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Bisphosphonates Overview
What They Are
Bisphosphonates are a group of compounds that are used in the treatment of myeloma bone disease. They are used specifically to
  • Help reduce the advancement of bone disease
  • Decrease bone pain
  • Reduce fractures
Bisphosphonates are also used in the treatment of bone metastases and hypercalcemia of malignancy (HCM) (increased calcium levels in the blood), also known as tumor-induced hypercalcemia (TIH), and in the prevention and treatment of osteoporosis (general bone thinning). Some are also used in the treatment of a bone disease called Paget's disease.

Examples of Bisphosphonates
Bisphosphonates that are approved in the US for the treatment of bone metastases and myeloma bone disease include the following intravenous agents: Aredia (pamidronate, Novartis) is available worldwide and several generic versions of pamidronate are available. Bonefos® (clodronate), which is not available in the US, is an oral bisphosphonate that is also used to treat bone metastases and myeloma bone disease.

You may be aware of other oral bisphosphonates on the market, such as Actonel® (risendronate), Boniva® (ibandronate), Didronel® (etidronate; also available as an intravenous formulation), Fosamax® (alendronate), and Skelid® (tiludronate). These are mainly used in the treatment of osteoporosis and other bone diseases rather than myeloma. In general, these bisphosphonates are not absorbed as completely in the body and are less potent, so they are not as effective in treating myeloma bone disease.

Ibandronate (Boniva, SmithKline/Roche) has been studied for use in myeloma in a Phase III trial, but the dose tested (2 mg) did not appear to be sufficient to demonstrate significant effects on preventing skeletal complications. (Menssen et al. J Clin Oncol. 2002;20:2353-2359.)

Other bisphosphonates, such as incadronate (Yamanouchi Pharmaceutical) are being studied in the laboratory for their effects on myeloma cells. The oral bisphosphonate minodronate (YM529, Yamanouchi) is in late-stage clinical trials in Japan for use in myeloma bone disease.
What They Do
Bisphosphonates inhibit the activity of bone-destroying cells called osteoclasts. Normally, osteoclasts work in harmony with bone-forming cells called osteoblasts in order to rebuild areas of bone that need replacing. However, in myeloma, bone resorption by the osteoclasts is increased and exceeds bone formation, resulting in loss of bone. This can lead to pain, bone fractures, spinal cord compression, and increased levels of calcium in the blood and urine.

•  Get more information on bone disease in myeloma


Different bisphosphonates appear to inhibit osteoclasts in slightly different ways. Some bisphosphonates appear to inhibit production of factors that stimulate osteoclasts, while others inhibit the actual development of the osteoclast cells or inhibit attachment of the osteoclasts to the bone surface. Some bisphosphonates do several of these things.
Benefits in Myeloma
In patients with myeloma, intravenous bisphosphonates delay and reduce the number of skeletal events (bone complications such as fractures, radiation therapy to bone, surgery to bone, or spinal cord compression) and reduce bone pain. They also normalize levels of calcium in patients with hypercalcemia of malignancy. Details about the benefits of specific intravenous agents can be found here:
Guidelines for Use of Bisphosphonates in Myeloma
In September 2002, the American Society of Clinical Oncology (ASCO) published clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of bone disease in myeloma. (Berenson et al. J Clin Oncol. 2002;20:3719-3736.) Upon review of published literature, the expert panel agreed that bisphosphonates reduce skeletal complications and provide a meaningful support benefit to myeloma patients with bone disease. Key points of the guidelines are summarized here.


Summary of Guidelines for Use of Bisphosphonates in Myeloma
  • For patients who have bone lesions that are visible on x-rays, the guidelines recommend the use of intravenous pamidronate (Aredia® and others) or zoledronic acid (Zometa®) every 3 to 4 weeks. No adjustments are required in patients with mild kidney disease.
    • Patients with bone loss that is detected by measuring bone density may also receive bisphosphonate therapy
    • Bisphosphonates may also be used to control bone pain in patients who have pain due to bone lesions and as an adjunctive treatment for patients receiving radiation therapy, pain medications, or surgical intervention to stabilize fractures or potential fractures
    • Use of bisphosphonates in patients with solitary plasmacytomas, monoclonal gammopathy of undetermined significance (MGUS), or smoldering or indolent myeloma who do not have documented bone lesions is not recommended
  • Patients receiving bisphosphonate therapy should be evaluated every 3 to 6 months for kidney function with blood and urine tests
  • Once therapy with bisphosphonates is started, it should be continued unless the patient's likely benefit is believed to be less than the inconvenience of receiving the treatment or until significant side effects are experienced


Potential Antitumor Effects
Certain bisphosphonates, particularly the newer, more potent nitrogen-containing compounds (eg, ibandronate, pamidronate, risedronate, and zoledronic acid), also appear to have antitumor activity. For example
  • Bisphosphonates have been shown to reduce production of the growth factor interleukin 6 (IL-6) by bone marrow cells from patients with multiple myeloma. IL-6 is known to play an important role in the growth and survival of myeloma cells
  • Recent reports also show that pamidronate can stimulate an immune response against myeloma that is mediated by T-cells
  • The bisphosphonates pamidronate and zoledronic acid (Zometa) have been shown to induce apoptosis (programmed cell death) in human myeloma cell lines grown in the laboratory
  • In laboratory studies, the bisphosphonates pamidronate, incadronate, and zoledronic acid inhibited myeloma cell growth and caused tumor cell death
  • In animal models of myeloma, pamidronate and zoledronic acid exert antimyeloma effects
However, it is not known whether these bisphosphonates have the same effects in patients with myeloma.

 

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