Pamidronate, which is available as Aredia® (Novartis) and other generic brands, is an intravenous, nitrogen-containing bisphosphonate. It is approved in the US for the treatment of bone metastases of breast cancer, bone lesions in myeloma, hypercalcemia of malignancy (HCM), also known as tumor-induced hypercalcemia (TIH), and a bone disease called Paget's disease.

Pamidronate inhibits bone resorption. Although the exact mechanism of action is not completely understood, several things are thought to occur. Pamidronate binds to bone and may block resorption. In addition, it inhibits osteoclast activity. Lastly, in animal studies, pamidronate inhibits the accelerated bone resorption that results from osteoclast hyperactivity induced by various tumors.

Pamidronate is administered as an intravenous infusion. The recommended dosage in patients with myeloma is 90 mg administered as a 2- to 4-hour infusion, given on a monthly basis. The optimal duration of therapy is not yet known. However, a study in myeloma that included up to 21 months of therapy showed there was benefit with continued treatment.

Studies have shown that

• Pamidronate reduced the rate of skeletal events and provided rapid reduction in bone pain in patients with Stage III myeloma who already had at least 1 bone lesion. In addition, therapy helped maintain the quality of life in these patients. (Berenson et al. N Engl J Med. 1996;334:488-493.)
• Long-term pamidronate therapy (21 monthly cycles) in combination with chemotherapy was more effective than chemotherapy alone in reducing the number of skeletal events in patients with Stage III disease who already had at least 1 bone lesion. The results suggested that pamidronate may also improve the survival of patients receiving salvage therapy. (Berenson et al. J Clin Oncol. 1998;16:593-602.)
• Prophylactic administration of pamidronate in the asymptomatic, initial phases of myeloma may limit the extent of bone disease in this patient population
• The combination of chemotherapy and pamidronate appears to enhance the activity of the individual drugs. In a study involving 62 newly diagnosed patients with myeloma (Terpos et al. Eur J Haematol. 2000;65:331-336.), the combination appeared to have a synergistic (additive) effect in
  
  

  • Reducing the activity of osteoclasts
  • Reducing markers of myeloma activity
  • Reducing myeloma-related pain
  • Improving patient quality of life

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.

For patients who have bone lesions or bone loss, the guidelines recommend the use of intravenous pamidronate 90 mg infused over 2 hours or zoledronic acid (Zometa^®) 4 mg infused over 15 minutes every 3 to 4 weeks. These bisphosphonates may also be used as part of a pain management strategy. The guidelines recommend that therapy, once started, be continued until the likely benefit is believed to be less than the inconvenience of receiving the treatment or until significant side effects are experienced.

Pamidronate also appears to have several potential antitumor effects. For example:

• It has 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
• Pamidronate appears to stimulate an immune response against myeloma that is mediated by T cells
• It has been shown to induce apoptosis (programmed cell death) in human myeloma cell lines grown in the laboratory
• In laboratory studies, pamidronate inhibited myeloma cell growth and caused tumor cell death
• Pamidronate exerted antimyeloma effects in mice that had implants of human myeloma cells growing in human bone fragments. (Yaccoby et al. Br J Haematol. 2002;116(2):278-290.)

However, it is not known whether pamidronate has the same effects in patients with myeloma.

Pamidronate is generally well tolerated. Some patients may experience mild and transient side effects, including fatigue, gastrointestinal effects, anemia, and skeletal pain, which may be related to their underlying disease. Although rare, long-term use of the drug at higher doses or pamidronate infused in less than 2 hours can affect the kidneys. For this reason, patients who receive pamidronate should have serum creatinine assessed prior to each treatment. In addition, blood tests such as calcium, electrolytes, phosphate, magnesium, and CBC, differential, and hematocrit/hemoglobin should be performed periodically. There is animal data to suggest there can be a problem when bisphosphonates are administered during pregnancy. Therefore, pamidronate should not be used during pregnancy unless a physician feels the benefits outweigh the risks.

Long-term therapy with pamidronate appears to be safe. Results of a study of 22 patients who received intravenous pamidronate or zoledronic acid for up to 6 years found that prolonged therapy was well tolerated. No significant calcium, phosphorus, electrolyte, or WBC count abnormalities were seen. A clinically insignificant decrease in hemoglobin and platelet count and an increase in creatinine were observed. There were no stress fractures of long bones with prolonged therapy and the fracture rate beyond 2 years was no greater than during the first 2 years of treatment. (Ali et al. J Clin Oncol. 2001;19:3434-3437.)

A number of cases of painful exposed bone in the jaw (a condition called osteonecrosis of the jaw) have been reported in patients receiving intravenous bisphosphonates (pamidronate or zoledronic acid) for hypercalcemia of malignancy related to myeloma or breast cancer. (Marx RE. J Oral Maxillofax Surg. 2003;61:1115-1118.) However, cancer patients in general are at increased risk for this condition due to other therapies they may receive, such as radiation, chemotherapy, and medications such as steroids. (Tarassoff P. J Oral Maxillofax Surg. 2003;61:1238-1239.) Although no cause and effect relationship between bisphosphonates and osteonecrosis has been established, it is recommended that cancer patients take adequate steps to maintain their oral health. This includes practicing good oral hygiene and scheduling regular dental visits. Patients may want to complete major dental procedures before they begin treatment with bisphosphonates. If a dental problem does occur, the least invasive conservative management strategy is preferred.

Pamidronate is being evaluated as an integral part of a treatment regimen for patients with smoldering or indolent myeloma to see if it can help prevent or delay the development of bone lesions.