I had this problem occasionally but have not run into it for a month or so now, so if not done already update Calibre to the latest version first just in case that is the resolution. If I recall correctly there have been a few gremlins that are now fixed.
Sometimes it would be because I had the book open in a reader at the same time for checking and had forgotten it was so
and the file was locked. Closing the reader fixed the problem then, of course.
But I had some cases where there was no obvious reason as to why the book would not save. In these cases I used the offered "save a copy" option and saved the copy straight into the Calibre library folder the book resided in (or the folder the book is in if it is not in the Calibre library), so over-writing the existing book file. I ran into no problems doing this and could just keep on editing and saving the book as normal without having to close and reopen the editor.