[fmichael]

Jim Broatch of the RSDSA sent out an email alert today regarding the results of a new study on a bisphosphonates, idicating that in a sample of 111 postmenopausal woman, all of whom had been taking bisphosphonates for at least four years. had an increased risk for an unusual type of femur fracture compared with 50 similar women who were taking calcium and vitamin D supplements for bone health:

Long-term use of popular osteoporosis drug may harm bone
By Shari Roan
Los Angeles Times

Medications called bisphosphonates are standard tools for the treatment of osteoporosis. They include Fosamax, Boniva, Actonel and Reclast. But new data released Wednesday raise some concern about whether the drugs are safe for long-term use.

Although the medications help increase bone quantity in the short term, two studies presented at the annual meeting of the American Academy of Orthopaedic Surgeons suggest that they may impair bone quality if used for four years or more. The drugs may suppress the body's natural process of remodeling (removal and replacement of bone tissue) resulting in brittle bones that are prone to fracture. In one study, 111 postmenopausal women who had been taking bisphosphonates for at least four years had an increased risk for an unusual type of femur fracture compared with 50 similar women who were taking calcium and vitamin D supplements for bone health.

The researchers stressed, however, that the drugs are still useful in the early years of use and people should not stop taking them. But more research is needed, said Dr. Melvin Rosenwasser of Columbia University Medical Center in a news release.

"Bisphosphonate use is still a very effective solution that prevents bone loss in most patients and no one is recommending that physicians avoid prescribing these," he said. "However, as baby boomers age and continue to remain active, it is important that we conduct more research and develop sustainable, safe and effective treatments for osteoporosis."

http://latimesblogs.latimes.com/boos...dications.html

I ran a couple of searches on PubMed, one for "Melvin Rosenwasser" and the other simply searching under "bisphosphonates," but as of a few minutes ago, nothing of immediate relevance was coming up, in any listing format.

Before getting too excited about this study, we need to see if all of the test subjects were being treated for oestioporosis. That could make a huge difference in terms of the generality with which it can be applied, e.g., for CRPS patients with no history of oestioporosis.

Mike

[Dubious]

And a slightly different spin...

http://www.sciencedaily.com/releases...0310083439.htm

But this apparently has been known for awhile...


Osteoporos Int. 2009 Aug;20(8):1353-62. Epub 2008 Dec 9.

Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study.
Lenart BA, Neviaser AS, Lyman S, Chang CC, Edobor-Osula F, Steele B, van der Meulen MC, Lorich DG, Lane JM.

Hospital for Special Surgery, New York, NY 10021, USA.

Comment in:

Osteoporos Int. 2009 Aug;20(8):1457-8.

SUMMARY: Recent evidence has linked long-term bisphosphonate use with insufficiency fractures of the femur in postmenopausal women. In this case-control study, we have identified a significant association between a unique fracture of the femoral shaft, a transverse fracture in an area of thickened cortices, and long-term bisphosphonate use. Further studies are warranted. INTRODUCTION: Although clinical trials confirm the anti-fracture efficacy of bisphosphonates over 3-5 years, the long-term effects of bisphosphonate use on bone metabolism are unknown. Femoral insufficiency fractures in patients on prolonged treatment have been reported. METHODS: We performed a retrospective case-control study of postmenopausal women who presented with low-energy femoral fractures from 2000 to 2007. Forty-one subtrochanteric and femoral shaft fracture cases were identified and matched by age, race, and body mass index to one intertrochanteric and femoral neck fracture each. RESULTS: Bisphosphonate use was observed in 15 of the 41 subtrochanteric/shaft cases, compared to nine of the 82 intertrochanteric/femoral neck controls (Mantel-Haenszel odds ratio (OR), 4.44 [95% confidence interval (CI) 1.77-11.35]; P = 0.002). A common X-ray pattern was identified in ten of the 15 subtrochanteric/shaft cases on a bisphosphonate. This X-ray pattern was highly associated with bisphosphonate use (OR, 15.33 [95% CI 3.06-76.90]; P < 0.001). Duration of bisphosphonate use was longer in subtrochanteric/shaft cases compared to both hip fracture controls groups (P = 0.001). CONCLUSIONS: We found a significantly greater proportion of patients with subtrochanteric/shaft fractures to be on long-term bisphosphonates than intertrochanteric/femoral neck fractures. Bisphosphonate use was highly associated with a unique X-ray pattern. Further studies are warranted.

PMID: 19066707 [PubMed - indexed for MEDLINE]

So it seems that osteoporotic women who have been taking biphosphonates for longer than 4 years are at increased risk for transverse intertrochanteric femur fractures. Not a happy thing...

[fmichael]

Agreed. While this may not effect everyone in our community - and I have to assume we have osteoporotic women in our klan - these developments will bring sorrow to many people.

And deep regrets to all for the last two paragraphs in my response to Sandy (on Thursday afternoon) in the "Agriculture Committees" thread. They were unnecessarily inflamatory, if reflective of my position on the issues. I had already made the point I needed with the Holmes via Frankfurter quote, and should have stopped there.

Mike

[mrsD]

You might be interested here on this thread to see animations that illustrate how bone is affected by various osteoporosis treatments.

The bisphosphonates mechanism of action was known for years before these new reports have appeared:

http://courses.washington.edu/bonephys/opmovies.html

What basically happens is the the osteoblasts (the cells that reincorporate calcium into bone), stop working.

[fmichael]

Thank you, mrsD.

It does indeed sounds as though biphosphonates may not be the wonder drugs for osteoporotis (another off-label use) they appeared to be only a couple of years ago. That said, if they still reduce the risk of vertebrae fractures, it might be worth it. I can only allude to what my maternal grandmother went through over the last 15 years of her life: it was pretty terrible stuff as her vertebrae turned into tissue paper.

Last I looked, biphosphonates had only been approved by the FDA to prevent bone uptake into the bloodstream of patients with mutiple meyloma and other metastatic conditions impacting bone tissue. Patients who would otherwise be looking at the prospects of near-term renal failure: not sure what role dialysis can play here, but in any event, it's not pretty. And I suspect that, with an average survival rate now approaching 3.5 years from diagnosis, patients with with full blown multiple myeloma would be willing to accept the risk of a femoral fracture four years hence.

That said, Novaris, the manufacturer of Zometa (Zoledronic acid) the biphosphonate I have been given, recommends 4 mg infused over 15 minutes "every three to four weeks" for cancer patients. http://www.us.zometa.com/hcp/product_info/dosing.jsp And that is significantly higher than than what had apparently been the prevailing practice of dosing osteoporotic patients with 5 mg, once a year. See, e.g., Kenneth W. Lyles, M.D., Cathleen S. Colón-Emeric, M.D. et al., Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture, NEJM Volume 357:1799-1809, November 1, 2007 FREE FULL TEXT at http://content.nejm.org/cgi/content/full/357/18/1799; Chapurlat RD, Treatment of osteoporosis with annual iv zoledronic acid: effects on hip fracture, Ther Clin Risk Manag. 2009 Apr;5(2):169-75, FREE FULL TEXT at http://www.ncbi.nlm.nih.gov/pmc/arti...6/?tool=pubmed

So it's possible that of the many bone fractures of MM patients, some were wrongly attributed to the disease, as opposed to its treatment, sad to say.

For what its worth, my pain doctor started me with three monthly infusion of 4 mg. each, followed up by no more than 1 booster infusion every 10 - 12 months thereafter. [In a much earlier post, I incorrectly stated the mg./dose and overshot the mark by an order of magnitide. I realized my mistake a few of weeks ago when I read the box the vial came in and then doubled checked with the doctor; I must have misunderstood him years ago.] As I now understand it, this appears, in the first year, to have be higher than the dose typically given to patients with osteoporosis, and comparable thereafter.

Accordingly, the comparative dosages may give no comfort to CRPS patients who already have osteoporosis, what's more interesting is in the case of those who have ever been found to have had bone density issues that were presumed seconday to their CRPS.

Whether CRPS patients without osteoporosis are at risk, may at present be an open question. That said, it shouldn't be too hard to put together a multi-center retrospective longetudinal matched pair study using CRPS patients, all of whom had a 3-phase bone denisity study (or an equivlent test) predating the arbitrary lookback date and in any event before the patient had been exposed to either either biphosphonates or pamidromates, and then matching for things like age, sex, prior bone density, length of illness, smoking, etc. At which point it should be straitforward enough to identify those "matching" characteristic (if not all of them) for which the continued use of biphosphonates is problamatic at best.

Finally, and this is just a total guess, but, at least in a perfect world, at least the retrospective aspect of a population study (it's possible to continue with follow up testing on the same people every few years) should be able to short-cut a lot of IRB red tape, to the extent the testing procedures are deemed sufficiently non-invasive. I can hope, right?

Mike

[fmichael]

Bumping to note the scrapping and replacement of final 2 paragraphs of last post, that and I caught maybe 8 bad typos.

[CRPSbe]

In Belgium, bisphosphonates are used to treat recalcitrant RSD; this according to an article that appeared in a rheumatology magazine in 1997.

This would be the one:

Treatment of severe, recalcitrant reflex sympathetic dystrophy: Assessment of efficacy and safety of the second generation bisphosphonate pamidronate
http://www.springerlink.com/content/722m672517805281/