Markers of bone remodeling and skeletal morbidity in patients with solid tumors metastatic to the skeleton receiving the biphosphonate zoledronic acid

The molecular triad, which includes the receptor activator of nuclear factor kappa-B ligand (RANKL), its receptor RANK, and the endogenous soluble RANKL decoy receptor osteoprotegerin (OPG), has emerged as an important determinant of bone metabolism. We aimed to evaluate the effect of treatment with the biphosphonate zoledronic acid (ZA) on biochemical markers of bone remodeling and to detect possible correlations of markerlevel changes with skeletal morbidity and clinical outcomes in patients with solid tumors and osseous metastases. The following serum markers were measured at the onset of skeletal metastases and after 6 months of treatment with ZA (4 mg intravenously monthly) in 70 patients with breast (n = 30), lung (n = 18), or prostate (n = 22) cancer: RANKL, OPG, C-terminal cross-linking telopeptide of type I collagen (CTX), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), bone-specific alkaline phosphatase (bALP), and osteopontin (OPN). Logistic regression models were applied to assess the correlation between marker-level changes and skeletal related events (SRE, primary endpoint), recurrence or progression, and death. Within a median follow-up of 32 months, 34 patients (48.6%) presented with at least 1 SRE and 48 patients (68.6%) relapsed. The RANKL/OPG ratio was upregulated in patients with breast and lung cancer, and it tended to decline after treatment with ZA, whereas prostate cancer patients presented with profound elevation of OPG only that persisted after treatment. CTX levels were significantly reduced after treatment in the whole study population (P = 0.003). None of the markers was able to predict skeletal morbidity or clinical outcomes independently of well-established prognostic clinical parameters.

Abbreviations: ECOG, eastern co-operative oncology group, OPN, osteopontin, NTX, N-telopeptide, collagen type I, CTX, C-telopeptide, collagen type I, TRACP-5b, 5b isoenzyme of tartrate-resistant acid phosphatase, bALP, alkaline phosphatase, bone isoenzyme, sRANKL, soluble receptor activator of nuclear factor kappa-B, NFκB, nuclear factor kappa-B, OPG, osteoprotegerin, LHRH, luteinizing hormone-releasing hormone, ELISA, enzyme-linked immunoSorbent assay 95%, CI, 95% confidence intervals, IQR, interquartile range, ANOVA, analysis of variance, PS, performance status, PSc, pain score, HR, hazard ratio, SRE, skeletal related events, NSCLC, non small-cell lung cancer