Updated 10 October 2022
In previous articles, I’ve discussed the dubious science behind the diagnosis of osteoporosis and osteopaenia, and the utter lack of evidence that high calcium intake prevents bone fractures.
But, not one to let facts get in the way of a good marketing campaign, the bogus broken bone business grinds on relentlessly. Despite the widely-admitted unsuitability of DXA scans for the task of identifying individuals at elevated risk of fracture, many of my older female clients (and some not-so-old ones, too) have been “diagnosed” with osteoporosis or osteopaenia on the basis of their scan results, and pressured to start taking medical treatment.
For many years, the most-prescribed treatment for low bone density was bisphosphonate drugs, such as Fosamax, Actonel, Didrocal and Aclasta.
More recently, as the limitations and dangers of bisphosphonates have become more evident, new categories of drugs have gained a share of this lucrative market, including monoclonal antibodies (denosumab [Prolia], romosozumab [Evenity]), a selective oestrogen receptor modifier (raloxifene [Evista]) and a recombinant human parathyroid hormone (teriparatide [Forsteo]).
I am not in the business of giving medical advice, and this article does not constitute such advice. But I am a staunch advocate of informed consent: each person must weigh up the risks and benefits of any diagnostic procedure, treatment or interventional procedure, taking into account their individual circumstances.
Here’s what that risk-benefit analysis looks like for osteoporosis drugs:
Bisphosphonates
On the benefit side, for post-menopausal women who have already had a low-trauma fracture (i.e. breaking a bone in circumstances where it wouldn’t be expected to break) or have very low bone density, 100 women would need to take a bisphosphonate drug for three years in order for six of them to avoid a fracture of some type. (This metric is known as the “number needed to treat”, or NNT, and along with its obverse, the “number needed to harm”, should always be discussed as part of the informed consent process, as these are the most patient-relevant outcome measures.)
However, the type of fracture which bisphosphonates are best at preventing is vertebral fractures (one prevented for every 20 women who take the drug for three years), and in the clinical trials used to gain regulatory approval for these drugs, vertebral fractures are usually detected through the use of screening radiographs (i.e. x-rays that are administered to all trial participants at pre-set intervals), rather than clinically (i.e. when a person presents with sudden-onset back pain or loss of height).
“In other words it is not clear that it would be important to prevent subclinical vertebral fractures, nor is it clear that reducing this outcome represents an aggregate benefit when one considers the adverse effects of the medicines.”
Bisphosphonates for Fracture Prevention in Post-Menopausal Women With Prior Fractures or With Very Low Bone Density – the NNT
When it comes to hip fracture, the most feared and consequential fracture type, 100 women with prior fracture or very low bone density need to take bisphosphonates for three years in order to prevent one of them from breaking their hip. That’s a huge benefit for the one woman who didn’t have a hip fracture, of course, but the 99 other women suffer the risks of treatment, without experiencing this benefit.
For postmenopausal women who do not have a history of low-trauma fracture or very low bone density, there is no benefit whatsoever – no fractures prevented, but all women taking these drugs are at risk of rare but serious harms.
Given the limited benefits, the following hazards of bisphosphonates should weigh heavily in the decision-making process.
Bisphosphonate drugs are known to cause:
#1. Fracture of the mid-femur (thigh bone).
Yes, you read that right: Prolonged use of bisphosphonate drugs, which are usually prescribed to reduce the risk of fractures of the hip and vertebral column, raises the risk of fracturing the shaft of the femur, a relatively rare type of fracture, by up to 140 times. Researchers reporting on this phenomenon attribute it to the drug over-suppressing bone metabolism.
So what’s going on here? Normal bone metabolism involves two major cell types: osteoclasts and osteoblasts. Osteoclasts break down bone that has suffered microfractures due to everyday activities, then osteoblasts move into the spaces left once osteoclasts have dissolved the old, worn-out bone, and build new, strong bone.
Bisphosphonates work by restraining the activity of osteoclasts, but they do not stimulate the osteoblasts; in fact, they suppress the formation of new bone by up to 95%.
Hence, the increased bone density seen in people taking these drugs is purely from the retention of old, damaged bone in the cortex (outer shell of the bone) – not the formation of new, healthy bone in either the cortex or the trabeculum (the inner, spongy part of the bone, which is responsible for the bone’s resilience under stress). This worn-out old bone is more brittle than healthy bones, and prone to snapping just from everyday activities like standing up and walking – what doctors call a ‘low-energy femoral shaft fracture’.
One team of researchers concluded that
“Low-energy fractures of the femoral shaft with a simple, transverse pattern and hypertrophy of the diaphyseal cortex are associated with alendronate [Fosamax] use. This may result from propagation of a stress fracture whose repair is retarded by diminished osteoclast activity and impaired microdamage repair resulting from its prolonged use.”
Low-energy femoral shaft fractures associated with alendronate use
Another research team noted that patients who sustained this type of fracture had been taking Fosamax for an average of only 4.8 years, and that 76 per cent of them had experienced “thigh pain, vague discomfort, or subjective weakness” before their fracture. Unfortunately, these warning signs are usually dismissed by doctors, rather than prompting investigation. In 23 per cent of patients, the thigh simply ‘gave way’ without warning, causing them to fall. And, in 64 per cent of cases, both legs were affected.
Given that bisphosphonates have an extremely long half-life (10 years in bone), even after bisphosphonate intake stops, suppression of bone turnover – and elevated fracture risk – will continue.
#2. Upper gastrointestinal tract ulceration, reflux oesophagitis and oesophageal cancer
Painful gastroesophageal reflux is such a well-known side-effect that patients are given comprehensive information on how to take bisphosphonates to minimise the risk. In patients who do suffer this adverse reaction and are endoscopically examined, “findings generally indicated chemical esophagitis, with erosions or ulcerations and exudative inflammation accompanied by thickening of the esophageal wall”.
It should be noted that these structural changes are a precursor to oesophageal cancer, and indeed, a British study found that patients who had received 10 or more prescriptions for bisphosphonates, and used them for over 5 years, had almost double the risk of developing oesophageal cancer – a notoriously deadly type of cancer.
Persistent reflux is likely to be medically treated with a proton pump inhibitor (PPI) such as Losec, Prilosec, Zoton, or Nexium. Patients taking these drugs for more than 1 year are 44 per cent more likely to suffer a hip fracture, with the risk increasing with higher doses of PPIs and longer duration of use. Yes, welcome to the wonderful, wacky world of Scientific Medicine. Higher doses and longer duration of PPI use were both associated with an even higher risk of hip fracture: a 60 per cent higher risk in people taking PPIs for more than 4 years, and 2.65 times the odds of fracture in patients prescribed long-term high-dose PPIs.
#3. Osteonecrosis of the jaw
This serious condition involves death of bone tissue around the jaws, resulting in localised pain, numbness and altered sensation, exposed bone in the oral cavity, soft tissue infection and, loosening of the teeth. The risk of developing osteonecrosis of the jaw is increased by almost eight times in those receiving intravenous bisphosphonates, but oral bisphosphonates are also implicated. No consistently effective treatment has yet been discovered.
#4. Bone, joint and muscle pain
Severe, and at times incapacitating bone, joint and muscle pain affect 2-5 per cent of patients treated with oral bisphosphonates, and can occur days, months or years after commencing treatment. Not only may this pain be a harbinger of impending fracture (as indicated in point #1, above); but severe musculoskeletal pain obviously makes exercise difficult, if not impossible:
“Many patients were unable to walk, climb stairs, or perform usual activities. Some became bedridden and others required walkers, crutches, or wheelchairs.”
Reports of severe pain with bisphosphonates
Given that exercise dramatically reduces the risk of falls, the fractures that result from them, and premature death due to these fractures – even in high-risk elderly, osteopaenic women, preventing a person from exercising is akin to handing the patient their own death warrant.
#5. Cardiac arrhythmia
Atrial fibrillation (AF) is a disturbance in heart rhythm due to irregular electrical activity in the upper chambers of the heart. It may lead to heart failure, and increases the risk of stroke.
Studies attempting to determine whether bisphosphonates increase the risk of atrial fibrillation have reported inconsistent findings. While an early study found that the risk of developing atrial fibrillation was increased by up to 86 per cent in people who had ever used bisphosphonates, recent meta-analyses have dismissed the link for all bisphosphonates except zoledronic acid (Zometa).
However, a large Italian study found that patients who were currently taking alendronate (Fosamax) were almost twice as likely to develop atrial fibrillation as patients who had stopped bisphosphonate therapy over a year ago.
When you put all these hazards together with the findings of the Fracture Intervention Trial (FIT) – that taking Fosamax for four years did not reduce the risk of fractures in women with osteopaenia, while wrist fracture risk almost doubled in women with a femoral neck (“hip”) T score of greater than −2.0 – it is very clear that the risks of bisphosphonate treatment outweigh the benefits for this group. And even for women with osteoporosis, the significant harms of bisphosphonates still need to be weighed against the benefits.
Non-bisphosphonate osteoporosis drugs
Mounting concerns about the safety and efficacy of bisphosphonates have driven the development of other classes of drugs to treat low bone density, including denosumab (Prolia), raloxifene (Evista), romosozumab (Evenity) and teriparatide (Forsteo).
Prolia, in particular, has been enthusiastically embraced. But the paeans of praise for its ability to raise bone mineral density and reduce markers of bone turnover significantly more than bisphosphonates miss a rather crucial point: Prolia is no better than bisphosphonates at preventing fractures.
Prolia’s effects on vertebral fractures are on par with those of bisphosphonates: the NNT for prevention of clinical vertebral fractures (those that the patient actually complains of) is 62, while for radiologic fractures (those detected through screening), the NNT is 22. But for prevention of hip fractures, Prolia’s NNT was higher than that of bisphosphonates, meaning more women are subjected to the risk of harms including increased risk of urinary tract infections and eczema, without experiencing any discernible benefit.
In addition, a dramatic rebound effect has been documented when patients discontinue taking the drug:
“Its favorable skeletal effects reverse quickly upon its discontinuation, because of a vast increase of osteoclast number and activity, which leads to a subsequent profound increase of bone turnover above pre-treatment values, a phenomenon commonly described as ‘rebound phenomenon’. More importantly, most patients experience rapid, profound bone loss due to this burst of bone resorption that may lead in a minority of these patients to occurrence of fractures, especially multiple vertebral fractures…
Discontinuation of Dmab is associated with a 3- to 5-fold higher risk for vertebral, major osteoporotic, and hip fractures… The [vertebral] fractures in this setting are typically clinical, occurring a few months after the effect of the last Dmab injection has been depleted [24], and are often described as rebound associated vertebral fractures (RAVFs).”
Denosumab Discontinuation and the Rebound Phenomenon: A Narrative Review
Even delaying a Prolia injection for four months significantly increases the risk of suffering a vertebral fracture. Think carefully before you hop on the Prolia train, because once you’re on it, it’s awfully hard to get back off it again.
In an exhaustive 342-page review of non-bisphosphonate osteoporosis treatments, a team of UK academics concluded that these much-hyped new drugs aren’t any better than the old ones – just a lot more expensive:
“All non-bisphosphonates reduced the risk of vertebral fractures compared with no treatment [again, bear in mind that most of these are detected radiographically rather than clinically, so preventing them has little bearing on patients’ quality of life]. For fractures at the hip or at any non-vertebral site, all of the non-bisphosphonates reduced the average number of fractures, but, for some non-bisphosphonates, we could not exclude the possibility that this was a chance finding [my emphasis]…
The benefits of denosumab, teriparatide and romosozumab are few compared with their costs. For raloxifene, the risks generally outweigh the benefits.”
Denosumab, raloxifene, romosozumab and teriparatide to prevent osteoporotic fragility fractures: a systematic review and economic evaluation
The bottom line
If you have osteopaenia, you need to be on an integrated program of muscle and bone strengthening, incorporating exercise and nutrition – not drugs (either bisphosphonate or non-bisphosphonate), which offer you no real-world benefit while exposing you to the risk of rare but potentially devastating adverse effects.
If you have osteoporosis, you still need to weigh the risks of increased fracture with either long-term use of bisphosphonates, or ceasing treatment with denosumab – which you might be forced to do if you have an adverse reaction to it – against the modestly reduced risk of fractures that genuinely affect your quality of life (clinical vertebral fractures, and hip fractures). Muscle and bone strengthening, and falls prevention, should be a major focus of your treatment plan whether you opt for pharmaceuticals or not.
Bones are truly remarkable structures – marvels of engineering which are strong yet light; rigid yet rigid yet capable of some degree of flexion under pressure. But they are also the living embodiment of the maxim, “Use it or lose it!” Bone responds to the forces of muscles pulling on them, and the impact of weight-bearing exercise, by remodelling to become thicker and stronger at the points of greatest stress. No drug on the market does this.
The best advice that I can offer you to maintain strong bones for life, so you never have to weigh the modest benefits of osteoporosis drugs against their risks, is to stay active over your whole lifespan.
1 Comment
maureen stephens
06/05/2016great article! Relevent to Col & me.Thanks for researching it.Surprised us with your research results.
Leave A Response