The International Myeloma Working Group, comprised of many of the world’s top myeloma experts, recently published a report that evaluated the use of key proteins to assess the severity of multiple myeloma-related bone disease. The group determined that some of these proteins are useful in monitoring bone metabolism and skeletal complications during myeloma treatments.

The majority of multiple myeloma patients suffer from bone disease. Approximately 20 percent of patients experience a fracture at the time of their myeloma diagnosis, and 60 percent of patients experience a fracture as their myeloma progresses. These bone lesions rarely heal, even for patients in complete remission, which places an added emphasis on finding novel ways to more effectively detect bone destruction before bone lesions develop.

Conventional methods for assessing bone lesions, such as X-rays, bone scans, and radiography, often cannot provide sufficient information about bone metabolism (the rate of bone formation and degradation). Bone metabolism is sometimes also called bone remodeling.

As a result, there has been an increased interest in using biochemical markers of bone metabolism (proteins that regulate bone formation and degradation) to better assess the rate of bone metabolism and the extent of bone destruction. Measurement of bone metabolism markers is non-invasive, and it is also comparatively inexpensive.

In the present report, the International Myeloma Working Group summarized the effectiveness of known biochemical markers of bone metabolism.

Role Of Biochemical Markers In Bone Disease And Myeloma Progression

The researchers found that myeloma patients had elevated urine levels of several biochemical markers of bone degradation. These markers indicate the level of bone that is broken down to release minerals such as calcium. The urine and serum levels of these markers correlated with the extent of bone disease.

Of the evaluated biochemical markers of bone degradation, serum ICTP and urinary NTX best reflected the extent of bone disease, the risk for fractures, and possibly even the risk for myeloma progression.

Several other studies suggested that biochemical markers of bone degradation strongly correlate with stage of myeloma and overall survival.

In particular, serum ICTP levels and urinary NTX levels were found to be higher in stage 2 and 3 myeloma than in stage 1, and high DPD urinary levels were linked to advanced myeloma stage.

Serum ICTP levels can also function as a prognostic factor for overall survival in patients treated with conventional chemotherapy. A recent study showed that patients with high ICTP levels had a median survival time of 3.5 years, compared to 4.1 years for patients with low ICTP levels.

Based on this data, the International Myeloma Working Group recommended that future clinical trials consider routine measurement of serum ICTP and urinary NTX to determine if these markers may also serve as prognostic factors in treatment with novel therapeutic agents.

Study results for markers of bone formation as prognostic tools have shown mixed results so far. Markers of bone formation do not seem to indicate the extent of bone disease. The experts therefore questioned their clinical usefulness.

Role Of Bisphosphonate Treatment On Bone Metabolism

Biochemical markers of bone metabolism have also been used to monitor patient response to bisphosphonate treatment, the standard treatment for myeloma bone disease.

Treatment with Aredia ^[1] (pamidronate) coupled with conventional chemotherapy significantly reduced the bone degradation marker urinary NTX and disease-related pain. Aredia plus interferon-alpha stimulated bone formation in myeloma patients.

Boniva (ibandronate) (2 mg) also showed substantial reduction of the CTX and osteocalcin (OC) biochemical markers.

Patients who had high levels of the bone degradation marker urinary NXT at beginning of Zometa (zoledronic acid) treatment had an increased risk of fractures if their urinary NXT levels remained high after three months of treatment.

Treatment with Bonefos (clodronate), which is currently not approved in the United States, resulted in a significant reduction of two of the biochemical markers, ICTP and PINP.

These results suggest that patients who respond to bisphosphonate treatment will have reduced biochemical marker levels and, accordingly, are at a lower risk for fractures and disease progression than patients who do not respond to treatment.

The researchers also noted that due to recent concerns about side effects associated with bisphosphonate treatment (such as kidney impairment, osteonecrosis of the jaw, and thigh bone fractures), the biochemical markers may be useful in determining the dosing regimens of bisphosphonates.

Role Of Novel Therapeutic Agents On Bone Metabolism

In response to the increased use of novel agents, such as thalidomide ^[2] (Thalomid), Revlimid ^[3] (lenalidomide), and Velcade ^[4] (bortezomib), in myeloma, the International Myeloma Working Group also evaluated the roles of these drugs in bone metabolism.

After six months of treatment with thalidomide (Thalomid) and dexamethasone ^[5] (Decadron), relapsed and refractory myeloma patients experienced a substantial reduction in the serum levels of biomarkers CTX, TRACP-5b, and sRANKL/OPG.

A second study showed that combining thalidomide, dexamethasone, and Zometa significantly reduced urinary NTX and serum CTX in patients who responded to treatment. The affected markers indicate the degree of bone degradation. The decreased levels of these markers suggest that thalidomide reduces the function of the cells responsible for bone degradation.

Little data is currently available on the effect of Revlimid on bone metabolism.

Treatment with single-agent Velcade (bortezomib) reduced the serum levels of TRACP-5b and CTX, two markers associated with bone degradation. It also increased the levels of bALP and OC, which are markers associated with bone formation.

However, when Velcade was combined with other treatments, the levels of bALP and OC did not increase. This suggests that although Velcade alone may increase bone formation, this beneficial effect is lost when Velcade is used in combination with other treatments.

Conclusions

Based on the available data, the International Myeloma Working Group concluded that biochemical markers of bone metabolism (particularly bone degradation) are useful tools in assessing the extent of myeloma bone disease.  Serum ICTP and urinary NTX were the most useful bone degradation markers. However, as these biomarkers are eliminated by the kidneys, their use may not be as effective in patients with kidney dysfunction.

The bone degradation markers serum ICTP and urinary NTX were the most accurate in reflecting the severity of bone destruction and the effectiveness of bisphosphonate treatment. These markers are also preferred for gauging an increase in risk for progressive bone disease, the development of fractures, and overall survival.

The experts advised that more clinical trials involving bone metabolism markers are needed before the markers are integrated into routine myeloma care.

For more information about this study, please refer to the journal Leukemia ^[6] (abstract).