A recently released Canadian research study confirms what has been shown in past preliminary studies; – inflammation of the eye as a possible side effect of bisphosphonate therapy is very rare. Bisphosphonates include Alendronate (Fosamax), Risedronate (Actonel), Etidronate (Didrocal) and Zoledronic Acid (Aclasta).

In this new study to evaluate the risk of inflammation of the eye while taking bisphosphonates, Dr Etminan and his colleagues reviewed the electronic medical records for specific diagnoses and medications in all British Columbia residents seen by an eye doctor from 2000 to 2007. They found that uveitis (inflammation of the uvea or middle layer of the eye) occurred in 0.29% of people using bisphosphonates for the first time. Uveitis also occurred in 0.20% of people not taking bisphosphonates. Uveitis can cause blurred vision, eye pain and redness. The researchers also found that episcleritis (inflammation of the sclera or white part of the eye) occurred in 0.63% of bisphosphonates users and in 0.36% of non-users. Episcleritis can cause eye pain, redness, tearing and light sensitivity.

To be clear, this study does not prove that bisphosphonates cause these types of eye problems. In addition, these eye conditions are quite rare and the number of people that are affected is very small. The overall risk of eye inflammation in people taking bisphosphonates is very low compared to the much larger risk of a fracture (broken bone) in people with osteoporosis who do not take bisphosphonates.

If you are taking a bisphosphonate and do not have any eye symptoms continue to take your bisphosphonate as you normally would. However, if you are taking a bisphosphonate and you do develop any symptoms of eye inflammation report these to your doctor as soon as possible. Your doctor will make sure that you get the proper treatment for your eyes and will advise you whether to continue with bisphosphonate therapy or to switch to a different type of therapy for your Osteoporosis.

A recently released Canadian research study confirms what has been shown in past preliminary studies; – inflammation of the eye as a possible side effect of bisphosphonate therapy is very rare. Bisphosphonates include Alendronate (Fosamax), Risedronate (Actonel), Etidronate (Didrocal) and Zoledronic Acid (Aclasta).

In this new study to evaluate the risk of inflammation of the eye while taking bisphosphonates, Dr Etminan and his colleagues reviewed the electronic medical records for specific diagnoses and medications in all British Columbia residents seen by an eye doctor from 2000 to 2007. They found that uveitis (inflammation of the uvea or middle layer of the eye) occurred in 0.29% of people using bisphosphonates for the first time. Uveitis also occurred in 0.20% of people not taking bisphosphonates. Uveitis can cause blurred vision, eye pain and redness. The researchers also found that episcleritis (inflammation of the sclera or white part of the eye) occurred in 0.63% of bisphosphonates users and in 0.36% of non-users. Episcleritis can cause eye pain, redness, tearing and light sensitivity.

To be clear, this study does not prove that bisphosphonates cause these types of eye problems. In addition, these eye conditions are quite rare and the number of people that are affected is very small. The overall risk of eye inflammation in people taking bisphosphonates is very low compared to the much larger risk of a fracture (broken bone) in people with osteoporosis who do not take bisphosphonates.

If you are taking a bisphosphonate and do not have any eye symptoms continue to take your bisphosphonate as you normally would. However, if you are taking a bisphosphonate and you do develop any symptoms of eye inflammation report these to your doctor as soon as possible. Your doctor will make sure that you get the proper treatment for your eyes and will advise you whether to continue with bisphosphonate therapy or to switch to a different type of therapy for your Osteoporosis.

VITAMIN D IS VERY IMPORTANT TO OUR BONE HEALTH

When taken in the appropriate amount, vitamin D decreases our risk of falling and breaking bones. It is very common to find inadequate vitamin D levels in Canadians. For that reason, Osteoporosis Canada recommends that all Canadians, particularly those of us over age 50, take a daily vitamin D supplement (at least 800 International Units a day for most adults). These vitamin D supplements are available without prescription at pharmacies across Canada.

Vitamin D is also available (by prescription only) as a larger once-a-week dosage. The results of some studies outside Canada have shown that vitamin vitamin D given in even larger doses (100,000 IU) spaced out as far as every 4 months can still be effective in decreasing the risk of fractures.

Please note that anyone considering a dose of vitamin D greater than 2000 IU in a single day should consult with their physician before doing so.

HOW MUCH VITAMIN D IS TOO MUCH?

A recent study published in the Journal of the American Medical Association (JAMA) showed that a single large dose of vitamin D, given once a year to a group of elderly patients, actually increased their risk of falls and fractures. This study recruited 2258 women, average age of 76 years, who were at increased risk of falling, and randomly assigned them to receive either a single dose of 500,000 International Units (IU) of vitamin D (ten 50,000 IU tablets taken in a single day) once a year or a placebo once a year for 3 to 5 years.

The Scientific Advisory Council of Osteoporosis Canada has reviewed the study and makes the following observations and recommendations:

The study was well designed and there are no obvious serious flaws or biases seen.

There is one other large dose, once-yearly, study of vitamin D (300,000 IU of vitamin D2, given by injection) that also has shown an increased risk of fracture. But studies using smaller, more frequent doses of vitamin D (averaging 700-800 IU/day with adequate calcium intake) have consistently tended to show decreased falls and decreased fracture risk.

There is no good explanation for the apparent danger of larger doses of vitamin D supplementation. The editorial accompanying the paper does suggest two possible mechanisms whereby a single dose providing a year’s supply might not be effective in protecting against falls and fractures:

• Our body normally converts vitamin D to a very potent active form of vitamin D that provides the bone and muscle benefits that would be expected to protect against falls and fractures. However, a huge dose of vitamin D might cause the body to over-produce the enzyme that allows the body to degrade this active form of vitamin D (and this was not measured in these studies).
• Half the patients in the large annual dose study had vitamin D levels below the normal range before the very first dose of vitamin D was given and it is possible the patients receiving vitamin D improved their muscle strength, felt better, and became more active than the placebo group. Activity levels and general health were not measured in this study, but when people are more active, they may also be at higher risk of falling.

In summary, the Scientific Advisory Council concludes that this recent study does not provide any evidence to change Osteoporosis Canada’s standard recommendation of a modest daily intake of vitamin D (800-2000 IU/day for most adults), or an equivalent dose of a once-weekly vitamin D by prescription from your doctor. However, a single large, yearly dose of vitamin D is not advisable.

COPN wishes to thank the following members of Osteoporosis Canada’s Scientific Advisory Council for their insight in the significance of the findings in he recent JAMA article: David Hanley, William D Leslie, Sophie Jamal, Jonathan Adachi, Alexandra Papaioannou, Suzanne Morin.

We are aware of recent press reports concerning the link between two drugs for osteoporosis (alendronate and zoledronate) and the occurrence of a heart condition characterized by an irregular heart beat (atrial fibrillation).

We recognize that you might find these reports concerning. Osteoporosis Canada takes your concerns seriously and we will continue to be vigilant in order to inform you about the latest research. The study cited in the newspaper articles has been reviewed by experts from the Scientific Advisory Committee at Osteoporosis Canada and their response is below.

It is a fact – all medications have risks associated with them. Osteoporosis medications are no exception. Every time a physician recommends and prescribes a medication, it includes carefully weighing the risks and benefits of taking a medication.

The study referenced above reported that among 719 women with atrial fibrillation 47 had used alendronate whereas among 966 women without atrial fibrillation 40 had used alendronate. The authors concluded that use of alendronate was associated with an increased risk of atrial fibrillation.

This study has some limitations, which were discussed by the authors but not mentioned in media reports, which should lead us to interpret the findings with caution. Two major limitations are the small number of women using alendronate and the fact that this was not a randomized controlled trial – as such it is not possible to state that alendronate causes atrial fibrillation.

To date, atrial fibrillation has not been reported with other commonly used osteoporosis medications including related bisphosphonates such as risedronate and etidronate. Other studies, evidence and data support that the notion that atrial fibrillation associated with bisphosphonate use is extremely rare.

Fractures (broken bones) due to osteoporosis, on the other hand, are extremely common. Osteoporotic fractures are linked to additional fractures, altered quality of life, worsening of other health conditions and in some cases – death. Bisphosphonate medications provide protection from osteoporotic fractures. It is important to remember that your physician carefully weighs the risks and benefits of taking a medication for your unique situation every time he or she recommends and prescribes a medication. Your healthcare team is available to review any concerns or questions you may have about this issue.

NOTE: On November 12, 2008, the FDA released its most recent conclusion regarding the association between bisphosphonates and atrial fibrillation. In its communication, the FDA emphasizes “no clear association between overall bisphosphonate exposure and the rate of serious or non-serious atrial fibrillation”. Please note that this is a US update and updated information from Health Canada is not currently available.

To read the entire summary of this conclusion, please follow this link: http://www.fda.gov/medwatch/safety/2008/safety08.htm#bisphosphonates2

For the full article on “Update of Safety Review Follow-up to the October 1, 2007 Early Communication about the Ongoing Safety Review of Bisphosphonates”, please follow this link: http://www.fda.gov/cder/drug/early_comm/bisphosphonates_update_200811.htm

These statements are US update. Updated information from Health Canada, if available, will be provided accordingly.

No link between the use of bisphosphonates and the risk of cancer of the esophagus or stomach has also been noted in a recent large study from the UK. This study evaluated the risk of cancer in 41,826 people using bisphosphonates and a similar number not on therapy. An increase in the risk of cancer was not seen with bisphosphonates.

We are also aware of previous reports on the association between oral bisphosphonate use and esophageal cancer1,2 .

We recognize that you might find these reports concerning. Osteoporosis Canada takes your concerns seriously and we will continue to be vigilant in order to inform you about the latest research. The publication has been reviewed by experts from the Scientific Advisory Council at Osteoporosis Canada and their response is below

It is a fact – all medications have risks associated with them. Osteoporosis medications are no exception. Every time a physician recommends and prescribes a medication, it includes carefully weighing the risks and benefits of taking a medication.

A letter sent to the editor of the New England Journal of Medicine from a member of the Food and Drug Administration (FDA) in the United States, reported that from October 1995 to mid May 2008 the FDA received reports of 23 patients who were diagnosed with esophageal cancer while taking the oral bisphosphonate medication, alendronate. There have been no reports of esophageal cancer associated with other oral bisphosphonates such as risedronate or etidronate in the United States. However, in Europe and Japan, there have been up to 10 cases of cancer of the esophagus with the other bisphosphonate medications. The author concludes that further studies are required to establish whether a clear association exists.

The major limitation of this report, (also highlighted by the author) is the fact that this was not a prospective randomized clinical trial – therefore it is not possible to state that bisphosphonates cause esophageal cancer. Indeed, it is possible that the patients who developed cancer had conditions that put them at risk for this type of cancer unrelated to the use of bisphosphonate medications.

That said inflammation of the esophagus (esophagitis) can occur with the use of bisphosphonates, usually when these medications are not taken according to directions. As a result, it is important to ensure you are taking your medication properly. You may wish to review this information with your health care professional to ensure that you are taking your medication properly.

It is important to remember that esophageal cancer is a rare condition. Fractures (broken bones) due to osteoporosis, on the other hand, are extremely common. Osteoporotic fractures are linked to additional fractures, altered quality of life, worsening of other health conditions and in some cases – death. Bisphosphonate medications provide protection from osteoporotic fractures. It is important to remember that your physician carefully weighs the risks and benefits of taking a medication for your unique situation every time he or she recommends and prescribes a medication. Your healthcare team is available to review any concerns or questions you may have about this issue.

1. Wysowski DK, Reports of Esophageal Cancer with Oral Bisphosphonate Use. N Engl J Med 2009;360;1:89-90.

2. Green, J et al, Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort. BMJ 2010; 341:c4444.