Overrated Medications Series: No. 3 Bisphosphonates To Prevent Hip Fractures
Bisphosphonates are well-known among post menopausal women. Examples of these drugs are Fosamax (Alendronate), Boniva (Ibandronate) and Reclast (Zoledronic Acid). These drugs treat osteoporosis and increase bone density by inhibiting the resorption of bone by osteoclasts. By increasing bone density, they reduce hip fractures and vertebral fractures. The drugs do work. Like the other medications reviewed in this series, they do not live up the hype surrounding them and do not work as well as their relative risk reduction would indicate. The absolute risk reduction tells their true effectiveness, which is small. Furthermore, physicians often prescribe them to women with osteopenia, a less severe form of bone thinning. For osteopenia their effectiveness is even less in preventing fractures, probably zero. Bone density is usually reported as a T-score, a measure of osteoporosis given as the number of standard deviations above or below the mean for a healthy 30-year-old adult of the same sex and ethnicity as the patient.
Let’s look at Fosamax first. A study from The Journal of the American Medical Association is here. Over the 4 years of the study only women with T scores of -2.5 or worse benefited from Fosamax. The absolute risk reduction was 1.2% fewer hip fractures over 4 years in women with severe osteoporosis (2.2% fractures in the placebo group and 1% in the Fosamax group). Therefore the approx. number of patients needed to treat (NNT) for 4 years to prevent 1 hip fracture is (100 / 1.2) = 83 (actual NNT = 81). This small 1.2% reduction over 4 years (0.3% per year) is boastfully reported by the Big Pharma reps as a 56% reduction in hip fractures. 56% is the relative risk reduction and exaggerates the effectiveness of the drug. It does not tell the patient the benefit they will get from investing their hard earned money in the drug.
Now let’s look at Reclast. This drug is very popular based on the requests for it I receive. Here is the article covering Reclast. Absolute risk reduction in hip fractures was 1.1 % for women with T scores of -2.5 or worse. NNT therefore is about 91 over the 3 years of the study. There is one adverse reaction worth mentioning: serious atrial fibrillation (see table 3 in the article). Serious atrial fibrillation occurred in 0.8% of the patients giving a number needed to harm (NNH) of (100 / 0.8) = 125. This is not far from the NNT to prevent the hip fracture.
An argument I hear from the Big Pharma reps (and physicians) pushing these drugs is that hip fractures carry a significant 1 year mortality rate. This is true. The 1 year mortality rate after a hip fracture ranges from 15 to 50% depending on the patient. Since bisphosphonates reduce hip fractures, I suppose the logical conclusion they wish for me to make is that bisphosphonates reduce mortality. This ain’t so. Once again look at table 3 in the Reclast article and notice 3.4% of the Reclast patients died versus 2.9% of the placebo patients. Slightly more deaths in the Reclast group. This was not statistically significant, but is relevant. Reclast costs $1,137.18 per dose, or $310,401 to prevent 1 hip fracture and no deaths.
For Fosamax and Reclast to be efficacious, women must take their calcium and Vitamin D supplements. Some brag of Fosamax’s once weekly dosing and Reclast’s once yearly dosing as enhancers of compliance. However, if the patient does not take her calcium and vitamin D, very likely all benefit will be lost.
Finally, there is evidence that using these drugs over the long run can increase the risk of femur fractures. The drugs do not build trabecular bone (the scaffolding of bones) but rather they build cortical bone. According to some studies bones become more brittle with bisphosphonate use leading paradoxically to more fractures after prolonged use. About 2 years ago the FDA cleared these drugs free of this concern, but is now re-investigating them. For more on this see here and here and here.
I can get behind Reclast in certain situations. If a patient suffers a low trauma hip fracture and receives a Fosamax infusion within 90 days, it will improve survival and reduce future fractures. The effect is real and the NNT is reasonable. The proof is here in a study titled Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture published in the New England Journal of Medicine. In this specific case the NNT to prevent 1 death is only 27 and NNT to prevent another hip fracture was only 66 (of course there was only 1 hip left to fracture). Length of the study was 1.9 years. This study has received some criticism for relying on composite end points.
Another bisphosphonate, Actonel (Risedronate) also seems to work best when given to women after they have suffered an event. Looking at this article from February 1, 2001 NEJM you can see looking at table 2 that if women have suffered a prior vertebral fracture, then Risedronate is very effective reducing hip fractures from 5.7% to 2.3% over the 3 years of the study. This gives a very respectable NNT of 29. Otherwise, the NNT was 167. Serious adverse events were slightly higher in the placebo group.
It seems bisphosphonates, like statins for coronary artery disease, are best used in patients who have already suffered an event. In seems reasonable to use them in that situation. In fact after more research on bisphosphonates, I think I might have been a bit hard on them. I do think they are over prescribed and offer little benefit unless patients are carefully selected.