Osteonecrosis of the Jaw, Fosamax like Drugs, and Dental Implants

Prevalence rate of necrotic jaw bone is low in patients taking Fosamax®-type drugs.

Dental implant success in Fosamax patients.

Two reports are described in this month’s newsletter relative to users of oral bisphosphonates. First, a low prevalence of osteonecrosis of the jaw bone (ONJ) was reported in a published comprehensive literature review on the prevalence, risk factors, and clinical manifestations of osteonecrosis of the jaw in patients receiving oral bisphosphonates for the treatment of osteoporosis. From a thorough search of the literature, the study authors identified only twenty-six cases of ONJ. The most commonly affected site was the mandible (16 patients), followed by the maxilla (6 patients). Among the 23 patients whose age was reported, 18 (78%) were >60 years. Among the 23 patients whose sex was reported, only 3 (13%) were men. Of the 15 patients with a history of invasive dental treatment, 12 (80%) had undergone dental surgery or experienced dental trauma at the site of ONJ. No clear relationship was observed between the duration of bisphosphonate therapy and the development of ONJ. Compared with the estimated millions of patients taking oral bisphosphonates, this study found the prevalence of ONJ to be very low. The second report, regarding the success of dental implants in bisphosphonate users, is described at the end of this newsletter. The report showed that patients who take oral bisphosphonates are no more at risk of implant or bone graft failure than other patients.

The report on low prevalence rate of ONJ in Fosamax® users

It has been very difficult to obtain and assess accurate numbers describing the rate of prevalence of ONJ in oral bisphosphonate users. This author has experienced a variety of anecdotal descriptions, from dentists and hygienists of patients expressing and/or exhibiting jaw bone problems and taking bisphosphonates, but none of these descriptions are usually published and have inconsistent interpretations as to any cause and effect. Until adequate observation studies are conducted and reported, the very best we can do is to accurately search the literature for reports on the presence of ONJ in oral bisphosphonate users and make comparisons to the oral bisphosphonate general population in the hopes of assigning some acceptable quantitative measure to its incidence.

Thus, the study described in this month’s newsletter is an important contribution to this process. The study authors were four physicians and one PhD who had associations with the University of Pennsylvania, University of Colorado Health Sciences Center, Roche Laboratories, and Cerner Life Sciences in California. The lead author was Michael Pazianas, MD and the entire report was published in Clinical Therapeutics, Vol. 29, No. 8, 2007, pp 1548-58. It is entitled “A review of the literature on osteonecrosis of the jaw in patients with osteoporosis treated with oral bisphosphonates: prevalence, risk factors, and clinical characteristics.”

Method

In the study, the MEDLINE database (United States) and the EMBASE database (Europe) were searched for medical literature articles reporting ONJ in oral bisphosphonate users. In addition, the Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials were searched to capture all key reviews. Also, the web sites of the American Society of Bone and Mineral Research, the National Osteoporosis Foundation International Symposium, and the International Osteoporosis Foundation World Congress were searched for conference-published abstracts. The search strategy consisted of combining medical subject headings and/or text words including bisphosphonates, alendronate, risedronate, ibandronate, etidronate, clodronate, zoledronic acid, pamidronate, and ONJ. The study used a variety of inclusion and exclusion criteria for article acceptance for review. And for purposes of the review, a case of ONJ was defined as the presence of nonhealing, exposed necrotic bone in the maxillofacial region in patients receiving bisphosphonates for treatment of osteoporosis.

From those articles accepted in the study, the following data were extracted: population characteristics (age, sex, comorbidities, concomitant medications, history of dental surgery or trauma, number of patients with ONJ), bisphosphonate treatment characteristics (specific bisphosphonate, dose, route of administration, treatment duration), clinical manifestations (site, signs, symptoms, time to onset of ONJ), and the treatment protocol to manage the ONJ. The study did not include the use of intravenous bisphosphonates in cancer patients.

The investigators identified 195 reports for full review. Of these, 11 met all the inclusion criteria, which consisted essentially of patients receiving bisphosphonates for the treatment of osteoporosis only; reported data included the baseline characteristics of the study population, the characteristics of bisphosphonates treatment, the clinical features of ONJ, the treatment protocol used to manage ONJ, or the prevalence of ONJ in patients with osteoporosis treated with bisphosphonates; and the publication involved a case report, case series, or observational study.

Results

Twenty-six cases of ONJ were reported in patients receiving bisphosphonates for the treatment of osteoporosis in the 11 reports. Seventeen cases were in the United States, 4 cases in Australia, 3 cases in Italy, and 1 case in Singapore. The remaining case location was not specified. No studies ever specifically investigated the prevalence of ONJ in patients receiving bisphosphonates for treatment of osteoporosis.

Age/sex information

The mean age of patients with ONJ was 68 years (range 39-83 years). ONJ was more common in females than males (8:1 ratio).

Medical history

Two patients were taking corticosteroids. Fifteen patients had a history of dental surgery. ONJ developed in 11 patients after tooth extraction and in 1 patient after periodontal surgery.

Specific drug and dose involved

Twenty-three patients received alendronate (Fosamax®); one patient each received risedronate (Actonel®) or pamidronate (Aredia®); one patient received a combination of alendronate (Fosamax) and zoledronic acid (Zometa®). No cases of ONJ were reported in patients receiving ibandronate (Boniva®) or etidronate (Didronel®).

Ten cases of ONJ provided information on the drug doses. Alendronate (Fosamax) was orally administered at a daily dose of 10 mg in 4 patients, at a weekly dose of 40 mg in 3 patients, and at a weekly dose of 70 mg in 3 patients. No cases of ONJ were observed in patients treated with a monthly bisphosphonate regimen.

Duration of drug use

Ten patients received alendronate (Fosamax) for a mean duration of 40 months (range 12-72 months). The break down of duration data was 12 months for 1 patient, 24 months for 1 patient, 28 months for 1 patient, 36 months for 3 patients, 43 months for 1 patient, 55 months for 1 patient, 60 months for 1 patient, and 72 months for 1 patient. No clear duration and onset of effect could be assessed from the reports.

Clinical manifestations of ONJ

Ten reports described the site of ONJ in 22 patients receiving bisphosphonates for the treatment of osteoporosis. Sixteen cases described the mandible site, and 6 described the maxilla site. The most common presenting signs and symptoms of ONJ were pain, (n=9), fistula/sinus (n=4), nonhealing open wound (n=4), discharge (n=1), and bleeding (n=1).

Management

Treatment was reported in 10 publications for 23 patients. Most common treatment modality was sequestrectomy (n=10), antibiotics (n=9), surgical/local debridement (n=4), mouth rinses (n=6), periodontal flap surgery (n=6), and curettage (n=1).

Study interpretation

This present report continues the observation that age, dental extractions, and use of corticosteroids are probable factors that increase the risk of developing ONJ in patients taking bisphosphonates for osteoporosis. These three factors have also been observed in other studies of ONJ. This current report noted that the majority of patients with ONJ were women over 60 years of age. Only 1 patient was less than 40 years of age. Also, 12 of the 15 patients for whom a dental history was reported had undergone a dental extraction or dental surgery before development of ONJ. And finally, among the patients in this review who were taking concomitant medications, 20% were taking a corticosteroid when ONJ was observed.

This study was important in that it adds more information about the prevalence of ONJ occurring in patients taking the Fosamax-type drugs to treat osteoporosis. The authors state in their conclusion that “considering that millions of patients have been prescribed bisphosphonates for the treatment of osteoporosis, the relative prevalence of ONJ in these patients is low.”

But, because of the lack of good quality observational studies and the lack of documentation of the presence of multiple confounding factors such as comorbid conditions and concomitant medications, assessment of a possible cause and effect relationship between bisphosphonates and ONJ in patients with osteoporosis was not possible.

The report on the success of dental implants in bisphosphonate users

The dental implant study, published in the Journal of Oral and Maxillofacial Surgery, Vol 66: 1022-4, 2008 (Bell BB and Bell RE), “Oral bisphosphonates and dental implants: a retrospective study”, was an analysis to determine whether patients who took oral bisphosphonates were at a greater risk of implant and bone graft failure than other patients. The study showed that patients who take oral bisphosphonates are no more at risk of implant or bone graft failure than other patients.

The medical records for all patients who had been seen since 1990 were reviewed, and those patients who took Fosamax-type drugs prior to surgery were used for the study population. One hundred implants were placed in 42 patients. Thirty of those also received bone grafts totaling 68 grafts. Patients had been taking bisphosphonates from 6 months to 11 years prior to implant surgery. Thirty-four patients were taking alendronate (Fosamax) at the time of surgery, 6 were taking risedronate (Actonel), and 2 were taking ibandronate (Boniva). All 42 patients were called in for a follow-up appointment to examine their jaws. The average length of follow-up was 3 years and 1 month with a range of 4 months to 7 years and 5 months.

Study results

There were 5 implant failures out of 100 implants placed, giving a 95% success rate. The study authors commented that this rate was comparable to the success rate of 96.5% for 734 implants placed in patients not taking bisphosphonates by one of the authors in 2006. No patients showed signs of ONJ. This was a limited study showing that, in 42 patients, implant placement and oral bone grafting appeared to be safe and successful in patients taking bisphosphonates for osteoporosis.

This study adds to some previous reports of implant success in bisphosphonates patients. In a previous newsletter (see archived article entitled Fosamax-type drugs do not cause osteonecrosis of the jaw in patients having dental implants), a report was described that showed that implant surgery on patients receiving Fosamax-type drugs did not result in bisphosphonate-associated osteonecrosis of the jaw (ONJ). That study, out of the Dentistry/Oral Surgery group at Montefiore Medical Center, Albert Einstein College of Medicine, reported that of 115 patients taking oral bisphosphonates, none showed evidence or had symptoms of osteonecrosis after implant placement. This report had findings similar to a previous report by Dr. M. Jeffcoat, who showed success in implant placement and no signs of necrosis in patients taking oral bisphosphonates. The Jeffcoat report was published in 2006 in the International Journal of Oral and Maxillofacial Implants, Vol 21: 349.

This is great info from our friends at Lexicomp by Dr. Richard L. Wynn Professor of Pharmacology at the University of Maryland Dental School.

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