Osteoprotegerin (OPG) is considered one of the main regulators of bone remodeling. Various patterns of serum OPG levels have been described in different types of tumors. We undertook this study to determine serum OPG levels in patients with squamous cell head and neck cancer (SCHNC), analyzing their relationship with other metabolic bone parameters and bone mineral density (BMD), as well as the possible influence of chemotherapy. Forty male patients with localized SCHNC were studied, and their results were compared with those of 40 healthy male controls. The type of treatment followed by each patient was noted. Age, weight, height, and lifestyle habits were recorded; and OPG, Ca(2+), intact parathyroid hormone (iPTH), 25-Hydroxyvitamin D (25OHD) and 1,25-Dihydroxyvitamin D (1,25(OH)(2)D), bone alkaline phosphatase, osteocalcin, and serum C-terminal cross-links telopeptide of type I collagen (ICTP) were determined. Dual-energy X-ray absorptiometry BMD at the lumbar spine, femoral neck, and hip was also measured. Serum OPG was higher in patients than in controls (91.7 +/- 25.8 vs. 77.2 +/- 26.3, P = 0.02). ICTP (a bone resorption marker) was 37% higher in patients (P = 0.007). Bone mass was lower in patients at the lumbar spine, femoral neck, and total hip. Lumbar spine Z-score showed a significant progressive decrease in controls, stage I-III patients, and stage IV patients. Logistic regression analysis showed a significant association between the disease and serum OPG levels, the odds ratio per standard deviation increase of this being 1.9 (95% confidence interval 1.1-3.8, P = 0.04) after adjusting for bone mass and ICTP serum levels, as well as for alcohol and smoking history. Adjustment for alcohol intake and tobacco use did not cancel out BMD differences between patients and controls. Patients with SCHNC show increased OPG serum levels, increased bone resorption, and decreased bone mass. The OPG rise appears to be unrelated to the BMD decrease, and the BMD decrease seems to be, at least in part, independent of smoking and drinking habits. No differences in either OPG or BMD were seen between patients with and without chemotherapy. Further studies are needed to clarify the mechanisms responsible for OPG and BMD changes in SCHNC.