Abstracts of 2nd Scientific Meeting on Bone Disease in Multiple Myeloma
Bone Markers in Myeloma
Henning W. Woitge, Berthold Fohr and Markus J. Seibel: Heidelberg
Common features of overt multiple myeloma (MM) are the circumscribed destruction of bone (i.e. osteolysis) or diffuse osteoporosis-like changes. Analyses of bone biopsies from MM patients revealed that the development of lytic bone lesions is related to increased osseous breakdown but also to the uncoupling of bone formation and bone resorption. Thus, during progression of MM-induced bone destruction, histomorphometric markers of bone formation decrease, while bone resorption remains at abnormally high levels.
The evaluation of the degree of bone involvement in plasma cell dyscrasias appears to be of particular importance for clinical guidance, but is limited by the invasiveness of the presently available standard method, the quantitative bone histology. Therefore, the use of specific biochemical markers of bone turnover as non-invasive measures of bone involvement may be a valuable tool in the evaluation of myeloma-induced bone disease.
Markers of bone resorption in multiple myeloma
We and others have previously demonstrated that biochemical markers of bone resorption are markedly elevated in MM patients. Comparing patients with MM, monoclonal gammopathy of undetermined significance (MGUS), and benign osteoporosis, Pecherstorfer et al (see Figure) found significantly higher levels of urinary pyridinoline (PYD) and deoxypyridinoline (DPD) in myeloma patients compared to healthy adults and the other disease groups. Measurement of pyridinium cross-link levels did not prove useful in the discrimination of patients with MGUS from early-stage myeloma patients, although increased DPD levels seemed to identify patients who where likely to benefit from bisphosphonate treatment.
More recently, serum bone sialoprotein (BSP) as a non-collagenous bone matrix molecule has been shown to reflect processes related to bone resorption. Highest values of serum BSP are usually seen in patients with untreated multiple myeloma. Interestingly, serum BSP concentrations increase continuously with disease progression, and most patients in stage III have serum BSP levels far above the upper limit of normal. Within the same disease stage, patients with osteolytic lesion have higher serum BSP levels than individuals diagnosed with non-lytic bone disease. In addition to its diagnostic value, serum BSP seems to reflect the response to chemotherapy in MM patients, as the treatment-induced changes in serum BSP values correlate with the changes in the monoclonal protein. Furthermore, serum BSP appears to be an independent prognostic factor in relation to the survival time of patients diagnosed with MM. Thus, serum BSP levels seem to be associated with skeletal involvement, tumour cell burden and disease outcome in MM patients [Woitge HW, Pecherstorfer M, Horn E, Keck AV, Diel IJ, Bayer P, Ludwig H, Seibel MJ: Br J Cancer 2000, in press]. These and other data indicate that the measurement of bone resorption indices may be of significant clinical value in the non-invasive evaluation of myeloma-induced bone disease.
Figure: Urinary excretion of
pyridinium cross-links in healthy adults and patients with MGUS
(monoclonal gammopathy of undetermined significance), MM (multiple
myeloma), and benign osteoporosis. Patients with smoldering myeloma
(closed circles) are included in the MGUS section. MM I + II: MM
patients with stage I (closed circles) and stage II (open circles)
disease; MM III: MM patients with stage III disease. Median (solid
line); upper limit (dotted line) of normal range. Urinary parameters
h-PYD and h-DPD, and i-DPD are expressed relatively to the creatinine
excretion (mmol/mol) and are measured
by HPLC (=h) or immunoassay (=i).
[from Pecherstorfer, Pecherstorfer M, Seibel MJ, Woitge H, Horn
E, Ziegler R, Ludwig 1997; Blood 90:3743].
Markers of bone formation in multiple myeloma
Some reports based on histomorphometric and biochemical analyses indicate that the inhibition of bone formation is of equal or even greater importance for myeloma-associated bone destruction than the increase in bone resorption. Both, serum osteocalcin (OC) and the serum activity of the bone-specific isoenzyme of alkaline phosphatase (BAP) are considered specific biochemical indices of bone formation. A number of investigations have studied biochemical markers of bone formation in MM patients. However, the results vary considerable between the studies and systematic analyses of the markers with regard to the tumor stage and the differentiation between benign and myeloma-induced bone disease are rare. In some reports, decreased OC concentrations seemed to indicate suppression of osteoblasts and were correlated with poor survival. Furthermore, chemotherapy-induced remission led to a normalization of serum OC levels in patients with MM [Carlson K, Ljunghall S, Simonsson B, Smedmyr B, J Intern Med 231:133-137, 1992; Bataille R, Delmas PD, Chappard D, Sany J Cancer 66:167-172, 1990]. Other studies have reported less optimistic results. In a recent investigation from our group, patients with plasma cell dyscrasias, including patients with MM, MGUS and benign osteoporosis, serum BAP, rather than serum OC, appeared to reflect a suppressed bone formation rate and may prove helpful in the differentiation between benign and myeloma-induced osteoporosis. However, the overall clinical use of biochemical markers of bone formation in patients with plasma cell dyscrasia seemed to be limited.
Summary
In summary, biochemical markers of bone turnover, particular markers reflecting processes related to bone resorption, appear to be helpful in the non-invasive assessment of bone involvement in patients with plasma cell dyscrasias. With regard to the diagnosis, the spontaneous follow-up, the therapeutic monitoring and the prognosis of patients with MM, biochemical markers of bone turnover seem to provide useful additional information to established invasive and imaging techniques.