PATHOGENESIS OF OSTEOPOROSIS AND RELATED FRACTURES

Pathogenesis of osteoporosis and related fractures

Normal characteristics of bone

Morphology

The bones of the adult skeleton comprise two types of tissue, cortical or compact, and cancellous or spongy bone. Most bones consist of an outer cortical sheath enclosing a trabecular network of cancellous bone that houses the marrow. The cortical sheath is bounded outside and inside by the periosteal and endosteal surfaces, respectively. The endosteal surface of the cortical sheath is connected to cancellous bone and consists of interconnected rods and plates. This structure maximizes strength while minimizing weight. The rods and plates of the cancellous network are preferentially oriented along the lines of mechanical strain of the bone. In adults, 80% of the skeleton is cortical bone. However, the relative proportions of cortical and cancellous bone vary in different parts of the skeleton. For instance, in the lumbar spine, cancellous bone accounts for about 70% of the total bone tissue, whereas in the femoral neck and radial diaphysis, it accounts for about 50% and 5%, respectively

Bone Cells

There are three special types of cells that are found only in the bone. These cell names all start with "OSTEO" because that is the Greek word for bone.

OSTEOCLASTS are large cells that dissolve the bone. They come from the bone marrow and are related to white blood cells. They are formed from two or more cells that fuse together, so the osteoclasts usually have more than one nucleus. They are found on the surface of the bone mineral next to the dissolving bone.

OSTEOBLASTS are the cells that form new bone. They also come from the bone marrow and are related to structural cells. They have only one nucleus. Osteoblasts work in teams to build bone. They produce new bone called "osteoid" which is made of bone collagen and other protein. Then they control calcium and mineral deposition. They are found on the surface of the new bone.

When the team of osteoblasts has finished filling in a cavity, the cells become flat and look like pancakes. They line the surface of the bone. These old osteoblasts are also called LINING CELLS. They regulate passage of calcium into and out of the bone, and they respond to hormones by making special proteins that activate the osteoclasts.

OSTEOCYTES are cells inside the bone. They also come from osteoblasts. Some of the osteoblasts turn into osteocytes while the new bone is being formed, and the osteocytes then get surrounded by new bone. They are not isolated, however, because they send out long branches that connect to the other osteocytes. These cells can sense pressures or cracks in the bone and help to direct where osteoclasts will dissolve the bone.

Composition of bone

Bone Mineral

The mineral component of bone accounts for about 65% of its total dry weight. Chemically, it is predominantly hydroxyapatite, Ca10(PO4)6(OH)2. Other constituents, such as carbonates, citrate, magnesium, sodium, fluoride and strontium, are either incorporated into the hydroxyapatite crystal lattice or adsorbed on to the surface.

Some substances, e.g. bisphosphonates, have a special affinity for bone mineral. Bone organic matrix The organic matrix accounts for approximately 35% of the total dry weight of bone. Approximately 90% of this matrix consists of bone-specific collagen; the remainder consists of non-collagenous proteins, such as osteonectin, osteocalcin (formerly referred to as bone Gla protein), osteopontin and bone sialoprotein. The matrix proteins are synthesized and laid down by osteoblasts. Collagen fibres are usually oriented in a preferential direction, giving rise to a typical lamellar structure. The lamellae are generally parallel to each other if deposited along a flat surface such as the surface of the trabecular network or the periosteum, or concentric if synthesized within cortical bone on a surface that borders a channel centered on a blood vessel. These concentric structures within cortical bone are known as osteons or haversian systems. The plasma concentration and/or the urinary excretion of collagen products and certain non-collagenous proteins such as osteocalcin reflect the rate of bone formation and resorption and are used clinically as biochemical markers of bone turnover. Bone cells Osteoblasts are bone-forming cells. They originate from local mesenchymal stem cells (bone marrow stroma or connective tissue mesenchyme), which undergo proliferation and differentiate to preosteoblasts and then to mature osteoblasts . The osteoblasts form a unidirectional epithelial-like structure at the surface of the organic matrix. The thickness of this layer, called osteoid, depends on the time between matrix formation and its subsequent calcification termed primary mineralization. Transport systems located in the plasma membrane of osteoblasts are responsible for the transfer of bone mineral ions, mainly calcium and phosphate, from the extracellular space of the bone marrow to the osteoid layer. The plasma membrane of osteoblasts is rich in alkaline phosphatase, which enters the systemic circulation. The plasma concentration of this enzyme is used as a biochemical marker of bone formation. Towards the end of the production of the bone matrix and the osteoblasts become either flat lining cells or osteocytes . A slow process of mineral deposition (secondary mineralization) completes the process of bone formation. Osteocytes originate from osteoblasts embedded in the organic bone matrix, which subsequently become mineralized. They have numerous long cell processes forming a network of thin canaliculi that connects them with active osteoblasts and flat lining cells. Fluid from the extracellular space in the bone marrow circulates in this network. Osteocytes probably play a role in the homeostasis of this extracellular fluid and in the local activation of bone formation and/or resorption in response to mechanical loads. Osteoclastic resorption takes place at the cell/bone interface in a sealed-off microenvironment. In this regard, the most prominent ultrastructural feature of osteoclasts is the deep folding of the plasma membrane, called the ruffled border, in the area apposed to the bone matrix. This structure is surrounded by a peripheral ring tightly adherent to the bone matrix, which seals off the subosteoclastic resorbing compartment.

The mechanism of bone resorption involves the secretion of hydrogen ions and proteolytic enzymes into the sub-osteoclastic resorbing compartment. The hydrogen ions dissolve the bone minerals, thereby exposing the organic matrix to the proteolytic enzymes. These enzymes, which include collagenases and cathepsins, are responsible for the breakdown of the organic matrix. The process releases the minerals that contribute to calcium and phosphate homeostasis. Accordingly, biochemical markers of collagen degradation, such as hydroxyproline and pyridinoline crosslinks, which are found in plasma and urine, can provide estimates of the bone resorption rate.

Physiology

Both the shape and structure of bone are continuously renovated and modified by the processes of modelling and remodelling.

Bone modelling

Bone modelling begins with the development of the skeleton during fetal life and continues until the end of the second decade, when the longitudinal growth of the skeleton is completed. In the modelling process, bone is formed at locations that differ from the sites of resorption, leading to a change in the shape or macroarchitecture of the skeleton. Longitudinal growth of a typical long bone, such as the tibia, depends on the proliferation and differentiation of cartilage cells in the epiphyseal (growth) plate. Cross-sectional growth, such as the increase in girth of the radial diaphysis, occurs as new bone is laid down beneath the periosteum. Simultaneously bone is resorbed at the endosteal surface.

Bone modelling may continue, but to a lesser extent, during adult life when resorption at the end endosteal surface increases the mechanical strain on the remaining cortical bone, leading to the stimulation of periosteal bone apposition. This phenomenon, which increases with ageing and is somewhat more pronounced in men than in women, offsets in part the negative effects of bone resorption at the endosteal

surface on mechanical strength.

Bone remodelling

Bone remodelling occurs simultaneously with modelling from fetal life through to skeletal maturity, when it becomes the predominant process that occurs throughout adult life. Remodelling maintains the mechanical integrity of the skeleton by replacing old bone with new. Bone resorption and bone formation occur at the same place, so that there is no change in the shape of the bone. This constant process of turnover enables the skeleton to release calcium phosphate whenever the net intestinal absorption of this mineral is less than the amount excreted in urine. In the adult skeleton, approximately 5–10% of the existing bone is replaced every year through remodelling. This does not occur uniformly throughout the skeleton, but in focal or discrete sites. The morphological dynamic structure of turnover is the “basic multicellular unit” (BMU), also called the “bone remodelling unit” (BRU). The morphological entity formed when the process is terminated is called the “bone structural unit”. The BSU corresponds to a “packet” in cancellous bone, and to an osteon in cortical bone. In both cortical and cancellous bone, the remodelling process begins with bone resorption by osteoclasts. This phase is over within a few days and is followed by the departure of multinucleated osteoclasts and the reversal phase. In the reversal phase, mononuclear cells line the resorption lacunae and deposit a cement line marking the limit of prior erosion and the newly formed bone. These mononuclear cells are subsequently replaced by osteoprogenitor cells, which differentiate into cuboidalshaped osteoblasts. Organic matrix is then laid down, followed by the deposition of minerals. The lacunae are gradually filled with new bone over several months. Thereafter, the osteoblasts change shape and eventually become flattened lining cells, and the osteoid seam narrows and eventually disappears. This process of bone resorption followed by formation at the same locus is termed “coupling”

The remodelling process is controlled by systemic and locally produced cytokines . The maintenance of a normal, healthy, mechanically competent skeletal mass depends on keeping the process of bone resorption and formation in balance. Failure to match bone formation with bone resorption results in net bone loss. This is what occurs in osteoporosis, whether as a result of deficiency of sex hormone, primary hyperparathyroidism, hyperthyroidism or endogenous or exogenous exposure to excess glucocorticoids.