The competition is being played on autumn Test and Six Nations weekends, meaning that the sides' international stars are unavailable.
The Ospreys suffered more than most, with 12 players on international duty and a further 16 unavailable due to injury.
That became 17 shortly before kick-off when full-back Barry Davies withdrew with a back injury, Nicky Thomas switching to 15 on his first Ospreys start, with Jon Vaughton coming onto the wing.
Filo Tiatia and Richard Hibbard played through injury, while James King, Ross Davies and Justin Tipuric came off the bench in the course of the game to debut for the 2008 Cup winners.
Northampton showed nine changes from the side beaten at Leicester, including Ben Foden starting at full-back following his release from the England squad and Alan Dickens coming in at scrum-half to lead the side.
The Liberty Stadium match was the Ospreys' first on a Thursday and their first game against Northampton.
Ospreys coach Sean Holley: "I'm pretty disappointed, we started poorly, there were a lot of errors in the game, but it turned into a brave performance.
"I'm pretty proud of some of the youngsters who came on and put in a brave show It could have been a different story.
"We wanted to win, we were dealt the cards [over selection and injuries] and have to deal with them."
Ospreys: N. Thomas, Vaughton, Parker, Bishop, K. Phillips, Owen, L. Davies, Bevington, Hibbard, Griffiths, Gough, Tiatia, Collins, Tandy, Smith. Replacements: Spratt for Vaughton (60), Shervington for Hibbard (65), King for Gough (35). Not Used: R. Davies, Taylor, Tipuric, Wells, Beck.
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