San Francisco 49ers running back Christian McCaffrey and top backup Jordan Mason are being placed on injured reserve.

McCaffrey left the snowy field in Buffalo on Sunday night after a 5-yard gain that was preceded by him heading to the sideline in apparent pain at the end of an 18-yard run.

McCaffrey was diagnosed with a posterior cruciate ligament injury in his right knee and did not play in the second half.

The 49ers also lost Jordan Mason, who emerged in a starting role with McCaffrey out the first two months of the season, to an ankle injury. Head coach Kyle Shanahan said Monday that Mason has a high-ankle sprain, which typically requires a recovery window of 4-6 weeks.

Those moves push rookie Isaac Guerendo into the RB1 spot. He scored the team’s only touchdown at Buffalo.

The IR slots in San Francisco are manned by multiple starters, including wide receiver Brandon Aiyuk, linebacker Dre Greenlaw, defensive tackle Javon Hargrave and safety Talanoa Hufanga.

Mason had a team-leading 789 rushing yards and scored three touchdowns. Being placed on IR means he’s not eligible to play until the regular-season finale at Arizona.

McCaffrey had 53 yards on seven carries on Sunday night and caught two passes for 14 yards before exiting. He was playing in just his fourth game of the season after missing the first eight because of Achilles tendinitis.

McCaffrey was the NFL Offensive Player of the Year last season, when he led the league with 2,023 yards from scrimmage: a league-leading 1,459 rushing yards and 14 touchdowns plus 67 catches for 564 yards and seven scores.

McCaffrey hasn’t scored a touchdown in his four appearances this season. He has rushed for 202 yards on 50 carries and caught 15 passes for 146 yards.

“It was frustrating,” Shanahan said after the game. “He had a great week of practice and I could feel his urgency and stuff and thought he came out great, looking really good, and it looked like he just got his shoestring there. … I hurt for him, and tough for our team not having him.”

The 49ers (5-7) played without defensive end Nick Bosa (oblique) and left tackle Trent Williams (ankle) in the 35-10 loss. San Francisco has lost three in a row heading into next Sunday’s game against the Chicago Bears (4-8) in Santa Clara, Calif. San Francisco resides two games behind the NFC West-leading Seattle Seahawks (7-5) with five games remaining on the schedule.

Seattle and San Francisco split their season series.

–Field Level Media