Bone is a dynamic, living tissue whose structure and shape continuously evolve during life. It has the ability to change architecture by removal of old bone and replacement with newly formed bone in a localized process called remodeling. This process consists of formation and resorption. Osteoblasts are specialized stromal cells that are exclusively responsible for the formation, deposition and mineralisation of bone tissue. Specifically, the mature osteoblasts synthesize and deposit calcium phosphate crystals, mainly hydroxyapatite, and various constituents of extracellular matrix, such as type 1 collagen and proteoglycans. Osteoclasts, instead, are responsable of the bone resorption breaking down and removing old bone tissue.
Osteoporosis is a disease of the bones. It happens when you lose too much bone, make too little bone or both. As a result, your bones become weak and may break from a minor fall, or, in serious cases, even from simple actions, like sneezing or bumping into furniture. There is a high susceptibility to fracture.
If you look at healthy bone under a microscope, you will see that parts of it look like a honeycomb. If you have osteoporosis, the holes and spaces in the honeycomb are much bigger than they are in healthy bone. This means your bones have lost density or mass and that the structure of your bone tissue has become abnormal. The disease is principally defined by an imbalance of bone remodelling favouring osteoclastic bone resorption.
This disease is affecting millions of people worldwide in which a decreased bone mass and a microarchitectural deterioration compromise bone strength leading to bone fragility and increased susceptibility to fracture.
Bone turnover increases at menopause, with osteoclast-mediated bone resorption exceeding bone formation. Osteoporosis is commonly associated with postmenopausal women and to a lesser extent elderly men: half of all women and a third of all men over the age of 60 suffer from fractures due to osteoporosis.
Incidence of Osteoporosis
|AGE (women)||INCIDENTAL RATE|
|60-64 year||24 %|
|65-74 year||32,3 %|
|Over 75 year||42,1 %|
|55-59 year||2,1 %|
|60-64 year||2,4 %|
|65-74 year||6,3 %|
|Over 75 year||11,3 %|
Physical activity is an important factor in skeletal development and can prevent and treat age-related reductions in bone strength due to the inherent sensitivity to mechanical loading in bone tissue.
Important workloads are required for physical excercise leads to an improvement in bone mineral density.
Suggested activities of high-impact weight-bearing:
• for teens and healty young adults: squash, tennis, jump, aerobics, volleyball, basketball, walking, running, going up and down the stairs, hiking, dancing;
• for postmenopausal women: aerobics, body motion, swimming, rhythmic dances;
• for the elderly: stretching and mobilization excercises, light running, cyclette, strengthening excercises.
The physical Activity Role on the Bone mineral Density
The mechanisms by which physical activity can have a positive influence on the process of bone remodeling are extremely complex.
The two main extrinsic forces acting on the bone are the gravitational force and the muscle strength.
Both act on the available bone mineral and collagen.
From a point of view it would seem that only cellular osteoblasts are provided with mechanoreceptors and that, precisely for this reason, they are able to respond positively against an increase of the compressive forces. Simultaneously to this, and for the same physiological reason, a decrease of the mechanoreceptors, induced by microgravity, is able to decrease the activity inducing osteoblastic bone formation, leaving unchanged the process of bone resorption. Furthermore, the sensitivity of the mechanoreceptors would seem to be regulated and modulated by age and by hormonal level (Evans, Campbell, Snelling). In the elderly, the mechanoreceptors located at the level of osteoblasts, with the same compressive load, would decrease their response. In this way, the balance between the osteoblastic and the osteoclastic activity becomes less, thereby causing a cascade of physiological phenomena that lead in a more or less significant loss of bone mass.
In animal experiments was documented the stimulation of the transformation of cells into osteoblast-line when subjected to a mechanical load.
Is showed an increase in the phosphorylation of protein kinase membrane in osteoblast cultures subjected to continuous mechanical traction. When stress in tension is maximal, the
osteoblasts stretch in a direction parallel to the stress and gradually began to play express osteogenic factors such as BMP-4. This action is performed by a membrane kinase (MAPK), which transmits signals from the external membrane, through the cell membrane, to the nucleus and by a phosphorylation cascade stimulates gene expression.
It is seen that the levels of c-fos mRNA increase when bone is subjected to mechanical loading, testimony of replicative cell precursors.
An army of cytokines and molecules is able to facilitate the proliferation and differentiation of osteoprogenitors to pre-osteoblastic and mature osteoblastic cells.
Bone Morphogenic Protein (BMP) is a family of proteins that can act on early osteoprogenitors to instigate their differentiation to pre-osteoblastic cells.
Bone mass and turnover are maintained by the coordinated balance between bone formation by osteoblasts and bone resorption by osteoclasts, under regulation of many systemic and local factors.
In addition to that previously illustrated, there are a lot of evidences that mechanoreceptors act on the osteoblasts, with different effects:
-inhibit the secretion of IL-1, RANKL and M-CSF.
-induce an increased production of OPG and AKT1;
Recent discoveries in bone biology have demonstrated that RANKL, a cytokine member of the tumor necrosis factor superfamily, is an essential mediator of osteoclast formation, function and survival.
RANKL is expressed on the surface of osteoblastic cells. It forces the cell to physically interact with osteoclastic precursors in order for RANKL to bind to its receptor RANK, located on the surface of osteoclastic precursor.
RANKL action is negatively regulated by osteoprotegerin (OPG).
Targeting the RANK/RANKL/OPG signaling pathway: a novel approach in the management of osteoporosis,2007
OPG, also known as osteoclast inhibitory factor (OCIF), produced and exposed by osteoblasts, is a potent negative regulator of osteoclastogenesis. It acts as a decoy receptor to compete with RANK for RANKL.
Furthermore, OPG strongly inhibits osteoclast formation induced by vitamin D3 and parathyroid hormone.
It is important to note that osteoblasts directly regulate osteoclasts both positively and negatively. For instance, studies have discovered that osteoclastic bone resorption pits increase in the presence of osteoblasts due to the maintenance of osteoclast survival and induction of osteoclastogenesis by the RANKL-RANK-OPG axis.
The relative ratio of immature and mature osteoblasts control the degree of osteoclastic activity.
Known that RANK, RANKL and OPG form fundamental cytokine system that is capable of inﬂuencing all aspects of osteoclast functions and, indirectly, the complete bone regulation.
Denosumab: RANKL inhibition in the management of bone loss,2008
Moreover a paracrine factor secreted by osteoblasts, known as macrophage colony stimulating factor (M-CSF), would bind to its receptor c-fms, espressed on osteoclastic precursors. Many experiments demonstrated osteopetrotic mice that lacked M-CSF had very few osteoclasts. Interestingly, the osteopetrotic phenotype was reduced when Bcl-2, an anti-apoptotic gene, was over-expressed in these mice, indicating that M-CSF may regulate the survival of osteoclastic precursors.
Phosphoinositide-dependent serine-threonine protein kinase (Akt) is one of the key players in the signaling of potent bone anabolic factors. This protein is found in various cell types. Some studies initially showed that the disruption of Akt1 in mice, led to low-turnover osteopenia through dysfunctions of both cells. Cell culture analyses revealed that the osteoblast dysfunction was traced to the increased susceptibility to the mitochondria-dependent apoptosis and the decreased transcriptional activity of runt-related transcription factor 2, a master regulator of osteoblast differentiation. Notably, some findings revealed a novel role of Akt1 in the apoptosis of osteoblasts: Akt1 phosphorylates the transcription factor FoxO3 to prevent its nuclear localization, leading to impaired transactivation of its target gene Bim which was also shown to be a potent proapoptotic molecule in osteoblasts. Akt1 was established as a crucial regulator of osteoblasts by promoting their differentiation and survival to maintain bone mass and turnover.
Interleukin-1 (IL-1)is another possible regulator of osteoclastogenesis produced by osteoblasts.
It was demonstrated that removal of estrogen from mice elevated the number of osteoclasts, which coincided with an increase in IL-1 activity.
The main reason for the high incidence in postmenopausal women is the change in hormonal balance associated with menopause. Estrogen, a potent endocrine hormone linked to osteoporosis, has been demonstrated to bind to osteoblastic cells and suppress the expression of several paracrine pro-osteoclast factors, such as IL-1, IL-6 and TNFa. Estrogen can further increase OPG and inhibit RANKL expression. Therefore, since menopause is associated with a decreased level of estrogen, the above hormonal action is reversed, leading to an increase in osteoclast formation, and thus bone resorption. For example, it is demonstrated that estrogen could inhibit the transcription factor Egr-1,which is involved in increasing production of M-CSF. Osteoporotic mice that are deficient in IL-1, IL-6, M-CSF, TNF or combinations of these cytokines recover from osteoporosis.
The role of TGF-b
is controversial: TGF
-b, as well as other growth factors and speciﬁc components embedded in the bone matrix, are released by osteoclasts during bone resorption. TGF
-b’s effect on osteoblasts is bi-directional depending upon the state of maturation of the osteoblasts. On one hand, TGF
-b has the potential to stimulate osteoblast recruitment, migration and proliferation of osteoblast precursors. On the other, TGF
-b inhibits terminal osteoblastic.
Osteoblastic Responses to TGF-β during Bone Remodeling,1998
Therefore, consistent, customized and extended physical activity prevents the onset of osteoporosis.
Physical exercise is also one of the components of major impact in non-pharmacological approach to osteoporosis.
It is indicated in all stages of the disease process and during the whole life of an osteoporotic patient.