Purton
LE
Lee
MY
Torok-Storb
B
Normal human peripheral blood mononuclear cells mobilised with granulocyte colony-stimulating factor have increased osteoclastogenic potential compared to non-mobilised blood.
Blood.
87
1996
1802
1808
33
Takamatsu
Y
Simmons
PJ
Moore
RJ
Morris
HA
To
LB
Lévesque
J-P
Osteoclast-mediated bone resorption is stimulated during short-term administration of granulocyte colony stimulating factor but is not responsible for hemopoietic progenitor cell mobilization.
Blood.
92
1998
3465
3473
34
Fewtrell
MS
Kinsey
SE
Williams
DM
Bishop
NJ
Bone mineralization and turnover in children with congenital neutropenia, and its relationship to treatment with recombinant human granulocyte-colony stimulating factor.
Br J Haemat.
97
1997
734
736
35
Jacob
A
Murray
JA
Holmes
J
Boivin
CM
Bone density after high dose therapy for myeloma.
Br J Haemat.
105(suppl 1)
1999
83
36
Bladé
J
Samson
D
Reece
D
et al
Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high dose therapy and haemopoietic stem cell transplantation.
Br J Haematol.
102
1998
1115
1123

Author notes

Richard E. Clark, Department of Haematology at the Royal Liverpool University Hospital, Prescot St, Liverpool L7 8XP, United Kingdom.

Sign in via your Institution