This study was designed to explore the value of markers of bone turnover, macrophage inflammatory protein-l alpha (MIP-l alpha), and osteopontin (OPN) in the diagnosis of myeloma bone disease. Twenty-five patients with newly diagnosed and untreated multiple myeloma (MM), and 22 age-, sex-, and bone mineral density-matched control subjects were enrolled. Levels of MIP-l alpha, OPN, carboxy-terminal telopeptide of Type-1 collagen (C-telopeptide or Ctx), deoxypyridinoline (DPD), Type-1 collagen propeptide (T1Pro), and bone-specific alkaline phosphatase (BALP) were assessed in both groups. Twenty-two of the patients had bone involvement documented by skeletal surveys and lumbar spinal magnetic resonance imaging. Levels of serum Ctx, OPN, MIP-1 alpha, and urine DPD were significantly higher in MM patients with bone disease than in controls (P < 0.01). Serum Ctx levels were elevated in 90.9% of patients with MM and 40.9% of controls (P < 0.001). Urine DPD levels were elevated in 90.4% of the patients and 31.8% of the controls (P < 0.001). The serum OPN and MIP-1 alpha levels of the patients were significantly correlated with beta 2-microglobulin and lactate dehydrogenase levels (P < 0.05). Our study indicates that Ctx and DPD are sensitive markers of bone disease in MM, and higher than normal values suggest presence of bone disease rather than benign osteoporosis in MM. The utility of OPN and MIP-1 alpha needs to be further investigated. Am. J. Hematol. 82:185-191, 2007. (c) 2006 Wiley-Liss, Inc.