Key findings
We studied the association between time, post-ICU administration of bone anti-fracture therapy and glucocorticoids, and annual change in BMD over a 2-year period after critical illness. In women a significantly greater loss of spine BMD was observed in the first year after ICU compared to the second. In women who did not receive anti-fracture therapy or glucocorticoids, a decrease in BMD was observed in both years after ICU discharge. However, post-ICU administration of anti-fracture therapy was associated with an increase in BMD, compared to a decrease in women who did not. In men, loss of femur BMD was significantly greater in the second year after ICU discharge. There was no association between use of anti-fracture therapy or glucocorticoids and change in BMD, although only a small number of men received post-ICU treatment.
Relationship to previous studies
Loss in BMD following critical illness has been reported in two previous studies. A significant decrease in calcaneal BMD was observed over 10 days in patients with acute respiratory distress syndrome [
26], although this result is limited by precision error of portable BMD devices and short time frame [
27]. We described a significant decrease in spine and femur BMD in the first year after ICU admission, greater than age- and gender-matched community controls, in the initial cohort from this study [
19]. In addition a number of studies have described abnormal BTMs during and after critical illness, of a magnitude similar to that described in postmenopausal women’s or metabolic bone disease [
19,
28‐
34]. High bone turnover and bone loss, due to negative remodelling balance at the basic multicellular unit, has been described as an independent risk factor for fracture [
29,
35]. An increased fracture risk in older women after intensive care compared to matched population controls has been described [
20].
The extension of BMD assessment to 2 years after critical illness in this study adds important information about the time course and magnitude of changes in BMD following critical illness [
19,
26]. In women we observed a loss in femur and spine BMD in the first 2 years after critical illness, with recovery of BMD observed in women receiving anti-fracture therapy. The reported change in BTMs after critical illness describes increased resorption markers during and after ICU [
19,
28‐
34], followed by increased formation markers and normalisation of resorption markers by 1 year [
19]. The magnitude of this decrease was greater than we have previously observed in community controls [
19], supporting the hypothesis that factors associated with critical illness contribute to an increase in bone loss, and that administration of anti-fracture therapy is a major determinant of BMD recovery after critical illness. The different pattern of BMD loss in men compared to women following critical illness is also of interest. The observed decrease in femur BMD is consistent with our previous study of change in BMD after ICU compared to community controls [
19]. The significantly greater loss in femur BMD in the second year after ICU discharge, the high proportion of men with osteoporosis and osteopenia at 2 years post-ICU discharge, and the low rate of post-ICU anti-fracture treatment, suggest further investigation of risk factors and consequences of bone loss in men is warranted.
The current literature regarding the relationship between anti-fracture therapy use and change in BMD following critical illness is limited. A small study reported a transient decrease in bone resorption markers after administration of intravenous ibandronate [
36], and a retrospective propensity-matched cohort study described an association between pre-ICU bisphosphonate use and reduced mortality [
37]. In addition, serial computed tomography (CT) assessment of vertebral BMD revealed bisphosphonate users had lower baseline bone density and an attenuated decrease in BMD during critical illness. This study is the first to prospectively describe an association between anti-fracture therapy use and change in BMD over a prolonged period following critical illness. The observed increased proportion of anti-fracture therapy use in women is expected, based on lower measured BMDs in the years after critical illness. The observed positive association between anti-fracture therapy use and BMD provides support for future interventional studies in this population.
The observation that use of glucocorticoid, a known risk factor for osteoporosis, was not associated with an increase in annual change in BMD was interesting, although limited by small sample size and the risk of type II error. More prospective data on the relationship between BMD changes following critical illness and the effect of known osteoporosis factors, including medications administered before and after critical illness, are required to further elucidate these relationships.
Study implications
This study implies that critical illness is associated with prolonged and sustained loss of BMD, with variable effects on femur and spine in women and men. Although recovery of BMD occurs overall in women, this may be associated with the use of anti-fracture therapy in the post-ICU period. This implies that anti-resorptive therapy may be an effective intervention to prevent bone loss in women with critical illness as has been shown in other at-risk patients.
Strengths and limitations
Our study has several strengths. It is the first study to collect prospective data on bone density using DXA, the gold standard for BMD assessment, over a 2-year period after critical illness. This is important because the previously described changes in bone mineral density that occur immediately after critical illness may be attenuated over time. Moreover, understanding of the natural history of these changes can be used to guide the need and design of interventional trials. In addition, the collection of post critical illness medication history allows assessment of factors that are known to modify bone turnover, over a time frame required to assess this effect.
There are limitations to this study. The loss of a large proportion of patients prior to the 2-year follow-up due to death or withdrawal introduces limitations due to small sample size, including ability to assess the impact of multiple risk factors on post critical illness change in BMD, perform subgroup analysis, and introduces the possibility of type II error. However, the ability to assess the effect of anti-fracture therapy and glucocorticoids, although limited by numbers, provides unique and valuable information about feasibility and design of an interventional study. Also, the assessment of glucocorticoid use following critical illness was defined as use for greater than 3 months in the previous year, and it is possible that shorter duration of glucocorticoids during critical illness or recovery were associated with a change in BMD that was not captured. However, glucocorticoids are a known risk factor for loss of BMD, and a much larger study would be required to assess the effect of glucocorticoids administered before, during, and after ICU. Also, data relating to a number of variables associated with BMD was not collected, including other medications that affect bone turnover, nutrition, falls, and fractures. However, given the small sample size, analysis of the relationship between these factors and BMD would not have been possible. Finally, anti-fracture medications were clinician-initiated rather than randomised, introducing selection bias into the results. However, anti-fracture therapies are initiated in the highest risk patients with the lowest BMD, with the effect observed in this study likely to underestimate that observed in a mixed population of critically ill patients.