When you put those truck diamond plated boxes in the back of your pick-up, they are usually installed with a J bolt. The bottom of the J fits under the frame lip of the bed rail and the top of the J goes through a hole in the box, the part that actually sits on the rails. You then put a nut on the top of the threaded J bolt and tighten it down. This keeps the box from moving, and prevents anyone from lifting it out. If you close the lid and lock it, its almost impossible to get the box out.
Rather than drilling a hole through the frame, is there a way you can drill a hole in the bottom of the box and then use a J bolt to catch under the frame, instead of through a hole? The only problem is, you can see the bolt and a pair of bolt cutters could probably snap it pretty quick, depending upon how concealed it would be. You might also be able to get a large U bolt, one wide enough to go completely around the frame.
I don't think drilling a hole in the frame will hurt anything. But at least, here's an alternative idea you might consider.