Friday, April 23, 2010

Fractures and Fosamax

Dang, what was this 60-something year old lady(1) doing that resulted in her femur breaking like a branch across a gardener's knee? The unsettling answer? Nothing. She just felt a "giving away" sensation in her leg and then she gave way and went to ground. Of note, however, she had been taking medications for 17 years to prevent osteoporosis: first Fosamax and then Boniva.

Our bones are in a state of constant turnover. Breakdown of bone matrix by cells called osteoclasts is balanced by a corresponding build-up of bone mass undertaken by osteoblasts--a process that continually replaces old bone with new. In adults, bone formed equals bone broken down as osteoblasts fill areas along the bone surface previously resorbed by osteoclasts. Such dynamic restructuring in response to the forces of gravity and activity is essential to bone strength. In addition, this active bone metabolism repairs micro-traumas caused by everyday wear and tear as well as macro-traumas such as fractures.

As we grow older, we tend to breakdown faster than we build-up (well duh!). Ongoing osteoclastic activity is no longer countered in kind by reciprocal action from aging osteoblasts especially in women who are estrogen-deficient, inactive, on steroids, or deficient in calcium and vitamin D. Now bone resorbed by osteoclasts exceeds bone built by osteoblasts resulting in bones that are not only thinner but also architecturally unsound. As a result, vulnerable areas such as the hip, the vertebrae, and the bones of the forearms lose strength and fracture easily.

One strategy developed to combat this scenario is a class of drugs called bisphosphonates (Fosamax, Actonel, Boniva, Reclast, and others) which inhibit normal bone-remodeling through inhibition of osteoclasts. Since bone resorption triggers bone formation, these drugs are better suited to slowing loss rather than gaining mass. While population studies show decreased risk of fractures in persons using bisphosphonates, disturbing patient histories, such as that from the unfortunate lady pictured above, suggest that extended use of Fosamax and friends may result in bone fragility through the accumulation of microdamage in bones weakened by a loss of the normal reparative functions.

Texas researchers had a look at bone chips from persons who had spontaneous--i.e. no antecedent trauma--fractures while on Fosamax(2) most of whom had delayed or absent healing at the site of the break. Scary stuff on microscopic exam--many of the patients showed "markedly suppressed bone formation" with little or no osteoblastic activity and diminished mineralized bone. Even those patients on concurrent estrogen therapy demonstrated decreased bone formation. While Fosamax was the first bisphosphonate 'out of the gate' and thus most likely to be associated with fractures related to long-term use, scientists believe that this brittle bone thing may well be found with ongoing use of the other agents in this class.

Well yikes, is it time to boycott Boniva? Act not on Actonel? Consider first, this meta-analysis of several bisphosphonate trials.(3) These scientists from four different countries supported by Merck (Fosamax) and Novartis (Aredia, Zolmeta) analyzed data from three large studies looking for risk of fractures of the femoral shaft (considered atypical when compared with the more common fractures of the femoral head) as they were associated with use of bisphosphonates. Most reassuringly, they found such drug-related breaks to be rare, occurring at a combined rate of 2.3 per 10,000 patient-years. In other words, of 1,000 women using a bisphosphonate for 10 years, 2.3 would have an unexpected fracture of their thigh bone. There was no elevated risk of this type of fracture between those on Actonel and those on placebo, and a relative risk of 1.5 for women on Zolmeta (an IV bisphosponate most often used in serious situations such as in women with metastatic cancer where the drug slows down the spread of the tumor through the bones).

In an editorial that accompanies this study(4), Dr. Elizabeth Shane of Columbia University emphasizes that such atypical fractures are extremely rare, and particularly unlikely in persons on bisphosphanates. In fact, she cites studies that show, on average, that these femoral shaft fractures are more commonly caused by osteoporosis than the medications that treat the condition, and high adherence to this drug regimen more often decreases the risk of this type of bone breakage. She concludes: "many more common and equally devastating hip fractures are prevented by bisphosphonates than are potentially caused by the drugs."

Several authors have suggested that women on bisphosphonates be given a drug holiday in order to allow for a time of normal bone remodeling. Bisphosphonates bind to bone and are slowly released by osteoclastic activity. Fosamax is present in the body long after its use is discontinued--one study found bone turnover suppressed for three years after five years of regular Fosamax use. There are no official guidelines to follow with respect to intermittent bisphosphonate use, but one year off does not seem to diminish the positive effects on fracture risk.

What should you do? Talk with your doctor about taking a drug holiday (no, not THAT kind of drug holiday) if you've been on bisphosphonates for more than five years.
_____
(1) X-ray and case history from:
Goddard MS, et al. Atraumatic Bilateral Femur Fracture in Long-Term Bisphosphonate Use. Orthopedics. 2009 Aug;32(8). pii: orthosupersite.com/view.asp?rID=41933. doi: 10.3928/01477447-20090624-27.
(2) Odvina, CV, et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab. 2005 Mar;90(3):1294-301. Epub 2004 Dec 14.
(3) Black, DM, et al. Bisphosphonates and Fractures of the Subtrochanteric or Diaphyseal Femur. Published Online March 24, 2010 (DOI: 10.1056/NEJMe1003064).
(4) Shane, E. Evolving Data about Subtrochanteric Fractures and Bisphosphonates. Published at www.nejm.org March 24, 2010 (10.1056/NEJMe1003064)

6 comments:

kenju said...

I'm very glad not to have been taking any of those meds. My neighbor, who had a hip replacement last Oct., came home and in a very short time, she fell and broke her femur. The fracture was lengthwise in the bone. She was in rehab for 9 weeks; came home and all of a sudden, she couldn't set foot to floor without severe pain. Turns out the hip replacement had come loose. And yes, she was on one of those meds.

Jeanne said...

The study you site was funded by Merck and is clearly not one to rely on. Only 622 women in the study had been on the drug for as long as five years and most had taken a lower dose than usual. This so-called study is Merck's attempt to fight back against the negative publicity. Fortunately, a group of us victims will be seeing the FDA next month. I am very disappointed that you would find a positive in a pharma-sponsored study. Look at Dr. Joseph Lane's latest report to the American Academy of Orthopaedic Surgeons (March). He found that after only four years on the drug, the bones had thickened by the quality was degraded.

These drugs are dangerous and there are many, many more of us out here than ever thought. Very underreported.

My leg broke in half as I was coming into my house from getting my morning newspaper. I took fosamax for 3 years and boniva for 3 years.

Words can't describe what this life-threating event has done to me.

Anonymous said...

Hmm, praise the Lord and pass the Forteo?

Shammickite said...

Oh dear, now I'm worried. I have been taking Fosamax once a week for a long time, probably close to 10 years. Now I'm hoping that I'm not one of the 2.3 women who is going to experience an unexpected fracture. perhaps I should talk to my doc when I next go to see him.

Anonymous said...

I wouldn't touch those drugs with a ten foot pole. You have to have a grand belief that drug companies are honest and I know how much they are not.

Vitamin K1 and K2 are the answers, Been taking them for several years and the more I read, the happier I am with my decision. This, for example:
Vitamin K promotes mineralization, osteoblast-to-osteocyte transition, and an anticatabolic phenotype by -carboxylation-dependent and -independent mechanisms
http://ajpcell.physiology.org/cgi/content/abstract/297/6/C1358

I strongly suggest these references on the value of K and building bone:

1. Weber P. Vitamin K and bone health. Nutrition. 2001; 17:880–7.

2. Feskanich D, Weber P, Willett WC, Rockett H, Booth SL, Colditz GA. Vitamin K intake and hip fractures in women: a prospective study. Am J Clin Nutr. 1999; 69:74–9.

3. Booth SL, Tucker KL, Chen H, et al. Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women. Am J Clin Nutr. 2000; 71:1201–8.

4. Booth SL, Broe KE, Gagnon DR, et al. Vitamin K intake and bone mineral density in women and men. Am J Clin Nutr. 2003; 77:512–6.

Anonymous said...

I HAVE JUST DEVELOPED A SACRAL FRACTURE,SPONTANEOUS.I AM SO ANGRY THAT MY LIFE IS ON HOLD AGAIN.I DID RESEARCH AND FOUND THE SEVERE FRACTURES IN PTS,WHO HAVE BEEN TREATED WITH FOSAMEX OR ACTONEL.I WAS DX'D.WITH OSTEOPOROSIS IN 1994/95,H/O SEVERAL STRESS FX'S OF MY FEET. IN 2000, I DEVELOPED SPONTANEOUS UPPER VERTEBRAL FX'S. 4 MONTHS LATER COLLAPSE OF MY VERTEBRAE DUE TO NUMEROUS FX'S.
DX.OSTEOPOROSIS. 3 KYPHOPLASTIES. 2004.SPONTANEOUS FEMORAL HEAD FX. 2006: SPONTANEOUS VERTEBRAL FX.
DEC.2010;SPONTANEOUS SACRAL FX. I THEN DID THE RESEARCH ON THE WEB & FOUND THE SUITS AGAINST MERK FOR FOSAMAX. I WILL SEEK ADVISE REGARDING THESE DRUG FINDINGS.