Evaluation and prognostic value of serum osteoprotegerin in multiple myeloma

Abstract

An essential cytokine system for osteoclast biology consists of the receptor activator of nuclear factor (NF)-B ligand (RANKL), its receptor RANK, and the soluble decoy receptor osteoprotegerin (OPG). Myeloma plasma cells have been shown to increase RANKL expression and to decrease OPG availability in the bone marrow microenvironment. These effects result in an increased RANKL:OPG ratio that favours the activation of osteoclasts. Conflicting reports exist regarding serum OPG levels in multiple myeloma (MM) and their correlation with lytic bone disease and survival (Seidel et al, 2001; Lipton et al, 2002; Kraj et al, 2003; Terpos et al, 2003; Corso et al, 2004; Kyrtsonis et al, 2004). We evaluated the serum levels of OPG in 140 newly diagnosed MM patients and assessed its prognostic value in the 101 symptomatic patients requiring treatment. The mean (± standard deviation) OPG levels in symptomatic MM, asymptomatic MM and controls represented by 41 healthy age- and sex-matched individuals were 3.4 ± 2.5, 2.9 ± 1.1 and 2.0 ± 0.7 ng/ml respectively. The median OPG concentration in symptomatic MM, asymptomatic MM and controls were 3.0 ng/ml (range, 0.8–24), 2.6 (1.6–7.2) and 1.6 ng/ml (1.2–3), respectively. OPG levels were higher in asymptomatic and symptomatic MM compared with controls (P < 0.001 in each case). In contrast, there was no statistically significant difference between asymptomatic and symptomatic MM patients (P = 0.28). Bone lesions were graded in three groups according to a standard radiographic evaluation: no osteolytic lesions, 1–6 lesions, >6 lesions. We found no significant differences of OPG values between the three groups. Significant correlations were found with β2-microglobulin (r = 0.23; P = 0.02) and creatinine (r = 0.22; P = 0.03) but not with haemoglobin, bone marrow plasmacytosis, M-component, albumin, lactate dehydrogenase (LDH) or C-reactive protein (CRP) levels. We assessed the prognostic value of OPG on overall survival (OS) and progression-free survival (PFS) in symptomatic patients. Median follow-up of the 101 patients was 68.4 months [95% confidence interval (CI): 60.2–76.6]. The median PFS and OS were 18.8 months (95% CI: 14.5–23.1) and 39.8 months (95% CI: 29.6–50.0) respectively. High serum levels of OPG were associated with a poorer OS and PFS in univariate analysis (P = 0.025 and P = 0.029 respectively) (Fig 1A,B). The other adverse prognostic factors were age >60 years (P = 0.019), albumin <35 g/l (P = 0.015), β2-microglobulin >2.5 mg/l (P = 0.025), bone marrow plasmacytosis >15% (P = 0.048), chromosome 13 deletion (P = 0.002), CRP > 16 mg/l (P = 0.037), IgA isotype (P = 0.012), LDH > 350 IU/l (P = 0.016), λ light chain (P = 0.021) for OS and β2-microglobulin >2.5 mg/l (P = 0.01), chromosome 13 deletion (P = 0.002), and IgA isotype (P = 0.012) for PFS. Interestingly, multivariate analysis showed that OPG ≥2.4 ng/ml remained an adverse independent prognostic factor for OS [relative risk (RR) 2.3, 95% CI: 1.2–4.5, P = 0.018] together with albumin <35 g/l (RR 2.4, 95% CI: 1.3–4.5, P = 0.005) and CRP >16 mg/l (RR 2.3, 95% CI 1.2–4.2, P = 0.008). Overall survival (A) and progression-free survival (PFS) (B) of the 101 symptomatic MM patients according to serum OPG level at diagnosis. The biological role of OPG in MM is possibly more complex than expected. There is no clear evidence that serum OPG reflects the availability of OPG in the bone marrow environment and we cannot exclude that OPG may have different functions on bone biology and tumor progression. OPG is a decoy receptor for tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), which inhibits TRAIL-induced apoptosis. In relation to this activity, it has been recently suggested that OPG may be a survival factor for human prostate cancer cells (Holen et al, 2002) and also function as a paracrine survival factor for human myeloma cells (Shipman & Croucher, 2003). These results, if they translate in vivo, raise the possibility that OPG might have the capacity to function as a deleterious factor on MM progression in some patients.