OSTEOPOROSI E MALATTIE REUMATICHE - Dynamicom...
Transcript of OSTEOPOROSI E MALATTIE REUMATICHE - Dynamicom...
OSTEOPOROSI E MALATTIE
REUMATICHE
Giovanni Minisola
Divisione di Reumatologia
Ospedale di Alta Specializzazione “San Camillo”
ROMA
Roma, 14 maggio 2015
OSTEOPOROSI E MALATTIE REUMATICHE
DISTRETTUALE
• Sindrome algodistrofica
• Varie (causalgia, osteoporosi regionale migrante, osteoporosi regionale
transitoria, osteoporosi transitoria dell’anca, sindrome da edema
midollare, …)
SISTEMICA
• Artrite Reumatoide
• Spondiloartriti Sieronegative
• Farmaco-indotta (cortisone, methotrexate, …..)
• Altre condizioni
Loeser RF. Osteoarthritis Cartilage 2013; 21: 1436-42
INTERACTIONS AMONG TISSUES AND BIOLOGICAL
MEDIATORS THAT CONTRIBUTE TO OP IN OA
THE COMPREHENSIVE SCENARIO
EROSIONS
BONE INVOLVEMENT IN RA
SYSTEMIC
FRACTURES
JOINT
DESTRUCTION
PERIARTICULAR
OSTEOPOROSIS
subchondral bone erosions
marginal joint erosions
SPECTRUM OF SPONDYLOARTHRITIS (SPA)
Psoriatic Arthritis
Reactive Arthritis
Peripheral
spondyloarthritis
AS
Axial
spondyloarthritis
Non-radiographic axSpA
Arthritis with
IBD
SAPHO syndrome
juvenile
spondyloarthritis
OUTSIDE-IN ATTACK
INSIDE-OUT ATTACK
TNF-α/RANKL-MEDIATED OSTEOLYSIS IN PsAr
Ritchlin CT et al. J Clin Invest 2013; 111: 821-31 Schett G. Oscar S Gluck Memorial Lecture. ACR 2009 – Philadelphia – October 17-21
PRINCIPALI FATTORI DI RISCHIO PER OP
ASSOCIATA A MALATTIE REUMATICHE
• Flogosi
• CKs
• Fattori meccanici
• Ridotta mobilità
• Trattamenti farmacologici concomitanti
• Ipovitaminosi D
• Introito di calcio insufficiente
• Menopausa (precoce)
• Età avanzata
• Propensione alla caduta
INFLAMMATION AND FRACTURE RISK
Schett G. Oscar S Gluck Memorial Lecture. ACR 2009 – Philadelphia – October 17-21
CKs AND OCs
• Substantial number of cytokines regulates
osteoclastogenesis
• IL-1, IL-6, IL-7, IL-17, IL-23, TNFα, and ……
increase RANKL and MG-CSF expression
• IL-1, IL-6, IL-7, IL-17, IL-23, TNFα, MG-CSF,
RANKL, and ….. increase OC survival
• Several act synergistically and enhance
osteoclastogenesis
sRANKL OPG WNT SCL DKK-1 CAT-K
BONE BONE
RANKL/RANK/OPG SYSTEM AND BONE RESORPTION
Stimulating
factors
RANKL
RANK
OPG
Activated
Osteoclast
CFU-M Pre-Fusion
Osteoclast
Multinucleated
Osteoclast
OBs
BONE
in presence of GM-CSF
RANKL mRNA IN ARTHRITIC SYNOVIUM
Boyle WJ et al. 2003
Activated OsteoclastBone Destruction
T Activated
T
Osteoclast
Dendritic Cell
OPG
RANKL
RANK
Macrophage
BONE
ROLE OF ACTIVATED T CELLS IN OSTEOCLAST
ACTIVATION AND BONE RESORPTION
PROPOSED MECHANISM OF INTRA-ARTICULAR BONE
DESTRUCTION IN INFLAMMATORY ARTHROPATIES
S
Y
N
O
V
I
U
M
B
O
N
E
synovial
fibroblasts
PROINFLAMMATORY CKs (IL-1/IL-6/TNFα, ….)
synovial
macrophages
(mb/s)RANKL
RA: mb>s?
AS: s>mb?
IFNγ
Sato K, Takayanagi H. Curr Opin Rheum 2006; 18: 419-26
Stupphann D et al. Rheumatol Int 2008; 28: 987-93
activated T cells
osteoclast
precursors
osteoclasts
RANKL+ B CELLS DETECTED IN RA SYNOVIAL TISSUE
Yeo L et al. Ann Rheum Dis 2011; 70: 2022–28
REGULATORS OF CTSK GENE EXPRESSION IN OC
OC
Cathepsin K is highly expressed in the osteoclast, where it is localized in
the lysosomes and released during bone resorption
Inhibitors
Estrogen, IFN-γ,
OPG, TSA, …..
CLASTOKINES (S1P, …)
Activators
RANKL, NFAT, Mitf,
PU.1, AP-1, TFE3, IL1,
PPARβ/δ, …..
CA-WNT SIGNALING PATHWAY AND ITS I/EC ANTAGONISTS
Wif-1
WISE
Modified from Khosla S et al. J Clin Invest 2008; 118: 421-8
OSTERIX
OSTERIX
Lef
Sfrp 1, 2, 3, 4
Baron R, Hesse E. J Clin Endocrinol Metab 2012; 97: 311-25
EFFECTS OF THE TWO MAIN ANABOLIC PATHWAYS (WNT
SIGNALING AND PTH) ON OBs, OCs AND OCYs
Appel H et al. Arthritis Rheuma 2009; 60: 3257-62
(Assessment by immunohistochemistry)
SCLEROSTIN EXPRESSION IN HUMAN JOINT DISEASES
*
**
* P <0.05 ** P <0.01
La più comune forma di osteoporosi
secondaria, potenzialmente prevenibile,
oggi ancora sottodiagnosticata e
sottotrattata nonostante le valide risorse
farmacologiche disponibili.
OSTEOPOROSI DA CORTISONE
Lymphoma
Hemolytic anemia
Inflammatory lung
diseases
Rheumatoid
arthritis
Giant cell
arteritis
Crohn’s disease
Behçet’s syndrome
Systemic lupus
PMR Asthma
Polymyositis
Wegener’s
granulomatosis
Immune-mediated
neuropathy
Polychondritis
Pseudotumor
cerebri
RS3PE Dermatomyositis
Ulcerative colitis
CONDITIONS ASSOCIATED WITH LONG-TERM USES OF GCs AND GIO
Vasculitides
……………….
G I O
sHPT? OC OB
BONE RESORPTION (EARLY AND TRANSIENT)
BONE FORMATION (CONTINOUS)
hypogonadism - sarcopenia - osteocytes apoptosis
↓ intestinal Ca absorption
PATHOFISIOLOGY OF GIO
Rizzoli R et al. Calcif Tissue Int 2012; 91: 225-43
FRACTUR
E
RISCHIO RELATIVO MEDIO ANNUO DI FRATTURA VERTEBRALE
IN SOGGETTI FEMMINILI
0 5 10 15 20 25
CS-PM
Trattate con CS
PM-Fratture prevalenti
PM-Non fratture
Adami S et al. Reumatismo 2000; 52: 77-85
Conclusions:
• In RA vitamin D deficiency is quite common
• Disease activity and disability scores are inversely related to 25(OH)D levels
Zhao S et al. Rheumatology (Oxford) 2014; 53: 1595-603
Main Risk Factors for Incidence and Progression of Osteoarthritis of the Knees, Hips and Hands
Petersson IF, Jacobsson LT. Clinical Rheumatology 2002; 16: 741-60
Degree of evidence for association
Strong Intermediate Suggested
Incidence
Knee Age Vitamin D (?) Quadriceps strength (protective)
Female sex Smoking (protective) Intensive sport activities
Physical activity Alignment
High BMI
Bone density
Previous injury
HRT (protective)
Hip Age Physical activity Injury
High BMI Intensive sport activities
Hand Age Grip strength Occupation
High BMI Intensive sport activities
Progression
Knee Age Vitamin D Intensive sport activities
HRT
Alignment
Hip Age Physical activity High BMI
Intensive sport activities
ASSOCIATION BETWEEN SERUM LEVELS OF 25-(OH)D
AND OSTEOARTHRITIS: A SYSTEMATIC REVIEW
Cao Y et al. Rheumatology (Oxford) 2013; 52: 1323-34
CONCLUSION. 25-(OH)D appears to be implicated in
structural changes of knee OA rather than symptoms, and
further well-designed RCTs are required to determine
whether vitamin D supplementation can slow disease
progression. There is insufficient evidence for other sites.
THE IMMUNOMODULATORY EFFECTS OF 1,25(OH)2D3
Tc
Th
Th1
Th2
Th1
Th1
Th1
Th1
Th2
Th2
Treg
1,25(OH)2D3
IL-10
TGF-β
IL-4
IL-5
IL-10
IL-1
TNF-α
Free radicals
IL-2
IFN-
IL-12 Ag CD80/86
CD28/CTLA4 Ig
CD40 MCH II
DC
Mo
TCR
CD40L
target tissue
Van Etten E et al. J Steroid Biochem Mol Biol 2005; 97: 93-101
Th17 Th17
• modula la produzione e l’attività dei linfociti
• previene la overproduzione di CKs
• stimola la sintesi di immunoglobuline
• inibisce la produzione di MMPs e PG
CONCLUSIONI
• L’osso è coinvolto in corso di molte malattie reumatiche
• L’interessamento, localizzato o sistemico, è multifattoriale
• Numerosi sono i fattori di rischio comuni
• I meccanismi molecolari del coinvolgimento osseo oggi sono
molto meglio noti che in passato e rappresentano le basi per
un trattamento efficace dell’osteoporosi associata a malattie
reumatiche