Category: Bisphosphonates

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Clinical data links oral bisphosphonates to increased jaw necrosis, according to research at the University Of Southern California School Of Dentistry. A study published today in January 1 Journal of the American Dental Association (JADA) is among the first to acknowledge that even short-term use of common oral osteoporosis drugs such as Fosamax may leave the jaw vulnerable to devastating necrosis.

Osteoporosis, or loss of bone density, currently affects 10 million Americans. And TV commercials like the one for Boniva featuring Sally Field ("I've got this one body") tend to popularize and even glamorize anti-osteoporosis drugs.

Fosomax is the most widely prescribed oral bisphosphonate, ranking as the 21st most prescribed drug on the market since 2006, according to a 2007 report released by IMS Health.

Post-menopausal women and cancer patients including prostate and breast cancer patients are among those most likely to take bisphosphates by prescription. Cancer patients, especially those who are hormonally suppressed or taking chemotherapy, are at serious risk of developing osteoporosis.

Today, cancer patients are more likely to take a potent, intravenous form of bisphosphonate, called Zometa, rather than an oral form such as Fosomax, Actonel, or Boniva, Some cancer patients have been quite widely informed for about the past 5 years that bisphosphonates do present a risk of osteonecrosis of the jaw.

But there has been some confusion and uncertainty over whether this risk applies as much with the oral forms like Fosamax as with the intravenous drugs such as Zometa.

First large study of oral bisphosphonates and jaw damage

"Oral Bisphosphonate Use and the Prevalence of Osteonecrosis of the Jaw: An Institutional Inquiry" is the first large  study in the U.S. to investigate the relationship between oral bisphosphonates and jaw bone death, said principal investigator Parish Sedghizadeh, assistant professor of clinical dentistry with the USC School of Dentistry.

After controlling for referral bias, 9 of 208 healthy School of Dentistry patients who take or have taken Fosamax for any length of time were diagnosed with osteonecrosis of the jaw (ONJ).

The study’s results contrast with drug makers' prior assertions that bisphosphonate-related ONJ risk is only noticeable with intravenous use of the drugs, not oral usage, Sedghizadeh said. "We’ve been told that the risk with oral bisphosphonates is negligible, but four percent is not negligible," he said.

Till now, most doctors prescribing bisphosphonates have not told patients about any oral health risks associated with the use of the drugs. But even short-term usage poses a risk due to the drug’s tenacious 10-year half life in bone tissue.

Lydia Macwilliams of Los Angeles said no one told her about the risk posed by her three years on Fosamax until she became a patient of Sedghizadeh at the School of Dentistry.

"I was surprised," she said. "My doctor who prescribed the Fosamax didn’t tell me about any possible problems with my teeth." Macwilliams was especially at risk for complications because she was to have three teeth extracted due to infection. This type of dental infection is a biofilm bacterial process, meaning that the bacteria infecting the mouth and jaw tissues reside within a slimy matrix that protects the bacteria from many conventional antibiotic treatments, and bisphosphonate use may make the infection more aggressive in adhering to the jaw, Sedghizadeh said.

The danger is especially pronounced with procedures that directly expose the jaw bone, such as tooth extractions and other oral surgery. After her extractions, two of the three extraction sites had difficulty healing, Macwilliams said. Luckily, with treatment as well as the rigorous oral hygiene regimen USC dentists developed especially for patients with a history of bisphosphonate usage, the remaining sites slowly but fully healed. "It took about a year to heal," she said, “but it’s doing just fine now.”

Sedghizadeh hopes to have other researchers confirm his findings and thus encourage more doctors and dentists to talk with patients about the oral health risks associated with the widely used drugs. The results confirm the suspicions of many in the oral health field, he said. "Here at the School of Dentistry we’re getting two or three new patients a week that have bisphosphonate-related ONJ," he said, "and I know we’re not the only ones seeing it."

SOURCES AND LINKS

Bisphosphonate Side Effects and a New Clinical Trial Jan 1, 2009

Doctors link bisphosphonates drugs, used against osteoporosis and cancer, to jawbone necrosis May 2004

Concern over osteoporosis drug Australian Broadcasting Corporation Broadcast: 11/12/2007

OSTEONECROSIS OF THE JAW (ONJ) 2006 (MS Word document) by Laurence C. Reichel, D.D.S.

Silent risk of osteoporosis in men with prostate cancer  PSA Rising 2004

Parish Sedghiuzadeh's professional page.

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NEW HYDE PARK, NY -- May 30, 2004. Doctors at Long Island Jewish (LIJ) Medical Center recently discovered a link between a common chemotherapy drug and a serious bone disease called osteonecrosis of the jaw (ONJ).

The discovery, published in the Journal of Oral and Maxillofacial Surgeons, prompted both the US Food and Drug Administration (FDA) and Novartis, the manufacturer of bisphosphonates used in cancer chemotherapy, to issue warnings earlier this fall to physicians and dentists about the risk for this potential adverse effect.

ONJ is a condition in which the bone tissue in the jaw fails to heal after minor trauma such as a tooth extraction, causing the bone to be exposed. The exposure can eventually lead to infection and fracture and may require long-term antibiotic therapy or surgery to remove the dying bone tissue.

The chief of the Division of Oral and Maxillofacial Surgery at LIJ, Salvatore Ruggiero, DMD, MD, and his staff reported that they were struck by a cluster of cancer patients with necrotic lesions in the jaw -- a condition they rarely saw, in only about one to two patients a year. When they launched a study of patients' charts, they found that 63 patients diagnosed with this condition over a three-year period shared only one common clinical feature: they had all received long-term bisphosphonate therapy.

In post-menopausal women, bisphosphonates to prevent osteoporosis are commonly used in the form of pills (tablets). Stronger forms are used for patients with advanced cancers that have metastasized to the bone. Cancer often causes bone pain and possibly even fractures. Several cancers can involve or metastasize to the bone, including lung, breast, prostate, multiple myeloma. In cancer chemotherapy, the drugs are given intravenously, for months or years.

In their study, Dr. Ruggiero teamed up with Bhoomi Mehrotra, MD, in the Division of Hematology-Oncology at LIJ, and dental specialists at the University of Maryland Medical Center. Of the 63 patients diagnosed with ONJ between February 2001 and November 2003 at their centers, 56 were cancer patients who had received infusions of bisphosphonates for at least a year and 7 were non-cancer patients who had been receiving long-term oral therapy for osteoporosis.

The patients developed ONJ after normal bone trauma, such as a tooth extraction, while receiving bisphosphonate therapy. Rather than healing, the bone began to die, and the majority of patients required surgery to remove the diseased bone.

In the FDA MedWatch and Novartis alerts issued in late September, oncologists and dentists were advised that osteonecrosis of the jaw thad been added to "Precautions" and "Adverse Reactions" sections on the labeling of injectable bisphosphonates.  Referring to spontaneous reports of the condition as found mostly in cancer patients, the alerts recommend a dental examination with appropriate preventive dentistry in patients with risk factors such as cancer, chemotherapy, corticosteroids and poor oral hygiene prior to initiating treatment with the bisphosphonates.

"Monitoring the dental health of patients on bisphosphonates is key because an early diagnosis may reduce the complications resulting from advanced destruction of the jaw bone," said Dr. Ruggiero. "Since our paper was published and dentists became aware of the connection, many more patients with the condition have been identified, even in our own center. Prevention and early detection are so important to preserving the jaw bone in these individuals." Individuals should attempt to avoid tooth extractions and other major dental work while on the drugs.

Bisphosphonates block the work of bone cells called osteoclasts, one of two important types of bone cells that are involved in the continuous process of bone remodeling in a delicate balancing act. During this process, osteoblasts -- "the good guys"-- put calcium in the matrix of the bone and make bone stronger, and osteoclasts -- "the bad guys" -- take calcium away, diminishing the internal strength of the bone. Bone remodeling is like a necessary game of tug-of-war between the goods guys and the bad. Bone mass and mineral content constantly adjust throughout the life cycle to support the places on the skeleton where the most outside force occurs.

Novartis's Aredia® (pamidronate disodium) and Zometa® (zoledronic acid) injections are the two intravenous bisphophosphonates used in chemotherapy regimens. Novartis changed their labeling in August. Merck's Fosamax® (alendronate) and Procter and Gamble Pharmaceuticals's Actonel® (risedronate sodium) are the most commonly used oral bisphosphonates, which are only indicated for osteoporosis. Labeling for the oral forms has not been changed.

More on this topic:

Bisphosphonate-Related Osteonecrosis of the Jaw: Diagnosis, Prevention, and Treatment. Ruggiero SL, Mehrotra B. Annu Rev Med. 2008 Oct 17. [Epub ahead of print, Expected final online publication date for the Annual Review of Medicine Volume 60, January 07, 2009.]

Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL.
Division of Oral and Maxillofacial Surgery, Long Island Jewish Medical Center, New Hyde Park, NY. J Oral Maxillofac Surg. 2004 May;62(5):527-34.

Ten Years' Experience with Alendronate for Osteoporosis in Postmenopausal Women. Henry G. Bone, M.D. et al. New England Journal of Medicine March 18 2004