Diffuse MRI Pattern of Marrow Infiltration Correlates with Suppressed Bone Formation and Increased Incidence of Vertebral Fractures in Multiple Myeloma.

Bone lytic disease is a major feature of multiple myeloma (MM) and is characterized by an increased osteoclast activity which is accompanied by a suppressed osteoblast function. Furthermore, increased angiogenesis is implicated in the pathogenesis of both bone disease and myeloma cell growth and survival. Magnetic resonance imaging (MRI) pattern of bone marrow involvement correlate with prognosis in MM. The aim of this study was to evaluate the MRI pattern of marrow infiltration in correlation with markers of bone remodeling and angiogenesis in 44 newly diagnosed, untreated, MM patients (42 with symptomatic and 2 with asymptomatic MM). MRI of the spine was performed at the same time with measurement of a series of biochemical serum indices of bone metabolism and angiogenesis:

• osteoclast stimulators [soluble receptor activator of nuclear factor-κB ligand (sRANKL), osteoprotegerin (OPG), and osteopontin],

• bone resorption markers [C- and N-telopeptide of collagen type-I (CTX, and NTX, respectively), and tartrate-resistant acid phosphatase isoform 5b (TRACP-5b)],

• bone formation markers [bone alkaline phosphatase (bALP), and osteocalcin (OC)], and

• angiogenic cytokines [vascular endothelial growth factor (VEGF), VEGF-A, angiogenin (ANG), angiopoietin-2 (ANGP-2), and basic fibroblast growth factor (bFGF)].

Myeloma patients had increased values of sRANKL (p<0.0001), OPG (p=0.01), sRANKL/OPG ratio (p<0.0001), NTX (p<0.0001), CTX (p=0.04), TRACP-5b (p<0.0001), VEGF (p=0.03), VEGF-A (p<0.0001), ANG (p<0.001), ANGP-2 (p=0.001), and bFGF (p=0.007) compared with respective values of 33, gender and age matched, controls. MRI revealed that 19 patients had focal pattern of marrow involvement, 11 diffuse, 10 normal, and 4 had a variegated pattern. Patients with diffuse MRI pattern also had reduced values of bALP (p<0.0001) compared to controls, while patients with normal pattern had reduced levels of both formation markers (OC and bALP; p=0.04 and <0.0001, respectively) and normal levels of OPG. On the contrary, patients with focal and variegated patterns had normal values of bALP and OC. Bone formation as assessed by bALP was more suppressed in patients with diffuse or normal MRI patterns compared to patients of focal or variegated patterns (mean±SD: 15.9±7.3 U/L vs. 29.3±24.5 U/L; p=0.02), while there was no difference between these groups in terms of resorption markers or osteoclast stimulators’ levels. In addition, patients with diffuse and normal MRI pattern also had increased levels of VEGF-A compared to patients of focal or variegated patterns (mean±SD: 83±68.4 pg/mL vs. 38.4±55 pg/mL; p=0.04). All but two patients of diffuse pattern (81%) had at least one vertebral fracture on radiographic evaluation of the axial skeleton compared to ten patients with focal pattern (52%). These results suggest that patients with diffuse MRI pattern have suppressed bone formation, increased levels of the major angiogenic cytokine VEGF-A, and increased incidence of vertebral fractures compared to patients who showed a focal pattern of myeloma infiltration.