The Use of Bisphosphonates in Patients With Breast Cancer

Catherine H. Van Poznak, MD

Cancer Control. 2002;9(6)

Palliative Bone Pain Therapy

Randomized, controlled trials evaluating intra-venous pamidronate, clodronate, ibandronate, and zoledronate have demonstrated that these bisphosphonates aid in the relief of bone pain.^{[12,14,29,30,31,32]} Prolonged administration of oral clodronate (1,600 mg daily) reduces the frequency of morbid skeletal events by more than 25%, although compliance can be a limiting factor with the high oral dose required for this compound.^[33,34] Although bisphosphonates have not had an impact on overall survival, they have reduced skeletal complications of breast cancer. In addition, intravenous bisphosphonates have clinically relevant analgesic effects in patients with metastatic bone pain. The current standards of care for cancer pain -- analgesics and local radiation therapy -- should not be displaced by bisphosphonates^[26]; bisphosphonates may complement other treatment modalities. Pamidronate has been shown to reduce pain even in patients in whom conventional antineoplastic therapy fails.^[35] Bisphosphonates also provide treatment for patients with widespread, poorly localized bone pain and in patients experiencing recurrence of pain in previously irradiated skeletal sites. The pain relief obtained from bisphosphonates can play a role in maintaining patient comfort during palliative care.^[36,37] The role of bisphosphonates in the hospice setting needs to be further defined.

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Table 1. Comparison of the Nitrogen-Containing and Non-Nitrogen-Containing Bisphosphonates
	Non-Nitrogen-Containing Bisphosphonate	Nitrogen-Containing Bisphosphonate
Pharmacologic Effects	Inhibition of bone resorption and stimulation	Inhibition of mevalonic pathway, inhibition of of apoptosis of osteoclasts osteoclast activation and function; promotes osteoclast apoptosis
Mechanism of Action	Form adenosine triphosphate analogs that inhibit enzymatic activity	Inhibition of prenylation of proteins involved in signal transduction pathways
Gastrointestinal Side Effects (Oral Administration)	Mild to moderate nausea, vomiting, and diarrhea in <10%; no severe gastrointestinal effects have been reported	Moderate to severe nausea, vomiting; endoscopic evidence of erosive esophagitis and gastritis in some patients
Other Side Effects	No acute phase response has been reported	Renal toxicity; proinflammatory properties that are thought to underlie an acute phase response (fever, malaise, myalgia, and transient decrease in lymphocytes)
Effects on Survival	No survival benefit but a suggestion of possible increased survival in breast cancer in one small study^[18]	No survival benefit but in subset analysis one study suggested that women aged <50 years with breast cancer on hormonal therapy had a longer survival^[14]

Table 2. Pivotal Trials Investigating Intravenous Bisphosphonates in Patients With Metastatic Breast Cancer
Trial	Intervention	Patients	Skeletal Complications	Toxicity
Hortobagyi et al,^[12] 1996	Pamidronate 90 mg IV every 3-4 weeks placebo x 12 cycles	MBC with lytic bone lesion on chemotherapy (N = 382)	Median time to first SRE: vs 13.1 vs 7.0 months (P=.005)	Incidence of adverse clinical the 2 study groups favoring pamidronate
Hortobagyi et al,^[12] 1996	Pamidronate 90 mg IV every 3-4 weeks placebo x 12 cycles	MBC with lytic bone lesion on chemotherapy (N = 382)	Proportion of patients with any SRE: 43% vs 56% (P=.008) favoring pamidronate
Hortobagyi et al,^[13] 1998	Pamidronate 90 mg IV every 3-4 weeks vs placebo x 12 cycles	MBC with lytic bone lesion on chemotherapy (N = 382)	The odds ratio of having SRE during placebo treatment compared to pamidronate: 2.3 (95% CI, 1.5-3.5)	No new tolerability or safety issues arose in the second treatment year
Theriault et al,^[14] 1999	Pamidronate 90 mg IV every 4 weeks vs placebo x 24 cycles	MBC with lytic bone lesion on hormonal therapy (N = 372)	Median time to first SRE: 10.4 vs 6.9 months (P=.049) favoring pamidronate	Pamidronate was well tolerated; pamidronate arm experienced slightly more vomiting, fatigue, leukopenia, injection site reactions, and hypocalcemia than placebo arm
			Proportion of patients with SRE: 56% vs 67% (P=.027) favoring pamidronate
			At 24 cycles of treatment, the odds ratio of having SRE during placebo treatment compared to pamidronate was 1.6 (95% CI, 1.1 to 2.5)
Rosen et al,^[15] 2001	Zoledronate 4 or 8/4 mg vs pamidronate 90 mg every 3-4 weeks	MBC with lytic or mixed bone metastases and multiple myeloma with lytic lesions (N = 1,648)	Primary endpoint: proportion of patients with at least 1 SRE (not including hypercalcemia of malignancy) was similar among all treatment groups (44-46%).	Both the 5-minute infusion and the 8-mg dose of zoledronic IV acid were associated with increased renal toxicity; the 4-mg zoledronic acid dose over 15 minutes has a safety profile similar to 90 mg of pamidronate infused over 2 hours
Rosen et al,^[15] 2001			Secondary endpoints: pain score, analgesic score, and performance status were similar among treatment groups

Table 3. Most Common Side Effects of Intravenous Bisphosphonates
Transient pyrexia (10%-41%) Nitrogen containing bisphosphonates are associated with an acute phase reaction Self limiting and the incidence decreases with subsequent doses Consider premedication with acetaminophen, dilute with greater quantity of infusate, or a longer infusion time
Phlebitis at injection site (erythema/pain: 18%) Utilize central venous catheter if available, if not, then alternate site of infusion Consider increasing the volume of infusate or a longer infusion time
Transient myalgia, arthralgia, bone pain, malaise (10%) Analgesics as needed Consider premedication with acetaminophen, a larger volume of infusate, or a longer infusion time
Hypocalcemia (5%-17% usually asymptomatic) To decrease the incidence of hypocalcemia, patients should use 500 mg of calcium supplement and daily dose of 400-500 IU of vitamin D daily unless contraindications to these supplements exist If symptomatic, short-term treatment with intravenous calcium supplementation may be required
Bisphosphonate: Warnings Bisphosphonates are not to be given during pregnancy Serial monitor of serum creatinine is required Renal insufficiency may require a change in dosing interval or dose given Serial monitor of complete blood count and biochemical profile is required Fracture healing or a new orthopedic implant is not a contraindication to bisphosphonate therapy

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