Pathophysiology: Biological Causes of Osteoporosis

Introduction

Bone maintenance is a delicate business. In adults, the daily removal of small amounts of bone mineral, a process called resorption, must be balanced by an equal deposition of new mineral if bone strength is to be preserved. When this balance tips toward excessive resorbtion, bones weaken (osteopenia) and over time can become brittle and prone to fracture (osteoporosis).

This continual resorption and redeposition of bone mineral, or bone remodeling, is intimately tied to the pathophysiology of osteoporosis. Understanding how bone remodeling is regulated is the key to the effective prevention and treatment of osteoporosis.

The big picture

Bones, like the framework of an aircraft, have evolved to be light yet strong. These properties are conferred to a large degree by architecture. The long bones are tubular in shape, with a strong outer shell, or cortical layer, surrounding a softer, spongier core called trabecular bone [1]. The combination makes these bones strong and light, but flexible enough to absorb the stress – from high impact exercises – without breaking. The vertebrae are similarly constructed, with a thick cortical layer surrounding sheets of trabecular bone. As a unit, each vertebra can compress when temporarily loaded and then return to their original size.

But unlike an aircraft frame, a skeleton is alive and must be able to grow, heal, and respond to its environment. This is where bone remodeling plays a crucial role. However, there is a downside. As we age, daily remodeling leads to a gradual restructuring of the bone. Resorption of the minerals on the inside of the cortical layer and in the bone cavity itself leads to an inexorable loss of trabecular bone and a widening of the bone cavity. This is partly compensated for by the gradual addition of extra layers of mineral to the outside of the cortical layer [2].

The upshot is that overall the bones get slightly thicker. But the danger is that they are not getting any denser. In fact, peak bone mass, reached in early adulthood, gradually declines as people get older [3].

Bone architecture and continual remodeling combine to have a huge impact on the pathophysiology of osteoporosis. For example, young adults with wider femurs might be at higher risk for hip fractures late in life because, on average, wider bones tend to have thinner cortical layers. The thinner this layer is, the more susceptible it will be to resorption later in life [reviewed in 4].

The cellular connection

The balance between bone resorption and bone deposition is determined by the activities of two principle cell types, osteoclasts and osteoblasts, which are from two different origins. Osteoclasts are endowed with highly active ion channels in the cell membrane that pump protons into the extracellular space, thus lowering the pH in their own microenvironment [5].

This drop in pH dissolves the bone mineral. Osteoblasts, through an as yet poorly characterized mechanism, lay down new bone mineral. The balance between the activities of these two cell types governs whether bone is made, maintained, or lost. The activities of these cells are also intimately intertwined. In a typical bone remodeling cycle, osteoclasts are activated first, leading to bone resorption.

Then, after a brief “reversal” phase, during which the resorption “pit” is occupied by osteoblasts precursors, bone formation begins as progressive waves of osteoblasts form and lay down fresh bone matrix [6]. Because the bone formation phase typically takes much longer than the resorption phase, any increase in remodeling activity tends to result in a net loss of bone. At various stages throughout this process, the precursors, osteoclasts, and osteoblasts communicate with each other through the release of various “signaling” molecules [see 4 and 7 for review]. How these signaling molecules and various other endogenous (such as hormones) or external (such as diet and exercise) factors influence the cells involved in bone physiology is a topic of intense research activity.

Factors influencing osteoclasts and osteoblasts

Hormones are possibly the most crucial modulators of bone formation. It is well established that estrogen [8], parathyroid hormone [9], and to a lesser extent testosterone [10,11], are essential for optimal bone development and maintenance. Of these, estrogen is now believed to have the most direct effect on bone cells, interacting with specific proteins, or receptors, on the surface of osteoblasts and osteoclasts [12].

This interaction sets off a complex chain of events within the cells, increasing osteoblast activity while at the same time interfering with osteoblast-osteoclast communication – one of the ironies of bone remodeling is that the osteoblasts release factors that stimulate osteoclasts and drive bone resorption, as we shall see below.

Estrogen effects are mediated through one specific type of cell surface receptor called the estrogen receptor alpha (ERα), which binds and transports the hormone into the nucleus of the cell where the receptor-hormone complex acts as a switch to turn on specific genes. ERα receptors are found on the surface of osteoblasts, as is estrogen receptor-related receptor alpha (ERRα), which may play an auxillary role in regulating bone cells [13]. Recent studies also suggest that sex hormone binding globulin (SHBG), which facilitates entry of estrogen into cells, may also play a supportive role [14].

Estrogen, of course, is made and secreted into the bloodstream some distance from bone and it also has profound effects on other tissues, such as the uterus and breast. But there are other, locally produced signalling molecules that have profound effects on bone physiology.

Prostaglandins, particularly progtaglandin E2 (PGE2), stimulate both resorption and formation of bone (15). PGE2 is a lipid that is formed in various bone cells from a precursor called arachidonic acid. The first step on PGE2 synthesis is carried out by an enzyme called cyclooxygenase 2 (COX2) and inhibitors of this enzyme can prevent bone formation in response to mechanical stress in animals (16). PGE2 may be required for exercise-induced bone formation.

There is evidence that fracture risk is increased in people taking non-steroidal anti-inflammatory drugs that inhibit COX-2 (17) may also increase. Another set of lipid molecules that appear to regulate bone remodeling are the leukotrienes. Also derived from arachidonic acid, these have been found to reduce bone density in mice [18].

How any of these hormones impact bone remodeling depends on how they alter osteoclasts and/or osteoblasts activity. Recently, scientists have started to uncover specific cell surface receptors that help transmit signals from outside bone cells into the cell nucleus, where different genes that regulate cell activity can be switched on or off. These include receptors for bone morphogenetic proteins (BMPs) a family of proteins which are potent inducers of bone formation.

BMP receptors have been found on the surface of osteoblasts precursor cells [19]. Another cell surface receptor called the low density lipoprotein (LDL)-related protein 5 receptor (LRP5) may also be important for bone formation because loss of LRP5 in animals leads to severe osteoporosis [20]. BMP receptors and LRP5 may cooperate to stimulate osteoblasts into action, though exactly how this might occur has not been clarified.

Scientists have had more success piecing together various components that stimulate osteoclast activity. It was discovered that a cell surface receptor called RANK (for receptor activator of NFkB) prods osteoclasts precursor cells to develop into fully differentiated osteoclasts when RANK is activated by its cognate partner RANK ligand (RANKL) [21,22].

RANKL, in fact, is produced by osteoblasts and is one of perhaps many signaling molecules that facilitate cross-talk between the osteoblasts and osteoclasts and help coordinate bone remodeling [23]. Osteoprotegerin, another protein released by osteoblasts (24), can also bind to RANKL, acting as a decoy to prevent RANK and RANKL from coming in contact. The balance of RANKL/osteoprotegerin may be crucial in osteoporosis. In fact, animal studies showed that increased production of osteoprotegerin leads to an increase in bone mass, while loss of the protein leads to osteoporosis and increased fractures (25). Inhibitors of RANKL have also shown promise as potential treatment for osteoporosis in humans.

A second, complementary cell signalling system that helps drive formation and activation of osteoclasts was also uncovered within the last few years. In the absence of DNAX-activating protein 12 (DAP12) and Fc Receptor common γ chain (FcRγ), two cell surface receptors, mice develop severe osteoporosis – the exact opposite of osteoporosis – characterized by a dramatic increase in bone density [26,27]. These two cell surface receptors interact with a group of proteins in the cell called ITAM (immunoreceptor tyrosine-based activation motif) adaptor proteins to cause an increase in intracellular calcium.

Studies suggest that the RANK/RANKL and the ITAM-mediated pathways cooperated to induce full osteoclasts activity. These two pathways may converge to activate a protein called the nuclear factor of activated T cells (NFAT) c1. NFATc1 serves as a master switch for bone resorbtion because it turns on the genes that osteoclasts precursor cells need to become fully active osteoclasts [for a review see 28].

The role of genetics and environmental factors

Subtle differences in the genetic code might explain why one person’s osteoblasts or osteoclasts are more active or responsive to their environment, and it might also lead to the discovery of unknown regulatory mechanisms. Environmental factors can also have an enormous impact on bone physiology. See Who's at risk? for more information.
 

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