Ghost-Peter struggling to remember his name as his identity is wiped out. Seeing him broken like that so that Otto can remain Spider-Man was heartbreaking.
Ghost-Peter forgetting who Uncle Ben was in the process was particularly heart breaking.
The fallout from the "Run, Goblin, Run" arc. Norah Winters has lost her job because she was too close to Phil, Ben Urich has had his nephew arrested and must take time off work since the unmasking was too public for the Bugle, Phil has lost everything and has switched over to full time villainy under the Green Goblin. Given that at one point he tried to be a hero, it makes his fall even more tragic.
The fallout from the Spider-Man 2099 arc is bitter over all: