Introduction
Based on its association with cardiovascular disease, the thiazolidinedione (TZD) rosiglitazone has been withdrawn in Europe and is on restricted licence in the USA. Last year the prescribing information for pioglitazone was updated by the European Medicines Agency (EMA) and other regulatory agencies because of reports of a risk ratio for bladder cancer ranging from 1.12 to 1.33 after 2 years' exposure. Pioglitazone was stated to be a valid treatment option for certain patients with type 2 diabetes, specifically when metformin has not been suitable or has failed to work adequately [
1‐
3].
However, another important adverse effect of TZD therapy is bone fracture. That TZDs can cause fracture was first suggested by the ADOPT clinical trial, in which rosiglitazone treatment increased distal fracture risk in women only [
4]. Since then other trials [
5‐
7] and observational studies [
8‐
13] have reported on fracture risk with TZD. These studies are generally consistent in finding an increased risk in older women for distal fracture but they are inconsistent with respect to effects in men and effects on hip fractures. Establishing whether TZDs cause hip fracture is important given the high rates of mortality associated with hip as compared with distal fractures [
14,
15]. Few studies have had adequate power to examine these effects and none have adjusted for prior exposure to all other main classes of drugs for diabetes. Meanwhile, the drug labels continue to emphasise that TZD-associated fracture risk is predominantly for distal fractures in women. In this analysis we have used data from a Scotland-wide diabetes register to examine whether cumulative exposure to TZDs also affects hip fracture rates in women and in men, whether exposure to other glucose-lowering drugs explains any associated risks and to compare the risks associated with rosiglitazone and pioglitazone.
Discussion
In this nationwide cohort TZD treatment was associated with an 18% relative increase in hip fracture rates for every cumulative year of TZD exposure, in both men and women. The risk was similar for rosiglitazone and pioglitazone. There was no evidence that cumulative exposure to insulin, sulfonylurea or metformin were independently associated with hip fracture.
Our data add to growing evidence from observational studies and trials on TZD-associated fracture and serve to clarify several remaining questions about this risk [
4‐
13,
22]. Our study was sufficiently large to be able to demonstrate effects in men and on hip fracture, for both of which smaller studies in the literature have reported inconsistent findings. Our study included more male TZD users (20,105 vs 3,064) than the extensive meta-analysis of randomised trial data carried out by Loke et al [
13] and this is likely to explain why we have detected effects in men not apparent in trials. A previous cohort study found that total fractures were increased in men but included few patients over 65 years old and so was underpowered for detecting effects on hip fracture [
8]. One self-controlled case series study reported an increase in hip fracture in women and total fracture in men though the effect on hip fracture in men did not reach statistical significance [
22]. The self-controlled case series design minimises between subject allocation bias but the method as originally conceived assumes that the observation time for each case is independent of the event time. Where the event has a high mortality rate (as we have shown is the case with hip fracture) this assumption is violated. Recent modifications to the method render it less sensitive to assumption but the modified method remains sensitive to the assumption that exposure is not event dependent–in the case of hip fracture and TZDs this assumption cannot be made; TZD exposure is less likely once fracture has occurred [
23]. One case–control study with 18,000 fracture cases found effects on total and hip fracture in women and no overall or hip effect in men but the levels of TZD exposure in men were low (only 1,971 exposed men were included) [
24]. A recent report also found evidence of a cumulative effect of TZDs on total fracture but not hip fracture [
25].
The data reported here also clarify that the fracture risks cannot be avoided by using pioglitazone instead of the now-restricted rosiglitazone. Three previous studies reported similar hazard rates for both drugs [
8], with one reporting larger effects for pioglitazone [
9] and one larger effects for rosiglitazone [
26]. However, none of them adjusted for exposure to the other TZD drug in their analysis as we did, so carry-over effects could not be excluded. In the previous study that involved an analysis for pioglitazone restricted to those with no prior exposure to rosiglitazone, pioglitazone was clearly associated with an increased risk [
22]. Another strength of our study is that we have also simultaneously modelled the effects of cumulative exposure to TZDs, metformin, sulfonylureas and insulin, thus ensuring that the association of fractures with TZDs cannot be attributed to these other diabetes drugs. This is important because previous observational studies were unable to adjust for time-varying exposure to all these drugs. Thus our data add to existing data and provide strong evidence for causality of the TZD's effect because of its magnitude and because of no similar cumulative effect with other glucose-lowering drug classes being evident.
Inference of adverse drug effects from observational data presents methodological challenges, especially confounding of the association of drug allocation with outcome by susceptibility. In Scotland, TZD recipients have a more favourable profile of risk factors for fracture (less use of thyroid drugs, less apparent need for bisphosphonates, more use of postmenopausal oestrogens, fewer previous admissions for fracture) and appear to be in better health (fewer previous admissions for cardiovascular disease) than non-users at the same age. Also the estimates of the ‘ever’ term for TZD exposure from the model are consistent with those being allocated TZD having a lower fracture risk than non-users at the outset of TZD exposure (as they are for metformin too). Thus a simple comparison of ever vs never-users of TZDs would be confounded by indication (i.e. subject to allocation bias). For this reason we have based inference only on the cumulative effect of TZD on risk since this is not affected by confounders that are not time-varying. This assumes that drug exposure has no stepwise effect on fracture risk but, as bone mass changes only slowly, this is a reasonable assumption unless the drug causes falls, which is unlikely since TZDs do not cause acute hypoglycaemia. The post hoc analysis categorising cumulative exposure into 1 day to 2 years, 2–4 years and ≥4 years suggests that some threshold of cumulative exposure may be needed before effects are apparent. The greater effect when follow-up is censored at cessation is consistent with a dropping off of the effect when the drug is stopped, though we have not modelled this explicitly. Thus the effects at a given level of ongoing exposure may be higher than we estimate. Of course while we have shown a dose–response effect that seems specific to TZDs these are not the only criteria for causality. It remains possible that long-term glitazone users may differ from short-term users in their base risk of hip fractures. Relevant in assessing causality too is that there is a biological rationale; while there are several possible mechanisms through which TZDs might lead to fracture (e.g. by increasing falls) there is considerable evidence that peroxisome proliferator-activated receptor gamma (PPAR-γ) activation with TZDs leads to unbalanced bone remodelling with bone resorption increasing and bone formation decreasing [
27].
A limitation of our analysis is that inference based on cumulative exposure does not exclude confounding by glycaemia. Although we do not have good coverage of HbA
1c in the first few years of follow-up, even if we had complete HbA
1c data simply adjusting for HbA
1c would be incorrect since it potentially determines exposure and is also altered by exposure [
28]. A much better test of whether HbA
1c is likely to be a relevant confounder here therefore is the specificity of association; if HbA
1c were a confounder then we would expect to also see such confounding causing an apparent relationship with other glucose-lowering drugs and fractures risk, which is not the case.
It is vital to consider the importance of the elevated risk of hip fracture compared with the possible elevated risk of bladder cancer in users of pioglitazone, which has recently led to a label change by the US Food and Drugs Administration (FDA) and EMA. The FDA estimated that the risk difference for bladder cancer associated with exposure to pioglitazone for more than 12 months was 28 cases per 100,000 person-years of follow-up [
29]. Five-year mortality for bladder cancer is about 50% [
30]. For comparison, an approximate estimate of the absolute risk difference for hip fracture in TZD users can be obtained from Figs
1 and
2 by comparing the age-standardised rate at, say, 0–2 years exposure with 2–4 years exposure. This risk difference is approximately 1.4 per 1,000 person-years in women and 0.7 per 1,000 person-years in men. Consistent with the established literature [
14,
15], we found high 90-day case-fatality rates of 15% in TZD users, similar to rates in never-users. Based on this case-fatality information we can thus estimate that TZD use for 2 years or more will carry an excess mortality of at least 21 per 100,000 woman-years from hip fracture, compared with an estimated excess mortality of about 14 per 100,000 person-years from bladder cancer in those exposed to pioglitazone.
Thus, hip fracture should be considered at least as important a potential adverse effect of pioglitazone exposure as bladder cancer to be balanced against its efficacy in reducing HbA
1c. Of note the recent EMA risk–benefit assessment of pioglitazone carried out following the emergence of bladder cancer data does not even mention fracture risk [
31]. This suggests that the importance of this adverse effect is not fully appreciated and should be emphasised to clinicians and patients. Current TZD drug labels state that ‘the risk of fracture should be considered’ but emphasise that effects are on distal fracture and mostly in women. These labels should be changed to reflect the accumulated data on hip fracture and risk in men.
Acknowledgements
We thank the diabetes patients in Scotland and the SCI-DC and NHS National Services Information Services Division Scotland who provided data for this study.