Biomedical Engineering Reference
In-Depth Information
until the resorbed bone is completely replaced by new bone. When this
phase is completed, the surface is covered with flattened lining cells and a
prolonged resting period begins until a new remodeling cycle is initiated.
The stages of the remodeling cycle have different lengths. Resorption
probably continues for about 2 weeks; the reversal phase may last up to 4
or 5 weeks, and formation can continue for 4 months until the new bone
structural unit is completely created.
It is noted that a bone, the major reservoir of body calcium, is under the
hormonal control of PTH [8]. PTH binds to cells of the osteoblast lineage [9]
and produces both anabolic and catabolic effects. The fact that PTH has dual
effects depending on its administration method raises important questions
about the mechanisms of its action on bone formation and resorption. The
clinical trial reported in Neer et al. [10] clearly demonstrated that intermittent
exposure of bone to PTH can increase bone formation and bone mass in
humans. Jilka et al. [11] further reported that daily PTH injections in mice with
either normal bone mass or osteopenia due to defective osteoblastogenesis
increased bone formation without affecting the generation of new osteoblasts.
This is in marked contrast to continuous PTH exposure, which causes net
bone loss (resorption) [12,13].
In summary, the overall effect of PTH on bone mass depends primarily
on its mode of administration. Whereas a continuous increase in PTH
levels decreases bone mass, intermittent PTH administration has an
anabolic action on a bone [14]. It has been recognized that PTH is the most
important regulator of calcium homeostasis in the bone remodeling process.
It maintains serum calcium concentrations by stimulating bone resorp-
tion and increasing renal tubular calcium reabsorption and renal calcitriol
production. PTH is secreted in response to a drop in plasma Ca
2+
levels.
With the goal of maintaining plasma Ca
2+
, PTH increases bone resorption
to release Ca
2+
stored in bones. Acting on osteoblasts, PTH alters the expres-
sion of RANKL and OPG (osteoprotegerin), leading to a large increase in the
RANKL/OPG ratio, thus stimulating osteoclastogenesis and bone resorption
[15,16]. RANKL here is the abbreviation for receptor activator for nuclear
factor kappa-B ligand, found on the surface of stromal cells, osteoblasts, and
T-cells. RANKL is a member of the tumor necrosis factor (TNF) cytokine
family, which is a ligand for osteoprotegerin and functions as a key factor for
osteoclast differentiation and activation.
Mathematical modeling provides a powerful tool to predict the net outcome
of multiple, simultaneous actions of autocrine, paracrine, and endocrine fac-
tors on the process of bone remodeling. Although only few attempts have
been made to reconstruct the process of bone remodeling mathematically at
a cellular level, there is increasing interest in this approach:
• Kroll [8] and Rattanakul et al. [17] each proposed a mathematical
model accounting for the differential activity of PTH administration
on bone accumulation.
