PBL 12- Osteoporosis Flashcards
What is the first line treatment for depression in the elderly?
• First line = SSRI
○ Monitor for hyponatraemia and serotonin toxicity
○ Avoid paroxetine- anticholinergic
○ Avoid fluoxetine: long half life
• Second life : SNRIs
○ Venlafaxine
○ Mirtazapine- less likely to cause hyponatraemia
• ECT -safe and effective in the frail aged
• Third line = tricyclics
How does bipolar present differently in the older aged?
- More irritable than euphoric
- Paranoid rather than grandiose
- May have dysphoric mania
What is the treatment for bipolar in the older person?
Lithium
○ May have decreased renal clearance and neurotoxic effects more common
○ Valproic acid is also helpful for behavioural disturbances
How common is psychosis in older people?
- up to 23% of the older adult population will experience psychotic symptoms at some time
- Main contributing factor is DEMENTIA
What are the risk factors for older people developing a psychosis?
- age related changes in the frontotemporal cortices
- Social isolation
- Sensory deficits
- Cognitive decline
- Polypharmacy
- Medical comorbidities
What are the diagnosis’ that account for 80% of psychotic older patients?
- Dementia
- Delirium
- Depression
- Organic
What is the First line medication choice for psychosis in older people?
• Haloperidol
What is used in the behavioural and psychological symptoms of dementia?
Risperidone
What is the DSM criteria for Dementia?
- Declining cognition, functional decline for at least 6 months duration
- Amnesia
PLUS 1 or more of the following:
• Aphasia
○ Impairment of language, affecting the production of comprehension of speech and ability to read or write
• Apraxia
○ Difficulty with the motor planning to perform tasks or movements
• Agnosia
○ Inability to process sensory information
• Executive function
○ Goal formation, planning, self monitoring, attention, response inhibition
What is the pathology found in Alzheimer’s disease?
• Damage in the medial temporal lobe (hippocampus)
○ Intracellular damage (neurofibrillary tangles)
○ Extracellular deposits (amyloid plaques)
• Spreads to effect cortical structures
• Memory and later language affected
• Both subserved by cortical structures
What is the treatment for dementia?
• Biological treatments ○ Cholinesterase inhibitors for AD ○ Aspirin for Vascular dementia ○ There are no disease modifying agents at this time. • Functional issues addressed ○ Home care ○ Residential placement • Legal issues • Carer support • Family issues ie genetic counselling • Behavioural and psychological symptoms of Dementia ○ Often need psychogeriatric input
How is bone mass normally maintained?
What regulates this?
Balance between activity of:
• Osteoblasts which produce matrix and bone mineralization
• Osteoclasts which break it down (degrade the matrix and cause resorption)
Process is tightly regulated by local endocrine factors • Hormones • Vitamins • Stress • Inflammation • Growth factors • cytokines
What factors affect formation and resorption by osteoblasts/clasts?
• Glucocorticoids ○ Inhibits osteoblasts • Estrogen ○ Inhibits osteoclasts and stimulates osteoblasts • Thyroid hormones ○ Stimulates osteoclasts • Growth hormone nd IGF1 ○ Stimulates osteoblasts • Calcitonin ○ Inhibits osteoclasts
What things can shift bone turnover to favour resorption?
- Decrease in sex hormones
- Drugs- glucocorticoids
- Hyperparathyroidism
- Cushings Syndrome
- Kidney disease
- GIT absorptive issues
- Genetic causes- affect enzymes that regulate bone metabolism
What is Osteoporosis?
· Systemic condition characterized by low bone mass and deterioration in bone microarchitecture
· Leads to increased bone fragility and increased fracture risk
Where is the bodies calcium usually stored?
Why is this clinically important?
· 99% is stored in the bone as ca hydroxyapatite
· 1% is dissolved in blood and ECF
• Bound to plasma proteins, small organic molecules (Phosphate) and free ions
· This means that If the body needs calcium, it needs to come from this store
Why is calcium homeostasis important?
· It is essential for key cellular processes
• Heart and muscle contraction
• Nerve conduction
• Exocytosis
• Activity of enzymes
· There is a tight control of extra and intracellular calcium levels via transporters, pumps and binding proteins
· If there is a dietary deficit in calcium it will be resorbed from the bone
What are the clinical consequences of high or low blood calcium?
· Hypercalcaemia • Fractures due to excessive resorption of bones making them prone to break after minor trauma • Formation of renal stones • Proximal myopathy • Pancreatitis • Mental changes • Usually due to primary hyperparathyroidism · Hypocalcaemia • Paraesthesia • Cramps • Tetany • Agitation • Seizures
What are the key players in calcium homeostasis, and how to they interact?
Parathyroid hormone
• Fast acting
• Responsible for the minute to minute control of serum calcium concentration
· Calcitriol
• Slow acting and maintains day to day control of serum calcium concentration
What are the main target organs in calcium homeostasis?
· Intestine
· Kidney
· Bone
Parathyroid hormone: What is its role? Where is it produced/Secreted? What regulates this ? What does it target and what are the effects?
Role:
· The most important regulator of blood calcium and phosphate
· Primary hormone regulating bone metabolism/remodelling
Produced and secreted:
· Parathyroid gland
· Synthesized as a preprohormone
Regulation:
· Secretion is dependent on serum calcium
• Calcium binds to a Calcium sensing receptor (CaR)
• This is a GPCR expressed on many cells
• Signalling cascade leads to SUPPRESSION of PTH secretion and cell proliferation
· Inhibited by - high plasma Ca
· Stimulated by- low plasma ca
Targets:
· Bone
• Causes resorption via increased osteoclast activity
• Increased calcium mobilisation
· Kidney
• Increased calcium reabsorption
• Decreased calcium excretion in urine
• Increased production of active vitamin D
○ This acts on the small intestine to increase calcium absorption from the diet
Effect:
· Increased blood calcium
What is the Ca/PTH axis feedback loop?
What is the clinical significance of this?
· PTH is the principal modulator of plasma ca levels
· ECF Ca levels are the primary determinant of PTH secretion
· Comparing calcium and PTH levels can show where there is a problem in the axis
· Examples
• Low calcium with low PTH = PTH not responding ? Hypoparathyroidism
• High Calcium with High PTH = Gland producing too much PTH ? Hyperparathyroidism
• Low calcium with high PTH = response is correct- need to evaluate for non parathyroid problem
Calcitonin
Where is it produced/Secreted?
What regulates this ?
What does it target and what are the effects?
Produced:
· Thyroid C cells (main source)
· Also in other tissues (lung, intestine and mammary gland)
Targets: · Kidney • Increases excretion of calcium · Bone • Increases deposition in bone by inhibiting osteoclasts • Prevents resorption · Intestine • Decreases uptake
Aim:
· Decrease blood calcium levels
Vitamin D2/D3
What are the different forms?
Where is it produced?
Solubility/trasnport?
Vitamin D2 = ergocalcigerol
• Sourced from plan and yeast
Vitamin D3 = Cholecalciferol
• Most is produced by the skin in photochemical synthesis
• Exposure of the precursor to UV radiation
• Some is ingested in small amounts in fish
Activity:
· In the D2 or D3 form it is a pro-hormone with little significant biological activity
· Needs to be metabolised to an active form
· Lipid soluble steroid hormone
· Transported in the blood by transcalciferin
• Vitamin D binding protein
• Long half life - 5-12 hours
Calcitriol:
How is it synthesized?
What are its actions?
Solubility/binding?
· Vitamin D3 must be metabolised within the body to become the active form - calcitriol
• Liver forms the intermediate form - Calcidiol
• Kidney transforms this into the active form calcitriol under the stimulation of PTH
· The lipid soluble hormone Binds to intracellular Vitamin D receptors
· Effects gene expression to cause protein synthesis
Acts on · Bone: • Regulates bone remodeling · Gut • Inreases calcium and phosphate absorption · Muscle • Increases growth , strength and contraction · Increases immune function · Decreases inflammation · Epithelial cells • Increases differentiation • Decreases proliferation • Causes apoptosis
What happens to calcium absorption when there is a vitamin D deficiency?
· It is not efficiently absorbed
· Calcitriol controls synthesis of genes and increases expression of proteins that promote transcellular transport of ca
What happens when blood Calcium levels fall?
PTH
· Low calcium causes stimulation of PTH secretion
· PTH acts directly on bone to induce osteoclastic resorption from bone
· PTH increases synthesis of Calcitriol by the kidney
· PTH increases reabsorption of calcium from the glomerular filtrate preventing loss in the urine
Calcitriol
· Calcitriol increases intestinal absorption of calcium
· Calcitriol can stimulate osteoclasts indirectly by stimulating osteoblasts to release factors that stimulate differentiation
• Not as potent as PTH
• Slow acting
• Role in normal bone remodeling
What do PTH , calcitriol and calcitonin do In the case of normal calcium levels?
PTH
· Inhibition of PTH synthesis
· Decrease in PTH levels
· Less mobilization of calcium from the bones
Calcitriol
· Enhances absorption of Ca and phosphorus from the small intestine
· This helps to maintain a proper balance that assists Calcitonin to mineralize the bone matrix
Calcitonin
· Reduces osteoclastic bone resorption and allows excess calcium to deposit in bones
· Decreases PTH synthesis
How common is Vitamin D deficiency?
What are the effects of a mild/Moderate deficiency?
What are the effects of a s
· More than 40% of the world is vitamin D deficient
· 1 in 5 children
· Can be due to : • Reduced intake • Age related factors • Decreased sun exposure • Sunscreen use • Decline in renal function
· Mild to moderate deficiency
• Decreased calcium absorption resulting in decreased serum calcium
• Increased PTH causing increased tubular resorption of calcium and bone resorption
• Decreased bone density
• High bone turnover
• Increased fracture risk in older people
· Severe Vitamin D deficiency
• <15 nM
• Blood calcium below normal
• Can cause secondary hyperparathyroidism
○ PTH also causes phosphorus loss via the urine leading to a decreased serum phosphate
○ This imbalance causes a defect in bone mineralization
• Children get rickets
• Adults get Osteomalacia
Phosphorus- How abundant is it? Where is it stored? What do cells use it for? Dietary sources?
· It is the most abundant mineral after calcium
· The bulk is stored in bone (85%) as mineralized hydroxyapatite ECM giving the bone strength
· Every cell contains phosphate anions
• Complexed to proteins or lipids
• Nucleic acids in DNA and RNA
• Needed for energy production
• Used as a chemical buffer in serum and urine
· Most unprocessed food has it
How is phosphate balance maintained- ie ?
Renal cotransporter:
• There are sodium- phosphate co transporters in the proximal renal tubular cells
• If there is low dietary phosphate intake there is an increase in expression of transporters leading to increased renal phosphate absorption
• In excess intake the opposite occurs and there is less transporters expression and more phosphate is excreted in urine
FGF-23
· FGF 23 = 23 fibroblast growth factor (phosphaturic hormone)
· Secreted from bone
· Works on the kidney
· Secreted in response to HIGH dietary intake or serum phosphate levels
· It works on the Sodium phosphate cotransporter to decrease expression of transporters
· Causes:
• Inhibition of phosphate reabsorption (Similar to PTH)
• Increased excretion of phosphate (Similar to PTH)
• Decreases calcitriol synthesis resulting in decreased gut phosphate absorption (Opposite to PTH)
· Aim:
• To decrease serum phosphate level
What happens if the FGF-23 is excessively elevated?
What causes it?
· Phosphate levels will become too decreased
· Linked to rare forms of hereditary hypophosphataemic rickets and osteomalacia
· Most often found in chronic kidney disease
• Decreased glomerular filtration
• Decreased kidney phosphate excretion
• Increased FGF 23 secretion from bone
• Decreased calcitriol through inhibition of hydroxylase in the kidney
• Low blood calcium
• Secondary hyperparathyroidism
Very broadly what are the effects of the following on ca and phosphate levels?
PTH
Calcitriol
PTH :
· Increases Calcium
· Decreases Phosphate
Calcitriol
· Increases Calcium
· Increases Phosphate
What are some causes of hypercalcaemia?
What is the reference range?
· > 2.6 · Hyperparathyroidism • Primary, secondary, tertiary · Increased absorption of calcium · Malignancy · Vitamin D intoxication · Thiazide diuretics · Renal insufficiency · Thyrotoxicosis · Familial hypocalciuric hypercalcaemia · Sarcoidosis
What are the effects of Hypercalcaemia?
· Neurological: • Confusion • Lethargy • Headaches • Depression • Coma · Abdominal: • Nausea and vomiting • Abdominal pain • Polyuria, polydipsia • Pancreatitis • Kidney stones · Other: • Dehydration • Bradycardia • Renal failure • Muscle fatigue
What are some causes of hypocalcaemia
What is the range?
· < 2.25 · Osteomalacia : vitamin D deficiency · Chronic renal failure · Hypoparathyroidism · Alkalosis · Hypomagnesaemia · Acute pancreatitis · Alcoholism · Chronic diarrhoea · Hyperventilation · Malabsorption
What are some effects of hypocalcaemia?
· Cardiovascular: • Long QT intervals • Hypotension • Heart failure · Neuromuscular • Cramps / spasms • Tetany • Bronchospasms · Neurological: • Irritability • Seizures /Convulsions • Hyperreflexia • Positive chvostek sign • Positive trousseau sign • Parathesias · Abdominal • Intestinal cramps • laryngospasm
What are some causes of hyperphosphataemia?
· Increase absorption of phosphate
○ Excess use of some laxatives and enemas
○ Excess Vit D
· Shift of phosphates from cells into blood
○ High levels of cell destruction –metastatic tumour cell lysis during chemotherapy
· Inadequate excretion of phosphate
○ Renal failure
○ Hypoparathyroidism
What are the clinical manifestations of hyperphosphataemia?
· Neuromuscular: • Muscle cramping / Muscle twitching • Tetany • Hyperreflexia • Hypotension · Neurological: • Confusion • Paraesthesia • Seizures • Coma · Other: • Soft tissue calcification – Aching, stiff joints • Alkalosis • Itching skin • Cardiac dysrhythmias
What are some causes of hypophosphataemia?
· Inadequate absorption of phosphate • Chronic diarrhoea • Vomiting • Malabsorption • Misuse of phosphate-binding antacids • Chronic alcoholism • Vit D deficiency · Shift of phosphate from blood into cells • Respiratory Alkalosis • Insulin administration • Adrenalin administration · Excessive phosphate excretion • Increased diuresis • Hyperparathyroidism · Other: • Severe burns • Severe sepsis
Magnesium:
What is its role in the body?
Where is it stored?
Where is it sourced from?
Role: · Nerve and muscle function · Neurotransmission · Bone structure · Constituent of several enzymes
Stored:
· 50% is stored in the bone and muscle
· 1/3 is bound to protieins
Dietary source: · Green vegetables · Cereal · Nuts · Dairy products
What are some causes of Hypermagnesaemia?
· Increased absorption of Mg: • Excessive use of Mg-containing antacids • Excessive infusion of Mg · Decreased excretion of Mg: • Renal failure • Metabolic acidosis
What are the clinical manifestations of hypermagnesaemia?
· Neuromuscular: • Decrease in deep tendon reflexes - Hyporeflexia • Muscular weakness • Paraesthesia • Paralytic ileus · Other: • Platelet aggregation • Hypotension • Dysrhythmia • Respiratory depression • Drowsiness and lethargy • Flushed skin and sweating • Cardiac arrest
