Thursday 31 October 2013

Osteoporosis drugs – cosmetic surgery for the bones?

One of the most popular drugs prescribed these days are the bisphosphonates. You may know them as Fosamax (alendronate) or Actonel (risendronate). They have been pitched as the drug that everyone with osteoporosis should take, and if you are a female over 50, you may have been advised to get your bone density measured, in case you need to take these drugs. Worldwide sales of Fosamax alone hit the $3 billion mark before it went off patent in 2008. We know the drugs increase bone density, but that is just cosmetic surgery for the bones. How much of that translates into fracture prevention? And how many people would want to take this drug if they were given an accurate description of the risks and benefits?

How bone works
Bone is a living organ. Structurally, it is in a constant state of turnover. On a microscopic level, new bone is continuously being laid down and old bone is being reabsorbed. Microscopic fractures are being gobbled up and new bone is laid down in their place .

How Fosamax works
Fosamax blocks bone resorption (bone breakdown). Bone continues to be laid down, but none is taken away. This makes the bone more dense, but it is no longer in balance and structurally, it is not the way the body thinks it should be.

Bone density is not everything
Bone that is 10% more dense is not necessarily 10% stronger. To use an extreme example, consider people with “marble bone disease” – osteopetrosis; they have the ultimate bone density. Bisphosphonate drugs for osteoporosis stop bone resorption by bone-eating cells called osteoclasts, so the bone-making cells (osteoblasts) work unopposed. In osteopetrosis, there is a congenital loss of osteoclasts, so the patient’s bones are extremely dense (see picture) and surgery on these patients requires special tungsten tip and diamond drills and is still almost impossible. Interestingly, these patients often sustain fractures because their bones are hard, but like concrete, they are also brittle.

Also, the biggest risk factor for a fracture is not bone density, it’s falling. Falling comes from confusion, poor vision, sedative medications, unfamiliar surroundings, or simply getting up at night and stumbling to the bathroom without a light, etc.

Does Fosamax work?
In any study looking at bone density, Fosamax increases the density. But because none of us can feel our bone density, that outcome is not patient-relevant. Does it prevent fractures? The answer is yes, but mainly in those who have a very high risk of fracture, i.e. those with osteoporosis who have already sustained a low-energy fracture, not for those who are healthy but happen to have low bone density.

In patients with low bone density (without a previous low-energy fracture), it only increases their density – it doesn’t reduce their risk of a clinically important fracture.

This Cochrane review summary gives you the comparative numbers for Fosamax versus placebo.

The upside
In patients with a previous low-energy fracture (like a hip or wrist fracture after a simple fall), Fosamax has repeatedly shown that it will reduce the risk of a hip fracture (probably the most important one to prevent) from 2% to 1% over 3 years. You can call that a 50% reduction, but I call it a 1% reduction. Still, multiply this number by the number of people at risk and you can save a large number of fractures with this drug, even though 100 people need to be on the drug for 3 years to prevent one hip fracture.

The downside
If taken for more than 3 years, the risk of inducing a stress fracture of the femur rises. This occurs because the stress fractures that usually occur in your body cannot heal properly, and although your bone is denser, it is also structurally inferior and the thigh bone cracks easier, often bilaterally, and often with normal walking, not a fall. These fractures usually don’t heal on their own and usually need surgery. The chance of getting one of these fractures is low, but the risk increases the longer you take the drug, and remains high for a long time after ceasing the drug.

The drug tastes bad and often causes heartburn, nausea or flu-like symptoms. This and the inconvenience often cause patients to stop taking the drug. This situation has been improved since it changed from daily to weekly dosing. The intravenous form only needs to be given once or twice per year, but is a bigger deal to administer.

There is a financial cost. Depending on your country’s medical system, it may cost you personally few hundred dollars per year, or it may cost society that much.

Rarely (about 1 in 10,000, but this risk increases the longer you are on the drug) the drug causes a problem with your teeth called “osteonecrosis of the jaw”. This means that the bone in your jaw dies and all your teeth fall out.

The balance of risk and benefit.
Most reviews (like these here, here and here) conclude that the risk of harm (from complications such as atypical femur fracture and osteonecrosis of the jaw) is much lower than the reduction in the rate of fracture. I agree with that, particularly for high risk patients, but the reviews tend not to include the effects of administration (gastro upset and inconvenience).

After the 3 year mark however, the balance of risk and benefit is harder to determine (FDA review here)

The bottom line
If you have sustained a low energy fracture from osteoporosis, these drugs will lower your risk of sustaining another fracture over the next 3 years, and the likelihood of having one of the major complications mentioned above is low, but it is up to you if that benefit is worth the potential risks, the cost and the inconvenience and discomfort of taking the pills. There is some evidence that people just don't like the idea of taking these drugs (here) and that even giving them all the information doesn't increase their likelihood of starting the drug (here). And maybe I am pitching it wrong, but when I tell my patients all of the numbers around risk and benefit, most of them say that they would rather not bother with it.


  1. A great post. Chasing surrogate markers. This one was really bolstered by Pharma teaming up with pcp's/etc... To get them in office dexa to diagnose and reorder often to make sure the "treatment" is improving your dexa, which we all know patients care about. Dexa itself is a poor test.

    I'd love to see a denosumab post. The cost per hip fx prevented by my calculation from package insert is over 3 million per.

    1. Thanks Michael, I am not up to speed with the cost effectiveness of denosumab, but I will make a note to look it up.

  2. Thanks for the article. Back in January of 2012, NPR did a great report titled: How a bone disease grew to fit the prescription ...


Note: only a member of this blog may post a comment.