Bisphosphonate drugs and osteonecrosis of the jaw (ONJ)

Advice from the Therapeutic Goods Administration

20 December 2007

The Therapeutic Goods Administration (TGA) continues to alert prescribing doctors, dentists, pharmacists and consumers to the uncommon but important association of the use of bisphosphonate drugs with osteonecrosis of the jaw.

The bisphosphonates are a very clinically useful class of medicines. They act by inhibiting the resorption of bone. Their uses include the prevention and treatment of osteoporosis, osteitis deformans ("Paget's disease of bone"), bony metastases of cancers (with or without hypercalcaemia), multiple myeloma and other conditions that feature bone fragility.

The approved uses for which the various members of the bisphosphonate class are registered in Australia vary between the individual medicines. Some bisphosphonates are given by mouth while others are given by intravenous injection.

For several years it has been recognised that the use of bisphosphonates has uncommonly been associated with a serious and difficult to treat adverse effect on the bone of the jaw, described as osteonecrosis of the jaw (sometimes called ONJ).

The factors increasing the risk of developing osteonecrosis of the jaw are thought to include:

  • use of the intravenous forms of bisphosphonates in the treatment of metastatic cancer of bone, tumour-associated hypercalcaemia and multiple myeloma (Note that this does not preclude orally administered bisphosphonates used for osteoporosis from causing osteonecrosis of the jaw); and
  • pre-existing poor dental hygiene and dental procedures conducted whilst or for some time after a bisphosphonate drug has been taken or injected.

Doctors prescribing bisphosphonate drugs or giving them by injections are encouraged to:

  • consider dental referral of the patient before starting treatment, especially for people at increased risk, such as the elderly;
  • reinforce the importance of good oral hygiene;
  • inform their patients of the symptoms of osteonecrosis of the jaw that may occur while taking or after being given a bisphosphonates, such as "toothache" or pain, swelling or numbness of an area of the jaw or a discharge around a dental implant;
  • advise their patients that they should notify their dentist that they are taking or have been given a bisphosphonate drug.

The TGA has taken several active steps to ensure that prescribing doctors, dentists and pharmacists are aware of this adverse association.

The TGA, in association with the Adverse Drug Reactions Advisory Committee (ADRAC) - an expert advisory committee to the TGA - has published items in the Australian Adverse Drug Reactions Bulletin in February 2005 and August 2006 drawing attention to the association of bisphophonates and ONJ. In these items, health professionals were alerted to the presenting clinical features of ONJ and offered advice on management strategies. The August 2006 article can be found on the TGA web site at: Osteonecrosis of the jaw with bisphosphonates. Information about ONJ has also been published in a letter to the Medical Journal of Australia (2005), while an article in the Australian Prescriber (August 2007) includes details of the clinical features of a case.

The TGA in association with the Australian Drug Evaluation Committee (ADEC) wrote to all State and Territory medical and dental boards in August 2006 to enlist their assistance in informing medical and dental practitioners of the risks associated with the use of bisphosphonates.

The association of this class of drugs with osteonecrosis of the jaw was also publicised in April 2007 in the publication Rational Assessment of Drugs and Research (RADAR), in an item about a revised Pharmaceutical Benefits Scheme (PBS) listing of alendronate for osteoporosis. It highlighted that osteonecrosis is a rare but serious adverse effect that may occur months to years after starting biphosphonates, including alendronate. RADAR is produced by the Commonwealth Government-funded National Prescribing Service and provided in hard copy form to all doctors and pharmacists. Information also appears as a prompt in the major prescribing software packages used by doctors to inform prescribers that there is a RADAR article available on the medicine.

The TGA has worked with sponsors of bisphosphonates to update their Product Information (PI) and Consumer Medicine Information (CMI) documents to provide adequate and appropriate warnings to healthcare professionals and consumers about the risks of ONJ associated with bisphosphonate use.

Precautionary statements about ONJ have been added to the PIs since early 2005. The TGA is monitoring the situation, and regularly considers whether new warnings are required. In regard to the Consumer Medicine Information (CMI), all products that bear warnings on ONJ are legally obliged to carry information in their CMI that is consistent with the PI.

The TGA has recently reviewed the information contained in the CMIs to ensure that they provide sufficient information for consumers who use these medicines and has required the updating of some CMIs.

In Australia, the TGA operates a scheme for the monitoring of adverse reactions to medicines. The TGA is assisted and advised in this work by the Adverse Drug Reactions Advisory Committee. As at 11 December 2007, 209 Australian reports of ONJ associated with the use of bisphosphonates had been received. A large proportion of these cases were preceded by a dental surgical procedure, usually dental extraction. Australian reports have implicated alendronate, pamidronate, ibandronate, risedronate, clodronate and zoledronic acid but not to date disodium etidronate.

In all the considerations of the association of these drugs with osteonecrosis of the jaw by the TGA and its expert advisory committees, the favourable overall balance between benefits of the drugs and risks has been confirmed. These drugs are depended on by many Australians with osteoporosis and other serious medical conditions. Any consumer concerned about the risks of osteonecrosis of the jaw should discuss their concerns with their doctor.

Bisphosphonate drugs that are registered in Australia and their brand names are:

ALENDRONATE SODIUM

Brand Names: AlendrobelL, Alendro 10, Alendro 40, Alendro Once-Weekly,Apo-Alendronate, GenRx Alendronate, ChemMart Alendronate, Fosamax, Fosamax Once Weekly, Ossmax, Terry White Chemists Alendronate.

ALENDRONATE SODIUM WITH COLECALCIFEROL

Brand Names: Fosamax Plus Once Weekly

DISODIUM ETIDRONATE

Brand Names: Didronel

DISODIUM ETIDRONATE WITH CALCIUM CARBONATE

Brand Names: Didrocal

DISODIUM PAMIDRONATE

Brand Names: Pamisol, Aredia, Disodium Pamidronate Hexal

IBADRONIC ACID/IBANDRONATE SODIUM

Brand Names: Bondronat, Bonviva Once Monthly; Bonviva Quarterly Injection,

RISEDRONATE SODIUM

Brand Names: Actonel, Actonel Once-a-Week

RISEDRONATE SODIUM WITH CALCIUM CARBONATE

Brand Names: Actonel Combi

SODIUM CLODRONATE TETRAHYDRATE

Brand Names: Bonefos

TILUDRONATE DISODIUM

Brand Names: Skelid

ZOLEDRONIC ACID

Brand Names: Zometa

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