Endocrinology 3 - Bone Metabolism Flashcards
What is the function of Rank and Rank-ligand
RANK is released by osteoblasts and binds to multinucleated osteoclasts, causing activation and bone resorption.
What changes occur in post-menopausal bone remodelling?
- increased osteoclast numbers
- increased resorption depth
- Incomplete filling by new bone
Outcome is negative bone balance
What are 4 mechanisms for arriving at low bone mass?
- Low peak bone mass
- premature menopause
- accelerated loss post menopause
- senile bone loss
What is secreted by osteoclasts?
H+
Cathepsin K
TRAP
Seals itself with alpha-v-beta-3
What are examples of secondary causes of bone loss?
Hypogonadism Vitamin D deficiency Hyperthyroidism Hyperparathyroidism Coeliac disease Multiple myeloma (
What proportion of patients over 60y have OP?
60% of women
30% of men
What are the sequelae of hip fractures?
33% totally dependent or in nursing home
25% will die
Who should be treated for osteoporosis?
Patients with existing fragility fracture (post menopausal women, or men >50)
risk of fracture increases with each new fracture - 3-5x more likely to have another fracture, compared to those whom have never had a previous fracture
Asmyptomatic vertebral fractures
Treat others according to risk
What are features of vertebral fractures?
only 1/3 of fractures come to clinical attention
decreased patient QoL
Increased mortality
adds to fracture cascade
increased risk of further vertebral fractures, but also hip fractures.
What are current reimbursement criteria for the treatment of osteoporosis?
Must have T score 70 with nil other risk factors.
Risk of fracture doubles for each SD below 0 (T-score)
What are factors used in the FRAX score?
Low BMD Age Previous fracture Family Hx Low body weight smoking rheumatoid arthritis corticosteroid use
When should patients receiving corticosteroids be treated for OP?
When T-score is
When should patients taking aromatase inhibitors be treated for OP?
When T-score
Risk of what fracture type increases markedly with >7.5mg of prednisone/day?
spinal fractures
What are risk factors for glucocorticoid induced osteoporosis?
Age - esp >60 Underlying disease - RA, PMR, IBD, COPD, transplant Dose and duration of GC Previous fracture Low BMD Low BMI (
What type of bone is predominantly lost in Glucocorticoid induced osteoporosis?
Cancellous bone - rapidly in the 1st year (6-12% loss), more slowly (3%) after that
Fractures occur in 30-50% of patients on long term GC
What are non-pharmacological measures in OP?
Falls prevention:
- vision
- proprioception
- quadriceps strength
- balance
Hip protectors - of no use in real world use
When is Vit D supplementation recommended, and at what dose?
Dietary intake is insufficient
Taking osteoporosis medication
Glucocorticoids >=7.5mg for >=3 months
Elderly, housebound or in residential care
500-600mg/day combine with supplementation if required (RDI is 1300mg/day in ostoporotic patients)
What are recommended doses of supplementation in deficiency of Vit D?
30-49 - mild deficiency - 1000-2000IU/day
12.5-29 - mod deficiency - 3000-4000units for 6-12 weeks, then 1000-2000IU maintance dose
What groups are at risk of vitamin D deficiency?
High latitudes in winter Elderly, particularly residential care Conditions where sun avoidance is required Dark skin malabsorption biliary cirrhotics anti-epileptics
What is the mechanism of action of odanacatib?
cathepsin K inhibitor
prevents bone remodelling by inhibiting osteoclast resorptive activity.
Significant improvements in T score in patients
What is the mechanism of action of SERMS?
non-hormonal, selectively estrogen like in bone, and blocks estrogen in breast.
blocks differentiation of prefusion osteoclasts into activated osteoclasts.
What are outcomes for patients treated with SERMS?
Reduces vertebral fractures by 36% in postmenopausal women with osteoporosis.
Prevents breast cancer
Raloxifene does not prevent vertebral fractures.
What is the mechanism of action of bisphosphonates?
farnesyl pyrophosphate synthase inhibitors - loss of ruffled border and inhibition of vesicle trafficking, accelerated apoptosis.
What type of bone benefit most from the administration of bisphosphotates (Alendronate)
trabecular bone gains more than cortical, due to increased rate of bone turnover - hence lumbar spine more than hip/femoral neck etc.
What is the effect of alendronate on fractures?
47% reduction in new vertebral fractures, 51% reduction in hip fractures
What is the effect of zolendronate on fractures?
70% reduction in vertebral fractures, 41% reduction in hip fractures
significant increase in serious atrial fibrillation
What is the mechanism of action of denosumab?
denosumab is a monoclonal humanised anitibody which binds rank ligand and inhibits osteoclast formation, function and survival, limiting bone resorption.
What effect does denosumab have on BMD?
increase in BMD by 9.2% at lumbar spine
- 9% increase at trochanter
- 0% total hip
What effect does denosumab have on fractures?
68% reduction in new vertebral fractures
40% reduction in hip fractures
20% non-vertebral fractures
What is the effect of stopping alendronate after 5 years of therapy?
No increase in fracture risk except for vertebral fracture risk.
What is the effect of stopping zoledronic acid after 3 years vs 6 years of therapy?
Higher incidence of new vertebral fractures in the 3 year group, however no increase rate of other fractures, and slight decline in BMD, however still above pretreatment levels in 3 year group.
What are features of atypical femoral fractures?
stress fractures BP therapy for average 7y 70% have prodrome 28% bilateral 26% delayed healing concomitant GC use in 34% Concomitant PPI use in 39%
What are x-ray features of atypical femoral fractures?
No comminution Transverse at lateral cortex Medial spike Diffuse cortical thckening Focal lateral thickening - beaking
What is management of AFFs?
discontinue antiresorptive
prophylactic nail fixation if pain or cortical lucency
if no pain or cortical lucency - limited weight bearing until no oedema on MRI/bone scan (? teriparetide)
monitor the contralateral hip.
What is the MoA of strontium ranelate?
stimulates osteoblasts, inhibits osteoclasts and increases tissue material strength.
What effect does strontium have on BMD?
8.2% increase, however strontium affects DEXA scan, 1/2 is ‘real’ increase
What effect does strontium ranelate have upon fractures?
49% reduction in vertebral fractures.
What are AEs of strontium ranelate?
Diarrhoea
VTE
Eosinophilic syndrome (Rare)
Myocardial Infarction
(now 2nd line therapy)
What is the effect of PTH when given once daily?
pulsed, once daily injection is anabolic for bone, vs continuous infusion which is catabolic. stimulates bone formation.
stimulates osteoblasts and later osteoclasts by Increase in RankL and decrease in OPG secretion from osteoblasts.
What do mutations in LRP5 cause?
severe activating mutations cause severe osteoporosis/pseudoglioma.
activating mutations cause high bone mass - sterosclerosis
What is the significance of LRP5?
LRP5/WNT/SOST pathway is a target for new skeletal anabolic treatments
What is the effect of sclerostin in Wnt signalling?
sclerostin secreted by osteocyte causes inhibition of bone formation via osteoclasts.
What is the typical presentation of osteomalacia?
bone pain fractures (typically stress) myopathy (waddling gait) elevated ALP Check Ca, phosphate, 25OHD, PTH levels Urinary phosphage (TmP/GFR) Bone Bx may be required
What are causes of osteomalacia?
Vitamin D Deficiency:
- nutritional
- malabsorption
- liver disease
- renal disease
- nephrotic syndrome
- anti-epileptics
- genetic causes (VDR, CYP27B1, 25-hydroxylase)
Hypophosphataemia
- Fanconi syndrome
- Tumor related osteomalacia
- Genetic causes (XLH, ADHR, ARHR, HHRH)
What are humoral causes of renal phosphate wasting?
FGS23 mediated: TIO - mesenchymal tumours (paraneoplastic) Iron Polymaltose XLH ADHR ARHR
What are renal causes of phosphate leakage?
Fanconi syndrome
HHRH
Anti-retrovirals
What is the effect of FGF-23 on the kidney?
Increases urinary phosphate excretion and decreases Vit D production
What are findings in tumour induced osteomalacia?
Hypophosphataemia, low TmP/GFR, low/N vit D, ALP often high.
Osteomalacia on bone Bx
Associated with mesenchymal tumours, also breast, prostate, SCLC, MM, CLL
Treatment: rocaltrol+/- phosphate, excision of tumour if fount
What can be used to find tumours in TIO?
DOTATATE-PET
How does perinatal, infantile or childhood hypophosphataemia present?
recurrent, slow healing metatarsal stress fractures
pseudofracture - proximal femur
chondrocalcinosis common, CPPD rare
50% have early loss of decidious teeth, rickets
What is a treatment option in perinatal/infantile/childhood hypophosphataemia?
teriparetide
What is the pathogenesis of paget’s disease?
significantly increased osteoclast activity with commensurate increase in activity from osteoblasts, new bone formed is abnormal.
What are the outcomes of paget’s disease?
increased overall bone turnover thickened and weakened existing bone severe pain in affected bone bone overgrowth may affect nerves sarcoma rarely in affect bones
What are clinical manifestations of skeletal disease in paget’s disease?
bone pain, nocturnal bone deformity OA of adjacent joints fractures spinal stenosis
What are investigations in paget’s disease?
ALP increased
X-ray
Bone scan
When is treatment for paget’s disease indicated?
Bone pain involvement of petrous temporal bone nerve or spinal cord compression cardiac failure involvement of critical bone cosmetic change bending of femur or tibia
What is therapy of paget’s disease?
bisphosphonate
calcitonin
analgesics
surgery
What is the biology in congenital paget’s?
activating mutations in RANK causes familial exapansile osteolysis
OPG mutation causes juvenile paget’s like disease
Mutation in sequestosome-1 causes familial paget’s disease
What is the most common cause of hypercalcaemia in primary care?
primary hyperparathyroidism
malignancy often in hospitalised patients
What are PTH dependent causes of hypercalcaemia?
Hyperparathyroidism (primary or secondary)
Abnormality of the CaSR - familial hypocalciuric hypercalcaemia, autoimmune hypercalcaemia
What are medications that cause hypercalcaemia?
lithium
thiazides
calcitriol
CaCO3 and antacids
What are PTH independent causes of hypercalcaemia?
Cancer - myeloma, PTHrP, Osteolytic mets, 1,25(OH)2D
Excess calcitriol - sarcoid, granulomatous disease
Excess gastrointestinal calcium - milk alkali syndrome
Endocrine - thyrotoxicosis, phaeo, cortisol def, VIPoma
Immobilisation
What are appropriate initial tests in hypercalcaemia?
Serum calcium, albumin, ionised ca PTH 25OHD Creatinine Urinary Calcium
What imaging should be performed if a patient is a surgical candidate for hypercalcaemia?
Parathyroid sestaMIBI
Parathyoid uss
When is surgery indicated in primary hyperparathyroidism?
Calcium >0.25 above ULN
CrCl 400 and/or nephrocalcinosis
BMD - T-score
What are skeletal complications of PHPT?
low BMD # osteitis fibrosa cystica brown tumours subperiostial resoprtion of phalanges tapering of distal clavicles salt and pepper skull
What are benefits of parathyroid surgery?
In RCTs - improved BMD at hip and LS, with improved QoL
Observational - improved Sx, reduced nephrocalcinosis, improved BMD, reduced # risk
What is the role of bisphosphonates in PHPT?
significant improvement in LS BMD, NS difference in total Hip.
NO change in serum calcium, PTH, urinary calcium
What is the significance of Vit D in PHPT?
ensure that patients are vit D replete, as clinical severity of PHPT is higher with low vit D.
increased risk of hungry bone syndrome/hypocalcaemia post PTectomy in vit d deficient patients
What malignancies are associated with PTHrP?
SCC, renal, ovarian, breast, endometrial
What malignancies are associated with osteolysis?
Breast, MM, lymphoma
What malignancies increase vitamin D?
Lymphoma.
