Note from the National Guideline Clearinghouse (NGC) and the American Society of Clinical Oncology (ASCO): In planning the 2011 update, ASCO changed the scope of the guidelines to reflect changes in the field since the previous guideline. Reflecting the Update Committee's anticipation that data on new types of agents, including osteoclast inhibitors, may be available for future updates of this guideline, this guideline uses the term bone-modifying agents. The terminology in Recommendations 1, 2, 4, 6, and 7 has been changed from bisphosphonate to bone-modifying agent. The recommendations within the guideline focus on the drugs denosumab, zoledronic acid, and pamidronate because they are currently available in the United States.
Six of the recommendations are substantively the same as in the 2003 guidelines for bone-modifying agents for metastatic breast cancer. The current guideline has added a new recommendation regarding osteonecrosis of the jaw (ONJ), a condition recognized after the preparation of the 2003 guidelines. This guideline on metastatic breast cancer also reviews data on a new bone-modifying agent, denosumab. In contrast with the previous version, this guideline now focuses solely on patients with evidence of bone metastases. (See Table 1, "Summary of the 2011 Recommendations" in the original guideline document for more detailed information.)
Clinical Question 1
What are the indications for using bone-modifying agents to reduce the risk of skeletal-related events (SREs) in patients with metastatic breast cancer? When is the best time to initiate treatment with bone-modifying agents?
Recommendation 1. For patients with breast cancer who have evidence of bone metastases, denosumab 120 mg subcutaneously every 4 weeks, intravenous (IV) pamidronate 90 mg delivered over no less than 2 hours, or zoledronic acid 4 mg over no less than 15 minutes every 3 to 4 weeks is recommended. Starting bone-modifying agents in women with an abnormal bone scan and an abnormal computed tomography scan or magnetic resonance imaging showing bone destruction, but normal plain radiographs, is considered reasonable by Panel consensus based on the findings in women with lytic or mixed lytic/blastic changes on plain radiographs. Starting bone-modifying agents in women with only an abnormal bone scan but without evidence of bone destruction on radiographs, computed tomography scans, or magnetic resonance imaging is not recommended outside of a clinical trial. There is insufficient evidence relating to efficacy to support one bone-modifying agent over another.
Clinical Question 2
What is the role of bone-modifying agents in the presence of extraskeletal metastases without evidence of bone metastases?
Recommendation 2. Starting bone-modifying agents in women without evidence of bone metastases even in the presence of other extraskeletal metastases is not recommended. This clinical situation has been inadequately studied using IV bisphosphonates or other bone-modifying agents and should be the focus of new clinical trials.
Clinical Question 3A
What are the renal safety concerns of bone-modifying agent therapy?
Recommendation 3A. In patients with a calculated serum creatinine clearance of more than 60 mL/min, no change in dosage, infusion time, or interval of pamidronate or zoledronic acid administration is required. Use of bone-modifying agents among patients with reduced renal function has been incompletely assessed. The packet insert of zoledronic acid provides guidance for dosing when baseline serum creatinine clearance is ≥30 and less than 60 mL/min. Infusion times less than 2 hours with pamidronate or less than 15 minutes with zoledronic acid should be avoided. The Panel recommends that serum creatinine be monitored before each dose of pamidronate or zoledronic acid, in accordance with U.S. Food and Drug Administration (FDA)-approved labeling. Serum calcium, electrolytes, phosphate, magnesium, and hematocrit/hemoglobin should also be monitored regularly. The risk of hypocalcemia with denosumab dosed at 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis. Monitor for hypocalcemia in patients with impaired creatinine clearance. There is no evidence to guide the interval for monitoring serum calcium, electrolytes, phosphate, magnesium, and hematocrit/hemoglobin in patients on denosumab, pamidronate, or zoledronic acid.
Clinical Question 3B
What are the osteonecrosis of the jaw (ONJ) safety concerns of bone-modifying agent therapy?
Recommendation 3B. ONJ is an uncommon but potentially serious condition associated with the use of bone-modifying agents. The Update Committee concurs with the revised FDA label for zoledronic acid and pamidronate and the FDA label for denosumab and recommends that all patients with cancer receive a dental examination and necessary preventive dentistry prior to initiating therapy with inhibitors of osteoclast function unless there are mitigating factors that preclude the dental assessment. These recommendations should be observed whenever possible. While receiving inhibitors of osteoclast function, patients should maintain optimal oral hygiene and, if possible, avoid invasive dental procedures that involve manipulation of the jaw bone or periosteum. Although most cases of ONJ have occurred in patients treated with IV bisphosphonates and bone-modifying agents who underwent an invasive dental procedure, cases have occurred spontaneously and have been reported in patients treated with other bone-modifying agents, including oral bisphosphonates and direct osteoclast inhibitors.
Clinical Question 4
What is the optimal duration of bone-modifying agent therapy for patients with metastatic breast cancer?
Recommendation 4. The Panel suggests that, once initiated, bone-modifying agents should be continued until evidence of substantial decline in a patient's general performance status. The Panel stresses that clinical judgment must guide what constitutes a substantial decline. There is no evidence addressing the consequences of stopping bone-modifying agents after one or more adverse SREs.
Clinical Question 5
What are the best intervals between dosing?
Recommendation 5. For patients with breast cancer who have evidence of bone destruction on plain radiographs, denosumab 120 mg subcutaneously every 4 weeks, IV pamidronate 90 mg delivered over 2 hours, or zoledronic acid 4 mg over 15 minutes every 3 to 4 weeks is recommended.
Clinical Question 6
What is the role of bone-modifying agents in control of pain secondary to bone metastases?
Recommendation 6. The Panel recommends that the current standards of care for cancer bone pain management be applied at the onset of pain, in concert with the initiation of bone-modifying agent therapy. This is required by good clinical practice. The standard of care for pain management includes the use of nonsteroidal anti-inflammatory agents, opioid and nonopioid analgesics, corticosteroids, adjuvant agents, interventional procedures, systemic radiopharmaceuticals, local radiation therapy, and surgery. Bone-modifying agents are an adjunctive therapy for cancer-related bone pain control and are not recommended as first-line treatment for cancer-related pain. IV pamidronate or zoledronic acid may be of benefit for patients with pain caused by bone metastases and contribute to pain relief when used concurrently with analgesic therapy, systemic chemotherapy, radiation therapy, and/or hormonal therapy. Bone-modifying agents have been associated with a modest pain control benefit in controlled trials.
Clinical Question 7
What is the role of biochemical markers of bone turnover to guide initiation of therapy in patients without a prior skeletal event, predict treatment response, guide adjustments to bone-modifying agent therapy, or independently predict future fractures?
Recommendation 7. The use of the biochemical markers to monitor bone-modifying agent use is not recommended for routine care.
Special Commentary on the Role of Vitamin D Deficiency and Bone-Modifying Agents
In the absence of definitive data, it is the Update Committee’s expert consensus that if there are no contraindications to calcium and vitamin D supplementation, then patients receiving bone-modifying agents should receive them at doses and schedules similar to those used in the clinical trials of the bone-modifying agents, both to support bone health and decrease the risk of bisphosphonate-induced hypocalcemia. U.S. health authorities generally recommend a minimum consumption of vitamin D of 200 U (5 µg) a day. For the prevention and treatment of osteoporosis in adults, vitamin D 800 U daily is often recommended.