Increased Osteoprotegerin Levels in Response to Increased Bone Resorption in AL Amyloidosis: Comparisons with Bone Remodeling of Multiple Myeloma.

Primary systemic amyloidosis (AL) and multiple myeloma (MM) are both clonal plasma cell disorders with distinct clinical characteristics. Bone disease is a hallmark of symptomatic MM in contrast to AL where lytic bone lesions are not found. Myeloma bone disease is characterized by an imbalance between osteoblastic and osteolytic activity induced by plasma cell-stroma interaction resulting in deregulation of numerous cytokines involved in bone remodeling. There are no data about bone metabolism in AL and the similarities or differences with MM. Levels of bone remodeling indices were measured in stored serum samples, collected from 62 previously untreated patients with AL amyloidosis. These included:

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

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

• osteoclast regulators [soluble receptor activator of nuclear factor-kB ligand (sRANKL), osteoprotegerin (OPG), macrophage inflammatory protein-1 alpha (MIP-1a), interleukin-6 (IL-6) and osteopontin (OPN)], as previously described.

These markers were also measured in serum collected from 35 age-matched healthy controls and 35 newly diagnosed, untreated, symptomatic myeloma patients. Median age of AL patients at diagnosis was 61 years (range 39–80 years); heart was involved in 60% and kidneys in 66% of patients, while in 64% ≥2 organs were involved. In 16% of AL patients creatinine was ≥2 mg/dl. Median b2-microglobulin was 1.8 mg/l (range 0.5–28 mg/l); 64% of patients had >10% bone marrow infiltration by plasma cells. None of AL patients had lytic bone lesions in plain radiography or other features suggestive of myeloma such as hypercalcemia, significant anemia unrelated to renal impairment or predominant Bence-Jones proteinuria. The levels of sRANKL and OPG were both increased in AL patients compared to controls (p=0.07 and p<0.001). OPG was significantly higher in AL than in MM patients (p<0.001), but not sRANKL; thus sRANKL/OPG ratio was not different between AL and controls but it was significantly lower than in MM patients (p=0.009). Other osteoclast stimulators (MIP-1a, OPN, IL-6) were also increased in AL compared to controls (p<0.02). Bone resorption markers (CTX, NTX, TRACP-5b) were elevated in both AL and MM (p=0.008, p<0.001 and p<0.001 for AL vs. controls, respectively, and p=0.006, p<0.001 and p<0.001 for MM vs. controls). On the contrary, bone formation markers were not different between AL patients and controls, while in MM both bALP and OC had lower values compared to controls. Renal involvement did not affect bone markers but in AL patients with a creatinine level of >2 mg/dl CTX and NTX were higher than in patients with a creatinine level of <2mg/dl (p<0.001 and p=0.016, respectively). Involvement of other organs or the number of involved organs did not appear to influence bone remodeling. This study suggests that bone metabolism in AL is characterized by increased bone resorption with a pattern similar to that found in MM. Increased OPG levels in AL indicate more effective compensation of osteoclast activation compared to MM, probably explaining the lack of lytic disease in AL and possibly reflecting differences in the pathophysiology of plasma cell-stroma interaction between AL and MM.