Percent change in bone mineral density (BMD) as a surrogate endpoint for fractures

A new paper in the Lancet and related twitter thread
https://www.thelancet.com/journals/landia/article/PIIS2213-8587(20)30159-5/fulltext

Using individual patient data for each trial we calculated mean 24-month BMD percent change together with fracture reductions and did a meta-regression of the association between treatment-related differences in BMD changes (percentage difference, active minus placebo) and fracture risk reduction

Many threads on the forum have covered the problems with precent change from baseline in general. Yet here is another influential result where investigators have chosen to go with percent change nonetheless.

Unlike psychiatric clinical outcomes, though BMD, which is a normed/studentized score, is perhaps a little less problematic in terms of the criteria that @f2harrell has outlined before.

  1. the post value must be linearly related to the pre value
  2. the variable must be perfectly transformed so that subtraction “works” and the result is not baseline-dependent
  3. the variable must not have floor and ceiling effects
  4. the variable must have a smooth distribution
  5. the slope of the pre value vs. the follow-up measurement must be close to 1.0 when both variables are properly transformed (using the same transformation on both)
    See http://hbiostat.org/bbr/md/change.html#sec:changegen

Anyone care to comment whether BMD is a positive example of when percent change is not egregious?

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It would be nice to have access to a dataset to demonstrate this, but I think that it is extremely unlikely that percent change of BMD is a valid quantity. Assumptions 2 and 5 are the most likely assumptions to be violated. One has to ask why researchers are so afraid of analyzing raw data when such analysis is more powerful and interpretable? Flexibly covariate adjust for baseline BMD and respect the parallel group design which exists to compare parallel groups, not to examine change from baseline.

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