Injured trio Sven Bender, Lars Bender and Toni Kroos will miss the 2014 World Cup qualifiers against Kazakhstan.
Germany coach Joachim Low received the disappointing injury news after this weekend's round of Bundesliga matches.
Kroos is being plagued by a knee injury and was already rested for Bayern Munich's 2-1 Bundesliga win over Bayer Leverkusen.
The midfielder was initially hopeful of recovering in time for Friday's match, but has now decided to withdraw from the Germany squad as the injury continues to trouble him.
Bender, meanwhile, featured for the full 90 minutes for Leverkusen on Saturday, but picked up a heel injury during the match.
Borussia Dortmund's Sven Bender has the flu and has withdrawn from the match in Astana.
Low has not yet called up any replacements and decide whether to make any additions later on Monday.
Germany meet Kazakhstan in Astana on Friday, before hosting Miroslav Beranek's men four days later.