Preventing Breast Cancer Cell Metastasis-- Copyright LEF Breast cancer cells frequently metastasize to the bone, where they cause severe degradation of bone tissue. The bisphosphonates are a class of drugs that protect against the degradation of bone, primarily by inhibiting excess activity of osteoclasts. The osteoclasts are bone cells that absorb and remove bone tissue so that the osteoblasts can bring together the minerals calcium, magnesium, and phosphorus to form new healthy bone. When osteoclasts become overactive, they break down too much bone, which can result in a pathological reduction of bone density. Among the known inhibitors of osteoclast activity, the bisphosphonates are the most promising drugs. Clodronate, one of the most investigated bisphosphonates, has been clinically utilized for over 15 years in treating malignant diseases. It is the most-used, most effective, and safest drug in the treatment of hypercalcemia (too much calcium in the blood). It inhibits bone destruction, prevents bone fractures, relieves bone pain, and prevents the development of new bone lesions. Clodronate may even reduce mortality. Bisphosphonates such as clodronate are potent osteoclast inhibitors that have opened the way for a nontoxic medical treatment of bone metastasis. Large-scale studies in humans with breast cancer indicate the benefits of prolonged administration of clodronate to reduce the frequency of pathological skeletal events and also the need for radiation therapy. A New England Journal of Medicine study (Aug. 6, 1998) confirmed many previous studies showing that breast cancer patients receiving clodronate experienced about half the number of metastatic lesions to the bone compared to the placebo group. What was remarkable about the New England Journal of Medicine study was that it showed that clodronate also prevented metastasis to the visceral organs and that it significantly improved patient survival over a 36-month time period. Another study showing improved survival was conducted in Finland, where breast cancer patients were treated with clodronate or placebo. Bone pain, extension of bone metastasis, and formation of new bony metastatic lesions were reduced by clodronate, and development of severe hypercalcemia was prevented during the first 12- month period. The patients were then withdrawn from clodronate treatment and were followed up for at least 12 months. There were fewer fractures and less hypercalcemia (too much calcium in the blood) in the patients previously treated with clodronate than in the placebo group. The survival rate was higher in the clodronate group compared to the placebo group. No side effects were observed in either group. While clodronate has been investigated as a therapy for advanced metastatic bone cancer in dozens of human studies, only two studies show that clodronate improved breast cancer patient survival. It would appear that if clodronate were administered earlier in the disease state, it could significantly prolong survival, as was demonstrated in the New England Journal of Medicine study. Since 1980, the Europeans have been studying the effects of clodronate in the management of hypercalcemia, bone pain, and skeletal complications in patients with bone metastasis. Controlled studies show that bone metastasis can be prevented or delayed in patients receiving clodronate. The bisphosphonate drug clodronate is now the standard therapy (after hydration) that German doctors use to treat malignant states of hypercalcemia. As was previously stated, tumor-induced hypercalcemia is essentially due to an increase in osteoclast-induced breakdown of the bone into the blood. During this process of bone destruction, substances such as growth factors are released that promote tumor-cell growth. Since the bisphosphonates are potent inhibitors of osteoclast activity, they represent an effective method of safely treating hypercalcemic events that frequently occur in patients with breast cancer and other diseases. In a double-blind multicenter study, the effect of intravenous clodronate plus hydration was compared with placebo plus hydration in the treatment of hypercalcemia in breast cancer patients with bone metastases. A significant difference in favor of clodronate was observed in the time to reach normal blood calcium. A total of 17 patients of 21 patients on clodronate achieved normal blood levels of calcium compared with only 4 of 19 patients on placebo. The only adverse event associated with clodronate was symptomatic hypocalcemia (too little calcium in the bone) in one patient. The reason hypocalcemia is such a rare event is that patients having a good response to clodronate normally show an increase in calcium- regulating hormones such as parathyroid hormone. This homeostatic response probably explains why hypocalcemia occurs rarely in clodronate-treated patients. In 1991, Italian scientists reviewed 126 publications on clinical studies concerning the use of clodronate in the therapy of bone disease. These studies evaluated a total of 1930 patients in order to ascertain the effects following the short- and long-term administration of clodronate. The results of the large number of studies indicate that clodronate therapy does not have any clinically significant side effects and confirm its tolerability and safety. It is still, however, advisable to have a blood test within 10 days of initiating clodronate therapy, just to make sure that clodronate is not removing too much calcium from the blood. Bisphosphonate drugs like clodronate exert their analgesic effect by several mechanisms. The long-term effects are probably due to osteoclast inhibition. The acute pain-relieving effect, which occurs within days or a week, is likely to be associated with the reduction of various potentially pain-producing substances. In a controlled trial using clodronate in patients with metastatic bone disease and pain, 57% of patients in pain chose clodronate, while 26% chose placebo, and eight (17%) had no preference. For the investigators who also made a blinded selection, clodronate was chosen in 65% of patients compared to placebo in 22% patients, and no difference was apparent in 13%. In an observational study involving 398 tumor patients with bone metastases or related hypercalcemia, the effect of treatment with clodronate over a period of 12 months was investigated. Bone pain, analgesic requirements, quality of life, and laboratory parameters were recorded at monthly intervals. The results showed that some 71.4% of all patients indicated an improvement in quality of life. In another study, 20 postmenopausal women (between 46 and 67 years old) with skeletal metastases from breast cancer were treated with clodronate for 15 days. All patients received standard hormonal therapy (tamoxifen). These results showed that clodronate provided pain relief in 75% of treated patients, and serum bone-marker levels indicated stabilization of skeletal metastatic lesions. In a randomized, double-blind, placebo-controlled trial of oral clodronate, 173 breast cancer patients with bone metastasis were treated with clodronate or an identical placebo. In patients who received clodronate, there was a 47% reduction in the number of episodes of hypercalcemia, a 32% reduction in the incidence of vertebral fractures, and a 43% reduction in the rate of vertebral deformity. Trends were seen in favor of clodronate for nonvertebral fracture rates and bone pain. In patients who receive clodronate before developing bone metastasis, the results are more dramatic, showing consistent 50% reductions in skeletal metastasis and fractures. An inevitable conclusion may be that all breast cancer patients should consider supplementing with an 800-mg clodronate supplement twice a day for prophylactic purposes. Women with primary breast cancer who receive chemotherapy may experience ovarian failure or early menopause, leading to a loss of bone-mineral density. A double-blind trial was conducted to evaluate women with breast cancer who were given clodronate or placebo for 2 years. Those who received oral clodronate showed reduced bone-density loss compared to placebo. All of the patients in the trial received conventional treatment for breast cancer. In another study, the effect of clodronate on bone-mineral density was studied in 121 postmenopausal breast cancer patients without skeletal metastases. At 2 years, clodronate combined with the anti-estrogen drugs tamoxifen or toremifene markedly increased bone-mineral density in the lumbar spine and femoral neck by 2.9 and 3.7%. There were no significant changes in the patients given anti-estrogen drugs only. Doctors often advise cancer patients using clodronate to take plenty of calcium, magnesium, and even phosphorus to enable the bone to regenerate. The molecular mechanisms by which tumor cells degrade bone involve tumor cell adhesion to bone as well as the release of toxic chemicals from tumor cells that stimulate osteoclast-induced bone degradation. Bisphosphonates inhibit cancer cell adhesion to the bone matrix and inhibit osteoclast activity. By preventing tumor cell adhesion, bisphosphonates are useful agents for the prophylactic treatment of patients with cancer that is known to preferentially metastasize to bone. There is evidence that growth factors such as insulin-like growth factor and transforming growth factor are released when the bone matrix is degraded. These growth factors could stimulate tumor cell proliferation throughout the body, which may be a reason that early use of clodronate significantly improved survival. In a study to determine the effects of clodro-nate in women with advanced breast cancer, 133 patients with recurrent breast cancer-but no evidence of skeletal metastases were randomly allocated to receive clodronate by mouth or an identical placebo for 3 years under double-blind conditions at two clinical oncology centers in the United Kingdom and Canada. The number of skeletal metastases was significantly lower with clodronate treatment than with placebo. The complications of skeletal disease were fewer by 26% in clodronate-treated patients compared to controls. Compared to placebo, significant effects in favor of clodronate were observed for vertebral deformities and nonvertebral fractures. The doctors concluded that oral clodronate significantly decreases the number and complications of skeletal metastasis in women with advanced breast cancer. The reported studies of clodronate in the management of bone metastasis suggest a significant palliative role for this drug in those with advanced disease. An analysis of the hospital costs associated with the management of metastatic disease suggested that there are significant savings to be gained from the use of clodronate if only a 20% reduction occurs in the incidence of fractures, hypercalcemia, and hospital-based treatment for pain control (via radiation therapy). Of the many compounds belonging to the bisphosphonate family, clodronate has been the most widely used in treating hypercalcemia and metastatic malignancy to the bone. All published reports indicate that clodronate can normalize plasma calcium in the majority of cancer patients. A large number of clinical studies indicate that clodronate is a safe and efficacious drug. Some Published Studies on Clodronate A study published in 1988 concluded: Breast-cancer patients with multiple bone metastasis were treated with clodronate (1600 mg/day) or placebo for 12 months. After withdrawal of treatment, the patients were followed up for at least 12 months. There were fewer fractures and less hypercalcemia in the clodronate group than in the placebo group. The survival rate was higher in the clodronate group than in the placebo group. No side-effects were observed in the clodronate group (Biomed. Pharmacother. (France), 1988, 42/2:111-116). Two studies published in 1987 state: The possibility of reducing symptomatic hypercalcemia and of maintaining total serum calcium concentrations with clodronate was evaluated in 28 patients with various types of malignant tumors. Oral clodronate successfully reduced a mean serum calcium concentration in 22 out of 25 patients after 3 to12 days (800 to 3200 mg/day). It is concluded that clodronate is a valuable clinical tool in the management of patients with malignancy-associated hypercalcemia (Acta Med. Scand. (Sweden), 1987, 221/5:489-494) We investigated the acute effect of hydration plus intravenously administered clodronate By the third day of observation, the clodronate produced a significant reduction in serum calcium levels compared to the placebo patients who received hydration only. There were no toxicities observed. Intravenously administered clodronate appears to be an excellent agent for the acute treatment of malignancy-associated hypercalcemia (Arch. Intern. Med. (United States), 1987, 147/5:937-939). A study published in 1985 states: We have assessed the effects of clodronate daily by mouth for up to 3 months in 17 episodes of hypercalcaemia and osteolysis due to carcinoma. Clodronate reduced serum calcium in 14 episodes and bone resorption in all patients. These remained suppressed for the duration of treatment, but recurred promptly when treatment was stopped. Clodronate may be a useful measure for controlling hypercalcaemia and osteolysis in patients with carcinoma (Br. J. Cancer (England), 1985, 51/5:665-669). A study published in 1984 states: Clodronate is very effective against osteoclasts. We studied its effects on calcium balance in patients with malignant osteolytic lesions. Ten normocalcemic patients with advanced metastatic bone disease or myeloma were randomized to a clodronate or placebo regimen. The results show that both calcium balance and calcium absorption increased from base line in the clodronate group and that these changes were significantly different from those in the placebo group. Our results suggest that clodronate may be a useful adjuvant in managing metastatic bone disease (Presse Med. (France), 1984, 13/8:479-482; also published in the N. Engl. J. Med., 1983, 308/ 25:1499-1501). A study published in 1981 states: Clodronate and etidronate were injected in various doses in 6 patients with one or multiple episodes of malignant hypercalcemia. All patients responded well to the drugs after a delay period of 2 to 7 days. The tolerance of the drugs was excellent. Etidronate, and especially clodronate, are promising agents for treating hypercalcemia and inhibiting bone resorption in malignant disorders (Cancer (Philadelphia), 1981, 48/8:1922-1925). A study published in 1980 states: [Thirty] patients with disorders of calcium metabolism were treated with clodronate by mouth (1.6 g/ day). Serum-alkaline-phosphatase and urinary hydroxyproline fell to normal or near-normal within 3 to 7 months, and there was a clinical improvement in all but 1 patient. Clodronate also reduced plasma-calcium and urinary calcium in 17 patients with hypercalcaemia due to primary hyperparathyroidism or secondary to malignant disease. Clodronate seems to be an effective oral drug for inhibiting excessive bone resorption in man (Douglas, D.L., Duckworth, T., Russell, R.G. et al., Dept. Hum. Metab., Univ. Sheffield Med. Sch., Sheffield, United Kingdom; Lancet (England), 1980, 1/8177:1043-1047). As mentioned earlier, clodronate is not approved in the United States, but the FDA did approve some expensive bisphosphonate drugs a few years ago. These drugs may not work as well as clodronate, and they produce side effects that could keep some breast cancer patients from using them for 3 to 5 continuous years. One FDA-approved bisphosphonate drug is called pamidronate and is sold under the trade name Aredia. The problem with Aredia is that it costs about $2,000 a month and must be administered in a medical setting via intravenous infusion. The high cost of Aredia has caused HMOs and other insurance companies to refuse to pay for it in early-stage breast cancer. What's worse, many physicians are not even familiar with bisphosphonate drug therapy, and therefore won't prescribe it to their patients. One reason insurance companies can avoid paying for Aredia in early-stage breast cancer is that the FDA has approved it for the treatment of "moderate to severe hypercalcemia associated with malignancy." Women with metastatic breast cancer often do not manifest serious hypercalcemia until the disease has significantly progressed. The FDA has thus restricted the use of Aredia in a way that makes it more of a palliative therapy in advanced disease rather than a potential life-saving therapy. Out of concern for toxicity, the FDA cautions against immediate retreatment with Aredia if the initial dose fails. Cancer patients are advised to undergo intravenous infusions of Aredia every 3 to 4 weeks. At $2,000 per infusion, few people can afford it. Clodronate, on the other hand, is so safe that cancer patients can start taking two 800-mg capsules a day as soon as they are diagnosed. The fact that clodronate is nontoxic, is not terribly expensive, and has been shown to improve survival would make it the drug of choice in a free market. Americans, however, are not free to make their own choices about medicines. The FDA does this for us. A review of the published literature provides conflicting results as to whether clodronate or Aredia is the better drug. Proponents of Aredia state it provides a longer period of remission from hypercalcemia. One study compared single infusions of either Aredia or clodronate at the highest doses commonly used. A total of 100% of patients in the Aredia group achieved normal serum calcium following infusion of Aredia, compared to 80% receiving clodronate. The median time to achieve normal serum calcium was a range of 4 days for Aredia and 3 days for clodronate. The median duration of normalized serum calcium was 28 days after Aredia and 14 days after clodronate. Two patients who failed to respond to clodronate were successfully treated with Aredia. Another two patients experienced fever after Aredia, but no significant toxicity was observed with either treatment. The doctors concluded by stating, "Both agents are effective in the management of hypercalcaemia of malignancy. At the doses studied, the effects of Aredia are more complete and longer lasting than those of clodronate." What the study did not mention is that clodronate can be taken orally every day, while Aredia administration is restricted to intravenous infusion. The fact that the calcium-normalizing effects of a single dose of Aredia lasted twice as long as a single dose of clodronate does not reveal much since it was already known that clodronate should be taken every day by mouth to maintain its effects. The major unpleasant side effect to Aredia is a transient fever, sometimes accompanied by flu-like symptoms such as myalgias and lymphopenia. These effects occur commonly after the first infusion of Aredia. Other reported adverse events include transient neutropenia, mild thrombophlebitis, asymptomatic hypocalcemia, and, rarely, ocular complications (uveitis and scleritis) and irritation at the site of infusion. Clodronate, on the other hand, appears to be free of unpleasant side effects other than the very rare case of it causing too little calcium in the blood (hypocalcemia). There is no evidence to show that Aredia increases survival or prevents the development of metastasis in breast cancer, while there are two studies that show clodronate can improve survival. The greatest concern to cancer patients, however, may be that Aredia has been consistently shown to significantly elevate blood levels of the cytokines tumor necrosis factor (TNF) and interleukin-6 (IL- 6). Clodronate does not increase these cytokines. TNF and IL-6 have differing effects on various cancer cell lines. One study to compare the effects of Aredia and clodronate on cancer patients showed a significant decrease in lymphocyte and leukocyte count in the Aredia group. In the same group, seven patients (24%) showed a transient increase of body temperature. These changes were not found in the patients treated with clodronate. Plasma IL-6 and TNF levels increased significantly after Aredia treatment, whereas no change was seen after clodronate infusion. Breast cancer patients already have elevated levels of TNF and IL-6. Elevation of these two cytokines reflects an advanced disease state and impending death. TNF is also involved in inducing autoimmune inflammatory disease. A study evaluated the possible anti-inflammatory action of Aredia and clodronate and found that low concentrations of Aredia induced the IL-6 secretion while higher levels of Aredia were toxic. The induction of IL-6 or toxic effects were not observed with clodronate. A study was undertaken to evaluate the relationship between serum TNF and cachexia (wasting syndrome) in patients with prostate cancer. Serum TNF activity was positive in 76% of the patients with relapsed disease, whereas only 11% of the untreated patients and 0% of the patients in remission as a result of endocrine therapy were positive. The serum total protein and albumin levels, hemoglobin levels, and body mass index of the patients with elevated serum TNF levels were significantly lower than the corresponding values in patients with undetectable serum TNF levels. There was a significant correlation between the detectability of serum TNF and performance status. Patients with elevated serum TNF levels had a significantly higher mortality rate than those with undetectable serum TNF levels. These findings suggest that TNF may be one of the factors contributing to cachexia in patients with prostate cancer. This study clearly shows that prostate cancer patients do not want to elevate TNF. Aredia elevates serum TNF, but clodronate does not. When it comes to prostate cancer, clodronate appears to be a lot safer. A high serum level of IL-6 is regarded as a predictor of poor prognosis in multiple myeloma. A 3-year study evaluated the effect of IL-6 on a large group of multiple myeloma patients. The patients with high levels of IL-6 were at very high risk of dying within 3 years from diagnosis. The doctors concluded that serum IL-6 is a significant marker of disease progression in multiple myeloma. A study on serum in human breast cancer patients revealed levels of serum IL-6 correlated with the stage of progression and with axillary lymph node involvement. The doctors concluded that high levels of IL-6 indicates more advanced disease. Aredia increases IL-6 levels, and is also used frequently by doctors in the United States to treat multiple myeloma. However, in the United States, doctors cannot treat patients with clodronate, even though it does not boost toxic IL-6, because the FDA will not allow it to be sold to American citizens. Angiogenesis (the formation of new blood vessels) is an essential requirement for tumor growth and metastasis. TNF is a factor known to promote tumor angiogenesis in breast cancers. Scientists are looking at therapies to lower TNF as a way of inhibiting tumor angiogenesis. It would appear that most cancer patients would not want to increase their TNF level because the resulting formation of new blood vessels would enable their tumor to grow and develop metastatic colonies. Aredia causes TNF to elevate, whereas clodronate does not affect TNF levels. Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.