It is safe to run the setup page at any time, it will not ever hurt anything by visiting the setup page in between upgrades. When upgrading though you do need to be careful to make sure you upload all the new files especially the ones under /Setup before you visit the setup page which is why I usually upload that folder first. Taking it offline while you do the uploading is not a bad idea because then you can be sure setup doesn't run with just some of the new files.
Also it is good to disable setup from user.config so that only admin users can run the page, then make sure you do login before you upgrade because it will run for admins even when it is "disabled" but if you are not logged in you would have to enable it again.
<add key="DisableSetup" value="true" />