Author: Patrick O'Mara

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.

A recent study, Annual High-Dose Oral Vitamin D and Falls and Fractures in Older Women, published in the Journal of the American Medical Association (JAMA), showed that a single large dose of vitamin D, given once yearly to a group of elderly patients, actually increased their risk of falls and fractures. The 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) or placebo, once a year for 3 to 5 years. There are no obvious serious flaws or biases in the study. There has been one other large dose, once-yearly, study of vitamin D (300,000 IU of vitamin D2, given by injection) that has shown an increased risk of fracture. In contrast, studies using small, more frequent doses of vitamin D (averaging 700-800 IU/day with adequate calcium intake) have tended to show fracture and fall prevention.

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

1. Our body normally converts vitamin D to a very potent active form that provides the bone and muscle benefits of vitamin D 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 (which was not measured in this study).

2. Half the patients had vitamin D levels below the normal range before the first dose of vitamin D was given and it is possible the patients receiving vitamin D improved their muscle strength, felt better, and were more active than the placebo group. Activity levels and general health were not measured in this study, but when people are more active, they are also at higher risk of falling.

Vitamin D deficiency or insufficiency is common in Canada. This study does not provide any evidence to change our standard recommendation of a modest daily intake of vitamin D (800- 2000 IU/day for most adults), or equivalent doses on a once-weekly basis. However, it is now reasonably clear that a single huge dose of vitamin D, given once yearly, is not advisable. We need more studies to determine optimal dosing of vitamin D supplements.

Prepared by: David Hanley, William D Leslie, Sophie Jamal, Jonathan Adachi, Alexandra Papaioannou, Suzanne Morin, members, Osteoporosis Canada Scientific Advisory Council

We are aware of a recent Food and Drug Administration (FDA) publication that reports on the association between use of zoledronic acid (Aclasta) and renal impairment. 1

We recognize that you might find this report concerning and it may raise questions about your care. 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 Committee at Osteoporosis Canada and their response is below.

From April 2007 until February 17, 2009 the FDA’s Adverse Event Reporting System received reports of 24 cases of renal impairment and some cases of renal failure associated with the use of zoledronic acid. Over half of the patients had underlying medical conditions such as diabetes, heart failure or chronic kidney disease that might have contributed to the renal failure; or were taking medication that could be damaging to the kidney. Fifty four percent of patients who developed renal disease had increases in serum creatinine after administration of zoledronic acid. Most patients improved after intravenous fluid administration or other supportive care.

It is important to note that all of the FDA reports occurred in patients at risk of developing renal dysfunction– those with underlying moderate to severe renal impairment or other risk factors including use of nephrotoxic medications, diuretic therapy, or severe dehydration. Physicians are encouraged to avoid the use of zoledronic acid in patients with severe renal impairment (creatinine clearance of <35 mL/min); monitor serum creatinine before each dose of zoledronic acid; consider interim monitoring of serum creatinine in at risk patients; assure that patients are adequately hydrated prior to administration of zoledronic acid; and to infuse zoledronic acid over a period of at least 15 minutes. 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. While the reports on the association between zoledronic acid and renal failure are concerning this happens very rarely. 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, such as zoledronic acid provide protection from osteoporotic fractures. Your healthcare team is available to review any concerns or questions you may have about this issue. 1. http://www.fda.gov/downloads/Drugs/DrugSafety/DrugSafetyNewsletter/UCM168579.pdf

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.

Prepared and reviewed by members of the Scientific Advisory Council of Osteoporosis Canada

• Dr. Rick Adachi, Rheumatologist, McMaster University

• Dr. Robert Josse, Endocrinologist, University of Toronto

• Dr. Aliya Khan, MD, FRCPC, FACP, FACE, McMaster University

• Dr. Heather McDonald-Blumer, Rheumatologist, University of Toronto

• Dr. Suzanne Morin, Internal Medicine, McGill University

• Dr. Bill Leslie, Internal Medicine and Radiology, University of Manitoba

• Dr. Alexandra Papaioannou, Geriatrician, McMaster University

Response to “Use of oral bisphosphonates and the Risk of Aseptic Osteonecrosis: A Nested Case Control Study” by Etminan, Aminzadeh, Matthew and Brophy and published online in the Journal of Rheumatology – January 2008.

Osteonecrosis of the jaw in association with bisphosphonate use has been discussed at length in the medical and lay press over the past year. Previous data have suggested that the localized death of bone in the jaw has occurred predominantly in the setting of intravenous bisphosphonate use in the cancer population where it is recognized that the patients are ill, have often undergone a variety of chemotherapies for their malignancy and that the bisphosphonate medications have been used in significantly higher doses than those used in our more conventional osteoporosis population. The role of poor baseline dental hygiene has also been highlighted. While there have been reports in the literature of osteonecrosis of the jaw in the osteoporosis population both on and off bisphosphonates, these reports have been rare. As such, the recent study published online in the Journal of Rheumatology which examines the risk of developing aseptic osteonecrosis at any site in the presence of past or current use of this class of medication is of great interest.

The recent study looks at data from administrative data bases in Quebec and selected a retrospective cohort of nearly 90,000 patients, all of whom had been hospitalized for procedure based cardiac assessment/treatment between 1995 and 2002. Within this group, the database was analyzed to determine the subset of patients for whom a diagnosis of Osteonecrosis had been made. This information was then matched to the data obtained through the provincial drug formulary records to identify which of the patients diagnosed with osteonecrosis had been/were taking oral bisphosphonate medication, specifically alendronate, etidronate or risedronate. Statistical analysis was then carried out with the conclusion that osteonecrosis at any site was approximately three times more common in those individuals who had ever or were currently taking an oral bisphosphonate medication.

Taken at face value, the conclusion raises concern.

The authors do list a number of important limitations in their study including lack of verification of the diagnosis of osteonecrosis – clearly important in determining the validity of their conclusion.

Additionally, the two groups had substantial and potentially important differences – aside from the presence of osteonecrosis. The authors indicate that prednisone use was higher in the target group on bisphosphonates (18% vs 5 %). Additionally, they also note that in this population of patients, the bisphosphonate taking cohort had higher co-morbidity and more malignancies. Use of corticosteroids and a number of illnesses are known etiological factors in the development of osteonecrosis so mismatches between the case and the control groups could have significant impact in the cause and occurrence of osteonecrosis and hence, substantially influence the conclusions of the study.

Finally, many methodologic and statistical concerns may be raised. For example the coding to diagnose avascular necrosis may not have been validated and the data itself was taken from a pre-existing cardiac database and used only hospital diagnostic codes which could have influenced the results positively or negatively. Avascular necrosis of the hip and osteonecrosis of the jaw could not be distinguished from the diagnostic codes. Rate ratios were adjusted for imbalances between the groups. However without seeing the unadjusted analysis, we really do not know how the joint adjusted effects of both corticosteroids and bisphosphonates may have been affected. Indeed, as has been pointed out bisphosphonate use may simply be coincidental, a matter of guilt by association.

While this study has put forward an interesting postulate, it is evident that there are major limitations in the study and the inter-relationship between osteonecrosis and bisphosphonate use remains unclear and likely, multi-factorial. More analysis of the data set particularly attempting to verify the diagnosis and type of osteonecrosis should have been attempted. The whole of this analysis depends on it! What isn’t in question is the high prevalence of low trauma fractures in our older population, the fracture-associated morbidity and mortality in this group and the significant reduction of clinical fractures with the use of bisphosphonates. In the high risk individual with osteoporosis, the known benefits of treatment frequently far outweigh the concerns that have been raised.