Bisphosphonates side effects, osteonecrosis, safety, danger, caution, drug information and dosages
June 3 2018 by
Ray Sahelian, M.D.

Bisphosphonates are a class of drug aimed at preventing bone fractures and offsetting bone loss associated with menopause. They include Fosamax, Roche Holding AG's Boniva, Novartis AG's Reclast and Procter and Gamble Co's Actonel.


Bisphosphonates are a class of drugs that inhibits the resorption of bone. They 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. These prescription medications once seemed safe and thought to be helpful for patients with cancer or osteoporosis. But at what risk? There is a concerns that bisphophonates cause osteonecrosis and heart rhythm problems.


Bone resorption is the process by which osteoclasts break down bone and release the minerals, resulting in a transfer of calcium from bone fluid to the blood.


Use for osteoporosis, benefits vs risks
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. The long-term risks and benefits of taking bisphosphonates, a class of drugs widely used for osteoporosis, require more research. These have been used in the United States since 1995 but it is still not proven that their benefits outweigh the risks.

Bisphosphonate side effects - Osteonecrosis, increased risk of esophageal cancer
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 these 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 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.
   Bisphosphonates seem associated with an increased risk of DVT and pulmonary embolism.
   Long-term bisphosphonate use reduces the structural integrity of the femoral shaft. This explains the atypical femur fractures that occur in long-term users, usually after 4 or more years of taking the medications. These breaks resemble the fractures seen with malignancy or metabolic bone disease. Study findings presented March 2010 at the annual meeting of the American Academy of Orthopedic Surgeons in New Orleans.
   Increased risk for esophageal cancer. Journal of the American Medical Association, August 2010.


It has been known for a while that injections of a class of anti-osteoporosis drugs might trigger jaw bone decay after certain dental procedures, and now it seems that pill forms of the so-called bisphosphonate medications could have the same side effect. A study conducted at the University of Southern California School of Dentistry in Los Angeles found that oral treatment with alendronate (more familiar as Fosamax) for as little as a year increases the risk for the jaw bone disease after a tooth extraction or other dental problem. Dr. Parish P. Sedghizadeh's team found that, of 208 patients who had taken alendronate pills, nine (4 percent) had active jaw bone decay, or osetonecrosis. All the affected patients were women, ranging in age from 63 to 80, who had taken 70 milligrams of alendronate once per week for 12 to 120 months. Four cases developed following tooth extractions and five were associated with denture-related ulcers. By contrast, the problem was not seen among some 13,500 dental patients who had not taken alendronate. Journal of the American Dental Association, 2009.


Calcif Tissue Int. 2012. Vitamin D reduces musculoskeletal pain after infusion of zoledronic acid for postmenopausal osteoporosis. Vitamin D reduces the intensity of musculoskeletal pain after infusion of zoledronic acid for postmenopausal osteoporosis.


Q. I read your article on the use of bisphosphonate drugs for patients with cancer and osteoporosis. My understanding after reading the article is that the drug is used in large dosages for cancer patients and can cause harmful side effects. There was one brief paragraph dedicated to the use of the drug for osteoporosis. Dr. Sahelian sounded positive for the use of this drug to prevent spinal and hip injuries. Did I understand him correctly, is that right? At the lower dosages prescribed for osteoporosis patients is it safe to take this drug? The drug has been prescribed to a patient who was recently diagnosed with osteoporosis induced by prolonged prednisone use. Thank you for any information you can provide.
   A. I am not yet convinced these drugs are safe or of benefit.


Eye and vision, uveitis
Digit J Ophthalmol. 2017. Diffuse ocular and orbital inflammation after zoledronate infusion-case report and review of the literature. We report the case of a 68-year-old woman who developed severe, unilateral, ocular inflammation, including corneal endotheliitis, anterior uveitis with hyphema, scleritis, and orbital inflammation beginning 12 hours after receiving her first zoledronate infusion. Symptoms escalated but ultimately resolved with topical steroids and high-dose systemic corticosteroids. To our knowledge, this is the first report of unilateral diffuse inflammation of the eye and orbit, including corneal inflammation developing within 12 hours of a first zoledronate infusion.


Femoral shaft fracture
There is evidence that long-term use of these widely prescribed bone loss drugs may increase the risk for uncommon but serious femur (thigh bone) fractures. In an analysis involving more than 200,000 postmenopausal women, those who took oral bisphosphonates for more than five years were more than twice as likely to experience the fractures as women who took the drugs only briefly.


2009 - Bone fracture - keywords: alendronate osteoporosis risedronic acid tamoxifen
Unusual mid-shaft fractures during long term bisphosphonate therapy;
Clinical Endocrinology, 2009.
Bisphosphonates are the most commonly prescribed medications for the treatment of osteoporosis. Although existing evidence supports a good safety profile, there is concern that chronic administration of these agents could result in severe suppression of bone turnover with increased risk of non-vertebral fractures. We report the clinical presentation, selected bone histomorphometry and x-ray images of patients who developed mid-shaft long bone fractures during bisphosphonate therapy, six of whom had bone biopsy for histomorphometery. Of the 13 patients who sustained atraumatic mid-shaft fractures, 10 were on alendronate and 3 were on risedronate therapy before the fractures. In addition to bisphosphonates, 3 patients were on estrogen and 2 on tamoxifen concomitantly. Four patients with glucocorticoid-induced osteoporosis were on alendronate for 3-11 years along with glucocorticoid therapy. Bone histomorphometry showed severe suppression of bone turnover in 5 patients and low bone turnover in 1 patient. Long-term bisphosphonate therapy may increase the risk of unusual long bone mid-shaft fractures. This is likely due to prolonged suppression of bone turnover, which could lead to accumulation of microdamage and development of hypermineralized bone. At present, the scope of this complication in the larger context of patients receiving bisphosphonate therapy is not known, but appears to be small.


Stroke risk
Cancer patients treated with these osteoporosis-fighting drugs are at increased risk of abnormal heart rhythms and stroke. Journal of Clinical Oncology, published online October 12, 2010.


Bisphosphonate 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.

Use after breast cancer
Bisphosphonates inhibit the growth of breast cancer bone metastases in a mouse model. Previous research has shown that they 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.
   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.


Bisphosphonate and Osteoporosis
Patients with low bone density usually take these 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. However, whether the long term use of these drugs outweigh the benefits is not clear at this time.


Long term use
Journal of Clinical Endocrinology & Metabolism 2010 - alendronate Osteoporosis risedronic acid zoledronic acid
Because bisphosphonates accumulate in bone and are released for months or years after treatment is stopped, it is reasonable to consider the clinical question of how long to treat. In this personal perspective, we review the pharmacology and mechanism of action of bisphosphonates and the clinical studies that support their efficacy. We then review the literature for longer-term studies and reports of possible side effects that were not seen in clinical trials. Bisphosphonates have demonstrated antifracture efficacy in randomized, placebo-controlled trials of 3 and 4 yr duration and have been widely used since the initial release of alendronate in 1995. For zoledronic acid and risedronate, an early effect (fractures reduced within 6-12 months of starting therapy) has been shown. A sustained effect for risedronate has been shown through 5 yr and suggested through 7 yr. Ten-year data with alendronate and 8 yr data with risedronate indicated good tolerability and safety; it is unlikely that longer-term studies will be done. Side effects that emerged in clinical trials include esophageal irritation with oral administration and acute phase response with iv treatment or high-dose oral therapy. Uncommon side effects that have been noted with wide clinical use include osteonecrosis of the jaw, musculoskeletal complaints, and atypical fractures. Because bisphosphonates accumulate in bone, they create a reservoir leading to continued release from bone for months or years after treatment is stopped. Studies with risedronate and alendronate suggest that if treatment is stopped after 3-5 yr, there is persisting antifracture efficacy, at least for 1-2 yr. Because they accumulate in bone and provide some residual antifracture reduction when treatment is stopped, we recommend a drug holiday after 5-10 yr of bisphosphonate treatment. The duration of treatment and length of the holiday are based on fracture risk and pharmacokinetics of the bisphosphonate used. Patients at mild risk might stop treatment after 5 yr and remain off as long as bone mineral density is stable and no fractures occur. Higher risk patients should be treated for 10 yr, have a holiday of no more than a year or two, and perhaps be on a nonbisphosphonate treatment during that time.