Well if we look at the timeline we only know that hashi is the only person known to have grandchildren which means that generation of Tsunade's parents and his brother Nawaki. We all know he was dead and Tobirama died also, we dont know whether he had kids or not, plus we dont know what happened to tsunade's parents. In the start of the series all OP clans were extinct Uzumaki, Uchiha and Senju and yet they form the backgroung of the story. If only they did not have an alliance probably they would be still alive