England prop Joe Marler will miss the start of the Six Nations after suffering a fracture to his lower left leg.
Marler has been ruled out for at least a month with the injury and will be unavailable for the Championship opener against France on February 4 and the clash with Wales seven days later.
"Joe will undergo a period of rehabilitation and is expected to be fit to play again in four to five weeks," his club Harlequins announced.
England must now complete a substantial portion of their Grand Slam defence without their two first choice loosehead props.
Mako Vunipola has a knee problem and will not be available until the end of February at best, with a visit to a specialist next week expected to set a more specific date for his comeback.
Now the second choice in the position has been added to England's concerning list of forward absentees, and the best case scenario is that Marler will be fit to face Italy on February 26.
Flanker Chris Robshaw will sit out the entire championship after undergoing shoulder surgery and number eight Billy Vunipola could also miss every match as he rehabilitates a knee issue.
A doubt hangs over James Haskell after his comeback for Wasps following seven months out with a toe injury lasted just 35 seconds on Sunday due to concussion, while captain Dylan Hartley must prove his fitness as he serves a six-week ban for striking.
More positive news has come in the second row, however, with Joe Launchbury poised to make his comeback from a calf injury for Wasps against Toulouse on Saturday and George Kruis cleared to recover from his fractured cheekbone in time to face France.