Juliet Compston Professor of Bone Medicine University of ... · Other bone diseases Juliet Compston...
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Other bone diseases
Juliet Compston
Professor of Bone Medicine
University of Cambridge School of
Clinical Medicine
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Clinical outcomes of bone disease
• Pain
• Deformity
• Fracture
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Determinants of bone strength
• Bone mineral density
• Bone geometry
• Bone quality
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Measurement of bone mineral density
•Reasonable predictor
of fracture risk in
untreated state
•Less good predictor
of fracture risk in
treated patients
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Relationship between therapeutically induced BMD
increase and vertebral fracture reduction
Cummings et al. Am. J. Med. 2002;112:281-289.
Sarkar, et al. JBMR 2002; 17(1): 1-10.
Li, et al. Stats & Med 2001; 20: 3175-88.
.
28%RisedronateLi
4%RaloxifeneSarkar
16%AlendronateCummings
% Fx reduction
explained by BMDTreatmentAuthor
Individual patient data analysis
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Determinants of bone strength
• Bone mineral density
• Bone geometry
• Bone quality
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Bone geometry: size and shape
Mainly determined by genetic factors
•Some aspects e.g. size, cortical thickness
can be modified by exercise, diet,
anabolic therapy
•Other aspects e.g. femoral neck
length are non-modifiable
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B3D-MC-GHAC
ASBMR Jiang
Patient 1124Baseline Follow-up
Effect of PTH peptide 1-34 on
cortical width and bone size
Female, age 65
Duration of therapy: 637 days (approx 21/12)
Baseline BMD:
Spine T-score = -2.0
Femoral neck T-score = -2.6
Response:
Spine +7.4%
Femoral neck +3.5%
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Determinants of bone strength
• Bone mineral density
• Bone geometry
• Bone quality
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What is bone quality?
• Bone quality refers to material and structural properties of bone
• Some, but not all of these are captured by measurements of bone
mineral density
• Changes in bone quality may contribute to changes in bone
strength in untreated and treated bone disease
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Components of bone quality
Bone turnover Bone microarchitecture
Matrix and mineral compositionMineralisation Microdamage
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What is bone turnover?
• Remodelling rate:
the number of remodelling
units
• Remodelling balance:
the relative amounts of
bone resorbed and formed
within individual
remodelling units
Bone turnover = remodelling rate x focal balance
(from Mosekilde Bone Miner 1990;10:13-35)
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Bone microarchitecture
Dufresne, et al, 2004
Cancellous bone connectivity
anisotropy
trabecular shape and size
Cortical bone cortical thickness
cortical porosity
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Degree of mineralisation of bone
Primary mineralisation: mineralisation during bone remodelling cycle
The degree of mineralisation of bone
is inversely related to bone turnover
Secondary mineralisation: subsequent slow and and gradual maturation of
mineral and increase in its amount
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Changes in collagen maturation with age
Immature
collagen
Mature
collagen14-yr old 72-yr old
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0.8 1.0 1.2
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0
0.2600
0.5200
0.7800
1.040
1.300
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MINERAL CRYSTALLINITY
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MINERAL CRYSTALLINITY
Normal OP OP + F
Fourier Transform Infra-Red (FTIR)
spectroscopy: mineral crystallinity
Courtesy of EP Paschalis
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Detection of microdamage in iliac crest biopsies
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Relationship between bone turnover and bone strength
Bone turnover
Bone strength
(from Weinstein, JBMR 2000)
Hypermineralisation Hypomineralisation
Impaired microdamage repair Reduced bone mass
Reduced osteocyte viability Stress risers
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High turnover states associated with increased
fracture risk
• Postmenopausal osteoporosis
• Post-transplantation osteoporosis
• Immobilisation osteoporosis
• Secondary hyperparathyroidism
• Paget’s disease
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Adynamic renal bone disease
• Characterised histologically by very
low bone formation rates and
presence of very little osteoid
• Associated with low or low-normal
serum PTH levels
• Fracture risk not well documented
but some evidence for higher
prevalence of vertebral and hip
fractures in patients with ESRD and
low PTH levels
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Effect of bisphosphonates on microdamage in dogs
0
10
20
30
40
50
60
70
Rib
cortex
Control
Ris
Aln
Rib
cortexL3
Incadronate
low
Cr.S.Dn µm/mm2
Incadronate
high
Mashiba et al 2000, 2001
Komatsubara et al 2004
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“Severely suppressed bone turnover” in patients
treated with alendronate: ? a causal association
• 9 patients receiving alendronate
for 3-8 yrs
• 3 also receiving HRT, 2
prednisolone
• Presented with spontaneous non-
spinal fractures ± non-healing of
fractures
• Bone biopsies all showed absence
of double tetracycline labeling,
cells virtually absent from bone
surfaces
• Only 2 had osteoporosis (T-score
! -2.5)
(Odvina et al, JCEM 2005;90:1294-1301)
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08/200506/2006
Atypical femoral stress fractures
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Hypomineralisation of bone is associated with
increased bone fragility: osteomalacia
• Characterised by
reduced mineralisation
of bone
• Associated with
pseudofractures and
pathological fracures
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Hypermineralisation of bone is associated with
increased bone fragility: osteopetrosis
• Diverse phenotypes and genotypes
• Associated with increased bone mass
and increased degree of
mineralisation of bone
• Osteopetrotic bone is stiff and brittle
• Often associated with fractures
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Sclerosteosis and Van Buchem disease
Courtesy of Wim van Hul
• Associated with absence/reducedproduction of sclerostin
• Autosomal recessive disorders
• Characterised by endostealhyperostosis
• Resistance to fracture
• Excessive height and syndactyly(sclerosteosis)
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Paget’s disease of bone
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Osteogenesis imperfecta
• Defective synthesis of type 1
collagen
• Associated with
– abnormal matrix/mineral
composition
– abnormal mineralisation density
of bone
– abnormalities of bone modelling
and architecture
– increased risk of fracture
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0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
SS genotype
Ss genotype
SS vs ss genotype:
• SMD spine BMD 0.20 (0.07-
0.34) Z score units; p=0.004
• OR fracture 1.86 (1.26-2.70);
p=0.001
Yield
strength
MPa
Apparent
density
g/cm3
Ratio
!1/!2
(1)(from Mann et al, JCI 2001;107:899-907)
Effect of COL1A1 genotype on BMD, fracture
risk, collagen protein and bone strength
p=
0.0
31
p=ns
p=
0.0
07
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Osteoclastic bone resorption
Mineralised bone
Sealing zone Clear zone
Ruffled border
H+ ATPase
+
chloride
channel
Proteases e.g.
cathepsin K
MMPs
Dissolution of bone mineral and matrix
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Cathepsin K deficiency: pycnodysostosis
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Fibrous dysplasia
• Monostotic and polyostotic
forms
• Extraskeletal manifextations
include hyperpigmentation of
skin, endocrine dysfunction
and renal PO4 wasting
• Caused by activating
mutations of the GNAS gene
(encoding the ! subunit of
Gs!)
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Fibrodysplasia ossificans progressiva
• Progressive, disabling
heterotopic osteogenesis,
chondrogenesis and joint
fusions
• Caused by an activating
mutation of ACVR1, a BMP
type 1 receptor (Shore et
al, Nature Genetics, 2006)
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Glucocorticoids increase fracture risk
independently of BMD
0
0.5
1
1.5
2
2.5
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3.5
4
4.55
OP fracture
Hip fracture
50 55 60 65 70 75 80
Age (yrs)
BM
D-a
dju
ste
d R
R
(from Kanis et al 2004)
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Direct effects of glucocorticoids on bone
Increased bone resorption Decreased bone formation
(early, transient) (long-term)
"RANKL
" M-CSF
PPAR#
$Wnt signalling
Activation of caspase 3
" Formation
$ Apoptosis $proliferation
"apoptosis
"apoptosis
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Time course of vertebral fractures during glucocorticoid
use
0
0.5
1
1 yearbefore
0-3 3-6 6-9 9-12
Months
%
(from van Staa et al, JBMR 2000)
>7.5 mg daily
2.5 - 7.5 mg daily
<2.5 mg daily
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• In vivo
– Clinical signs
– X-rays
– Bone biochemistry
– pQCT
• Bone biopsies
– Turnover
• Histomorphometry
– Architecture
• µCT, histomorphometry,MRI
– Mineralisation
• QBSE, microradiography
– Mineral crystal structure
• FTIR, EM, SAXS
– Matrix composition
• FTIR
Assessment of bone quality in clinical practice
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Clinical assessment of bone quality:
future priorities
• Regional measures of bone turnover
• In vivo assessment of microarchitecture
• Biochemical measures of bone matrix composition