Depression following hip fracture is associated with increased physical frailty in older adults: the role of the cortisol: dehydroepiandrosterone sulphate ratio

With the ageing of the population, hip fractures are a growing issue, with UK rates predicted to increase to 117,000 per annum by 2016 [1]. At least half of hip fracture patients never regain their previous function [2], and post-hip fracture mortality at one year has been recorded as high as 33% [3]. The factors influencing recovery from hip fracture are poorly understood although depression is a common co-morbidity in these patients [4].

The prevalence rate for depression in hip fracture patients across eight US and UK studies ranged from 9–47% [5]. However, most previous research has included patients with depression prior to hip fracture, so the health consequences of new onset depression, i.e., depression occurring shortly after hip fracture and most likely attributable to this traumatic event, are unclear. Depression may affect the recovery of walking independence [6], as well as being associated with poorer rehabilitation participation [7], increased risk of falling again [8], increased susceptibility to infectious disease and higher mortality rates [4]. Depression coincident with the physical trauma of hip fracture may therefore accelerate progression from health to frailty. Understanding the mechanisms mediating the link between depression and poor health outcomes after hip fracture may reveal novel approaches to improving recovery.

Cortisol levels are often higher in individuals with depression [9, 10]. A reduction in physical function may also be driven by age-related increases in the ratio between cortisol and the anti-glucocorticoid dehydroepiandrosterone sulphate (DHEAS). Higher cortisol levels in older adults have been associated with characteristics of frailty including a reduction in grip strength over a six year period [11] and standing and walking performance [12]. Low levels of serum DHEAS have been associated with poorer physical function [13]. Importantly, the cortisol:DHEAS ratio is higher in older hip fracture patients than in healthy controls [14] or younger comparable fracture patients [15]. Adrenocortical hormone balance may thus be a major determinant of frailty in older hip fracture patients, particularly in those with depression. However, the combined effects of both hip fracture and depression in the context of potential mechanisms for frailty outcomes have not been examined until now. The present analysis sought to examine the associations between post-hip fracture depression, in patients without a prior diagnosis and history of depression before age 50 years, and physical frailty in older adults, and the potential role of cortisol and DHEAS.

Recruitment and withdrawal data are shown in Figure 1, including two individuals who were later found to violate the inclusion criteria and thus were not included in analyses. Ineligibility was mainly due to the stringent inclusion criteria we had set in order to be able to meaningfully assess the impact of stress on immune function. Main reasons for declining to participate were feeling too ill to want to undergo the procedures, which were time consuming and demanding. Other reasons mainly consisted of loss to follow-up in the time between identification via the hospital patient database and consenting. This was due to Ethics committee procedures requiring 48 hours minimum decision time from receiving information until consent. Consequently, during this time many patients were discharged, or moved to other wards or facilities and were unable to be traced anonymously from their original admission records. Drop-out post-consent but prior to testing at six weeks (N = 97) was most commonly due to a change of mind by the patient or family members. From the minimal information available at this stage we are able to confirm that there was no age (p = .68) gender (p = .15) or hospital recruitment site (p = .36) bias between those who consented then withdrew and those who remained in the study for the six week testing session. Reasons for withdrawal between week 6 and month 6 included: death or being too unwell to be tested (N = 17), not being able to continue in the study for a variety of reasons including feeling they had too much to cope with, now receiving treatment for depressive symptoms or other medication/illnesses on the list of exclusion criteria, or being non-contactable (N = 18). Again, there was little evidence of selection bias between the sample who withdrew or remained in the study at six months in terms of gender (p = .26), initial depression group status (p = .72), BMI (p = .34), number of medications being taken (p = .09), and hospital recruited at (p = .26). However, those who withdrew were marginally more likely to be from the manual occupational group, (p = .05), were, on average, 3.9 years older (p = .02), and had 0.5 more comorbidities on average (p = .03).

In the current study, depression post-hip fracture was associated with poorer ADL and slower walking speed six weeks and six months post-hip fracture. Depressed participants also had significantly poorer physical functioning, as reflected in lower Berg Balance scale scores at week 6. These group differences were not driven by differences in demographics or health behaviours. The cortisol:DHEAS ratio differed between the groups at both time points and mediated the relationship between depression and slow walking speed at month 6.

The incidence rates for depression in our study are higher than a previous report showing 17% of patients had new-onset depression at 6 weeks post hip fracture [9]. The much higher incidence of depression post-fracture found here may reflect that co-morbidities were relatively low in our sample and thus injury and loss of independence may have had a greater impact on wellbeing. This requires further investigation given the considerable impact of depression on patients’ quality of life as well as on hip fracture outcomes [26].

Regarding physical frailty, a detrimental effect of depression on ADL has been reported previously in those with or without prior depression [27]. In the present study we found that this relationship was still present at 6 months post-hip fracture. As self-reported ADL may be affected by depressive symptomatology [27], objective levels of physical function were also measured. The detrimental impact of post hip fracture depression on walking speed reported here is in accordance with most previous studies [28] with one exception, in which depressive symptomatology was not predictive of walking ability at one-year post discharge [29]. This contrast with the present results may reflect differences in the timing and type of measurement; we assessed depression at 6 weeks post-fracture predicting TUG at 6 weeks and 6 months, whereas this previous study was examining predictors of walking ability at one year, and walking ability was not directly assessed but rated over the telephone.

This study included a measure of dynamic balance which differed between the depression groups at week 6 but not at month 6. In contrast, it has been reported previously that depression can have a detrimental effect on physical function at 12 months [28], although this effect was very small. The mean balance score for both groups at 6 months was lower than that reported for community dwelling older adults [29], although it was similar to that reported for institutionalised older adults [30]. This suggests that hip fracture severely impaired balance, but given improvements, institutionalisation is not necessarily a consequence.

That the week 6 cortisol:DHEAS ratio was higher among the depressed hip fracture group is supported by previous studies [14]. In the present study, the ratio was also associated with poorer physical function, and mediated the association between depression and walking speed at month 6. This underlines the previously reported associations between higher cortisol, lower DHEAS and physical frailty [12, 13] and is likely to be due to the effects of high levels of cortisol on the degradation of muscle [31], or reduction in bone density [32]. It is possible to argue that the cortisol:DHEAS ratio could, however, be acting as a confounder in the depression-frailty association rather than a mediator, as it is expected that the trauma of hip fracture would contribute to an increased cortisol:DHEAS ratio which could then underlie both depressive symptoms and frailty in terms of walking speed. However, analyses conducted as part of a parallel manuscript has confirmed that the cortisol:DHEAS ratio only significantly differed between those patients with depression and those without (p = .004) and controls (p = .001), but not between those with hip fracture but no depression and controls (p = .12). This would suggest that the depression and frailty association was not a consequence of changes in the cortisol:DHEAS ratio as a consequence of the hip fracture. Thus, mediation would appear a more compelling explanation than confounding.

That cortisol:DHEAS did not mediate all of the associations between depression and physical function suggests that other mechanisms also may underlie this relationship, such as reduced motivation to participate in rehabilitation or levels of pro-inflammatory cytokines.

This study has several limitations. First, it was primarily designed to investigate the synergistic effect of what we perceive as depressive symptoms that present post-onset and potentially as a result of hip fracture on physical function, through exclusion of patients with a history of depression pre-fracture prior to age 50 years. However, we do realise that in the absence of a pre-fracture measure of depressive symptoms, this is an assumption. Despite excluding those with a previous diagnosis of depression prior to age 50 years and those taking anti-depressants, it is possible that some participants may have had symptoms post-age 50 years but prior to their hip fracture although none were undergoing treatment at the time of fracture. Further, our exclusion of previously depressed patients or those with cognitive decline, or immune-related comorbidities means our findings may not be generalisable to the wider hip fracture population and may have introduced some non-assessable selection bias in the absence of more general socio-demographics of patients not being available prior to informed consent. However, these exclusions do suggest that the associations reported here would be even stronger had patients with poorer physical or mental status been included as these factors are associated with poor recovery [33]. Third, the sample only included Caucasian patients, thus further investigation within diverse ethnic groups is needed. Fourth, the sample comprised mainly women. However, the ratio of women to men in our sample reflects the reported sex ratio of hip fractures in the UK. Fifth, we did not measure pain in our sample, and it is possible that pain could contribute to both depression and cortisol levels [34], although individuals with depression tend to report lower pain levels [35] and our present depressed and non-depressed groups did not differ significantly on whether or not they were taking analgesic medication. Finally, there were a relatively high number of withdrawals but this is common in studies of hip fracture in older patients; the rapid changes in setting make it difficult to track hip fracture patients post-discharge and many felt too unwell to participate. The sample of patients included in this group was therefore likely to be in relatively good health compared to those who withdrew. This highlights that the effect of depression on outcomes is not restricted to patients with poor health post hip fracture.

In conclusion, depression emerging post-hip fracture in older adults impairs physical function, including walking speed, balance, and activities of daily living. This is the first time that depressive symptoms in the absence of longer term pre-fracture depression diagnosis have been shown to relate to recovery and physical frailty. Effects on walking speed were mediated by alterations in the cortisol:DHEAS ratio which was heightened among the depressed group. This novel finding implies that in order to speed recovery of physical function and independence following hip fracture, patients should be assessed and treated for depressive symptoms. This is of relevance to surgeons and health professionals alike involved in rehabilitation post-fracture surgery who currently do not screen this patient group for depressive symptoms. Identification and treatment of depression in these patients would improve patient outcomes and quality of life as well as impacting upon health service costs incurred through treatment of those with slower recovery and decreased independence post-fracture. We propose that correcting the cortisol:DHEAS imbalance by oral supplementation with DHEA may be one means of improving depressed mood and contributing to better physical function after hip fracture. However, such an intervention would need to be cautiously informed by the intervention literature in order to determine an effect dosage and regime for an effect in these patients.