Osteoporosis, calcium, vit D, phos Flashcards
Risk factors for OP
FHx Female Previous minimal trauma # Post menopausal Late menarche, early menopause Age Glucocorticoids Androgen deprivation therapy (prostate ca) Aromatase inhibitors (breast ca) Smoking ETOH+++ Physical inactivity Low calcium intake Vitamin D deficiency Low protein intake Low body weight CT disease Haematological disorders Chronic disorders e.g. CKD
Endocrine disorders e.g. sex hormone deficiency, cushing’s, hyperthyroidism, hyperparathyroidism, DM
Malabsorption disorders e.g. coeliac, bariatric surgery
How is OP diagnosed?
1) Fragility fracture after age 50 - any fracture other than fingers, toes, skull, face. Particularly in the spine, hip, wrist.
OR
2) BMD measurement
- T-score ≤-2.5 is consistent with osteoporosis, whereas a T-score between -1 and -2.5 is low bone mass (osteopenia)
What’s the fracture risk assessment tool?
In the US, diagnosis of OP can be made calculating the absolute fracture risk.
In Australia, using this score to guide treatment is grade D evidence, and not covered by PBS.
What’s the Z score?
Z score compares your bone density to the average person your age and gender
Initial Investigations for OP
25OHD, CMP, renal function, liver function, TSH
BMD (DXA)
Thoracic and lumbar spine xray (in selected cases)
Further investigations SPEP FLC/urine bence jones protein PTH TSH ESR CRP Testosterone (males only) Coeliac screen Estrogen FSH/LH Hypercorticolism screen 24h urine calcium and creatinine excretion
What’s a fracture risk calculator?
FRAX and GARVAN most commonly used
- Primarily driven by BMD, age, previous #
Calculates 10 year probability of fracture at hip or any site
What’s a trabecular bone score?
Has a role in fracture risk assessment
Low TBS is associated with increased fractures
Its a texture analysis, related to bone microarchitecture
Compares adjacent areas of bone to each other. When there is a bigger difference between adjacent bone the trabecular bone score will be worse
When is antiresorptive medication subsidised by PBS for OP?
1) Minimal trauma fracture regardless of BMD
2) 70 years + OP at spine or hip
3) T score ≤-2.5
Rx OP
Antiresorptive therapy Vitamin D Calcium Exercise - weightbearing exercise Smoking cessation
Which antiresorptive medication do we use for post-menopausal women?
Start with PO bisphosphonates - alendronate or risedronate
Which antiresorptive medication should we use in patients with oesophageal disorders, GI intolerance to PO bisphosphonates, inability to remain upright after dose?
IV bisphosphonate - zoledronic acid is preferred
When to follow up after commencing anti-resorptive therapy?
DEXA hip and spine after 2 years
If BMI is stable or improved, less frequent monitoring thereafter
Risks with bisphosphonates
Atypical femoral fractures*
- Prodrome with thigh pain; 1/3 bilateral
- Need xray or bone scan
- SE Asian women are most at risk
- Rx: stop antiresorptive therapy (risk of contralateral femur), surgery
Osteonecrosis of the jaw*
- Exposed alveolar bone
- Confirmed: >8 weeks after extraction
- Rx: stop antiresorptive therapy, daily antimicrobial rinses, abx, occasionally surgical debridement
*Both risks increase with duration
Oesophagitis
Risk with denosumab
Rapid loss of bone and increased risk of spontaneous vertebral # if dose delayed by 4 weeks so need continuous lifelong therapy
Hypocalcaemia particularly in impaired kidney function, vitamin D deficiency or a malabsorptive disorder
Osteonecrosis of the jaw
When to do BMD testing?
> 70 years
After minimal trauma fracture
Comorbidities
Management post minimal trauma fracture
Minimal trauma hip fracture in post menopausal woman (or man >50 years) = treat
“Asymptomatic” vertebral fracture = treat
How to take oral bisphosphonates?
Empty stomach
At least 2 hours apart from calcium, iron, magnesium, antacids (can limit absorption of bisphosphonate)
What’s raloxifene and when is it used?
Selective estrogen receptor modulator
Reduces post menopausal bone loss, risk of breath cancer
Most appropriate for younger postmenopausal women (<60 years) with spinal OP
What’s tibolone and when is it used?
Oestrogenic effects on bone
Reduces risk of # in postmenopausal women (similar extent to estrogen therapy)
Used for women <60years with menopausal symptoms but not explicitly for OP
What’s teriparatide and when is it used?
Synthetic form of PTH. Increases bone formation.
Reduces incidence of vertebral and nonvertebral fractures in postmenopausal women.
Increases BMD
Very strict PBS criteria (must be started by a specialist)
- T score of -3 or less
- At least 2 minimal trauma fractures, including a fracture after at least one year of antiresorptive therapy
When can you not use teriparatide?
<25 years old
Known or suspected Paget disease of bone
Previous radiotherapy involving bone
Pre-existing hypercalcaemia, malignancy, severe kidney disease or primary hyperparathyroidism
How long can you use teriparatide for?
Max 24 months in one lifetime
When can you not use bisphosphonates?
Severe kidney disease
What’s osteonecrosis?
Avascular necrosis of bone
Causes of osteonecrosis
Steroid use
Alcoholism
Bisphosphonates
SLE
What increases your risk of osteonecrosis of the jaw with bisphosphonates?
If bisphosphonates are used to treat metastatic cancer or plasma cell myeloma (rather than OP)
IV administration
Dose and duration of exposure
Dental extractions, implants, poorly fitted dentures, preexisting dental disease
Glucocorticoids
Smoking
Diabetes
How does osteonecrosis present?
Pain, swelling, exposed bone, local infection, pathological fracture of the jaw
When should we withhold bisphosphonates?
Prior to many dental procedure and don’t restart until after healing
Do you need a dental visit before starting bisphosphonates?
No
Explain calcium homeostasis. How does calcium, vitamin D and PTH work?
Low serum Ca2+ –> increased PTH (from parathyroid gland)
PTH
- Increases bone osteoclast activity –> releasing Ca2+ and phos
- Increases renal conversion of 25-hydroxycholecaiferol to 1,25-dihydroxycholecalciferol –> increases small bowel absorption of Ca2+ and phos
- Increases renal calcium reabsorption (distal tubule) and decreases phosphate reabsorption (proximal tubule)
= Ultimately increases Ca2+ back to normal
How is calcium transported in the blood?
45% bound to protein (mostly albumin)
15% bound to phosphate and citrate
40% ionised state
Which part of calcium is metabolically active?
Only ionised calcium
What’s pseudohypocalcaemia?
When the total calcium is low but the ionised calcium is normal
Can happen in low protein (nephrotic syndrome, malnutrition, chronic illness), fluid overload
How does pH affect calcium levels?
Acidosis reduces binding of calcium to albumin
Alkalosis enhances
Causes of hypercalcaemia
90% caused by hyperparathyroidism or malignancy
PTH dependent
1) Excess PTH
- Primary parathyroid tumours (adenomas, hyperplasia, carcinoma) or tertiary
- Familial hypercalciuric hypercalcaemia - impaired Ca2+ sensing in parathyroid glands/kidneys
- Ectopic PTH (rare)
PTH independent
2) Malignancy
- PTHrP (PTH mimic)
3) Excess 1,25 vitamin D
- Granulomatous disorders (sarcoid, TB, silicosis)
- Lymphoma
- Vitamin D intoxication
4) Increased bone resorption
- Multiple myeloma, thyroxicosis, immobilisation, vitamin A toxicity, osteolytic metastasis
5) Endocrine - adrenal insufficiency, pheochromocytoma
6) Medications
- Lithium - alters calcium sensing receptors at the parathyroid and kidneys –> increases PTH release and Ca2+ reabsorption from kidneys
What is familial hypocalciuric hypercalcaemia?
Inherited condition
Mutation in the calcium sensing receptor gene expressed in parathyroid and kidney tissue –> impaired Ca2+ sensing –> ongoing PTH release and Ca2+ reabsorption from the kidneys despite hypercalcaemia –> hypercalcaemia
Investigations in hypercalcaemia
Always measure PTH first +/- urinary calcium excretion +/- vitamin D metabolites
> If elevated or high normal –> likely primary hyperparathyroidism; consider familial hypercalciuric hypercalcaemia –> Measure urinary calcium excretion –> if high, its primary hyperparathyroidism; if low, its FHH
> If low –> measure PTHrP and vitamin D metabolites
- Elevated PTHrP –> scan for malignancy
- Elevated 1,25D –> CXR (lymphoma, sarcoid)
- Normal PTHrP, vit D –> consider other causes (measure SPEP, UPEP, TSH, vitamin A)
- Elevated 25D –> check medications
How does cinacalcet work?
Binds to the calcium sensing receptor (parathyroid) and tricks it into thinking there is more calcium than there is –> reduce PTH release –> reduce calcium
Who gets primary parathyroidism?
Post menopausal women
Really common! 2%
20% somatic mutation MEN-1 tumour suppressor gene
DDx of solitary parathyroid adenoma in primary parathyroidism
Solitary adenoma (85%)
Hyperplasia
Parathyroid carcinoma (<1%) - can cause parathyroid crisis
Familial hypocalcuric hypercalcaemia
Is parathyroidectomy an option in familial hypocalciuric hypercalcaemia?
No, its contraindicated
They become hypocalciuric
What happens in parathyroid crisis?
Severe hypercalacemia
Medical emergency
Without emergency surgery, people can die
Consequences of “mild” primary hyperparathyroidism
Increased mortality mostly CV mortality
Explain how we absorb vitamin D
Vitamin D from diet and sunlight –> transported to liver –> converted to 25-hydroxycholecalciferol by 25-hydroxylase –> goes to kidney and gets converted to 1,25-dihydroxycholecalciferol (potent) by 1-alpha-hydroxylase
Explain the effects of vitamin D
1,25-dihydroxycholecalciferol (potent form)
- Increases gut absorption of calcium and phos
- Reduces renal excretion of calcium and phos
- Activates osteoclasts and mobilises calcium from bone
= Increases serum calcium
What is the active form of vitamin D?
1,25-dihydroxycholecalciferol
What’s the function of calcitonin?
Opposite of PTH
- Increases urinary excretion of calcium and phos
- Inhibits bone resorption
= Decrease serum calcium and phos
What secretes calcitonin?
Parafollicular cells in the thyroid
What happens to bone in vitamin D deficiency?
Increase PTH release –> bone resorption
ALP will start to rise in mild vitamin D deficiency
What’s pseudohypoparathyroidism?
Rare
PTH resistance syndrome
Hypocalcaemia
Hyperphosphataemia
PTH is high (due to low Ca2+) –> decreases phos reabsorption in proximal tubule
Consequences of severe hypophosphataemia
1) Bone mineralisation defect
- Phos is required for hydroxyapatite (component of bone) formation
- Bone pain, deformity, fracture
2) Reduced conscious state
3) Impaired cardiac and skeletal muscle function
- Muscle pain, weakness
- Heart failure
Causes of hypophosphataemia
Insulin mediated
TEMPORARY #Respiratory alkalosis
- Refeeding
- Treated ketoacidosis
CHRONIC #Inadequate phosphate intake - ETOH +++ - Eating disorders - Antacid abuse (binds phos in the gut) - Severe Vitamin D deficiency - Diarrhoea - Malabsorption syndromes
- Congenital - hypophosphataemic rickets, vitamin D resistant rickets
- Hyperparathyroidism
- Fanconi syndrome (glycosuria, aminoaciduria, renal tubular acidosis)
- Volume expansion
- Vitamin D deficiency
- Thiazides
- Oncogenic osteomalacia
What’s hungry bone syndrome?
After parathyroidectomy for severe primary hyperparathyroidism, bones are no longer exposed to high PTH so all of a sudden they stop bone resorption and there is rapid and profound hypocalcaemia, hypophosphataemia.
Where is phosphate reabsorbed in the kidneys?
Proximal tubule 70% reabsorbed
PTH reduces reabsorption
Consequences of hyperparathyroidism
Increased CV mortality
Ectopic calcium deposition
- Vascular –> increased mortality
- Valves
- Other tissues
ESKD
What is FGF23?
Fibroblast growth factor 23
Secreted in response to calcitriol
Mainly regulates plasma phosphate level
Acts in the kidneys to reduce calcium reabsorption and increase phosphate excretion
= hypocalcaemia, hypophosphataemia
If calcium and phosphate go in the opposite direction, the primary defect is in….
PTH/PTHrP
If calcium and phosphate go in the same direction, the primary defect is in…
Vitamin D
Symptoms of hypercalcaemia
Stones, moans, groans, bones
Kidney stones
Vague neuropsych symptoms - concentration, depression, personality changes
GI - nausea, constipation, pancreatitis, PUD
Fractures and bone pain (if chronic)
Lethargy, coma
Polyuria, polydipsia
Cardiac: bradycardia, AV block, short QT
Causes of hypocalcaemia
Autoimmune
Low PTH (hypoparathyroidism)
Due to destruction of the parathyroid gland
#Surgical
- Most common cause
- Post thyroid, parathyroid, neck surgery
- 2nd most common
- Destruction of the parathyroid gland or calcium sensing receptors
#Infiltrative disease - Haemochromatosis, Wilson disease, granulomas, metastatic cancer
- Suppresses PTH release
- When you correct Mg, Ca2+ will normalise within hours
High PTH #Vitamin D deficiency
#ESKD - Due to decreased conversion to 1,25-dihydroxycholecalciferol (kidney) and hyperphosphataemia
#PTH resistance ie pseudohypoparathyroidism - Kidney and bone are resistant to PTH
#Extravascular deposition - In tissue or vascular space
- CKD
- Increased phosphate intake
- Excess tissue breakdown (rhabdo, tumour lysis)
#Osteoblastic metastasis - Prostate mets, breast mets
- Receive large volumes of blood - anticoagulant in blood chelates ionised calcium
- Volume expansion and hypoalbuminemia
Investigations in hypocalcaemia
Look at the albumin-corrected calcium or ionised calcium
PTH
- Inappropriately reduced in hypoparathyroidism
- Elevated in CKD, vitamin D deficiency, pseudohypoparathyroidism (PTH resistance)
Magnesium
Phosphate
Creatinine
Vitamin D metabolites (25-hydroxycholecalciferol, 1,25-dihydroxycholecalciferol)
ALP - elevated in osteomalacia (severe vitamin D deficiency) and bony mets
Lipase - pancreatitis
Urinary calcium and magnesium
What does high urinary calcium mean in hypocalcaemia?
Renal calcium losses
Untreated Hypoparathyroidism
Vitamin D deficiency
What do the vitamin D metabolites tell us in hypocalcaemia?
Hypocalcaemia –> stimulates PTH –> make kidneys convert 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol (potent)
In vitamin D deficiency, typically get low 25-hydroxycholecalciferol and high 1,25-dihydroxycholecalciferol (when’s there no renal dysfunction)
In hypoparathyroidism, typically get normal 25-hydroxycholecalciferol and low 1,25-dihydroxycholecalfierol
What do phosphate levels tell us in hypocalcaemia?
High
- ESKD
- Increased tissue breakdown
- Hypoparathyroidism
- Pseudohypoparathyroidism (PTH resistance)
Low
- There is excess PTH secretion in the context of hypocalcaemia (vitamin D deficiency)
Normal
- Mild vitamin D deficiency
- Hypomagnesaemia (causes PTH resistance/deficiency)
How does magnesium affect potassium and calcium?
Low magnesium causes renal potassium wasting
You can’t adequately replace potassium until magnesium is replete
Low magnesium also suppresses PTH release –> low 1,25-dihydrovitamin D –> hypocalcaemia
You can’t adequately replace calcium until magnesium is replete
Causes of hypomagnesaemia
GI losses
Diarrhoea
Acute pancreatitis
PPIs
#Renal losses Diuretics Calcineurin inhibitors e.g. cyclosporin Cisplatin Aminoglycosides Uncontrolled diabetes ETOH++ Hypercalcaemia
When do you get refeeding syndrome?
When you aggressively feed a chronically malnourished patient –> causes fluid and electrolyte shifts
How does refeeding syndrome happen?
Low phosphate stores –> aggressive nutritional supplementation (glucose) –> insulin secretion –> cells uptake phosphate, potassium, magnesium –> hypophosphataemia, hypokalaemia, hypomagnesaemia
What are the effects of refeeding syndrome?
Low phos, mg, K+
Tissue hypoxia Myocardial dysfunction Respiratory failure (inability of diaphragm to contract) Haemolysis Rhabdo Seizures
Most common cause of malignant hypercalcaemia
Cancer!
Produce PTHrP
Squamous cells, breast, renal, lymphoma
MM (different mechanism - increased bone turnover)
Management of malignant hypercalcaemia
1) Rehydration with normal saline 4-6L over 24h
- Will take 2-4 days for calcium to come down
2) Telemetry
3) Frusemide only if fluid overload, otherwise can make hypercalcaemia worse
2nd line
4) IV zoledronic acid
- CI in CrCl <30ml/min
- Takes 2-4 days to work, so don’t give further bisphosphonate before the 4 day mark
3rd line
5) Denosumab
- Can be used in renal impairment
- High risk of causing hypocalcaemia
6) Calcitonin
- Rapid effect
- Stops bone resorption and renal reabsorption of calcium
7) Glucocorticoids
- Only useful when hypercalcaemia is due to sarcoidosis, lymphoma, vitamin D intoxication or MM
- Takes days to work
What do these 3 cells do?
Osteoclast
Osteoblast
Osteocyte
Osteoclast - resorbs bone, from mononuclear cell
Osteoblast - makes collagen which is mineralised to from new bone, from mesenchymal stem cell
Osteocyte - terminal differentiation of osteoblast encased within bone, primarily involved in mechanosensing and secretion of FGF23 and sclerostin
Cortical bone vs trabecular bone
Cortical bone
- Dense outer shell of compact bone
- 80% skeletal mass
- Turn over rate 2-3%/year
- Highest quantity in mid radius
Trabeulcar bone
- Sponge like network of delicate plates of bone known as trabeculae
- 20% skeletal mass
- Higher turnover rate
- Highest quantity in axial skeleton
What’s bone modelling and remodelling?
Bone continues to recycle
Modelling
- During growth. Purpose is to shape the skeleton.
- Bone formation, bone resorption is not coupled
Remodelling
- Once the bone is fully grown, its purpose is to repair micro damage and mineral homeostasis
- Bone formation and resorption is coupled = called basic multicellular unit
Rank ligand and OPG
Rank ligand
Secreted by osteoblast
Binds to prefusion osteoclast –> important for differentiation of osteoclasts so it can resorb bone
OPG prevents RANK ligand binding to RANK = inhibits osteoclasts
4 Steps of bone remodelling (basic multicellular unit)
1) Resting
Bone is resting
2) Resorption
Bone gets activated - osteoclasts come to resorb the bone and make pits
3) Reversal
Osteoclasts become apoptotic and leave. Pre-osteoblasts come
4) Formation
Pre-osteoblasts mature to become osteoblasts –> secrete osteoid (unmineralised collagen) –> gets mineralised
What happens to bone in post-menopause?
Increased osteoclast numbers, increased resorption depth, incomplete filling by new bone
Result
- Cortex becomes thinner, increased porosity
- Trabecular bone increased thinning, loss of connectivity
= Osteoporosis
Treatment of osteoporosis
Target osteoclast in 3 ways
1) Bisphosphonates
- Coat surface of bone and stops osteoclast mediated bone resorption
2) Estrogen/SERMS
- Reduces rank ligand relative to OPG
3) Anti-RANKL e.g. denosumab
- Stops RANK ligand and stops osteoclast
Most common OP fracture
Vertebral fracture
As we get older, increased hip and wrist fracture
Vertebral compression fracture definition
Mild: >20% loss of height
Moderate: >25%
Severe fracture: >40%
Secondary causes of bone loss
Hypogonadism E.g. post menopause
Vitamin D deficiency
Hyperthyroidism
Hyperparathyroidism
Coeliac disease
Multiple myeloma
Drugs: corticosteroids, AEDs, GnRH agonist, aromatase inhibitors
Chronic disease: liver, kidney, RA
The risk of future fracture rises with each new fracture. True or false
True
‘cascade effect’
When to use anti-resorptive therapy in glucocorticoid use?
Risk factors for #
PO corticosteroid over 7.5mg for >3/12 steroid
Affects particularly cancellous bone
Particularly spine #, but also hip #
# occurs in 30-50% on long-term GCs
Risk factors
- Age
- Underlying disease particularly RA
- Dose and duration of GC
- Previous #
- Low BMD
- BMI <24
When to use anti-resorptive therapy in aromatase inhibitor?
Treat if T ≤-2 or fracture
When to use anti-resorptive therapy in androgen deprivation?
Treat if T ≤-2.5 or fracture (same as normal person)
Non pharmacological rx in OP
Falls prevention
- Vision
- Proprioception
- Quads strength
- Balance
Hip protectors
- Airbags for the femur
- Effective but low adherence due to discomfort, ugly, difficult to put on
Pharmacological therapy in OP
Calcium
Vitamin D
HRT
SERM (estrogen like effects in bone, anti-estrogenic effect in breast) e.g. ramloxifene used in breast ca
- Reduces vertebral # risk by 36% in postmenopausal women with OP
- No effect on non-vertebral #
Bisphosphonates
- Alendronate reduces vertebral and hip fracture by 50%
- Zoledronic acid reduces vertebral # by 70%, hip fracture by 40%
Denosumab (RANK ligand inhibitor)
- Reduces vertebral fracture by 70%, hip fracture by 40%, non-vertebral fracture by 20%
- BMD continues to rise with continued therapy - 18% increase after 8 years in spine, 8% increase after 8 years in hip (bisphosphonate plateaus after 3 years of therapy)
IV Zoledronic acid
AE
Flu like effect (1st dose effect)
Serious AF
Can we stop alendronate after 5 years of treatment?
BMD does decrease slowly over time, accompanied by increased risk of #
There are 2 available skeletal anabolics for OP
How do they work?
When are they used?
1) PTH (teriparatide)
- Stimulates osteoblasts to make new bone
- This is weird as hyperPTH can cause osteoporosis. If single daily PTH is used, get bone formation; but continuous PTH infusion leads to bone loss
- Reduces vertebral and non-vertebral #
- Available on special authority scheme for those with severe OP and recurrent # despite anti-resorptive therapy
2) Romosozumab
- In genetic syndromes with LRP5 mutation, people have VERY HIGH BMD like T score >10
- Romosozumab binds to sclerostin so it can’t bind to LRP5 –> increased bone formation
- Available for those with recurrent # despite anti-resorptive therapy and T score >-3
- AE: may have increased CV events
Why do we only use teriparatide for 18 months?
“Anabolic window” - first 18 months of treatment, you get exponential rise in bone formation markers (OPG), but after 18 months, you get rise in bone-resorption markers which will counteract the bone formation markers. Hence we only use teriparatide for 18 months.
Paget’s disease
Mechanism
Increased osteoclast activity –> diminish strength of bone –> bone pain, bone bends on weightbearing, stress fractures
Increased bone turnover with areas of bone sclerosis, but the primary mechanism is that it’s weak
Rarely get osteosarcoma
Paget’s investigations
Raised ALP (increased turnover)
Xray
Bone scan
Paget’s treatment
Zoledronate 5mg once yearly or even every 3-5 years
Indications for treatment in Paget’s
Bone pain Involvement of petrous temporal bone Nerve or spina cord compression Cardiac failure Involvement of critical bone e.g. cervical vertebrae Involvement of skull Cosmetic change Bending of femur or tibia
