I can't offer any general wisdom on the topic, but I can describe what I've noticed personally.

Leg position definitely affects my aging knees. In the short-term, this means I have to be careful dismounting after a ride so that my knees don't collapse, taking me down with them. Long-term, my knees definitely deteriorate when I'm riding a lot (i.e., long trips on which I'm riding most days for weeks and months on end). Dropping the pedals on my DL650 helped noticeably, as did raising the seat. My KLR is definitely easier on the knees than the DL, but it's hard to see how a similar leg position could be accomplished on a shorter bike. Neither is particularly healthy for long trips any more.

You didn't ask about back issues, but I personally can't tolerate bikes which lack an upright riding position. That's a given.

My shoulders, elbows and wrists behave better when I raise handlebars a bit and (more importantly) bring them back towards me. This can be done with risers and/or the handlebars themselves, and it's taken some messing around to find the best combination on each bike. In particular, I struggle to find a shoulder position which doesn't aggravate various injuries but which provides good control of steering, throttle, brakes and switches. Riding for long periods can definitely do some damage if I'm not careful--and I have a history of not being careful, which is how my body became such a mess in the first place.

Executive summary: Hoping that your body will "adjust" to a certain position is probably a poor idea. You might learn to tune out the pain, but in so doing you're likely to cause trouble and/or exacerbate existing issues. On the other hand, I'm no expert.

Hope that's helpful.

Mark