Metabolic Bone disorders

Question 1

Role of Osteoclasts

Answer 1

Reabsorb bone
Do so by secreting H, CATK and TRAP
Secrete FGF 23

Develop from mononuclear cells

Question 2

Role of Osteoblasts

Answer 2

Create new bone from osteoid –> mineralised bone

Develop from mesenchymal stem cells

Question 3

Bone microstructure

Answer 3

Matrix of type 1 collagen 35%

Hydroxyapatite crystals 65%

Question 4

Types of bone

Answer 4

Cortical bone:

• Provides bone strength
• Dense outer shell of bone
• 80% of skeletal mass
• slow turnover rate

Trabecular bone:

• Provide Calcium and phosphate during times of stress
• A sponge like network of delicate plates of bone
• 20% of skeletal mass
• High turnover rate

Question 5

What is bone modelling?

Answer 5

Uncoupled osteoclast and osteoblast activity which results in bone growth

Question 6

What is bone remodelling?

Answer 6

Mechanism of bone repair and allows for mineral homestasis

Bone goes from resting state –> resorption by osteoclasts –> osteoclasts apoptose and osteoblasts develop –> osteoid formation by osteoblasts –> mineralisation

Coupled osteoclast and osteoblast activity

Question 7

What happens during osteoporosis?

Answer 7

Increased osteoclast numbers –> increased reabsorption of bone with incomplete new bone formation by osteoblasts

Results in thinning of bone and loss of connectivity in trabecular bone and porosity in cortical bone

Question 8

Mediator of osteoclast formation, function and survivial?

Answer 8

RANK- Ligand

Question 9

Decoy molecule which prevents RANK to RANK-L binding?

Answer 9

OPG - binds RANK-L –> cannot bind to RANK –> osteoclast apoptosis

Question 10

What is Osteoporosis?

Answer 10

T score < - 2.5 OR minimal trauma fracture

A metabolic bone disease characterized by low bone mass and deterioration of bone architecture resulting in bone fragility and fracture

Question 11

What is Z score used for?

Answer 11

Z score < - 2 = look for secondary causes of bone loss

Question 12

Secondary causes of bone loss?

Answer 12

Hypogonadism/menopause
Vitamin D deficiency
Hyperthyroidism
Hyperparathyroidism
Coeliac disease
Multiple myeloma
Corticosteroids
Chronic disease

Question 13

Rates of osteoporosis?

Answer 13

60% of women and 30% of men aged 60yrs or older

People with fragility fractures 3-5% more likely to to have another fracture in the next year

Question 14

PBS for treatment of OP?

Answer 14

T score < - 2.5 aged 70yrs or more OR

Previous low trauma fracture/vertebral fracture >50yrs

Question 15

Special cases for PBS?

Answer 15

Corticosteroids - treat if T score < - 2

Aromatase inhibitors or androgen deprivation treatments = treat if BMD < - 2.5

Question 16

Glucocorticoid-induced osteoporosis?

Answer 16

Bone loss in cancellous bone - rapid in the first year then slows

Fracture in 30-50% on long term Steroids

High risk:

• > 7.5mg for more than 3 months
• Age 60-80yrs
• Underlying inflammatory disease
• Previous fracture

Question 17

Non-pharm prevention of OP?

Answer 17

Falls prevention - vision, proprioception, quads strength, balance

Question 18

Calcium supplementation?

Answer 18

1300mg daily for OP patients recommended intake

Supplementation =500-600mg/day

Supplement when:

• Dietary intake low
• Taking OP meds
• Steroids >7.5mg/day for >3/12
• Elderly and housebound/in NH

Question 19

Vitamin D Supplementation?

Answer 19

1000-2000IU/day supplementation

Supplement when:

• Housebound/NH
• Work indoors/sun avoiders
• Dark skin
• Malabsorption
• Biliary cirrhosis
• Antiepileptics

Question 20

SERMs?

Answer 20

Selective esterogen receptor modulators

Tamoxifen and raloxifene

Non-hormonal but bind to oestrogen receptors –> anti-osteoclast action in bone

Helps prevent VERTEBRAL fractures only
Reduces rates of ER+ breast cancer

Question 21

Bisphosphonates?

Answer 21

Alendronate, Risedronate and Zoledronate

Bind to hydroxyapitate –> inhibits osteoclast activity and causes accelerated apoptosis

Reduce both vertebral and hip fractures

Zoledronate –> AF

Question 22

Denosumab?

Answer 22

RANK Ligand inhibitor

–> inhibits osteoclast formation, function and survival

Reduces vertebral and hip fractures

Can have rebound vertebral fractures on discontinuation –> transfer to another agent like bisphosphonates

Question 23

Rare side effects of Antiresorptives?

Answer 23

Osteonecrosis of the jaw:

• Bisphosphonates and denosumab
• Usually after 2yrs of treatment
• Usually in the mandible
• Treat with daily rinses and antibiotics –> surgery if not healed
• Requires dental review prior to commencement of treatment

Atypical femoral fractures:

• Bisphonates
• Stress fractures in mid thigh
• Usually have pain prior to fracture
• Usually after 7yrs of treatment
• TX –> stop bisphos and nail fixation

Question 24

Skeletal anabolics?

Answer 24

PTH

• Gives as once daily injection –> stimulates new bone formation
• Only can give 18 months of treatment –> PTH causes late stimulation of osteoclasts

Question 25

? LRP5 activation?

Answer 25

Sclerosteosis = high bone density due to LRP5 mutation --> inactivation of sclerostin --> increased wnt signalling --> increased osteoblast proliferation

Question 26

Osteomalacia?

Answer 26

Deficiency of mineralised bone High osteoid

Question 27

Presentation?

Answer 27

Bone pain Fractures Waddling gait Elevated ALP Check Ca, PO4, 25OHD, PTH Urinary PO4

Question 28

Causes of Osteomalacia?

Answer 28

Vitamin D deficiency Hypophosphataemia - fanconi or tumour induced RENAL DISEASE: - FGF-23 - Iron infusions - Phosphate leak - fanconis or tenofovir

Question 29

Role of FGF-23?

Answer 29

Secreted by osteoclasts Results in increased urinary phosphate and low Vitamin D

Question 30

Hypophosphatasia?

Answer 30

Usually presents in childhood Results in high phosphate loss in urine and low serum PO4 and Vitamin D Low ALP on bloods Rickets Recurrent fractures and psuedofractures Soft teeth Chrondocalcinosis common Treatment is PTH

Question 31

Paget's disease?

Answer 31

Increased osteoclast activity --> increased and abnormal bone formation Present with: - Bone pain - Bone deformity - OA - Fractures - HIGH ALP Treat with bisphosphonates if pain or if bone growth is causing damage to critical structures

Question 32

Calcium metabolism

Answer 32

IN = INTESTINE + VITAMIN D The active absorption of calcium from the gut is regulated by the calcitriol concentration in the blood. OUT = KIDNEY + PHOSPHATE + PTH Increased excretion by increased PO4 and low PTH STORAGE = BONE Calcium release from bone is regulated by PTH in conjunction with calcitriol under the influence of PTH.

Question 33

Vitamin D Metabolism

Answer 33

Calcitriol is a cholesterol derivative. Under the influence of ultraviolet light on the skin, cholesterol is converted to previtamin D3 which spontaneously isomerizes to vitamin D3. Under the influence of parathyroid hormone, the kidneys convert cholecalciferol into the active hormone, 1,25 dihydroxycholecalciferol.

Question 34

Causes of Hypercalcaemia?

Answer 34

PTH dependant: - Primary or tertiary hyperparathyroidism - Abnormal CaSR = familial hypocalcinuric hypercalcaemia PTH independant: - CANCER - myeloma, PTHrP, bone metastasis, vitamin D - Excess vitamin D - sarcoidosis and granuloma disease - Milk-alkali syndrome - Endocrine disorders - Hyperthyroid, pheo, cortisol deficiency, VIPoma - IMMOBILISATION Medications: - Li - Thiazide diuretics - Vitamin D - Ant-acids

Question 35

Primary Hyperparathyroidism

Answer 35

Mostly asymptomatic High Ca and high PTH --> increased bone loss by stimulation of osteoblasts Results in fractures and kidney stones --> parathyroidectomy as treatment if surgical candidate or bisphosphonates is not REPLACE VITAMIN D Ask about family history - ? MEN1

Question 36

What is romosozumab?

Answer 36

A monoclonal antibody against sclerostin Sclerostin produced by osteocytes to decrease osteoblast proliferation If blocked --> increased wnt signalling --> increased osteoblast proliferation