Summary Safety Review - Bisphosphonates - Assessing the Risk of Jaw Bone Loss (osteonecrosis of the jaw)
November 25, 2016
Oral and injectable bisphosphonates (alendronate, clodronate, etidronate, pamidronate, risedronate and zoledronate)
Potential Safety Issue
Jaw bone loss (osteonecrosis of the jaw)
- Bisphosphonates are prescription drugs used to strengthen bones and to treat a variety of bone-related diseases.
- Health Canada's safety review of bisphosphonate use and the known risk of jaw bone loss was triggered by the European Medical Agency's (EMA) review of a side effect report where zoledronate was used.
- Health Canada's review confirmed the known risk of jaw bone loss with bisphosphonate product use, and further concluded that this risk is higher with intravenous bisphosphonate products, especially in cancer patients.
- Health Canada is working with manufacturers to update safety information of the intravenous bisphosphonates products to reflect this risk, and to mention the additional factors that may play a role in jaw bone loss for all bisphosphonate products.
Health Canada reviewed the potential risk factors that may play a role in osteonecrosis of the jaw (jaw bone loss) with bisphosphonate use in light of updates to the European product safety information for injectable bisphosphonates. Osteonecrosis of the jaw is a condition where bones of the jaw begin to weaken and die. There are many factors that may place a person at greater risk for jaw bone loss such as radiation therapy, use of certain medications, dental conditions and procedures, and other medical conditions (diabetes, low red blood cells count, and weakened immune systems). The risk of jaw bone loss with the use of bisphosphonates is well-known and described in the Canadian product safety information.
Use in Canada
- Bisphosphonates are used to strengthen bones in a variety of bone-related diseases such as:
- bones that become weak and brittle (osteoporosis);
- bones that grow too large and weak (Paget's disease of bone);
- the spread of cancer to bone (bone metastases);
- an increase in calcium levels in the blood due to cancer (hypercalcemia of malignancy); and
- blood cell (plasma cell) cancer (multiple myeloma).
- There are different kinds of bisphosphonate formulations currently marketed in Canada:
- used orally: alendronate (brand names Fosamax and Fosavance), risedronate (brand names Actonel, Actonel DR and Actonel Plus Calcium), etidronate (brand names Didronel and Didrocal);
- used intravenously (IV): all generics of pamidronate, zoledronate (brand name Zometa and Aclasta); and
- used either orally or intravenously: clodronate disodium (brand names Clasteon and Bonefos).
Safety Review Findings
- At the time of the review, Health Canada received 125 unique Canadian reports of jaw bone loss associated with the use of bisphosphonate products. Jaw bone loss was commonly reported in cancer patients.
- A review of recent publications and an analysis of the Canadian reports above showed a higher risk of jaw bone loss with the use of bisphosphonates, especially when IV formulations are used compared to oral formulations. Higher doses and strengths as well as longer treatment periods also contribute to the risk.
- This review also found other risk factors for jaw bone loss including dental conditions and procedures, radiation therapy, and medical conditions such as having fewer than normal red blood cells (anaemia) or bleeding disorders where blood clotting ability is impaired (coagulopathies).
- At the time of the review, the product information for all bisphosphonates already included a warning about the risk of jaw bone loss, but there were differences in the way the risk was described for the different drugs in this class.
Conclusions and Actions
- Health Canada's safety review concluded that there is a higher risk of osteonecrosis of the jaw with the use of intravenous bisphosphonate products compared to the oral form, especially in cancer patients.
- Health Canada will be working with the manufacturers to update the Canadian product safety information for bisphosphonate products:
- Intravenous formulations will reflect the increased risk of jaw bone loss including stopping bisphosphonate use if jaw bone loss occurs while on treatment and delaying the start of bisphosphonate use in patients with unhealed open wounds in the mouth.
- All formulations will mention the additional factors that may play a role in jaw bone loss.
- Health Canada will also issue a notice in the Health Product InfoWatch when the product information is updated.
- Health Canada will continue to monitor side effect information for bisphosphonates, as it does for all health products on the Canadian market, to identify and assess possible harms. Health Canada will take appropriate and timely action, if and when any new health risks are identified.
The analysis that contributed to this safety review included scientific and medical literature, Canadian and international adverse reaction reports and what is known about the use of these drugs both in Canada and internationally.
For additional information, contact the Marketed Health Products Directorate.
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