13Bone loss in inflammatory arthritis: mechanisms and therapeutic approaches with bisphosphonates
Section snippets
What is the effect of synovial inflammation on bone?
Rheumatoid arthritis is accompanied by three types of bone loss: (1) focal articular bone erosion; (2) juxta-articular osteopenia adjacent to inflamed joints; and (3) systemic osteoporosis.1 This bone loss is attributed to fundamental alterations in bone remodelling that result in disturbed bone homeostasis to favour bone resorption over bone formation.2 It is clear that radiographic joint destruction is strongly associated with systemic osteoporosis.3, 4 Therefore, these types of bone loss are
What is the molecular basis of bone loss in RA?
Over 20 years ago, Bromley and Woolly described a ‘bi-directional attack’ on the joint, whereby pannus drives ‘outside-in’ erosions and osteoclast cutting cones arising in the bone marrow erupt through the subchondral bone to cause ‘inside-out’ erosions.29, 30 The MRI morphology of bone lesions in RA, which are always associated with synovitis, yet not always characterized by ‘outside-in’ breaches of cortical bone, apparently supports this hypothesis.10, 11, 12, 31 Until very recently, the
Targeting osteoclasts in inflammatory arthritis
The most obvious drugs to invoke for bone protection in arthritis are bisphosphonates (BPs). Chemically, the BPs are analogues of inorganic pyrophosphate in which an oxygen atom has been replaced with a carbon atom. The resulting phosphate-carbon-phosphate moiety confers a unique high-affinity binding property of BPs to hydroxyapatite mineral, generating high local concentrations of drug on bone surfaces where these agents can preferentially interfere with osteoclast-mediated bone resorption.55
Summary
Bone erosion is a prognostic turning point for patients with RA. The link between the inflammatory disease process and all types of bone loss in RA is indisputable. Tumour necrosis factor is a pivotal cytokine for inflammatory synovitis and promotes bone loss in many ways. In the presence of permissive amounts of RANKL, TNF-α drives massive osteoclast recruitment which results in local and systemic bone resorption. Targeting osteoclasts directly is a logical approach. The investigation of
Acknowledgements
This work was funded by The National Health and Medical Research Council (Project Grant: 247909).
References (81)
- et al.
Bone biology
Baillieres Clinical Endocrinology and Metabolism
(1997) - et al.
Generalised bone loss in patients with early rheumatoid arthritis occurs early and relates to disease activity
Lancet
(1994) - et al.
Involvement of receptor activator of NFkappaB ligand and tumor necrosis factor-alpha in bone destruction in rheumatoid arthritis
Bone
(2002) - et al.
Activated T lymphocytes support osteoclast formation in vitro
Biochemical and Biophysical Research Communications
(1999) - et al.
Osteoprotegerin reduces osteoclast numbers and prevents bone erosion in collagen-induced arthritis
The American Journal of Pathology
(2002) - et al.
TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis
The American Journal of Pathology
(2001) - et al.
Bisphosphonates: from the laboratory to the clinic and back again
Bone
(1999) - et al.
Differentiating the mechanisms of antiresorptive action of nitrogen containing bisphosphonates
Bone
(2003) - et al.
Mechanisms of bone loss in inflammatory arthritis: diagnosis and therapeutic implications
Arthritis Research
(2000) - et al.
Radiographic joint destruction in postmenopausal rheumatoid arthritis is strongly associated with generalised osteoporosis
Annals of the Rheumatic Diseases
(2003)
The skeleton in rheumatoid arthritis: common mechanisms for bone erosion and osteoporosis?
The Journal of Rheumatology
Anti-cyclic citrullinated peptide antibodies are highly associated with severe bone lesions in rheumatoid arthritis
Autoimmunity
The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis
Arthritis and Rheumatism
Prognostic factors and diagnostic criteria in early rheumatoid arthritis
Scandinavian Journal of Rheumatology
Joint erosions and patients with early rheumatoid arthritis
British Journal of Rheumatology
Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals a high prevalence of erosion at four months after symptom onset
Annals of the Rheumatic Diseases
New radiographic bone erosions in the wrists of patients with rheumatoid arthritis are detectable with magnetic resonance imaging a median of two years earlier
Arthritis and Rheumatism
Bone edema scored on magnetic resonance imaging scans of the dominant carpus at presentation predicts radiographic joint damage of the hands and feet six years later in patients with rheumatoid arthritis
Arthritis and Rheumatism
The relationship between synovitis and bone changes in early untreated rheumatoid arthritis. A controlled magnetic resonance imaging study
Arthritis and Rheumatism
A preliminary study of ultrasound aspiration of bone erosion in early rheumatoid arthritis
Rheumatology
Osteoclast differentiation and activation
Nature
Assessing periarticular bone mineral density in patients with early psoriatic arthritis or rheumatoid arthritis
Annals of the Rheumatic Diseases
Peripheral bone density in patients with rheumatoid arthritis and factors which influence it
European Journal of Internal Medicine
Quantitative histologic studies on the pathogenesis of periarticular osteoporosis in rheumatoid arthritis
Arthritis and Rheumatism
Bone mass in patients with rheumatoid arthritis
Annals of the Rheumatic Diseases
Cross-sectional and longitudinal study of osteoporosis in patients with rheumatoid arthritis
Clinical Rheumatology
Determinants of axial bone loss in rheumatoid arthritis
Arthritis and Rheumatism
A multicenter cross-sectional study on bone mineral density in rheumatoid arthritis
The Journal of Rheumatology
Bone mineral density and frequency of osteoporosis in female patients with rheumatoid arthritis: results from 394 patients in the Oslo County Rheumatoid Arthritis register
Arthritis and Rheumatism
Prevalence of vertebral deformities and symptomatic vertebral fractures in corticosteroid treated patients with rheumatoid arthritis
Rheumatology (Oxford)
Osteoclastic activation is the principal mechanism leading to secondary osteoporosis in rheumatoid arthritis
The Journal of Rheumatology
Markers of bone metabolism in postmenopausal women with rheumatoid arthritis. Effects of corticosteroids and hormone replacement therapy
Arthritis and Rheumatism
Urinary cross-linked N-telopeptides of type I collagen levels in patients with rheumatoid arthritis
Calcified Tissue International
Excretion of pyridinium crosslinks correlates with disease activity and appendicular bone loss in early rheumatoid arthritis
Annals of the Rheumatic Diseases
Chondroclasts and osteoclasts at subchondral sites of erosion in the rheumatoid joint
Arthritis and Rheumatism
Bidirectional erosion of cartilage in the rheumatoid knee joint
Annals of the Rheumatic Diseases
Elucidation of the relationship between synovitis and bone damage: a randomized magnetic resonance imaging study of individual joints in patients with early rheumatoid arthritis
Arthritis and Rheumatism
Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis
Endocrine Reviews
Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor
Arthritis and Rheumatism
Involvement of receptor activator of nuclear factor kappaB ligand/ osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis
Arthritis and Rheumatism
Cited by (55)
High water-soluble curcuminoids-rich extract regulates osteogenic differentiation of MC3T3-E1 cells: Involvement of Wnt/β-catenin and BMP signaling pathway
2021, Chinese Herbal MedicinesCitation Excerpt :Anti-resorptive agents that inhibit osteoclastic bone resorption and anabolic agents that stimulate osteoblastic bone formation, have been used to treat such a disease. Anti-resorptive agents such as bisphosphonates, selective estrogen receptor modulators and calcitonin are currently available for the treatment of osteoporosis (Romas, 2005). However, these anti-resorptive agents have disadvantages, such as causing unusual fractures in the femur and shaft of the bone and causing flu-like symptoms (Feldbrin Luckish, & Shargorodsky, 2016).
Effects of targeted therapies on the bone in arthritides
2017, Autoimmunity ReviewsCitation Excerpt :Increased inflammation as measured by CRP level and mechanistically pro-inflammatory cytokines and activation of the RANK-RANKL axis have been implicated in the development of secondary osteoporosis. OPG not only inhibits formation of local bone erosions, but in human TNF-transgenic mice it protected against systemic bone loss [1,2,159–161]. Certainly, traditional risk factors, such as female sex, postmenopausal age, physical inactivity, low vitamin D levels and corticosteroid intake may also be involved in the development of secondary osteoporosis [1,2].
Targeted delivery to bone and mineral deposits using bisphosphonate ligands
2016, Advanced Drug Delivery ReviewsCitation Excerpt :In some cases, targeted delivery reduced systemic toxicity compared with the free drug and/or free BP [96,104,109]. Inflammatory bone diseases include osteomyelitis, which is an infection in the bone that causes an inflammatory response and bone necrosis [110], and rheumatoid arthritis, which is an autoimmune disorder that can eventually lead to bone erosion [111]. Both of these diseases must be treated with large doses of pharmaceuticals in order to deliver a sufficient amount to the bone [112].
Osteoclasts in RA: Diverse origins and functions
2013, Joint Bone SpineCitation Excerpt :The close interactions between osteoclasts and immune cells underlined in this review may open up new avenues of research aimed at elucidating the direct effects of DMARD on osteoclastogenesis. Bisphosphonates are the osteoclast-targeting drugs that have been the most extensively studied in RA [58]. The antiresorptive effect and potential extraosseous effects (inhibition of inflammation and angiogenesis) provide a rationale for bisphosphonate therapy in RA [59].
Osteoclasts in rheumatoid arthritis: Heterogeneity of their origins and functions
2013, Revue du Rhumatisme (Edition Francaise)