Abstract
Objective: Monitoring of bone disease in multiple myeloma is becoming increasingly important because bone-protecting treatment with bisphosphonate is becoming restricted after the awareness of osteonecrosis of the jaw. Despite the potential of biochemical markers of bone remodeling to monitor dynamic bone turnover, they are not used in everyday practice. Here, we investigate their usefulness to detect imminent progressive osteolysis in relapsing patients with multiple myeloma. Methods: In an unselected cohort of 93 patients, we measured the bone resorption markers C-terminal telopeptide of collagen type I (CTX-I), C-terminal cross-linked telopeptide of type-I collagen generated by MMPs (ICTP), N-terminal cross-linked telopeptide of type-I collagen (NTX-I), and the bone formation marker bone-specific alkaline phosphatase (bALP) monthly for 2 yr. Retrospectively, we identified 40 cases where patients had progressive disease. We investigated how the bone markers developed prior to disease progression. Results: We observed that CTX-I and bALP changed significantly before progressive disease were recognized. More interestingly, these changes differed depending on whether concurrent progressive osteolysis was present. In patients with progressive osteolysis, there was a large increase in bone resorption which was not compensated by increased bone formation. In contrasts, patients with stable bone disease had only a slight increase in bone resorption which was compensated by concurrent increased bone formation. By calculating a patient-specific CTX-I/bALP ratio, we quantified the risk a patient experiences if the ratio increases. Conclusion: By analyzing patient-specific changes in the ratio of CTX-I/bALP, we might tailor treatment with bone-protecting agents in the individual patient.
Highlights
Even though bone-specific alkaline phosphatase (bALP) levels were very low, with a mean level of 14.15 Units ⁄ L, a significant 17 % increase was observed at first sign of Progressive disease (PD) (Fig. 1). bALP levels remained low during the entire period, and the average increase became statistical significant 2 months prior to the detection of PD by conventional markers, values started to decline again before PD was reached (Fig. 2)
The bone formation marker bALP remained highly suppressed in patients with progressive osteolysis, whereas a small increase was observed in patients with stable bone disease compensating for the small CTX-I increase
With MM because of use of novel agents, most patients will get to a point where the potential benefits and disadvantages of continued bisphosphonate treatment should be considered
Summary
An unselected cohort of patients with multiple myeloma followed at Vejle Hospital, Denmark, had the bone degradation markers CTX-I, ICTP, NTX-I and the bone formation marker bALP measured every 4 wk for 2 yr. In cases with PD, the patients own bone marker values at the time point when disease activity was lowest prior to the relapse, defined by nadir of M-component or FLC ratio, were compared to the patient-specific values observed when PD was detected. Ten patients experienced two episodes of disease progression and one patient three episodes, giving a total of 40 episodes of PD for evaluation in this study For these 40 cases, a retrospective analysis was performed in the prospectively collected and analyzed bone markers to see whether patient-specific changes in. Of the remaining 47 patients in the cohort, 15 patients had a limited number bone marker measure points, 10 patients were on continuous anti-myeloma treatment, 2 patients had smoldering myeloma only, and 5 patients were either lost to follow-up because of transfer to other hospital or were not evaluable as they were not fasting or nadir values were missing. Urine NTX-I was normalized and expressed relative to urine creatinine
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