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Bisphosphonates: Preventing Cancer Spread to the Bones
Functions
Bisphosphonates (BpN) are synthetic analogs of pyrophosphate, an endogenous regulator of bone turnover. Bisphosphonates bind readily to the hydroxyapatite bone matrix and therefore concentrate in the bone. The bisphosphonates adsorbed on the hydroxyapatite crystals are phagocytosed (swallowed) by the cells that break down bone (osteoclasts) and thus impair their activity. In far simpler terms, bisphosphonates work by blocking the breakdown of bone. Their functions are:

1. Limit the formation of osteoclasts
2. Limit the accession of osteoclast precursors to bone
3. Limit the breakdown of bone by mature osteoclasts

The result of inhibiting bone breakdown is a net increase in bone mass. Also the growth factors that are locked up in the bone matrix, factors that can stimulate cancer growth are released from the matrix at a slower rate. The ideal bisphosphonate is one that inhibits bone absorption without affecting bone mineralization. The bisphosphonates most commonly in use at the present time are Alendronate (Fosamax™ ) and Risedronate (Actonel™) which are both oral agents. Another oral agent only available in Europe is called Clodrinate. Zolidronate (Zometa™) and Pamidronate (Aredia ™) are bisphosphonates that are administered intravenously. They are substantially more potent than the oral bisphosphonates because 100% of the drug is absorbed (compared to 1-2% being absorbed from the GI tract into the blood stream with the oral bisphosphonates.

Osteoporosis
Bisphosphonates, as would be expected, have an obvious application in the treatment and prevention of osteoporosis. As there is a link between lack of estrogen and osteoporosis in women, so also are there studies that show a relationship between a lack of testosterone and osteoporosis in men. Thus, bisphosphonates can help prevent as well as correct osteoporosis.

As a first line of defense against osteoporosis the oral agents, Fosamax or Actonel are convenient ways to reduce the risk of fracture by increasing bone mineral density (BMD). A three-year study of 994 postmenopausal women from 16 countries found that Fosamax increased BMD of the spine by 8.8 percent; the hip by 5.9 percent; and the thigh by 7.8 percent. The risk of fractures was decreased by 48 percent. These increases in BMD were maintained for months following cessation of bisphosphonate treatment indicating superiority of bisphosphonates over estrogen or calcitonin.

A double-blind, multi-center study was performed in 241 men comparing Fosamax with placebo over a two year period. Fosamax increased spine bone density by 7% and hip density by 2.5%. The incidence of vertebral fractures was 0.8% in the men receiving Fosamax and 7.1% in the men treated with placebo. (Orwolll, Eric et al: Alendronate for the treatment of osteoporosis in men. New England Journal of Medicine Volume 343 Page 604 2000)

In the previous study the men were not being administered any testosterone inactivating pharmaceuticals (TIP). It is well known that TIP can deplete up to 10% of bone mass in the first 12 months of treatment. Therefore in our office we performed a study to see if Fosamax and Actonel can offset this effect. The result of the study was that with either of the oral agents bone density loss was greatly slowed by not completely eliminated. (Lam R, Oral bisphosphonates for the prevention of androgen deprivation therapy associated bone loss ASCO Abstract #4749 2004)

The potential adverse effects of Fosamax are abdominal pain (6.6%) and muscle pain (4.1%). The dose of Fosamax is 70 mg taken orally with plain water 30 minutes before breakfast once a week. The dose of Actonel is 35 mg taken in a similar fashion. Fosamax may be slightly more potent that Actonel. Actonel may have slightly less side effects. These prescription drugs cost about $60 per month, but most private insurances cover the cost.

Both Aredia and Zometa, the intravenous bisphosphonates, have been evaluated in randomized placebo controlled trials for their ability to prevent bone loss in men treated with 12 months of TIP. In the Aredia study men were administered 60 mg intravenously every 3 months. Bone density was unchanged at the end of the study in the men treated with Aredia while the men in the placebo group lost and average of 8.5% of the trabicular bone in the spine measured by quantitative CT scans. (Smith, Matthew, Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. New England Journal of Medicine. Volume 345 page 948 2001) A similar study with Zometa 4mg administered every 3 months was performed by Dr. Smith in 106 men who were undergoing treatment with TIP. In this study the bone density of the spine increased 5.6%. (Smith, Matthew, Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. Journal of Urology, Volume 169 page 2008, 2003). The results of these studies would seem to indicate that the intravenous bisphosphonates are more effective than the oral agents at preventing bone loss in men being treated with TIP.

Bisphosphonates should be used in combination with calcium citrate 1,000 mg per day given as 500 mg with dinner and 500 mg at night before sleep. Calcium taken in the morning is of little value. Synthetic vitamin D called Calcitriol (Rocaltrol™) 0.5 micrograms per day (a prescription item) should also be administered. When calcium without vitamin D is administered it can cause vitamin D deficiency. Vitamin D deficiency is very undesirable in men with prostate cancer as it results in accelerated bone breakdown. Men who are taking bisphosphonates or Calcitriol should have their blood calcium levels monitored periodically to make sure that the calcium concentration in the blood continues to be in the normal range. Please see our booklet titled "Osteoporosis" for a more complete treatment of this extensive subject.

Bone pain
Aredia and Zometa were originally approved by the FDA to ameliorate bone pain in patients with metastatic cancer. In a report by Clarke Aredia was used in 25 patients with prostate cancer and bone pain. Patients received 30 mg of Aredia weekly times 4 and then every other month. Eleven out of 17 patients with pain at the start of the study were pain free at the end. In addition, fasting morning calcium excretion decreased during Aredia therapy. Hydroxyproline excretion in the urine, a measure of bone metabolism, decreased in 13 of 20 patients. These laboratory trends are indicators of positive calcium metabolism and reflect a decrease in bone breakdown. In some patients bone scans stabilized and cancer blood markers decreased. (Clarke NW, Holbrook IB, McClure J & George NJR. Osteoclast inhibition by Pamidronate in metastatic prostate cancer: a preliminary study. British Journal of Cancer Volume 63 pages 420-423, 1991)

Bone metastases
Bisphosphonates have an exciting role to play in the management of prostate cancer patients. Bisphosphonates appear to be able to prevent the growth of cancer in the bones. This hypothesis first originated is animal studies done with rats. In one rat study involving human breast cancer cells that have a known propensity to metastasize heavily to bone, it was found that Risedronate decreased the tumor burden. In all experiments, "Risedronate either inhibited the development of new bone metastases or slowed progression of already established bone metastases. Furthermore, mice that underwent treatment continuously with Risedronate showed significantly longer survival than did control mice." It appears unlikely that Risedronate has direct anti-cancer effects since the volume of cancer that metastasized to soft tissues besides bone was not decreased in Risedronate treated animals. The authors emphasize that in their animal model that the drug was most effective when given "from the beginning of cancer cell inoculation or in a prophylactic manner. It is, therefore, possible that prophylactic administration of the bisphosphonates to cancer patients with high risk of bone metastasis might not only be preventing spread to bone but be able to prolong life expectancy." (Sasaki A, Boyce BF, Story B, et al: Bisphosphonate Risedronate reduces metastatic human breast cancer burden in bone in nude mice. Cancer Research Volume 55 page 3551, 1995.)

The theoretical explanation for these findings is that the bisphosphonates are inhibiting the osteoclasts (the cells that break down bone) from releasing growth factors and cytokines that are normally locked up in the bone matrix. When these growth factors are being released from the bone matrix at an accelerated rate they provide a favorable microenvironment for cancer cells to set up house and grow in bone. These cytokines are identical or similar to those that are involved in tissue repair mechanisms and in the growth of tumor cells. Bisphosphonates that inhibit bone turnover by stopping osteoclast activity in bone not only help osteoporosis but also help to prevent bone metastases from occurring and decrease the growth rate of established bone metastases.

In a rat model of prostate cancer, the bisphosphonates Clodronate and Aredia were shown to delay the effects of skeletal metastasis in comparison to a placebo treated group. Bisphosphonates would appear to be reasonable candidates to use in combination with other anti-cancer treatments in the initial management of men with prostate cancer who are at risk for future bone metastases. (Yu-cheng S, Geldof AA, Newling DW, et al. Progression delay of prostate tumor skeletal metastasis effects by bisphosphonates. Journal of Urology 148:1270-1273, 1992)

Three large randomized prospective human studies have been performed to see if Clodrinate can prevent the development of bone metastasis in women who have been diagnosed with breast cancer. Two of the three studies have shown a significant reduction in bone metastasis with prophylactic administration of this drug. (Diel I, Reduction in new metastases in breast cancer with adjuvant clodronate treatment New England Journal of Medicine volume 339 page 357, 1998) There are two reasons to consider that Zometa or Aredia may be even more effective in men with prostate cancer. First Zometa and Aredia are more potent that Clodrinate. Secondly, prostate cancer tends to spread to preferentially to bone while most other tumor types including breast cancer are indiscriminate and spread to multiple organs such as liver, lung, and brain as well as bone. Therefore, because bisphosphonates only inhibit spread to bone, you can see how prostate cancer patients would seem to have greater potential benefit.

These conclusions are extrapolations from animal data, women with breast cancer, and men with advanced prostate cancer. The data seems to indicate that intravenous bisphosphonates can prevent the development of prostate cancer in the bone. On the down side recent reports indicate that high doses of bisphosphonates administered frequently (monthly) for extended periods (more than 2 years) may rarely increase the incidence of dental problems. Men who have been on long term therapy should consult their oncologists before having dental extractions. Fortunately this problem only seems to occur in a small minority of men. As of the date of this publication we are using Aredia or Zometa on a quarterly or bimonthly basis with the goal of preventing the development of bone metastasis. Dental problems have not been seen in men using drugs in this bimonthly or quarterly schedule. Further studies and clinical trials of the use of bisphosphonates for the prevention and treatment of malignancies with a high predilection for bone are in process.

Pills verses intravenous infusions?
Some men have gastric side effects from Fosamax or Actonel. In this situation the best alternative is to bypass the stomach and administer the medicines intravenously (switch to Aredia or Zometa). One other reason to consider the intravenous bisphosphonates is cost. Some men don't have insurance coverage for pills but do have insurance coverage for intravenous treatments. Lastly, when we get down to the important issue of to preventing cancer from growth in the bones, or treating men with more severe degrees of osteoporosis or treating osteoporosis that is not responding to oral therapy, the more potent intravenous bisphosphonates are clearly the treatment of choice.

PROSTATE ONCOLOGY SPECIALISTS are one of the nation's few medical oncology practices focusing exclusively on prostate cancer. Medical oncologists are internal medicine doctors trained in the treatment of all types of cancer. Our physicians limit their focus to the research and treatment of a single type of cancer: prostate cancer. Our goal is to guide patients in selection and implementation of therapy that is appropriate for each individual's unique situation. Our foundations in Internal Medicine assure a holistic approach that addresses the overall health of the entire person.

Mark Scholz, MD
Richard Lam, MD
4676 Admiralty Way, Suite101
Marina del Rey, CA 90292
T. 310.827.7707
F. 310.574.4002
prostateoncology.com