Bisphosphonates are one of the most commonly prescribed drug classes. Their intended purpose is to strengthen bones, and thereby prevent fractures. They are primarily prescribed to postmenopausal women with evidence of bone thinning, either because a bone scan has shown that they have a weak skeleton, or because they’ve experienced a fracture from relatively low energy trauma. Examples of drugs in this class are alendronate, risedronate, and zoledronic acid. Basically, any drug that has a name ending in “-dronate” or “-dronic acid” is a bisphosphonate.
The mechanism of action is pretty ingenious. Our skeleton is continuously recycling itself throughout our lifetimes, and the work of recycling is primarily carried out by two types of cell: osteoblasts and osteoclasts. Osteoblasts build new bone and osteoclasts destroy old bone. What bisphosphonates do is to selectively poison and kill osteoclasts. This changes the balance of bone recycling to one that favours build-up of bone, which is why bisphosphonates have been unequivocally shown to make bone thicker.
But do they actually prevent fractures? And what are the downsides to a drug that inhibits the normal recycling of bone?
There are about a bazillion different studies of bisphosphonates, so for the sake of brevity and simplicity, I’m going to focus in this article on just a few, which are representative of the whole.
The first study we’re going to talk about was published in JAMA (the Journal of the American Medical Association) in 1998. It was a four year long randomized controlled trial in which roughly 4,300 post-menopausal women with evidence of bone thinning on scans were randomized to receive either alendronate or placebo. Alendronate is a bisphosphonate that is taken as a pill, either as a lower dose once a day or a higher dose once a week. In this particular study the participants were taking the lower dose once a day.
The study was funded by Merck, the company that held the patent for alendronate. Unfortunately, big independent studies of bisphosphonates don’t exist, so we’re forced to rely on what the pharmaceutical industry feeds us. It’s been shown that industry funded studies systematically overestimate benefits and underestimate harms, so the results presented here should be considered best case scenarios. As I’ve written about previously, there is evidence that in the real world, side effects are three to four times more common than they appear to be in industry funded randomized trials.
Another thing worth noting is that 1998 is pre-2000, which means that the study was carried out before the birth of clinicaltrials.gov, and before there was any serious expectation that companies register trials before beginning them. In theory that means that Merck could have run five different studies, and only published the results from the one the provided the best results, while “disappearing” the other four. In this particular case, that is unlikely, for the simple reason that this was a 4,000 person study, which is probably just too damn big and expensive to “disappear” if the outcome proves unsatisfactory.
The fact that it’s a pre-2000 study however also means that Merck could easily have engaged in various post-hoc manipulations of the study design, in order to maximize apparent benefits and hide harms, without anyone being any wiser. That’s unfortunately something we have to live with. So, again, the results should be considered best case scenarios.
Anyway, let’s take a look at what those results were.
14.1% of women in the placebo group experienced an osteoporotic fracture during the four year study period, as compared with 12.3% in the alendronate group. This gives a 1.8% absolute reduction in risk of a fracture after four years of treatment, which means that you would need to treat 55 women for four years in order to prevent one fracture.
On closer inspection, however, the alendronate only appeared to provide a benefit to those with the very weakest skeletons (defined as having a bone density more than 2.5 standard deviations below the mean bone density of a healthy young person). Among these women, 19.6% of those in the placebo group experienced a fracture over the four years, compared with 13.1% in the alendronate group. This gives a 6.5% absolute reduction in risk, which would mean that one in 15 women treated for four years would benefit from the treatment.
That really isn’t bad for a drug that is taken for the purpose of prevention. For comparison, statins generally require that 200 people be treated for five years in order to prevent one heart attack. And blood pressure lowering drugs require that 70 people be treated for five years to prevent one stroke. So by those standards, one in fifteen odds of benefit are really good.
Alendronate somewhat prevented the loss of height that gradually happens due to compression of the spine when you have a weak skeleton, by about 1.5 mm over four years. The placebo group lost 8.5 mm over four years, while the alendronate group lost 7 mm. The result is statistically significant. Clearly, however, 1.5 mm over four years is a difference that is too small to be noticeable to the patient, so it isn’t clinically significant, and thus isn’t a reason to take the drug.
Ok, so now we know the size of the benefit. What about harms?
Unfortunately, the information on harms provided in the trial report is extremely limited. We are told that 1.8% of participants in the placebo group died, compared with 1.7% in the alendronate group, so there is no signal that the alendronate is causing excess deaths, which is good. There were slightly more hospitalizations in the alendronate group, with 29.1% in the alendronate group being hospitalised, compared with 26.9% in the placebo group. This is concerning, because the whole point of taking alendronate is to avoid ending up in hospital, and this suggests that the alendronate actually increases the risk slightly. Of course, the increase is small enough that it could just be due to chance, but it certainly doesn’t suggest that the alendronate decreases risk.
The only more specific information that is provided on harms in the trial report concerns stomach issues. The reason stomach issues are given special attention is that earlier studies have found that bisphosphonates when given daily can cause inflammation in the esophagus. There was a signal of that here also, with 10 cases of esophagitis in the placebo group, compared with 19 in the alendronate group, which would, if taken at face value, mean that roughly one in 230 patients develop esophagitis as a result of the treatment (although the small absolute numbers make it impossible to draw any firm conclusions).
Nowadays, bisphosphonates are often given weekly in order to avoid the risk of esophagitis. Unfortunately, weekly dosing has instead been found to cause its own set of side effects: aches in muscles, bones and joints during the days immediately following intake of the drug. Researchers at the Charité hospital in Berlin looked at the frequency of these side effects in their patients treated weekly with alendronate or risedronate and found that the risk of muscle pain, joint pain, or bone pain developing during the first 48 hours after a weekly oral dose, and which is severe enough to cause the patient to decide to stop taking the bisphosphonate, is 20-25%. If one in four to one in five patients have aches and pains severe enough that they decide to stop the drug, then it’s reasonable to think that there are many more who experience at least some aches and pains as a result of the bisphosphonate, but who don’t decide to stop the drug.
There is an upside to this though – daily dosing causes one type of side effect, and weekly dosing causes another type of side effect. Since it’s unlikely that it’s the exact same group that experiences the stomach issues and the musculoskeletal pain issues, that means that someone who experiences stomach issues with daily dosing can try switching to weekly dosing instead, while someone who experiences aches and pains with weekly dosing can try switching to daily dosing.
Let’s move on to the next study. Like I said earlier, bisphosphonates can either be taken as a pill or be given as an annual injection. With this in mind, let’s take a look at a trial that was published in the New England Journal of Medicine in 2007. Like the previous trial, it was double-blind, randomised, and placebo-controlled. And like the previous trial, it was funded by the company that held the patent on the drug, in this case Novartis.
8,000 postmenopausal women with osteoporosis were randomised to receive either an injection of zoledronic acid or placebo once a year, and then followed for three years to see whether they had any fractures. So, what were the results?
At three years, 12.8% of participants in the placebo group had a clinically noticeable (i.e. symptomatic) osteoporotic fracture, compared with 8.4% in the zoledronic acid group. That gives an absolute reduction in risk of 4.4%. In other words, for every 23 postmenopausal women with osteoporosis that are treated with zoledronic acid for three years, one fracture is prevented. That is very similar to the benefit seen in the previous trial.
In terms of height loss, the patients in the zoledronic acid group lost an average of 4 mm of height, while the patients in the placebo group lost 7 mm. So that’s a 3 mm difference after three years, which is more impressive than the previous trial, but still so little that it’s unlikely to be enough to cause a meaningfully noticeable difference in height, even with extended use.
What about side effects?
Serious adverse events (i.e. death, hospitalisation, or lasting disability) were very similar between the two groups. 30.1% experienced a serious adverse event in the placebo group, and 29.2% did in the zoledronic acid group. So, unlike in the previous trial, there’s no signal that the drug increases the risk of a serious adverse event, which is encouraging. However, there were slightly more deaths in the zoledronic acid group than in the placebo group (3.4% vs 2.9%), which isn’t. Both sets of differences are so small though that they can easily be due to chance.
People who received the injection with zoledronic acid were quite likely to experience influenza-like symtoms (fever, muscle pain, joint pain, headache) during the days immediately post-injection. After the first of the three annual injections, fully 32% of patients in the zoledronic acid group experienced these symptoms, compared with only 6% in the placebo group. With each additional injection, this side effect became less and less common, however.
People might be willing to put up with a few days of influenza-like symptoms for improved odds of avoiding a broken bone. What’s more concerning, however, is that the study participants on zoledronic acid were more likely to develop atrial fibrillation than the participants in the placebo group, with 50 serious events in the zoledronic acid group, compared with only 20 in the placebo group. This works out to roughly one in 260 people who are treated with zoledronic acid developing a serious case of atrial fibrillation (i.e. requiring hospitalisation) over three years of treatment.
Of course, in a study you look at lots of different adverse events, and so a difference between the groups in any one might appear just by chance. However, in this case the risk does appear to be a real – a meta-analysis of observational studies and randomised trials of bisphosphonates published in 2013 found that they do significantly increase the risk of atrial fibrillation.
There are two very serious side effects associated with bisphosphonates that I haven’t yet mentioned – osteonecrosis of the jaw (a debilitating condition in which the jawbone breaks down) and atypical hip fractures (fractures that happen in weird parts of the hip, that are never seen in people not treated with bisphosphonates). Does this massive trial with 8,000 people shed any light on how frequent these side effects are?
Well, in the trial there was one case of osteonecrosis in the placebo group, and one case in the zoledronic acid group, so no signal of harm. With 8,000 people in the trial, that is reassuring, suggesting that osteonecrosis caused by zoledronic acid is very rare (at least in otherwise healthy elderly women with osteoporosis). So we have to look elsewhere for information on how frequently osteonecrosis occurs in patients treated with bisphosphonates.
An observational study carried out in Australia found that osteonecrosis occurs in roughly one in 4,000 people treated with bisphosphonates, although this rises massively to one in 500 people who have a tooth extraction while undergoing treatment. That is why it’s generally recommended that patients have a dental appointment and get any bad teeth taken out before they start taking bisphosphonates. The risk of osteonecrosis rises even higher to one in 100 people who have cancer in their bones. So for this group bisphosphonates are quite risky.
What about atypical hip fractures? Both this trial and the one I discussed earlier found a reduction in overall hip fractures among those treated with bisphosphonates, with a decrease from 1.1% to 0.9% over four years in the first trial, and a decrease from 2.5% to 1.4% over three years in the second trial. No specific information is provided about atypical hip fractures, but whatever increase in atypical fractures is seen with the drug appears to be more than made up for by a decrease in regular hip fractures.
Ok, so let’s sum up. With the caveat that we are as usual forced to rely on industry funded studies, bisphosphonates do appear to result in a meaningful reduction in risk of fractures in patients with radiographically confirmed osteoporosis (i.e. a T-score of -2,5 or worse), with roughly one in 20 treated patients benefiting after a couple of years of treatment.
What about harms? Well, that’s where it gets complicated, and where benefits and risks need to be weighed carefully. The alendronate trial showed a two percent increased risk of ending up in hospital overall, while the zoledronic acid trial showed a one percent decreased risk. This suggests that the net effect of these drugs on risk of hospitalisation is somewhere close to zero. That would mean that the overall benefit in terms of a decreased risk of experiencing a fracture is made up for by an increased risk of other things (atrial fibrillation, esophagitis, osteonecrosis, etc). So a conversation really needs to be had with the patient about which set of risks they’d rather be taking.
Even if the patient does decide to take the bisphosphonate, a high protein diet prevents just as many fractures as bisphosphonates do without the risks, and resistance training also offers massive benefits, decreasing the risk of a fracture while improving overall quality of life. Bisphosphonates should therefore primarily be used as a complement to lifestyle changes, not as a stand-alone treatment.