Serum levels of OPG, RANKL and RANKL/OPG ratios in newly-diagnosed patients with multiple myeloma. Clinical correlations

Abstract

Serum levels of OPG and RANKL and their clinical correlations were analyzed in 66 newly–diagnosed patients with multiple myeloma (MM). RANKL and RANKL/OPG ratios were significantly increased in advanced clinical stages and high grade myeloma bone disease (MBD), while OPG showed a tendency to decrease. Renal failure modified the expression of OPG. RANKL and RANKL/OPG ratios are informative markers for myeloma tumor burden and MBD.

OPG/RANKL system is a critical regulator of bone metabolism. A serious imbalance of the system has been found in multiple myeloma (MM). Myeloma cells participate directly in this process. They induce RANKL expression by the bone marrow stromal cells and osteoblasts and most probably produce certain amounts of RANKL themselves. On the other hand myeloma cells bind, internalize and degrade OPG,1 and inhibit the activity of osteoblasts. While the experimental data for OPG/RANKL system in MM are well-founded, there are few clinical studies on the problem in MM patients.

To contribute to the understanding of the role of OPG/RANKL system in myeloma patients, we analyzed the serum levels of OPG and RANKL in 66 newly–diagnosed patients with MM and 32 healthy controls, their expression in the clinical stages and grades of myeloma bone disease (MBD), the influence of renal failure on their levels and their correlations with basic parameters of disease activity. Mean age of the patients was 61.3±9.2 years, 29 males and 37 females. Fifty-three percent were in clinical stage III (ISS). Renal failure (RF) was confirmed in 40.9% and MBD in 84.8% (graded according to the Merlini scale). Analyses were carried out with ELISA (Biomedica, Vienna kits). Statistical analyses were carried out using the Mann-Whitney test, one-way ANOVA and Spearman’s correlations. OPG levels were significantly higher in MM patients compared with the controls, but the OPG/creatinin ratio eliminates the difference. Literature reports three possible types of results: low levels of OPG,2–4 high5–7 and no difference with controls.8 In MM patients, the levels of RANKL and RANKL/OPG ratio were more than two times higher than controls (p<0.001). This agrees with most other studies.4,8,9 OPG shows a tendency to decrease in the advanced clinical stages (NS) and in high grade MBD (S). The lowest OPG level was measured in patients with severe bone lesions (4.26±0.36 pmol/L). RANKL and RANKL/OPG ratios significantly increase in advanced clinical stages and in patients with severe bone lesions. They are highest in clinical stage III and in MBD grade 2+3 (Table 1). Reasonably OPG and OPG/creatinin ratios correlate reversely with MBD and bone marrow infiltration. RANKL and RANKL/OPG ratios have positive correlations with the clinical stage, grade of MBD, percentage of bone marrow infiltration and LDH. The strongest correlation was found between the RANKL/OPG ratio and MBD (Table 2). OPG is high in early clinical stages and in patients with minimal bone lesions because, as in the patients with MGUS and benign osteoporosis, osteoblast function is still coupled to the intensified osteoclast function. Its decrease as the disease evolves is a result of the suppressive effects of myeloma cells. In advanced clinical stages, RANKL and RANKL/OPG ratios rise significantly. Other studies observed differences between each clinical stage, between clinical stage I and MGUS, and between MGUS and healthy controls.8 They are elevated even in myeloma patients without bone lesions, and are significantly higher in patients with multiple bone lesions.9 Not surprisingly, significant positive correlation between RANKL and extent of MBD have also been found by other investigators.10

Table 1.Serum levels of OPG, RANKL and RANKL/OPG ratio in patients with multiple myeloma and controls.

Table 2.OPG/RANKL system in multiple myeloma –clinical correlations.

Renal failure (RF) has a specific influence on OPG/RANKL system. MM patients have significantly higher levels of OPG, RANKL and RANKL/OPG ratios compared with controls. But patients with severe bone lesions + RF have significantly lower OPG compared with the group with minimal or no bone lesions + RF (4.92±0.62 pmol/L vs. 9.97±2.42 pmol/L; p<0.05). We interpret this finding as the skeletal response to the combined but opposite effects of renal insufficiency and osteolytic activity produced and/or induced by myeloma cells. In advanced clinical stages, although RF progresses, OPG is significantly lower because of the accumulation of the myeloma tumor mass. RANKL and RANKL/OPG ratios are very informative markers of MBD and myeloma tumor burden. OPG level in MM is influenced by many factors and has specific dynamics, depending on the counter-active signals for its production and inhibition.