Androgens in Health and Disease.pdf - E Library

222 Kenny and Raisz
with a cartilage framework that then is converted to bone either through endochondral
ossification in the long bones and vertebra or membranous bone formation adjacent to
the cartilage in flat bones. During childhood, the skeleton grows by periosteal apposition
and endosteal resorption, thus enlarging the marrow cavities (1). This change in the form
of bone is termed “modeling.” At puberty, there is a rapid increase in bone mass (2).
There is both periosteal and endosteal apposition, particularly in males during puberty.
After epiphyseal closure there is relatively little modeling of the skeleton. However,
some increase in periosteal diameter can occur with aging, perhaps as a compensation
for endosteal bone loss and weakening of skeletal structures (3).
The continuous removal and replacement of packets of bone in the skeleton throughout
life is termed “remodeling” (4). The bone structural units (BSU) in remodeling are
irregular platelike structures on the trabecular surfaces or cylindrical osteons in cortical
bone. The remodeling cycle begins with activation. The activation process involves the
effects of hormones and local factors on the previously inactive lining cells covering the
bone surface and as well as stromal cells of the osteoblast lineage in the marrow or
periosteum. These cells have a ligand for receptor activator of nuclear factor-κβ
(RANKL), which binds to a receptor on hematopoietic cells (RANK). This interaction
results in replication, differentiation, and fusion of osteoclast precursors to form large
multinucleated bone-resorbing cell (5). There is a decoy receptor, osteoprotegerin (OPG),
which can block this interaction and is an important local regulator (6). In humans, the
resorption phase lasts 2–3 wk and is followed by a reversal phase during which mononuclear
cells are present on the bone surface. Osteoblast precursors then migrate to the
bone surface and lay down successive layers of new bone. This formation phase replaces
the removed tissue over a period of several months. Thus, the entire remodeling cycle
may last 3–6 mo in humans (7).
The regulation of bone remodeling is complex. Remodeling may be driven in part by
the need to repair microdamage that results from repeated impact on the skeleton. Cortical
and trabecular remodeling are clearly influenced by mechanical forces. Impact
loading of the skeleton can stimulate new bone formation, and this process can also result
in realignment of structure or modeling (8).
Bone remodeling is also under the control of local factors and systemic hormones.
Parathyroid hormone (PTH) stimulates bone remodeling, but depending on the dose and
whether the increases in PTH are continuous or intermittent, there may be maintenance,
loss, or gain of skeletal mass with PTH (9,10). Vitamin D is critical for the supply of
calcium and phosphorous for bone mineralization, but it can also stimulate bone resorption.
Calcitonin is an inhibitor of bone resorption that appears to have relatively little role
in regulation of bone remodeling in adult humans. The local regulators include cytokines,
lipid mediators such as prostaglandins, and growth factors (11–13). These factors may
mediate the effects of systemic hormones and mechanical forces and are probably also
responsible for the interactions between marrow and bone (14). Physiological and pathological
expansion of the marrow occurs at the expense of skeletal tissue, and marrow
cells can produce factors that increase bone resorption.
Bone remodeling is normally tightly coupled; that is, the amount of bone removed by
resorption is replaced by a similar amount of new bone through formation. However,
during the pubertal growth spurt, bone mass is gained, partly because the new BSUs are
larger and partly because new bone is added through modeling (15). Menopausal and
age-related bone loss are associated with an increase in both resorption and formation,