ASCO Adds Jaw Osteonecrosis Recommendations to Bisphosphonate Guideline

The American Society of Clinical Oncology's updated guideline for the use of bisphosphonates in patients with multiple myeloma warns of osteonecrosis of the jaw as a potential adverse effect, and agrees with the recommendations in revised FDA labels for the bone-strengthening drugs.

In line with current prescribing information, ASCO describes ONJ as "an uncommon but potentially serious complication of intravenous bisphosphonates."

The guideline, which also includes updated recommendations for treatment duration, dosage, and monitoring, will be published in the June 10 issue of the Journal of Clinical Oncology.

Labels for the two intravenous bisphosphonates approved by FDA to treat bone loss from multiple myeloma - Novartis' Aredia (pamidronate) and Zometa (zoledronic acid) - have been updated in recent years to warn of ONJ as an adverse effect. ONJ is a bone deterioration condition with symptoms including jaw infection, pain, swelling, loose teeth and exposed bone.

The guideline abstract states, "The Update Committee agrees with the recommendations described in the revised FDA label for zoledronic acid and pamidronate, Dear Doctor letters, a white paper, and various position papers or statements."

It recommends that "all cancer patients should receive a comprehensive dental examination and appropriate preventive dentistry before bisphosphonate therapy. Active oral infections should be treated, and sites at high risk for infection should be eliminated. While on therapy, patients should maintain excellent oral hygiene and avoid invasive dental procedures, if possible."

Labels for Aredia and Zometa were updated after an upsurge in postmarketing reports of ONJ in cancer patients receiving bisphosphonates. FDA convened its Oncologic Drugs Advisory Committee in 2005 to discuss the increase and highlight ONJ as a safety concern with the class, noting that 138 cases were reported to FDA between the years 2001 and 2004 (¹ (Also see "Zometa, Aredia May Have Different Jaw Osteonecrosis Risk Profiles" - Pink Sheet, 14 Mar, 2005.), p. 21).

Novartis updated Zometa's label with the precaution in 2004, and informed 17,000 physicians of the label change in a "Dear Doctor" letter (² 'The Pink Sheet' Oct. 4, 2004, In Brief).

Zometa labeling states, "Cases of osteonecrosis (primarily of the jaws) have been reported in patients treated with bisphosphonates. The majority of the reported cases are in cancer patients attendant to a dental procedure. Osteonecrosis of the jaws has multiple well documented risk factors including a diagnosis of cancer, concomitant therapies (e.g. chemotherapy, radiotherapy, corticosteroids) and co-morbid conditions (e.g. anemia, coagulopathies, infection, pre-existing oral disease)."

"Although causality cannot be determined, it is prudent to avoid dental surgery as recovery may be prolonged," it adds.

Aredia's label advises that "a dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g., cancer, chemotherapy, corticosteroids, poor oral hygiene). While on treatment, these patients should avoid invasive dental procedures if possible."

It continues: "For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment."

In 2005, FDA requested that all oral bisphosphonate manufacturers update their labels to include ONJ as an adverse effect (³ (Also see "Boniva Labeling Reflects Class Osteonecrosis, Musculoskeletal Pain Risk" - Pink Sheet, 4 Apr, 2005.), p. 6).

In addition to the ONJ language, ASCO has added a new dosage recommendation to the myeloma guideline. It states that "for multiple myeloma patients who have, on plain radiograph(s) or imaging studies, lytic destruction of bone or compression fracture of the spine from osteopenia, intravenous pamidronate 90 mg delivered over at least 2 hours or zoledronic acid 4 mg delivered over at least 15 minutes every 3 to 4 weeks is recommended."

ASCO notes that, due to a 9.5-fold greater risk of ONJ with zoledronic acid compared to pamidronate, "patients may prefer pamidronate to zoledronic acid until more data become available."

The Update Committee also has added recommendations that zoledronic acid be given in reduced doses to patients with mild-to-moderate renal impairment, and not at all to patients with severe renal impairment, as the drug has not been studied in that population. The guideline states that "although no dosing guidelines are available for patients with pre-existing renal impairment, the Update Committee recommends that clinicians consider reducing the initial pamidronate dose in that setting."

Additional monitoring suggestions include "intermittent evaluation (every 3 to 6 months) of all patients receiving pamidronate or zoledronic acid therapy for the presence of albuminuria."

Also new to the guideline is a suggested duration of therapy, which is in line with the approximate duration of therapy in pivotal trials for Aredia and Zomata.

ASCO suggests that bisphosphonate treatment be administered monthly for two years, at which point "the physician should seriously consider stopping bisphosphonates in patients with responsive or stable disease, but their further use is at the discretion of the treating physician. There are no data to support a more precise recommendation for duration of bisphosphonate therapy in this group of patients. For those patients in whom bisphosphonates were withdrawn after 2 years, the drug should be resumed upon relapse with new-onset skeletal-related events."

- Jamie Hammon ([email protected])