I've had a problem after using the reg cleaner of Ccleaner, which basically stopped the computer from starting. Lot of remedial work required.
This is rare; Ccleaner is generally safe.
I think TweakNow is possibly even safer. It's very good.
I've also had to manually delete reg items (Some were locked and I needed to grant self permission to do so) to re-install or delete certain software, notably stuff from Comodo. Interesting exercise. I would undertake this only after reading a tutorial or two about the functioning of the registry.
So there is no easy "tick the box" answer, sorry.
As stated: Small benefit possibly gained vs potentially a lot to lose.
If you want to know what "junk" is in your registry that is not detected/removed by Ccleaner, you'll have to manually look at it, after learning about what can be removed/altered etc.
I occasionally (once every two months or so) use a reg defrag. Part of the
Erunt stable. No problems. Usually only saves about 2-4%. (Erunt is a very good auto-backup reg tool.)