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Spring 1998 Volume 2, Issue 10:
Bisphosphonates For Myeloma - Current Approach To Treatment
By Phillip R. Greipp, MD, Mayo Clinic, Rochester, MN
Two types of cells normally work together to constantly remodel and strengthen the existing bone. Those cells called osteoclasts normally resorb old bone while osteoblasts build new bone. In myeloma, this balanced relationship between osteoclasts and osteoblasts is uncoupled and bone is damaged. This happens not because myeloma cells themselves destroy bone, but because they affect changes in the normal function of these bone cells. Myeloma increases osteoclast bone resorption and decreases osteoblast bone building. As a result, bone density and bone strength are decreased and bone lesions develop. A goal of myeloma therapy is to restore the balanced cooperation between osteoclast and osteoblast activity to produce more normal bone.

Bisphosphonates are often used as an adjunct to chemotherapy to prevent the complications of myeloma bone disease. The most commonly used bisphosphonate, now approved by the FDA for use in myeloma and breast cancer with bone disease, is pamidronate (Aredia). It is typically given by intravenous infusion over 2-4 hours once every 4 weeks. A total of 90 mg of pamidronate is diluted in 250 to 500 ml normal saline and infused. The pharmaceutical company has data which confirm no loss in activity for 1 and 2 hour infusions compared to 4 hour infusions. Pamidronate has been shown to reduce the number of skeletal related events (SREs) in patients with bone lesions. SREs included fractures, orthopedic surgery and radiation to bone. Bisphosphonates also effectively lower the high blood calcium level that can occur when myeloma is more active. Pamidronate (Aredia) also reduces the frequency of subsequent episodes of hypercalcemia. In the clinical trials led by Dr. James Berenson at UCLA, differences in the rates of SREs have been observed for up to 21 months of use.

What are bisphosphonates, what do they do?

Bisphosphonates are inorganic chemical compounds that bind to hydroxyapatite in bone and prevent osteoclastic absorption of bone. They directly affect osteoclast number and activity. Bisphosphonates also work to restore the critical linkage between bone destruction and formation. Finally, bisphosphonates appear to reverse the decrease in bone density induced by glucocorticoids, often used to treat myeloma.

Bisphosphonates are absorbed poorly from the intestinal tract. After absorption or intravenous administration, 20-80% of the available dose may quickly wind up in bone. The rest is excreted by the kidneys. Most trials have been with intravenous formulations including: etidronate, clodronate, tiludronate, pamidronate, risendronate, ibandronate, and alendronate (in order of increasing potency). The more potent oral compounds are effective in preventing post menopausal osteoporosis. Oral doses sufficient to affect myeloma bone disease can cause inflammation and damage to the esophagus.

Which bisphosphonate is best for patients with myeloma?

Pamidronate (Aredia) is the only approved bisphosphonate for myeloma bone disease. In a placebo controlled trial, pamidronate, 90 mg intravenously over 4 hours, repeated monthly for 9 months, reduced the number of skeletal related events by about half compared to the rate observed in the placebo group. Bone pain, pathological fractures, and the need for palliative radiotherapy were all significantly reduced. This trial led to FDA approval of pamidronate for use in myeloma bone disease. Side effects were minimal and included transient hypocalcemia in some patients. This was easily treated.

Are there other beneficial effects to bisphosphonates?

Observations of an anti-interleukin-6 effect in vitro has prompted theories that pamidronate might have a beneficial effect on myeloma disease progression, but this is unproven. One of the results of the placebo controlled trial of pamidronate versus placebo was the observation of somewhat prolonged survival in a subset of patients with relapsed disease. This observation requires confirmation. Another benefit of bisphosphonates is the prevention or reversal of glucocorticoid induced osteoporosis. The benefits of bisphosphonates in patients without bone disease (about 15% of myeloma patients) is not established.

Should I be taking a bisphosphonate?

If you have myeloma bone disease and no contraindication to the use of bisphosphonates, then you should be taking a bisphosphonate. Oral bisphosphonates such as alendronate (Fosamax) in doses used for osteoporosis are not effective in myeloma. Whether higher oral doses may be effective is not known but esophagitis is a potential problem. Soon there will be published guidelines concerning bisphosphonate use in myeloma. At the same time, we will also be seeing new more potent bisphosphonates and also new doses and schedules for old bisphosphonates. Guidelines will likely need to be adapted to reflect knowledge gained from new modes of administrations, changes in dose and schedule, and the new agents themselves.

How can I tell if the bisphosphonate is doing any good?

Patients may not notice the benefits immediately, but eventually they may have less pain and function better. Accurate assessment of response to bisphosphonates in the individual patient is difficult because successful chemotherapy may produce similar benefits. Bone mineral density may be measured by dual photon absorptiometry. In addition there are measures of bone turnover, including the urinary cross-linked collagen telopeptide assay. The proper use of these tests and their interpretation should become more clear as the results of recent trials become available.

For how long should I take bisphosphonate?

No one knows the ideal duration of therapy. Dr. Berenson's trial suggests pamidronate (Aredia) produces benefits for at least 21 months. In osteoporosis trials, bone loss can be measured in only a few months after discontinuation of bisphosphonate. We advise treatment with bisphosphonate be continued indefinitely.

Are there any precautions for the use of bisphosphonates?

Bisphosphonates such as pamidronate taken at the prescribed dose and schedule are safe and effective. Rapid infusion can cause a chemical inflammation at the injection site along the path of the vein. Slower infusion may avoid this complication. Too rapid an infusion can also cause a low blood calcium. Most patients, however, tolerate infusions over 2 hours rather than 4 hours without side effects. Dosage in kidney failure should be reduced since bisphosphonate excretion is delayed. Intravenous pamidronate can cause inflammation of the eyes, but this side effect is treatable. High doses have been reported to exert a negative effect on bone mineralization in children or in Paget's disease.

If some bisphosphonate is good for my bones... is more better?

We simply don't know the answer to this question. Investigators are now testing the relative merits of higher doses and more frequent administration of bisphosphonates. Charges for a single pamidronate infusion vary from $700 to $1600, or more. Over a period of 3 years of pamidronate administration, charges may range from $25,200 to $57,600. Increasing the standard dose and shortening the interval between treatments could further increase the cost for that period up to $150,000 per patient. The cost of preventing one fracture or SRE could be many multiples of that. A cost of over a million dollars per skeletal event would be hard to justify for routine use, unless it impacted quality of life in a major way. Clearly, more cost effective formulations and delivery are needed.

Are there better bisphosphonates on the way?

More potent bisphosphonates could reduce costs by shortening the time required for intravenous infusions and by allowing the development of other formulations that eliminate the need for intravenous infusions, such as a patch or an oral preparation.

What is the Mayo Clinic philosophy about the use of bisphosphonates for myeloma?

We recommend pamidronate (Aredia) for patients with myeloma bone disease. Discontinuation of bisphosphonate in patients with osteoporosis is associated with resumption of bone loss in a few months. Because of this observation and because an extended trial shows continued benefit in myeloma patients, we recommend it be used indefinitely. If a skeletal related event occurs, pamidronate should still be continued.

We do not recommend the routine use of pamidronate (Aredia) in myeloma patients without bone disease. However there are two situations in which patients without significant bone disease may benefit from the use of bisphosphonates: 1) when patients are being treated with significant doses of glucocorticoids, they may benefit from the use of a bisphosphonate to prevent progression of osteoporosis or even reverse it; and 2) in smoldering or indolent myeloma bisphosphonates may prevent or delay myeloma bone disease.

The thinking with regard to the use of bisphosphonates in smoldering or indolent myeloma is evolving. If a skeletal MRI shows unequivocal myeloma bone disease when the bone radiograms are negative (rare in our experience), or if bone density is decreased due to myeloma, we recommend pamidronate (Aredia) therapy. If the patient has incidental post-menopausal osteoporosis, we consult with our metabolic bone disease specialists and recommend estrogens or a trial of alendronate (Fosamax) orally with follow-up bone density in six months.

Higher doses, a more frequent schedule, or a more potent formulation of bisphosphonate may be needed to have a measurable impact on the progression of myeloma. We hope zoledronate and other more potent bisphosphonates are developed as oral agents or as a patch, overcoming both the high cost and inconvenience of intravenous formulations. We are actively engaged in studying the efficacy of zoledronate. We await results of trials of other agents like gallium nitrate that may also inhibit bony osteolysis in myeloma.

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