Summary Safety Review - Bisphosphonates - Assessing the Potential Risk of Severe Bone Damage (osteonecrosis)

February 21, 2017

Product

Bisphosphonates [Fosamax and Fosavance (alendronate); Clasteon and Bonefos (clodronate); Actonel, Actonel DR and Actonel Plus Calcium (risedronate); Didronel and Didrocal (etidronate)]

Potential Safety Issue

Severe bone damage (osteonecrosis), beyond the area of the jawbone

Key Messages

• Bisphosphonates are prescription drugs that are authorized for sale in Canada to strengthen the bones and to treat a variety of bone-related diseases. They are known to be associated with a risk of severe jawbone damage (osteonecrosis of the jaw).
• Health Canada reviewed the risk of severe bone damage other than to the jaw from bisphosphonate use. This was due to product information updates in Europe that warn about the risk of bone damage in the outer part of the ear canal.
• In Canada, the labels for some of the bisphosphonate-containing products already include warnings about the risk of bone damage in the outer ear canal and/or other bones of the body. The current review was to determine if such warning statements should apply for all bisphosphonate-containing products.
• Health Canada’s review of the available information did not establish a link between the use of these other bisphosphonates and the risk of severe bone damage (osteonecrosis) of the external ear canal or other parts of the body other than the jaw. Health Canada will continue to monitor the safety of bisphosphonates.

Overview

Health Canada reviewed the potential risk of severe bone damage (osteonecrosis) with bisphosphonate use because of product information updates in Europe that warn about the risk of severe bone damage in the outer part of the ear canal. Previously, Health Canada completed a safety review of the risk of severe jawbone damage associated with bisphosphonate use. Therefore, the current safety review focused on severe bone damage other than to the jawbone.

In Canada, the labels for some bisphosphonate-containing products already warn about the risk of severe bone damage of the outer ear canal and/or other areas of the body and include:

• Zometa and Aclasta (zoledronic acid) warn about this risk for both the outer ear canal and other areas of the body;
• Fosamax and Fosavance (alendronate), and Clasteon (clodronate) warn about this risk for the outer ear canal.

Therefore a safety review was carried out for the following products:

• Fosamax and Fosavance (alendronate), and Clasteon (clodronate) to assess the potential for severe bone damage in areas other than the outer ear canal and;
• the remaining bisphosphonate products that do not warn about the risk of severe bone damage in the outer ear canal and other areas of the body. This included: Actonel, Actonel DR and Actonel Plus Calcium (risedronate); Didronel and Didrocal (etidronate); and Bonefos (clodronate disodium).

Use in Canada

• Bisphosphonates are prescription drugs which are authorized for sale in Canada to treat 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
  • a particular type of blood cell cancer known as multiple myeloma.
• Bisphosphonates have been marketed in Canada since 1991 under the following names and formulations:
  • 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 15 unique Canadian reports,^{Footnote a} of severe bone damage related to the use of those bisphosphonates that do not have a warning about osteonecrosis. Among these reports, none were related to severe bone damage of the external ear canal. Out of the 15 reports, 7 were excluded from the safety review because the bone damage was established before the patient took the bisphosphonate product. For the remaining 8 reports, a link between severe bone damage (osteonecrosis) and the use of the bisphosphonate could not be established. This was either due to lack of information, the existence of other health conditions such as previous bone fracture or the patient being exposed to cortisone.
• This safety review found 11 patient reports in the scientific literature on the use of bisphosphonates that do not have a warning about severe bone damage. Severe bone damage to the external ear canal was noted in 5 reports. In the remaining 6 reports, severe damage to other bones was noted. Overall, the review of these 11 cases could not conclude whether bisphosphonate use played a role in the severe bone damage because of other factors such as the patient having other diseases (for example, diabetes) or receiving other treatments (for example, cancer treatments).

Conclusions and Actions

• Health Canada’s review of the available information did not establish a link between the use of the following bisphosphonates [Actonel, Actonel DR and Actonel Plus Calcium (risedronate); Didronel and Didrocal (etidronate); and Bonefos (clodronate disodium)] and the risk of severe bone damage of the external ear canal or other parts of the body other than the jaw. The review also did not establish a link between the use of Fosamax and Fosavance (alendronate), and Clasteon (clodronate) and the risk of severe bone damage (in areas other than the outer ear canal and the jaw).
• Health Canada encourages consumers and healthcare professionals to report any side effects related to the use of these health products.
• Health Canada will continue to monitor safety information involving bisphosphonates, as it does for all health products on the Canadian market, to identify and assess potential harms. Health Canada will take appropriate and timely action if and when any new health risks are identified.

Additional Information

The analysis that contributed to this safety review included scientific and medical literature, Canadian and international information and what is known about the use of these drugs both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.