If you use clip-in pedals, do they have any float? Otherwise, I'll take your word for it on set-up issues.
I broke my left leg in a car wreck in my mis-spent youth. The knee has never been right since. Every year, when the intense and long rides kicked in, the knee would develop this achy-dull pain. I would favor it, soft-pedaling that side, resulting in a particularly weaker left leg. I started taking glucosamine chondoitrin last fall, and while it hasn't completely prevented pain, it's been insignificant this year.
My understanding is G-C works by encouraging cartiledge growth, which forms protective layering in joints. It's kind of pricey, and you have to take it for about 3 months before effects become noticable.