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.
Denosumab and Its Association With Osteonecrosis of the Jaw: More Reports
This month's article describes more reports of osteonecrosis of the jaw (ONJ) associated with the use of denosumab. A previous article described the first reports of ONJ with the use of this drug. The rate of incidence was approximately 2%, similar to the incidence with zoledronic acid (Zometa®), when used in the treatment of certain malignancies. Since then, more reports of denosumab-associated ONJ have surfaced.
Denosumab, under the brand name of Prolia®, is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture. Denosumab, under the brand name of Xgeva™, is indicated for the prevention of bone loss due to androgen deprivation therapy in non-metastatic prostate cancer, prevention of bone loss due to aromatase inhibitor therapy in breast cancer and treatment of bone destruction caused by rheumatoid arthritis.
Prior to submission to the Food and Drug Administration (FDA), denosumab was tested in a Phase III study for its effectiveness in treating certain malignancies. It was compared with a bisphosphonate zoledronic acid (Zometa®). Part of the evaluation included documentation of adverse reactions, including any signs of ONJ. ONJ was observed in both treatment arms, with an incidence of 2.0% in the denosumab group and 1.4% in the zoledronic acid group.
Phase III studies are required by the FDA as the last phase of clinical evaluation of a drug prior to submission as a new drug application. This study, reported in the Journal of Clinical Oncology, was a randomized study comparing denosumab, a fully human monoclonal antibody, against Receptor Activator of Nuclear factor Kappa B (RANK) ligand (also known as RANKL), with zoledronic acid, in delaying or preventing skeletal-related events (SREs) in patients with breast cancer with bone metastases.
Zoledronic acid (Zometa) is a bisphosphonate indicated in breast cancer patients who have evidence of bone destruction. There have been some problems with the bisphosphonates, including an association with ONJ, risks of nephrotoxicity and reports of "flu-like" symptoms with intravenous infusions. Thus, denosumab, a non-bisphosphonate, was of interest since it represented a new class of drugs having a unique mechanism of action.
Metastatic tumor cells in bone may secrete growth factors that cause the osteoblasts to release the RANK ligand. The RANK ligand is a mediator of osteoclastic formation and function. Osteoclasts resorb bone, which then promotes tumor cell proliferation to perpetually cause bone tumor expansion and bone resorption. The denosumab binds to the RANK ligand to inhibit osteoclastic activity, resulting in reduced bone resorption.
The use of denosumab in postmenopausal women with osteoporosis and in women with early-stage breast cancer showed suppression of bone turnover and increased bone mineral density when administered subcutaneously as a 60 mg injection every 6 months.
Based on this information, Stopeck et al conducted a Phase III trial to compare denosumab to zoledronic acid in delaying or preventing skeletal-related events in patients with breast cancer metastatic to bone. A dose regimen of 120 mg every 4 weeks was selected for this trial.
Patients were randomly assigned to receive subcutaneous denosumab 120 mg and intravenous placebo (n=1,026) or intravenous zoledronic acid 4 mg and subcutaneous placebo (n= 1,020) every 4 weeks for 3 years. All patients were strongly encouraged to take daily calcium and vitamin D supplements. The primary endpoint was the time for the appearance of the first skeletal-related events defined as pathologic fracture, radiation or surgery to bone or spinal cord compression. The occurrence of ONJ in patients was also evaluated and documented as to frequency of occurrence.
The results showed that denosumab was superior to zoledronic acid in delaying or preventing skeletal-related events in patients with breast cancer metastatic to bone and was generally well-tolerated. Compared to the bisphosphonates, denosumab represents a potential treatment option for patients with bone metastasis because it can be given by subcutaneous injection, rather than intravenously, and it has no requirement for renal monitoring.
Adverse drug reactions were recorded as observed during the study. The proportion of patients with adjudicated positive ONJ was compared by treatment group. ONJ occurred in both treatment groups; the incidence was 2.0% in the denosumab group and 1.4% in the zoledronic acid group. These rates of ONJ were not statistically significantly different between treatment groups. ONJ occurred as early as 6 months after random assignment. The cumulative incidence in the denosumab and zoledronic acid groups, respectively, was 0.8% and 0.5% at 1 year, 1.9% and 1.2% at 2 years and 2.0% and 1.4% at 3 years. According to the authors, the known risk factors for ONJ, including history of dental extraction, poor oral hygiene or use of dentures, occurred in 18 of 20 (90%) denosumab patients and 10 of 14 (71%) zoledronic acid patients. Fifteen (75%) denosumab-treated and 11 (79%) zoledronic acid-treated patients who developed ONJ were receiving or had received chemotherapy, and four (29%) patients in the zoledronic acid group vs zero in the denosumab group had received prior oral bisphosphonate therapy for osteoporosis. Antiangiogenic therapy (ie, bevacizumab) has been associated with an increased risk of ONJ. Four (20%) ONJ events in the denosumab group and two (14%) in the zoledronic acid group occurred in patients receiving antiangiogenic therapy. Of the patients exhibiting ONJ, 10 (50%) of the denosumab group and six (43%) of the zoledronic acid group eventually had resolution of the ONJ event. Ten (50%) of denosumab-treated patients and nine (64%) zoledronic acid-treated patients reported local infections; seven patients in each group (35% denosumab and 50% zoledronic acid) reported undergoing surgical procedures such as debridement and sequestrectomy.
Comment by the authors
The trial provided additional insight into the incidence of ONJ. Both treatment groups had similar numbers of patients who experienced ONJ at a fairly consistent rate throughout the 3-year trial. Known risk factors for ONJ including prior dental extractions, poor oral hygiene and dentures were present in the majority of the on-study observed cases. This indicated that the risk for ONJ could be identified. Also, the rate of incidence was relatively small (2.0% or less).
The complete report can be found at Stopeck AT, Lipton A, Body JJ, et al, "Denosumab Compared With Zoledronic Acid for the Treatment of Bone Metastases in Patients With Advanced Breast Cancer: A Randomized, Double-Blind Study," J Clin Oncol, 2010, 28(35):5132-9).
Additional Reports on ONJ Related to Denosumab
1. Stopeck AT, et al, "Effect of Denosumab Versus Zoledronic Acid Treatment in Patients With Breast Cancer and Bone Metastases. Results From the Extended Blinded Treatment Phase," Presented at the 33rd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-12, 2010.
The above report was an update on the original Stopeck study. After an additional 4 months of blinded treatment, the ONJ frequency increased to 1.8% in the zoledronic acid arm and 2.5% in the denosumab arm. In the original study, the incidences after 3 years were 1.4% zoledronic acid and 2.0% denosumab.
2. Fizazi K, et al, "A Randomized Phase III Trial of Denosumab Versus Zoledronic Acid in Patients With Bone Metastases From Castration-Resistant Prostate Cancer," J Clin Oncol, 2010 ASCO Annual Meeting Proceedings (Post-Meeting Edition) 28(18):Suppl (June 20 Supplement), 2010:LBA4507.
This trial was the same design as the Stopeck study described above. It tested the efficacy and safety of denosumab vs zoledronic acid in patients with metastatic castration-resistant prostate cancer. This study used 1,901 patients with the cancer (having no prior intravenous bisphosphonate use) and receiving either subcutaneous denosumab 120 mg and intravenous placebo (n=950) or subcutaneous placebo and intravenous zoledronic acid (n=951). Osteonecrosis of the jaw occurred in 22 (2.3%) denosumab patients compared with 12 (1.3%) zoledronic acid patients.
3. Henry D, et al, "A Double-Blind Randomized Study of Denosumab Versus Zoledronic Acid for the Treatment of Bone Metastases in Patients With Advance Cancer (Excluding Breast and Prostate Cancer) or Multiple Myeloma," Presented at the European Cancer Organisation 15 European Society for Medical Oncology 34 European Multidisciplinary Congress, Berlin, Germany, September 20-24, 2009.
This study evaluated denosumab and zoledronic acid in patients with myeloma or bone metastases from solid tumors (excluding breast and prostate patients). The incidence of ONJ in patients receiving zoledronic acid was 1.3%; in patients receiving denosumab, it was 1.1%.
4. Lipton A, et al, "A Meta-Analysis of Results From Two Randomized, Double-Blind Studies of Denosumab Versus Zoledronic acid (ZA) for Treatment of Bone Metastases," J Clin Oncol, 2010 ASCO Annual Meeting Proceedings (Post-Meeting Edition) 28(15):Suppl (May 20 Supplement), 2010:9015.
This meta-analysis evaluated the Fazizi and Henry trials above in terms of the effectiveness of denosumab and zoledronic acid in the cancer population. Among the parameters evaluated was the incidence of ONJ in both treatment groups. This study concluded that ONJ occurred in 30 (1.6%) denosumab patients and in 25 (1.3%) zoledronic acid patients.
More to ponder
In an interesting correspondence by Fusco, et al, published in the Journal of Clinical Oncology, May 2, 2011, the incidence of ONJ in cancer patients receiving bisphosphonates is most likely underestimated. The authors pointed out that in Italy there have been 425 ONJ cases reported to the national Drug Surveillance System as of June 2009. But Fusco et al calculated that Italian investigators have reported at annual meetings and/or peer-reviewed journals at least 1,200 different ONJ cases and that one could speculate that many other cases have not been reported. They claim that a similar discrepancy of reported cases has been observed in the U.S. In addition, it has been estimated that 30% of patients with ONJ do not demonstrate bone exposure and are therefore included in the so-called stage 0 according to the definition from the American Association of Oral and Maxillofacial Surgeons. These stage 0 patients are often undiagnosed and escape from incidence statistics.
Applying these considerations to the incidences of ONJ with denosumab or zoledronic acid in cancer patients, it may be a more significant problem than what it appears.
Finally, the dental clinician should be aware of the labeling for denosumab (Prolia) and the association with ONJ. It states the following:
ONJ, which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients receiving Prolia. An oral exam should be performed by the prescriber prior to initiation of Prolia. A dental examination with appropriate preventive dentistry should be considered prior to treatment in patients with risk factors for ONJ. Good oral hygiene practices should be maintained during treatment with Prolia.
For patients requiring invasive dental procedures, clinical judgment should guide the management plan of each patient. Patients who are suspected of having or who develop ONJ should receive care by a dentist or an oral surgeon. Extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of Prolia should be considered based on individual benefit-risk assessment.
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