Cancer Treatment: The Critical Factors
Step Seven: Maintaining Bone Integrity
Some types of cancer (ie, breast, prostate, and multiple myeloma) have a proclivity to metastasize to the bone.79,80 The result may be bone pain, which also may be associated with weakening of the bone and an increased risk of fractures.92,93
Patients with prostate cancer have been found to have a very high incidence of osteoporosis or osteopenia even before the use of therapies that lower testosterone levels.94 In settings such as prostate cancer, when excessive bone loss is occurring, there is a release of bone-derived growth factors, such as TGF-beta-1, which has been associated with aggressive prostate cancer.95 In turn, prostate cancer cells produce substances such as interleukin-6 (IL-6), which causes effects the further breakdown of bone.84,87 Thus, a vicious cycle results: bone breakdown, the stimulation of prostate cancer cell growth, and the production of interleukin IL -6 and other cell products, which leads to further bone breakdown.
The administration of any of the drugs called bisphosphonates, such as Aredia, Zometa, and Fosamax or Actonel can be used to stop this vicious cycle. These agents inhibit excessive bone breakdown and favor bone formation.88,96-99
The problem that prostate and breast cancer patients face is that bisphosphonate therapy is usually only prescribed for preexisting bone metastasis. If bisphosphonates were administered to those with cancer preventatively, then the risk of bone metastasis could theoretically be reduced,100 though not all studies substantiate this. A study published in 2008 revealed that premenopausal women with early-stage breast cancer (ie, no bone metastasis) given Zometa experienced a trend towards decreased bone metastasis and greater survival.101 A subsequent study found an improvement in survival in women with breast cancer who were five years past menopause who took Zometa preventatively. However, premenopausal and perimenopausal women did not experience a survival benefit.102
Other studies have documented the ability of Zometa to prevent the onset of bone metastasis. In one study, patients with advanced solid tumors and no evidence of bone metastases were randomized to receive Zometa or no further treatment. After 12 months, 60% of those receiving Zometa were free of bone metastasis, compared to only 10% in the control group. After 18 months, 20% of those in the Zometa group were free of bone metastasis, compared to only 5% in the control group.100 Zometa has also been shown to benefit those with multiple myeloma when given preventatively, by improving survival and reducing the risk of bone metastasis.103
The benefits of Zometa in women with breast cancer are not limited to the prevention of bone metastasis. Many women with breast cancer are given a drug called an aromatase inhibitor. This class of drugs are estrogen blockers and are frequently used in place of tamoxifen in postmenopausal women with estrogen receptor positive breast cancer. Aromatase inhibitors can cause bone loss and can increase the risk of osteoporosis. In addition to preventing bone metastasis, Zometa has also been shown to protect against the loss of bone density from the use of aromatase inhibitors.104
Note: Bisphosphonate drugs have potentially serious adverse effects. The use of bisphosphonate drugs has been associated with an increased risk of osteonecrosis of the jaw (death and decay of the jaw bone). The incidence of osteonecrosis of the jaw during therapy with Zometa was found to be 1.3%.105 This risk is considerably greater in those who had major dental work (ie, tooth extraction) performed during bisphosphonate use. Individuals should avoid undergoing tooth extractions during therapy with Zometa. Individuals who use bisphosphonate medications under a physician’s guidance can help reduce their risk of osteonecrosis of the jaw by receiving a dental examination and undergoing any necessary dental procedures such as tooth extractions before initiating drug therapy.106 Those taking bisphosphonate drugs should also take bone-protecting minerals like calcium, magnesium, and boron, along with vitamins D and K.
Additionally, people treated with Zometa have an increased risk of atrial fibrillation, or irregular heart rhythm causing the heart to pump blood less efficiently, potentially resulting in pulmonary edema (fluid in the lungs), congestive heart failure, stroke, or death. A study showed that 2.5‒3% of patients taking bisphosphonates developed atrial fibrillation and 1‒2% developed serious atrial fibrillation, with complications including hospitalization or death.107
It should be noted that 6.9% of individuals treated with Zometa experienced kidney toxicity. Zometa should be used with caution in those with preexisting kidney disease and is contraindicated in those with severe kidney disease.105
New research has produced an alternative to Zometa for the treatment of bone metastasis. Denosumab (Xgeva) is a monoclonal antibody that inhibits osteoclastic-mediated bone resorption by binding to osteoblast-produced RANKL. By reducing RANKL binding to the osteoclast receptor RANK, bone resorption and turnover decrease.108 Denosumab has recently been shown to be more effective than Zometa in the treatment of bone metastasis. In one study, 1,904 men with prostate cancer with bone metastasis were randomized to receive Zometa or Denosumab. The time it took for a subsequent bone metastasis related event (ie, fracture, spinal cord compression, or radiation/surgery to bone) was longer in the denosumab group, demonstrating the superiority of denosumab over Zometa.109
Denosumab was also compared to Zometa in women with breast cancer with bone metastasis. This trial found that Denosumab was superior to Zometa in delaying the time to bone metastasis related events.105 Unfortunately, osteonecrosis of the jaw is also a side effect of treatment with Denosumab. Indeed, the incidence of osteonecrosis of the jaw was slightly higher with Denosumab compared to Zometa. As with Zometa, renal toxicity has been associated with the use of Denosumab.
A COX-2 inhibitor drug presents another option for the prevention of bone metastasis. As discussed in Step Four of this protocol: Inhibiting COX-2 enzyme, breast cancer patients treated with a COX-2 inhibitor drug had a 90% reduced risk of developing bone metastases compared to those not treated with a COX-2 inhibitor.
Life Extension advises that the status of bone integrity should be evaluated periodically by means of a quantitative computerized tomography bone mineral density study—called QCT. At the very least, this should be done annually. We prefer to use the QCT scan over the standard DEXA scan since the QCT is not falsely affected by arthritis or calcifications in blood vessels that are commonly seen in individuals over age 50. It is fairly common to see patients with a normal DEXA scan and yet the QCT scan will be blatantly abnormal. The radiation exposure with QCT is only marginally greater than with DEXA scan.
QCT testing sites possibly near you can be found via Mindways, Inc. at (877) 646-3929 or Image Analysis at (800) 548-4849.
Tests that assess bone breakdown are inexpensive and involve a simple urine collection. One such accurate test of bone resorption is called DPD (deoxypyridinoline). This test provides information on excessive bone breakdown. The DPD cross links urine test can be ordered through the Life Extension by calling 1-800-226-2370.
How to Implement Step Seven
If you have a type of cancer with a proclivity to metastasize to the bone (ie, multiple myeloma, breast, or prostate), consider speaking to your oncologist regarding Zometa or Denosumab. If either of these medications are contraindicated, then consider the COX-2 inhibitor drug Celebrex. Please see step four of this protocol for a complete discussion of COX-2 inhibition.
One must always weigh the risks versus the benefits when evaluating a given treatment. This is certainly the case when considering the use of Zometa, Denosumab, or Celebrex for the prevention of bone metastasis. Given the excellent prognosis and low risk of bone metastasis, Life Extension does not recommend the use of Zometa, Denosumab, or Celebrex for women with stage 1 and stage 2A breast cancer. With higher risk cancer, the benefits of these medications likely outweigh the risks. Life Extension recommends the use of medications for the prevention of bone metastasis in women with stage 2B, stage 3, or stage 4 breast cancers.
With regard to prostate cancer, a large percentage of men will be cured with surgery or radiation. Treatment failure is easily detected by a rising PSA after initial treatment. Furthermore, it usually takes several years for bone metastasis to form once a rising PSA has detected treatment failure. This prolonged time frame for the formation of bone metastasis allows for the use of proactive therapies once treatment failure has been detected by a rising PSA. For this reason, Life Extension recommends the use of medications for the prevention of bone metastasis only when treatment failure has been detected by a rising PSA after initial treatment. An exception to this recommendation would be men with osteoporosis receiving androgen deprivation therapy for their initial treatment. Androgen deprivation therapy can result in further loss of bone density. Given that Zometa can protect against the loss of bone density, the benefits of using this medication may outweigh the risks in men with osteoporosis receiving long-term androgen deprivation therapy.
Since excessive bone breakdown releases growth factors into the bloodstream that can fuel cancer cell growth, the DPD urine test should be done every 60‒90 days to detect bone loss. A QCT bone density scan should be done annually. If either of these tests indicates bone loss, ask your physician to initiate bisphosphonate therapy.
To support bone integrity, the use of bone-supporting nutrients is highly recommended. These include optimal amounts of vitamin K, vitamin D, calcium, magnesium, boron, and silica. Please see the “Osteoporosis” protocol for a detailed discussion of the use and dose of these nutrients for bone support.