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I-1
PATHOGENESIS AND PREVENTION OF FRACTURES AMONG ELDERLY PEOPLE
P. Kannus1,2
1Medical School, University of Tampere, Finland
2Accident & Trauma Research Center, UKK Institute,
Tampere, Finland
The number and age-specific incidence of low-trauma
fractures among the older adults have dramatically increased in many countries during the
recent decades and without any population-level intervention the increasing trend is
likely to continue thus creating a true public health problem to our aging societies.
There is thus a clear need to better understand the etiology, risk factors, pathogenesis,
and injury mechanisms of these fractures since improved knowledge on these issues is
likely to provide important clues and possibilities for fracture prevention.
Low-trauma fracture (often also called age-related
fracture, mild-moderate energy fracture, or osteoporotic fracture) of an older adult is
defined as a bone fracture that occurs in an elderly person as a consequence of a
mild-moderate trauma only. The most typical trauma of this category is a fall to the floor
from standing height or less. Compromised bone strength (osteopenia or osteoporosis) and
falling, alone, or more frequently in combination, are the main independent and immediate
risk factors of these fractures through which all the other, more distant risk factors
(such as aging, inactivity, poor nutrition, smoking, use of alcohol, diseases,
medications, impairments, and disabilities) operate.
Of these two, falling, not osteoporosis, is the strongest
single risk factor for a fracture, and when a person falls, the type and severity of
falling (fall height and energy; fall direction; fall mechanics; anatomical site of the
impact; and energy absorption capacity and impact force attenuation of the body-landing
surface complex) are crucial in determining whether or not a fracture occurs. In fact,
only minority of fractures of older adults are truly osteoporotic (that is, most fractures
in the community come from the larger segment of population without osteoporosis), but
this does not mean that osteoporosis prevention is useless: we just have to understand
that in planning a successful prevention strategy both of these major risk factors have to
be taken into account.
Prevention of elderly people's fractures can be divided
into three parts: 1. Prevention and treatment of osteoporosis, 2. Prevention of falling,
and 3. Prevention of fractures despite osteoporosis and falling (injury-site protection).
Osteoporosis: Osteoporosis is an independent,
moderate-level risk factor for fracture and should therefore become prevented and treated.
Maximizing peak bone mass and preventing bone loss by exercise, calcium, and vitamin D,
and, treatment of established osteoporosis with bone-affecting drugs (HRT,
bisphosphonates, SERMs, calcitonin), have a strong scientific basis and have been
recommended by many authorities and consensus conferences. A sufficient long-term
compliance and adherence to any of these interventions may, however, be a problem. The
same naturally concerns programs of fall prevention and injury-site protection.
Falling: Since falling is the strongest single
risk factor for a fracture of an older adult, fall prevention is essential. Recent
randomized trials have consistently shown that training balance and strength is able to
reduce the older person's risk of noninjurious and injurious falls - even
cost-effectively. This is to be expected since exercise is able to improve many risk
factors of falling, such as muscle strength, flexibility, balance, coordination,
proprioception, reaction time, and gait - even in very old and frail people. As yet, only
one randomized trial has examined whether fractures can be reduced by exercise, and, this
10-year follow-up study showed that in postmenopausal women regular back-strengthening
exercises for 2 years reduced the risk of vertebral fractures by 63%. This finding is in
line with many epidemiologic studies, which consistently show that both past and current
physical activity is protective against hip fracture, the risk reduction being 20-70%.
Many of these studies have even found a dose-response relation between the exercise
exposure and the fracture risk. Thus, it seems that we can well recommend regular
weight-bearing and other exercises for elderly people - not only to maintain bone health
and muscular performance but also to keep the older persons safely on their feet.
In addition to exercise, reducing the number and doses of
psychotropic medication has been shown to reduce elderly persons' risk of falling. A
similar effect has been seen after cardiac pacing of older adults with cardioinhibitory
carotid sinus hypersensitivity. More multifaceted risk factor-modifying interventions have
also been successful in preventing falls of the older adults by simultaneously affecting
many intrinsic and extrinsic risk factors of falling. The problem with these interventions
is that they can not distinguish between the independent role of each modified risk
factor, and so it cannot be determined which part of the intervention is effective and
which is not. Such multifactorial approaches are also labor intensive and their
cost-effectiveness has not been ascertained.
Injury-site protection: Since great majority hip
fractures are caused by a sideways fall with direct impact on the greater trochanter of
the proximal femur, a fascinating option to prevent the fracture is a specially designed
external hip protector, so that at the time of the fall-impact, the impacting force and
energy are weakened and diverted away from the greater trochanter by the protector. We
conducted a large (n=1801) randomized multicenter trial with the KPH Hip Protector
(Respecta, Helsinki) and showed, with intention-to-treat analysis, that the risk of hip
fracture was 60% less in the protector group than in the control group (adjusted relative
hazard 0.4, 95% CI, 0.2-0.8), and that by protector efficacy or active treatment analysis,
the risk reduction was more than 80% if the protectors were actually worn at the time of
falling (adjusted relative hazard 0.1, 95% CI, 0.03-0.5). The number needed to treat (NNT)
to avoid one hip fracture was 41 persons for one year (95% CI, 25-115), or 8 persons for
five years (95% CI, 5-23). These results are rather encouraging to recommend
scientifically tested external hip protectors for high-risk frail elderly people,
especially those who have fallen before, had fractures, poor balance, and impaired
mobility.
Little is known about the injury mechanisms of the
age-related fractures other than hip fracture. A recent controlled study from The Accident
& Trauma Research Center of the UKK Institute, Tampere, Finland indicates that a great
majority of the elderly persons' upper extremity fractures is caused by a direct,
fall-induced impact on the fractured site. Although this finding is encouraging concerning
possibilities for prevention of these fractures by injury-site protection, no such study
has been conducted, and therefore definite recommendations for protecting the older
adults' sites other than the hip can not be made at present.
[Programme]
I-2
ROLE OF THE WNT/LRP5 PATHWAY IN REGULATION OF BONE MASS AND OSTEOBLAST
FUNCTION
M. Warman
Cleveland OH, USA
Abstract not supplied
[Programme]
I-3
THE TRANSCRIPTION FACTOR OSTERIX IS REQUIRED FOR OSTEOBLAST
DIFFERENTIATION AND BONE FORMATION
B. de Crombrugghe*, X. Zhou, K. Nakashima
The University of Texas M. D. Anderson Cancer Center
The Osterix (Osx) gene, which is specifically
expressed in osteoblasts, specifies a polypeptide with typical features of transcription
factors. Its DNA binding domain consists of three C2H2-type zinc fingers that have a high
degree of identity with similar DNA binding domains in the transcription factors Sp1, Sp3,
and Sp4 and its N-terminal segment contains a strong transcription activation domain.
Homozygous Osx-mutant mice completely lack bone formation in both endochondral and
membranous skeletal elements although they show normal cartilage development. In these
mutants mesenchymal precursor cells are arrested in their differentiation into
osteoblasts. Indeed osteoblast marker genes such as BSP, osteonectin, osteopontin, and
osteocalcin are not expressed and Type I collagen expression is severely reduced to levels
commonly seen in other mesenchymal cells. However, Runx2, which encodes a
previously identified transcription factor needed for bone formation, is expressed at
levels comparable to those found in wild-type osteoblasts. Since no Osx transcripts
were detected in skeletal elements of Runx2-null mice, Osx must be downstream of
Runx2 in the pathway of osteoblast differentiation.
These properties reveal an essential new step in the
pathway of osteoblast differentiation and suggest the following model. Osteoblast
progenitors first differentiate into 'preosteoblasts', a process in which Runx2 and its
Cbf-beta subunit play an essential role. These preosteoblasts then differentiate into
mature, functioning osteoblasts that express characteristic osteoblast marker genes, a
process that requires Osx.
Interestingly, Runx2-expressing Osx-null cells
arrested in their differentiation into osteoblasts acquire a cell fate characterized by
the expression of a series of genes that are typical of chondrocytes. The acquisition of
this chondrocyte cell fate by Osx- defective cells implies that Osx is a negative
regulator of the chondrocyte phenotype. We, therefore, propose that Osx has a role in the
mechanism that segregates the osteoblast and chondrocyte lineages from a common
osteochondroprogenitor during endochondral bone formation. By being a negative regulator
of Sox9 expression, Osx would commit Runx2-expressing precursor cells to the
osteoblast lineage and prevent these cells from adopting a chondrocyte phenotype.
[Programme]
I-4
BIOLOGY ON SMART SILICON - SPECULATIONS ON THE NANOTECHNOLOGY OF 2010
W. Poon
Edinburgh, UK
The 'laboratory on a chip' is one of today's big ideas.
In the form of 'gene chips' (or DNA microarrays, to give them their proper name), such
technology is already making a big impact on biomedical research. But where is this
technology heading? Taking my cue from the history of microelectronics, I will speculate
on the future of 'laboratory on a chip' technology. Just as memory chips have moved from
ROM (programmed in the factory) through EPROM (one-off programmable by users) to RAM
(fully programmable and reusable), I want to compare current 'gene chips' to ROMs, and
suggest how the nanotechnology of the next decade may produce fully programmable
laboratories on chips. This should enable, for example, interactive (or 'smart')
combinatorial synthesis where steps further down stream can be influenced in a
controllable way by real-time 'on-chip' analysis of intermediate products from previous
steps. Some speculative ideas, based on a recently published method for
producing surfaces with switchable hydrophobicity, will
be briefly discussed. In my account, I will emphasize how nanotechnology is providing many
opportunities for fruitful collaborations between physical and life scientists of the 21st
century.
[Programme]
I-5
PROBING BONE CELL FUNCTION WITH AFM
M. A. Horton*, G. Charras
Bone and Mineral Centre, Dept. of Medicine, University College London,
London, UK
AFM is evolving from its traditional use in
high-resolution imaging and measurement into a tool for the analysis of biological
processes at lower resolution. Driven by the ability of AFM to act as a precise
'nanomanipulator', we have developed a microscope for cell biology applications based upon
commercially available equipment. This system has been used to investigate cell adhesion
molecules (single molecule receptor-ligand binding, receptor mapping, downstream signaling
in living cells) and cellular biomechanics (material properties, strain activated receptor
analysis). Our data suggest that AFM can be developed for a wide range of bio- technical
applications in biology. An exemplary application is the study of bone cell function (1).
The skeleton adapts to mechanical use, though, at the cellular level, the distribution and
size of strains generated and their detection are ill understood. The magnitude and nature
of strains to which osteoblastic cells respond have been investigated by using the
cantilever probe of an atomic force microscope (AFM) as an indenter, with cellular
responses analysed via a linked confocal microscope. Two different downstream
cell-signaling pathways have been identified in response to mechanical deformation. One is
activated upon contact of the AFM tip with the cell surface and depends on activation of
stretch-activated ion channels. The second follows stress relaxation after withdrawal of
the indenter and requires an intact microtubular cytoskeleton. The cellular responses were
modulated by selectively disrupting components of the cytoskeleton or modifying signaling
pathways to identify possible transducers of mechanical stimuli. Using these techniques,
we have estimated the magnitude of cellular strains required to elicit an intracellular
calcium response (a generic 'marker' of activation of cellular signaling), and propose a
model that links single cell responses to whole bone adaptation. This AFM-based technique
may also aid our understanding of the process of cellular/tissue adaptation to mechanical
usage in other organs, such as in skeletal and vascular smooth muscle, systems that are
exposed to mechanical forces under normal physiological conditions and in various
pathologies.
1: Charras G, Lehenkari P, Horton M. Biotechnological
applications of atomic force microscopy. Methods Cell Biol. 2002 68:171
[Programme]
I-6
NANOTECHNOLOGY OF COLLAGEN AND BONE: INTERACTION AND STRUCTURE
P. K. Hansma1*, T. Gutsmann1,2, G. Fantner1,
J. Kindt1, M. Venturoni1,3
1University of California, Santa Barbara, USA
2Research Center Borstel, Germany
3Bologna University, Italy
The Atomic Force Microscope has been used to study the
interactions between collagen molecules both in bone and in pure collagen samples as a
function of their ionic environment (James Thompson, Johannes Kindt, Barney Drake, Helen
Hansma, Daniel Morse, and Paul Hansma. Bone Indentation recovery time correlates with bond
reforming time. Nature 414: 773-775). A great deal is known about bone microstructure and
the microcracks that are precursors to its fracture, but little is known about the basic
mechanism for dissipating the energy of an impact to keep the bone from fracturing. Bone
is a nanocomposite of hydroxyapatite crystals and an organic matrix. Because rigid
crystals such as the hydroxyapatite crystals cannot dissipate much energy, the organic
matrix, which is mainly collagen, must be involved. A reduction in the number of collagen
cross links has been associated with reduced bone strength and collagen is molecularly
elongated ('pulled') when bovine tendon is strained.
Using an atomic force microscope, a molecular mechanistic
origin for the remarkable toughness of another biocomposite material, abalone nacre, has
been found. Here we report that bone, like abalone nacre, contains polymers with
'sacrificial bonds' that both protect the polymer backbone and dissipate energy. The time
needed for these sacrificial bonds to reform after pulling correlates with the time needed
for bone to recover its toughness as measured by atomic force microscope indentation
testing. We suggested that the sacrificial bonds found within or between collagen
molecules may be partially responsible for the toughness of bone.
[Programme]
I-7
HOW DO WE ASSESS BONE QUALITY?
C. H. Turner
Indiana University, Indianapolis, USA
Bone 'quality' is a poorly defined term used to describe
important properties of bone tissue other than bone mineral density (BMD). There are a
number of diseases that affect bone quality, including osteogenesis imperfecta,
osteopetrosis, and osteomalacia. In addition many pharmacological treatments for
osteoporosis change bone quality (in addition to BMD). Important examples include
fluoride, which can cause mineralization defects and changes mineral crystal size;
antiresorptive drugs that reduce resorption pits in trabeculae; bisphosphonates, which can
increase mineralization and microdamage accumulation; and teriparatide that increases bone
porosity. Some drug effects on bone quality are advantageous and reduce fracture risk
disproportionate to changes in BMD. Other drug effects may be detrimental for bone
quality. The most detrimental outcome was with high dose fluoride therapy, which caused
mineralization defects and increased fracture rates. These data demonstrate the severe
compromise of bone quality that can result if mineralization is compromised. Other effects
on bone quality, including increased porosity, mineralization and microdamage
accumulation, reduce bone strength and/or toughness in animal models but have not yet been
shown to increase fracture risk.
Changes in bone tissue quality are extremely difficult to
measure non-invasively. Proper assessment requires direct examination of the tissue. The
bone biopsy is the best approach. Many of the tissue-level changes that affect bone
quality, including mineralization, porosity, microdamage, and bone turnover, can be
measured accurately using standard histomorphometric techniques. Additional information
about fracture risk, independent of BMD, can be had with measurements of bone size and
shape. Assessment of cross-sectional moment of inertia or section modulus can be done from
standard densitometry or CT scans. This information complements BMD. In fact, one can
calculate a bone strength index (BSI) as the product of volumetric BMD and the bone
section modulus. Measurements such as BSI may determine fracture risk better than BMD
alone.
[Programme]
I-8
ROLE OF BONE TURNOVER IN BONE QUALITY
P. Delmas
University Claude Bernard and Inserm Research Unit 403, Lyon, France
Although initial studies of bone turnover in osteoporosis
have used dynamic histomorphometry of the iliac crest, most studies performed in the past
15 years have used biochemical markers of bone turnover. Bone markers can be used to
predict the rate of bone loss in postmenopausal women. Three independent studies have
shown that high bone turnover is associated with increased bone loss over 4 to 15 years in
women 50 to 70 years of age. In addition, we have shown in elderly women that increased
bone resorption, i.e. above the premenopausal range, is associated with a twofold increase
in the risk of hip fractures and that those with both a low BMD (T score below -2.5) and
increased bone resorption have a 4 to 5 fold increase in hip fracture risk. These results
have been confirmed by several independent studies in other cohorts. We have recently
shown that increased bone turnover predicts the risk of all fragility fractures (including
hip, spine and other sites) in a younger cohort of postmenopausal women followed for an
average of 5 years. The mechanisms underlying the increased bone turnover in some -but not
all- postmenopausal women is unknown. The increase appears to be independent from the
residual secretion of 17 b estradiol, (E2), assessed
by a highly sensitive radioimmunoassay. Indeed, we found that a low serum E2
predicts the risk of fragility fractures in late postmenopausal women -but not in the
elderly- independently of the rate of bone turnover. Some of the post translational
modifications of bone collagen may influence bone strength. We have found recently that
the degree of isomerization of the C-telopeptide of type I collagen is associated with the
subsequent risk of fragility fractures in postmenopausal women, independently of the rate
of bone turnover. Experimental data suggest that the ratio of various cross links present
in bone matrix is also a significant determinant of bone strength.
In summary, amongst the multiple component of bone
quality, bone turnover and the biochemical component of bone matrix appear to play an
important role.
[Programme]
I-9
IMPORTANCE OF MINERALIZATION FOR BONE STRENGTH AND RESPONSE TO
THERAPEUTIC AGENTS
P. J. Meunier*, G. Boivin
INSERM Unité 403, Faculté de Médecine R. Laennec, Lyon, France
Bone strength is determined not only by the volume of
bone tissue and the microarchitectural organization of this bone, but also by the degree
of mineralization of bone matrix (DMB). The mineralization process consists of a primary
deposition of mineral substance on the calcification front, followed by a slow and
progressive increase of the mineral deposition named secondary mineralization. In
osteoporosis, there is a negative imbalance between bone resorption and bone formation,
resulting in bone loss, and microarchitectural deterioration of the trabecular network.
Therapeutic agents for osteoporosis could increase bone strength by three separate, but
interrelated effects on bone tissue : 1) the prevention of bone loss and thus the
preservation of bone microarchitecture, 2) an increase in the volume of bone matrix, and
3) an increase in the DMB to a level similar or higher to that seen in healthy
premenopausal women, through a prolongation of the duration of secondary mineralization.
Our model is based on the impact of changes in bone remodeling rate on the DMB. Thus, any
agent (parathyroid hormone) or event (menopause, ovariectomy) which provoke an
augmentation in the 'birthrate' or activation frequency of BMU, induce a decrease of the
'lifespan' of BSU, in other words on the time available for the secondary mineralization.
This leads to the fact that new BSU are
resorbed before they have fully completed their secondary
mineralization, as proven by the presence of a large amount of uncompletely mineralized
BSU and a low mean DMB. Conversely, antiresorptive agents (bisphosphonates, estrogen,
SERMs) which cause a marked reduction in the 'birthrate' of BMU, prolong the 'lifespan' of
the BSU, allowing a more complete secondary mineralization. This should finally provoke an
increase of DMB. This new approach of the determinants of bone strength and the results of
our recent studies using antiresorptive (alendronate, raloxifene), forming (teriparatide)
and decoupling (strontium ranelate) agents used in the treatment of osteoporosis,
emphasize that bone mineral substance is an important factor to take into account in the
pathophysiology and the response to therapeutic agents for osteoporosis and other bone
conditions.
[Programme]
I-10
MODULATION OF ESTROGEN ACTION BY ER ISOFORMS
J-Ĺ. Gustafsson
Huddinge, Sweden
Abstract not supplied
[Programme]
I-11
RISKS AND BENEFITS OF HRT AND SERMS
E. Barrett-Connor, MD, Department of Family and
Preventive Medicine, University of California, San Diego, La Jolla, CA 92093-0607, USA
The Women's Health Initiative (WHI) demonstrated for the
first time (in a clinical trial) that HRT prevents clinical spine and hip fractures in
healthy women unselected for osteoporosis. Raloxifene, the only selective estrogen
receptor modulator (SERM) with fracture outcome data in clinical trials, was studied in
women selected for low bone density or prior fracture. In these women, raloxifiene was
shown to prevent morphometric spine fractures, but not hip fractures. Estrogen is less
expensive than raloxifene, but the choice between these regimens will probably be based on
extra-skeletal effects.
In the WHI and other clinical trials, HRT increased the
risk of heart disease and stroke or had no effect. In the Multiple Outcomes of Raloxifene
Evaluation (MORE) there was no overall effect on cardiovascular disease, but in women at
high risk of heart disease raloxifene reduced the risk of cardiac events and stroke.
In the WHI, HRT significantly increased the risk of
breast cancer in women treated for more than 4 years. In MORE, raloxifene significantly
reduced the risk of invasive estrogen-receptor positive breast cancer, with
(nonsignificant) differences beginning in the first year.
In WHI, HRT reduced the risk of colon cancer; no effect
on colon cancer has been observed with raloxifene.
In separate studies, HRT has not been shown to improve
memory in women with or without memory loss/dementia. One raloxifene study showed no
change in cognitive function tests overall, but did show improvement in two tests in women
aged 70 and older.
In clinical trials, HRT improves quality of life only in
women with severe menopause symptoms; HRT is clearly the best medication for hot flushes.
Raloxifene does not relieve hot flushes, and makes them worse in 10-20% of women. In
clinical trials the hot flushes associated with raloxifene were rarely severe enough to
cause women to stop the medication, but women with severe menopause symptoms are not
included in long-term trials looking at chronic disease outcomes. Nevertheless,
continuation rates in clinical trials are better with raloxifene than with HRT. Main
reasons for stopping HRT are bleeding and breast pain.
HRT has serious side effects, the most common of which is
deep vein thrombosis/pulmonary emboli. The risk is the same for raloxifene. Raloxifene has
no other known serious side effects, while estrogen clearly increases breast cancer risk,
and probably increases stroke and heart disease risk.
In terms of chronic disease, the risks of HRT are small,
but exceed the benefits, with regard to prevention of chronic disease. The raloxifene
risk-benefit ratio in women with osteoporosis appears to be more favorable, with
reassuring results presented at this meeting. These results are, however, based on
post-hoc analyses, and results from ongoing trials including CORE and RUTH will be needed
to better assess the global risk benefit ratio of raloxifene. For the moment, raloxifene
is certainly safe with regard to cardiovascular disease and breast cancer, two of the big
worries when prescribing HRT to prevent chronic disease in healthy women.
[Programme]
I-12
DEVELOPMENT OF NOVEL ANTI-RESORPTIVE THERAPIES TARGETING THE RANKL-RANK
SIGNALING PATHWAY: FROM FUNCTIONAL GENOMICS TO BEDSIDE
D. L. Lacey
Amgen, Inc, Thousand Oaks, CA, USA
The discovery of the TNF/TNFR-related osteoprotegerin
(OPG)/RANKL/RANK axis and its central role in osteoclast biology has provided the basis
for the generation of therapeutics. At Amgen, the OPG/RANKL pathway was fortuitously
discovered using functional genomics. Transgenic mice expressing osteoprotegerin
hepatically (apoE) had normally-shaped, dense bones histologically consistent with
osteopetrosis. While the apoE OPG transgenics had incisors, col1A OPG transgenics exhibit
classic rodent osteopetrosis with runting, misshapen long bones, and lack of incisor
eruption. The OPG k/o exhibited profound high turnover osteopenia with spontaneous
fractures. Recently, Whyte et al have reported that juvenile Paget's disease, an autosomal
recessive osteopathy, characterized by rapidly remodeling woven bone, osteopenia,
fractures, and progressive skeletal deformity can be attributed to the absence of OPG in
humans. The ligand for OPG was identified in a 32D cell library and was identical to
RANKL, a ligand for RANK, a TNFR superfamily member found on dendritic cells. RANKL
promotes the differentiation, activation, and survival of osteoclasts through RANK. The
signaling pathway includes both the JNK and NFkB pathways and also involves members of the
TRAF family, notably TRAF6. Knockouts for both RANKL and RANK yielded mice with severe
osteopetrosis in addition to uncovering a role for this axis in immune system and mammary
gland development. Numerous OPG-based protein constructs were evaluated in mice using the
Shenck screening assay. Effective constructs led to the accumulation of metaphyseal bone
and cartilage within 5 days of administration and were effective in proresorption
challenges (cytokines, hormones) and models of osteoclast-mediated skeletal disease.
Overall, RANKL binding proteins have shown beneficial effects in rodent models of
postmenopausal osteoporosis, hypercalcemia of malignancy, metastatic bone disease,
weightlessness, rheumatoid arthritis, and multiple myeloma. Two forms of OPG have entered
early clinical trials and both have shown profound antiresorptive activity following
single dose exposures. OPG dose-dependently suppressed bone resorption markers up to 80%
rapidly following a single exposure and was well tolerated. While the ultimate success of
any therapeutic is difficult to predict in early development, this program is an example
of how basic discoveries have provided a strategy to target osteoclasts in diseases
characterized by excessive bone resorption.
[Programme]
I-13
RELEVANCE OF THE RANKL/RANK/OPG PATHWAY IN CLINICAL PRACTISE
L. C. Hofbauer
Division of Gastroenterology and Endocrinology, Philipps-University,
D-35033 Marburg, Germany
The recent characterization of the essential cytokine of
osteoclast cell biology, receptor activator of NF-kappaB ligand (RANKL) and its antagonist
osteoprotegerin (OPG), have led to a detailed molecular and cellular understanding of bone
metabolism in health and disease. RANKL and OPG play an essential role for osteoclast
formation and activation, and various metabolic, inflammatory and malignant bone diseases
employ this cytokine system to trigger osteoclastic bone resorption. Elucidation of the
RANKL/RANK/OPG pathway has important implications for the pathogenesis, diagnosis and
treatment of human bone diseases. Most disorders characterized by enhanced osteoclastic
bone resorption are due to an imbalance of the RANKL-to-OPG ratio, with RANKL exceeding
OPG, including various forms of osteoporosis. Constitutively activating RANK mutations
have been reported in familial expansile osteolysis, and inactivating OPG mutations
leading to the absence of OPG protein and unopposed effects of RANKL are the cause and
mechanism in juvenile Paget's disease. Malignant tumors (multiple myeloma) and
inflammatory bone diseases (periodontal disease, rheumatoid arthritis) are characterized
by an excessive overproduction of RANKL by tumor and immune cells that overwhelms the
endogenous safeguard mechanism of OPG production. OPG (and more recently soluble RANKL)
serum levels have been evaluated as novel biochemical markers of bone metabolism.
Unexpectedly, OPG serum levels are increased in several forms of osteoporosis and in
vascular diseases. This apparent paradox may indicate that OPG serum changes are a
consequence rather than a cause of disease. OPG serum levels are decreased in patients
with multiple myeloma which is due to degradation of the OPG protein by myeloma cells.
Blockade of RANKL by administration of OPG or OPG derivatives, neutralizing RANKL
antibodies or inhibitory RANK antibodies has been successfully used to treat various bone
diseases including malignant bone diseases, where it has been proven to prevent
osteolysis, to mitigate hypercalcemia, to halt tumor progression, to reduce
tumor-associated pain, and to prolong survival. Two preliminary controlled studies in
humans have demonstrated that administration of an OPG-Fc fusion protein is a safe and
efficient therapy that prevented alterations of biochemical markers of bone turnover in
postmenopausal osteoporosis and myeloma bone disease.
[Programme]
I-14
WHAT TYPE OF EXERCISE IS BENEFICIAL TO THE SKELETON?
A. Heinonen
UKK Institute for Health Promotion Research, Tampere, Finland
Results from a number of animal experiments have
suggested that the rate, magnitude, distribution, frequency and duration of the dynamic
strain stimulus are among the important components in bone adaptation. That is, either
intensive or unusual exercise programs lead to adaptation in bone architecture. These
experiments suggest that some components of total mechanical loading of bones are more
effective in influencing bone architecture than others. Application of these basic rules
from animal studies to practical exercise regimen include: high-magnitude, repetitive,
high- impact and uncustomary loading. In other words a loading pattern that differs from
what the bone accustomed to. Physical activity generates loads on bone by means of the
magnitude of the physical force and the rate at which this force is applied. Thus, the
loads on bone can be determined primarily by the movement conditions (velocity of the
segments in motion, number of repetitions, muscular activities) and boundary conditions
(anthropometry, fitness level, performance surface, type of shoe). Accordingly, any change
in the movement conditions affects the kinetics of the movement and probably also the
mechanical stress in different exercise regimens. In terms of skeletal loading, weight
training, for instance, creates high-magnitude loading and more specifically, extreme
torques in upper extremities whereas lower extremities experience large compressive
stresses. The most commonly practised exercise is walking that involves a large number of
repetitive loading in lower limbs but is more suited to cardiovascular performance than
local bone loading. Exercises that involves speed and power are characterised by fast,
forceful, accelatory, impact producing movements often in multiple directions seems to be
an appropriate type of training with which to influence osteogenic response, as it would
place a variety of forces on bone. Previous studies have reported that athletes engaged in
sports producing high strain rates via versatile impact-type movements have much higher
bone mass (9-40%), better geometry and stronger structure (the largest differences over
50%) than their sedentary controls. Adaptation to this loading seemed to occur in a
site-specific fashion by gross-geometric changes, structural or architectural changes or
by their combination. Clinical trials also support the high-impact loading concept.
Consequently, the important components of osteogenic exercise stimulus are high strain
rates (speed and power) and high peak forces in versatile movements.
[Programme]
I-15
NEUROTRANSMITTER FUNCTION IN BONE
T. Skerry
Department of Veterinary Basic Sciences, Royal Veterinary College,
London, UK
In light of the conservation of genetic information
across the animal kingdom, it should not be surprising that signalling systems identified
originally in one tissue should have functions in others. Expression by bone cells of
bradykinin, VIP, glutamate, dopamine, serotonin and P2 ATP receptors suggests novel
mechanisms of intercellular signalling that occur in bone. Since pathophysiology of bone
diseases is a function of orchestrated activity of cells that control formation and
resorption, novel signalling systems cast new lights on understanding of normal function
and disease.
However, involvement of neurotransmitters in
intercellular signalling in bone raises a fundamental question: why there should there be
similarities between such disparate tissues as the nervous system and bone?
Intercellular communication in the nervous system is
rapid, with ability to resolve high frequency repetitions, modulate signals in response to
inhibitory or potentiating stimuli and retain persistent record of events as memory. Why
should bone, which changes its properties more slowly, require such a mechanism? One
reason could be that responses of bone to mechanical loading requires ability to
discriminate different rates of application of strains, where important events occur in
less than 40msec. In addition, only very short durations of exercise/loading are necessary
to induce maximal osteogenic effects. While the idea that strain memory could exist has
been considered for some years, data on a possible mechanism for it are sparse. Recently,
the potential involvement of neurotransmitter mediated signalling in bone cells has raised
the possibility that neuronal-like memory mechanisms may be involved in bone. Preliminary
data shows that all the molecules necessary for long term potentiation, the process in the
CNS by which memory formation may occur are present in osteoblasts, and that loading in
vitro activates the same sequence of events in those cells as neurones.
The implications of understanding of these novel
signalling pathways are not clear. However, the density of research effort in neuroscience
means that information, reagents and even candidate drugs exist to modify neurotransmitter
function. These could impact on bone strength and treatment of osteoporosis.
[Programme]
I-16
MECHANICAL LOADING, OSTEOCYTES AND APOPTOSIS
B. S. Noble
Musculoskeletal Research Unit, University of Edinburgh, Edinburgh, UK
Bone is the ultimate 'smart' structural material. It is
self-designing, adapting as it does to the prevailing mechanical needs of the organism by
adding new bone in regions that require it and undertaking targeted sculpting of each bone
internally and externally to remove redundant material. It is also self-repairing,
sensing, removing and replacing damaged or mechanically insufficient volumes of bone. The
effector cells for this process are the osteoclasts, which share the early part of their
lineage with monocyte/macrophages. The mechanism by which cells are precisely targeted to
areas requiring resorption is poorly understood.
The osteogenic effects of load engendered strains have
been evident for some time, as has the resorption inducing effect of under-loading our
skeletons, but the cell types responsible for orchestrating the targeted function of the
effector cells is still in question. It is generally considered that the osteocyte is the
most likely candidate for this role due to their distribution throughout the bone matrix,
their responsiveness to strain and their existence as part of a syncitial network.
However, until recently, it has not been possible to identify osteocyte-specific behaviour
that is related spatially to the damage / strain environment and is associated with
localised remodelling activity.
Some years ago we noted that osteocytes death by
apoptosis is over represented in bone tissue which is for a variety of reasons undergoing
rapid remodelling. We proposed that the marked apoptosis of osteocytes observed in women
and female rats subjected to acute estrogen withdrawal provides a targeting mechanism for
inducing the well-documented removal of bone by osteoclasts under osteoporotic conditions.
Since then a number of reports have confirmed and extended our findings and a relationship
between load engendered, targeted osteoclast activity and osteocyte apoptosis has been
noted.
These observations raised the exciting possibility that
the targeted removal of bone which is under loaded or contains microcracks might also
involve the apoptotic death of the osteocyte. I shall discuss work undertaken which would
strengthen this possibility. We will consider the possible mechanisms by which controlled
cell death might contribute to the signals for bone removal and repair in the light of
work involving cells in other tissue systems.
[Programme]
I-17
ROLE OF BIOCHEMICAL MARKERS IN MONITORING ADHERENCE TO TREATMENT
R. Eastell
University of Sheffield, Sheffield, UK
Bone turnover markers may be useful in monitoring the
response to treatment with antiresorptive therapy. The changes in bone resorption markers
are large and occur within the first few weeks of treatment. The size of the change in the
individual is related to the reduction in the risk of fracture. The goal of therapy is to
decrease bone resorption into the lower half of the reference range for premenopausal
women by an amount greater than the least significant change. Not all biochemical markers
are the same, for bone resorption markers, the telopeptide assays (NTX, CTX) appear to
show the best 'signal to noise' ratio. These markers show large day-to-day variability and
this can be minimised by obtaining more than one baseline sample and taking the average.
The aims of monitoring treatment with bone turnover markers is to identify patients who do
not respond to therapy and to encourage patients to comply with long- term medication.
Long-term compliance with medications for osteoporosis is low, and could be improved by
knowledge that the treatment is effect after just three months.
[Programme]
I-18
ROLE OF BONE DENSITOMETRY AND QUANTITATIVE ULTRASOUND TECHNIQUES IN
MONITORING TREATMENT RESPONSE
C. C. Glüer
Medical Physics, Department of Diagnostic Radiology, University Hospital
Schleswig-Holstein , Kiel, Germany
The slow response of bone to treatment requires
monitoring over several years to establish efficacy of treatment. The small magnitude of
changes in bone mineral density (BMD) requires techniques with small long term precision
errors. In order to assess the value of radiological techniques such as bone densitometry
or Quantitative Ultrasound (QUS) two aspects need to be considered: (1) the technique must
offer sufficient longitudinal sensitivity (a function of the ratio of response rate and
precision error) to allow decision making after within 1-2 years and (2) the changes
measured should reflect changes in bone strength, i.e. probability of fracture. Both of
these aspects may depend on the type of treatment selected, e.g. they can be different for
bone forming versus anti-resorptive medications and need to be interpreted differently
when interpreting bone changes due to exercise.
In view of the increasing variety of different treatment
agents it has become apparent that change in bone strength cannot be fully understood if
only change in areal density is considered, The association of change in areal BMD with
change in fracture rate is modest. Other skeletal aspects including micro-structural
changes or alterations in bone tissue quality need to be considered and measured in
addition. However, techniques to perform this in vivo are only beginning to emerge.
Regarding changes in BMD, a large amount of data on longitudinal sensitivity exists for
Dual X- ray Absorptiometry, much less for other densitometry methods such as (peripheral)
Quantitative Computed Tomography. Similarly the information on QUS response to treatment
is limited and the association of change in QUS variables with change in fracture rate is
not known.
We will review existing data for the various techniques
and medications. Based on these data and in view of competing techniques such as bone
turnover markers the role of bone densitometry and QUS techniques in monitoring treatment
response will be outlined.
[Programme]
I-19
DO WE NEED TO MONITOR ANTI-OSTEOPOROSIS TREATMENT ANYWAY?
J. E. Compston
Dept of Medicine, University of Cambridge School of Clinical medicine,
Cambridge UK
Wider recognition of osteoporosis and development of
effective interventions have resulted in a large increase in the number of individuals
undergoing treatment. Bone densitometry and/or measurement of biochemical markers of bone
turnover are often recommended as means of monitoring the response to treatment, creating
a huge industry in the private sector and overburdening osteoporosis services in state-run
systems. For monitoring to be justifiable, it must be shown to be cost-effective. This
requires randomized controlled trial evidence that monitoring reduces fracture rate by a
clinically significant amount and that these benefits outweigh the financial costs
involved.
Monitoring is often justified on the basis that it is
comforting for the patient and her/his doctor to know that the treatment is working.
However, this requires a considerable degree of subterfuge and obfuscation on the part of
the physician, since in most cases he/she will not know whether the treatment is working
but will be anxious to reassure the patient and encourage their compliance. Far from being
reassuring, monitoring may cause anxiety, since to the patient it implies that treatment
may fail. Furthermore, although monitoring might improve compliance in a small number of
individuals, it may have the reverse effect if an individual is wrongly accused of
non-compliance, Finally, since evidence points to a global non-compliance rate of >50%
with long-term osteoporosis therapies in clinical practice, the majority of monitoring
tests will be performed in patients who are not taking any treatment. When reassured that
they are responding, their motivation to take therapy will be further reduced.
A problem central to the issue of monitoring is that
there is no agreed definition of a non-responder; indeed, it is uncertain whether true
non-responders exist at all. Individuals who fracture whilst on treatment are often
described as non-responders but might have sustained more fractures had they not been on
treatment. Changes in bone mineral density or biochemical markers only explain a
relatively small part of the variance in fracture reduction and cannot be reliably used as
indicators of response in individual cases. In the absence of evidence that monitoring
significantly improves clinical outcome, there is no justification for its use and the
substantial resources dedicated to this practice should be reallocated to more important
priorities.
[Programme]
I-20
MODELLING HUMAN GENETIC BONE DISEASES USING TRANSGENIC AND OTHER
APPROACHES
S. Mundlos
Charité, Berlin, Germany
Inherited diseases of the skeleton are clinically and
genetically heterogeneous. Some affect primarily the overall pattern of the skeleton,
others, in contrast, result in growth disturbances or in abnormal bone homeostasis. The
identification of specific gene defects in these conditions has unraveled some of the
basic principles of bone biology and has opened new avenues for understanding and possibly
treating inherited diseases of bone. However, the identification of a gene together with
the disease causing mutation is not sufficient to explain the pathobiology behind the
condition. Models are needed to characterize the function of a gene within a given
biological process and to understand its role in the network of molecular pathways.
Mutations have to be modeled in order to understand their consequences. Some mutations
result in a loss of function (hypomorph/amorph) whereas other in a gain of function
(hypermorph) or even in a new function (neomorph). Examples will be presented how such
effects can be studied in animal models. Cleidocranial dysplasia (CCD), for example, is
caused by heterozygous loss of function mutations in Runx2, a transcription factor
expressed during bone development. Inactivation of one Runx2 allele in the mouse results
in a CCD-like phenotype whereas inactivation of both alleles results in a complete loss of
osteoblasts and, consequently, bone. This proves that Runx2 is necessary for bone
formation. However, overexpression of Runx2 in chick embryos using a retroviral system
(RCAS) does not result in extra bone formation indicating that Runx2 is not sufficient to
induce bone formation. Rather, Runx2 appears to have an important role in maintaining the
early chondrocyte phenotype as indicated by the formation of extra cartilage in infected
wings. Furthermore, Runx2 promotes chondrocyte differentiation. The chondrogenic effects
of Runx2 can be blocked by expressing a dominant negative form of Runx2 selectively in
chondrocytes using a transgenic approach with the collagen type II promotor. Thus, the
combination of gene inactivation together with specific or global overexpression in model
systems allows the thorough analysis of gene function.
[Programme]
I-21
GENETIC DETERMINANTS OF OSTEOPOROSIS
A. G. Uitterlinden
Departments of Internal Medicine, Clinical Chemistry and Epidemiology
& Biostatistics Erasmus MC, Rotterdam, The Netherlands
Like other complex diseases and traits, osteoporosis has
strong genetic influences. DNA analysis is expected to be a powerful tool in diagnostics
of those at risk of disease, in identifying potential drug targets, and in predicting
response-to-treatment, and the field of osteoporosis is no exception to those
expectations.Therefore intense academic and commercial efforts are ongoing to identify the
responsible gene variants.
Linkage analysis by 'genome searches', which should
identify chromosomal regions containing disease gene(s), has had limited success sofar to
identify complex trait genes. More promising is the analysis of human candidate genes with
a known involvement in the biological pathway of interest. Such genes can be identifed by
expression analysis of target cells, linkage analysis of monogenic bone diseases, and also
by mouse models of the disease. Sofar, candidate genes have come from classic bone
pathways, involving estrogen and vitamin D, and from bone matrix molecules such as
collagen type I. However, mouse models and analysis of human Mendelian bone disease has
also identified novel or hitherto unsuspected 'bone proteins', such as leptin, SOST, and
LRP5. Subsequently, genetic-epidemiological analyses of polymorphisms in these candidate
genes are performed in large population studies to determine the contribution to
phenotypic endpoints of interest, such as risk of fracture.
Candidate gene studies, however, have had their share of
scepticism because effects were small, functionality of polymorphisms was not always
known, and associations have not always been reproducable across populations. However,
while probably hundreds of genes each play a role in bone metabolism, only very few of
these have been properly scrutinized for their genetic contribution to osteoporosis
including meta-analyses to estimate the true effect size and functional studies to
establish mechanism of action.
Importantly, we now also know that a single gene usually
carries several polymorphisms which influence its activity and, thus, comprehensive
analysis of all genetic variation in a gene (haplotype analysis) is important. In
addition, several gene products within a certain biological pathway interact with each
other and bio- activities might be modified by environmental factors. Once individual gene
effects have been categorized, evaluating these interaction effects will be the major
challenge in determinng the role of genetic factors in osteoporosis.
[Programme]
I-22
ROLE OF THE PTH/PTHRP RECEPTOR IN BONE GROWTH AND REMODELLING
E. Schipani
MGH-Harvard Medical School, Boston MA, USA
The parathyroid hormone/parathyroid hormone-related
protein receptor (PTH/PTHrP receptor) mediates both the endocrine actions of parathyroid
hormone (PTH) and the auto/paracrine actions of parathyroid hormone-related protein
(PTHrP). This places the PTH/PTHRP receptor as a central regulator of both mineral ion
homeostasis and bone development. Jansen's metaphyseal chondrodysplasia, a rare autosomal
dominant disorder characterized by short-limbed dwarfism and hypercalcemia, is caused by
mutant, constitutively active PTH/PTHrP receptors. Consistent with the observation in
patients, a transgenic model in which a mutant Jansen PTH/PTHrP receptor was targeted to
the growth plate (H223R-Col II) showed delayed mineralization and decelerated chondrocyte
maturation in skeletal segments that are formed by endochondral bone development. This
finding indicates that the PTH/PTHrP receptor is the main mediator of PTHrP action in the
developing endochondral bone. Targeted overexpression of the same mutant Jansen receptor
in vivo in cells of the osteoblast lineage (H223R-Col I) demonstrated that stimulation of
the PTH/PTHrP receptor in osteoblasts is responsible for both the bone forming and the
bone resorbing actions of PTH. Further analysis of H223R-Col I transgenic model also
revealed that activation of the PTH/PTH receptor has differential effects on cortical and
trabecular bone, and that collagenase activity could be involved in the differential
effects of this receptor on discrete bone compartments. Clonogenic marrow stromal cells
were isolated from normal and mutant mice, expanded in culture, and transplanted
subcutaneously into immunocompromised mice. Normal stromal cells generated a complete
ossicle (bone and marrow). In contrast, no marrow was detectable at 4-8 weeks
post-transplantation of mutant stromal cells. Interestingly, however, H223R- Col I
transgenic had increased hematopoietic stem cell numbers. The hematopoietic stem cell
effect was mediated by stroma from these animals, and it could be recapitulated by
exogenous application of PTH to wild type stroma containing hematopoietic stem cell
cultures. Taken together, these findings strongly suggest that the PTH/PTHrP receptor not
only modulates bone growth, but has also a complex and not yet fully elucidated action on
the hematopoietic compartment
[Programme]
I-23
ROLE OF PTH IN THE PATHOGENESIS AND TREATMENT OF OSTEOPOROSIS
R. Lindsay
Helen Hayes Hospital and Clinical Medicine, Columbia University NY, USA
1-34hPTH is now approved for treatment of osteoporosis in
both men and women at high risk of fracture, in the USA. PTH represents a new paradigm for
osteoporosis treatment, since it is the first drug demonstrated to stimulate bone
formation and increase the mass of bone tissue in the skeleton. The result is a decreased
risk of vertebral and non-vertebral fractures. PTH effects this by two mechanisms. First
there is a rapid stimulation of bone formation, within the first few days of initiation of
treatment. This is followed by a stimulation of remodeling activity. Both effects are
transient and despite continued administration of the drug, bone formation and remodeling
activity return to baseline within 2 years. Clinical trials were discontinued when
osteosarcomata were found in a rodent toxicology study, although the relevance of this for
human use of 1-34hPTH remains unknown. The consequence of these 2 different findings is
the recommendation of PTH use for not more than 2 years. One fascinating aspect of PTH
action is that bone formation appears to be stimulated on all surfaces of bone, including,
at least at some sites, the periosteum. The result is a modest but significant increase in
bone size, which may have marked effects on strength. While cellular and molecular
mechanisms are still being worked out, one hypothesis, delayed osteoblast apoptosis
resembles the finding in mice with the so- called high bone mass gene.
[Programme]
I-24
ANTI-TNF THERAPY FOR RHEUMATOID ARTHRITIS: PROSPECTS FOR THE FUTURE
M. Feldmann*, F. M. Brennan, B. M. J. Foxwell, E. Paleolog, R. N. Maini
Faculty of Medicine, Imperial College of Science, Technology and
Medicine, UK
Analysis of cytokine disregulation in samples of human
synovium provided the major rationale for blocking TNF in rheumatoid arthritis. Clinical
trials established this hypothesis using a number of different TNF inhibitory
'biologicals' which are now licensed for human use - first a chimeric antibody,
infliximab, then a TNF-receptor fusion protein, etanercept, and most recently a human
antibody, adalimumab. All of these induce marked clinical benefit in a majority of
patients resistant to other anti- rheumatic therapy. Analysis of the mechanism of action
revealed that many processes were affected, with production of many cytokines, chemokines,
adhesion molecules down-regulated.
Perhaps the major single mechanism of clinical benefit is
the reduction in influx of inflammatory cells into joints. RA is not the only chronic
inflammatory disease that benefits from TNF blockade. Crohn's diseases, psoriatic
arthritis, ankylosing spondylitis, psoriasis have reported convincing clinical trial data
and await approval, many others have successful results. It is likely that the widespread
benefit is due to the impact on cell recruitment. In terms of bone biology it is striking
that TNF blockade can arrest joint damage in about half the patients, improves others, and
in about a third there is improvement in joint images which suggests healing of bones and
cartilage damage. That is a very exciting prospect which while needing confirmation in
other clinical trials, suggests that some degree of joint repair is possible in humans
provided the inflammatory process is sufficiently controlled.
[Programme]
I-25
REGULATION OF BONE CELL FUNCTION BY PRO- INFLAMMATORY CYTOKINES
S. R. Goldring
Harvard Medical School, Boston, Massachusetts, USA
Cytokines play a critical regulatory role in the
initiation, perpetuation and destructive activities of many inflammatory disorders.
Rheumatoid arthritis (RA) represents a paradigm for investigating the role of these
pro-inflammatory cytokines on skeletal remodeling. In this condition, proliferation of the
synovial lining of diarthrodial joints is accompanied by progressive focal peri-articular
bone loss, manifest radiographically by the development of focal joint erosions. This
local joint pathology is associated with systemic bone loss and an increased risk of
fracture. Histopathological analysis of joint tissues from patients with RA using
immunostaining and in situ hybridization techniques indicate that osteoclasts are
associated with the development of focal joint erosions. Animal models of inflammatory
arthritis, including adjuvant arthritis (Kong et al. Nature 1999; 402:304), serum transfer
arthritis (Pettit et al. Am J Pathol 2001;159:1689) and TNF- transgenic mice with
spontaneous arthritis (Redlich et al. Arthritis Rheum 2002; 46:785), confirm that
osteoclasts are the principal cell type responsible for the pathogenesis of focal bone
erosions. Additional studies have helped to identify the cytokines and inflammatory
mediators that are involved in the recruitment and activation of bone resorbing cells
associated with inflammatory arthritis. Tumor necrosis factor alpha, interleukin-1,
receptor activator of NF-kb ligand (RANKL) and a number of other products of activated T
cells and synovial fibroblasts are among the factors implicated in the increased focal
articular and systemic bone loss. Pro- inflammatory cytokines represent rational
therapeutic targets for specifically inhibiting or slowing the progressive bone loss
associated with RA and related inflammatory disorders.
[Programme]
I-26
MECHANISMS OF BONE LOSS IN ASEPTIC PROSTHETIC LOOSENING
E. M. Schwarz*, D. Campbell, S. Totterman, A. Boyd, R. J. O'Keefe, R. J.
Looney
University of Rochester, New York, USA
Although total hip replacement (THR) is amongst the most
successful and beneficial medical procedures to date, long-term outcomes continue to
suffer from aseptic loosening secondary to periprosthetic osteolysis. Extensive research
over the last two decades has elucidated a central mechanism for osteolysis in which wear
debris generated from the implant stimulates inflammatory cells to promote
osteoclastogenesis and bone resorption. The cytokine tumor necrosis factor alpha (TNF) has
been demonstrated to be central to this process and is considered to be a leading target
for intervention. Unfortunately, even though FDA approved TNF antagonists are available
(etanercept), currently there are no reliable outcome measures that can be used to
evaluate the efficacy of a drug to prevent periprosthetic osteolysis. To the end of
developing an effective outcome measure, we evaluated the progression of lesion size in 20
patients with established peri-acetabular osteolysis (mean = 29.99 cm3, range = 2.9-92.7
cm3) of an uncemented primary THR over one year, using a novel volumetric computer
tomography (3D-CT) technique. We also evaluated polyethylene wear, urine N-telopeptides
and functional assessments (WOMAC, SF-36 and Harris Hip Score) for comparison. At the time
of entry into the study baseline CT scans were obtained and the patients were randomized
to etanercept (25mg s.q., twice/week) and placebo in a double-blinded fashion. CT scans,
urine and functional assessments were also obtained at 6 and 12 months. No serious adverse
drug related events were reported, but one patient had to have revision surgery before
completion of the study due to aseptic loosening. No remarkable differences between the
groups were observed. However, the study was not powered to see significant drug effects.
3D-CT data from the 19 patients was used to determine the mean increase in lesion size
over 48-weeks, which was 3.19 cm3 (p<0.0013). Analysis of the urine N-telopeptides and
functional assessment data failed to identify a significant correlation with wear or
osteolysis. In conclusion, volumetric CT was able to measure progression of osteolysis
over the course of a year, thus providing a technology that could be used in therapeutic
trials. Using the data from this pilot we provide a model power calculation for such a
trial.
[Programme]
I-27
OSTEOGENESIS IMPERFECTA
N. J. Bishop
Academic Unit of Child Health, University of Sheffield, Children's
Hospital, Sheffield, S10 2TH, UK
Osteogenesis imperfecta (OI) is the commonest inherited
form of bone disease causing osteoporosis. Affected individuals suffer recurrent fractures
with resulting pain, deformity and disability. The clinical phenotype varies very widely.
Mildly affected individuals have little or no bone deformity or loss of height. Severely
affected infants may die at birth or in the first year of life. The Sillence
classification defines four forms of OI, but three new types have been described over the
last three years. Defining the molecular pathophysiology and its relation to clinical
phenotype remains a challenge in all forms of the disease.
The management of OI is multidisciplinary. Recent
attention focussed on anti- resorptive therapy using bisphosphonates, with the majority of
reported studies being observational in nature. Increases in bone mass, cortical thickness
and the height of previously crush-fractured vertebrae, together with the relief of
chronic bone pain are consistently reported for children treated with these agents.
Multidisciplinary management is required in the majority of moderately to severely
affected individuals. Surgery, occupational and physiotherapy remain important aspects of
treatment.
This review of OI will provide information on the current
system of classification, response to therapy with bisphosphonates and the pathophysiology
of the disease at a cellular and molecular level.
[Programme]
I-28
AUTOSOMAL DOMINAT OSTEOPETROSIS (ADO). FROM THE PATIENT TO THE MUTATION
J. Bollerslev
Section of Endocrinoloy, Natl. University Hospital. Oslo, Norway
Imbalance between the bone resorptive and formative
process can lead to different sclerotic skeletal dysplasias characterised by increased
bone mass. Among these, osteopetrosis is caused by defective bone resorption leading to a
diffuse, symmetrical osteosclerosis without major modeling defects. ADO is recognised as a
rather benign condition, where the diagnosis often is reached by change, however
heterogeneity between types and even within families is well known.
Based on a systematic search for the condition, two
different types (Type 1 and 2) were described in the County of Funen, Denmark. Both types
showed increasing sclerosis with age and both were seen in childhood. Further studies
revealed distinct differences between the types at the clinical, biochemical,
histomorphometric, and electron microscopic level. ADO 1 is a typical osteoclastopenic
disorder, as seen in several murine models characterised by maturation defects in
development of the osteoclastic lineage. Interestingly, the disease seems to have
increased trabecular bone strength and decreased fracture rate. Linkage analyses mapped
this type to chromosome 11q12-13, and further mutation analyses disclosed a missense
mutation in exon 4 of the LDL receptor-related protein 5 (LRP5). Mutations in this gene
have been associated among others with the High Bone Mass (HBM) phenotype. However, ADO 1
and HBM differs significantly at the clinical and biochemical level and further studies
may reveal the exact mechanism by which the LRP5 gene regulates bone mass.
In ADO 2 (Albers-Schönberg disease), numerous huge
multinucleated osteoclasts are found at the histological level with a TRAP-positive
substance covering adjacent bone trabecular surfaces. This type resembles in many ways the
more severe juvenile forms of osteopetrosis, associated with a mutation in the gene
encoding for the chloride channel ClCN7. ADO 2 has recently been associated with a
missense mutation in the same gene. Chloride channels function as dimers, thus the
identified mutation seems to exert a dominant negative effect.
In conclusion, ADO is a heterogeneous group of rather
benign osteosclerotic bone dysplasias where the underlying mutations recently have been
found. ADO 1 resembles murine mutations with well- known maturation defects in the
osteoclastic lineage and is now associated with the LRP5 gene. The defective osteoclast
function in ADO 2 is related to the acidification process by mutation in the ClCN 7-gene.
[Programme]
I-29
SKELETAL DISPLASIAS
M. P. Whyte
St Louis MO, USA
Skeletal dysplasias are generalized developmental
malformations that cause symmetrical bony disturbances. Although individually rare,
cumulative prevalence is about 1 per 4,000 - 10,000. Most are heritable and
remarkable recent progress is identifying their genetic basis and thereby elucidating
their pathogenesis. Consequently, dysplasias are moving increasingly from the domain of
dysmorphologists to "metabolic bone disease." Endocrinologists are also
consulted for chondrodysplasias because growth plate disturbances can cause metaphyseal
irregularity mimicking rachitic disease or vertebral distortion suggesting compression
fracture. Although more than 100 seemingly distinct phenotypes have been reported,
molecular studies are rapidly improving classification. Indeed, by the end of the 20th
Century, a large proportion were known to result from mutations in a small number of genes
("allelism"). Remarkably, 10 genetic loci actually account for the majority of
chondrodysplasias. Hence, "consolidation" occurred. For others, separation
became possible for clinically and radiographically similar conditions. Graded severity
for skeletal dysplasias can involve a single gene (resembling osteogenesis imperfecta
where numerous mutations disturb the two genes that encode type I collagen). Aberrations
in endochondral bone formation often represent a fundamental pathogenetic defect. The
genes are essential and nonredundant for the production of cartilage. Pathogenesis-based
classification now places chondrodysplasias, by and large, in two principal groups: (1)
gene defects encoding type II collagen (and sometimes other matrix proteins), and (2)
craniosynostoses involving FGFR3 mutations. Cartilage matrix protein gene mutations
compromise chains of types II, IX, X and IX collagen, matrilin and COMP (typically acting
in a dominant negative fashion). Spondyloepiphyseal dysplasias, multiple epiphyseal
dysplasias, Stickler dysplasia, Schmid metaphyseal chondrodysplasia, and
pseudoachondroplasia represent this category. Mutations that activate receptors (whose
downstream signals negatively regulate physeal chondrocyte proliferation and
differentiation) include FGF3 defects causing achondroplasia, and PTH/PTHRP receptor
mutations causing Jansen syndrome. A third major category disturbs cellular sulfate uptake
required for synthesis of cartilage proteoglycans. Nevertheless, diagnosis of dysplasias
still is achieved primarily by radiographic "pattern recognition." However,
several laboratories [accessed at "GeneTests" on the web (www.genetests.org)]
provide either commercial or research laboratory mutation analyses to help with diagnosis.
[Programme]
I-30
PATHOGENESIS OF HYPOPHOSPHATAEMIC RICKETS
M. J. Econs
Indianapolis IN, USA
Abstract not supplied
[Programme]
I-31
RECENT ADVANCES IN SCLEROSING BONE DYSPLASIAS
W. Van Hul
Dept. Med Genetics, University of Antwerp, Belgium
The group of sclerosing bone dysplasias has longtime been
poorly understood at the molecular level. The combination of increased availability of
human genome sequence data and newly developed tools and technologies have expedited
position cloning efforts aiming at the identification of disease causing genes. This has
resulted in the recent identification of a large number of disease genes. The study of the
extended group of conditions with an increased bone density has, in some cases, lead to
the identification of previously unknown genes involved in bone homeostasis. In other
cases, by proving the involvement of previously known genes in sclerosing phenotypes,
further insights have been gained on the precise functioning of these genes and the
pathways they participate in.
Long time after carbonic anhydrase II-deficiency was
proven to lead to an osteopetrotic phenotype, the study of other forms of osteopetrosis
has resulted in the characterization of other important partners in the bone resorption
process (the Vacuolar H(+)-ATPase and ClCN7). Mutations in coupling factors between bone
formation and bone resorption (including TGFb1, OPG and RANK) are also found in conditions
with an increased bone density. Finally, the previously unknown SOST gene and the LRP5
gene turned out to be important regulators of the bone formation process by acting on BMP-
and Wnt signaling respectively.
In conclusion, positional cloning efforts on monogenic
conditions with an abnormal bone density have contributed to the present understanding of
bone homeostasis. Furthermore, currently performed association studies with natural
variants within the genes identified, will most likely illustrate a role in the
pathogenesis of osteoporosis for at least some of these genes.
[Programme]
I-32
BASIC RESEARCH STRATEGIES TO IDENTIFY NEW OSTEOPOROSIS TREATMENTS
R. Baron
Yale University School of Medicine, New Haven, CT, USA
ProSkelia Pharmaceuticals, Romainville, France
Advances in the biology of bone cells and of the
regulation of bone remodeling have lead to innovative approaches to the treatment of
osteoporosis. Osteoporosis drug discovery follows 3 approaches: 1) Pathophysiological,
attempting to correct the mechanisms that lead to altered bone remodeling, 2)
Anti-resorptives, targeting the osteoclast lineage and 3) Anabolics, targeting the
osteoblast lineage. In the pathophysiology of osteoporosis, three major findings have been
the discovery of a second receptor for estradiol (ER beta), the finding that the ERs may
affect bone cell apoptosis through non-genomic mechanisms and via the AR as well, and the
validation of the concept of the SERMs, raising the possibility to selectively target bone
and to develop similar compounds for the AR or the PR. In the field of antiresorptives,
and beyond bisphosphonates and calcitonin, several recent findings have lead to programs
in drug discovery. The main targets are : the vitronectin receptor, cathepsin K, c-Src,
the vacuolar proton pump, and the pathway of RANK Ligand and its receptor RANK. In
addition, the mevalonate pathway has been demonstrated to be the target for
bisphosphonates, leading to a new drug discovery approach. The therapies of the future
will also involve bone anabolics. First and foremost, the anabolic potential of PTH given
intermittently has been firmly established in human studies, validating the concept of
anabolics. An alternative to the use of PTH is the regulation of its secretion by
targeting the calcium receptors in the parathyroid gland, antagonising the binding of Ca
and thereby increasing PTH levels (calcilytics). Other major findings in this area are the
identification of Cbfa-1, the central hypothalamic regulation of bone formation via the
adrenergic receptors, and the recent identification of LRP5, a receptor involved in bone
mass regulation in humans. Finally, most companies are currently engaged in genetic,
genomic and gene expression profiling studies to identify novel genes involved in bone
formation that can then be used as novel targets for drug discovery.
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I-33
NEW TREATMENTS, NEW TRIALS, NEW PARADIGMS FOR PREVENTING FRACTURES
S. R. Cummings
SF Coordinating Center, Pacific Research Institute, San Francisco, CA,
USA
Clinical trials have taught us that antiresorptive drugs
reduce fracture risk, especially in women with osteoporosis. Additionally, they have
taught us that these drugs reduce fracture risk more than can be expected from
improvements in BMD. These drugs work quickly but their long-term effects are uncertain.
Even long-term treatment with antiresorptives is unlikely to reduce risk of fractures to
normal or acceptable levels in patients with sever osteoporosis. One trial of PTH suggests
that bone forming agents could change the paradigm of anti-fracture treatment . An
effective bone-forming agent could change current paradigm of practice (treatment to
maintain moderately reduced risk) to a new paradigm of
treating to achieve goals of nornal bone strength and normal fracture risk. I propose that
we need trials of the old vs. new paradigm of prevention.
Despite proving several treatments to effectively reduce
fracture risk, only a small proportion of people at high risk of fracture are receiving
effective treatment. We need trials of new approaches to delivering care outside of
specialist-based osteoporosis practices. We need to find and test new ways to increased
the identification of high risk women. We need trials of the effectiveness of inexpensive
treatments. And we need to work with companies and governments to make effective
treatments affordable world-wide to those who need them most.
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