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Originally published as JCO Early Release 10.1200/JCO.2005.02.911 on June 27 2005 © 2005 American Society of Clinical Oncology.
High Bone Turnover Markers Predict Poor Outcome in Patients With Bone MetastasisUniversity of Pittsburgh Medical Center, Pittsburgh, PA Bone is a frequent site for metastasis in patients with solid tumors such as breast cancer, prostate cancer, and lung cancer. It may be the first, or even the only, site for metastases in these patients. It is estimated that more than 350,000 patients a year in the United States die with bone metastasis.1 Bone metastasis is responsible for some of the most devastating complications of malignancy, including pathologic bone fractures, spinal cord compression syndromes, excruciating bone pain, and hypercalcemia. These skeletal metastases can require surgery or radiotherapy to bone, in addition to aggressive analgesic therapy. Furthermore, bone metastases have a major impact on the quality of life and even the survival of these patients. This is clearly illustrated by the authors of the current article, who have reported on patients from the placebo arms of their trials.2 They found that 143 of 454 patients with bone metastasis from prostate or other solid tumors on the placebo arms of these trials experienced pathologic fractures throughout the 21 months of study.2 Two hundred forty of these 454 patients required radiotherapy to their bone lesions. The median survival for prostate cancer patients on the placebo arm of the trial was 16.8 months and was only 5.6 months for patients with bone metastasis from other solid tumors. These results demonstrate the extreme toll bone metastasis takes on these patients. In this issue, Coleman et al examined the ability of bone turnover markers to predict negative clinical outcomes in a cohort of almost 2,000 patients with baseline bone metastasis from prostate cancer, breast cancer, myeloma, or other tumors, who were treated with bisphosphonates.3 Previous reports of the predictive value of bone turnover markers in these types of patients have been conflicting. However, most of the other studies included much smaller numbers of patients. The overwhelming majority of the patients in the current trial received zoledronate, an extremely potent bisphosphonate. Even patients receiving this very potent bisphosphonate still had progression of their bone disease, experiencing one skeletal-related event per year during the 17 months that they were followed up on. These investigators report on two markers of bone turnover, urinary Ntx (N-telopeptide of collagen type 1) and serum bone-specific alkaline phosphatase (BAP). Ntx is a marker of bone degradation by osteoclasts, and BAP is a marker for bone formation. These markers were chosen because patients with solid tumors and bone metastasis have both increased bone destruction and bone formation. In contrast, patients with myeloma have suppressed bone formation. They found that Ntx levels were better predictors of outcome for these patients than BAP. Patients with hormone refractory prostate cancer had the highest Ntx levels, most likely reflecting the combined effects of increased bone turnover from their metastasis, and bone loss due to low testosterone levels. Furthermore, high levels of Ntx at study entry predicted a poor outcome, and the most recent Ntx level was an even better predictor for outcome. Patients with high Ntx levels in their urine had a four- to six-fold increased risk of death and a two-fold increase in the risk of future skeletal events compared with patients with low Ntx levels. Interestingly, once patients were on therapy, Ntx levels did not correlate with tumor burden markers such as prostate-specific antigen in patients with prostate cancer, though it is likely that high Ntx levels reflected increased tumor progression in patients compared with those with low Ntx levels. Furthermore, although Ntx levels reflect bone events, it is reasonable to assume those visceral metastases are also progressing in patients with high Ntx levels. Importantly, high levels of bone resorption markers seem to identify a group of patients who are not responding to their current therapy and may need additional antiresorptive therapy as well as changes in their chemotherapy, or may be candidates for trials of novel agents. Further support for patients with persistently elevated Ntx levels having tumor progression in other sites in addition to bone is the shortened survival of these patients compared with those with low Ntx levels. An alternative interpretation of the results is that the patients are dying from their bone involvement. If this were the case, overall survival would be greatly improved if bone resorption were further inhibited in these patients. This would suggest that adding other antiresorptive therapies, possibly with a different mechanism of action, such as a cathepsin-K inhibitor that would block bone resorption or an inhibitor of a signaling pathway critical for osteoclast activity or survival, could further improve the outcome of these patients. Studies in animal models of bone metastasis (breast, prostate, or myeloma) have shown that blocking bone resorption decreases both tumor growth and enhances survival of these animals.4,5 However, to date, there has been no clear demonstration in patients with bone metastasis that decreasing bone turnover decreases tumor burden. The finding that Ntx, a bone resorption marker, was a better predictor of outcome than BAP, a bone formation marker, most likely reflects that bone formation markers also measure new bone formation in response to bone destructiont since bone resorption and bone formation are normally coupled. This was true even in patients with prostate cancer who have osteoblastic metastasis. Alternatively, BAP is not a sensitive indicator of bone formation and other markers of formation such as osteocalcin or pro–collagen type I amino-terminal propeptide may have had a greater association with outcome events. The question remains whether bone resorption markers can also be used to identify patients at risk for developing bone metastasis. Bone resorption markers do not appear to be as sensitive as standard imaging techniques such as bone scans, or other types of imaging studies for detecting bone metastasis. Schoenberger et al have evaluated the clinical utility of bone turnover markers to detect the development of bone metastasis in patients with solid tumors.6 They found that markers of bone metabolism showed a lower sensitivity and/or specificity than imaging techniques. However, as demonstrated by the current study, once bone metastases are established, bone turnover markers are highly predictive of both survival and skeletal related events. Based on the findings in this article, measurements of bone resorption markers, in particular Ntx levels, should be performed routinely in patients with bone metastasis at regular intervals. This would help stratify patients for treatment and allow identification of subgroups of patients who have progression of disease and who may need to have their therapy changed. Author's Disclosures of Potential Conflicts of Interest The following author or their immediate family members has indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES
1. Roodman GD: Mechanisms of bone metastasis. N Engl J Med 350: 1655-1664, 2004
2. Brown JE, Cook RJ, Major P, et al: Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst 97: 59-69, 2005
3. Coleman RE, Major P, Lipton A, et al: The predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol 23: 4925-4935, 2005 4. Croucher PI, DeHendrik R, Perry MJ, et al: Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: Evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival. J Bone Miner Res 18: 482-492, 2003[CrossRef][Medline] 5. Yaccoby S, Pearse RN, Johnson CL, et al: Myeloma interacts with the bone marrow microenvironment to induce osteoclastogenesis and is dependent on osteoclast activity. Br J Haematol 116: 278-290, 2002[CrossRef][Medline] 6. Schoenberger J, Rozeboom S, Wirthgen-Beyer E, et al: Evaluation of the clinical value of bone metabolic parameters for the screening of osseous metastases compared to bone scintigraphy. BMC Nucl Med 4: 3, 2004[Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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