October 20, 2020

expert reaction to study of steroid treatments for asthma and osteoporosis

Research, published in Thorax, looked at steroid treatments for asthma and osteoporosis.

Prof Kevin McConway, Emeritus Professor of Applied Statistics at The Open University, said:

“This is an interesting and potentially important piece of research. It’s generally statistically sound, in my view.

“It’s an observational study, and as always with such studies, it’s not easy to say what is causing what. The basic issue is that there are several differences between the people who were prescribed oral (OCS) or inhaled (ICS) corticosteroid drugs for their asthma, and it could be one or more of these other differences that cause the people who took the steroids to be more likely to get osteoporosis or fragility fractures (FF), and not the drugs at all. Or maybe the steroids are only part of the explanation. The researchers made statistical adjustments to allow for several differences between the takers and non-takers of steroids, that might have been confusing the picture. After these adjustments, the people taking steroids still had a higher risk of osteoporosis or FF. There is certainly some circumstantial evidence that the steroids do have a cause-and-effect role in increasing the risk. Other studies, some of them under different circumstances, have also shown similar possible effects. The increase in osteoporosis or FF risk depended on the dose of steroids that the asthma patients had taken over a year – the higher the dose, the bigger the increase in risk, just as you’d expect if the steroids are really causing the disease. But there still remain other possible explanations. For example, probably there’s a relationship between the numbers of steroid prescriptions, or the dose, and the severity of their asthma. Doctors don’t prescribe different amounts of these drugs for no reason. So it’s plausible that people who took more steroids had more severe asthma. Maybe it’s some other feature of the severity of their asthma, or something else related to that, which is the real cause of osteoporosis or FF, and not directly the steroid drugs at all. I’m certainly not claiming here that the steroids don’t have any causal effect on osteoporosis or FF – simply that there are other possibilities that this one study can’t entirely rule out, and that’s why these new findings can’t be the last word on the matter.

“How big are the risks anyway? It’s slightly awkward to work out the absolute risks, because of the nature of this study. However, here are some rough estimates. Suppose we have 100 people with asthma, broadly like those in this study. If they do not take oral corticosteroids over the course of a year, then about 2 of them on average would get a new diagnosis of osteoporosis, and about 3 would have a fragility fracture. If instead they took oral corticosteroids at the highest dose level considered (more than 2500 milligrams over the year), then on average about 8 would get osteoporosis and about 6 would suffer a fragility fracture. This assumes that either OCS does have a causal effect, or that the pattern of other factors remains the same so that the risk increases in the same way.

“For inhaled corticosteroids, the position is rather different in detail, and the increases in risk are smaller. Again consider the 100 people with asthma. If they do not take inhaled corticosteroids over the course of a year, then again about 2 of them on average would get a new diagnosis of osteoporosis, and about 3 would have a fragility fracture. If instead they took inhaled corticosteroids at the highest dose level considered (more than 120 milligrams over the year), then on average about 3 would get osteoporosis, and the number suffering a fragility fracture would have risen very little, so still about 3.

“It’s important to point out that these increases in risk are those for the highest doses of OCS or ICS. The increases for smaller doses are considerably less, and indeed for ICS, the statistical evidence for there being any increase at all in the risk of FF, for doses less than the maximum considered, is pretty weak.”

Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:

“This paper seems reasonably well conducted. These effects have been well known such that regulators have included warnings for many years for oral corticosteroids. Although there are some warnings about effects on bone mineral density for the inhaled forms.

“In general the effects, particularly on fracture or for inhaled use, are not dramatic in relative terms.

“There are two disappointing aspects. Firstly, the absolute risks are not given clearly. While such estimates are not directly obtainable from a case-control study, the database used for the study, CPRD, is very clearly able to obtain these data. Warnings to patients should always be given in absolute terms even if the main analysis is done on a relative scale. Secondly, the most dramatic result was the unadjusted 25 times higher risk for osteoporosis with bisphosphonates. While this is clearly heavily affected by confounding by indication (patients with osteoporosis risks are given bisphosphonates), the authors in commending the use of those drugs for patients with corticosteroids might have shown that their adjustments for confounding could show benefits for these drugs.

“This paper should not cause panic among those with asthma but they need to be aware of the effects, and ensure that they do all they can to protect their bones.”

Prof Sir David Spiegelhalter, Chair, Winton Centre for Risk and Evidence Communication, University of Cambridge, said:

“The results of this study are only given in terms of relative risks, and it is difficult to assess their importance without knowing the absolute risks.  The case-control design makes this challenging, but it is possible to estimate that, for 100 people with asthma who did not take oral corticosteroids, on average two developed osteoporosis and three suffered fragility fractures.  In contrast, out of 100 who had more than nine prescriptions of oral corticosteroids, we would expect eight to develop osteoporosis and six to suffer fragility fractures. 

“Full descriptions of these results, with accompanying graphics, can be found in https://url.wintoncentre.uk/mSAL2 and https://url.wintoncentre.uk/wVgW3 “

‘Risk of osteoporosis and fragility fractures in asthma due to oral and inhaled corticosteroids: two population-based nested case-control studies’ by Christos Chalitsios et al. was published in Thorax at 23.30 hours UK time Tuesday 20 October 2020.

doi:10.1136/ thoraxjnl-2020-215664

Declared interests

Prof Kevin McConway: “I am a Trustee of the SMC and a member of the Advisory Committee, but my quote above is in my capacity as a professional statistician.”

Prof Stephen Evans: “No conflicts of interest.  I am funded (1 day/week) by LSHTM.  They get funding from various companies, including Astra Zeneca and GSK but I am not funded by them, I have no involvement in obtaining funding from them and I am not an investigator or any grants obtained from them.  I am the statistician to the “meta-Data Safety and Monitoring Board” for CEPI.  I will probably be paid for my attendance at meetings and expenses for travel.”

No others received.