What are the bisphosphonates?
The bisphosphonates are a class of drugs that are generally prescribed, primarily for women who are late pre-menopausal, menopausal or post-menopausal to reduce and possibly reverse the demineralization of bone through calcium loss, usually targeting the two areas of the body where calcium loss causes the most damage: the spinal column (vertebrae) and the hip and thigh. They are also prescribed for certain cancers (mostly myeolomas, but also metastases from breast cancer in women and prostate cancer in men ), and diseases (Paget’s Disease, Osteogenesis Imperfecta, AIDS, certain types of renal failure) which have the direct unfortunate effect of inducing bone thinning and fractures of themselves, or which involve treatments that have those adverse side effects.
Why are these drugs in the news?
On October 13, 2010, the US Food & Drug Administration added some new information to be given to patients taking these medications, as well as to their prescribing physicians. It concerns a potential for a somewhat higher statistical chance for certain rare types of hip and thigh bone fractures for those who have been taking bisphosphonates for several years vs. the overall incidence of vertebral, hip and thigh fractures.
Why would this be news?
It most likely became news primarily because we as a public in the United States and perhaps elsewhere in the developed world, have become almost paranoid about drug recalls, and are often morbidly entertained by conspiracy thinking about “Big Pharma” and doctors who prescribe drugs allegedly because they are incentivized with free vacations, subsidized continuing medical education junkets, or some other type of underhanded inducements. Less than a month earlier, Avandia™ , a drug given to diabetics to forestall heart disease (ironically diabetes is not the direct cause of death for the vast majority of diabetics, the number one direct killer of diabetics is actually heart disease) counter-intuitively actually increased the chances of a small, but significant number of Avandia™-taking patients, to develop heart disease, and therefore was severely restricted.
What actually did the FDA advisory say to patients about these bisphosphonates?
On its website, www.fda.gov/Drugs/DrugSafety/ucm229009.htm the FDA advises patients to:
- Continue to take your medication unless you are told to stop by your healthcare professional.
- Talk to your healthcare professional if you develop new hip or thigh pain (commonly described as dull or aching pain), or have any concerns with your medications.
- Report any side effects with your bisphosphonate medication to FDA’s Medwatch program using the information at the bottom of the page in the “Contact Us” box.
What did the FDA advisory say to Doctors about these bisphosphonates?
On its website, www.fda.gov/Drugs/DrugSafety/ucm229009.htm the “FDA recommends that healthcare professionals should:
- Be aware of the possible risk of atypical subtrochanteric and diaphyseal femur fractures in patients taking bisphosphonates.
- Continue to follow the recommendations in the drug label when prescribing bisphosphonates.
- Discuss the known benefits and potential risks of using bisphosphonates with patients.
- Evaluate any patient who presents with new thigh or groin pain to rule out a femoral fracture.
- Discontinue potent antiresorptive medications (including bisphosphonates) in patients who have evidence of a femoral shaft fracture.
- Consider periodic reevalutation of the need for continued bisphosphonate therapy, particularly in patients who have been treated for over 5 years.
- Report any adverse events with the use of bisphosphonates to FDA’s MedWatch program using the information at the bottom of the page in the “Contact Us” box.
Any information provided to MedWatch should be as detailed as possible and include information concerning fracture location/configuration, magnitude of trauma, fracture details (complete or incomplete, bilateral, or comminuted), presence and duration of prodromal thigh or groin pain, duration of bisphosphonate use, relevant medical history, and concomitant use of other medications. “
What is the key point involved in these advisories?
There appears to be a tiny increase in the relative (but not necessarily absolute) number of subtrochanteric and femoral shaft fractures, largely in elderly women taking one of the bisphosphonates for several years. Depending on your means of calculating odds with the worst case statistics, this means that there is a worst case possibility that 3%-5% of all the patients at high risk for an osteoporosis-related fracture might get a different and fairly rare (“atypical” is the term used) fracture farther down the thigh than the usual location for such fractures, and it would be wise to monitor them for dull pain in the thigh and/or groin if they have been taking bisphosphonates for a long time (several years), because most patients (70%) who eventually have such a fracture had this tell-tale symptom first.
Does this mean that not taking bisphosphonates actually decreases your chance of getting a vertebral, hip & thigh fracture?
Absolutely not! Probably the best estimate, taken from Shane et al (2010) is that prescription bisphosphonates cut the number of vertebral fractures by 1000/10,000 patient years and the number of hip and thigh fractures by 700/10,000 patient years. This is an astonishingly positive benefit to risk ratio. Quite literally millions of people have benefited from taking these drugs, while at the worst perhaps 300-400 cases drawn from about 170 pooled articles, have been documented in the medical literature as having these rare fractures or other complications, in conjunction with their taking bisphosphonates .
Are there any confounding conditions connected with the women taking bisphosphonates and subsequently having one of these atypical fractures?
Yes, while the number of studies and case reports are scattered and do not all follow the same protocols for diagnosis and classification of these traumas, it appears, that a fair number were older and in generally poorer health, had been using proton pump inhibitors for gastric reflux, had a history of osteoarthritis, had previous bone fractures and in some cases had taken cancer chemotherapeutic or immunosuppressive drugs. In other words, they had rather lengthy prior histories of medical importance. There is also some suggestion that Asian women were at greater risk. However, other studies of women without all these complications or predispositions, or with matching records of having them to the same degree, still show some increased risk of having these atypical fractures. There is little doubt that the risk of these atypical fractures is real, but significant doubt as to just how small the number of affected individuals might be when compared to the overall pool of people at risk for osteoporosis-related fractures: 5%?, 4%, 3%?, 2%?, 1%?, 0.1%, 0.01%? To determine better just what the odds are, and to track what happens when the bisphophonates are discontinued at the earliest signs of trouble, a registry of cases is being proposed (Shane et al 2010). Nonetheless, no fewer than 20 of the articles cited below still regard prescription bisphosphonates as the strategy of choice for patients seriously at risk for osteoporosis-related fractures.
What about bisphosphonates might be causing this small number of atypical fractures?
Fractures from osteoporosis related causes tend to be owing to the thinning of the cortical (outermost) structural layer of bone, and/or from accumulating defects in the microarchitecture of the minerals in the bone. Bisphosphonates may be better at strengthening the cortical thickening than they are at repairing microarchitecture, or the methods or route by which they strengthen the cortex has the unintended side-effect of further weakening the microarchitecture. This microarchitecture weakness would make help us make sense of the tiny minority of patients who also have a necrotic reaction to bisphosphonates that manifests itself in the jaw to the degree that it causes the drug’s discontinuance, and makes dental procedures problematic. (But even in the cases of jaw misadventure, the patients are older, poorer, and sicker on average). In other words, bisphosphonates may not be the perfect medicine for this condition, albeit they are the best we currently have in production and have been proven safe and effective for millions thus far.
So, should we not be glad that the FDA stopped this "Big Pharma" conspiracy?
Well, even the worse conspiracy theorists would be dumbfounded when they learn that 21 of the 23 researchers involved in the key Task Force of the American Society for Bone and Mineral Research overview (Shane et al 2010) on which the FDA’s modified patient and physician advisories were based, either worked for, or had taken funding from, those allegedly evil folks in Big Pharma. It is little understood by many in the investigative reporting business that sometimes the greatest pool of expertise really does come from people who do research within or are funded by, businesses who generally make our lives much better, because developing new drugs that help us manage or cure diseases is pretty much their life’s work.
What would be the most likely health outcomes if people were scared off taking their bisphosphonates by overhyped media reports?
Funny that you should ask, because a study of this has already been done in Australia where medical and prescription drug records are available to researchers owing to governmental benefits programs. According to Sambook et al 2010, adverse media reports on the side effects and risks for bisphosphonates appearing in Australia last year probably resulted in the ensuing nine months in 70 more hip fractures, 60 more other fractures (largely vertebral) and 14 more deaths, than would have occurred if the patients had simply stuck to taking them.
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