Devin Toner and Garry Ringrose will miss Ireland's clash against Scotland in Murrayfield on Saturday.
Toner picked up an ankle injury during last weekend's defeat to England, which was a recurrence of a previous problem that cost him to miss several Leinster games.
Munster lock Billy Holland has been called up the squad as cover and he trained with the squad at Carton house this morning.
Ringrose was forced off with a hamstring problem at the Aviva Stadium and he will not be risked for the trip to Edinburgh.
"Devin's ruled out for this week with his ankle and Garry Ringrose also, his hamstring isn't quite right so he won't be with us either," scrum coach Greg Feek confirmed.
"We've got the fallow week after (Scotland) so it does give us a bit of a window. With the way the S&C department work, they're incredible in what they do and every year they get better.
"We'll have to wait and see. Devin's so tall, with his ankle, he's got to get his balance back and he'll be right.
"Hendy's (Iain Henderson) still a wee way away. He's got a bit of a reputation for healing quite quickly, but he's still a wee way away. Tadhg (Beirne) could be right in a couple of weeks, we just have to wait and see. We'll get an update next week."
Ireland remain hopeful that both players will be fit enough to return later in the tournament, while the same optimism applies to CJ Stander, who is also out of the Scotland game having suffered a suspected fractured eye socket and cheek bone.
In more positive news however, Keith Earls trained fully today and is set to start on the wing, despite having had to be replaced at half-time in the loss to England with a hip issue.
Feek revealed that Rob Kearney has been flying in training as he looks likely to return to full-back with Robbie Henshaw reverting to outside centre in place of Ringrose.
"He's (Kearney) good, he got through yesterday and today," Feek added.
"Rob gets on with it. When his body's feeling good, he's got good energy and experience. I'd say he's probably delivering coffees to Joe over the last few days as well."
Quinn Roux meanwhile, is set to replace Toner and partner James Ryan in the engine room against Scotland.
"Quinn did really well at the weekend, he came on and put a couple of big hits in," Feek added.
"He's been leading the line-out in Connacht this year, he's really progressed there and matured as a player.
"He's been in our environment since the South Africa tour (2016). Good in the scrum, mauling, as a tight forward he ticks a lot of the boxes.
"Luckily for us, we have good depth there at the moment."