Tag: Healthcare Professionals

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

Calcium is essential for the achievement and maintenance of normal bone health. The current daily requirements for elemental calcium are approximately 1200 mg daily preferably from dietary sources and if this is not possible then supplements are recommended ideally in the form of calcium carbonate or calcium citrate. Recently concern has been raised regarding potential increased risk of coronary events in association with calcium supplements.

Research from New Zealand evaluated the results of 11 randomized controlled trials of calcium supplementation involving more than 12,000 patients. Ian Reid and his colleagues found an increase in the risk of heart attacks by 31% in the groups receiving calcium in comparison to placebo with 143 women experiencing a heart attack in the calcium groups and 111 women experiencing a heart attack in the placebo groups. This analysis however included studies in which women reported the presence of a heart attack based on their own opinion and the facts were not confirmed by medical records. In the review of the Women’s Health Initiative women who were taking calcium and vitamin D in addition to their own personal use of calcium did not have an increased risk of heart attacks or stroke. There was also no relationship between daily dose of personal calcium supplements and the risk of a heart attack or stroke

Li and colleagues evaluated 23,980 men and women from the European Prospective Investigation into Cancer and Nutrition cohort study (EPIC study). Participants completed questionnaires providing information on dietary calcium intake and the use of supplements. Those people with an increased intake of dietary calcium had a lower risk of heart attacks by approximately 31%. People using calcium supplements actually had an almost 2 fold increased risk of heart attacks. This study also has been criticized as the questionnaire simply asked the people if they took “vitamins” but did not ask which ones and the amounts taken. The presence of heart attacks was however confirmed by following medical records or reviewing the death certificates.

In summary the research studies which have been completed have been relatively small and have been of less than ideal design. Further research with large well designed studies is needed.

Osteoporosis Canada recommends that daily intake of calcium be obtained largely from dietary sources. If this is not possible then supplements may be used preferably calcium carbonate or calcium citrate following discussion with your doctor regarding the safe dose for each individual.

An atypical femoral fracture is an uncommon type of hip fracture which has been associated with long term use of certain osteoporosis medications. This type of hip fracture affects the shaft of the femur bone and is often preceded by thigh or groin pain which may occur for several weeks or months before the fracture. If you are taking osteoporosis medications and you are experiencing thigh or groin pain you should discuss this with your physician. The fracture is confirmed on xray; it may however require additional imaging to identify the fracture in the early stages and a bone scan or an MRI may be required. Atypical femoral fractures have been seen in people taking bisphosphonates or denosumab for several years. They have also been reported to occur without the use of osteoporosis therapy and a causal relationship between the use of osteoporosis medications and these fractures has not yet been confirmed.

Related Links:

Prolia (denosumab) product monograph: http://www.amgen.ca/Prolia_PM.pdf

We are aware of recent media reports that long-term use of bisphosphonates for osteoporosis (sold under the names of Fosamax [alendronate] and Actonel [risedronate]) may be associated with the occurrence of unusual fractures, most commonly reported to affect the thigh bone.

It is a fact that all medications have risks associated with them. Osteoporosis medications are no exception. Every time a m edication is recommended or prescribed, a car eful weighing of the risks and benefits associated with taking that medication is included.

The concern raised in some recent press reports relates, in part, to two studies presented at the annual meeting of the American Academy of Orthopaedic Surgeons in March 2010. 1 One study, from Columbia University, evaluated bone structure in 111 women, half of whom had been taking bisphosphonates for a minimum of 4 years. Using a research technique called Hip Structural Analysis, the study found that in the early treatment period bisphosphonates improved the structural integrity of bone, but that the effects were diminished with long term use. The second study examined bone biopsies from 12 patients treated with bisphosphonates for an average of 8 years and 9 without bisphosphonate therapy. They found no differences in the architecture between the groups, but the group treated with bisphosphonates had less microscopic variability in bone tissue. Other reports have not seen a definite link between prolonged bisphosphonate use and atypical femoral fractures. Using national observational register-based data from Denmark, the ratio b etween h ip an d s ubtrochanteric/diaphyseal femur f ractures w as i dentical i n alendronate-treated patients and the control cohort even in the limited number of patients who received long-term treatment.2 The other study reviewed data from three large randomized trials and concluded t hat s ubtrochanteric/diaphyseal femur fractures w ere v ery r are, even among women w ho ha d be en treated with bisphosphonates a s long a s 10 y ears, without a significant increase in risk associated with bisphosphonate use. 3

This data prompted the Food and Drug Administration (FDA) to state that they were going to undertake a thorough review of possible association between bisphosphonate use and thigh bone fractures. Specifically, the FDA worked with outside experts, including members of the recently convened American Society for Bone and Mineral Research Subtrochanteric Femoral Fracture Task Force to gather additional information that might provide more insight into this issue. It is important to note that the FDA did review the data concerning the link between oral bisphosphonates and thigh bone fractures in 2008 and concluded t hat t here w as no clear association be tween bisphosphonate use and these fractures.

The ASBMR Subtrochanteric Femoral Fracture Task Force report has now been published in the Journal of Bone and Mineral Research (JBMR). As mentioned in the task force report, atypical fractures are very rare, but one should be aware of warning signs and symptoms in someone on long t erm bi sphosphonate t herapy ( new groin or thigh pa in): “ we know t hat bi sphosphonates prevent many, many common fractures. F or t his r eason, w e w ant t o e mphasize t hat pa tients should not stop taking these drugs because they are afraid of the much more uncommon femur fractures. They should talk to their health professionals about their concerns and should let them know if they experience any new groin or thigh pain.”4 The exact cause for these unusual atypical fractures is still uncertain and more research is needed to identify who is at risk and why these fractures occur.

Other studies, evidence and data support the notion that thigh fractures associated with bisphosphonate use are extremely rare with less than 1% of femur fractures being atypical. The risk of other osteoporotic fractures is significantly reduced with bisphosphonate therapy and the benefits far exceed the risks. Nonetheless, if groin or thigh pain is present, this should be further evaluated with bone scans or MRI and if necessary a change in therapy may be required.

References: 1. http://www6.aaos.org/news/pemr/releases/release.cfm?releasenum=877

2. Abrahamsen B, Eiken P, Eastell R. Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register-based national cohort study. J Bone Miner Res. 2009;24:1095-102.

3. Black DM et al N Engl J Med 2010; 362: 1761-71

4. http://www.asbmr.org/About/PressReleases/Detail.aspx?cid=a68f2b70-a117-4094-9f6fb5993c6a6149

Related Links:

1. For more information on the ASBMR task force report and to access the press release, please visit: http://www.asbmr.org/About/PressReleases/Detail.aspx?cid=a68f2b70-a117-4094-9f6fb5993c6a6149

2. Journal of Bone and Mineral Research: http://www.jbmr.org

3. National Osteoporosis Foundation press release

4. American Academy of Orthopaedic Surgeons : http://www6.aaos.org/news/pemr/releases/release.cfm?releasenum=877

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.

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.