The effect of age on bones and joints: Osteoporosis and Osteoarthritis Flashcards
1
Q
What is osteoarthritis?
A
- Not a single disease
- Heterogeneous group of disorders with similar pathological and radiological features
- Characterised by degeneration of articular cartilage, remodelling of subchondral bone and formation of osteophytes
- Clinical and pathological expression of ‘joint failure’ in response to a variety of aetiological factors
2
Q
Describe the epidemiology of OA
A
- Commonest type of arthritis
- Major cause of musculo-skeletal pain & mobility disability in the elderly
- Up to 40% of those over 65 years in some communities have symptoms associated with knee or hip OA
3
Q
What are the primary classifications of OA?
A
- localised
- generalised (often nodal in post menopausal women)
4
Q
What are the secondary classifications of OA?
A
- Developmental (hip dysplasia, slipped epiphysis)
- Traumatic (intra-articular fracture, menisectomy, occupational, hypermobility)
- Metabolic (alkaptonuria, haemachromatosis, Paget’s)
- Endocrine (acromegaly)
- Inflammatory (RA, gout, haemophilia, joint sepsis)
- Aseptic necrosis (corticosteroids, sickle-cell disease)
- Neuropathic (diabetes, syringomyelia, tabes dorsalis)
5
Q
What are the signs and symptoms of OA?
A
- Pain- worse on use of joint
- Stiffness- mild in morning, severe after immobility
- Loss of movement
- Pain on movement/ restricted range
- Tenderness (articular or periarticular)
- Bony swelling
- Soft tissue swelling
- Joint crepitus
- Heberden’s nodes (distal), Bouchard’s nodes (proximal) in fingers
6
Q
What are the radiological features of OA?
A
- Narrowing of joint space
- Osteophytosis
- Altered bone contour
- Bone sclerosis and cysts
- Periarticular calcification
- Soft tissue swelling
7
Q
How do we differentiate OA from RA?
A
OA
-Distribution (DIP and PIP)
-Bony swelling
-Limited stiffness
RA
-Distribution (MCP, PIP, carpal bones, spares DIP)
-Soft tissue swelling
-Stiffness permanent
-Symptoms and signs of systemic inflammation
-Serology
-Erosions, without osteophytes or sclerosis
8
Q
Describe the pathology of OA affecting all joint tissues
A
- Thickened capsule
- Cyst formation and sclerosis in subchondral bone
- Shelving ‘fibrillated’ cartilage
- Osteophytic lipping
- Synovial hypertrophy
- Altered contour of bone
9
Q
Which joints develop OA?
A
- Spine> DIPJ> Knee> Hip
- Prevalence of OA increases with age at all sites
- Common: cervical and lumbar spine, hip, knee, distal and proximal interphalangeal, carpometa-carpophalangeal, first metatarsophalangeal
- Uncommon: temporomandibular, sternoclavicular, shoulder, ankle, midtarsal, talocalcaneal
10
Q
What risk factors lead to a susceptible joint so an increased risk of incident OA?
A
Modifiable Local Risk Factors
- Muscle strength
- Physical activity/ occupation
- Joint injury
- Joint alignment
- Leg length inequality
11
Q
What are the risk factors that lead to a predisposed individual so an increased risk of incident OA?
A
Modifiable Systemic Risk Factors: -Obesity -Diet -Bone metabolism Non-modifiable Systemic Risk Factors: -Age -Sex -Genetics -Ethnicity
12
Q
Describe the key pathways that promote pathologic remodelling of cartilage
A
- Inflammation= changes to subchondral bone + osteophytes, cytokine enzymes= cartilage damage so OA
- Altered biomechanics= changes to subchondral bone + osteophytes, cartilage damage so OA
13
Q
Describe the ways to enter the cycle/ key pathways
A
- Prior inflammatory arthritis, joint injury= inflammation
- Cytokine enzymes= abnormal lubrication= cartilage damage (+joint injury)
- Joint injury, dysplasia, malalignment= altered biomechanics
14
Q
What are catabolic factors?
A
Increases degradation, decrease synthesis -IL-1, IL-6 -IL-7, IL-8 -TNFa, TGFa -Nitric oxide/ ROS -IL-17, IL-18, LIF -Oncostatin M -bGFG S100 proteins -Matrix fragments
15
Q
What are anabolic factors?
A
Increase synthesis, decrease degradation
- IGF-1
- OP-1 (BMP-7)
- TGFb
- IL-4
- BMP-2, CDMPs
16
Q
What are other factors leading to OA?
A
Increased:
- MMPs (matrix metalloproteinases)
- Aggrecanases, other proteases
- Hypertrophic phenotype (type X collagen, MMP-13)
17
Q
What biological processes are enriched for OA-associated genes?
A
- Transcriptional regulation
- Hyaluronan and aminoglycan metabolic processes
- Osteoblast development and differentiation
- Chondrocyte development and differentiation
- Cell proliferation and differentiation
- Regulation of apoptosis
- Skeletal development and morphogenesis
18
Q
What are OA GWAS studies?
A
- Point to genes in a number of biological pathways and to transcriptional regulators
- Genes for structural proteins not apparently contributing to susceptibility
- Account for only a small fraction of disease hereditability
19
Q
Why do genes account for only a small fraction of disease hereditability?
A
- Poor definition of clinical phenotypes
- Low penetrance polymorphisms
- Inheritance of epigenetic modifications
20
Q
Describe the cycle that leads to OA presentation
A
-Abnormal stress
-Abnormal cartilage
CAUSES
-Chondrocyte apoptosis
-Collagen fibril damage
-Loss of proteoglycans
LEADS TO
-Cartilage fibrillation
-Osteophyte formation
-Subchondral bone sclerosis
21
Q
What causes abnormal stress?
A
- Genetic
- Trauma
- Dysplasia
- Obesity
- Malalignment
- Muscle weakness
- Loss of proprioception
22
Q
What causes abnormal cartilage?
A
- Genetic
- Ageing
- Inflammation
- Metabolic changes
- Endocrine factors
23
Q
Describe the biochemical cartilage changes in experimental canine OA in weeks 1-4
A
- Increased hydration
- Proteoglycans more easily extracted
- Smaller PG subunits
- Increase in PG synthesis
- Increase in collagen synthesis
24
Q
Describe the biochemical cartilage changes in experimental canine OA in weeks 8-16
A
- Changes in PG structure
- Longer CS chains
- Increased expression CS epitopes
- Loss of PG’s
25
Describe the histological cartilage changes in experimental canine OA in weeks 1-4
- Disruption superficial collagen
- EM changes in chondrocytes
- Increase in cellular lipids
- Angiogenesis
- Early osteophyte formation
26
Describe the histological cartilage changes in experimental canine OA in weeks 8-16
- Chondrocyte cell division
- Loss of safranin-O
- Fibrillation
27
What are the differences in the biochemical properties of normal ageing and osteoarthritic cartilage?
- Keratan sulphate: A= increased, O= decreased
- Water: A= decreased, O= increased
- Protein/ uronate: A= increased, O= decreased
- Extractability of proteoglycans: A= decreased, 0= increased
28
What causes increased stress on cartilage?
Insufficiently protected impulsive loading:
- Cartilage damage= loss of force distribution
- Bone changes, microfracture stiffening= loss of shock absorption
29
What are the age-related physiological changes contributing to the development of OA?
- Decline in proprioception
- Decrease in muscle strength (sarcopenia)
- Changing shape of bones (hip and CMC joint of thumb)
30
What are the cellular and molecular hallmarks of ageing?
- Genomic instability
- Telomere attrition
- Epigenetic changes
- Loss of proteostasis
- Dysregulated nutrient sensing
- Mitochondrial dysfunction
- Cellular senescence
- Stem cell exhaustion
- Altered intercellular communication
31
What does 'infammageing' lead to?
- Cognitive decline, mental health and well-being
- Altered body composition and loss of mobility
- Immune decline and increased susceptibility to infections
- Cancer
- Atherosclerosis and vascular disease
- Insulin resistance and type 2 diabetes
32
What are the age-related changes in matrix molecule metabolism?
- Decreased type 2 collagen turnover
- Decreased aggrecan turnover
- Accumulation of glycation end products
- Cleavage products of matrix molecule (fibronectin)
- Decreased antioxidant defences
33
What is chondrocyte cellular senescence?
-Decreased mitotic activity
-Increased beta galactosidase
-Increased epigenetic hypermethylation
-Decreased telomere length
(Can be reversed experimentally by transfection of human telomere genes)
34
What are the aims of treatment for OA?
- Reducing pain and stiffness
- Maintaining/ improving joint mobility
- Reducing physical disability/ handicap
- Improving health-related quality of life
- Limiting progression of joint damage
- Educating about the nature of OA and its management
35
Describe the management of OA
- >50 modalities non-pharmacological, pharmacological and surgical therapy
- Few areas of medicine where clinicians have a greater need for balanced, impartial evidence-based advice
36
What are the international treatment recommendations for OA?
-Non-pharmacological= education, self-management, weight loss, regular telephone contact, aerobic, muscle strengthening and water based exercises; referral to a physical therapist and use of a stick, shoe insoles and knee braces
-Pharmacological= paracetamol, topical and oral NSAIDs (both non-selective with misoprostol/PPi and selective COX-2), duloxetine, topical capsaicin and IA steroids
-Surgical= joint replacements, osteotomy, knee fusion, knee aspiration and debridement in case of locking
+ combination of non-pharmacological and pharmacological modalities
37
What is the stepwise algorithm for the management of patients with OA?
Severity of symptoms= mild to severe
1. Non-pharmacological management (education, exercise, weight loss, appropriate footwear)
2. Non-pharmacological management (physiotherapy, braces, and begin pharmacological treatment with simple analgesics; paracetamol)
3. Pharmacological management (NSAIDs, opioids, if effusion present= aspirate and inject)
4. Surgery (osteotomy, total joint replacement)
38
What are the current approaches to try to develop a disease-modifying drug (DMOAD) for OA?
- Aggrecanase (ADAMTS 4,5) inhibitors
- MMP inhibitors
- Pro-inflammatory cytokine inhibitors
- Bisphosphonates
- Calcitonin
- iNOS inhibitors
- Strontium ranelate
- Cathepsin K inhibitors
- Selective oestrogen-receptor modulators (SERMS)
- PTH and analogues
- Bone morphogenetic proteins (BMPs)
- Sprifermin (recombinant human FGF 18)
39
What is osteoporosis?
Systemic skeletal disease, characterised by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture
40
What are the common osteoporotic fractures?
- Wrist
- Spine
- Hip
41
What does osteoporosis present with?
- Back pain
- Thoracic kyphosis
- Loss of height
- Fractures
42
What is the cumulative lifetime risk in 50 year old Caucasian woman?
Forearm 15%
Hip 16%
Vertebrae 32%
(1 in 3 women, 1 in 12 men)
43
What are the phases of bone remodelling?
- Resting (lining cell)
- Resorption (osteoclast)
- Formation (osteoblast, osteoid)
- Resting
44
What are the causes of age-related bone loss?
- Decreased bone formation
- Increased bone resorption
- Increased sensitivity to PTH and hydroxy vitamin D in the absence of oestrogens
45
What are the modifiable risk factors for osteoporosis?
- Oestrogen deficiency syndromes (premature menopause= idiopathic, surgical oophorectomy, hysterectomy/ amenorrhoea= athletes, anorexia nervosa, prolactinoma)
- Smoking
- Alcohol abuse
- Prolonged immobilisation and inactivity
- Some drugs like corticosteroids
- Nutritional factors= low calcium and vitamin D intake
- Certain diseases= hyperparathyroidism, Cushing's
- Low body mass index
- Susceptibility to falls
46
What are the non-modifiable risk factors for osteoporosis?
- Age
- Nulliparity
- Race (Caucasian or Asian)
- Positive family history
- Prior fragility fracture
- Short stature for small bone
47
What does the WHO fracture risk assessment tool measure?
- Country
- Bone mineral density
- Age
- Gender
- Clinical risk factors= low body mass index, previous fragility fracture, parental history of hip fracture, glucocorticoid treatment, current smoking, alcohol intake (3+ units per day), RA, other secondary causes of osteoporosis
48
What are the approaches to the prevention and treatment of osteoporotic fractures?
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-Lifestyle Modification
=Diet, Exercise
=Smoking, Alcohol
=Muscle tone & muscle strength
=Falls prevention
-Drug treatments that affect bone
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49
What are the Antiresorptive drug treatments for osteoporosis?
```
-Bisphosphonates
=Alendronate (Fosamax)
=Risedronate (Actonel)
=Ibandronate (Bonviva)
=Zoledronate (Aclasta)
-HRT
-Calcitonin
-Raloxifene (Evista)
-Strontium (Protelos)
-Denosumab (Prolia)
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50
What are the Anabolic drug treatments for osteoporosis?
```
-Parathyroid Hormone
=Teriparatide (1-34)
=Abaloparatide
=Preotact ( 1-84)
-Strontium?
-Anti sclerostin antibody
=Romosozumab
-Nutritional supplements
=Calcium and Vitamin D
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