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Summer 1995 Volume 1, Issue 10:
Myeloma Bone Disease
By Gregory R. Mundy, MD, University Of Texas
Although in most parts of the world myeloma is a condition which is treated by hematologists or oncologists, the most striking clinical manifestation is bone disease, and a complication related to the skeleton (bone pain, fracture, hypercalcemia) is the means by which the disease usually presents. The majority of patients, approximately 80%, present with painful bone lesions, and almost all patients, certainly more than 95%, have destructive bone lesions which are detectable on x-ray. In fact, the characteristic x-ray appearance of the bones is usually one of the important components of the initial diagnosis.

Despite the obvious importance of the skeleton to this disease, we still understand little about how myeloma destroys bone or what to do about it. Nevertheless, there is hope that with recent advances in our understanding of how bone cells interact with myeloma cells, this situation is being clarified and exciting new treatments aimed at addressing the effects of myeloma cells on bone are now on the horizon.

Frequency of Skeletal Complications of Myeloma

Myeloma is unique among the malignancies which occur in the blood-forming cells for its effects on the skeleton. More than 80% of patients have bone pain which is often severe and intractable. Patients with myeloma are particularly susceptible to pathological fractures of involved bones, occurring either spontaneously or following trivial injury. In some patients, the extent of bone destruction (or bone resorption) which is caused by the presence of the myeloma cells is so great that hypercalcemia (an increase in the calcium level in the serum) occurs because the entry of calcium into the extracellular fluid overwhelms the normal compensatory mechanisms for maintaining calcium homeostasis. This occurs in about 30% of patients some time during the course of the disease and is most common in those patients with extensive tumor burden, and usually occurs in the presence of impaired renal function. In fact, the combination of fixed impairment of renal function in a patient with hypercalcemia of malignancy points very strongly towards a diagnosis of myeloma rather than one of the solid tumors such as carcinoma of the lung or carcinoma of the breast which frequently cause a similar hypercalcemic syndrome associated with osteolytic bone lesions.

The skeletal lesions which occur in myeloma not only cause pathological fractures but sometimes deformity and occasionally nerve compression syndromes. This occurs most commonly in the vertebrae. The appearance of the vertebral spine may resemble osteoporosis very closely radiologically, but in fact the histologic abnormalities in bone are quite different from those of postmenopausal osteoporosis. Although spinal cord compression occurring as a consequence of postmenopausal osteoporosis is extremely rare, it is not uncommon in patients with severe myeloma.
Although pain is by far and away the most common manifestation, we still understand very little about what causes this bone pain. I have always been struck by the variability in bone pain. Some patients have pain which waxes and wanes without any apparent change in the radiological lesions. We are very ignorant not only about the mechanisms for the bone pain which occurs in myeloma, but also in the other common skeletal diseases as well.

Why Does Bone Disease Occur in Patients with Myeloma

The great majority of patients with myeloma develop destructive bone lesions, also known as osteolytic bone lesions. These bone lesions occur particularly in the axial skeleton and proximal ends of the long bones. They are frequently seen in the vertebral column, in the ribs, in the pelvis and in the skull. They occur in the red bone marrow, where nests of myeloma cells accumulate. Myeloma cells cause bone destruction not because they themselves have a direct effect on the skeleton, but rather because they produce soluble signals (cytokines) which activate normal bone cells (also called osteoclasts) to resorb bone. Characteristically in myeloma, accumulations of multinucleated bone resorbing osteoclasts occur adjacent to the collections of myeloma cells. The stimulus to osteoclast activity in myeloma has not been clearly identified. A number of cytokines have been implicated, including lymphotoxin, interleukin-1, and interleukin-6. It is possible (in fact, probable) that a combination of these cytokines is responsible.

Understanding the mechanism by which myeloma cells destroy bone is very important, not just for understanding the pathophysiology of this major manifestation of this disease, but also for designing rational ways to treat it. The fact that the destructive bone lesions in myeloma are due to increased osteoclast activity is very good news for patients with this disease. It means that we have a cellular target in bone whose activity we can inhibit with a number of very effective drugs, such as the bisphosphonates. Drugs which inhibit osteoclast activity such as the bisphosphonate pamidronate (Aredia), calcitonin and even glucocorticoids in some circumstances may be used successfully in reducing the increased bone resorption which occurs in myeloma.

Although much of the interest in myeloma has been focused on understanding the mechanisms by which myeloma cells affect osteoclasts, it is also likely that there are important effects of osteoclasts on myeloma cells. There must be a special reason that myeloma cells grow so avidly in bone and destroy it. In fact, the bone microenvironment probably acts like fertilizer for the growth of myeloma cells, and enhances the capacity of myeloma cells to destroy bone. This is an important interaction which can be likened to seeds growing in fertile soil. In this analogy, the bone microenvironment is the soil and the seeds are the myeloma cells. We think that the cytokine interleukin-6 (IL-6) may be particularly important in this regard. Osteoclasts produce more IL-6 than any other cell in the body, and even more IL-6 when they are stimulated. This is important because IL-6 is probably the most important growth factor for myeloma cells. If we are to understand and counteract the effects of myeloma cells on the skeleton, then we need to make the soil (the bone microenvironment) a less favorable site for myeloma cells to grow. This may involve blocking the production and/or effects of IL-6.

There is currently a large amount of active work directed at understanding the mechanisms by which bone is destroyed by myeloma cells. Some of the most interesting studies have been performed in animal models of myeloma. These types of studies are very difficult to perform in patients with the disease, since patients are often receiving other forms of therapy which makes it difficult to assess the effects of drugs alone. For example, many patients with myeloma are treated with drugs which may affect bone cell function such as alkylating agents (Melphalan, cyclophosphamide); corticosteroids, alpha-interferon and other cytotoxic drugs or radiation therapy, and possibly other agents which also affect the skeleton. There is one animal model of myeloma in which the bone disease seems to mimic human myeloma bone disease in all features. This model has been described by Radl and his colleagues in Holland, and occurs spontaneously in a special strain of mice as they age. In these mice, about one in every 200 spontaneously develops myeloma and most of these mice, like humans with the disease, develop osteolytic bone lesions. Some of the mice develop hypercalcemia. Since injection of myeloma cells from one mouse to a normal mouse induces the disease and all its manifestations, we can study the disease course from the very beginning to the time the mouse dies. It should be possible in this animal model of myeloma to identify the cellular and molecular mechanisms by which bone is destroyed (often not possible in humans), and to use these mice to study the effects of new drugs which inhibit bone resorption and hopefully improve the outlook for myeloma bone disease, without the simultaneous use of cytotoxic drugs which may make the results more difficult to interpret.

Treatment of Bone Disease in Myeloma

The treatment of bone disease in myeloma should be considered under two categories. Firstly, there is the treatment of the patient with hypercalcemia where the primary goal is to treat the hypercalcemia and its potentially dangerous complications. In myeloma, hypercalcemia occurs in about 30% of patients. In these patients, hypercalcemia is always associated with increased bone resorption and frequently with impairment of renal function. The best treatment is to effectively treat the myeloma itself, and to treat the hypercalcemia with drugs which inhibit bone resorption combined with the careful and judicious use of intravenous fluids. Fluid treatment (preferably normal saline) must be administered with due consideration to the state of renal function. I try to avoid loop diuretics unless the patient is suffering from fluid overload. Loop diuretics are very disappointing as calciuretic agents, but may be necessary for patients with impairment of renal function or in patients who are elderly with poor cardiac reserve to prevent incipient cardiac failure. Bisphosphonates have been remarkably effective in the treatment of the hypercalcemia of myeloma. The best one currently available in the United States is pamidronate (Aredia), which when administered in doses of 60-90 mg by intravenous infusion can be almost guaranteed to reverse hypercalcemia.

In patients in whom the renal function is so severe that bisphosphonates cannot be used, I recommend the use of calcitonin and corticosteroids. This combination almost always works in patients with myeloma, rapidly reducing the calcium into the normal range. The problem is that calcitonin must be given by injection and the hypercalcemia tends to recur after a few days. Although this loss of effectiveness (called "escape") can be countered by withdrawing calcitonin for 48 hours and then recommencing it, this is not a convenient form of therapy for patients who are ambulant or at home.

An even more common situation is the patient with myeloma bone disease who does not have hypercalcemia. These patients until recently have been treated for their bone disease only with symptomatic therapy, namely analgesics for pain, orthopedic treatment for fractures, or local radiation therapy for localized bone pain such as occurs following vertebral body fracture or collapse. However, recent information suggests that these patients may benefit from the use of powerful inhibitors of bone resorption such as the bisphosphonates. These drugs inhibit bone resorption and markedly reduce the frequency of skeletal complications, such as fracture and hypercalcemia. They may also relieve bone pain, although this cannot be guaranteed since some patients will have significant pre-existing bone disease before bisphosphonates are started. It is probable that in the majority of patients bisphosphonates prevent the bone disease getting worse, but do not reverse the damage that has already occurred.

The quality of life is certainly better in patients who are treated with bisphosphonates. One interesting question which has not been settled as yet is whether bisphosphonates alter tumor burden and prolong survival. In some patients with solid tumors treated with bisphosphonates, it appears likely that bisphosphonates, by reducing rates of bone resorption, may produce a much less favorable environment for some tumors such as breast cancer to metastasize and to grow, and the bisphosphonates actually decrease total tumor burden in the body by reducing the tumor bulk in bone. Whether or not this is so in myeloma still remains to be determined. However, this issue notwithstanding, it is clear that there is a marked reduction in the frequency of skeletal complications in bisphosphonate-treated patients, and on these grounds I recommend a new generation bisphosphonate such as pamidronate (Aredia) in the therapy of myeloma with or without hypercalcemia. Bisphosphonates have not been approved by the FDA for this purpose as yet. However, there are investigative studies currently underway both in the U.S. and in Europe which point to their efficacy in normal patients.

The earlier bisphosphonate etidronate (Didronel), which is still on the market in the US, is not as effective as pamidronate. A reasonable approach for the patient with osteolytic bone lesions is to administer Aredia in doses of 30-60 mg intravenously by infusion every 4 weeks. Many questions however do remain such as how long should this be continued, whether all patients should receive Aredia or just those with severe bone lesions, and the most important of all, does Aredia not only prevent skeletal complications and prolong useful life, but does it also decrease total tumor burden? Answers to these questions will hopefully be available in the next few years.

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