What is bone?

Bone is a material and a tissue

Bone tissue is a characteristic of Chordate animals. Other phyla have other hard materials. Before the existence of bone, our worm-like ancestors had a dorsal string composed of cartilage-like material which enabled efficient coiling movements so that they could swim like fish, something that a worm without a dorsal string is not able to do. During the Cambrian period, 500 million years ago, the ability to control the deposition of hydroxyapatite chrystallites in connective tissue arose in these animals, giving them the ability to form hard tissue, first as primitive teeth and then, to avoid being bitten, as body armour. Enamel and dentine have therefore been around on earth a bit longer, but bone soon appeared as reinforcements to the jaws and as body shields. The inner skeleton, the spine, still consisted of cartilage.

Bone is therefore connective tissue, mainly collagen, mixed with small crystallites of the mineral hydroxyapatite. This acts as a composite material, where the collagen provides the tensile strength and the mineral the compressive strength. During fetal development when the first bone is formed, the collagen fibres are laid down haphazardly. In English this is called woven bone which is somewhat misleading, as an organised collagen structure appears considerably later both during evolution and in fetal development. Better organized, new bone needs to be deposited on a smooth surface, and such a surface can only be created by woven bone being ”planed” smooth by by bone resorbing cells) which were a more recent invention of evolution). The new bone is laid in regular layers onto this surface. Collagen can now be organised so that the fibres in each layer lie parallel to each other on the surface plane, like lamellae, but in different directions in each plane. This makes it much stronger than woven bone, and also prevent cracks from growing. Almost all bone in adult humans is lamellar bone.

So far we have only talked about bone as a single material. This material can build different structures, such as cancellous (spongy) bone or cortical (compact) bone. A whole bone in the body, for example a long bone, can then be built from these structures.

Let us return to the early fish who had bones on the skin (fish scales!) and a cartilage skeleton inside the body. Gradually, the ability to deposit bone on cartilage surfaces appeared so that the cartilage structures became stronger and more rigid. The next step in evolution was to remove the cartilage inside these structures and replace it with bone. This required a new, cartilage-degrading cell type, developed from the phagocytic cells of the immune system. Bone could now also be formed inside the cartilage; this is enchondral bone formation. We then had a skeleton that consisted entirely of bone. However, even if the body could form bone when needed, it could not yet remove it and modify its shape, so bones were therefore heavy and clumsy. The next important step was the development of bone resorbing cells, the osteoclasts. When these had been developed, the tools were available to form a modern, efficient skeleton.

Bone can be seen boths as a material and as a tissue.  We can drill, cut and put screws in bone, but still it contains evenly outspread cells, osteocytes. The osteocytes communicate with each other over longdistances via a network of thin dendrite-lite cytoplasmic extensions, which forma a surveillance system. The bone is covered by lining cells. These can be activated to bone forming cells, osteoblasts, which debosit bone matrix on the surface. If the osteoblasts surround themselves with bone matrix they end up inside the bone as osteocytes.

Bone has its own way of growing

When most tissues grow, they do so by dispersed cells dividing and producing more matrix, leading to a homogeneous expansion, like rising bread. Since bone is hard and its cells are trapped in their lacunae, it cannot grow in the same way. The only possibility is therefore to form new bone on the outside of the old bone, like rings in  trees. In this way, the long bones can become thicker as we grow. However, this mechanism cannot cope with growth in height, since the ends of our long bones are parts of joints, covered with articular cartilage. Primitive vertebrates (crocodiles) grow by the articular cartilage expanding homogeneously. The part of the cartilage that is closest to the underlying bone is resorbed and replaced successively with bone. More modern animals, such as dinosaurs and mammals, have a more refined mechanism which facilitates elegantly formed bones.

During fetal life our bones develop from a cell condensations forming a cartilaginous, rod-shaped model sometimes referred to with the German word anlage. Bone is formed on the surface of the anlage, on what will become the shaft. At the ends of the rod, a core of bone forms inside the cartilage. The cartilage then remains between these cores and the shaft, and forms specialised growth areas called physes. The physes expand homogeneously in a well-regulated manner, and just as in crocodiles, the cartilage that faces towards the shaft is continuously replaced with new bone. This occurs through a series of linked processes that comprise the highly regulated enchondral bone formation. It is not until puberty that cartilage growth ceases. Enchondral bone formation continues a little longer, until it has replaced the cartilage so that no further growth is possible. In adults the parts of a bone are also named after the physes; the shaft is the diaphysis and the ends are the metaphyses. In a child, the bone between the physis and the joint is the epiphysis.

Bone needs to keep young

During growth, bone needs to be successively rebuilt to adapt to mechanical demands. In adulthood, bone needs to be gradually replaced to avoid it becoming too old and brittle; all materials, including bone, become brittle with prolonged use. This replacement of bone occurs through remodelling. In spongy bone, this happens by one or more osteoclasts digging a trench in the surface of a trabecula (trabeculae form the lattice of spongy bone). This trench can be quite large, around a tenth of a millimeter wide and half as deep. Osteoclasts are efficient, and this only takes a few days. During the weeks that follow, the osteoblasts fill the trench with lamellar bone. Remarkably, the osteoblasts do not stop until the whole trench is filled, nor do they continue after this has been completed. How this is regulated is not known, but many assume that the degree of deformation in the bone plays a role as described below. Remodelling occurs in a separate micro-anatomical structure called the bone remodelling unit. There are mesenchymal cells and inflammatory cells above the trenches that are thought to have a regulatory function, and above these a canopy of cells that separates the remodelling unit from the adjacent bone marrow. The remodelling unit has its own vascular and nerve supplies.

Cortical bone needs to be remodelled deeper into the bone, so the remodelling unit is adapted for this. Instead of a trench, the osteoclasts dig a tunnel in the bone somewhat like a mine-shaft. Blood vessels, nerves and osteoblasts follow the osteoclasts into the tunnel. The tunnels are initially wide, but the osteoblasts form lamellar bone on the tunnel walls, so the tunnel becomes gradually narrower until only a thin channel for the blood vessels remains in the middle (Haversian canal). The osteoclasts dig their tunnels mainly in the direction of mechanical loading of the bone, so in cortical bone the tunnels run parallel to the bone shaft. It is unclear how they find the ditrection. If the bone is cut crosswise, the new lamellar bone can be seen as concentric rings around the central small blood vessel. This structural unit is called the osteon. An adult human long bone consists mainly of osteonal bone.


Bone can feel mechanical load

A couple of generations ago, it was popular in the field of biology to emulate the success of physics by formulating ”laws”. An example of this is the so-called Wolff’s law, which states that the structure of a bone reflects the mechanical loading that it has been subjected to. The orientation of trabeculae in spongy bone therefore indicates the lines of loading. The question as to how bone cells know the direction they are being loaded has been asked for decades. In soft tissue, this is not a problem as the cells are deformed by mechanical stress and deformation of the cytoskeleton is easy to detect and react to. However, bones are rigid and deformation amounts to one part in a thousand at most. How can cells perceive this? In recent years, this mystery has begun to be solved. The osteocytes within the bone are understood to represent a specialised sensory network. Osteocytes have lots of thread-like cellular outgrowths, which extend to neighbouring osteocytes and to the cells on the bone surface. These outgrowths communicate via gap junctions. They run in very thin channels through the bone material. When the bone is mechanically loaded and deformed imperceptibly little, this is sufficient to affect the fluid pressure in the channels. Pressure gradients arise, and fluid rushes at high speed through the channels. Due to the high speed, this is detected as shear forces on the surface of the osteocyte outgrowths. Needless to say, the flow rate can only be high if the loading occurs suddenly, so blows, impacts and vibrations are much more important for stimulating bone than heavy weights. When the osteocyte has detected a load, it signals through its outgrowths to the inactive cells on the surface of the trabecula that they should become active osteoblasts and start to form bone. After a while this leads to the trabecula being thicker and stronger, so they deform less, and the signal ceases. Several biochemical signals are involved in this system, including PGE2, which means that treatment with NSAIDs decreases the bone’s ability to adapt to loading. A key signal is, however, the protein sclerostin, which is produced by the non-loaded osteoclasts and forces the osteoblasts at the bone surface to remain inactive. With loading, the production of sclerostin can cease and the osteoblasts are triggered. However, this is far from the whole story.

The osteocyte network also has another function. In most textbooks remodelling is understood as stochastic, that is chance determines where the remodelling units appear. More recently, however, it has been understood that remodelling is often targeted. When bone tissue becomes old and brittle, an increasing number of microscopic cracks appear. These injuries are detected by the osteocytes, which might die if too many of their outgrowths are damaged by microscopic cracks. Damaged osteocytes and the cells neighbouring dying osteocytes produce large amounts of an osteoclast stimulating substance (RANKL). This directs the osteoclasts to the damaged area, which is then resorbed and replaced with new fresh bone.

Osteoporosis is one of several causes of fracture

Oestrogen and male sex hormones inhibit remodelling. When old age approaches and hormone levels decrease, remodelling will therefore increase. In addition, osteoblasts become rather tired in the absence of oestrogen. This means that they do not manage to completely fill the growing number of trenches and tunnels that the osteoclasts dig. Therefore with each remodelling cycle there is a reduction in the amount of bone. Since there are now many more remodelling cycles, what happens is that trenches and tunnels run into each other more often, or the osteoclasts dig in the same trabecula from opposite directions and meet in the middle. This means there is no surface left to build new bone on, and the trabecula disappears. The loss of individual trabeculae can have a devastating effect on the stability of the whole structure, as it can lead to an incorrect distribution of forces.

This is the background to why even a moderate decrease in bone mass can severely impair bone strength.

Osteoporosis is defined as a bone mineral density of more than 2.5 standard deviations below the average for a young healthy population. Osteoporosis is associated with an increased risk of fracture, especially in spongy bone. The spongy bone, with its large area available for the osteoclasts, is the first to decrease. Only later in the development of osteoporosis do we also see an obvious reduction of the cortical bone. Typical osteoporotic fractures are for example, vertebral compression fractures, hip fractures, fractures of the proximal humerus and radial fractures. However, it is important to remember that most ’osteoporotic fractures’ affect people who do not have osteoporosis. They may have osteopenia, which is a bone density of between 1.5 and 2.5 standard deviations below that of a young healthy population. A fracture rarely occurs without a person falling and the way in which the person falls can be crucial in determining whether they are injured or not. A young person with fast reflexes and strong muscles can easily adjust his fall so he doesn’t get hurt. Many elderly can’t.

Osteoporosis, although probably not osteopenia, can be successfully treated with medication. There are two principles to this: speed up bone formation or inhibit bone breakdown. The latter is the most common, and was introduced in the 1990s, when the bisphosphonates appeared. The bisphosphonates were derived from the development of additives to washing machine detergents, but were later found to have extraordinary effects on the skeleton. The bisphosphonates are small molecules that bind very strongly to the hydroxyapatite in bone and stay attached for many years. The molecule is largely harmless, does not enter the cells, and if not bound to bone, it is rapidly excreted by the kidneys. When an osteoclast resorbs bone, the remains of the bone pass through the osteoclast and out into the circulation. If the bone contains bisphosphonate this therefore ends up, for the first time, inside cells. Once inside, bisphosphonates are toxic and the osteoclasts are deactivated or go into apoptosis. The main effect of bisphosphonates in osteoporosis is to reduce the number of remodelling units. This not only inhibits the progression of osteoporosis, but also allows the bone time to mature to its full mechanical strength. The high turnover in osteoporosis otherwise means that the bone does not have time to mineralise fully before it is remodelled again.

The bisphosphonates also have beneficial effects in other conditions, such as reducing the growth of bone metastases (tumours need bone resorption to make room for them to grow). In an orthopedic context bisphosphonates have been seen to improve the fixation of prosthetic joints and probably reduce the risk of them coming loose.

Among other medicines used for treating osteoporosis, parathyroid hormone is particularly worth noting, which when given intermittently has a stimulating effect on osteoblasts. This leads not only to reduced bone breakdown, but also an increasing bone mass, especially in the vertebral column.

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