Morrowind has me re-thinking this.
|Map edited from here. The red dots are the Mage guilds which all can be accessed from each other.|
You start the game in Seyd Neen in the South West.
Magic available in the game helps with the ease of travel too. There are spells (and magic items) that allow for teleportation to both native and Imperial temples. Crafty use of these can let you take shortcuts in travel-- popping over to a temple that is near a Silt Strider port, for example. There is also a Mark/Recall set of spells that allows you to set a specific anchor you want to easily return to later.
The danger is still present between these points of civilization, but there is much more flexibility in travel and exploration than I have experienced in any other video game sandboxes. If you don't want to mess about in the grimy swamps along the coast you can spend time in the dry ashlands further inland, or head to the grassy grazelands far to the west.
Danger is fairly well signaled; any old ruins are likely to have things you shouldn't mess with and as you near the center of the island more of the creatures are blighted and contagious. So your choices about where to travel can be informed choices.
The settlements offer pretty much redundant services, for example temples and Imperial garrisons. This means if you have a particular kind of character you like to play, you can take of advantage of all these travel opportunities without being penalized. The cities aren't identical, though, and you often need to travel around to find a spell or item you need.
I think one way this is possible is the sandbox is circular and several hops of travel doesn't take you so far away as to be unable to still access other environments. In a more traditional rectangular map, traveling towards a desert environment most likely leads you farther and farther from your original location.
I suppose a traditional D&D sandbox is also bigger, though, in-game this world feel huge. I wouldn't want to have to walk across the island real time.
I guess it all comes down to how much prep you can do. The video game all has to be ready for players from the moment play starts. So, as long as you can compartmentalize real danger (shove it into ruins and underground) you can let the player amble about all over. For a DM, having multiple areas that players could choose to start from sounds like lots of work.
But I will certainly think more about safe, clearly marked, ways players can move about so they can have choices where they want to explore.