Bone growth and remodelling

Growth
As a child grows, long bones lengthen by addition of
bone material at the cartilaginous epiphyseal plate. In
this process, chondrocytes are produced mitotically
on the epiphyseal side of the plate. The chondrocytes
then die and the cartilage is replaced by bone on the
diaphyseal side. In this way, the thickness of the plate
remains almost constant, but the bone on the diaphyseal
side increases in length. Eventually, chondrocytes
stop dividing and bone replaces the cartilage in the
epiphyseal plate. The newly formed bony structure
is called the epiphyseal line and, with its appearance,
bone stops growing in length but continues to
thicken. In the thickening of long bones, bone lining
the medullary cavity is fi rst destroyed by osteoclasts in
the endosteum so that the cavity increases in diameter.
At the same time, osteoblasts from the periosteum
add new bone tissue to the outer surface. During the
growth spurt, there is a rapid increase in bone mineral
60 Vitamins: their role in the human body
density, followed by a slower increase until peak bone
mass is achieved sometime in young adulthood. Exercise
and sports activity in children and young adults
increases peak bone mass, particularly if the sport is
weight-bearing.
Before puberty, bone growth is stimulated mainly
by growth hormone. Oestrogens and testosterone, the
sex hormones produced at puberty, are responsible
for the acceleration in growth of the long bones during
the teenage years. The sex hormones also promote
morphological changes in the skeleton that are typical
of males and females.
Remodelling
The mineral component of bone, although nonliving,
is capable of being continuously resorbed and
reformed. This turning over of bony material is called
remodelling and is a natural process of renewal and
repair. Remodelling occurs at discrete foci called basic
multicellular units (BMUs) and involves a sequence of
highly co-ordinated cellular events.
Cancellous bone remodelling starts on the bone
surface, which is covered by a single layer of fl at lining
cells. These cells respond to stimuli such as parathyroid
hormone or mechanical stress, which initiate the
remodelling cycle. Firstly, the lining cells retract and
the underlying layer of osteoid is digested, possibly by
enzymes secreted by osteoblasts. Osteoclast progenitor
cells are recruited to the site by chemotaxis and,
stimulated by contact with mineralized bone matrix,
are transformed to osteoclasts. The osteoclasts then
begin to excavate resorption pits in the bone matrix.
After removing a suitable volume of bone, osteoclasts
undergo apoptosis and dissolve away. Osteoblasts
then move in and begin to replace the resorbed bone
with new bone. When this renewal process is fi nished
at a particular site, osteoblasts remaining at the surface
become quiescent and transform into lining cells,
effectively sealing the new bone surface. Osteoblasts
imprisoned within the bone become osteocytes.
The remodelling of cortical bone is triggered by
signals which may originate in cells lining the Haversian
canals or in osteocytes. Osteoclasts excavate a
cone-shaped tunnel which is refi lled by the products
of activated osteoblasts.
During bone turnover in healthy young adults, the
amount of bone removed by osteoclasts is quantitatively
replaced by osteoblasts. This phenomenon,
known as coupling, is achieved by a complex chemical
communication network between osteoblasts and osteoclasts.
An imbalance in bone remodelling leads to a
progressive decrease in bone density (osteopenia) and
a breakdown of bone architecture which, in combination,
results ultimately in osteoporosis. Remodelling
imbalance may be due to increased osteoclastic activity,
creating resorption pits which are too deep for
normal osteoblasts to fi ll; alternatively, or in addition,
osteoclastic activity may be normal but the ability of
osteoblasts to fi ll the resorption pits is impaired.
The sex hormones (oestrogens, androgens and progestins)
are essential in maintaining proper coupling
during bone remodelling. Oestradiol and oestrone
are the predominant circulating sex hormones in premenopausal
women, while testosterone predominates
in men. However, androgens and oestrogens circulate
in both men and women and there is evidence that
these hormones affect bone homeostasis in both
sexes. In women, when oestrogen levels fall following
menopause, circulating androgens may have signifi -
cant infl uences on bone metabolism (Oursler et al.,
1996).
3.8.7 Osteoporosis
Elderly women during their lifetime lose about a
third of cortical bone mass and half of cancellous
bone mass from the skeleton (Riggs & Melton, 1986).
Osteoporosis is a disease in which reduced bone mass
and deterioration of bony microarchitecture render
the bones so fragile that they fracture after only minor
trauma, such as falling from a standing height. We are
concerned with involutional osteoporosis, of which
there are two types, I and II (Kassem et al., 1996).
Type I osteoporosis
This syndrome manifests in women typically between
50 to 75 years of age, and results from an acceleration
of cancellous bone loss after the menopause. About
one in fi ve postmenopausal women will develop type
I osteoporosis unless treated. Within the fi rst 1 to 5
years after the onset of menopause, the rate of cancellous
bone loss is two to six times the pre-menopausal
rate of about 1% per year, but it gradually returns to
the pre-menopausal rate about the 10th year after
onset of menopause (Krall & Dawson-Hughes, 1999).
There is only a slight corresponding increase in cortical
bone loss. Fractures occur most commonly in the
distal radius (forearm) and the spinal vertebrae. The
Background physiology and functional anatomy 61
vertebral fractures are of the crush or collapse type,
causing a >25% reduction of vertebral height, and
may be acutely painful.
Osteoporosis in post-menopausal women is due to
the dramatic decrease in oestrogen production that
accompanies menopause; this is evident by the wellestablished
effi cacy of hormone replacement therapy
(Lindsay, 1993). The accelerated phase of bone loss is
associated with increased osteoclastic resorption and
oestrogen exerts its protective effect against bone loss
mainly by inhibiting resorption. Inhibition is due to
both decreased osteoclastogenesis and diminished
resorptive activity of mature osteoclasts. Oestrogen
receptors have been found in both osteoblasts
and osteoclasts. Oestrogen could therefore directly
modulate the secretion of local regulatory factors by
these cells or modulate the cells’ response to regulatory
factors. Oestrogen could also act indirectly by
modulating the production of factors involved in
bone resorption (Pacifi ci, 1996). For example, the
cytokines interleukin-1 (IL-1) and tumour necrosis
factor (TNF), which stimulate bone resorption, activate
osteoclasts indirectly via a primary effect on osteoblasts.
In addition, these two cytokines stimulate
osteoclast progenitor cell proliferation and fusion.
Furthermore, they act synergistically to increase the
secretion of other bone-resorbing cytokines such as
macrophage-colony stimulating factor (M-CSF) and
IL-6. The fi nding of increased expression of IL-1 and
TNF in the bone cells of women with post-menopausal
osteoporosis is consistent with the suppressive
effect of oestrogen (when present) upon the production
and activity of these cytokines. Oestrogen can
also act positively by increasing the production of
transforming growth factor β (TGFβ), a cytokine
which decreases both recruitment and activity of
osteoclasts.