Generally speaking, except in the TIGHTEST of houses, closing off ducts tends to be neutral to the heating & cooling costs at bests, and usually results in higher outdoor-air infiltration due to the induced pressure differentials from a less-balanced system, making the great-outdoors carry a fraction of the air flow. Basically, don't close it off when nobody is using it, since it's cheaper to heat/cool the unused room than take the efficiency hit of the imbalanced system. This hasn't always been well-understood, but was the clear result of real-world testing done by the utilities in CA for the Lawrence Berkeley National Labs over the past decade or so.
If it takes a booster fan to get sufficient flow to the upstairs, that too may unbalance things, and simply turning it off when the upstairs isn't in use is likely the best solution. The only way to know for sure would be to measure the pressure differences in-situ with the fan running vs. off, while the main air handler is running.