Real Madrid's Isco picked up an ankle problem in training ahead of Spain's 2-0 win over Finland in a World Cup qualifier on Friday night and hasn't travelled with the squad that will arrive in Switzerland on Monday afternoon.
Likewise, Manchester City's Silva suffered a slight muscular injury during training on Sunday and has also been sent back to his club as a precaution.
Neither man had been involved however as Vicente del Bosque's men took a huge step towards sealing their place at the World Cup next year with a comfortable win in Helsinki.
Spain are now three points ahead of France with just two games to play in Group I after Didier Deschamps' men could only manage a 0-0 draw in Georgia.
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