Dr. Schneider's background:** In October 2001 I was riding on the subway in New York City _when the train jolted as it pulled into a station. As I shifted my weight from my left to my right leg, I felt and heard a crack in my right thigh, and then I fell to the floor. I knew I had broken my femur. The doctors in the emergency room were mystified as to how the strongest bone in the body could just snap. I had had pain in that thigh for 3 months, had seen an orthopedic surgeon and had it x-rayed, but nothing was found.It took me several years to have an explanation. A medical article published in 2005 described several cases of unusuallow-impact fractures in people on long-term Fosamax (alendronate) and suggested that the drug could have oversuppressed the normal turnover of bone which is required to keep bones healthy and repair the usual wear and tear on bones, and thus could have caused those fractures.
I had been taking Fosamax for more than 6 years for osteopenia (that is, to prevent osteoporosis). It made sense to me. Since then, hundreds of similar cases have occurred.
Bio: Until I retired from patient care 3 years ago, I practiced internal medicine, addiction medicine, and pain medicine in Tucson_,_ AZ. I am certified by the American Board of Internal Medicine and by the American Society of Addiction Medicine, and am also a Diplomat of the American__Academy of Pain Management. I obtained my PhD in molecular genetics from the University of Michigan and my MD from the University of Arizona_. I've written numerous articles published in medical journals about the treatment of chronic pain and I wrote a book
Living with Chronic Pain for people who have chronic pain._
Help me welcome Dr. Schneider!
Dr. Schneider, I understand you were diagnosed with osteopenia and took Fosamax for that; was this your decision, or did your doctor feel it was the right treatment for your particular t-scores and fracture risk?
My doctor and I discussed this. I did not have osteoporosis at the time, but my T-score on the DXA scan was in the osteopenia range and my mother had had osteoporosis. Back then Fosamax was a relatively new drug and there was a lot of enthusiasm for the prospect of preventing osteoporosis and fractures.I didn't smoke, I exercised, and I wanted to do whatever I could to keep my bones healthy.
Some physicians feel that we should not treat osteopenia with a bisphosphonate, would you agree, and is there some other treatment that can be used instead?
Osteopenia isn't a disease, but rather a test result-a DXA scan T-score between -1 and -2.5. (Osteoporosis is defined as a T-score of -2.5 or worse).
A low T-score is only one risk factor for fracturing a bone, but there are other important risks. There are many people who have a T score of -1 to -2.5 but aren't at significant risk of fracture and don't need to be on a bisphosphonate.
Bone experts and organizations such as the North American Menopause Society (NAMS) and National Osteoporosis Foundation (NOF) now recommend that instead of treating just a number, the decision should be made on the basis of evaluating multiple risks via the FRAX score. This is a tool developed by the World Health Organization (WHO) that combines a person's age, gender, height and weight, if they had a previous fracture, family history of hip fracture, current smoking or drinking, whether or not taking certain drugs (steroids) or having rheumatoid arthritis, and the T-score.
If the FRAX score shows that the person has a 10-year risk of at least 3% for hip fracture or 20% overall fracture, then it makes sense to consider drug treatment.
I have an online support group for people who experienced an atypical femur fracture (AFF). The majority of people in my online support group, 70%, were started on a bisphosphonate just because of a T-score in the osteopenia range.
Could you explain what an atypical femur fracture is and why these medications can cause this type of break of the femur bone, considering it's the largest bone in the body and probably not one we'd think would break easily unless there was a traumatic injury involved?
The femur is indeed one of the strongest bones in the body, and a fracture of the shaft of the femur usually occurs only after a car accident or ski accident or some other major trauma.A normal femur doesn't just crack for no reason. Osteoporotic bone has a low bone density (T=-2.5) and certain bones are likely to break, including the vertebrae and the hip.
_The hip joint consists of the top of the femur, which is shaped like a ball, and fits into a socket in the pelvic bone. Hip fractures occur just below the top of__the femur, in an area where the ball connects with the rest of the femur. In contrast, an atypical femur fracture (AFF) occurs lower down, in the upper third of the shaft of the femur, and often in bone that isn't osteoporotic. It happens without any trauma, just when you're walking, or turning your body, or getting up from a chair. You fall because the bone broke, not the other way around.
The reason the bone is brittle is that bisphosphonates suppress bone turnover.Bone is living tissue, and it suffers daily wear and tear. Living bone is constantly repairing tiny breaks that happen all the time.Bone cells called osteoclasts remove the damaged bone, and then bone cells called osteoblasts build new bone.For some reason older women tend to have increased activity of the bone break-down cells, so that the bone loses mass.Bisphosphonates suppress the activity of those bone break-down cells. Apparently in some people, and we don't yet know who, the drug works too well, there is excessive suppression of the bone turnover, and the wear and tear isn't repaired.The result is that the bone gradually becomes more fragile. Think of a bisphosphonate-affected femur like china - it is dense, it looks good, but it's very brittle.Why the femur is especially vulnerable to this process could be because of the type of bone that the femur is made of.
_Other ways that an AFF differs from an osteoporotic hip fracture is (1) it is often preceded by weeks or months of pain specifically in the thigh or groin (2) there is often delayed healing or nonunion of the fracture, and (3) there is a high likelihood that the other femur will also fracture at any time up to a couple of years later.
What does the fracture feel like, when it happens, for those wanting to know more about it?
You're walking, or getting up from a chair or going down a step when suddenly the leg gives way and then you fall.In my case, I heard and felt my femur snapping while I was still standing.It was very painful!!I had no idea why this had happened! I did have pain in my thigh for over 3 months before then, worse when I walked or twisted my leg.I saw an orthopedic surgeon for it, had it x-rayed, but nothing showed up.Now the Food and Drug Administration (FDA) recommends that if you've been on a bisphosphonate for several years and develop persistent pain in your thigh or groin, that you see your doctor and that the doctor considers the possibility that it could be an incomplete fracture of the femur.
An incomplete or stress fracture is a crack through one side of the bone. It is very vulnerable to breaking completely.
What type of medical test is best to identify these femur fractures? Atypical femur fractures (AFFs) usually start out as incomplete or stress fractures, tiny breaks that have a thin fracture line on one side of the cortex (outer part of the bone) without displacement of the bone. That is, the pieces** haven't** separated.Most commonly, these fractures are not visible on a plain x-ray. They can be diagnosed using a bone scan (a nuclear medicine procedure, not the same as a bone density (DXA) scan) or an MRI scan.
Are there specific bone breakdown tests you could have to evaluate how you are progressing on one of the bisphosphonates?
_It is possible to get an idea of whether one's bones are oversuppressed by getting a laboratory test that measures the amount of bone collagen breakdown products called telopeptides in the urine or serum.After menopause, women usually have an increase in bone breakdown and therefore an increase in their urinary Ntx (N-telopeptides) and serum Ctx (C-telopeptides).
Conversely, with oversuppression, the results of these tests will show very low levels -- those typical of premenopausal women or even lower.
There is some question about the accuracy of these tests because there's quite a bit of variability, but I do think they can give you a good idea of whether bone turnover is excessive, normal premenopausal, or suppressed given your menopausal status.
Are there warning signs for these fractures?
Do you have certain symptoms prior to the fracture of this bone?
Atypical femur stress fractures often cause pain in the thigh or groin, especially when you walk or twist the leg. The pain can go on for months. Sometimes they eventually heal, but the healing may be delayed, and during the time before it heals, the femur is very vulnerable to a complete fracture.
How is this fracture treated and repaired?
Complete AFFs are treated surgically, usually by inserting a steel or titanium rod along the length of the femur (intramedullary rodding). It is held in place by screws placed near the top and bottom of the rod. I had 3 incisions, one in my hip, a second along the shaft of the femur, and the third just above the knee.
Because stress AFFs are so vulnerable to fracturing completely, they too are often treated surgically with an intramedullary rod in order to prevent a complete fracture.
Inserting a rod into an intact femur is a lot simpler than operating on a femur that is in pieces which have to be realigned, where there is tissue damage and blood loss, etc.
I can tell you this from personal experience: My femur fracture didn't heal, so after many months my orthopedic surgeon operated again, this time to remove the original rod and insert a larger one (called "exchange nailing"). The second operation took a lot less time to recover from.
How long is the recovery period and do you need to keep the weight off your leg until it's healed?
The rod stabilizes the leg, so it's safe to put weight on it very soon after the surgery.However, you will need to use a walker or crutches for weeks.Unfortunately, AFFs often have delayed healing, so this may go on for months. I used a walker for some months and ended up having a second operation about 8 months later because the bone wasn't healing. You will definitely need physical therapy and home exercises for months after the fracture.
Is there anything patients need to watch for if they have one of these fractures?
May other bones be at risk as well?
An AFF often has delayed healing, and sometimes additional surgery months later is required to get it to heal. Also, the other femur is just as vulnerable as the first one to fracture, and this can happen up to a couple of years later. 36% of my support group members had a stress or complete fracture of the second femur, which is a very high risk. It also looks like the metatarsal bones of the foot are also vulnerable to fracture.
Is it possible that we don't have an accurate figure on the number of these fractures yet?
I understand that when an ER doctor sees one of these fractures they may miscode the diagnosis and call it a hip fracture rather than an atypical femur fracture.
Do you have any concrete evidence that would tell us the true total numbers of these fractures, so we'd know how prevalent this type of injury is with these drugs in the U.S. or worldwide?
There have been studies published that claim that the risk of an AFF is "minuscule" or very rare, but these are studies that were based on hospital records where very likely a lot of the fractures had been called hip fractures rather than atypical femur fractures.It's only recently that radiologists, who read the x-rays, have become familiar with the difference between hip fractures and AFFs.Also, these studies calculated the frequency of these fractures as a proportion of ALL patients who were on bisphosphonates. Since AFFs happen in people who are on BPs for several years, the relevant statistic is, what is the risk of an AFF in people who've been on a bisphosphonate for say 4 or 5 years? A recent epidemiologic study from Ontario (Park-Wyllie et al), where they did look at x-rays, and they did separate out the patients who'd been on a bisphosphonate for 5 years and looked what the risk was in those patients, they found that the risk of AFF in 5-year users of bisphosphonates was about 1 in 500, or 0.2%.
That would translate in the U.S. to about 600 cases per year, which is not minuscule or rare.Especially when you consider that this isn't a typical fracture - it's one where delayed healing is common, where the risk of having the same thing happen to the other leg is high, around 35%.
Since your injury, you've created a support group for those with this type of fracture that is an online information and advocacy support group.
How are you helping those who want to join, and desperately need some form of assistance and support?
The group provides support and sharing of experience, information, and advocacy.Group members answer other members' questions. We post links to recent relevant medical articles and also articles in magazines and newspapers. We share email addresses of professionals in the field to whom members want to write.Members of our group have met with the FDA twice regarding bisphosphonates and femur fractures.We have members from many states in the U.S. and also from other countries. Anyone who has sustained a bisphosphonate-related atypical femur fracture is welcome to join.They just need to email me and tell me what happened to them. My email address is: email@example.com.** You were a speaker at the recent FDA meeting on bisphosphonates on September 9, 2011, and we were wondering what you had hoped would happen as a result of your testimony?**
Currently, the FDA has no recommendations for when to stop taking a bisphosphonate. Although there is no good published evidence that it is beneficial to take them forever, that is the assumption that most doctors have been working with all these years.Once a patient starts taking a BP, they are encouraged to just keep doing this. We know now, however, that there is a significant risk (perhaps 1 in 500) of a disastrous consequence of long-term use. I had hoped a committee of experts that the FDA brought in for that meeting would decide to recommend that bisphosphonates be stopped after some time period, say 3-5 years, unless there are strong reasons to continue.
The FDA group did agree that there should be some statement about stopping bisphosphonates, but they couldn't agree on the time period, so they tabled the recommendation.
I am hoping that soon they will come to agreement and put out a recommendation.
I would also hope that they recommend not to start a bisphosphonate solely on the basis of the patient's bone density (T-score) rather than the total fracture risk.
The FDA did decide to include stronger label warnings on these drugs, but do you feel this is enough or should something else be done with these medications to protect the consumer?
Stronger label warnings are very important. Also, the FDA should issue a stronger version of the advisory about bisphosphonates and femur fractures that they issued in October, 2010. That advisory waffled about a causal relationship between bisphosphonates and femur fractures. I think it's pretty clear that atypical femur fractures are a result of long-term bisphosphonate use.If the FDA affirms that connection, then doctors would take it more seriously.
Do you feel that there still remains a population of patients that warrant the use of these drugs, or should they not be used at all?
_I have never said that bisphosphonates should not be used at all.Bisphosphonates have prevented many osteoporotic fractures.But any drug,_no matter how useful, which has a 1 in 500 risk of causing a very serious adverse effect after long-term use needs to be used with caution.Bisphosphonates should be begun only when really needed, and continued for a specified period of time rather than forever.Doctors need to be aware of the long-term risks and what the symptoms are of a stress fracture of the femur.
**If someone is on one of these bisphosphonates, should they stop taking it and when?
Is a drug holiday in order or a complete cessation of the medication a better indication for those using any of these types of drugs for osteoporosis?
Drug holiday versus complete cessation is up in the air at present. Considering that alendronate and zoledronic acid stay in the bones for many years, stopping for a year or two and then resuming doesn't make sense to me.Of course, for people with osteoporosis who responded well to a bisphosphonate with improved bone density, stopped for some years and then again their T scores dropped significantly, resuming a bisphosphonate might make sense.
_I think it's different for two groups of people. (1) I know of many who were treated with a bisphosphonate for years, never really improved, but were continued on the drug (or a different bisphosphonate) because of concerns that things would be even worse without it.
If a medication doesn't work, I don't see the rationale for continuing it.
(2) We don't yet know why certain people respond badly to bisphosphonate and break their femur.
When we have that answer, we might know who shouldn't even start on a bisphosphonate.
_For now, I don't believe that anyone who has had an AFF should be treated with a bisphosphonate again. I would hesitate to take any antiresorptive. There aren't many other options these days for people like me - Forteo (teriparatide), strontium (which is not FDA-approved) - but I hope there will be others in the future.
I took Forteo
® for established osteoporosis and did really well, and I understand this is the treatment of choice after one of these unusual breaks, can you explain how Forteo works to heal these fractures and why it's chosen for this purpose.
Unlike antiresorptives, which work by suppressing bone breakdown, Forteo (teriparatide), which is synthetic human parathyroid hormone, works on the osteoblasts, the cells that build bone.
When bone turnover is suppressed, healing of a broken bone is likely to be suppressed, which would explain the high likelihood of delayed healing of atypical femur fractures. Forteo results in new bone being laid down. I think of it as unblocking the oversuppression. It has had good results in promoting healing, and is effective in treating osteoporosis in general. Forteo of course has its own cautions - high doses used for a long time in rats have caused a malignant bone tumor called osteosarcoma. For that reason, the drug is prescribed for only 2 years.
Once you've had one of these fractures, I'd assume you couldn't take antiresorptives anymore, is this correct, or are the bisphosphonates the only form of antiresorptives you'd want to steer clear of due to their ability to oversuppress bone?
There is clearly a need for research for new classes of drugs other than antiresorptives to treat osteoporosis.Most of the currently used drugs are antiresorptive - that is, they slow down the resorption of bone by suppressing the action of osteoclasts, bone cells that break down bone. People who've experienced at least one atypical femur fracture most likely already have oversuppression of those cells.So adding another antiresorptive drug will most likely not benefit them.I think steering clear of any antiresorptive makes sense, although this is uncharted territory.I think it would be less risky to take an antiresorptive that is not stored in bone, or is stored for a very short time. Examples are denosumab (Prolia®), estrogens, and calcitonin nasal spray (Miacalcin
But I'm not sure they would be beneficial in these patients.
Is it true that Reclast and Fosamax have the longest half-life of these drugs and could you explain the ramifications this might have on atypical femur fractures?
These drugs stay in the bones for many years, up to 10 for Fosamax, and they are recycled. As the bone is broken down and rebuilt, the drug returns to the circulation and continues to be active.This is probably why in the very important FLEX trial about the long-term use of Fosamax (alendronate), women who stopped Fosamax after 5 years had about the same fracture risk at 10 years as did women who continued the Fosamax for the full 10 years.
This was a good thing for them. But it means that if the drug is having a negative impact in some patients, then the problem continues for years after the drug is stopped. We don't know how long after stopping the drug the risk of an atypical femur fracture persists, but there are patients who suffered an atypical femur fracture in one leg, stopped the bisphosphonate at that time, but then broke the other femur 2 years later.
So clearly the risk persists for some time.
It's likely that the risk is shorter for drugs that aren't stored in the bones or are stored for a shorter time.
**In closing, do you have any advice for those who are taking one of the bisphosphonates, are contemplating taking one of them or for someone who has sustained an AFF already?
For those taking a bisphosphonate, and are benefiting, I would recommend stopping after 4-5 years unless your doctor believes that you are at a particularly high risk of a fracture should you stop.It is always possible to resume later if your bone density drops. Recognize that switching to a different bisphosphonate will not eliminate your risk of an AFF; these have occurred in people who were on bisphosphonates other than alendronate. There are also other options for osteoporosis such as Forteo.If you've been on a bisphosphonate for several years and develop persistent thigh or groin pain, see your doctor for a work-up to be sure you don't have a stress fracture in the femur; and remember that an x-ray will often not show up a stress fracture.If you do develop an atypical femur fracture, stop the bisphosphonate and also ask to have your other femur evaluated for a possible stress fracture, especially if you have or develop pain in the other thigh. For those contemplating beginning to take a bisphosphonate, I would make that decision not just on the basis of your bone density (T-score) or age or menopausal status, but rather on the basis of your risk as determined by the FRAX questionnaire.
Thank you Dr. Schneider for a wonderful interview on atypical femur fractures; your expertise in this area will be a great help to those suffering from this type of injury.
If anyone would like to join Dr. Schneider's online support group, you can contact her at: firstname.lastname@example.org
Dr. Schneider's testimony, before the FDA may be accessed at the FDA's pdf on the hearings last September 2011.
To see Dr. Schneiders testimony, put her name in the search box, and it will pull up her testimony on several different pages.
This transcript is very long, so finding her testimony is easier using the search feature.