Use of Bisphosphonates in Patients With Metastatic Bone Disease

The bisphosphonates have now joined an elite group of drugs that have annual sales greater than $1 billion. Although the major therapeutic target of these agents is osteoporosis, their use in cancer, particularly in osteolytic bone disease due to breast cancer and myeloma, is growing very rapidly. Pamidronate (Aredia), the only bisphosphonate currently approved for this indication in the United States, is now prescribed for the majority of patients with myeloma, as well as a substantial number of patients with breast cancer.

Berenson and Lipton have been at the forefront of studies of pamidronate in osteolytic bone disease due to myeloma and breast cancer. The current widespread use of this drug in patients with osteolytic bone disease is due, in large part, to their efforts and those of their collaborators. Therefore, it is very useful to read about their current thoughts on the application of these agents in patients with osteolytic bone disease. Their perspective is particularly instructive because of the many outstanding questions regarding the use of bisphosphonates in cancer patients. These include:

Which bisphosphonate should be used for osteolytic bone disease?

How should these agents be administered, and for how long?

What is the mechanism of action of bisphophonates in this setting?

Are any better bisphosphonate agents on the horizon?

Berenson and Lipton address a number of these questions in their article. However, at present most of the answers are based on educated guesses rather than experimental data. This is due, in large part, to difficulties in interpreting studies conducted in patients with advanced disease because of the presence of so many confounding variables. These questions, however, require definitive answers as soon as possible.

Effects of Bisphosphonates on Survival

The issue of the effects of these agents on survival is very important. One would expect that the reduction in skeletal-related events noted in both patients with myeloma and breast cancer would lead directly to increased survival. However, there is another issue, namely, that bisphosphonates may actually reduce tumor burden. This cannot be doubted from the animal studies,[1-2] and is also apparent from recent clinical studies reported by Diel et al[3] and Powles et al.[4] In these studies, bisphosphonates not only reduce osteolytic bone lesions and skeletal-related events but also decrease tumor burden in bone.

These findings raise the question of how the reduction in tumor burden is occurring, and whether it has any significance for the patient. I believe it may. By the time that the patient develops advanced bone metastases, the actual burden of tumor cells in bone may be relatively large since bone is such a great potential reservoir for tumor cells. Any successful reduction in total tumor burden is likely to improve patient outcome.

How Do Bisphosphonates Reduce Tumor Burden?

An obvious question that arises from these studies is, by what mechanism do bisphosphonates reduce tumor burden? One possibility is that these agents may increase target cell apoptosis, as has been previously shown in osteoclasts in vivo[5] and myeloma cells in vitro.[6] Another, and in my opinion more likely, explanation is that bisphosphonates may reduce tumor burden by changing the bone microenvironment; specifically, they may decrease the production of active forms of bone-derived tumor growth factors, which can enhance the aggressive behavior of the tumor cells in these sites.[7]

With regard to the use of bisphosphonates in bone disease due to myeloma, Dr. Berenson’s experience has been limited to pamidronate, and he is a great advocate for its use. The data reported by Berenson are very impressive. Pamidronate is clearly effective in reducing skeletal-related events by about 50%.

Berenson and Lipton are quite critical of studies of other bisphosphonates, and emphasize that agents such as clodronate are less potent than pamidronate. My view is that, when used in appropriate doses, clodronate or any of the other newer bisphosphonates (with the exception of etidronate [Didronel]) will likely be as effective as pamidronate in this situation. It is difficult to compare directly the efficacy of these drugs without side-by-side comparisons of their use at maximal doses.

A Striking Finding

A recently published paper by Diel et al[3] suggests that clodronate reduces tumor burden not only in bone but also at other sites. Drs. Berenson and Lipton mention but do not discuss this article. Since Dr. Lipton has been at the forefront of studies in breast and osteolytic bone disease, it would have been useful to have heard his comments about this article.

This is a very striking finding that is very controversial and will obviously need confirmation by other groups and with other bisphosphonates. Its recent publication in The New England Journal of Medicine was also widely publicized in the lay press (eg, Wall Street Journal, August 6, 1998, and USA Today, August 6, 1998).

These striking results in myeloma and breast cancer raise the possibility that other cancers may also be responsive to the bisphosphonates. This looks like a foregone conclusion with respect to tumors that destroy bone by mechanisms similar to those operating in breast cancer and myeloma (namely, osteoclastic resorption).

However, in tumors, such as prostate cancer, that cause osteoblastic metastases, the appropriate role for bisphosphonates remains unclear. There is a paradox inherent in this situation. These tumors are frequently associated with a marked increase in markers of bone resorption,[8,9] and yet the pathologic and radiologic lesions are predominantly osteoblastic. Some clinical data suggest that bisphosphonates may be useful in prostate cancer.[10] However, these data are not as convincing as those in osteolytic bone disease.

What Does the Future Hold?

Finally, what does the future hold for these agents? Clearly, even more potent bisphosphonates are on the horizon that will likely be introduced in the next few years. However, it is not clear whether these new agents will have increased efficacy or produce greater effects than those currently observed with pamidronate.

Nevertheless, the greater potency of new bisphophonates may be helpful in other respects. One problem with pamidronate is that it is approved for administration only via a monthly intravenous infusion. A drug that can be given by a simple intravenous push or taken orally without causing the problems associated with oral pamidronate would be much more convenient, and presumably less expensive. This may be the major advantage of the new-generation, more potent bisphosphonates for osteolytic bone disease.

References:

1. Sasaki A, Boyce BF, Story B, et al: Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice. Cancer Res 55:3551-3557, 1995.

2. Yoneda T, Sasaki A, Dunstan C, et al: Inhibition of osteolytic bone metastasis of breast cancer by combined treatment with bisphosphonate and tissue inhibitor of matrix metalloproteinase-2. J Clin Invest 99:2509-2517, 1997.

3. Diel IJ, Solgmayer EF, Goerner R, et al: Reduction of new metastases in breast cancer by clodronate. N Engl J Med 339:657-663, 1998.

4. Powles TJ, Patterson AHO, Nevantaus A, et al: Adjuvant clodronate reduces the incidence of bone metastases in patients with primary operable breast cancer (abstract). Proc Am Soc Clin Oncol 17:468a, 1998.

5. Hughes DE, Wright KR, Uy HL, et al: Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Min Res 10:1478-1487, 1995.

6. Shipman CM, Rogers MJ, Apperley JF, et al: Bisphosphonates induce apoptosis in human myeloma cell lines: A novel anti-tumour activity. Br J Haematol 98:665-672, 1997.

7. Mundy GR, Yoneda T: Bisphosphonates may be anti-cancer drugs. N Engl J Med 339:398-400, 1998.

8. Vinholes J, Guo CY, Purohit OP, et al: Metabolic effects of pamidronate in patients with metastatic bone disease. Br J Cancer 73:1089-1095, 1996.

9. Pecherstorfer M, Ludwig H, Zimmer-Roth H, et al: The diagnostic value of urinary pyridinium cross-links of collage, alkaline phosphatase and urinary calcium excretion in neoplastic bone disease. J Clin Endocrinol Metab 80:97-103, 1995.

10. Adami S: Bisphosphonates in prostate carcinoma. Cancer 80(8; suppl):1674-1679, 1997.