Bone microstructural changes revealed by high-resolution peripheral quantitative computed tomography imaging and elevated DKK1 and MIP-1α levels in patients with MGUS

Abstract

Recent population-based studies demonstrate an increased fracture risk with monoclonal gammopathy of undetermined significance (MGUS). The etiology of this increased risk remains unclear, however, because areal bone mineral density (aBMD) measurements by dualenergy x-ray absorptiometry cannot assess bone microstructural properties critical to determining bone quality and strength. To better define the skeletal effects of MGUS, we performed aBMD and high-resolution peripheral quantitative computed tomography volumetric bone mineral density (vBMD) measurements in 50 MGUS patients (20 females, 30 males; mean ؎ SEM age, 70.5 ؎ 1.4 years) and 100 matched control subjects. Relative to controls, MGUS patients had decreased aBMD at the femoral neck (P ‫؍‬ .05) and total femur (P < .05) but no differences at other sites. In contrast, highresolution peripheral quantitative computed tomography showed markedly diminished cortical thickness (P < .05) and increased endocortical area (P < .01). Average vBMD (P < .01), cortical vBMD (P < .001), and trabecular thickness (P < .01) were all significantly decreased in MGUS patients, suggestive of impaired bone formation. Serum levels of the Wnt pathway inhibitor Dickkopfrelated protein 1 (P < .001) and osteoclastactivating factor MIP-1␣ (P < .05) also were significantly elevated in MGUS patients. Our data provide the first evidence of altered bone microstructure in MGUS and suggest that cytokines elevated in osteolytic myeloma also may be associated with bone loss in MGUS. (Blood. 2011;118(25):6529-6534) IntroductionMultiple myeloma (MM) results from the clonal expansion of malignant plasma cells within the bone marrow. Bone disease is nearly universal in MM. Roughly 80% of patients develop a pathologic fracture at some point during their disease, and nearly 90% have radiographic evidence of skeletal lesions. 1 At the other end of the monoclonal gammopathy spectrum, monoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition, with an ϳ 1% annual risk of progression to an MMrelated malignancy. 2 MGUS is a common finding in clinical practice, with a prevalence of ϳ 3.2% in white persons 50 years of age and older. 3 This increases with age, such that in persons older than 85 years of age, the prevalence of MGUS is ϳ 7.5%.By definition, MGUS patients lack lytic bone lesions. 3 Nonetheless, population-based studies show that MGUS is associated with a significantly increased risk of fracture, 4,5 suggesting that alterations in bone quantity, quality, or both are present even before disease progression to MM. 6 However, little is known about the skeletal phenotype of MGUS and whether abnormalities exist to explain this increased fracture risk. Indeed, even whether bone loss is increased in MGUS is a subject of debate. Thus, some studies 7,8 but not others 9,10 have reported that biochemical markers of bone resorption are increased in MGUS. Furthermore, although several studies have reported that fractures are increased in MGUS, 4,[10][11][12] some of these same s...

Pre‐diagnostic blood immune markers, incidence and progression of B‐cell lymphoma and multiple myeloma: Univariate and functionally informed multivariate analyses

“…Although the markers identified in our study have been identified previously in clinical studies of MM or its precursor states ( i.e ., MGUS and SMM),45, 46, 47, 48, 49, 50 the direction of our findings is in general opposite to observations among subjects diagnosed with MM, where higher concentrations of these markers seems to be related to generally poorer disease outcome. The reason for this difference in direction of the effect is not known but may hint toward a preclinical deregulation of these important biological systems in subjects developing MM later in life which at the time of clinical manifestation reverse in overexpression.…”

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

“…These results are in accordance with the findings of Ng et al, wherein DXA measurements on 50 MGUS patients, compared with 100 controls, showed no significant difference in areal BMD at lumbar spine, femur neck, or total radius, although they did find a significant difference in areal BMD at total femur. 16 In a previous large screening study, a 20% increased risk for a diagnosis of osteoporosis was found in individuals with MGUS. 6 This is contradictory to our results, but might be explained by the increased surveillance of individuals with MGUS, thus leading to more investigations (DXA scans) and diagnoses of osteoporosis, and not necessarily indicating a lower BMD in the group.…”

“…26.3 mg/L). 1 A total of 39 individuals were excluded from analysis due to previous lymphoproliferative disease at baseline (21), missing blood sample (16), missing consent form (1), or M-protein concentration above the limit for MGUS (1).…”

“…High-resolution peripheral QCT (HRpQCT) imaging showed an overall increase in bone size, diminished cortical thickness, increased endocortical area of the distal radius, higher cortical porosity, and reduced bone strength in MGUS patients. 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.…”

“…15 Two studies have used skeletal imaging techniques to compare bone disease in MGUS patients to matched controls. 16,17 In a study on 50 MGUS patients, compared with 100 controls, MGUS patients were found to have decreased BMD at the total femur, but no differences were found at other sites. High-resolution peripheral QCT (HRpQCT) imaging showed an overall increase in bone size, diminished cortical thickness, increased endocortical area of the distal radius, higher cortical porosity, and reduced bone strength in MGUS patients.…”