is increasingly being recognized that multiple pathogenetic mechanisms interact in the

development of the osteoporotic state. Understanding the pathogenesis of osteoporosis starts with
knowing how bone formation and remodeling occur.

Normal bone formation and remodeling

Bone is continually remodeled throughout our lives in response to microtrauma. Bone remodeling
occurs at discrete sites within the skeleton and proceeds in an orderly fashion, and bone resorption
is always followed by bone formation, a phenomenon referred to as coupling.

Dense cortical bone and spongy trabecular or cancellous bone differ in their architecture but are
similar in molecular composition. Both types of bone have an extracellular matrix with mineralized
and nonmineralized components. The composition and architecture of the extracellular matrix is
what imparts mechanical properties to bone. Bone strength is determined by collagenous proteins
(tensile strength) and mineralized osteoid (compressive strength).[18] The greater the
concentration of calcium, the greater the compressive strength. In adults, approximately 25% of
trabecular bone is resorbed and replaced each year, compared with only 3% of cortical bone.

Furthermore, in periods of rapid remodeling (eg, after menopause), bone is at an increased risk for
fracture because the newly produced bone is less densely mineralized, the resorption sites are
temporarily unfilled, and the isomerization and maturation of collagen are impaired.[20]

The receptor activator of nuclear factor-kappa B ligand (RANKL)/receptor activator of nuclear

factor-kappa B (RANK)/osteoprotegerin (OPG) system is the final common pathway for bone
resorption. Osteoblasts and activated T cells in the bone marrow produce the RANKL cytokine.
RANKL binds to RANK expressed by osteoclasts and osteoclast precursors to promote osteoclast
differentiation. OPG is a soluble decoy receptor that inhibits RANK-RANKL by binding and
sequestering RANKL.

Alterations in bone formation and resorption

The hallmark of osteoporosis is a reduction in skeletal mass caused by an imbalance between

bone resorption and bone formation. Under physiologic conditions, bone formation and resorption
are in a fair balance. A change in either—that is, increased bone resorption or decreased bone
formation—may result in osteoporosis.

Osteoporosis can be caused both by a failure to build bone and reach peak bone mass as a young
adult and by bone loss later in life. Accelerated bone loss can be affected by hormonal status, as
occurs in perimenopausal women; can impact elderly men and women; and can be secondary to
various disease states and medication

Osteoclasts, derived from hematopoietic precursors, are responsible for bone resorption, whereas
osteoblasts, from mesenchymal cells, are responsible for bone formation (see the images below).
The 2 types of cells are dependent on each other for production and linked in the process of bone
remodeling. Osteoblasts not only secrete and mineralize osteoid but also appear to control the
bone resorption carried out by osteoclasts. Osteocytes, which are terminally differentiated
osteoblasts embedded in mineralized bone, direct the timing and location of bone remodeling. In
osteoporosis, the coupling mechanism between osteoclasts and osteoblasts is thought to be
unable to keep up with the constant microtrauma to trabecular bone. Osteoclasts require weeks to
resorb bone, whereas osteoblasts need months to produce new bone. Therefore, any process that
increases the rate of bone remodeling results in net bone loss over time

Bone mass peaks around the third decade of life and slowly decreases afterward. A failure to attain
optimal bone strength by this point is one factor that contributes to osteoporosis, which explains
why some young postmenopausal women have low bone mineral density (BMD) and why some
others have osteoporosis. Therefore, nutrition and physical activity are important during growth and
development. Nevertheless, hereditary factors play the principal role in determining an individual's
peak bone strength. In fact, genetics account for up to 80% of the va

Aging and loss of gonadal function are the 2 most important factors contributing to the
development of osteoporosis. Studies have shown that bone loss in women accelerates rapidly in
the first years after menopause. The lack of gonadal hormones is thought to up-regulate osteoclast
progenitor cells. Estrogen deficiency leads to increased expression of RANKL by osteoblasts and
decreased release of OPG; increased RANKL results in recruitment of higher numbers of
preosteoclasts as well as increased activity, vigor, and lifespan of mature osteoclasts.

ESTROGEN DEFICIENCY

Estrogen deficiency not only accelerates bone loss in postmenopausal women but also plays a role
in bone loss in men. Estrogen deficiency can lead to excessive bone resorption accompanied by
inadequate bone formation. Osteoblasts, osteocytes, and osteoclasts all express estrogen
receptors. In addition, estrogen affects bones indirectly through cytokines and local growth factors.
The estrogen-replete state may enhance osteoclast apoptosis via increased production of
transforming growth factor (TGF)–be

In the absence of estrogen, T cells promote osteoclast recruitment, differentiation, and prolonged
survival via IL-1, IL-6, and tumor necrosis factor (TNF)–alpha. A murine study, in which either the
mice's ovaries were removed or sham operations were performed, found that IL-6 and granulocyte-
macrophage CFU levels were much higher in the ovariectomized mice.[22] This finding provided
evidence that estrogen inhibits IL-6 secretion and that IL-6 contributes to the recruitment of
osteoclasts from the monocyte cell line, thus contributing to osteoporosis.

IL-1 has also been shown to be involved in the production of osteoclasts. The production of IL-1 is
increased in bone marrow mononuclear cells from ovariectomized rats. Administering IL-1 receptor
antagonist to these animals prevents the late stages of bone loss induced by the loss of ovarian
function, but it does not prevent the early stages of bone loss. The increase in the IL-1 in the bone
marrow does not appear to be a triggered event but, rather, a result of removal of the inhibitory
effect of sex steroids on IL-6 and other genes directly regulated by sex steroids.

T cells also inhibit osteoblast differentiation and activity and cause premature apoptosis of
osteoblasts through cytokines such as IL-7. Finally, estrogen deficiency sensitizes bone to the
effects of parathyroid hormone (PTH).

AGING

In contrast to postmenopausal bone loss, which is associated with excessive osteoclast activity,
the bone loss that accompanies aging is associated with a progressive decline in the supply of
osteoblasts in proportion to the demand. This demand is ultimately determined by the frequency
with which new multicellular units are created and new cycles of remodeling are initiated.

After the third decade of life, bone resorption exceeds bone formation and leads to osteopenia and,
in severe situations, osteoporosis. Women lose 30-40% of their cortical bone and 50% of their
trabecular bone over their lifetime, as opposed to men, who lose 15-20% of their cortical bone and
25-30% of trabecular bone.

Calcium deficiency

Osteoporotic fractures
Osteoporotic fractures represent the clinical significance of these derangements in bone. They can
result both from low-energy trauma, such as falls from a sitting or standing position, and from high-
energy trauma, such as a pedestrian struck in a motor vehicle accident. Fragility fractures, which
occur secondary to low-energy trauma, are characteristic of osteoporosis.

The Wnt signaling pathway and bone

The Wnt family is a highly conserved group of proteins that were initially studied in relationship with
cancer initiation and progression due to their involvement in intercellular communication.[25] In the
past decade, the Wnt signaling cascade has been recognized as a critical regulator of bone
metabolism.

There are also several antagonists to the Wnt pathway. Two of the most well-known are Dkk-1 and
sclerostin (SOST). Dkk-1 is secreted by MSCs[34] and binds to LRP-5 and LRP-6,[35] thereby
competitively inhibiting Wnt signaling. Interestingly, serum levels of Dkk-1 positively correlate with
the extent of lytic bone lesions in patients with multiple myeloma.[36] Clinical trials of a monoclonal
antibody to Dkk-1 are ongoing

Calcium, vitamin D, and PTH help maintain bone homeostasis. Insufficient dietary calcium or
impaired intestinal absorption of calcium due to aging or disease can lead to secondary
hyperparathyroidism. PTH is secreted in response to low serum calcium levels. It increases
calcium resorption from bone, decreases renal calcium excretion, and increases renal production
of 1,25-dihydroxyvitamin D (1,25[OH]2 D)—an active hormonal form of vitamin D that optimizes
calcium and phosphorus absorption, inhibits PTH synthesis, and plays a minor role in bone
resorption

Wnt signaling plays a key role in the fate of mesenchymal stem cells (MSCs), which are the
progenitor cells of mature bone-forming osteoblasts.[26] MSCs have the capability to differentiate
into adipocytes, chondrocytes, neurons, and muscle cells, as well as into osteoblasts.[27] Certain
Wnt signaling pathways promote the differentiation of MSCs along the osteoblast lineage. The
emerging details about the specific molecules involved in the Wnt pathway have improved the
understanding of bone metabolism and led to the development of new therapeutic targets for
metabolic bone disease

Wnt signal activation may progress along one of three pathways, with the “canonical” pathway
involving β-catenin being most relevant to bone metabolism. The canonical Wnt signaling pathway
is initiated by the binding of a Wnt protein to an extracellular co-receptor complex consisting of
“Frizzled” (Fr) and low density lipoprotein receptor–related protein–5 or –6 (LRP5, LRP6).[28] This
activation recruits another protein, “Disheveled” (Dvl) to the intracellular segment of the Fz/Dvl co-
receptor.[29] This is where β-catenin comes into play

β-Catenin is an important intracellular signaling molecule and normally exists in a phosphorylated

state targeted for ubiquination and subsequent degradation within intracellular lysosomes.
Activation of the Wnt pathway leads to dephosphorylation and stabilization of intracellular β-catenin
and rising cytosolic concentrations of β-catenin. As the concentration of β-catenin reaches a critical
level, β-catenin travels to the nucleus, where it activates the transcription of Wnt target genes.
Ultimately, canonical Wnt signaling inhibits the expression of transcription factors important in the
differentiation of MSCs such as peroxisome proliferator-activated receptor gamma (PPAR-γ) and
promotes survival of osteoblast lineage cells.

Several human bone abnormalities have been linked to the Wnt pathway. For example, a single
amino acid substitution in the LRP5 receptor gene has been associated with high bone mass
phenotypes in humans; specifically, the mutant LRP5 receptor had an impaired interaction with the
Wnt signal inhibitor Dickkopf-1 (Dkk-1).[31] Similarly, other missense mutations of LRP5 have been
implicated in other high bone mass diseases such as Van Buchem disease and osteopetrosis.[32]
Conversely, loss-of-function mutations of LRP5 have resulted in a rare but severe congenital
osteoporosis in humans