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It is well known that calcium is a necessary nutrient because it plays an essential role in human health, not only for bone development but also for the heart, muscle and nerve functions. However, there have been some unsettling news reports this past week about a possible connection between excess calcium supplements and the risk of heart attacks. Some of us have been asking ourselves if it is time to reduce or even stop our calcium supplements. We therefore are happy to provide you with some information to help you get your calcium the best and healthiest way possible.

Osteoporosis Canada now recommends that everyone obtain their calcium through nutrition whenever possible. Even if you take excess calcium from your diet, that is not harmful. However, some individuals just can’t seem to get enough calcium in their diet. These persons may need to take a calcium supplement, but this should be discussed with a physician as calcium supplements can have some side effects and have been associated with some risks.

To know whether or not you need to take a calcium supplement, you really need to figure out how much calcium you are getting in your diet. Here is a very simple way to calculate this.

First, give yourself a baseline of 300 mg of calcium simply for eating anything at all. This is because there is a small amount of calcium in a variety of foods such as breads, muffins, oranges, etc. At the end of the day, even without eating any high calcium foods, you can’t help but get about 300 mg of calcium in your daily diet.

Now, add another 300 mg for any of the following high calcium foods: ฀

• 1 cup (250 ml) of cow’s milk or goat’s milk (including whole milk, 2%, skim or chocolate milk) ฀
• 1 cup (250 ml) of fortified soy, almond or rice beverage ฀
• 1 cup (250 ml) of fortified (or calcium rich) orange juice ฀
• ¾ cup of yogurt (175 ml) ฀
• 2 slices of cheese ฀
• one chunk of cheese (a 3 cm cube).

Three servings of any of the above will give you about 900 mg of calcium, and if you add the 300 mg of baseline calcium for eating anything at all, this will ensure the 1200 mg of calcium you need if you are over 50. Don’t forget to add in any calcium you might be getting from a multivitamin tablet.

If you are already getting close to the recommended amount of calcium for your age group, then you are doing great. Your body needs calcium and you are already getting the calcium you need from your diet.

Extra dietary calcium is not harmful. However, getting more calcium than you need from supplements can be harmful. Excess calcium from supplements has been associated with kidney stones, heart problems, prostate cancer, constipation and digestive problems. Do not take extra calcium from supplements if your diet is already giving you enough calcium.

If you are not getting or cannot get the recommended amount of calcium for your age group from your diet, or if you are not certain if your diet is giving you enough calcium, then you should discuss whether you need to take a low dose calcium supplement with your doctor. You should not just arbitrarily take a calcium supplement on your own.

There has been recent media coverage concerning a rare atypical femoral fracture that may be a side effect of denosumab (Prolia), an osteoporosis medication manufactured by Amgen. Osteoporosis Canada’s Scientific Advisory Council has reviewed the information from Amgen and Health Canada and provides the following statement for patients:

An atypical femoral fracture is a rare type of fracture of the thigh bone. It often has warning signs of thigh or groin pain that may occur for several weeks or months before the fracture occurs. This fracture can usually be found on a simple X-ray but sometimes a bone scan or MRI is needed.

Some of these rare fractures have occurred in individuals on long-term use of certain osteoporosis medications. However, they have also been seen to occur in people who have not taken any osteoporosis medications. Therefore, it is not yet certain what role the long-term use of osteoporosis medications plays in these rare fractures.

If you have osteoporosis or are at high risk of fracture, the benefits of taking a bone drug far outweigh the risks of experiencing a rare fracture of the thigh bone. However, if you do experience persistent thigh or groin pain please contact your doctor. For more information on osteoporosis drugs and their side effects please follow this link for Osteoporosis Canada’s Drug Treatments Fact Sheet.

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 cancer(1,2).

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.

Last week, Osteoporosis Canada heard a news story that suggested that there is an increased risk of developing osteonecrosis of bone if you are taking a bisphosphonate medication for osteoporosis. This was based on a research study published in the Journal of Rheumatology. This news item caused some concern for many osteoporosis patients who take these medications.

Osteoporosis Canada put its team of experts to work to review this study. Six of our top medical advisors contributed to this effort:

• 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

Here is a summary of what they found:

What is osteonecrosis of bone?

Osteonecrosis is a condition of bone where the blood supply to a small portion of the bone is disrupted. Without sufficient blood supply, that portion of the bone may break down. Typically this occurs close to a joint such as the hip, knee, shoulder or ankle. Osteonecrosis usually leads to pain and eventually to arthritis of the affected joint.

What is a bisphosphonate?

Bisphosphonates are a class of drugs used to treat osteoporosis. These drugs are very effective at preventing fractures (broken bones) in patients with osteoporosis.

Bisphosphonates used in the treatment of osteoporosis in Canada include: alendronate (Fosamax®), etidronate (Didrocal®), risedronate (Actonel®) and zoledronic acid (Aclasta®).

What did the study show?

The study was trying to see if bisphosphonates can cause osteonecrosis of bone. The authors of the study did conclude that there was an increased risk of osteonecrosis of bone in patients who take bisphosphonates. However, according to our team of medical experts, there were a number of weaknesses in the way the study was designed that severely limit what anybody can conclude from the results. Because of the poor design of the study and a significant lack of information, it is not clear which bones of the body are affected and which patients would be at high risk of developing this condition or whether there is any connection at all. January 25, 2008.

Our experts conclude that we need more research in order to see if there is any sort of connection between osteoporosis or the medications we use to treat it and osteonecrosis of bone. What remains clear is that the risk of fracture in those with osteoporosis is high and that bisphosphonates can decrease this risk very significantly.

What does this mean to you?

Osteoporosis is a disease of bone that leads to increased risk of broken bones (fractures). The bones most likely to break are the bones in the spine, hip and wrist. Fractures caused by osteoporosis can have very serious consequences including pain, disfigurement, loss of independence and even death. It is very important that, if you have osteoporosis, you decrease the risk of having a fracture.

If you have osteoporosis and are on treatment with one of the bisphosphonates, you are getting a huge benefit. These drugs very significantly decrease your chance of suffering a fracture.

No drug is without the possibility of side-effects. Osteoporosis drugs are no exception. In the case of bisphosphonates, the risk of any serious side-effects is extremely rare.

In the balance, most individuals who have osteoporosis are much better taking an osteoporosis medication. On a bisphosphonate, you are a great deal more likely to prevent a fracture than to ever get a serious side-effect.

A number of recent medical reports have linked high doses of intravenous bisphosphonates given to patients for the treatment of multiple myeloma, breast cancer or other cancers, to a condition known as Osteonecrosis of the Jaw (ONJ).

Osteonecrosis of the Jaw typically appears as an area of exposed bone in the upper and/or lower jaw that does not heal after a period of 6 weeks. It may or may not be painful. Most cases have occurred in patients with past or ongoing treatment with intravenous bisphosphonates, usually in high doses for treatment of cancer. Many of these individuals have been on other medications for their cancer. It appears that in addition to the bisphosphonate therapy, most have undergone some dental work such as tooth extraction or dental implants or treatment for an oral infection or had other local trauma to the oral cavity prior to the development of ONJ. In a few individuals, there was no history of dental work or injury prior to the occurrence of ONJ. It is reported that individuals who develop ONJ have been on bisphosphonates for some time (the average duration of treatment was approximately 2 years) prior to the development of the lesions. ONJ is treated by dentists or dental surgeons with local treatment to the mouth such as rinces, antibiotics and local surgical procedures.

Oral bisphosphonates, such as alendronate (Fosamax®), etidronate (Didrocal®) and risedronate (Actonel®) are often used in the treatment of osteoporosis. Infrequently, intravenous bisphosphonates such as pamidronate or zoledronate are also used in the treatment of osteoporosis.

A smaller number of ONJ cases have been reported in patients receiving oral bisphosphonates for the treatment of osteoporosis and/or Paget’s Disease. These cases are quite rare and estimated to occur in between 1 in 10,000 and 1 in 100,000 of patients taking oral bisphosphonates for osteoporosis. Unfortunately, limited information is available about the dose and duration of bisphosphonate therapy and the general health of the patients who developed ONJ while on treatment for osteoporosis or Paget’s Disease.

To date there have been no reports of this condition in association with other medications used in the treatment of osteoporosis namely calcium, vitamin D, raloxifene (Evista®), calcitonin (Miacalcin®) and teriparatide (Forteo®).

The reports of ONJ in patients with osteoporosis have caused great concern among health care professionals and patients alike.

Clinical Recommendations

At present, there is simply not enough medical information to prepare fact-based guidelines for the prevention and treatment of ONJ in patients taking oral bisphosphonates for treatment of osteoporosis or Paget’s Disease. The risk of developing ONJ with oral bisphosphonates is known to be very low (between 1 in 10,000 and 1 in 100,000), however it would be prudent for patients on oral bisphosphonates for osteoporosis to consider the following:

• Maintain good oral hygiene by regular visits to your dentist and dental hygienist. This advice is the same for everyone whether or not you are on a bisphosphonate.
• Report any oral or dental problems to your dentist and to your physician. This would include pain, swelling, problems with your gums or loosening of your teeth.
• Inform your dentist or dental surgeon that you are on a bisphosphonate. Should your dentist be concerned about this treatment and your dental health, he/she may contact your physician.
• Some health care professionals recommend stopping bisphosphonates for several weeks before and after invasive or traumatic dental work (such as tooth extraction or dental implant). Currently, there is no proof that this will help prevent ONJ. However, given the long term benefits of bisphosphonates to bones, it is unlikely that stopping these medications temporarily will have any adverse impact on the treatment for osteoporosis. Always be sure to check with your own doctor first.
• Routine dental work such as dental cleaning, fillings or root canals have not been reported to increase the risk of ONJ.
• ONJ does not cause any problems with the jaw joint. If you experience pain, snapping or cracking in the jaw joint, this is not related to ONJ nor to your bisphosphonate.
• Remember, the osteoporosis medication was prescribed to help you prevent a fracture (broken bone). You are much more at risk of suffering a fracture than to ever develop ONJ. The benefits to you are much greater than possible risks from these medications. You should always discuss with your physician prior to stopping/changing your osteoporosis medication.

For the Future

Further research is needed to better understand the incidence and mechanism of ONJ, and to identify specific patient risk factors which would predispose some individuals to ONJ when these drugs are used in the recommended doses for treatment of osteoporosis and/or Paget’s Disease.

Because of the urgency to clarify how and by what mechanism ONJ occurs, the American Society of Bone and Mineral Research (ASBMR), has initiated a forum that would bring together physicians, oral surgeons, dentists and scientists with expertise in key areas of the disease, to address this clinical problem and together, provide further guidance into best clinical practices. The Scientific Advisory Council of Osteoporosis Canada supports this endeavour.

Osteoporosis Canada will update this statement when new information becomes available.

Further reading

>> Article written by the American Society of Bone and Mineral Research on Osteonecrosis of the Jaw (ONJ). It is felt this article reflects the current and most up to date research on this subject that has currently made news headlines linking ONJ with use of bisphosphonates.