Real Madrid and Barcelona can set the stage for another pair of “clasicos” by beating Malaga and Osasuna when Spanish football returns from its annual winter break this week with the Copa del Rey's round of 16. Madrid and Barcelona both play their first leg at home, and big victories there would all but end their opponents' hopes of pulling off an upset in the return match. Strong results for the Spanish giants would also set up another likely matchup between them later this month, as the winners will meet in the two-legged quarterfinals of the cup competition. Malaga hasn't beaten Madrid since its return to regular first division football in 1999, , while Osasuna will face a Barcelona side that has won its last five matches at the Camp Nou by a combined score of 26-0. Malaga's ambitious owners have gone on a spending spree lately to buy players in a bid to see the Andalucian club compete at the top of the table, but Madrid has won the last three meetings between the sides by a combined score of 15-1. “In my mind they are the second best team in the world, behind Barcelona, they've shown it day-in, day-out,” Malaga forward Santi Cazorla said ahead of Tuesday's match. “Hopefully we can manage a positive result so we have a chance in the return.” Madrid, which beat Barcelona in last year's final, will likely be without injured players Angel di Maria, Sergio Ramos and Ricardo Carvalho, while Malaga remains without Brazilian striker Julio Baptista. In-form winger Jose Callejon is expected to fill in for Di Maria, while either Raul Albiol or Rafael Varane can replace Ramos if the Spain international doesn't recover from a leg injury in time to play at the Santiago Bernabeu stadium. “Di Maria's absence will affect them some,” Cazorla said. “But whoever plays, it's going to be a complicated match.” Barcelona, meanwhile, has 12 wins and two draws in 14 games at the Camp Nou this season, where it has outscored opponents 59-4. It already beat Osasuna 8-0 on home soil this season. Chile forward Alexis Sanchez could return from injury, while defenders Carles Puyol and Eric Abidal's forms are questionable in the buildup to Wednesday's game. Lionel Messi's availability is also questionable as the Argentine forward did not train with the team on Monday after just returning from a winter holiday. Osasuna is in good form and has climbed to a surprising fifth place in the league after going unbeaten in its last seven games, a streak that includes four wins. “Every game is different,” Barcelona midfielder Thiago Alcantara said. “They can change their tactics from then since they now know us a little more. I don't know how the game will play out.” Valencia faces Sevilla Thursday in perhaps the most even matchup of this round, while all four remaining lower-tier clubs host their first-leg matches against topflight clubs. Second-tier Alcorcon, which knocked Madrid out of the competition in 2009 and beat Villarreal this time around, plays early-season surprise Levante, with the winner of that series going on to play either Valencia or Sevilla. Madrid and Barcelona are also on that side of the draw, leaving the eight teams on the other half with a golden chance of reaching the final.