Metabolic Bone disorders Flashcards
Role of Osteoclasts
Reabsorb bone
Do so by secreting H, CATK and TRAP
Secrete FGF 23
Develop from mononuclear cells
Role of Osteoblasts
Create new bone from osteoid –> mineralised bone
Develop from mesenchymal stem cells
Bone microstructure
Matrix of type 1 collagen 35%
Hydroxyapatite crystals 65%
Types of bone
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
What is bone modelling?
Uncoupled osteoclast and osteoblast activity which results in bone growth
What is bone remodelling?
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
What happens during osteoporosis?
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
Mediator of osteoclast formation, function and survivial?
RANK- Ligand
Decoy molecule which prevents RANK to RANK-L binding?
OPG - binds RANK-L –> cannot bind to RANK –> osteoclast apoptosis
What is Osteoporosis?
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
What is Z score used for?
Z score < - 2 = look for secondary causes of bone loss
Secondary causes of bone loss?
Hypogonadism/menopause Vitamin D deficiency Hyperthyroidism Hyperparathyroidism Coeliac disease Multiple myeloma Corticosteroids Chronic disease
Rates of osteoporosis?
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
PBS for treatment of OP?
T score < - 2.5 aged 70yrs or more OR
Previous low trauma fracture/vertebral fracture >50yrs
Special cases for PBS?
Corticosteroids - treat if T score < - 2
Aromatase inhibitors or androgen deprivation treatments = treat if BMD < - 2.5
Glucocorticoid-induced osteoporosis?
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
Non-pharm prevention of OP?
Falls prevention - vision, proprioception, quads strength, balance
Calcium supplementation?
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
Vitamin D Supplementation?
1000-2000IU/day supplementation
Supplement when:
- Housebound/NH
- Work indoors/sun avoiders
- Dark skin
- Malabsorption
- Biliary cirrhosis
- Antiepileptics
SERMs?
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
Bisphosphonates?
Alendronate, Risedronate and Zoledronate
Bind to hydroxyapitate –> inhibits osteoclast activity and causes accelerated apoptosis
Reduce both vertebral and hip fractures
Zoledronate –> AF
Denosumab?
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
Rare side effects of Antiresorptives?
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
Skeletal anabolics?
PTH
- Gives as once daily injection –> stimulates new bone formation
- Only can give 18 months of treatment –> PTH causes late stimulation of osteoclasts
? LRP5 activation?
Sclerosteosis = high bone density due to LRP5 mutation
–> inactivation of sclerostin –> increased wnt signalling –> increased osteoblast proliferation
Osteomalacia?
Deficiency of mineralised bone
High osteoid
Presentation?
Bone pain
Fractures
Waddling gait
Elevated ALP
Check Ca, PO4, 25OHD, PTH
Urinary PO4
Causes of Osteomalacia?
Vitamin D deficiency
Hypophosphataemia - fanconi or tumour induced
RENAL DISEASE:
- FGF-23
- Iron infusions
- Phosphate leak - fanconis or tenofovir
Role of FGF-23?
Secreted by osteoclasts
Results in increased urinary phosphate and low Vitamin D
Hypophosphatasia?
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
Paget’s disease?
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
Calcium metabolism
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.
Vitamin D Metabolism
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.
Causes of Hypercalcaemia?
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
Primary Hyperparathyroidism
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
What is romosozumab?
A monoclonal antibody against sclerostin
Sclerostin produced by osteocytes to decrease osteoblast proliferation
If blocked –> increased wnt signalling –> increased osteoblast proliferation
