Will Reggie Bush hold up?
It's a collision sport. You could ask the same question about every player who dons a uniform.
Andre Wadsworth was a few pounds heavier than Bush and his knees got mangled. Someone should compare percent of down time to playing time for Barry Sanders and Jerome Bettis. (I suspect Sanders will win).
How can anyone predict whether or not Bush will hold up any better than Shawn Alexander or Edgerring James will hold up? It's all a matter of luck, how they use him, genetics (bones, tendons, ligaments, aging process), playing style, training regimen etc.
So what do we know? (1) He's not considered a "big" RB. (2) He's cut out of marble. (3) He's said to be in terrific condition and figures to stay that way. (4) He doesn't give tacklers much of a target, (5) He does take risks when he hurdles people and tries to cut in three different directions at the same time. (6) He does seem to be a relatively intelligent person who'll probably be careful about protecting his body.
You can probably find a half-dozen examples of other guys who fit that profile who remained relatively healthy and another half-dozen whose careers ended prematurely.
But I don't think Reggie's risk-factor is any higher or any lower than any other NFL player. And he sure does play good.