Role of receptor activator of nuclear factor‐kappa B ligand (RANKL), osteoprotegerin and macrophage protein 1‐alpha (MIP‐1a) in monoclonal gammopathy of undetermined significance (MGUS)

Abstract

Summary The aim of this study was to evaluate the role of markers of bone remodelling, and osteoclast activation/function in patients with monoclonal gammopathy of undetermined significance (MGUS). We have measured serum levels of soluble RANKL (sRANKL), osteoprotegerin (OPG), macrophage inflammatory protein‐1alpha (MIP‐1α), markers of bone resorption [N‐telopeptide of collagen type‐I (NTX), and tartrate‐resistant acid phosphatase isoform‐5b (TRACP‐5b)] and bone formation [bone‐alkaline phosphatase (bALP)] in 40 MGUS patients. These parameters were compared with those of 42 newly diagnosed myeloma patients, and 45 healthy, gender‐ and age‐matched controls. MGUS patients had elevated levels of NTX, sRANKL, and sRANKL/OPG ratio compared with controls (P < 0·0001). Furthermore, TRACP‐5b, MIP‐1α and NTX were decreased in patients with MGUS compared with myeloma patients (P < 0·001), while OPG and bALP were increased (P < 0·001). Serum levels of MIP‐1α, as well as TRACP‐5b, and sRANKL/OPG ratio were reduced, while bALP was increased in MGUS patients, even when compared with myeloma patients who had stage I/II disease. These results demonstrate that increased osteoclastogenesis leading to increased bone resorption is present in MGUS but seems to be compensated for by normal bone formation, which is absent in MM. Furthermore MIP‐1α, bALP, and sRANKL/OPG may be useful tools for distinguishing between cases of MGUS and early myeloma.

Monoclonal Gammopathy of Undetermined Significance and Smoldering Myeloma: New Insights into Pathophysiology and Epidemiology

“…28 Interestingly, excess bone resorption measured by quantitative bone biopsy and biomarkers of bone turnover suggest that bone disease not detectable by skeletal survey is present even in some MGUS patients. 29,30 This finding may explain the previously reported excess risk of bone fractures in MGUS patients independent of malignant transformation. [31][32][33] Along the same lines, smaller studies have used magnetic resonance imaging (MRI) in patients otherwise defined as having SMM, and found occult bone lesions in some patients.…”

The pathogenesis of the bone disease of multiple myeloma

“…In patients with multiple myeloma, the ratio of RANKL and OPG has been shown to be markedly dysregulated, with an increase in RANKL expression, and a concomitant decrease in OPG expression and serum concentration (20)(21)(22)(23)(24) An increase in the serum RANKL:OPG ratio has been demonstrated in patients with multiple myeloma, which correlates with both bone disease and survival (25). There is evidence to support both an increase in RANKL expression by bone marrow stromal cells and osteoblasts (20)(21)(22), and also for expression of RANKL by myeloma cells (26,27).…”

Bone disease in monoclonal gammopathy of undetermined significance: results from a screened population-based study

“…16,17 In addition to this, bone metabolism in MGUS may be altered, although studies on bone markers have shown inconclusive results. [17][18][19][20][21] In summary, these data indicate that MGUS patients have an increased risk of fractures and altered bone microstructure. However, it is uncertain whether the risk of fractures is a result of loss of BMD, or due to other factors affecting bone strength.…”