endocrine and metabolic bone disorders

Question 1

how much Ca does bone store *

Answer 1

>95% body’s Ca

Question 2

what are the 2 components of bone

Answer 2

organic components (osteoid - unmineralised bone - 35% bone mass) 95% is made of Type 1 collagen fibres

inorganic mineral component - 65% bone mass - calcium hydroxyapatite crystals fill the space between the collagen fibrils

Question 3

describe the dynamic remodelling process of bone *

Answer 3

osteoblasts synthesise osteoid and participate in mineralisation/calcification of osteoid (bone formation)

osteoclasts release lysosomal enzymes - break down bone (bone resorption) - they are multinucleated cells with ruffelled membranes

Question 4

describe osteoclast differentiation

Answer 4

RANKL is expressed on the osteoblast surface (L stands for ligand)

RANKL binds to RANK-R (R=receptor) on osteoclast precurser to stimulate osteoclast formation and activity

Question 5

how do osteoblasts control bone formation and resorption balance *

Answer 5

tehy ave receptors for pth and active vit d

Question 6

what are the structures of bone

Answer 6

cortical bone (hard) and trabecular bone (spongy)

both formed in lamellaar pattern = ccollagen fibrils laid down in alternating orientations - mechanically strong

woven bone is dysfuctional bone - has disorganised collagen fibrils so is weaker

Question 7

what are the effects of vit D deficiency on bone *

Answer 7

= inadequate mineralisation of newly fomred bone matrixx (osteoid) - vit d is needed for this

in children this causes rickets - affects the cartilage of the epiphysial growth plates and bone = skeletal abnormalities and pain, grpwth retardation (short stature) and increased fracture risk

in adults - osteomalacia - this is after epiphysial closure so dont get bowing of legs seen in rickets - just affects bone = skeletal pain, increased fracture risk and proximal myopathy.

normal stresses and weight on abnormal bone cause insufficiency fractures = looser zones (fracture to unmineralised bone). - these are stress fractures

Question 8

why does vit d deficiency cause waddling gate

Answer 8

from the skeletal pain and proximal myopathy

Question 9

describe primary hyperparathyroidism

Answer 9

caused by adenoma in the parathyroid gland

cause increased pth production = high ca because increased reabsorption in bone and kidney and pth activates vit d

autonomous production of pth so no -ve feedback

both pth and ca are igh

Question 10

describe ssecondary hyperparathyroidism

Answer 10

caused by renal failure or vit d deficiency

low or normal ca because need vit d to reabsorb ca from gut (renal failure = cant activate vit d - no 1a hydroxylase)

by -ve feedback this causes a high pth - tis si a physiological response

ca can be normal if pth is raised enough to increase ca reabsorption from bone and kidney

Question 11

describe tertiary hyperparathyroidism

Answer 11

eg from chronic kidney disease

cant make ccalcitriol (avtive vit d) = ca fall - pth increase = secondary hyperparathyroidism

then all parathyroid glands make more pth to try to increase ca - become autonomous so dont swich off

so have high pth and high ca

Question 12

how is primary different to secondary hyperparathyroidism

Answer 12

dont have CKD in primary

Question 13

describe how renal failure relates to bone disease

Answer 13

low renal func = cant 1a hydroxylase vit d = low active vut d = low ca absorption from the gut = hypocalcaemia

also cant excrete phosphate - binds to ca = serum ca decrease = hypocalcaemia

hypocalcaemia = increase in PTH = increased bone resorption = cysts in bone

hypocalcaemia also causes low bone mineralisation (also because low vit D)

increased bone resorption and low bone mineralisation = osteitis fibrosa cystica

high plasma phosphate = vascular calcification of blood vessels

Question 14

what is osteitis fibrosa cystica

Answer 14

hyperparathyroid bone disease - rare

because of excess bone reabsorption because of high pTH

causes ‘brown tumours’ - not tumours - they are cysts (radiolucent bone lesions)

Question 15

how do you treat osteitis fibrosa cystica

Answer 15

treat the causes:

• hyperphosphtaemia: low phosphate diet, pospate binders - reduce GI phosphate absorption

give alphacalcidol ie calcitriol analogues - tis is active vut d

paratyroidectomy in tertiary hyperparathyroidism - if have hypercalcaemia and/or hyperparatyroid bone disease

Question 16

what is osteoporosis *

Answer 16

there is a loss of the bony traberculae = reduced bone mass = weaker bone = predisposed to fracture after minimal trauma

as age get reduction of bone mass - accelarated post menopause

have bome mineral density (BMD) >/=2.5 standard deviations below average value for young healthy adults - referred to as a t score of -2.5 or lower

BMD predicts fracture risk

osteopenia is when you have a BMD on way to osteroporosis

Question 17

how do you measure BMD

Answer 17

using a DEXA scan - dual energy x-ray absorptiometry of femoral neck lumbar and spine

it involves radiation

mineral (Ca) content of teh bone is measured, te more mineral = te greater the bmd ie bone mass = strength

Question 18

what is the difference between osteoporosis and osteomalacia

Answer 18

they both predispose to fracture

malacia - due to vit d def = unmineralised bone - serum biochem abnormal: low active vit d, low or low normal ca, high pth - secondary hyperparathyroidism (diagnose on blood test) have painful proximal myopathy

osteoporosis - boen resorption exceeds formation, decreased bone masss, biochem fine, diagnosis with DEXA scan

Question 19

what are the predisposing factors for osteoporosis

Answer 19

postmenopausal oestrogen deficiency = loss of matrix = increased risk of fracture

age related deficiency in bone homeostasis - men and women - osteoblast senescense

hypogonadism in young women and men - deficient in testosterone or oestrogen

cusings, hyperthyroidism, primary hyperparatyroidism

prologued use of glucocorticoids = reduced bmd

heparin

Question 20

what are the consequences of a hip fracture

Answer 20

death

permanent disability

not being able to walk

impairment in daily life

Question 21

what is the treatment for osteoporosis

Answer 21

oeestrogen/selective oestrogen receptor modulators

bisphosphonates

denosumab

teriparatide

Question 22

how does oestrogen work to treat osteoporosis

Answer 22

it is hormone replacement therapy

it as anti-resorbitive effects on the skeleton adn prevents bone loss

cant give long term - increased risk of breast cancer and venous tromboembolism

if have intact uterus have to have progesterone to prevent endometrial hyperplasia and cancer

Question 23

what is the mechanism of bisposphonates for osteoporosis

Answer 23

they promote osteoclast apoptosis

they bind to hydroxyapatite which normally mineralises bone

osteoclasts ingest the bispospate bound hydroxyapetite and die - reduced ability to reabsorb bone

= reduced bone turnover

Question 24

what do you use bisphosphonates for

Answer 24

first line treatment for osteoporosis

hypercalcaemia of malignancy eg zoledronate - reduce bone turnover = reduce bone pain from metastasis and ca release - might improve survival in breast cancer because suppress bone turnover so less likely for micrometastises to become real metastises

pagents disease - to reduce bony pain

if severe hypercalcaemia emergancy - iv fluid initially than bisphosphates

Question 25

what are the pharmacokinetics of bisphosphonates

Answer 25

orally active but poorly absorbed

take on an empty stomach - food, especially milk reduces drug absorption - can cause dyspepsia = bad compliance

accumulates at te site of bone mineralisation and is part of the bone until it iss resorbed - can be years therefore concerned about use in younger patients

Question 26

what are the unwanted effects of bisphosponates

Answer 26

oesophagitis - irritate the oesophagus - may require switc to iv

osteonecrosis of the jaw - greatest risk in cancer pts taking iv bisphosponates - made bone adynamic - if having dental surgery ave to have it before you start on this

atypical fractures - oversuppression of bone remodelling

Question 27

how does denosumab treat osteoporosis

Answer 27

it is a human monoclonal ab

binds to RANKL - inibit osteoclast formation and activity - inibit resorption

it is taken as a subcutaneous injection every 6months

2nd line to biphosphates

Question 28

ow is teriparatide used to treat osteoporosis

Answer 28

it is a recombinant pth fragment, amino-terminal 34 aa of native pth

inccreases bone formation adn resorption but formation dominates because of the dose you give

3rd line treatment

daily sc injection

expensive

Question 29

what is pagents disease of bone

Answer 29

when there is accelarated, localised but disorganised bone remodelling

excessive bone resorption - overactive osteoclasts, followed by overactive increase in osteoblast activity

therefore woven bone is formed - this is disorganised and weak so cant withhold stress = vulnerable to fracture

cause bone frailty and hypertrophy and deformity

Question 30

describe the epidemiology of pagent’s disease

Answer 30

often positive fh - suggesting genetic cause

evidence for viral origin

high prevalence in te uk, n america, australia, scandinavia

men and women affected equally

not usually apparent in people <50 - disease of aging

most asymptomatic until get bone deformity

characterised by abnormal large osteoclasts - excessive in number

Question 31

what are te clinical features of pagents disease of bone

Answer 31

skull, toracolumbar spine, pelvis, femer and tibia most commonly affected

skull gets frontal bossing

arthritis

fracture - bone not mecanically strong

pain

bone deformity

bowed legs - bone remodelling is all over the place - bot in a structured way

increased vascularity - warmth over affected area because of underlying activity

deafness because of coclear impairment - bone conducntion doesnt work

radiculopathy due to nerve compression - nerve root pain

Question 32

how do you diagnose pagents disease of bone

Answer 32

normal plasma ca

hig plasma alkaline phosptase - produced by bone, hig because of bone remodelling

plain x rays - lytic lesions (early), thickened, enlarged deformed bones (later)

radionucleotide none scan demonstrate extent of skeletal involvement - it goes to the busy parts of the bone

tibia common place for bone abnormality

Question 33

what are the treatment options for pagents disease

Answer 33

bisphosphates - elpful to reduce bony pain and disease activity

simple analgesia

Question 34

what is the outcome you are looking for with statins *

Answer 34

40% reduction in non HDL cholesterol by 3 months

Question 35

what are SE of statins *

Answer 35

muscle aches and rabdomyolesis (breakdown of muscle) = creatine kinase increase