Billy Vunipola will miss England's Six Nations title defence after Saracens confirmed the No 8 will be sidelined for 12 weeks with a fractured forearm.
Vunipola suffered the injury in Saracens' 15-15 draw with Ospreys last weekend, in what was only his second appearance since returning from a four-month knee injury.
After seeing a specialist, Saracens have announced Vunipola will be out for 12 weeks, leaving him unable to play until early April.
"We will continue to monitor Billy's injury and of course provide the necessary support framework to get him back and fully fit," Saracens said in a short statement.
England begin their Six Nations campaign against Italy on February 4 and finish against Ireland on March 17.
The injury means Vunipola will have missed the best part of a year once he eventually returns, following separate injuries to his shoulder and knee in 2017.
With Wasps' Nathan Hughes also injured, head coach Eddie Jones finds himself short of options when it comes to ball-carrying back-rows.
In Vunipola and Hughes' absence, Exeter's Sam Simmonds or the uncapped Zach Mercer of Bath could start at No 8 against Italy, while Chris Robshaw could be moved over from flanker.
Despite selection headaches Jones has maintained England will have no excuses if they fail to win the competition.
Jones has won 22 of his 23 Tests as England head coach and is seeking to mastermind an unprecedented third successive Six Nations title.