Fracture Risk and Acid Blocking Medications: What Should You Do?

Yesterday, the FDA released a Drug Safety Communication warning about a possible risk of increased fractures with acid blocking medications called proton pump inhibitors or PPI's.

PPI's have been a major advance in medical science. Prior to these and ealier medications, the treatment for severe gastroesophageal reflux disease (GERD) was major surgery. PPI's are now commonly prescribed for GERD and less serious heart burn, many are generic, and some are now sold over the counter. The popular PPI's include Nexium (esomeprazole), Prilosec (omeprazole), Prevacid (lansoprazole), and Protonix (pantoprazole) which are available by prescription. Prilosec OTC and Prevacid 24HR are sold over-the-counter (OTC). Given the use and popularity of these medications, this warning may cause great concern among patients who rely on these medications.

What did the FDA find?
The FDA analyzed the data from several epidemiologic studies in thousands of patients studied for several years and in 6/7 studies found a greater risk for certain kinds of fractures when patients took PPI's. These risks seemed to be the greatest when patients were taking the medications regularly, for a long time, and at a high dose.

So is this a real problem?
Maybe. It is important to know that the gold standard of studies is the randomized clinical trial (RCT). Only RCT's can prove a cause and effect. None of the RCT's with PPI's thus far have shown and increase fracture risk with PPI's. The problem with RCT's is that they are hard to do and are usually limited in time (6 months) and have fewer patients. So a rare but serious side effect is unlikely to be picked up in an RCT. The epidemiologic studies are useful, but have limitations (which the FDA readily points out). These studies are case-control, meaning they look for people who had fractures, find similar people who didn't have fractures, and then see how common PPI use was in each group. Though the studies show that people with fractures were more likely to take PPI's than people without fractures, this doesn't mean that PPI's cause fractures. Maybe the folks who took PPI's had stomach troubles and were less likely to take things that prevent fractures like Calcium or Bisphosphates (drugs which prevent fractures but are relatively contraindicated in those patients with GERD). In addition, these studies use claims databases. This means that to get the data, doctors never examined or interviewed patients, rather the investigators looked at insurance claims for fractures, medication use, etc. For example, we don't know what the bone density scores (DEXA) were for the patients in this study. It is very possible (and even likely) that the patients in the fracture group had lower DEXA scores, and this more than the PPI use accounted for fracture. Also, if you have ever received a bill or claim notification from your insurance company, you problem know that the information they contain is not always 100% accurate. That said, the number of patients studied and the consistency of this relationship suggests that there may indeed be a cause and effect.

What should you do?
It is unlikely that short term use of PPI's substantially increase risk of fractures. So if you need an occasional Prilosec OTC (like after a big barbecue this Memorial Day weekend), this is probably fine. If you need to take PPI's, either prescription or over the counter, on a daily basis and have symptoms when you do not take them regularly, this could be a sign of more serious disease and should be investigated by a physician (regardless of a fracture risk). For those patients who have had an extensive medical work up for a stomach condition and told by a physician that taking a PPI on a daily basis for years to come is the recommended treatment, then they should discuss the risks and benefits of PPI's as it relates to fractures. This would be particularly important if you have an increased risk for fracture such as a previous fracture, family history of osteoporosis, or low bone density.

Stop Fosamax After Five Years

There has been a flurry of news about osteoporosis drugs in the media being dangerous. The class of drugs are called bisphosphonates and include medications like Fosamax (now available as generic alendronate), Actonel, and Boniva- the drug pitched by celebrity spokesperson Sally Field. These drugs are designed to treat osteoporosis which is a condition where the bones become brittle. Osteoporosis is common in older women because estrogen, which decreases after menopause, prevents bones from breaking down. In the past, hormone replacement was the primary treatment and preventative agent for osteoporosis, except the Women's Health Initiative study found hormone replacement to be associated with increase cancer and heart attack. Since that study, bisphosphonates have dramatically increased in use. In fact, there is good data to show that bisphosphonates not only strengthen bones, but can prevent fractures. Fractures of the spine and hip can be extremely debilitating.

However, reports from two recent studies surfaced and have created a media storm, and likely significant confusion for the millions of women that take these drugs. Today, the USA Today reported Long-term use of osteoporosis drugs linked to hip breaks and proud ABC boasted in its headlines: FDA to Investigate Possible Osteoporosis Drug-Femur Fracture Link After ABC News Report . This occurred after a Diane Sawyer story about a physician taking a bisphosphonat, who suffered a femoral fracture by doing nothing more than walking. The femur is the long bone in the leg. It is a strong bone, and rarely fractures, unless there is extreme trauma. Thus, it was surprising when reports surfaced of women similar to the doctor Ms. Sawer interviewed having sudden, non-traumatic fractures of their leg bones.

This is not the first we have heard of these reports. In today's FDA statement in response to the media attention (see FDA Drug Safety Communication: Ongoing safety review of oral bisphosphonates and atypical subtrochanteric femur fractures ) the FDA stated:

"Based on published case reports of atypical subtrochanteric femur fractures occurring in women with osteoporosis using bisphosphonates, FDA, in June 2008, requested information from all bisphosphonate drug manufacturers regarding this potential safety signal. All available case reports and clinical trial data were requested. FDA's review of these data did not show an increase in this risk in women using these medications."


In other words, the FDA knew about this, looked at the data, and didn't find a connection. Nonetheless, today's excitement is over two studies presented yesterday at the 2010 Annual Meeting of the American Academy of Orthopaedic Surgeons (AAOS). In one report (here is the link to the actual study ), researchers obtained bone biopsies from 21 postmenopausal women with femoral fractures; nine who did not take a bisphosphonate and twelve who did. They found some differences in the structure of the bone for the women who had taken a bisphosphonate. Of note, the average duration of bisphosphonate therapy in this study was 8.5 years. The second study was done at Columbia University, where researchers evaluated the bone structure of 111 postmenopausal women with primary osteoporosis, 61 of whom had been taking bisphosphonates for a minimum of four years and 50 controls taking calcium and vitamin D supplements. The study found that during the first four years, there was improvement in bone, but after 4 years, the trend started to reverse, and with longer treatment any gains made were diminished.

It is important to point out that femoral fractures are very rare, whereas osteoporotic fractures of the hip and spine are common, which is why bisphosphonate therapy is so important. However, even though the FDA's review in 2008 found no association, it appears there is a least a signal of a potential harmful type of fracture with the use of these drugs. Most importantly, these harmful effects appear to occur only in patients on long term use of these medications. The patient Diane Sawyer interviewed had been on Fosamax for over 10 years. The good news is that the beneficial effects of 5 years woth of taking a bisphosphonate are seen 5 years after stopping! In a study published in JAMA in 2006, Effects of Continuing or Stopping Alendronate After 5 Years of Treatment , patients who had been taking bisphosphonates for 5 years were randomized to taking 5 more years of a bisphosphonate or stopping. Though there were some decreases in bone structure in those patients that stopped the bisphosphonates, there were no differences in hip and spine fractures in the two groups. In other words, for patient taking bisphosphonates, it appears that after 5 years on the drug, at least a 5 year "holiday" should be taken.

Bottom Line: Osteoporotic fractures are a major source of disability for older women in the US. Bisphosphonates are an effective form of treatment for osteoporosis and can prevent fractures. Whether or not bisphosphonates can cause rare femoral fractures is unclear, but if they do, it appears to occur only after long term use. The real benefits of bisphosphonates are seen in the first 5 years of therapy, and experts are now recommending stopping bisphosphonates after 5 years, which should also diminish if not eliminate the risk for femoral fractures. If you are taking a bisphosphonate, don't stop.....unless you have taken it for 5 years or more, in which case you should discuss with your doctor about stopping the medication. (This goes for you too Sally).