Introduction

Bone metastases are a common complication of advanced cancer, and are most often seen in patients with breast, prostate and lung cancers. Almost 80% of patients with advanced breast and prostate cancer and 30% of those with lung cancer will develop bone metastases. They occur in almost all cases of myeloma. Melanoma and cancers of the genitourinary tract, thyroid, colon and rectum also have a propensity to spread to the bone. More than 80% of bone metastases occur in the axial skeleton (skull, spine, ribs, pelvis), although they can ultimately occur in any bone. As a result of bony involvement with cancer, patients may suffer from bone pain, pathologic fractures, spinal cord compression and hypercalcemia. These can lead to chronic pain, decreased mobility, and an inability to carry out activities of daily living, all significantly impacting quality of life. Nurses are in a position to provide support, education and symptom management to patients with bone metastases.

Pathophysiology
Bone is a common site of metastasis due to its rich blood supply, the fact that tumor cells secrete adhesive molecules that can bind to bone marrow and matrix, and the fact that growth factors produced in bone can promote the survival and further growth of tumor cells. Normal bone remodeling is a balancing act of the activity of osteoclasts (which reabsorb bone) and osteoblasts (which replace the bone destroyed by the osteoclast). Bone metastases upset this balance, and are classified as either osteolytic, characterized by

destruction of normal bone, or osteoblastic, which involves deposition of new bone, albeit weak and unhealthy new bone. In reality, this is a spectrum ranging from purely osteolytic to purely osteoblastic metastases, with a mix of the two in between. In fact, an individual bone metastasis can contain elements of both. For example, breast cancer primarily causes osteolytic lesions, but some 15-20% of cases are mainly osteoblastic, while others are mixed. Bone lesions in prostate cancer are typically osteoblastic, although mixed or osteoclastic lesions can also occur. In the case of multiple myeloma, lesions are always osteolytic. As the cancer cells invade the bone, numerous growth and angiogenic factors are released, some of which promote further tumor growth, leading to a vicious cycle of bone destruction and tumor growth. Osteoclasts are activated by a number of factors, including receptor activator of nuclear factor kb ligand (also called RANKL). RANKL binds to receptors on tumor cells, stimulating further osteoclast production, and is the target of one monoclonal antibody therapy. Osteoblastic activity creates new bone, but this bone is weak and prone to fracture. The pathophysiology behind osteoblastic lesions is only beginning to be understood. Studies suggest that there may be a similar cycle involved, where tumors induce osteoblast activity which, in turn, releases growth factors that promote tumor growth.

Clinical Presentation & Diagnosis

Pain is the most common presenting symptom of bone metastases. This pain is often localized to one site, but can occur in more than one

site and tends to increase over the weeks or months prior to reporting the symptom. Pain is often described as aching and localized to specific areas, aggravated by movement and activity. Pain in bone lesions can be a result of pressure of the tumor tissue within the bone (sometimes called mechanical or primary pain) or caused by the release of cytokines and other factors by tumor cells in the bone (biologic or secondary pain). Mechanical pain may be more distressing during activity due to the effect on bone strength and functional integrity. Bone metastases can present with pathologic fracture in 10-30% of all cases, with the femur being the site of more than half of these fractures. Pathologic fracture is most commonly reported in breast cancer. Cord compression occurs in approximately 5% of cases and is most commonly seen in breast cancer (20-30% of cases) and lung cancer (15%). New or worsening back pain in a patient with cancer should be evaluated promptly as neurologic recovery is unlikely if compression is not detected and relieved within 24-48 hours. Hypercalcemia is a presenting symptom in 10% of cases. In addition, patients may have elevated levels of alkaline phosphatase and phosphorus. Anemia can be present if there is significant bone marrow involvement.

Diagnosis
When bone metastases are suspected, imaging is needed to confirm the suspicion and determine the location and extent of involvement. Typically, the first test is a bone scan, which is a good whole-body screening test, followed by plain films to further characterize any

lesions found on the bone scan. CT scan and MRI can be helpful in areas that remain in question or in cases where metastases were not detected, but suspicion is high. For myeloma patients, a skeletal survey with plain films (rather than a bone scan) is the first step, as plain films are better at detecting osteolytic lesions. While it may seem logical to start with MRI, it is estimated to cost 2-3 times as much as a bone scan. PET scan has proven superior to bone scan in studies for detecting metastases in myeloma, lung and breast cancers. However, this comes at an estimated cost 8 times higher than that of a bone scan. An MRI is the test of choice when evaluating back pain and the suspicion of cord compression in the patient with cancer.

Treatment Options
Radiation Therapy & Radioisotopes
Radiation therapy is indicated for the treatment of spinal cord compression, treatment of bones at risk for pathologic fracture and palliation of pain caused by bone lesions. The American Society for Radiation Oncology Guidelines for palliative radiotherapy in bone metastases state that a single dose of radiation (8Gy) is as effective in providing pain relief as fractionated courses. Fractionated courses have lower retreatment rates (8% versus 20%), however, the single treatment is more convenient for the patient and retreatment is usually feasible when needed. Treatment of spinal cord compression typically requires a longer course of 10 fractions. Radioisotopes are a viable treatment option for multifocal bone metastases, and are typically used in prostate and breast cancer

cases with osteoblastic lesions. Strontium-89 and samarium-153 are the isotopes currently used. These are effective in providing pain relief in 80% of patients, with 10% becoming pain free, with relief lasting 3-6 months. Both isotopes are myelosuppressive and are contraindicated in patients with leukocyte counts below 2400/mm3 and/or platelet counts below 60,000/mm3. Chemotherapy must be held typically for 6 weeks after treatment, something to consider for patients in need of systemic treatment.

Surgery
Surgery may be indicated when there is a fracture (or high risk of fracture) of the long bones or hips, as well as spinal cord or nerve compression. Post surgical radiation is also indicated to prevent further tumor growth. New, less invasive, surgical techniques are being investigated, including kyphoplasty and vertebroplasty. Both techniques involve injection of a bone cement into the collapsed vertebral bodies. In kyphoplasty, a balloon is inflated prior to adding the cement to recreate the normal height of the vertebrae. Both are outpatient procedures with few complications that are effective in providing pain relief.

Bisphosphonates
Bisphosphonates decrease bone loss by inhibiting osteoclast activity. Second generation bisphosphonates, including pamidronate and zoledronic acid, are more potent osteoclast inhibitors than their first generation counterparts. These agents are effective in reducing the frequency of skeletal-related events in patients with bone metastases and in decreasing pain related to bone lesions in both multiple myeloma and solid tumors. Studies have shown zoledronic acid to be a more potent inhibitor and it may be given in a shorter infusion than

pamidronate. However, side effect profiles may lead some to prefer pamidronate over zoledronic acid- an acceptable decision per National Comprehensive Cancer Network (NCCN) recommendations. The recommended dosage schedules are 90mg intravenously, given over 2 hours, every 3 to 4 weeks for pamidronate and 4mg intravenously, given over 15 minutes, every 3 to 4 weeks for zoledronic acid.

Side Effects
Bisphosphonate therapy is generally well tolerated. There may be an acute reaction of a flu-like syndrome with fever, chills, myalgia and arthralgia, in approximately 50% of patients. This typically occurs within 48 hours of the infusion and resolves in 24 to 48 hours. Acetaminophen or NSAIDs may be used to relieve the symptoms and can be given prophylactically prior to the infusion. Bisphosphonates are cleared renally and can, in turn, cause increased serum creatinine. There are several important nursing considerations in preventing renal dysfunction. Renal toxicity is related to the agent used (appears more common in zoledronic acid versus pamidronate), the dose, schedule and duration of infusion. Starting with a lower dose and prolonging the infusion time can both decrease the risk of toxicity. American Society of Clinical Oncology (ASCO) guidelines recommend that pamidronate should be infused over no less than 2 hours and zoledronic acid over no less than 15 minutes. Patients should be adequately hydrated prior to the infusion and serum creatinine should be checked prior to each infusion. Dose should be reduced in patients with mild to moderate renal impairment and not used in those with

severe impairment. If renal dysfunction develops, recovery varies greatly. Osteonecrosis of the Jaw (ONJ) is a rare, but debilitating side effect associated with the chronic use of IV bisphosphonates. ONJ most often occurs after a dental procedure or trauma (poor fitting dentures), and is defined as an area of exposed necrotic bone in the mandible or maxilla that does not heal after a period of 8 weeks. These lesions often present with jaw pain or numbness, gingival swelling, drainage and loose teeth, although approximately one-third of lesions are painless and some patients may be asymptomatic. ONJ has been most commonly reported in patients with myeloma, breast and prostate cancer and appears to occur more commonly with zoledronic acid than other bisphosphonates. Preventive interventions should include complete dental evaluation, cleaning, optimization of dental health and removal of any unsalvageable teeth prior to beginning therapy. Dental cleanings should be performed every 6 months while on therapy. Patients should be educated to report any concerning symptoms, such as jaw pain or numbness, exposed bone or drainage. If a patient remains on therapy for more than 3 years and requires dental surgery, the American Association of Oral Maxillofacial Surgery recommends discontinuing bisphosphonates for 3 months prior to surgery. This group has also defined the staging and treatment of ONJ (See reference Ruggerio et al. 2009). Bisphosphonates may cause hypocalcemia, therefore ASCO recommends periodic monitoring of serum magnesium, calcium and phosphate during therapy. If there are no contraindications, patients

receiving bisphosphonates should receive supplemental calcium and vitamin D.

Anti-tumor Effects in Breast Cancer

Studies are ongoing looking at the possibility that these agents also have some antitumor and/or antiangiogenic effects. In the ZometaFemara Adjuvant Synergy Trial (Zo-FAST), the addition of zoledronic acid to adjuvant hormone therapy in postmenopausal women with early stage breast cancer was found to decrease recurrence in bone and non-bone sites. A second study, Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE), did not show improvement in disease free survival. The ABCSG-12 Trial was designed to look at the efficacy of 3 years of ovarian suppression with hormone therapy (tamoxifen or anastrozole) with or without zoledronic acid. Recently, mature results were released, demonstrating improved disease free survival with the addition of zoledronic acid to hormone therapy (92% versus 88%, p=0.008), though there was no significant improvement in overall survival. The improvement in disease free survival was present in both node positive and node negative participants.

Other Solid Tumors

The majority of studies of bisphosphonates have been conducted in myeloma, breast and prostate cancers. Zoledronic acid is the only agent with clinical data for use in patients with other solid tumors. Use in these populations should be driven by the potential to provide palliative benefit by decreasing skeletal events and decreasing pain related to bone disease.

Other Osteoclast Inhibitors

Denosumab is a monoclonal antibody that inhibits RANKL, which in turn inhibits osteoclast activity. In clinical trials, denosumab significantly prolonged the time to a skeletal event in patients with bone metastases from breast and prostate cancer, when compared to zoledronic acid. In another study, early results show the median time to a skeletal event was significantly longer with denosumab (20.5 versus 16.3 months), in other malignancies, including myeloma, renal cell and lung cancers. The dosage schedule of denosumab is 120 mg given subcutaneously, every 4 weeks. Side effects include nausea, renal toxicity, hypophosphatemia, hypocalcemia and ONJ. Patients should receive the same dental care and education as those receiving bisphosphonates. They should also take supplemental calcium and vitamin D if there are no contraindications and be educated to report symptoms of hypocalcemia, including numbness or tingling sensation around the lips, muscle stiffness, twitching, spasms or cramps.

Pain Management
In addition to treating the underlying cancer and the previously discussed bone directed interventions, nurses must provide education and treatment for pain management. Most patients will require a combination of NSAIDs, non-opioid and opioid analgesics. Tramadol is a non-opioid analgesic that can be effective in managing mild to moderate pain. A dose of 100mg is reported to be more effective than 60mg of codeine.

NSAIDs are more effective than acetaminophen due to their antiinflammatory properties. Ketorolac (Toradol) is a potent NSAID, with a dose of 30mg IV equaling the pain relieving ability of 15mg of IV morphine. NSAIDs have concerning side effects (gastrointestinal, renal insufficiency) and should be used cautiously when taken for more than 5 days. COX2 inhibitors do not cause gastrointestinal side effects and may be preferred for patients in whom this is a concern. Moderate to severe pain will typically require opioid analgesics for relief. Nurses should provide education to dispel misconceptions about pain medication. The fear of addiction is a common barrier, however, the risk of addiction for cancer patients with pain is extremely low. Patients may fear becoming immune to the effect of the medication; that it will not work if more severe pain develops. Due to these and other fears, patients may wait until pain is severe to take medication, though at that point, relief can be more difficult to achieve. Encourage patients not to wait until pain is unbearable to take pain medication. When choosing an opioid, the side effect profile, onset and duration of action should be considered. In some cases, more then one agent may need to be tried before adequate relief is achieved. When beginning a pain medication, educate the patient about side effects such as nausea and constipation. Provide tips to preventing nausea, such as taking with food or using antinausea medications prophylactically. Provide suggestions for prevention of constipation such as a stool softener and stimulant (senna), increased hydration and exercise if possible. If constipation occurs, encourage patients to try stronger agents such as lactulose and polyethylene glycol.

Conclusion

Nurses play an important role in the detection and management of bone metastases. Patient education is crucial, as most patients are in the outpatient setting, managing their own care at home. Bone metastases can cause fear and anxiety about prognosis and quality of life. Nurses have the opportunity to assist patients in finding appropriate psychosocial support, managing pain and side effects of treatment and providing reassurance that the oncology team will do all it can to optimize quality of life.