Calibre keeps a copy of the book in its storage, let's call it the reference copy. When you Send to device, a new temporary copy is made, updated with the current metadata, and delivered to the device, iTunes in this case.
When iTunes gets the file, it writes some additional content into the ePub, specific to iTunes and iBooks. It's not a good idea to allow iTunes to write to calibre's reference copy, because this could have a negative impact on future exports to other devices.
I'll review this to see if there's another way to deal with it, but iTunes is very finicky about storage and writing to its copies of the books, as is calibre.