Osteoporosis
A systemic disease characterised by low bone mass and structural deterioration of bone. A value for BMD (bone
mass density) that is more than 2.5 SD below the young adult mean value. High prevalence in post-menopausal
women - 2% at 50 years and 25% at 80 years in women.
Causes nearly 9 million fractures annually worldwide:
- Fragility fractures: caused by a fall from a standing height or less (commonly in the spine, hip and wrist)
- 300,000 fragility fractures in the UK each year
- Hip fractures are fatal in 20% of cases and permanently disables in 50% of cases
Bone cells
Osteoblasts = form bone matrix. Derived from mesenchymal cells. Metabolically active. Control osteocytes.
Osteocytes = maintain bone tissue. Lower metabolic activity. Connected by canaliculi (for nutrient diffusion and cell-
cell communication)
Osteoclasts = bone resorption. Very large. Contain lysosomes and mitochondria. Derived from mononuclear cells in
marrow.
Pathogenesis
Bone mass increases with age until it peaks in 20/30s. At ages of >50/60s the bone mass decreases due to genetics
(Wnt pathway), diet (low calcium), exercise (no loading), oestrogen (decrease by 90% post menopause), disease
(decreases calcium absorption) and drugs (corticosteroids).
Diagnosis
Bone mineral density is assessed using dual-energy x-ray absorptiometry – non-invasive, low radiation x-ray that can
discriminate between soft and mineralised tissues and is used to measure different skeletal sites to predict risk of
fracture at that site. Osteopenia = too little bone.
Therapies
Raloxifene targets oestrogen, decreases risk of vertebral fractures but increases risk of thromboembolism.
Calcitonin targets calcium homeostasis, limited efficacy, increases risk of cancer.
Biophosphates target osteoclasts, decrease vertebral and hip fractures (40-70%), atypical hip fractures,
osteonecrosis of jaw.
Denosunab targets osteoclasts, decreases vertebral (68%) and hip fractures (40%), also causes atypical hip fractures,
osteonecrosis of jaw as well as fast bone loss after withdrawal from drug.
Osteoprotegerin
A protein produced in the body, discovered in 1997 in a genomic screen. It is a decoy receptor which blocks RANK
ligand from binding to the osteoclast, preventing bone resorption. Denosumab mimics the action of OPG.
Bone remodelling
There is a chunk of bone that activates …
Freedom
A phase 3 trial which recruits post-menopausal women with osteoporosis. They are given 60 mg of denosumab
subcutaneously, or a placebo, every 6 months for 3 years. 7-year extension with long-term (10 years total of
denosumab) and cross-over group (7 years total of denosumab). Aim: examine safety monitoring and efficacy.
Conclusion: 7-10 years of treatment reduces fracture, increases in BMD without a plateau and no adverse effects.
Osteonecrosis
Osteonecrosis of the jaw is a painful, non-healing wound that exposes the jaw leaving it susceptible to breaks.
Occurs in 1-15% of cancer patients on high dose bisphosphonates/denosumab. ~0.001% in OP patients treated with
denosumab.
Treatment
Parathyroid hormone (PTH) is a peptide hormone, stimulates bone formation, then resorption, with a balance in
favour of formation. Risks include hypercalcaemia, osteosarcoma (rats). Further problems are expense and delivery.
Sclerosteosis
A rare, autosomal recessive disorder where skeletal overgrowth occurs causing intercranial pressure which can cause
sudden death.
Van Buchem
A rare, autosomal recessive disorder causing skeletal growth causing thickening of the skull, ribs, long bones. Exon
prediction software determined the gene - SOST
SOST
,High bone mass associated with the dysfunctional SOST gene – possibility for treatment. SOST encodes the
glycoprotein sclerostin with distant homology with BMP antagonists = Inhibits bone formation.
Hypothesis = Unloading increases osteocyte sclerostin and decreases bone mass. Knockout mice with no sclerostin
were protected against unloading-induced bone loss. Sclerostin antibody increased bone volume and bone
formation.
, Osteoarthritis
Osteoarthritis = progressive loss of articular cartilage + new bone formation and often synovial proliferation that may
culminate in pain, loss of joint function and disability. (Wear and tear)
- Primary form = old age
- Secondary form = previous joint injury
Effects the entire joint including meniscus and ligaments. Commonly effects knees, hips, hands, and spine. NOT
ankles.
OA initiated by multiple factors: Genetics, traumatic, metabolic, developmental (e.g. walking with toes in). Different
causes but the same biologic, morphologic and clinical outcomes. OA is a phenotypic manifestation of a number of
different pathways leading to a common end-stage pathology.
Statistics
Sought treatment for OA: ~8.75million people aged >45 and >33% of the UK.
This number will increase due to ageing population and increasing obesity.
97% of initial knee replacements are due to OA.
91% of initial hip replacements are due to OA.
No current cure or disease-modifying drugs for OA (DMOAD). Total replacement is only option.
Causes: Obesity. Age. Overuse. Trauma (PTOA). Deformity. Instability (abnormal forces). Genetic
predisposition. Infection. Crystal deposition (gout).
Articular cartilage composition
Water – 70%
Collagens – 20%
Proteoglycans – 7%
Cells – 2% (Hypocellular = small proportion of cells compared to the extracellular content)
Other proteins – 1%
Type II collagen – 94%: Major fibrillar collagen that provides tensile strength.
Aggrecan: Responsible for compressive stiffness of AC. Bottle brush features of aggrecan are what attract water into
the tissue and give it the ability to deform reversibly.
HIFα: Articular cartilage is not vascular = low oxygen environment, so you need transcription factor HIFα to maintain
the phenotype in these conditions.
Postnatal AC: Cellular organisation + tissue height reduction occurs after load bearing begins at a young
age. Once maturity is reached, chondrocytes do not divide again unless pathology occurs. Healthy cartilage retains
the same cell number.
Chondrocyte phenotypes: Immature, hypertrophic, and articular (permanent) cartilage .
1. Immature phenotype = Chondroblast (collagen IIA). Can differentiate into 2 other forms.
2. Permanent (articular) cartilage = Chondrocyte (collagen IIB). Makes the end of long bones.
3. Hypertrophic = chondrocyte (collagen X). Seen in growth plates and eventually leads to endochondral
ossification.
AC and OA
In OA, biosynthetic anabolic activity is unable to keep pace with the
degradative catabolic activity and degeneration of the tissue results.
Why does this happen?
- abnormal distribution forces in cartilage leads to altered mechanotransduction in the chondrocytes and
subsequent activation of catabolic and inflammatory genes, deregulated cartilage matrix synthesis +
structural and functional changes to the periarticular bone.
Not always caused by age - There is a reduction in height of AC in older people – however, Old age ≠ OA.
Why is it bad to lose cartilage?
A systemic disease characterised by low bone mass and structural deterioration of bone. A value for BMD (bone
mass density) that is more than 2.5 SD below the young adult mean value. High prevalence in post-menopausal
women - 2% at 50 years and 25% at 80 years in women.
Causes nearly 9 million fractures annually worldwide:
- Fragility fractures: caused by a fall from a standing height or less (commonly in the spine, hip and wrist)
- 300,000 fragility fractures in the UK each year
- Hip fractures are fatal in 20% of cases and permanently disables in 50% of cases
Bone cells
Osteoblasts = form bone matrix. Derived from mesenchymal cells. Metabolically active. Control osteocytes.
Osteocytes = maintain bone tissue. Lower metabolic activity. Connected by canaliculi (for nutrient diffusion and cell-
cell communication)
Osteoclasts = bone resorption. Very large. Contain lysosomes and mitochondria. Derived from mononuclear cells in
marrow.
Pathogenesis
Bone mass increases with age until it peaks in 20/30s. At ages of >50/60s the bone mass decreases due to genetics
(Wnt pathway), diet (low calcium), exercise (no loading), oestrogen (decrease by 90% post menopause), disease
(decreases calcium absorption) and drugs (corticosteroids).
Diagnosis
Bone mineral density is assessed using dual-energy x-ray absorptiometry – non-invasive, low radiation x-ray that can
discriminate between soft and mineralised tissues and is used to measure different skeletal sites to predict risk of
fracture at that site. Osteopenia = too little bone.
Therapies
Raloxifene targets oestrogen, decreases risk of vertebral fractures but increases risk of thromboembolism.
Calcitonin targets calcium homeostasis, limited efficacy, increases risk of cancer.
Biophosphates target osteoclasts, decrease vertebral and hip fractures (40-70%), atypical hip fractures,
osteonecrosis of jaw.
Denosunab targets osteoclasts, decreases vertebral (68%) and hip fractures (40%), also causes atypical hip fractures,
osteonecrosis of jaw as well as fast bone loss after withdrawal from drug.
Osteoprotegerin
A protein produced in the body, discovered in 1997 in a genomic screen. It is a decoy receptor which blocks RANK
ligand from binding to the osteoclast, preventing bone resorption. Denosumab mimics the action of OPG.
Bone remodelling
There is a chunk of bone that activates …
Freedom
A phase 3 trial which recruits post-menopausal women with osteoporosis. They are given 60 mg of denosumab
subcutaneously, or a placebo, every 6 months for 3 years. 7-year extension with long-term (10 years total of
denosumab) and cross-over group (7 years total of denosumab). Aim: examine safety monitoring and efficacy.
Conclusion: 7-10 years of treatment reduces fracture, increases in BMD without a plateau and no adverse effects.
Osteonecrosis
Osteonecrosis of the jaw is a painful, non-healing wound that exposes the jaw leaving it susceptible to breaks.
Occurs in 1-15% of cancer patients on high dose bisphosphonates/denosumab. ~0.001% in OP patients treated with
denosumab.
Treatment
Parathyroid hormone (PTH) is a peptide hormone, stimulates bone formation, then resorption, with a balance in
favour of formation. Risks include hypercalcaemia, osteosarcoma (rats). Further problems are expense and delivery.
Sclerosteosis
A rare, autosomal recessive disorder where skeletal overgrowth occurs causing intercranial pressure which can cause
sudden death.
Van Buchem
A rare, autosomal recessive disorder causing skeletal growth causing thickening of the skull, ribs, long bones. Exon
prediction software determined the gene - SOST
SOST
,High bone mass associated with the dysfunctional SOST gene – possibility for treatment. SOST encodes the
glycoprotein sclerostin with distant homology with BMP antagonists = Inhibits bone formation.
Hypothesis = Unloading increases osteocyte sclerostin and decreases bone mass. Knockout mice with no sclerostin
were protected against unloading-induced bone loss. Sclerostin antibody increased bone volume and bone
formation.
, Osteoarthritis
Osteoarthritis = progressive loss of articular cartilage + new bone formation and often synovial proliferation that may
culminate in pain, loss of joint function and disability. (Wear and tear)
- Primary form = old age
- Secondary form = previous joint injury
Effects the entire joint including meniscus and ligaments. Commonly effects knees, hips, hands, and spine. NOT
ankles.
OA initiated by multiple factors: Genetics, traumatic, metabolic, developmental (e.g. walking with toes in). Different
causes but the same biologic, morphologic and clinical outcomes. OA is a phenotypic manifestation of a number of
different pathways leading to a common end-stage pathology.
Statistics
Sought treatment for OA: ~8.75million people aged >45 and >33% of the UK.
This number will increase due to ageing population and increasing obesity.
97% of initial knee replacements are due to OA.
91% of initial hip replacements are due to OA.
No current cure or disease-modifying drugs for OA (DMOAD). Total replacement is only option.
Causes: Obesity. Age. Overuse. Trauma (PTOA). Deformity. Instability (abnormal forces). Genetic
predisposition. Infection. Crystal deposition (gout).
Articular cartilage composition
Water – 70%
Collagens – 20%
Proteoglycans – 7%
Cells – 2% (Hypocellular = small proportion of cells compared to the extracellular content)
Other proteins – 1%
Type II collagen – 94%: Major fibrillar collagen that provides tensile strength.
Aggrecan: Responsible for compressive stiffness of AC. Bottle brush features of aggrecan are what attract water into
the tissue and give it the ability to deform reversibly.
HIFα: Articular cartilage is not vascular = low oxygen environment, so you need transcription factor HIFα to maintain
the phenotype in these conditions.
Postnatal AC: Cellular organisation + tissue height reduction occurs after load bearing begins at a young
age. Once maturity is reached, chondrocytes do not divide again unless pathology occurs. Healthy cartilage retains
the same cell number.
Chondrocyte phenotypes: Immature, hypertrophic, and articular (permanent) cartilage .
1. Immature phenotype = Chondroblast (collagen IIA). Can differentiate into 2 other forms.
2. Permanent (articular) cartilage = Chondrocyte (collagen IIB). Makes the end of long bones.
3. Hypertrophic = chondrocyte (collagen X). Seen in growth plates and eventually leads to endochondral
ossification.
AC and OA
In OA, biosynthetic anabolic activity is unable to keep pace with the
degradative catabolic activity and degeneration of the tissue results.
Why does this happen?
- abnormal distribution forces in cartilage leads to altered mechanotransduction in the chondrocytes and
subsequent activation of catabolic and inflammatory genes, deregulated cartilage matrix synthesis +
structural and functional changes to the periarticular bone.
Not always caused by age - There is a reduction in height of AC in older people – however, Old age ≠ OA.
Why is it bad to lose cartilage?
