For a long time, specialists from the
medical world have been expressing the opinion and accumulating arguments that
something else was the cause of the problems and
s regulators have responded slowly to increasing demand for
action. This is very reminiscent
of the 19th century where the jaw problem was causing much misery but was being brought to the attention of
the public and the regulatory agencies by slowly accumulating voices
contradicting the alternate explanations offered by the manufactures of the
profitable matches. But the persistence of some dedicated individuals and a
genuine sense of responsibility for the public good eventually led to the
restrictive legislation which eliminated the toxic exposure. The United States
was the last major nation to regulate the problem, at least a decade after
Europe had agreed to do so.
Rosenberg: Sounds like what is happening with the bone drugs today. Regulatory agencies in England and in Europe recognize the drugs as contributing to fractures, but in the US, the FDA has stopped short of that. They are still highly marketed.
Hinshaw: The bisphosphonates are a very polarizing class of drugs. The enthusiastic industrial support of the clinical trials has created a cadre of dedicated bisphosphonate supporters, convinced that the presumed benefits outweigh any possible risk. Many appear to believe the bisphosphonates will conquer cancer and polish off malaria and schistosomiasis as well as eliminate the specter of "osteoporosis." Despite a trend toward less use (for which I credit the good sense of the patients) Fosamax, in its cheap generic form [alendronate] is still the most prescribed drug for postmenopausal treatment or prevention of osteoporosis. Because of its attractive price, it is still the first choice of the insurance companies who pay for the drugs, and there is no evidence that this is going to change any time soon.
Rosenberg: How did your bisphosphonate skepticism develop? Did you once prescribe them and change your mind?
Hinshaw: My wife, with whom I share a gynecological practice for women of menopause age, and I have not prescribed them since 1998 when it became apparent to us that their action does not make sense metabolically or chemically. They suppress bone remodeling as if bone remodeling were the "bad guy" in osteoporosis and doesn't have the purpose of renewing and strengthening bone. They create a temporary improvement in the balance between bone loss and bone formation which are normally linked--but in a short time bone formation is suppressed, too.
Rosenberg: So the drugs do not even work?
carefully controlled clinical trials showed a reduction in fracture risk, usually
over 3 years of use, for a subset of the types of patients currently being
treated, but the use of these drugs has been extended to many persons with
clinical profiles which do not correspond to the trial evidence. The use of these drugs in community medicine is very
different than in the monitored trials. One major difference is that the drugs
have been used for prolonged periods greatly exceeding the length of the
trials. The problems have mostly
developed after approximately 6 years. Some studies
have been unable to detect any benefit at all like one of thousands of women at Kaiser Permanente treated between 1996 and 2006
and finally published in 2009. Roughly one in
500 bisphosphonate patients sustains an unusual thigh fracture on the drugs which
adds up to a large and increasing
ly number of cases because of their
widespread international use. In 81 patients whose cases we studied, fractures
occurred not just in the thigh but in the pelvis, feet and ribs as well and
many were "announced" by persistent pain. Subsequent or simultaneous
fracture of the opposite thigh was also common.
Rosenberg: Clinical trials of bisphosphonates has been impeded by the difficulty in finding women who don't have the drug in their system. How long do the drugs remain?
Hinshaw: Bisphosphonates are nonmetabolizable, resident drugs that never completely leave the body--never. After treatment stops, the burden decreases but there is no point when the resident molecules can be expected to be completely gone. They are not found in circulating serum (except temporarily with an injectable bisphosphonate like Reclast) because they attach s o rapidly to calcium/bone. When they happen to be released from one cache, they can be "recycled" into others. They have such a strong attachment to calcium that patients who swallow calcium supplements when they take bisphosphonates, against directions I may add, may be doing themselves a favor--because bisphosphonates will bind to the calcium instead of their bone.