The Biology of Bone Remodelling

Prof. Dr. Peter Barling, Department of Biomedicine and

Therapeutics, School of Medicine, UMS
 Osteoporosis

A polygenic disease
The outcome can be modified by:
pharmacological interventions
environmental modifications
nutritional changes
lifestyle adaptations
 Outline

What do bone cells do?

How do bone cells talk to each other?
Paracrine communication
RANKL
osteoprotegerin
CASR
BMP2
Implications for prevention and treatment
of osteoporosis
 Calcium turnover in bones
Calcium kinetic analysis - the whole
skeleton is estimated to turn over perhaps
every 5 -10 years.

Tetracycline double labelling

(histomorphometry)

long bones - 5 - 11% per year

ribs - 14 - 44% per year
skull - very low turnover
Hypothetical
transduction
of
mechanical
signals. The
sensor cells
are
osteocytes
which
transmit
signals to
the effector
cells, i.e.
osteoblasts,
bone lining
cells or
osteoclasts,
which, in
turn, either
lay down
new bone or
resorb the
matrix.
 How do bone cells talk to each other by
paracrine signalling?
Cells of the osteoblast lineage must talk to
osteoclasts and vice versa.
Communication has to happen both ways in
order for the amount of bone being reabsorbed
to be matched later by the same amount being
later deposited.
Major players include:
RANKL
BMP2
Activation of osteoclastogenesis by
PTH or PTHrP
 Osteolytic factors that induce RANKL
production and decrease OPG production
from osteoblasts and their precursors
Parathyroid hormone and PTHrP
1:25 DHCC (vitamin D)
Interleukins 1 and 6
Tumour necrosis factor
Prolactin
Corticosteroids
Oncostatin M
Leukemia inhibitory factor
 Screening for gene
polymorphisms
May provide a reliable way to predict
tendency for osteoporosis.
A start has been made with
polymorphisms in the osteoprotegerin
gene.
Polymorphisms in the osteoprotegerin
gene are associated with osteoporotic
fractures.

Langdahl et al (2002) found 12

polymorphisms in the human OPG
gene.
The rare alleles A163-G and T245-G in
the promoter region of the gene were
significantly more common among patients
with vertebral fractures than in matched
controls.
How do osteoclasts talk to osteoblasts?

Signalling has to happen both ways.

1. Ionised calcium detection by the osteoblast

2. Release of bone morphogentic proteins while
the lacuna is being formed through osteoclastic
dissolution
The BMP pathway is important for
stimulating osteoblastic activity

So it will soon become a therapeutic

target for reversal of osteoporosis
 Inhibition of RANK signaling as a
means of suppressing ostoporosis:
Denosumab
A humanised monoclonal antibody to
RANKL in advanced trials.
 Denosumab clinical progress
Developed by Amgen under the trade
name of Prolia.
Reduction of osteoclast differentiation,
activation, and survival.
Shows encouraging phase II clinical
results
Approved by the U.S. Food and Drug
Administration (FDA) fn June 2010 for use
in postmenopausal women with risk of
osteoporosis.
 Statins

Enhance new bone formation and reduce

fracture risk, although this is a subject of some
controversy.
In vitro studies show statins stimulate BMP-2
and BMPR-II gene expression.
Statins may thereby increase bone formation
by enhancing the secretion of BMP2 and the
activity of the BMP pathway.
Statins given to post-menopausal
women

Results have been controversial

Generally support the view that statins
can increase bone density
But not all studies affirm this.
Wide range of potencies in the ability
of different statins to stimulate BMD
Cerivastatin showed effects at 10 to 100-
fold lower doses than most other statins
(Garrett, I. R., ASBMR abstract).
However the FDA has removed Baycol
(cerevastatin) from the market in 2001.
It was claimed to be responsible for
several deaths from rhabdomyolysis
(skeletal muscle cell failure)
Bisphosphonates will be covered by
Dr. Lee Joon Kiong
Bisphosphonates chelate calcium and are
deposited specifically in bone.
After osteoclastic attack on bone, they enter the
osteoclast.
The N-containing bisphosphonates inhibit
farnesyl diphosphate synthase, thereby
indirectly preventing the prenylation of GTPases
required for intracellular signalling.
Bisphosphonates thereby induce premature
apoptosis of osteoclasts.
 In summary
An understanding of the pathways of communication
between osteoblasts and osteoclasts and factors
which alter this communication are an important
prerequisite for the development of interventions to
predict, control or reverse osteoporosis.
There are more than a hundred factors that influence
the ontology and/or activity of bone cells.
Identification of specific SNPs in the DNA of many of
these factors (including osteoprotegerin and the
CASR) is a possible approach to predicting
osteoporosis risk in at least a proportion of patients.
Among these factors, RANKL and BMP2 are
promising candidates for pharmacological
interventions
Activation of the bone morphogenetic
protein-2 promoter by statins
Mundy (1990) screened more than
30,000 natural compounds for
activation of the promoter for BMP-2.
He identified lovastatin as being
osteoinductive.
Lovastatin, fluvastatin, simvastatin, and
mevastatin in vitro effect on
osteoblast-like cell lines

Specifically increased production

of BMP2 mRNA
More than doubled BMP2
production
 Statins given to ovariectomized
female rats by mouth
A very good model of human post-
menopausal osteoporosis.
Increase in trabecular bone volume of
39% to 94%.