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