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Use of Bisphosphonates in Patients With Metastatic Bone Disease

Use of Bisphosphonates in Patients With Metastatic Bone Disease

The urge to control the manifestations of incurable chronic diseases, such as the anemia, renal failure, and bony disease of myeloma and the bone disease of breast cancer, is understandable. Successful control of these disease manifestations greatly improves a patient’s quality of life. This is especially important since patients with either of these malignancies may live with the disease for 20 years or more. Considerable success has been achieved in the correction of anemia with erythopoietin (Epogen, Procrit), and simple hydration has reversed renal failure and improved the survival of patients with myeloma.[1] Anyone who has witnessed the frightening spasms of back pain in myeloma patients, precipitated by a sneeze or an attempt to turn over in bed, understands the dreadful fear that patients have of uncontrolled bone pain.

As Berenson and Lipton report, there have been many attempts to strengthen bone and relieve pain in myeloma and breast cancer patients with bisphosphonates. Oral therapy has been largely ineffective, probably because < 1% of the drug is absorbed. However, the clinical trials cited by Berenson and Lipton convincingly demonstrate that the intravenous administration of 90 mg of pamidronate (Aredia) every 4 weeks has reduced bone pain and the number of skeletal-related events in both myeloma and breast cancer patients, although the survival of patients with either malignancy has not been prolonged.

Bone Lesions in Myeloma and Breast Cancer Differ

Increased bone resorption and lytic bone lesions develop in patients with myeloma and breast cancer as a result of the release of osteoclast-activating cytokines by malignant cells and activated marrow stromal cells. Generalized osteoporosis frequently occurs in patients with myeloma and breast cancer, but the bone lesions differ strikingly. In myeloma, most bone lesions are purely lytic, visualized as "punched-out holes" on bone radiographs, with no sign of new bone formation or osteosclerosis. A few myeloma patients do develop sclerotic bone lesions in the polyneuropathy, organomegaly, endocrinopathy, M-protein and skin change (POEMS syndrome) version of myeloma,[2] but this syndrome is uncommon. In contrast, skeletal metastases in breast cancer patients always show a vigorous osteoblastic reaction.

Bisphosphonates are taken up preferentially in bone, where they remain until the bone is remodeled. Bisphosphonate treatment results in marked suppression of osteoclastic activity with two effects: (1) reduced bone resorption, and (2) a decrease in the amount of interleukin-6 (IL-6) produced by osteoclasts and, hence, less stimulation of myeloma growth

MGUS and Smoldering Myeloma

Clonal populations of plasma cells of at least 5 billion cells are present in subjects with monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma. These clonal populations are stable, neither expanding nor contracting, and patients are asymptomatic for many years. However, these patients are at increased risk of progressing to a lymphoplasmacytic malignancy, usually myeloma (1% to 2% progress per year). Starting treatment early during the asymptomatic phase does not improve the response rate or survival of asymptomatic patients[3]; therefore, chemotherapy is not indicated until disease progression leads to the development of signs or symptoms.

Since pamidronate has been reported to induce apoptosis in myeloma cells,[4] and suppress the production of the myeloma growth factor IL-6,[5] treatment with this agent has the potential to both inhibit tumor growth and prolong survival. Furthermore, in his editorial heralding the initial report of the intravenous pamidronate study,

Bataille[6] noted that there is evidence of increased bone destruction early in the course of plasma cell neoplasia, even in patients with asymptomatic MGUS. He proposed that ".... these results suggest that bisphosphonates should be started very early, probably in all patients--not only because of their beneficial skeletal effects, but also because they slow tumor growth." I do not know whether early pamidronate is beneficial. Clinical trials will have to decide that issue. However, jumping the gun, like Bataille has done, is more akin to wishful thinking than good medicine. Pamidronate therapy is expensive; we should not add this cost to our already overburdened health-care system before well-designed clinical trials determine whether it is useful and safe.


1. MacLennan ICM, Falconer Smith JF, Crockson RA, et al: Analysis and management of renal failure in fourth MRC myelomatosis trial: MRC working party on leukemia in adults. Br J Med 288:1411-1416, 1984.

2. Bergsagel DE, Pruzanski W: Syndromes and special presentations associated with plasma cell neoplasia, in Wiernik PH, Canellos GP, Kyle RA, et al: Neoplastic Diseases of the Blood, 2nd ed. New York, Churchill Livingstone, 1991.

3. Hjorth M, Hellquist L, Holmberg E, et al: Initial vs deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I: A randomized study. Eur J Haematol 50:95-102, 1993.

4. Aparicio A, Gardner A, Tu Y, et al: In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates. Leukemia 12:220-229, 1998.

5. Savage AD, Belson DJ, Vescio RA, et al: Pamidronate reduces IL-6 production by bone-marrow stroma from multiple myeloma. Blood 88:409, 1996.

6. Bataille R: Management of myeloma with bisphosphonates. N Engl J Med 334:529-530, 1996.

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