Dr. Richard L. Wynn is Professor of Pharmacology at the University of Maryland Dental School. He holds a BS degree in pharmacy and a PhD degree in pharmacology. More »He chaired the Department of Pharmacology at the University of Maryland Dental School from 1980 to 1995. He is the lead author of the Drug Information Handbook for Dentistry, co-author of many other dental drug publications, author of over 300 refereed scientific journal articles, consultant to the Academy of General Dentistry, featured columnist, and a featured speaker presenting more than 500 courses in continuing dental education. One of his primary interests continues to be keeping dental professionals informed of all aspects of drug use in dental practice.
Recent data on the value of the CTX test as predictive of osteonecrosis of the jaw bone in patients exposed to bisphosphonates.
CTX is an acronym for C-terminal telopeptide. During bone resorption, the dominant type 1 collagen is degraded and, during this collagen breakdown, the telopeptide (CTX) is released. Thus, serum levels of CTX can be used as an indicator of bone breakdown/resorption. The CTX blood test, as a risk marker for osteonecrosis of the jaw bone (ONJ), first proposed by Marx in 2007, was used in an Australian study to determine its effectiveness in the prevention and management of ONJ in patients taking bisphosphonates. Essentially, this test was found to be able to identify those individuals in the "risk zone" for developing ONJ, which was defined as a blood level of 150 picograms/mL (pg/mL) to 200 picograms/mL (pg/mL). It was not found to be predictive of the development of ONJ in an individual patient. The Australian study found that, if medically appropriated, the bisphosphonate can be discontinued so that the CTX value increases to bring the patient out of the risk zone.
CTX blood levels can be used as an indicator of bone breakdown/resorption. In patients with increased bone turnover, the CTX levels are high. When bone turnover is decreased by a bisphosphonate, the CTX levels are low. It is claimed that these effects can be seen within weeks of beginning bisphosphonate therapy. The use of the CTX test as an indicator of the risk of ONJ was first suggested by Marx in his textbook on osteonecrosis of the jaw bone (Quintessence Publishing, 2007). He reported that serum values less than 100 pg/mL represent a high risk of ONJ; 100 to 150 pg/mL, moderate risk; greater than 150 pg/mL, minimal or no risk. For example, Marx et al reported mean CTX levels of of 73 pg/mL in a sample of 17 subjects with ONJ after exposure to oral bisphosphonates. They also reported an increase in CTX levels of about 26 pg/mL per month after discontinuation of the oral bisphosphonate, measured over a 6-month period.
The CTX test has yet to gain broad acceptance as a predictor of ONJ in oral bisphosphonate users. For example, in an American Dental Association (ADA) report, ("Updated Recommendations for Managing the Care of Patients Receiving Oral Bisphosphonate Therapy: An Advisory Statement from the American Dental Association Council on Scientific Affairs," J Am Dent Assoc, 139(12):1674-7), it was stated that "the use of serum levels of the collagen breakdown product C-terminal cross-linking telopeptide of type I collagen (CTX) has been advocated by Marx et al (J Oral Maxillofac Surg, 2007; 65(12):2397-410) as a risk predictor for development of BON [bisphosphonate-associated osteonecrosis ]". The ADA report further stated that other studies suggest that dental treatment decisions should be based on the results of serum CTX level tests. However, although a panel of experts from the ADA recognized the value in predicting and mitigating the risks of developing bisphosphonate associated ONJ in individual patients, "until objective research studies document and correlate the specificity, predictive value and reliability of such tests, the ADA can make no recommendations relative to the CTX marker test". Also, in an editorial in Journal of Oral and Maxillofacial Surgery (December, 2007 issue) by Dr. Leon Assael, there is the suggestion that more studies are needed to directly measure the association between bisphosphonate exposure and serum CTX values. And until these data are available, it is up to individual interpretation by the clinician as to how they might use the CTX measures in given situations in their practice.
If acceptance has been coming slowly, one of the reasons may be lack of data and clear evidence on the predictive value of the test. More data, necessary to support and confirm Marx's idea, would be of benefit. Recently, an Australian study by Kunchar et al provided new information on CTX levels in subjects exposed to bisphosphonates with ONJ and a control group of patients exposed to bisphosphonates without ONJ.
The protocol was established as a single-center study reflecting all the clinical case referrals during a 14-month period. It was not a carefully controlled scientific trial.
Patients were referred for extractions and for the management of ONJ to a South Australian Oral and Maxillofacial Surgery Unit over a 14-month period. A morning-fasted CTX test was performed for all patients. ONJ was diagnosed according to the definition previously published in a position statement by the Oral and Maxillofacial Surgeons and defined as an area of exposed bone lasting for longer than 8 weeks. Patients referred for extractions who were taking oral or intravenous bisphosphonates were clinically assessed for the presence of risk factors and the need for extraction, and had informed discussion of the risks of extraction and alternative dental treatment. The CTX test was performed in most cases prior to the extraction. All patients with ONJ were independently assessed by two oral and maxillofacial surgeons. The CTX was done when these patients presented.
Patients were divided into the following groups: patients referred for extractions; patients with ONJ; and control patients without extractions or ONJ.
The CTX test uses a small blood sample obtained in the morning from a fasted patient and is currently available from Quest Diagnostics. The Kunchar study used a test available from their institution that was identical to the test from Quest Diagnostics used by Marx.
Summary of study results
Patients taking bisphosphonates all had low, but variable, CTX values. Patients with ONJ and still taking bisphosphonates had values at 200 pg/mL or less.
Out of 222 patients referred for extractions, 1 developed ONJ. That patient had a CTX value of 126 pg/mL. Of the 222 patients, 37% had a low CTX value, 42% less than 150 pg/mL, and 19% less than 200 pg/mL. Whether a patient would have a low CTX value could not be determined by the known risk factors of age, gender, comorbidity group, bone disease, or duration.
The results found that the probable safe zone is a CTX value greater than 200 pg/mL. The safe zone value recommended by Marx was 150 ng/mL. If a drug "holiday" was instituted, a return to more normal bone turnover occurs. The rate of increase of 26.4 pg/mL per month was similar to the increase reported by Marx. This finding in the 2 reports is similar and represents the beginnings of a confident database, particularly considering that the 2 studies were conducted on 2 different continents with 2 different populations and the CTX test done at 2 separate and independent laboratories.
Therefore, based on the study results, it is possible to calculate how long a patient needs to not take an oral bisphosphonate so that the bone turnover can return to safer levels. One should allow a rate of 25 pg/mL. An example was the following: If the patient had a level of 100 pg/mL and should be at a level of 200 pg/mL, they would need a drug holiday of 4 months.
In general, the oral health status of the patients in the Australian study was poor, with the periodontal state worse compared to that of the community level.
In the Australian study, the CTX value did help the clinician determine whether the patient was in the "risk zone". However, for developing ONJ, it was not a simple "safe/unsafe" test for the individual patient.
Study results in detail
According to the authors, the study indicated that the CTX test was an aid in the clinical decision process but not an absolute determination of the individual risk of developing bisphosphonate-associated ONJ. Three patients who had a CTX test at the time of ONJ presentation had values lower than 100 pg/mL. In patients whose bisphosphonate had been ceased and the CTX then performed at a stated subsequent time, as they slowly recovered, the value progressively increased. This showed that there is value in ceasing the bisphosphonate before tooth extraction and in the management of established ONJ to allow bone recovery.
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