Some of the cells for this process (osteocytes) are present in the bone in pockets (lacunae).
Others will come in, responding to the call of proteins released at the time of the fracture (mainly bone morphogenetic proteins,
BMPs). These cells are either ready-formed bone producing cells (osteoblasts) or bone munching cells (osteoclasts),
or they are primitive forms of these. Cells which could become bone cells (but could become other cells too) are circulating
in the blood in small numbers (maybe 1 in 10 000 cells) and are called mesenchymal stem cells (MSCs). These are not
quite like stem cells you hear about in the papers. Much of the current scientific excitement about stem cells refers to ‘pluripotent’
stem cells (cells that can become almost any cell type). These come from foetal tissue normally and can be found in placental
tissue and umbilical cord blood.
The MSCs however have already decided to be at least one type of tissue: mesenchymal tissue
– that is the bit between skin on the outside, and gut on the inside. They can become fat, muscle, nerve, scar, tendon,
ligament or bone.
In response to the BMPs, they will become bone forming cells.
The BMPs will also guide the cells to where they need to be (the cells climb up the concentration
gradient – a process known as chemotaxis)
They also instruct the cells to divide more quickly, and to make the kind of proteins they become
entitled to make from their DNA, once they become a bone forming cell.
There are many different types of BMP – probably more than 15. All appear at slightly different
times and these important proteins all have slightly different jobs. We aren’t sure what these are yet. Some are more
powerful than others at stimulating the bone repair process, with BMP 2 and BMP 7 seeming the most exciting at present.
The clever thing about the human body is that everything has a control
process – a negative feedback loop. For the BMPs, antagonists have already been found: these proteins tend
have silly names made up by wacky scientists – eg. noggin and gremlin. I am not making
this up: scientists do this regularly! Deep in science-land there is a lot of this: one of the controlling
genes in this process is called the sonic hedgehog gene for example. The proteins that take the BMP messages to the cell nucleus
are called Smads: this is a mixture of Small and Mothers Against Drosophila (a play on the US anti-drunk driver campaign popular
at the time of discovery of the protein, Mothers Against Drunk Drivers) – you couldn’t make this up! You get an
idea of the mood in science labs…
The BMPs are not the only controlling proteins – there are VEGF, FGF, PDGF,
ILGF, TGFbeta, and others – all growth factors, controlling parts of the repair process.
VEGF (vascular endothelial growth factor) is very important for the control of the ingrowth of
blood vessels into the healing fracture – without the vessels, of course, nothing happens. No nutrients or oxygen gets
to the cells and a general strike or famine prevails.
By the second week, the situation should be organised: the right sort of cells
should be in the right places, making the right proteins.
The fracture site is not just one homogeneous ‘blob’. It, like the city, has a centre
and suburbs.
In the marrow bit in the city centre, cells tend to start forming a cartilage-like substance, and
the cells are cartilage-forming. In the bit under the membrane covering the bone (the periosteum), the cells are forming primitive
bone already (the suburbs). Healing bone is called callus. The
bit in the centre is called the soft callus, and the bit around the edge is called the hard callus.
It has to be this way because the most strength is derived from the flared out bits around the margin of the fracture (the
city analogy continues!).
The hard callus is forming disorganised bone though, and this is called woven bone –
it has none of the structure that later, remodelled bone will have. It does have the right sort of cells, matrix and vessels
etc, but no structure.
Because the new bone is forming in the whole area of the blood clot, the new bone tends to form
a hard blob in the area of the fracture. This is good from the point of view of stability – it is much stronger, sooner.
But the shape will remodel later.
After a few weeks of maturing, the cells start to release calcium into
the matrix. It forms salt crystals with phosphate in the blood and the calcium phosphate crystals give the matrix extra strength
and give the fracture healing process some visibility on X rays.
At this point the fracture is getting very stiff. Forces seem to be important
at this stage. If there is too much movement, the cells give up trying to form bone and form cartilage and a sliding surface.
If there is not enough stimulus to form bone for other reasons (eg no blood vessels arriving, poor nutrition, infection present)
then fibrous scar tissue may form. If the fracture does not move at all, it seems that fracture healing is very slow. If the
stability is just right, bone formation gets on quite nicely. Optimum movements are microscopic.
It doesn’t seem to matter whether the movement is quick or slow, so long
as it is not to much movement, in terms of distance (presumably tearing the repair tissue apart).
In fact, walking pace loading seems to be very good at stimulating fracture healing
(1-2Hz).
Shaking the fracture a bit more quickly with ultrasound also seems to move things
along more quickly (about 40% more quickly actually).
Electrical stimulation with a magnetic field seems to stimulate the process to
a similar degree and this may be related to natural electrical fields set up when the calcium phosphate crystals are moved
(the piezo-electric effect).
If the fracture environment is favourable, the process continues, leading to union
of the fracture over the next few weeks. 
