High Bone Turnover Markers Predict Poor Outcome in Patients With Bone Metastasis

Abstract

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 thesetrialsexperiencedpathologicfracturesthroughoutthe 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. Inthisissue,Colemanetalexaminedtheabilityofbone turnover markers to predict negative clinical outcomes in a cohort of almost 2,000 patients with baseline bone metastasisfromprostatecancer,breastcancer,myeloma,orother 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 Ntxlevelwasanevenbetterpredictorforoutcome.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 suchasprostate-specificantigeninpatientswithprostate 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 ag roup 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.