A bit more on the bone loss - it varies from astronaut to astronaut, and takes some years to recover after a long mission.
Valeri Polyakov did a lot of exercise every day, and was ill towards the end of the mission - you have to exercise a lot in space to try to keep at health levels equivalent to someone who spends the same time in bed rest on Earth- and even so - you deteriorate compared to someone on Earth.
A few more effects of zero gravity apart from bone loss.- the blood pools in the upper half of the body because it's not pulled down by gravity.
Red blood cell count is lower, and resting heart beat is higher. This is almost immediate, e.g. the Apollo astronauts were affected by this.
You can't lose much heat by convection any more because warm air doesn't rise in zero gravity - you can only lose heat by sweating. So astronauts sweat more and that leads to magnesium deficiency.
It's harder to digest food and also astronauts tend not to drink so much - so they get dehydrated and also malnourished somewhat.
Medicines that you need to take in pill form no longer work as well as they do on the Earth because of changes of the functioning of internal organs.
There's a difference on the cellular level also - at least - microbes in thin films behave differently in space than they do on Earth - your whole body at many different levels is just not functioning in the same way in zero g, as it is on Earth..
BULLET POINT LIST OF EFFECTS
Here is a list of some of the known issues of zero g:
bone loss, lose 1 or 2% of your bone mass every month in load bearing parts of your skeleton such as feet. (Your skull and other parts that don't bear weight are unaffected by this - see Robert Frost's answer).
eye problems (many astronauts have short term issues after their flight, and there's been one case of irreversible damage to sight as a result of zero g),
thinner blood (reduction in blood cell count can be as much as 15% after two weeks in space),
more blood in the upper body,
increased resting heart rate,
greatly increased levels of adrenaline,
reduced digestion leading to malnutrition
issues in liver and kidney function,
changes in function of immune system,
reduced thirst leading to dehydration,
increased core temperatures,
can only get rid of heat by sweating, not by convection so increased sweating
The sweating leads to magnesium deficiency,
increased iron,
can't take most medicines orally, only subcutaneously because of the stomach, liver and kidney issues,
THROUGHOUT EVOLUTION, THE ONE CONSTANT IS GRAVITY - AND IT STILL REMAINS THE ONE THING WE CAN'T ADJUST IN EXPERIMENTS ON EARTH
Neither humans nor microbes even have evolved in anything except full gravity. Throughout the whole of evolution - the one constant that's never been changed at all is gravity.
Before the first spaceflights, nobody knew if humans could survive even an hour in zero g. That's one of the reasons why they sent so many Monkeys and apes in space. Now we know that humans can survive well over a year - if they are careful to exercise a lot every day. Nobody knows for sure if humans can survive two years in zero g.
LOW GRAVITY EFFECTS - E.G COULD HUMANS LIVE LONG TERM IN LUNAR GRAVITY?
The same is true of low gravity such as lunar and Martian. We didn't evolve in those conditions - and the body will not automatically adapt to them because no creature in the billions of years of evolution of Earth has ever had to adapt to less than full gravity.
Nobody knows what the long term effect on the body would be of lunar or Martian gravity because we haven't done the experiments in space and can't do them on the Earth.
Could be same as Earth g (normal health and lifespan), could be like zero g (not sure humans can survive two years), could be somewhere in between, could even be worse or better for health than either.
Also the various symptoms of zero g might well change in different ways in response to increases in gravity. E.g. blood pooling in upper body, bone loss, red blood cell count, sweating and magnesium deficiency, immune system etc - they might very well all respond in different ways to the effect of changing levels of gravity long term.
JOE CARROLL'S INGENIOUS IDEA FOR A WAY TO ANSWER SOME OF THESE QUESTIONS - AND INVESTIGATE POSSIBILITIES FOR HUMAN ARTIFICIAL GRAVITY IN SPACE
Joe Carroll suggested an ingenious method for doing first experiments in low gravity on a routine mission to the ISS. It could be done by adding a tether to the mission (he is an expert on space tethers) - to connect final stage to the Soyuz TMA - and for no extra fuel over an crewed ordinary mission to the ISS. (Same method could be used for the Dragon also if that gets approved).
If this tether method works and the spin rates can be tolerated by humans - you could also use tethers to generate artificial low or even full gravity in space to counteract the effects.
There - the two unknowns are - what are the effects of spinning motions on humans in artificial gravity conditions (different from spinning motions on Earth with full g acting usually along the spin axis) - and - what level of artificial gravity do humans need for long term health. Nobody knows the answer yet.
So - Joe Carroll's experiment could be used to investigate the spinning motions - and as a "space artificial gravity lab" to study the effects of low gravity on humans, something that's never been tested - except for the few days of astronauts on the Moon - and they didn't spend long enough there or have detailed enough observation to tell anything conclusive about long term effects of low g on humans.
WHY HAVE WE NEVER DONE THIS EXPERIMENT?
It's rather surprising - that we've known about the harmful effects of zero gravity for decades now - but so far - nobody has tried generating artificial gravity in space. Often been suggested, over and over - but never yet tested in space. (That is except for rats, the Russians tested it on rats in small centrifuges, and the results were promising suggesting it helps a lot with the problems of zero g - but for some reason it was never followed up for humans).
Joe Carroll says that he first suggested his experiment as an experiment for the space shuttle. He wrote down the ideas in his paper when it became pretty clear that it was never going to happen in his professional lifetime - in hope that some day someone else could use the ideas he developed.
I don't understand why that is myself. You'd think it would be top priority.
If we had artificial gravity in space - then humans could survive on the ISS for years on end - and not need to be rotated on and off every three months - huge cost saving.
It is an easy experiment - that we could have done probably as long ago as Gemini. They did a tether experiment but just for a short time to generate micro-gravity - and no follow up was ever done.
Perhaps the private space sector will do this experiment eventually, if NASA and Russia don't?
As well as the tether idea, there's also the idea of small personal centrifuges inside of a space station - and as an intermediate idea, the centrifuge sleeping quarters of the Nautilus X design.
With small personal centrifuges particularly - that's a relatively easy experiment that nobody has ever done. Seems likely that many people could easily stand 24 rpm for at least a few minutes, and very probably for an hour or more, after adaptation to spinning motion - and - nobody knows again - if for instance an hour a day of full gravity might be all that you need to stay healthy in space.
Again - nobody has every done the experiment and the human body is far too complex to hope to predict the effects without testing.
So anyway - the answer to your question then is, first, nobody knows if humans can survive zero g for more than two years. And worst case scenario is that you die from the combined effects of all those changes in your body long term.
But we might be able to solve all those problems with artificial gravity. Nobody knows how easy or hard that is, as even the simplest most basic experiments in human artificial gravity in space have not yet been done.
COSMIC RADIATION
As for cosmic radiation - then if we can send lots of mass into space - or mine it in space - or live underground (e.g. on the Moon) then we can shield the habitats.
You need roughly 4.5 tons of shielding per square meter for total protection from cosmic radiation, roughly equivalent to the Earth atmosphere - in the form of rocks or water. Ideas for permanent settlements in space such as Stanford Torus are designed around those figures.
But can get by with smaller amounts than that for shorter term stays. And very short times e.g. for space walks with almost no shielding at all. The main risk is cancer - that you could get cancer that shortens your life by a decade or more (is different from the types of cancer you get from smoking which you only get late in life - and can prevent by stopping smoking).
Astronauts are like anyone else who works in a hazardous radiation environment - they have to monitor their total exposure And an astronaut who goes over his lifetime limit won't be permitted into space any more.