Week 5

Question 1

Bone matrix includes

Answer 1

1. Osteoid (35%)
   -type 1 collagen
   -smaller amounts of glycosaminoglycans
   -other proteins
   - e.g., calcium-binding proteins, osteonectin, cell adhesion proteins, osteopontin, cytokines (RANKL)
2. Mineral component (65%)
   -hydroxyapatite
   -99% body’s calcium
   -85% of body’s phosphorus

Question 2

bone remodelling

Answer 2

bone is dynamic, constantly turning over (i.e. remodelling) to maintain the structural, biochemical and biochemical integrity.

• 10% if bone is replaced annually

-cortical bone: makes sup 80% of skeletal mass, but only accounts for small proportion of total bone turnover

-cancellous bone: represents 20% of skeletal mass, but due to large surface to mass ratio, accounts for much greater proportion (80%) of bone turnover.

Question 3

RANKL, RANK, AND OPG pathway

Answer 3

RANKL is a mmember of the tumour necrosis factor TNF, cytokine family.

binds to RANK which is expressed on osteoclast precursors

RANKL is a key factor for osteoclast differentiation and activation.

Question 4

regulators of bone remodelling includes systemic regulation and local regulation

Answer 4

systemic regulation:
-growth hormone
-PTH and vitamin D
-thyroxine
-cortisol
-oetrogens
-androgens
-calcitonin

local regulation:
-mechanical forces
-RANK/RANKL
-osteoprotegrin (OPG)
- M-CSF
-Sclerostin
-dickkopf-related protein 1 (DKK-1)
-insulin- like growth factor-1 (IGF-1)

Question 5

osteoporosis

Answer 5

a systenic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fractures.

it is chronic and progressive; multifactorial aetiology

often does not become clinically apparent until a fracture occurs

most common metabolic bone disease in Australia

may result in devastating physical and economic consequences and premature death

Question 6

osteomalacia and rickets

Answer 6

osteomalacia affects adults while rickets affects children

aetiology: usually due to vitamin D deficiency, but can also result from low phosphate levels, certain medications, or genetic disorders

pathogenesis: vitamin d deficiency reduces calcium absorption, leading to soft and weakened bones

clinical features:
rickets: bone pain, delayed growth, bowed legs, and skeletal defromities

osteomalacia: bone pain, muscle weakness, and fractures

diagnosis: blood tests ( low calcium, phosphate, vitamin D levels), x ray and sometimes bone biopsy

complications: bone deformities in children rickets, and frequent fractures in adults

Question 7

pagets disease of bone

Answer 7

overview: a chronic disorder with abnormla bone remodeling, where bones become enlarged an structurally weak

aetiology: unknown though geentc factors and possibly viral infections are through to contribute

pathogenesis: accelerated bone turnover results in disorganised boen formation, leading to enlarged and softened bones

clinical features: bone pain, deformities (e.g. bowed legs), increased warmth over affected bones, and fractures. it most commonly affects the pelvis, spine, skull,a nd long bones of the legs.

diagnosis: elevated alkaline phosphatase levels in blood, x -rays,a nd sometimes boen scans.

complications: increased risk of fractures, arthritis, nerve compression, and in rare cases, bone cancers.

Question 8

Hyperparathyroidism and secondary hyperparathyroidism

Answer 8

overview: excessive secretion of parathyroid hormone (PTH), which regulates calcium levels in the blood

aetiology: primary hyperparathyroidism often results from a parathyroid adenoma. secondary hyperparathyroidism is usually due to chronic kidney disease or vitamin D deficiency.

pathogenesis: excess PTH leads to increased bone resorption, causing loss of bone density.

clinical features: bone pain, muscle weakness, kidney stones, and in severe cases, skeletal deformities.

diagnosis: high PTH levels, hypercalcemia, andimaging may reveal characteristic bone changes.

complications: osteoporosis, fractures, and in chroniccases severe skeletal abnormalities

Question 9

with agiing youre at an increased of osteoporosis because

Answer 9

there is decreased replicative activity of osteoprogenitor cells

decreased synthetic activity of osteoblasts

decreased biological activity of matrix-bound growth factors

reduced physicla activity

Question 10

RANKL/RANK/OPG pathway is crucial for bone metabolism and involves

Answer 10

1. RANKL: this a member of the tumor necrosis factor TNF cytokine family. it is produced by osteoblasts (cell formation) and stromal cells and plays avital role in bone remodeling by promoting the formation, function, and survival of osteoclasts.
2. RANK is a receptor expressed on the surface of osteoclast precursors. when RANKL binds to RANK, it triggers the differentiation and activation of osteoclast (bone resorption)
3. OPG (Osteoprotegerin): OPG is a decoy receptor produced by osteoblasts and stromal cells. it binds to RANKL, preventing it from interacting with RANK. this inhibition is crucial for regulating bone resorption and painting bone density.

Question 11

menopause increases the risk of osteoporosis because

Answer 11

there is decreased serum estrogen

increased IL-1, IL-6, TNF levels

increased expression of RANK, RANKL

increased osteoclast acitvity

Question 12

RANKL binds to RANK

Answer 12

this interaction is essential for the differentiation and activation of osteoclasts, leading to bone resorption

Question 13

OPG inhibits RANKL

Answer 13

by binding to RANKL, OPG prevents it from interacting with RANK, thereby inhibiting osteoclast formation and activity.

Question 14

Bone specific alkaline ALP is an enzyme…..

Answer 14

found in the blood, that is produced by the osteoblasts (bone formation)

Question 15

Basic Multicellular UNit BMU, or Bone remodeling unit BRU, here is how it works

Answer 15

1. Activation: the process begins with the activation of osteoclasts, which are recruited to the site where bone needs to be resorbed.
2. resorption: osteoclasts breaks down the old or damaged bone tissue, creating small cavities. this lasts about 2 weeks
3. reversal: after resorption, the site is prepared for new bone formation. this involves the removal of debris and the preparation of the bone surface. ( 2 weeks)
4. formation: osteoblasts are then recruited to the site, where they produce new bone matrix and facilitate its mineralisation. (13 weeks)
5. termination: once the new bone is formed, the remodeling cycle is completed, and the BMU disbands.

BMU overall lasts about 17 weeks ( 4 months)

Question 16

regulators of bone remodelling involves systemic regulation and local regulation

Answer 16

systemic regulation:
1. PTH parathyroid hormone; increases bone resorption by stimulating osteoclast activity
2. clacitonon: inhibits bone resorption by reducing osteoclast activity
3. vitamin D: enhances calcium absorption and bone mineralization
4. sex hormones: promote bone formation and inhibit bone resorption
5. IGF which stimulates bone formation and GH which promotes bone growth

local regulation:
1. mechanical forces
2. TGF-B: regulated bone matrix production and remodeling
3. BMP promotes osteoblast differentiation
4. Interleukins IL-1 IL-6, involved in the regulation of bone resorption and formation.
5. cell-cell interactions
6. osteocytes

Question 17

sheet of calcium metabolism

Question 18

Vitamin D metabolism

Answer 18

1. Synthesis and absorption;
   VItamin D3 (cholecalciferol): synthesised in the skin upon exposure to sunlight
   Vitamin D2 (Ergocalciferol) obtained from dietary sources and supplements
2. Transport: both forms of vitamin D are transported in the bloodstream bound to the vitamin D-binding protein DBP
3. hydroxylation in the liver: vitamin D is converted to 25-hydroxyvitamin D [25 (OH)D] by the enzyme 25-hydroxylase (OHase). this is the major circulating form of vitamin D and is used to assess vitamin D status.
4. Hydroxylation in the kidneys: 25 OH d is further hydroxylated to 1,25-dihydroxyvitamin D [1,25(OH)2D] by the enzyme 1x-hydroxylase. this is the active form of vitamin D, which regulates calcium and phosphate metabolism

PTHormones increases the production of active vitamin D in the kidneys

vitamin D deficiency: leads to poor clcium absorption, resulting in conditions like rickets in children and osteomalacia in adults.

Question 19

osteoporosis

Answer 19

is a systemic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and
susceptibility to fractures. it is Chronic and progressive; multifactorial aetiology.

Question 20

what is BMD bone mineral denisty

Answer 20

ratio of bone mineral content BMC to bone area expressed in g/cm square

Question 21

what is the T score

Answer 21

sex and ethnicity matched comparision to BMD at age of peak bone mass

Question 22

what is the z score

Answer 22

sex and ethnicity matched comparision to BMD of age matched person (someone of the same age)

Question 23

WHO definition and the z -score should be used for

Answer 23

prmenopausal women
men <50 years
children
z < -2SD = below the expected range for age
z > -2SD = within the expected range for age
diagnosis of osteoporosis in these groups should not be based on BMD alone

Question 24

osteoporosis in australia

Answer 24

3% of men / 13% of women 50-69 years of age hav eosteoporosis
13% of men / 43% of women >70 years of age have osteoporosis

Question 25

what are the causes of osteoporosis

Answer 25

-localised osteoporosis: this occurs when a limb has been immobolised or disused for a long time. -primary tpe 1 osteoporosis (post menopausal osteoporosis); this occurs in a women after menopause due to a decrease in estrogen levels, which affects bone density. -primary type 2 osteoporosis (age-related); this type affcets both women and men as they age, typically after teh age of 70, due to the natural decline in bone denisty over time. -secondary osteoporosis: this condition is caused by othe rmedical conditions or medications that affect bone health.

Question 26

Bone mass chnages throughout the life cycle

Answer 26

1. growth phase: 0-20 years 2. peak bone mass phase (prevent premature bone loss) : 20-50 3. increased fracture risk phase: prevent and treat osteoporosis and reduce falls risk: 50-80

Question 27

clinical manifestations of osteoporosis

Answer 27

- asymptomatic until fracture occurs -two thirds of vertebral fractures are painless -fractures may follow a fall or minor trauma -the pain in vertevral fractures is described as sharp, nagging or dull; movement may exacerbate pain -pain often accompanied by paravertebral muscle spasms excerbated by activity and decresed by lying supine -patients ooften remain motionless in bed because of fear of causing an exacerbation of pain

Question 28

common fracture sits due to osteoporosis

Answer 28

- hip -wrist -spine

Question 29

diagnosis of osteoporosis

Answer 29

- bone density scan - DEXA scan

Question 30

second line treatment or osteoporosis

Answer 30

Denosumab is a second-line treatment for osteoporosis, typically administered as a subcutaneous injection every six months. Here's a breakdown of its key features: Antibody against RANKL: Denosumab is a monoclonal antibody that targets RANKL (Receptor Activator of Nuclear Factor Kappa-Β Ligand), a crucial factor in the formation, function, and survival of osteoclasts, which are cells responsible for bone resorption. Reduces Osteoclast Activity: By inhibiting RANKL, denosumab reduces the formation, function, and survival of osteoclasts, leading to decreased bone resorption and increased bone density. Fracture Risk Reduction: Clinical studies have shown that denosumab can reduce the risk of fractures by approximately 70%. Well Tolerated: Denosumab is generally well tolerated, though there is a small risk of infection due to its immune-suppressing effects.

Question 31

first line treatment for osteoporosis

Answer 31

The first-line treatment for osteoporosis typically involves the use of bisphosphonates. These medications help to prevent bone loss and reduce the risk of fractures. Here are some commonly used bisphosphonates: Alendronate: Taken orally, usually once a week. Risedronate: Also taken orally, either once a week or once a month. Zoledronic Acid: Administered as an intravenous infusion once a year. These medications work by inhibiting the activity of osteoclasts, the cells responsible for bone resorption, thereby helping to maintain or increase bone density2.

Question 32

other medications

Answer 32

1. Teriparatide (Recombinant Human PTH): - Anabolic Agent: Teriparatide is an anabolic agent that stimulates bone formation by acting on osteoblasts, the cells responsible for bone synthesis. - Administration: It is administered subcutaneously (s/c). - Mechanism: Teriparatide increases bone density by promoting the formation of new bone tissue, making it effective in treating osteoporosis 2. Raloxifene: - Selective Estrogen Receptor Modulator (SERM): Raloxifene acts as an estrogen agonist in bone, promoting bone density, and as an estrogen antagonist in breast tissue, reducing the risk of breast cancer in post-menopausal women4. - Inhibits Bone Resorption: It helps to inhibit bone resorption, thereby maintaining bone density. - Administration: Raloxifene is taken orally. - Efficacy: While it is effective in maintaining bone density, it is not as effective as alendronate in increasing bone mineral density (BMD). - Side Effects: Common side effects include deep vein thrombosis (DVT), leg cramps, and hot flushes

Question 33

10 important clinical features in rickets

Answer 33

- delayed closure of frontanelles -frontal bossing -dental hypoplasia -pectus carinatum -swelling in wrists and ankle joints -bowing of legs -harrison's sulcus -rachitic rosary -craniotabes -wide sutures

Question 34

cuases of osteomalacia

Answer 34

- inadequate mineraisation of bone - due to vitamin D defieciency ( in children this results in rickets) -other causes very rare; hypophosphatamia, Vitmain D receptor mutations)

Question 35

vitamin D deficiency is due to

Answer 35

skin: inadequate exposure to sunlight gut: reduced intake, coeliac disease kidney failure liver disease

Question 36

vitamin D deficiency and its effect

Answer 36

↓ Vitamin D: Low levels of vitamin D lead to decreased calcium absorption in the intestines. ↓ Ca2+: Reduced calcium absorption results in lower blood calcium levels. ↑ PTH: The parathyroid glands respond to low calcium levels by increasing the secretion of parathyroid hormone (PTH). Actions of PTH Mobilisation of Ca2+ from Bone: PTH stimulates osteoclasts to break down bone tissue, releasing calcium into the bloodstream to normalize calcium levels. Increases Phosphate Excretion from Kidney: PTH also increases the excretion of phosphate (PO4^3-) in the urine, which helps to maintain a balance between calcium and phosphate levels. Outcomes Ca2+ Normalises: In mild cases of vitamin D deficiency, the increased PTH can normalize blood calcium levels. However, in severe deficiency, calcium levels may remain low. ↓ PO4^3- and Normal/↓ Ca2+: The combination of low phosphate and normal or low calcium levels can lead to impaired bone mineralization, resulting in conditions such as osteomalacia (softening of the bones). This process highlights the critical role of vitamin D in maintaining calcium and phosphate balance, which is essential for healthy bone formation and maintenance. If you have any more questions or need further details, feel free to ask!

Question 37

VITAMIN D DEFICIENCY: CLINICAL MANIFESTATIONS

Answer 37

* Bone pain and pathologic fractures * Muscle weakness * Difficulty walking (waddling gait) * Decreased bone density * Hypophosphatemia, increase in ALP and serum PTH levels * Late hypocalcaemia

Question 38

Hyperparathyroidism and Metabolic Bone Disease

Answer 38

Hyperparathyroidism is a condition characterized by excessive secretion of parathyroid hormone (PTH). It can be classified into three types: Primary Hyperparathyroidism: Causes: Approximately 85% of cases are due to a single adenoma, 15% are due to multiple adenomas or hyperplasia, and rarely, it can be caused by parathyroid carcinoma. Hallmark: The excessive secretion of PTH leads to increased resorption of calcium from the bones, resulting in hypercalcemia (high levels of calcium in the blood). Clinical Manifestations: Symptoms are due to the effects on bones and the elevated calcium levels, which can include bone pain, fractures, kidney stones, and neuropsychiatric disturbances. Secondary Hyperparathyroidism: Causes: This occurs as a compensatory response to chronic hypocalcemia (low calcium levels), often due to chronic kidney disease or vitamin D deficiency. Mechanism: The parathyroid glands produce more PTH to try to maintain normal calcium levels. Tertiary Hyperparathyroidism: Causes: This develops after long-standing secondary hyperparathyroidism, where the parathyroid glands become hyperplastic and autonomous, continuing to secrete PTH even after the initial cause of hypocalcemia is corrected. Clinical Implications Bone Effects: Excessive PTH leads to increased bone resorption, weakening the bones and increasing the risk of fractures. Hypercalcemia Effects: High calcium levels can cause symptoms such as fatigue, depression, confusion, constipation, and kidney stones.

Question 39

Hallmark of PTH Excess

Answer 39

Increased Osteoclastic Activity: Excessive parathyroid hormone (PTH) leads to increased activity of osteoclasts, the cells responsible for bone resorption. This means that more bone tissue is broken down than is formed. Effects on Bone Increased Osteoclast Numbers: There is a significant increase in the number of osteoclasts, which tunnel into the bone, particularly affecting cortical bone (the dense outer surface of bone). Osteopenia: This increased bone resorption can lead to osteopenia, a condition where bone mineral density is lower than normal but not low enough to be classified as osteoporosis. Osteitis Fibrosa Cystica: In severe cases, the excessive bone resorption can result in osteitis fibrosa cystica, a condition characterized by the formation of fibrous tissue and cyst-like brown tumors in the bone. These "brown tumors" are not true tumors but rather areas of bone that have been replaced by fibrous tissue and blood.

Question 40

Hypercalcaemia (due to any cause) may result in:

Answer 40

Neuropsychiatric manifestations (e.g. anxiety, depression, confusion; coma if severe) *Gastrointestinal symptoms (esp. constipation, anorexia, nausea, abdominal pain; pancreatitis and peptic ulcer disease are less common) *Muscle weakness *Nephrolithiasis (renal stones) *Cardiac arrhythmias in severe cases

Question 41

symptoms of hyperparathyroidism

Answer 41

- Painful bones * Renal stones * Abdominal “groans” * “Psychic moans” or “psychiatric overtones”

Question 42

Renal Osteodystrophy in Chronic Kidney Disease (CKD-MBD)

Answer 42

Renal osteodystrophy, also known as chronic kidney disease-mineral and bone disorder (CKD-MBD), encompasses a range of bone disorders that occur in patients with chronic kidney disease. Here are the key components: Osteitis Fibrosa Cystica / ‘Brown Tumour’: Phosphate Retention: In CKD, the kidneys are unable to excrete phosphate effectively, leading to phosphate retention. Vitamin D Conversion: The kidneys fail to convert 25-hydroxyvitamin D [25(OH)D] to its active form, 1,25-dihydroxyvitamin D [1,25(OH)2D]. Hyperparathyroidism: High phosphate levels and low calcium levels stimulate the parathyroid glands to secrete more PTH, leading to secondary hyperparathyroidism. Increased Osteoclastic Activity: Excessive PTH increases osteoclastic activity, resulting in bone resorption and the formation of osteitis fibrosa cystica, characterized by ‘brown tumors’. Osteomalacia: Reduced Activation of Vitamin D: The impaired kidney function reduces the activation of vitamin D. Reduced Calcium: This leads to decreased calcium absorption and inadequate mineralization of the bone, resulting in osteomalacia. Osteoporosis: Reduced Bone Formation: Chronic kidney disease can also lead to reduced bone formation, contributing to osteoporosis.

Question 43

paget's disease of bone

Answer 43

* Common (5-10% ageing population) * Common in the UK, Central Europe and Greece, and in countries with European immigrants * A disorder of increased but disordered and structurally unsound bone mass * May involve single bone (monostotic PDB) or multiple sites (polyostotic PDB) * Common sites include skull, spine, pelvis and long bones of lower limbs

Question 44

three phases of pagets disease

Answer 44

Three phases: 1. An initial osteolytic stage, followed by 2. A mixed osteoclastic-osteoblastic stage with a predominance of osteoblastic activity (and hence new bone formation); this evolves ultimately into 3. A final burnt-out quiescent osteosclerotic stage. The net effect is a gain in bone mass; however, the newly formed bone is disordered & architecturally unsound

Question 45

Bone Renewal and Repair: Normal vs. Paget's Disease

Answer 45

Normal Bone Renewal and Repair 1. Bone Remodeling: -Continuous Process: Bone remodeling is a lifelong process where old bone tissue is replaced by new bone tissue. -Osteoclasts and Osteoblasts: Osteoclasts break down old bone (resorption), and osteoblasts form new bone (formation). -Balance: The activities of osteoclasts and osteoblasts are balanced, maintaining bone strength and integrity. -Purpose: Regulates calcium homeostasis, repairs micro-damage from daily stress, and shapes the skeleton during growth. 2. Bone Repair: -Fracture Healing: When a bone fractures, the body initiates a repair process. -Stages: Inflammation: Blood clots form around the fracture. Soft Callus Formation: Cartilage and tissue form a soft callus around the fracture. Hard Callus Formation: The soft callus is replaced by a hard bony callus. Remodeling: The hard callus is remodeled into strong bone3. however in Paget's Disease of Bone Abnormal Bone Remodeling: Disrupted Process: Paget's disease disrupts the normal bone remodeling process. Excessive Resorption and Formation: There is excessive bone resorption followed by rapid and disorganized bone formation. Osteoclasts and Osteoblasts: Osteoclasts are overly active, leading to excessive breakdown of bone. Osteoblasts try to compensate by forming new bone rapidly, but the new bone is structurally abnormal and weaker5. Characteristics of Paget's Disease: Thicker but Weaker Bones: The new bone formed is thicker but less organized and weaker than normal bone. Bone Pain and Deformities: The rapid and abnormal bone remodeling can lead to bone pain, deformities, and an increased risk of fractures. Commonly Affected Areas: Pelvis, skull, spine, and legs are commonly affected6. Comparison Normal Process: Balanced activity of osteoclasts and osteoblasts ensures strong and healthy bones. Paget's Disease: Imbalance in bone resorption and formation leads to structurally abnormal and weaker bones. Contrast Normal Bone: Maintains strength and integrity through a well-regulated remodeling process. Paget's Disease: Results in bones that are thicker but weaker due to disorganized and excessive remodeling.

Question 46

pathogenesis of pagest disease

Answer 46

* Abnormal osteoclasts (phenotypically and physiologically) * Genetic factors: * SQSTM1 gene (~40-50% of people with the inherited version of Paget's disease have a mutation in the SQSTM1 gene) * SQSTM1 encodes a protein called p62 that regulates osteoclasts * RANK-RANKL mutations * Measles virus

Question 47

PAGET’S DISEASE Clinical Manifestations

Answer 47

– Usually mild or asymptomatic (70-90%) – Diagnosis is often based on incidental findings * Elevated total or bone-specific serum alkaline phosphatase * Radiological findings – Patients may present with symptoms that are nonspecific or suggestive of other conditions * Pain * Pathological fracture * Deformity * Osteoarthritis * Compression of peripheral nerves and other structures; sensorineural deafness occurs in 50% of cases * High-output congestive heart failure * Osteosarcoma (rare)

Question 48

Congenital Defects

Answer 48

Congenital Defects in Osteogenesis Achondroplasia - **Cause**: Achondroplasia is caused by a mutation in the FGFR3 gene, which affects the conversion of cartilage to bone during fetal development. - **Characteristics**: It results in short-limb dwarfism, with individuals having short arms and legs, an enlarged head, and an average-sized torso. - **Symptoms**: Common symptoms include physical deformity, short stature, bowlegs, excessive inward curvature of the lower back, short fingers, and a hunched back. - **Complications**: Individuals may experience back pain, frequent middle ear infections, misaligned teeth, snoring, and other complications. Osteogenesis Imperfecta (OI) - **Cause**: OI is caused by mutations in the COL1A1 or COL1A2 genes, leading to abnormal collagen production. - **Characteristics**: Known as brittle bone disease, it results in bones that break easily. Other features include blue sclera, dental fragility, and hearing loss. - **Symptoms**: Symptoms vary widely and can include multiple broken bones, bone deformities, loose joints, small stature, and respiratory problems. - **Types**: There are several types of OI, ranging from mild (Type I) to severe (Type II and III), with varying degrees of bone fragility and other complications. Both conditions are genetic and present at birth, affecting bone development and leading to various physical challenges. If you need more detailed information on either condition, feel free to ask!