Bisphosphonates are a class of drugs that inhibits the resorption of bone. Bisphosphonates are used for the prevention and treatment of osteoporosis, osteitis deformans ("Paget's disease of bone"), bone metastasis, multiple myeloma and other conditions that involve bone fragility. In the last 10 years, millions of patients have taken bisphosphonate for the prevention of osteoporosis. Bisphosphonates once seemed safe and thought to be helpful for patients with cancer or osteoporosis. But, at what risk? There seems to be concerns that bisphophonates cause osteonecrosis and heart rhythm problems.

The oral bisphosphonates, Fosamax, Actonel, Boniva, Skelid and Didronel, are largely used to treat and prevent the brittle bone disease osteoporosis. Other more powerful drugs in the same class, Zometa, Aredia and Bonefos, are given intravenously and are used to treat bone pain and other cancer-related bone problems.
 

Bisphosphonate Side Effects - Bisphosphonates and Osteonecrosis
The potential side effects of bisphosphonates began in 2003 with a letter in The Journal of Oral Maxillofacial Surgery calling osteonecrosis of the jaw "a growing epidemic." Its author, Dr. Robert E. Marx, chief of oral and maxillofacial surgery at the University of Miami, reported on 36 patients who had received intravenous bisphosphonates. All had "painful bone exposure," as is typical with the condition, and "were unresponsive to surgical or medical treatments."
     Many women have been taking a bisphosphonate drug thin that these drugs are safe. However, there may be a risk for osteonecrosis of the jaw. Osteonecrosis of the jaw is an uncommon complication, but it is estimated that among the 500,000 American cancer patients who take the drugs because their disease is affecting their bones, 1 to 10 percent may develop the problem. Some dentists are refusing to treat patients taking the drugs, fearful that the dental work will induce a case of osteonecrosis, and lawyers are lining up to sue the drugs' makers, saying they failed to give patients adequate warning.
     Even if patients stop taking the bisphosphonate drugs, they are not free of them. Bisphosphonates remain in bone for years, and no one knows how long the osteonecrosis risk remains. Some doctors and dentists suggest stopping the drugs for a few months before and after an invasive dental procedure. Others say six months to a year may be better.

     The reason for the association between the bisphosphonate drugs and osteonecrosis is not entirely known, but researchers speculate it may be due to the action of the drugs, which decrease the breakdown of bone, thereby making bones denser in the short term. However, since healthy bone constantly goes through a process of breakdown and formation (i.e. bone remodeling), reducing the breakdown of bone also inhibits the formation of new bone, such as that needed in the jaw after dental extractions or other trauma.

Bisphosphonate Side Effects - heart problems
Two research reports suggest a possible link between two bone-building drugs and irregular heart rhythms. The signs of a heart problem were more pronounced with Reclast, a drug made by Novartis AG and given as a once-a-year, 15-minute intravenous infusion. But there was a hint of similar trouble in a few women who took the leading osteoporosis pill, Fosamax by Merck & Co. Atrial fibrillation, an irregular heart rhythm that can cause strokes is a major concern for those using bisphosphonates.
   Fosamax, the Merck brand name for alendronate, is now used by an estimated 1.8 million American women. In a letter to the medical journal, Cummings reported evidence of the heart problem found in a recent review of a 1997 Merck-sponsored study of postmenopausal women on Fosamax. There appeared to be 50 percent more risk of the serious heart rhythm in women who took the daily pill than among those who didn't take it. About half of the 6,459 women took Fosamax, and 47 developed atrial fibrillation, compared with just 31 cases among the other women.
   This study of 7,736 postmenopausal women with bone-thinning osteoporosis focuses on Reclast. Novartis recently won approval to sell Reclast, known generically as zoledronic acid, for Paget's disease, another bone condition. The company hopes to get an OK later this year to sell it for osteoporosis use. The new study, funded by Novartis, shows that Reclast works at least as well as existing drugs in the same class, researchers say. However, the risk of a serious case of irregular heart rhythm was more than double that in the other patients -- 50 cases in the drug-taking half, compared to 20 cases in the others.

Bisphosphonate and Cancer
Cancer patients, mostly those with multiple myeloma and breast cancer whose disease has spread to their bones, generally take one of two bisphosphonates, Zometa or the older Aredia, intravenously.

Bisphosphonate and Osteoporosis
Osteoporosis patients usually take bisphosphonates as pills, in much lower doses that patients with cancer. Those bisphosphonate drugs — Fosamax, Actonel and Boniva — reduce the risk of fractures of the spine or hip, injuries that can create a steady downward spiral in patients' condition.

Bisphosphonates use after breast cancer
Bisphosphonates inhibit the growth of breast cancer bone metastases in a mouse model. Previous research has shown that bisphosphonates can reduce skeletal tumor burden and inhibit the formation of bone metastases in animal models. They also inhibit the proliferation of various human tumor cell lines in vitro. Dr. Philippe Clezardin from Faculte de Medecine Laennec, Lyon, France and his associates investigated the effects of zoledronic acid and clodronate on osteolysis and skeletal tumor growth in a mouse model of bone metastases of human breast cancer. Treatment with bisphosphonates, beginning 18 days after tumor cell injection, reduced the size of osteolytic lesions, while preventing bone loss and decreasing skeletal tumor burden. Pretreatment with bisphosphonates was effective in reducing osteolytic lesions and improving bone mineral density only when daily or weekly regimens were used (as opposed to a single dose). Similarly, daily or weekly bisphosphonate treatment, but not single-dose treatment, reduced the homing of tumor cells to bone marrow. "Our results show that clinically relevant doses of bisphosphonates produced meaningful antitumor effects in an animal model of breast cancer bone metastasis, as long as the bisphosphonate was administered at a low dosage on a daily or weekly dosing schedule," said Dr. Philippe Clezardin. The findings "also suggest that, in the clinical setting, bisphosphonate therapy with a long dosing interval could reduce osteolysis by inhibiting bone resorption, whereas therapy with a more frequent dosing interval could also directly affect the growth of tumor cells resident in bone." J Natl Cancer Inst 2007;99:322-330.
   Comments: Sometimes positive results are obtained with drugs in animal models or short term human studies, however, there is no evidence that the use of bisphosphonates decreases overall mortality.