Sunday, August 22, 2010

A New Class of Drugs Called Anti-RANKL Agents May Be Associated With Osteonecrosis of the Jaw

One of the many things I love about Lexicomp is the fact that their information is specific to the practice of oral medicine. Whether it's their drug databases or their email updates, you can always count on the info being something you can use. When I got the latest email form Lexi I was shocked to learn about more drugs that are potentially associated with an increased risk of ONJ. Read on for the full article.

Denosumab represents a new class of drugs called anti-RANKL agents that are indicated for treatment for osteoporosis. It is marketed under the brand name Prolia® and was developed by the Amgen® company. It gained Food and Drug Administration (FDA) approval for the treatment of postmenopausal women with osteoporosis at high risk for fracture. It is supplied as an injection for subcutaneous use. The labeling for denosumab (Prolia) states that osteonecrosis of the jaw (ONJ), which is generally associated with tooth extraction and/or local infection with delayed healing, has been reported in patients receiving denosumab (Prolia). A dental examination with appropriate preventive dentistry should be considered prior to treatment with denosumab (Prolia) in patients with risk factors for ONJ such as dental surgery, diagnosis of cancer, corticosteroid concomitant therapy, or pre-existing dental disease. Good oral hygiene should be maintained during drug treatment with denosumab (Prolia).

Denosumab (Prolia) represents the first of its class of U.S. approvals known as anti-RANKL drugs. These agents work by decreasing bone turnover, resulting in a significant increase in bone mineral density - more on its mechanisms is described below.

Prolia was developed by Amgen, and is manufactured by Amgen Manufacturing Limited, a subsidiary of Amgen Inc. In addition to the U.S., it has also gained approval for marketing in Europe and Australia. It is approved for the treatment of postmenopausal women with osteoporosis at high risk for fracture. It is supplied as an injection for subcutaneous use. Recently, denosumab (Prolia) has been granted a Food and Drug Administration (FDA) priority review designation for the reduction of skeletal related events in advanced cancer patients. Priority review designation by the FDA is granted to drugs that offer major advances in treatment or provide a treatment where no adequate therapy exists. Consistent with priority review guidelines, the FDA will target an Agency action within six months of the application submission date.

The monograph for denosumab (Prolia) can be found in the Lexi-Comp database. Product labeling for denosumab (Prolia) states that osteonecrosis of the jaw (ONJ) has been reported in the osteoporosis trial program in patients treated with Prolia. That trial program has been described by Kyrgidis and Toulis (see below).

It is not known, at this time, what the prevalence or incidence of ONJ is in patients receiving denosumab (Prolia). However, it is suggested that, for patients requiring invasive dental procedures and are exposed to denosumab (Prolia), clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit-risk assessment. Further, patients who are suspected of having ONJ, or who develop ONJ while exposed to denosumab (Prolia), should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of denosumab (Prolia) therapy should be considered, based on individual benefit-risk assessment.

Patient counseling information provided by Amgen advises patients to maintain good oral hygiene during treatment with denosumab (Prolia) and to inform their dentist, prior to dental procedures, that they are receiving denosumab (Prolia). Patients should inform their physician or dentist if they experience persistent pain and/or slow healing of the mouth or jaw after dental surgery.

These labeling statements can be found on the Amgen website at: (accessed July 24, 2010).

The Kygidis/Toulis report

Kyrgidis A and Toulis KA, "Denosumab-Related Osteonecrosis of the Jaws," Osteoporos Int, DOI 10. 1007/s00198-010-1177-6.

Kyrgidis and Toulis described the results of two unpublished randomized clinical trials of denosumab in cancer patients with bone metastases. The results reported that ONJ occurred as adverse effect cases reported from preliminary results of clinical trials comparing denosumab with zolendronate (a bisphosphonate) for the treatment of bone metastases in patients with cancer. In one study, 20 out of 1,026 subjects exposed to denosumab were observed to have developed ONJ and 14 out of 1,020 subjects exposed to zolendronate were observed to have developed ONJ. In terms of percent incidence, those cases accounted for 2.0% for denosumab and 1.4% for zolendronate. In the second study, 10 out of 888 subjects exposed to denosumab were observed to have developed ONJ and 11 out of 888 subjects exposed to zolendronate were observed to have developed ONJ. In terms of percent incidence, those cases accounted for 1.1% for denosumab and 1.3% for zolendronate. Because these were head-to-head trials, the incidence of ONJ in the control population was assumed to be zero.

Both of these trials had current or prior intravenous or oral bisphosphonate administration in their exclusion criteria; thus, previous exposure to bisphosphonates as a factor for ONJ in those participants who received denosumab could be ruled out. And, since ONJ has not been previously described to be associated with other drugs administered to cancer patients, it can be suggested that these cases of ONJ were related to denosumab exposure.

Kyrgidis and Toulis suggested that the medical community may be facing a new agent that can induce ONJ. Up to now, ONJ has never been reported to be associated with pharmaceutical agents except bisphosphonates.

The association between denosumab exposure and ONJ may be related to dosing interval and cumulative doses. In studies evaluating denosumab in postmenopausal women with osteopenia or osteoporosis (Anastasilakis AD, Toulis KA, Polyzos SA, et al, "RANKL Inhibition for the Management of Patients With Benign Metabolic Bone Disorders," Expert Opin Investig Drugs 2009,18(8):1085-102), ONJ was not observed in any of the subjects exposed to denosumab. Those studies included a dosing interval longer than 3 months and a cumulative dose of not more than 210 mg per 6 months. On the other hand, the results of the two trials that described the appearance of ONJ in denosumab subjects included a monthly dosing interval and a dose of 120 mg per month.

In terms of bisphosphonate related ONJ, ONJ is a much more common event in patients receiving those agents for the treatment and prevention of cancer-related skeletal events compared to patients receiving bisphosphonates for non-malignancy indications. Kyrgidis and Toulis suggest that a broad introduction of denosumab into clinical practice would allow for recognition of the denosumab-related ONJ adverse effect in a much wider spectrum of prescription indications, including those for nonmalignancy.

The following are two case reports describing the appearance of ONJ in patients exposed to denosumab (Prolia):

Case report #1

Aghaloo TL, Felsenfeld AL, and Tetradis S, "Osteonecrosis of the Jaw in a Patient on Denosumab," J Oral Maxillofac Surg, 2010, 68(5):959-63.

A 65 year old woman presented to the oral surgery clinic at the UCLA Dental School with exposed bone of unknown duration in the posterior mandible. Her history included multiple medical conditions including noninsulin-dependent diabetes, hypertension and other cardiovascular problems, and a sacral giant cell tumor (GCT). She was on multiple medications for her medical conditions, none of which had ever been associated with ONJ. The GCT was partially resected in 2005. In 2007, the patient fell and sustained an L2-L5 fracture. At that time, she was placed on 120 mg denosumab subcutaneous injections weekly for 3 weeks, followed by a 2-week hiatus, and continued with a single injection of 120 mg every 4 weeks. Approximately 2-3 years prior to the clinic visit, the patient reported a 4-month course of alendronate 70 mg per week "for bone problems."

The patient's history, along with clinical and radiographic findings, was consistent with a working diagnosis of ONJ. The disease was classified as stage 2 -characterized by exposed and necrotic bone with pain and erythema, without purulent drainage. The patient was treated with antibiotics and chlorhexidine daily rinses. The patient was seen 2 and 4 weeks after the initial visit, with no change in severity of bone exposure. After 8 weeks, the patient had clinically exposed bone and the condition was diagnosed as ONJ; in this case, not associated with bisphosphonate therapy. The patient was eventually admitted to the hospital for intravenous antibiotics, incision, and drainage. After surgery, the infection subsided and the patient was discharged.

The authors believed that the potent inhibition of osteoclastic acitivty by denosumab played a central role in the development of ONJ in this patient. Although the patient reported a history of alendronate use, the short treatment duration (4 months) was unlikely to have contributed to the ONJ.

Comment by the authors

Denosumab inhibits osteoclastic differentiation and function. As osteoclasts are the common target of both bisphosphonates and denosumab, potent osteoclastic inhibition appeared to play a central role in the pathophysiology of ONJ. As more osteoclastic inhibitors enter clinical practice to be used in managing disease associated with increased bone turnover, the possibility that these agents might cause ONJ should be anticipated.

Case report #2

Taylor KH, Middelfell LS, and Mizen KD, "Osteonecrosis of the Jaws Induced by Anti-RANK Ligand Therapy," Br J Oral Maxillofac Surg 2010, 48(3):221-3.

A 60-year-old man was referred to an oral surgery clinic with an ulcerated area of exposed bone in the left mandible that was discharging pus. He had a history of laryngeal carcinoma that had been treated with laser surgery (no radiotherapy) and metastatic prostatic adenocarcinoma. He had never been prescribed bisphosphonate medication and he had completed a course of chemotherapy of docetaxel and prednisolone. He was currently participating in a trial for a phase 3 study of denosumab comparing it with zolendronate. The clinical and radiological features of the lesion were diagnostic of probable osteonecrosis. The patient was prescribed amoxicillin 500 mg 3 times daily for a week along with chlorhexidine mouthrinse. The phase 3 trial records indicated that the patient was on the denosumab arm of the trial, and exposure to denosumab was discontinued immediately. Subsequently, he had symptoms associated with nonvital lower left teeth numbers 1, 2, and 3. The teeth were extracted, and he was prescribed postoperative chlorhexidine mouth rinses and amoxicillin 500 mg 3 times daily. The necrotic bone sequestered 12 months later and, on review 15 months after initial presentation, the mucosa had healed and he had no symptoms. The authors believed that the patient had osteonecrosis of the jaw induced by denosumab treatment.

Mechanism of denosumab-type drugs

Denosumab (Prolia) is a human monoclonal IgG2 antibody that binds selectively to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. RANKL is an acronym for Receptor Activator of Nuclear factor-KB Ligand, or receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cells. Denosumab (Prolia) prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. RANK is an acronym for Receptor Activator of Nuclear factor -KB. Prevention of the RANKL/RANK interaction inhibits osteoclastic formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone. Thus, denosumab is classified as an anti-RANKL agent. As these agents are increasingly used for treatment of postmenopausal osteoporosis and being investigated for treatment of metastatic bone disease, it is possible that the number of cases of osteonecrosis induced by anti-RANKL treatment will increase in the future.

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