The main aim of the investigators exploring bone tissue characteristics and pathogenic turnover is to search for agents with capacity to enlarge the bone mass. Most of the pathogenesis cases in bone diseases are based on the decreased bone tissue. The normal metabolism of the bone is equilibrium between reduction and increase of bone mass. Recruitment of osteoclasts (cells that are responsible for bone resorption) and osteoblasts (bone forming cells) is well-balanced process. In normal bone, bone formation and bone resorption are closely coupled processes involved in the normal remodeling of bone. In most bone diseases, the net rate of bone resorption exceeds the rate of bone formation, resulting in a decrease in bone mass. Most of the created therapies target the processes of bone formation and resorption (respectively osteoblasts and osteoblasts).

Normal and pathological physiology of bone tissue

The cells responsible for bone metabolism are known as osteoblasts, which secrete new bone, and osteoclasts which break bone down. The structure of bones as well as adequate supply of calcium requires close cooperation between these two types of cells. It relies on complex signaling pathways to achieve proper rates of growth and differentiation. These signaling pathways include the action of several hormones, including parathyroid hormone (PTH), vitamin D, growth hormone, steroids, and calcitonin, as well as several cytokines. It is in this way that the body is able to maintain proper levels of calcium required for physiological processes.

Drugs that change the bone turnover

1. Anabolic agents
Anabolic agents directly stimulate bone formation. The hope is that they can have a more potent effect on bone mass and can further reduce fracture risk.
- PTH
PTH is peptide hormone with 84 amino acids. It is synthesized by parathyroid gland.
When PTH is administered intermittently and in low dose, it produces an anabolic or bone forming effects. The response to the PTH is different, according to the exposure and to the osteoblasts stage of differentiation. The opposite - continuous exposure causes the opposite response – bone resorbtion.
This hormone increases the plasma concentration of calcium and decreases the concentration of phosphates. The main reasons of that activities are the stimulation of re-absorption of calcium in the distal tubules, inhibition of re-absorption of phosphates in proximal tubules and indirectly the intestinal resorption of caltium via stimulation of Vitamin D3 production.
Stimulation is indirect since osteoclasts do not have a receptor for PTH; PTH binds directly osteoblasts. Binding stimulates osteoblasts to increase their expression of RANKL, which can bind to osteoclast precursors containing RANK, a receptor for RANKL. The binding of RANKL to RANK stimulates these precursors to fuse, forming new osteoclasts which ultimately enhances the resorption of bone.
Parathyroid hormone regulates osteoblast differentiation positively or negatively depending on the differentiation stage.
- Strontium ranelate
Strontium ranelate, may both promote bone formation and inhibit bone resorption.
- Statins
Statins are HMG-CoA reductase inhibitors, a class of hypolipidemic drugs used to lower cholesterol levels in people with or at risk of cardiovascular disease. After years of application in lipids turnover, it became clear that statins helps preventing osteoporosis. Statins are statins as the inducers of BMP-2.
- Fluoride
Fluoride stimulates bone formation in vivo by not well defined mechanisms. Fluoride enhances bone cell proliferation by altering tyrosine kinase or phosphatase activity specifically in bone cells. It happens by inhibition of phosphatases by fluoride, which dephosphorylate tyrosine kinases. Excessive exposure to fluoride causes an arthrtiic bone disease called skeletal fluorosis.

2. Anti-resorptive agents
- Bisphosphonates
Pyrophosphates inhibit precipitation of calcium carbonates. Pyrophosphates bind extremely to calcium phosphate and decrease both the formation of calcium phosphate crystals in vitro and in solution. Bisphosphonates shows similar physical and chemical activity, but resist enzymatic activity.
Bisphosphonates bind to the surface of bone at sites of active remodeling where two distinct molecular mechanisms are thought to be responsible for the ability of bisphosphonates to modify osteoclast function. Non-nitrogen-containing bisphosphonates
(etidronate, clodronate, and tiludronate) alter cellular function by being metabolized to cytotoxic ATP-bisphosphonate analogues. The nitrogen-containing bisphosphonates (alendronate, risedronate, ibandronate, and zolendronic acid) inhibit farnesyl pyrophosphatase and other steps in the intracellular mevalonate pathway. As a result, the post-translational modi?cation by prenylation of proteins such as Ras and Rho is decreased, leading to diminished recruitment or differentiation of osteoclast precursors and to osteoclast death. The loss of osteoclast activity results in a decrease in the rate at which new bone remodeling units are activated and a decrease in the amount of bone resorbing activity in each bone remodeling unit. The resulting reduction in bone turnover indirectly decreases osteoblast function and bone formation.
Bisphosphonates inhibit the osteoclast function by altering the cytoskeleton and the ruf?ed border, decreasing acid extrusion and
enzyme activity and increasing osteoclast apoptosis. A second target cell is the osteoblast, which secretes an osteoclast recruitment inhibitor that is stimulated by the action of bisphosphonates.
- Calcitonin
The calcitonin is an endogenous inhibitor of bone resorption. It inhibits the osteoclast formation and attachment in bone resorption.
- Bioflavonoids
The term bioflavonoid refers to a class of plant secondary metabolites. According to the IUPAC nomenclature, they can be classified into:
* flavonoids, derived from 2-phenylchromen-4-one (2-phenyl-1,4-benzopyrone) structure
* isoflavonoids, derived from 3-phenylchromen-4-one (3-phenyl-1,4-benzopyrone) structure
* neoflavonoids, derived from 4-phenylcoumarine (4-phenyl-1,2-benzopyrone) structure.

3. Combinated drugs
The combinated drugs consist of organic (osein) and inorganic (hydroxyapatite) compound. The osein stimulate the bone formation. It includes osteocalcin, TGF-beta, IGF-1 and IGF-2. The osteocalcin is protein, that stimulate collagne formation and helps differentiation of bone marrow mesenchymal stem cells into osteoblasts. The hydroxiapatite is the normal compound of the bone matrix and helps inhibition of bone resorption.

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Neli
neli.petkova@lifesciences.bg