The word skeleton brings to mind images of a Halloween decoration. However, this static picture of bones could not be further from reality. Through a process called remodeling, our bones are dynamic and ever changing. We may remodel our homes once or twice in our lifetime, but when it comes to our bones, the remodeling is constant and never ending.

Remodeling results from the interplay of three bone cell types: osteocytes, osteoclasts, and osteoblasts. More than 95 percent of the bone cells of an adult are osteocytes. Osteocytes are the cells buried in bone, and they maintain a dense network of connection with each other. They sense mechanical strain when the bone is bent or deformed, which happens all the time as muscles pull and tug on the bone. Higher mechanical strain is produced with exercise. Osteocytes are presumed to respond to this strain by sending signals that cause either new bone formation or existing bone removal.

Osteoclasts are the cells that break down bone. Osteoblasts are the cells that form new bone. These two types of cells work in concert to keep bone repaired and in good shape.

Bone resists breaking apart by relieving the stresses that develop from everyday life. These stresses cause tiny cracks called microcracks. Bone remodeling occurs in response to these microcracks in order to maintain the structural integrity of the skeleton and to serve its function as a storehouse of calcium.

Bone has a crack repair team that sets up bone remodeling units. Old bone is removed by the osteoclasts that dig around the cracks. They create actual pits or holes in the surface of the bone using acids to dissolve the old bone. The osteoblast cells migrate in and line the pits to form new bone. The bone is restored to its former level. Later, the new bone is hardened through a process called mineralization, so that the new bone becomes indistinguishable from the surrounding bone. It is similar to a painter filling in a hole in the wall with spackle and then painting over it.

Types of Bones

 

• There are two types of bone. Compact cortical bone makes up the outer shell of all bones and the shafts of the long bones of the arms and legs. It comprises about 80 percent of the skeleton. Spongy trabecular bone makes up the inner parts of the bones found in the spine (vertebrae), the pelvis, and the end parts of long bones.
• The spongy bone resembles a rigid sponge with a plate-like meshwork of beams. The plates within this kind of bone are called trabeculae; they act as cross braces to give support and prevent collapse of the structure.
• Remodeling occurs at different rates in the two types of bone. The spongy trabecular bone is metabolically faster than the dense cortical bone. This is a function of a greater number of cells in trabecular bone and a larger surface area where remodeling occurs. The spine therefore shows changes more quickly than the dense bone in the hip.

SPEED: CRUISE CONTROL

If the amount of new bone equals the amount being broken down, bone mass stays stable and does not change. A balance is maintained into your thirties and bones remain strong. Packets of old bone are replaced with packets of new bone in perfect synchrony.

Normal Bone Remodeling

• On average, your entire skeleton is renewed every ten years.
• Lifespan of an osteoclast is approximately three weeks.
• Lifespan of an osteoblast is approximately three months.
• One new remodeling site starts about every seven to ten seconds.
• Therefore, three to four million new bone-remodeling sites are initiated each year.
• One million sites operate at any given moment in your skeleton.

However, even at an early age, bone remodeling is not perfectly efficient. There is a small deficit in bone following each cycle. Given the number of bone remodeling cycles operating in the adult skeleton, this imbalance causes age-related bone loss that results in a bone deficit that probably increases with age.

SHIFT TO OVERDRIVE

Anything that increases whole-body bone remodeling will aggravate bone loss.

Menopause, with the accompanying loss of estrogen support, results in an increase of osteoclast activity. Bone breakdown happens much faster than the osteoblasts can form new bone. The rate of bone formation is unable to match the increased bone breakdown. This revving up of the cycle results in a net loss of bone tissue that can be significant. The plates of bone slowly become rod-like structures. The connections in the spongy trabecular bone become broken. Multiple areas of bone become structurally fragile and this eventually leads to increased fracture risk. The bones become thinner and weaker and are therefore prone to break more easily.

Many other factors, such as certain medicines and illnesses, may also accelerate bone breakdown so that the osteoblasts can't keep up.

Prescription medicines for osteoporosis are classified based on their action on bone cells. Most osteoporosis drugs target the activity of the osteoclast. Since the breaking down of bone is referred to as resorption, the medicines are called antiresorptives. Antiresorptives work by decreasing the action of osteoclasts, which decreases the rate of bone breakdown. Bone formation agents, on the other hand, work by activating the osteoblasts to increase the making of new bone. The response to therapy is based on rates of bone remodeling in different parts of the skeleton. For example, larger increases in bone density are seen at the metabolically more active spine than at the hip.

SYSTEM CONTROL: THE GOVERNATOR

Remodeling is regulated not only by hormones but also by local factors. A complex series of intricate steps activates the system. The hormones interact with local factors that regulate the repair. The two cell types, osteoclasts and osteoblasts, are functionally coupled. How they communicate with one another was discovered only in the mid-1990s.

Messenger System

 

Osteoblasts originate from bone marrow mesenchymal stem cells. Osteoclasts are derived from blood-related stem cells. The development of osteoclasts is based on communication from osteoblasts. The osteoblast sends a messenger to deliver a signal to the osteoclast to grow up and get to work. This regulator of bone cycle has a long, complicated name: receptor-activating nuclear factor kappa B ligand, shortened to RANKL. This intermediary messenger binds to receptor sites on the surface of the immature precursors of osteoclasts called RANK.

Another factor called osteoprotegerin (OPG) is secreted by osteoblasts that bind RANKL and prevent it from stimulating the osteoclasts. Therefore, less osteoclast activity and less bone breakdown occurs with more OPG. It is as if the workers on the demolition team get a day off. These two factors produced by the osteoblasts regulate the creation of osteoclasts and their activity.

Identification of this messenger system lead to the development of a novel way to treat osteoporosis. Amgen's drug Prolia® has similar action to the body's own OPG. Prolia binds to RANKL to prevent the birth of new osteoclasts, to decrease the activity of osteoclasts, and to shorten the life span of osteoclasts. As a result, bone breakdown is dramatically decreased with a resulting increase in bone density and lower risk of fractures.

IS THE GUT REALLY IN CONTROL?

New research points to a Wizard of Oz manipulating bone growth from behind the scenes. The switches are controlled by an unlikely source—serotonin. Serotonin transmits signals between nerve cells in the brain but it cannot pass through a barrier to leave the brain.

 

Serotonin used in other parts of the body is produced mainly in the gut. Scientists at Columbia University found a gene called Lrp5 that regulates the production of serotonin in the gut. They found that bone cells take up serotonin like nerve cells. The serotonin signals bone to slow production of new bone. By turning off production of serotonin in the gut, the team could increase bone formation. In the lab, using mice that were undergoing menopause, the team was able to prevent the usual bone loss associated with menopause.

 

Stay tuned for more; it is a hot new area of research. Multiple research groups are investigating this approach for treatment of osteoporosis. Since only one medicine is available currently to increase bone formation, new therapies using this pathway to increase bone formation would broaden the choices for treatment of osteoporosis.

The Bare Bones

• Bone is constantly breaking down and building back up in a process called remodeling.
• The bone cells—osteoclasts and osteoblasts—work in concert to remodel the bone.
• When bone breakdown equals bone formation, bones remain strong.
• Bone loss occurs when bone breakdown exceeds formation.
• Women experience acceleration of bone loss at menopause with loss of estrogen.