Bisphosphonates for Osteoporosis or Bone Metastasis
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By: Mark Scholz, M.D.

Prostate Oncology Specialists

October 2010

Bisphosphonates come in oral and intravenous forms. They can be used to treat osteoporosis and/or metastatic cancer in the bones. The oral agents, Fosamax®, Boniva® and Actonel® are primarily for osteoporosis. The intravenous agents, Zometa® and Aredia®, are primarily for cancer, though they are also potent anti-osteoporosis agents.

Mode of Action

Normal bone is metabolically active.  The bone matrix is constantly being remodeled and bone density is the net effect of two very active processes, the rate of bone breakdown affected by the osteoclasts and the formation of new bone by the osteoblasts. Weakening of the bones through calcium loss—osteoporosis—occurs when the formation of new bone lags behind the rate of bone breakdown. Bisphosphonates counteract osteoporosis by slowing the rate of bone breakdown and allowing the osteoblasts to “catch up”.

The osteoclasts are inhibited by bisphosphonates via three mechanisms: 1) Slowing the formation of new osteoclasts. 2) Limiting the accession of osteoclasts to bone. 3)  Diminishing the breakdown of bone by mature osteoclasts. In regards to the anti-cancer effect of bisphosphonates, by inhibiting bone breakdown, growth factors in the bone matrix are kept “locked up,” out of reach to the cancer cells.  Without access to these growth factors, cancer cell growth is inhibited.

Bone pain

Aredia and Zometa were first studied to ameliorate bone pain in patients with metastatic cancer. In one study, Aredia was used in 25 patients with prostate cancer and bone pain. Patients received four weekly doses of Aredia followed by treatments every other month. Eleven out of 17 patients with pain at the start of the study became pain free. In some patients bone scans stabilized and cancer blood markers decreased.1

Subsequently, a randomized prospective trial of Zometa was performed in men with metastatic prostate cancer.  Zometa delayed the onset of bone fractures and also showed a trend toward longer survival. These studies led the FDA to approval.2

Osteoporosis

Calcium loss from the bone is a silent phenomenon until a fracture occurs. Common fracture sites from osteoporosis are the spine, rib, wrist, and hip. Bone fractures result in higher mortality in men with prostate cancer.3 Compression fractures of the spine can be extremely painful, and lead to a loss in height. Advanced osteoporosis causes an ugly forward curvature of the spine commonly termed the “dowagers hump.”

A common misperception is that osteoporosis occurs mainly in females. But fully a third of all hip fractures are in men. There are many causes. Slender men have less bone reserve and are more predisposed. Thyroid or parathyroid hyperactivity, excessive alcohol, caffeine, or tobacco all contribute. Cortisone, used to treat asthma or arthritis, is another common culprit. Excess vitamin A has also been associated with osteoporosis and fractures.4 Lack of exercise, lack of sunlight (low vitamin D), and low calcium intake are additional potential causes.

Osteoporosis-induced bone fractures are even more frequent in men treated for prostate cancer with testosterone inactivating pharmaceuticals (TIP).5,6  Loss of testosterone and the estrogen (that is derived from testosterone) accelerates calcium loss from bone.7,8

Bone Density Scanning

Osteoporosis needs to be diagnosed before a fracture occurs. Unfortunately, the most common scanning technique, the DEXA scan, grossly underestimates calcium loss from the spine in men.9 This is because degenerative arthritis with calcium deposition in the ligaments surrounding the spine is mistakenly read as bone.

Fortunately, another more accurate technique called quantitative CAT scan or QCT is available. This scan measures the calcium density in the center of the vertebral column, avoiding the problem of surrounding calcium in the ligaments. A lack of awareness of the limitations of DEXA scans among health care providers is common, even though these limitations have been well documented in a study from Massachusetts General Hospital.10 This study compared DEXA and QCT in 41 men with prostate cancer. The average age of the participants was 68. QCT detected osteoporosis in 26 men (63%) but DEXA only found osteoporosis in two (5%) showing that osteoporosis is widespread in this age group.

Other Measures to Combat Osteoporosis

Supplementation with calcium and vitamin D should be routine.  We recommend 500 mg of calcium with dinner and 500 mg at bedtime. Vitamin D should be started at 2000 iu daily.  After three months vitamin D levels in the blood should be measured.  If the level is less than 40 the dose should be increased to 5000 iu daily.

Older studies have raised concerns that excess calcium increases the incidence of prostate cancer. More recent reports have not borne this out11 perhaps because vitamin D levels are being better maintained. Excess calcium depletes vitamin D and vitamin D inhibits prostate cancer growth. 12 The safest approach to calcium supplementation is to maintain adequate vitamin D intake (confirmed by monitoring blood levels) and keeping the daily calcium dose under 1200 mg.

If possible, medicines that cause osteoporosis should be stopped. But sometimes, for medical reasons, osteoporosis-inducing treatments like cortisone or TIP cannot safely be stopped. Studies do show that using TIP intermittently (compared to continuous TIP) prevents excess bone loss.13 Despite the negative impact of TIP and cortisone on bone density, it appears that bisphosphonates are able to counteract these negative effects.14,15,16  In addition to using bisphosphonates, men should do strength-training exercise, eliminate tobacco and reduce the use of excess alcohol and caffeine.

Method of Administration

Oral bisphosphonates need to be administered on an empty stomach or the medicine won’t be absorbed into the bloodstream. The most common side effect of the oral agents is heartburn. To minimize esophageal irritation incurred by drug reflux, the manufacturer recommends staying erect for an hour after taking the drug.

In general, the different brands appear to have comparable efficacy and side effects. One study suggests that the incidence of stomach irritation may be slightly less with Actonel.17 Another study suggests that Fosamax may be slightly more effective. Most studies of oral bisphosphonates are in women. One large study shows that Fosamax is effective in men.18

The advantage of the intravenous agents of Zometa or Aredia is that they bypass the stomach, avoiding concerns about stomach irritation. Also, 100% of the drug is guaranteed to get into the bloodstream. Their most common side effect is muscle soreness lasting a day or so. The soreness does not usually recur on subsequent infusions. The risk of muscle soreness can be reduced by giving intravenous Decadron®, a type of cortisone, just prior to the infusion.

For osteoporosis, Zometa or Aredia is given every three months. For the treatment of cancer in the bones, the recommended frequency of infusions is monthly. This recommendation is being modified in many centers because osteonecrosis of the jaw is seen in greater frequency in patients when monthly therapy is continued for prolonged periods. As a result, centers vary in their protocols. A common schedule is monthly treatment for 6-12 months followed by infusions every 3 months.

Osteonecrosis

Osteonecrosis of the jaw is a bone spur breaking through the skin of the gums leaving exposed bone.  When the bone gets infected, it can be quite painful. Antibiotics give relief but pain returns when they are stopped. When osteonecrosis was first reported, the connection with bisphosphonates was not immediately recognized. In many patients the treatment was unknowingly continued. This led to the discouraging conclusion that the osteonecrosis was irreversible and untreatable. We now know that osteonecrosis resolves after the bisphosphonates are stopped.

Osteonecrosis is usually triggered by an ill-advised tooth extraction. Men on bisphosphonates should never have a tooth pulled without first discussing the situation with their doctor.  Other forms of dental work such as cleaning, fillings and root canals are not a concern.  The proper period of time to remain off bisphosphonates prior to a tooth extraction is unknown.  Some experts say 6 months. Others recommend a year. If extraction cannot be delayed, slow extraction using orthodontic techniques can be considered. Spontaneous osteonecrosis (without a prior tooth extraction) occurs less commonly though occasionally it is seen in cancer patients on monthly therapy for several years.  A thorough dental exam is recommended before initiating bisphosphonate therapy.

Clinical Studies Using Bisphosphonates to Treat Osteoporosis

A three-year study of 994 postmenopausal women from 16 countries found that Fosamax increased bone density of the spine by 8.8 percent; the hip by 5.9 percent; and the thigh by 7.8 percent compared to estrogen. The risk of fractures was decreased by 48 percent.

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.19 In this study, the men did not receive any testosterone inactivating pharmaceuticals. It is well known that TIP can deplete up to 10% of bone mass in the first 12 months of treatment. Therefore at Prostate Oncology Specialists, Fosamax and Actonel were evaluated to determine if they would be protective. The degree of bone loss was reduced but not completely eliminated.20

Both Aredia and Zometa have been studied to determine if they can prevent bone loss in men treated with TIP.21 In the case of Aredia, Smith et al evaluated 47 men who were randomized to either Lupron plus Aredia 60 mg every 3 months vs. Lupron alone. QCT bone density was obtained at the start of therapy and repeated after one year of treatment. There was no loss of bone in the men treated with Aredia whereas in the men treated with Lupron alone, 8.5% lost bone.

Smith et al performed another trial in 106 men comparing TIP alone vs. TIP plus Zometa every 3 months. After one year spine bone density increased by 5.5% in men who received Zometa. Bone density decreased by 2.2% in the men receiving TIP alone.

So it appears that oral and intravenous bisphosphonates prevent bone loss during TIP though the intravenous forms may be somewhat more effective than the oral agents. Since accelerated bone loss can be anticipated with TIP we recommend that all men be administered bisphosphonates as a preventive measure.

Osteoporosis Unresponsive to Bisphosphonates

Two articles published in the New England Journal of Medicine demonstrate that a medicine called Forteo®, a synthetic parathyroid hormone, builds bone.22,23 Forteo represents an effective alternative to bisphosphonates. However, Forteo may not be appropriate for prostate cancer patients because it may stimulate cancer growth.24,25  Cancer patients should avoid Forteo until more information is available about its safety.

Pills verses intravenous infusions?

When gastric side effects from Fosamax, Boniva or Actonel occur, Aredia or Zometa represent a good alternative. Another reason to consider the intravenous approach is cost. Some insurance companies don’t cover pills. Lastly, the more potent intravenous bisphosphonates are clearly the treatment of choice for preventing cancer growth in the bones, for treating men with more severe degrees of osteoporosis or treating osteoporosis that is not responding to oral therapy.

Conclusion

Bisphosphonates are both well-tolerated and effective. While rare side effects like osteonecrosis and stomach problems do occur, bisphosphonates effectively counteract osteoporosis. Most importantly, studies show that bisphosphonates inhibit cancer growth in the bones, the most common site of spread for prostate cancer.

References

1. Osteoclast inhibition by Pamidronate in metastatic prostate cancer: a preliminary study. British Journal of Cancer Volume 63:420, 1991.

2 Saad F. Clinical benefit of zoledronic acid for the prevention of skeletal complications in advanced prostate cancer. Clin Prostate Cancer. 2005 Jun;4(1):31-7.

3 Skeletal fractures negatively correlate with overall survival in men with prostate cancer. Journal of Urology 168:1005, 2002.

4 Excess dietary intake of vitamin A is associated with reduced bone mineral density and increased risk of hip fracture. Ann Intern Med Vol. 129:770, 1998.

5 Osteoporosis after orchiectomy for prostate cancer. Journal of Urology 157:439, 1997.

6 Osteoporosis in men treated with androgen deprivation therapy for prostate cancer.  Journal of Urology 167:1952, 2002.

7 Association of hypogonadism and estradiol levels with bone mineral density in elderly men from the Framingham study. Annals of Internal Medicine 133: 951, 2000.

8 Diethylstilbesterol revisited: androgen deprivation, osteoporosis and prostate cancer. Journal of Urology 167:535, 2002.

9-10 Low bone mineral density in hormone-naïve men with prostate cancer. Cancer 91:2238, 2001.

11 Calcium intake and prostate cancer risk in a long-term aging study: The Baltimore longitudinal study of aging. Urology 60:1118, 2002.

12 Treatment of early recurrent prostate cancer with 1,25-dihydroxyvitamin D3 (Calcitriol). Journal of Urology 159:2035, 1998.

13 Prospective evaluation of bone mineral density in prostate cancer patients without bone metastases treated with intermittent androgen suppression therapy. Oncology 17:32, 2003.

14 In corticosteroid-treated respiratory diseases, monofluorophosphated increases lumbar bone density: a double-masked randomized study. Osteoporosis Int. Vol. 6: 171, 1996.

15 The antiosteoporotic efficacy of intravenous pamidronate in men with prostate carcinoma receiving combined androgen blockade. Cancer 92:1444, 2001.

16 Zoledronic acid increases bone mineral density in men undergoing androgen deprivation therapy for prostate cancer. Oncology 17:33, 2003.

17 Endoscopic comparison of esophageal and gastroduodenal effects of risedronated and alendronated in postmenopausal women. Gastroenterology 119:631, 2000.

18-19 Alendronate for the treatment of osteoporosis in men. New England Journal of Medicine 343:604, 2000.

20 Oral bisphosphonates for the prevention of androgen deprivation therapy associated bone loss ASCO Abstract #4749, 2004.

21 Pamidronate to prevent bone loss during androgen deprivation therapy for prostate cancer. New England Journal of Medicine 345:13, 2001.

22-23 The effect of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. New England Journal of Medicine 349:1207, 2003.

24 Prostate cancer – production of bioactive factors. Cancer 88:3002, 2000.

25 The Physiology of parathyroid hormone-related protein. New England Journal of Medicine 342:177, 2000.