BoneKEy-Osteovision | Commentary
Effects of inhaled steroids on bone mineral density: Are the conclusions misleading?
DOI:10.1138/2001044
Inhaled glucocorticoids are a major treatment of asthma and so it is important to appreciate whether there are any adverse effects on bone. This has proven a difficult area to investigate. Firstly, it is difficult to find patients taking long-term high-dose inhaled steroids who have not taken oral glucocorticoids during an asthma attack. Second, the study of inhaled glucocorticoids in healthy volunteers have given misleading results - the systemic absorption is probably much greater than in patients with asthma.
A recent study in the New England Journal of Medicine by Israel et al. () attempted to overcome some of the limitations of previous studies. This group took great care in characterising their population and monitoring the dose of inhaled steroid and used a single agent, triamcinolone. They selected a large group of young women (109 women ages 18 to 45 years) and studied them for a long period (3 years). They measured bone density using good methodology (DXA of the spine and hip) and bone turnover using appropriate bone turnover markers (serum osteocalcin and urinary NTX).
They reported that there was significant bone loss from the femoral trochanter and total hip regions and warned that ‘inhaled steroids should be used in the lowest dose necessary to achieve control of symptoms.’
This conclusion is quite misleading. The fundamental problem with this study is that it was designed as a comparison of three groups but analysed with the dose of inhaled steroids as a continuous variable. The three groups were a group with asthma but no inhaled steroids, a group with asthma taking low to moderate doses (4 to 8 puffs per day) and a group with asthma taking high doses (greater than 8 puffs per day). Inspection of figure 2 indicates that the relationship between the dose of steroid and bone loss was not linear. It is quite possible that those patients with the high doses may have lost less bone than those on small to moderate doses; this is a phenonomenon reported before () and is likely to result in the improved BMD when patients are recovering from the oral steroids they took before the improved asthma control during the trial - improved because the dose of inhaled steroid was increased to reduce the need for oral steroids.
There were three other problems with this study. The rate of bone loss in the whole group was tested against zero change in BMD, and it was concluded that there was significant bone loss. However, it has been recognised for many years () that there is significant bone loss before the menopause, and so the rate of loss of 0.4%/year for 10 puffs per day of triamcinolone may be close to the expected rate of loss. Second, there was inconsistent pattern of loss - there was no significant bone loss from the lumbar spine or femoral neck. The lumbar spine is usually the most sensitive site to glucocorticoids and so this is an unexpected finding. This kind of inconsistency between the response of bone density sites to inhaled steroids has been a feature common to several studies (). The magnitude of effect is likely to be of no clinical importance. Even if these effect sizes are accurate, the rate of bone loss on high dose triamcinolone (e.g. 10 puffs a day) would only be 4% over 10 years of continued use. The authors suggest that such patients should have monitoring of their bone loss, but this magnitude of bone loss could only be detected in the hip in most patients after 10 years or more.
I think the authors have analysed their results incorrectly and the consequence could result in poorer care of patients with asthma. The appropriate use of high dose inhaled steroids prevents the need for oral steroids, agents clearly associated with bone loss and fractures. The authors failed to cite the seminal work of van Staa et al. () who reported on the effects of inhaled steroids on fracture rates in the UK General Practice Research Database. In this study of 450,000 subjects, it was reported that there was a small increase in the risk of fractures e.g. a relative risk of hip fracture of 1.22, but this increase was also found in subjects taking bronchidilators alone. It is unlikely that inhaled steroids increase the risk of fracture in subjects with asthma.
Thus, inhaled steroids have either no effect on bone, or else a very small effect on bone mineral density that does not translate into an increase risk of fractures. It is important that the use of inhaled steroids is not compromised as the alternative, oral steroids, clearly do have adverse effects on bone density and fracture risk ().
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