Bone Resorption in Multiple Myeloma and in Monoclonal Gammopathy of Undetermined Significance: Quantification by Urinary Pyridinium Cross-Links of Collagen

Abstract

To quantify osseous breakdown in multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), and benign osteoporosis, we measured urinary levels of pyridinium cross-links of collagen in 50 patients with newly diagnosed and untreated MM, 40 patients with MGUS, 40 untreated patients with osteoporotic vertebral fractures, and 64 healthy adults. Ion-paired, reverse-phase high-performance liquid chromatography (HPLC) was used to measure total urinary excretion of pyridinoline (h-PYD) and deoxypyridinoline (h-DPD). Urinary excretion of free immunoreactive deoxypyridinoline (i-DPD) was determined with an enzyme immunoassay. MM patients had significantly (P < .0001) higher levels of h-PYD, h-DPD, and i-DPD than the healthy adults, patients with MGUS, or patients with osteoporosis. The MGUS and osteoporosis groups presented with elevated (P < .05) levels of urinary pyridinium cross-links when compared with healthy controls. In 20 MM patients who subsequently received chemotherapy, the percent changes in i-DPD did not correlate with the changes in the monoclonal protein. In one of three patients experiencing a transition of initial MGUS into stage I MM, i-DPD increased above the upper limit of the normal range. In 13 patients with stable MGUS, i-DPD remained normal in repeated measurements. Based on the upper limits of the normal range, the sensitivity of urinary pyridinium cross-links in stage I and II MM was low (<50%), but it was between 78% (h-DPD) and 93% (i-DPD) in stage III MM. Specificity in patients with MGUS was between 87% (h-PYD) and 97% (h-DPD). In conclusion, determining the urinary excretion of pyridinium cross-links seems to be a promising noninvasive and thus easily repeatable method for evaluating the actual degree of osseous breakdown. Although measurement of pyridinium cross-link levels is not useful in discriminating patients with MGUS from early-stage myeloma patients, determination of i-DPD levels may contribute importantly to clinical guidance, since increased i-DPD levels seem to identify patients who are particularly likely to benefit from osteoclast-inhibiting drugs such as bisphosphonates. The fact that in a number of patients paraprotein concentrations and i-DPD levels did not change in parallel but instead diverged strongly after chemotherapy might explain the observation that bone lesions sometimes progress even in patients who achieve complete remission.

Serum concentrations of Dickkopf‐1 protein are increased in patients with multiple myeloma and reduced after autologous stem cell transplantation

“…In MGUS patients, serum concentration of the sRANKL/OPG ratio and urinary NTX is elevated, suggesting that increased bone resorption is present in at least some of these patients. 11,12 This is also supported by histomorphometric studies 13 and recent data demonstrating that these subjects are at increased risk of fracture, particularly vertebral compression fractures. 14 This observation has led to the hypothesis that although osteoclast activity is increased in some MGUS patients, it is compensated for by the normal function of osteoblasts; thus, lytic lesions do not develop.…”

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)

“…In previous studies, markers of bone resorption such as NTX, carboxy-terminal telopeptide of type-I collagen (ICTP), and urinary deoxypyridinoline (uDPYD) were evaluated in MGUS patients. All markers were found to be significantly decreased in MGUS patients compared with MM patients (Pecherstorfer et al, 1997;Vejlgaard et al, 1997;Corso et al, 2001;Diamond et al, 2001;Jakob et al, 2002).…”

Ability of myeloma cells to secrete macrophage inflammatory protein (MIP)‐1α and MIP‐1β correlates with lytic bone lesions in patients with multiple myeloma

“…Urinary excretion of the pyridinium derivative of type I collagen, deoxypyridinoline (Dpd), can be measured as a bone resorption marker for evaluating the actual degree of osseous breakdown (Khosla & Kleerekoper, 2003). Urinary levels of Dpd are significantly elevated in MM, and can be used to determine the initiation of antiresorptive therapy such as bisphosphonates and monitor effectiveness of the therapy (Pecherstorfer et al, 1997). On the other hand, both serum bone-specific alkaline phosphatase (BALP) and osteocalcin are considered as bone formation markers.…”