The Science of Bisphosphonate-Related Osteonecrosis of the Jaws: The Thin White Line

In James Jones’ classic novel of World War II, The Thin Red Line, a clearly insufficient primary force of US marines were sent to Guadalcanal to stem the Japanese surge across the Pacific. They stood waist deep in swamps for weeks, dying one by one, to hold their ground until reinforcements arrived. The title of the book in fact refers to another event in the Crimean War where a thin line of Highlander redcoat infantry, including wounded soldiers awaiting evacuation, repelled an overwhelming force of Russian cavalry. The British force was so terribly undermanned that they had to stand just 2 deep against the cavalry, creating a thin red line of uniforms and bloody steel bayonets glinting on the horizon. Their situation became so desperate that at one point their commander cried out, “There is no retreat from here men. You must die where you stand.” “Aye sir,” they replied, “We will, if we must.”1

Since that time, “the thin red line” has been a metaphor for the qualities necessary to succeed when the need is great, the task is enormous, the resources are meager, and the odds of success are long. So it is with medical research today, well illustrated by the initial research efforts to understand and treat bisphosphonate-related osteonecrosis of the jaws (BRONJ). A “Thin White Line” of clinical investigators is now addressing the critical issues in the understanding of this new disease.

These men in the Pacific and in Crimea had to exhibit courage, competence, a sense of duty, individual motivation, healthy skepticism, organization, innovation, planning, and persistence, in order to survive. They also needed to understand the complex goals of those who sent them to battle. In the era of eroding government interest in clinical research, and the business goals of private research funding, these same personal qualities are now necessary in biomedical researchers.

Erosion of the public trust by government and industry is a societal trend, the latest example of which is the intentional entry of an obvious poison into the food supply, melamine. Like the olive oil scandals of decades ago, producers intentionally spiked the food supply with toxic substances in order to appear to have higher protein content and thus increase profits. Unlike previous events, it took several months after melamine was found in pet food before government and the press considered the possibility that this substance had entered the human food chain. It has since been found in chicken and pork.

The age of urgency in government/society attention over important threats to human health has long since passed. (As this editorial is written, 6 months after the initial reports of this food poisoning, a second toxin, easily identified, has been found to have been intentionally put in grain for years. No one checked for it until today.) One of the most remarkable aspects of this debacle is the matter of fact way it has been handled by the public, press, and government. It is a message that reflects on our times and the battles to eradicate diseases that we face.

One can only look with pride to past efforts to eradicate polio, yellow fever, and to provide clean, fluoridated water. Now we are facing a resurgence of tuberculosis, measles, food-borne illnesses, and other infectious diseases. Legislatures are again backsliding on our most successful public health measure to battle the dental caries infection, fluoridation. Today we seem to be in an era where, at least for now, there is but a Thin White Line to stem the tide.

BRONJ 

The discovery of BRONJ should have also engendered a sense of public urgency. Twenty-four million prescriptions were written in 2006 alone for bisphosphonates. With the discovery reports by Ruggiero, Marx, and Pogrel, among others, of BRONJ, a new and serious side effect to the use of these important and essential drugs, the scientific questions needing to be answered were obvious. These are the unremitting questions in this battle for which we must have answers. Only biomedical research can provide these.

What exactly is BRONJ? Is the spectrum of disease completely described by the AAOMS position paper of March 20072 including exposed bone and the history of bisphosphonates use, or will future investigations find that signs and symptoms such as the following represent prodromal findings in BRONJ, in the spectrum of bisphosphonates disease of the jaws?

Symptoms

•Bone pain

•Paresthesia especially mental nerve

•Neuropathic pain

•Localized loosening of teeth

•Odontalgia

•Postextraction persistent dry socket

Signs

•Alveolar bone loss

•Bone resorption

•Changes in trabecular pattern

•Dense woven alveolar bone

•Thickening/obscuring of periodontal ligament

•Inferior alveolar canal narrowing

What is the pathogenesis of BRONJ?

How can BRONJ be prevented?

Is there a therapeutic dose of bisphosphonates that will create the desired systemic outcome without resulting in BRONJ?

What is the incidence of BRONJ?

What is the spectrum of BRONJ?

What is the natural clinical course of BRONJ?

What therapies for BRONJ will be proven to be beneficial?

The Thin White Line 

Fortunately, like James Jones’ US marines, there are a motivated few with the sense of urgency and commitment to human health to organize and conduct clinical studies with meager resources to answer some of these essential questions. This month, the Thin White Line is represented in JOMS by Drs Freiberger, Padilla-Burgos, Chhoeu, Boneta, Kraft, Moon, Piantadosi,3 Wang, Kaban, Strewler, Raje, and Troulis.4 As with the initial scientific papers in 2004 of this new disease, JOMS remains the leader in publishing essential medical research on BRONJ.

In the Freiberger et al3 article, conventional wisdom regarding the utility of hyperbaric oxygen therapy (HBO) for BRONJ is powerfully challenged. The size and number of lesions were improved in the majority of patients after HBO treatment. Freiberger et al were also able to assess relapse of symptoms over time via the Kaplan-Meier method to increase our understanding of the course of this disease.

Patients and oncologists initiating bisphosphonate therapy for patients with metastatic disease need to understand the risks as well as benefits of therapy. Wang et al4 examined a cohort of 1,086 patients receiving IV bisphosphonates for breast cancer, prostate cancer, and multiple myeloma. They found an incidence of BRONJ to be at least 3% to 4% for the respective groups.

These studies in this month’s JOMS represent important new scientific communications providing essential knowledge in our understanding of BRONJ. These authors, on the Thin White Line, are to be congratulated for the qualities they exhibit in their work, especially for their courage, competence, sense of duty, individual motivation, healthy skepticism, organization, innovation, planning, and persistence.