Wednesday, January 09, 2008

Bisphosphonate induced pain in osteoporosis - statistical analysis discovered

The FDA issued an alert yesterday warning of "severe and sometimes incapacitating bone, joint, and muscle (musculoskeletal) pain" sometimes induced by bisphosphonates used to treat osteoporosis. Bisphosphonates include Actonel (Procter and Gamble) and Fosamax (Merck).

The formal statistical analysis reportedly produced by one pharmaceutical company for the FDA is shown.

Formal pain analysis - bisphosphonate therapy

According to today’s FDA warning, the severe musculoskeletal pain associated with bisphosphonates may occur within days, months, or years after starting a bisphosphonate. Some patients have reported complete relief of symptoms after discontinuing the bisphosphonate, whereas others have reported slow or incomplete resolution. The risk factors for and incidence of severe musculoskeletal pain associated with bisphosphonates are unknown. The FDA recommended that healthcare professionals should consider whether bisphosphonate use might be responsible for severe musculoskeletal pain in patients who present with these symptoms and consider temporary or permanent discontinuation of the drug.

Bisphosphonates have been linked to a variety of other safety problems. In October, the FDA announced that it was reviewing the drugs after studies showed patients taking bisphosphonates ran a higher risk of irregular heartbeat. Research published in the May 7 issue of the New England Journal of Medicine found that bisphosphonates appeared to increase the risk of irregular heartbeats in some older women. Researchers conducting a review of a 1997 study of postmenopausal women on Fosamax found that there appeared to be 50 percent more risk of the serious heart rhythm irregularities in women who took the daily pill than among those who didn’t take it. About half of the 6,459 women took Fosamax, and 47 developed atrial fibrillation, compared to just 31 cases among the other women.

Fosamax has also been linked to Osteonecrosis of the Jaw (ONJ), also known as Dead Jaw Syndrome, a condition in which the bone tissue in the jaw fails to heal after minor trauma such as a tooth extraction, causing the bone to be exposed. The exposure can eventually lead to infection and fracture and may require long-term antibiotic therapy or surgery to remove the dying bone tissue. In 2005, the Fosamax label was updated to include warnings about ONJ.
These are good drugs when used appropriately. However, I'm not sure that the risks and benefits (and possibility of unknown risk) have been appropriately weighed so as to allow correct, cost effective and safe targeting of therapy. We know nothing about the long term (30 year) benefits or risks of bisphosphonates.

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Anonymous said...

FOSAMAX will also cause sever heartburn and sever chest and stomach pain. It will also cause you to get sever scar tissue in your throat.

Anonymous said...

This website with patient reports:

They listen to patients but about 10 years too late.


Anonymous said...

Again here for the other

Ask Patient

Anonymous said...

Dear Dr. Blumsohn

There are obvious similarities between bisphonate adverse effects and the disease pycnodysostosis.

Toulous Lautrec’s genetic disease was a cathepsin K deficiency in the osteoclasts. Bisphosphonates work by chemically impairing osteoclasts. Current osteoporosis drug research is underway looking for more cathepsin K enzyme inhibitors.

Cathepsin K and osteoporosis

from Nature:

"Cathepsin K is a lysosomal cysteine cathepsin predominantly located in osteoclasts and is the major enzyme involved in bone resorption. The first evidence for this role came from a genetic study on pycnodysostosis, a rare genetic disorder associated with severe defects in bone growth, which revealed that an inactivating mutation in the gene encoding cathepsin K is a causative factor."

Missing Data? has raised the question of missing data from the Goodman study, Goodman RL. The effect of risedronate on the risk of hip fracture in elderly women. New Engl J Med May 31, 2001; 344: 1720 - 1721.

Note: worst requires a $15 membership fee to enter.

Risedronate (ACTONEL)

Quote from

"Risedronate, like alendronate, is associated with a modestly favorable effect on the risk for vertebral fracture. Vertebral fracture is a spinal fracture that may or may not be symptomatic. The absolute reduction in the risk of a new vertebral fracture in women taking risedronate is 5 percent compared to women taking an inactive placebo. The most benefit was seen in women with two or more vertebral fractures before they started taking risedronate.7

A published study sponsored by risedronate manufacturer Procter & Gamble suggests that risedronate may reduce the risk of hip fracture, the most serious consequence of osteoporosis, in elderly women with low bone mineral density by about 1 percent (the same result as alendronate).8 However, this study has been criticized on a number of grounds, including the fact that follow-up information was not available for 3,324 of the 9,331 women in the study.9 This could have biased the results in favor of risedronate by leaving out women who had fractures.

Risedronate is retained in bones for many years, but long-term effects remain uncertain. Concern exists because some bisphosphonates increase the occurrence of spontaneous fractures in animals."

Increased Fracture Rates

Is it widely known that fracture rates for women with osteopenia (T greater than -2.5) actually increases on bisphosphonates? Cummings JAMA 1998 FIT. The following Abramson Overdosed America quote is openly available on his website:

Excerpts From Overdosed America Chapter 13

"In 1995, Fosamax, the brand name for alendronate, was the first of the new generation of drugs approved by the FDA for the treatment of osteoporosis.....
What about using these drugs to prevent osteoporosis? The study of Fosamax published in JAMA in 1998 (mentioned earlier) also included women with osteopenia. Did Fosamax reduce their risk of fracture? The results show that the risk of hip fractures actually went up 84 percent with Fosamax treatment.* The risk of wrist fractures increased by about 50 percent." Quote attributed to John Abramson MD.

Bisphosphonates for Osteoporosis, A Closer Look at the Data by Jeffrey Dach MD

Fosamax, Actonel, Osteoporosis and Toulouse Lautrec by Jeffrey Dach M.D.

Jeffrey Dach MD
my web site