Abstract
Background: Receptor Activator of Nuclear factor KappaΒ Ligand (RANKL) and its endogenous inhibitor osteoprotegerin (OPG) are important determinants of bone remodeling in patients with solid tumors metastatic to the skeleton. We aimed: a) to assess the levels of the RANKL/OPG system and of a panel of biochemical markers in patients with solid tumors metastatic to the bone in relation to the type of malignancy and the neoplastic burden to the skeleton b) to evaluate the effect of treatment with the biphosphonate zoledronic acid on markers of bone remodeling and c) to detect possible correlations of marker response with skeletal morbidity and clinical outcomes. Patients and Methods: Levels of soluble RANKL (sRANKL), OPG and RANKL/OPG ratio were assessed in 70 patients with breast (N=30), lung (N=18) and prostate (N=22) cancer with newly-diagnosed metastasis to the bone and in 40 healthy age and sex-matched volunteers. Biochemical markers of bone resorption, including C-telopeptide of type-I collagen (CTX), tartrate-resistant acid phosphatase-5b (TRACP-5b) and osteopontin (OPN) and of bone formation, including bone-alkaline phosphatase (bALP), osteocalcin (OC), and C-terminal propeptide of collagen type-I (CICP) were also assessed at the onset of skeletal metastases and six months after initiation of treatment with zoledronic acid (4 mg monthly). Logistic regression models were applied to assess the correlation between bone marker level changes and Skeletal Related Events (SRE, primary endpoint), recurrence and death. Results: Patients had elevated serum levels of RANKL, OPG, OPN, TRACP-5b, and bALP, and reduced OC levels compared to controls. OPG correlated with the extend of metastatic bone burden. Patients with breast and lung cancer shared increased levels of RANKL, OPG, and OPN whereas prostate cancer patients had elevated values of OPG and bALP only. After a median follow-up of 32 months, 34 patients (48.6%) presented with at least one SRE and 48 patients (68.6%) relapsed. RANKL/OPG ratio tended to decline after treatment with zoledronic acid with the exception of patients with prostate cancer. CTX levels were significantly reduced in the whole study population at the second compared to the initial measurement (p=0.003). Decrease in TRACP-5b levels tended to correlate with reduced incidence of SRE (HR=0.39, 95%CI: 0.14-1.10, p=0.076) and the model fit was improved when Performance Status (PS) at diagnosis was added in logistic regression analysis (p=0.051). Tumor type (lung or breast vs prostate) and PS (PS³2 vs <2) were the only significant predictors for recurrence and death and none of the bone markers was able to improve predictive value when added to the model. Conclusions: Patients with solid tumors metastatic to the bone have severe disruption of the RANKL/OPG axis. Breast and lung cancer seem to exert their osteolytic action through upregulation of the RANKL/OPG system whereas prostate cancer seems to provoke profound elevation of OPG levels only, thus leading to increased osteoblastic activity. Imbalance in the RANKL/OPG axis tends to normalize after treatment with zoledronic acid, as reflected by decrease in serum bone resorption markers. Marker level responses are not predictive for SRE, disease progression or survival.
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