Background: Critical illness is associated with increased risk of fragility fracture and loss of bone mineral density (BMD), although the impact of medication exposures (bone anti-fracture therapy or glucocorticoids) and time remain unexplored. The objective of this study was to describe the association of time after ICU admission, and post-ICU administration of bone anti-fracture therapy or glucocorticoids after critical illness, with change in BMD. Methods: In this prospective observational study, conducted in a tertiary hospital ICU, we studied adult patients requiring mechanical ventilation for at least 24 hours and measured BMD annually for 2 years after ICU discharge. We performed mixed linear modelling to describe the association of time, and post-ICU administration of anti-fracture therapy or glucocorticoids, with annualised change in BMD. Results: Ninety-two participants with a mean age of 63 (+/- 15) years had at least one BMD assessment after ICU discharge. In women, a greater loss of spine BMD occurred in the first year after critical illness (year 1: -1.1 +/- 2.0% vs year 2: 3.0 +/- 1.7%, p = 0.02), and anti-fracture therapy use was associated with reduced loss of BMD (femur 3.1 +/- 2.4% vs -2.8 +/- 1.7%, p = 0.04, spine 5.1 +/- 2.5% vs -3.2 +/- 1.8%, p = 0.01). In men anti-fracture and glucocorticoid use were not associated with change in BMD, and a greater decrease in BMD occurred in the second year after critical illness (year 1: -0.9 +/- 2.1% vs year 2: -2.5 +/- 2.1%, p = 0.03). Conclusions: In women a greater loss of spine BMD was observed in the first year after critical illness, and anti-fracture therapy use was associated with an increase in BMD. In men BMD loss increased in the second year after critical illness. Anti-fracture therapy may be an effective intervention to prevent bone loss in women after critical illness.