Understanding the risk/benefit of bone drugs

The most commonly prescribed drugs for increasing bone mineral density and reducing the risk of fractures is a class of drugs called bisphosphonates, which include the following:

• alendronate (Fosamax, Fosavance)
• risedronate (Actonel)
• zoledronic acid (Aclasta, Zometa)

These drugs resemble natural phosphate-containing compounds that are used to help the body regulate the buildup of minerals in the bone.

Bisphosphonates are very stable molecules and after a dose is taken they quickly attach themselves to bone. They work by impairing the body’s ability to tear down or resorb bones.

In clinical trials these drugs have been found to reduce the risk of fractures, particularly at important places such as the spine and hip. When adherence rates are as good in the community as they are in clinical trials, the effectiveness of bisphosphonates is the same as in clinical trials.

Like all drugs, bisphosphonates can sometimes cause side effects. In this report we explore some possible adverse effects associated with these drugs, focusing on the parts of the body or the specific adverse effects.

Stomach and intestine

Some bisphosphonates can be taken intravenously and so the digestive tract is not affected. However, among oral formulations of these drugs, instructions for taking them must be adhered to, otherwise adverse events may occur that affect the stomach. Thus, upon waking in the morning and arising from bed, the following instructions are standard:

• The drug must be taken with a full glass of water (between 200 and 250 ml) and on an empty stomach.
• After taking the drug the person must remain upright for 30 minutes and not eat for between 30 and 60 minutes.

These steps allow water to carry the pill into the stomach and intestines, where it breaks down and is absorbed. If these instructions are not followed, the pill may lodge in the tube that connects the mouth to the stomach (the esophagus) or in the stomach itself, and then irritate these tissues. If that happens, the following symptoms can occur:

• difficulty swallowing
• sore throat
• burning sensation in the stomach

Such symptoms can appear regardless of whether the drug is taken daily, weekly or monthly.

Acute phase reactions (APR)

Temporary flu-like symptoms are more common among people who take intravenous formulations of these drugs; they rarely occur in people taking intermittent oral bisphosphonates. In one randomized, placebo-controlled study of zoledronate, after the first infusion 32% of participants who received this drug and 6% who received placebo experienced temporary symptoms such as the following:

• feeling feverish
• muscle pain
• bone and joint pain
• fatigue
• headache

However, after the second infusion, rates of these adverse effects among zoledronate users were around 7% (and 2% in placebo recipients). After the third infusion, rates were 3% for zoledronate users (and 1% for placebo recipients). All of these differences between zoledronate and placebo were statistically significant.

These symptoms usually occurred within a day after the infusion and cleared in about three days in most participants.

In another study, women who were deficient in vitamin D were more likely to experience these symptoms than other women. The greater the degree of vitamin D deficiency, the greater the risk of developing APR symptoms.

Doctors experienced in the use of intravenous bisphosphonates have prescribed standard doses of acetaminophen (Tylenol) at the time of the infusion and then for the next 72 hours as needed. This tends to minimize APR symptoms.

Cancer of the esophagus

In 2009, there were reports of 23 cases of esophageal cancer in the U.S. and 31 cases in Europe and Japan among people who had used bisphosphonates. However, these reports cannot prove that the drugs caused this particular form of cancer. Subsequently, observational studies in the U.S. and Europe did not find any link between these drugs and the development of cancer.

In the UK, researchers have amassed a large database—the General Practice Research Database (GPRD)—containing health-related information from about 42,000 people who have used bisphosphonates. Two studies have attempted to explore the issue of exposure to bisphosphonates and cancer using this database. One study gave the impression that bisphosphonates were not significantly associated with an increased risk for esophageal cancer, while the other study gave the opposite impression.

To resolve this apparent discordance, two scientists who engage in bone research reviewed the data from the two UK studies. They noted that there have been previous cases of studies into other drugs that have arrived at seemingly different conclusions when data from the GPRD has been analysed. However, when those previous studies with other drugs were carefully re-analysed, the reasons for differing conclusions became apparent.

In re-examining the two apparently conflicting bisphosphonate studies, the researchers found that important differences about the studies emerged:

• one study monitored people for 4.5 years
• the other study monitored people for up to 7.6 years

This difference in monitoring has the potential to have a huge impact on conclusions drawn by the study authors. By taking this difference in monitoring into account, the bone health experts were able to form useful conclusions about bisphosphonates. Here is what they suggested:

1. “For every 10,000 patients not exposed to bisphosphonates aged 60 to 79 years we can expect 10 cases of esophageal cancer over a five-year period.” This information helps to place the studies’ findings into perspective and the bone researchers encourage readers to make sense of so many (10,000) people by thinking of such a number being equivalent to a small town.

2. “There seems to be no increased risk [of cancer] in the first three years of treatment, although for every 10,000 patients treated with bisphosphonates, there may be anywhere between three fewer and seven additional esophageal cancers. “

3. After three years of use, for every 10,000 patients treated with bisphosphonates, there are likely to be about five additional cases of esophageal of cancer, although it is possible that there will be between five fewer and 24 additional cases of esophageal cancer.

Due to the observational nature of the studies, the bone researchers cannot provide firm estimates of cancer risk, and so there is some uncertainty about the actual number of people that could develop esophageal cancer.

4. Results from randomized clinical trials show that for every 10,000 postmenopausal women who receive bisphosphonates and who take them exactly as directed, about 1,000 fractures that might otherwise have occurred are prevented.

Unusual fractures

There have been isolated reports of unusual fractures (so-called atypical femur fractures) in some users of bisphosphonates. Mostly the bones that have broken are in the thigh. Some patients with this problem tend to experience thigh pain for weeks to months before a fracture spontaneously occurs. However, reviews of data from people who took bisphosphonates suggest that this problem is very rare and no clear link between the use of these drugs and atypical femur fractures has been proven.

Bone experts who have reviewed data on this problem suggest that among 10,000 patients using bisphosphonates there may be between “zero and two additional cases” of this problem per year. Thus the risk is very, very small.

Osteonecrosis of the jaw

Severe damage to the jawbones of some people who used bisphosphonates has been reported. However, it should be noted that the majority of such cases (95%) have almost always occurred among people who have received very high doses of bisphosphonates to prevent or treat bone disease arising from cancer. While most cases have occurred among people who received intravenous bisphosphonates, some cases have been reported among people who took oral formulations.

The quality of the data collected on cases of osteonecrosis of the jaw associated with exposure to bisphosphonates is mixed and so it is very difficult to draw robust conclusions. Therefore, the risk of developing osteonecrosis of the jaw among otherwise healthy users of bisophosphonates is not clear. If there is a risk, it is probably very, very low.

Eye problems

There have been reports about inflammation affecting the eye among people who received bisphosphonates. Much of this data comes from case reports or retrospective studies, which are not ideal for making robust conclusions about risks. In a controlled clinical trial with 7,765 women, the risk of eye inflammation or eye pain was 0.6% among participants who received zoledronate and 0.1% among people who received placebo. This difference was statistically significant.  However, based on these figures, the risk of eye inflammation is still very, very small.

Abnormal heart rhythms

The heart is usually considered a large muscular pump that moves blood. This pumping action is enabled by changes in electrical activity within the heart. Atrial fibrillation (AF) is the most common type of disorder affecting the speed or rhythm of heartbeats. AF can cause chest discomfort, chest pain, stroke and heart attack.

Examining data from a large placebo-controlled trial found that AF occurred in 1.3% of participants who received zoledronate and 0.5% who received placebo. This difference was statistically significant. Note that there were no significant differences between drug and placebo in rates of stroke, stroke-related death, heart attack or death from cardiovascular causes.

A reanalysis of data from other studies with bisphosphonates—specifically alendronate, ibandronate and zoledronate—has generally not found an increased risk of AF, even in cases where high doses were used because of cancer.

It is possible that since bisphosphonate users are generally older people that they are at increased risk for AF and there is no real connection to exposure to these drugs. Therefore, there is probably either no increased risk for AF or if there is a risk, it is very, very small.

REFERENCES:

1. Lewiecki EM. Safety of long-term bisphosphonate therapy for the management of osteoporosis. Drugs. 2011 Apr 16;71(6):791-814.
2. Dixon WG, Solomon DH. Bisphosphonates and esophageal cancer—a pathway through the confusion. Nature Reviews Rheumatology. 2011 Jun;7(6):369-72
3. Watts NB, Diab DL. Long-term use of bisphosphonates in osteoporosis. Journal of Clinical Endocrinology & Metabolism. 2010 Apr;95(4):1555-65.