Biochem: Calcium homeostasis and bone Flashcards
Name as many physiological functions of calcium
Bone mineralisation Tooth formation Muscle contraction Enzyme co-factor First extracellular messenger Second intracellular messenher Secretion and exocytosis Stabilistion of membrane potentials Regulation of cellular division, proliferation and apoptosis
How much of the 1.2kg of Ca2+ is stored in the skeleton?
What is the mineral component?
99%
Hydroxyapatite
1% intracellular
0.1% extracellular
Where is the calcium intracellular
Sequested in intracellular organelles (endoplasmic reticulum, mitochondria, skeletal muscle sarcoplasmic reticulum)
What id the intracellular concentration of calcium
Serum concentration
100nmol/l
Serum: 2.5mmol/l
How does serum calcium circulate?
Effect of albumin levels
Effect of acidosis
45% free ionised form (free calcium)
55% bound (45% to albumin) - changes in albumin changes rain free to bound calcium, in acidosis H+ competes for albumin binding sites
How efficient is the absorption of Ca from the diet.
Where does it mostly occur?
Poor only 20-30% absorption
From the small intestine
Depends on Vit D availability
How does the Calcium balance change throughout a woman lifetime
Child positive
Adult neutral
Post menopausal negative
What are the 3 main hormones that control calcium levels
Parathyroid hormone (increases levels)
Vitamin D/Calcitriol (increase levels)
Calcitonin (decrease levels)
Where is parathyroid hormone produced. Which receptors does it act on?
Chief cells in parathyroid
G protein coupled receptor (PTHR1)
Where does PTH act? What changes does it illicit?
Bone: Activate osteoclasts resorb bone - release Ca and phos
Kindey: Increased phosphate excretion
Kindey: Decreases Calcium excretion
Kidney: Activated Vitamin D
What causes primary hyperparathyroidism?
What happens to levels of Ca/phos/vit d/PTH
Excess of PTH from parathyroid (often benign tumour) High Ca Low phos High Vit D High PTH
What causes secondary hyperparathyroidism?
What happens to levels of Ca/phos/vit d/PTH
Defect in kidneys (CKD), unable to respond to PTH, renal reabsorption Ca not promoted and Vit D not reactivated.
Lead to bone demineralisation (osteomalacia)
What causes tertiary hyperparathyroidism?
Complication of secondary PTH continously excreted leading to parathyroid hyperplasia and appears similar to primary hyperparathyroidism.
Seen in end stage renal failure
Which hormone is released by malignant cells leading to hypercalcaemia
Parathyroid hormone related peptide (PTHrP) (no effect on active vitamin D)
How much vitamin D is from dietary intake vs synthesised in the skin?
10-20% diet
80-90% skin
What is the role of vitamin D
Normal bone remodelling
Increases levels of Ca2+ and phosphate by increasing intestinal absorption
What is considered the active metabolite
Calcitriol
Describe the synthesis of vitamin d in humans
7-dehydrocholesterol in kertinocytes is actived into vitamin D3 (cholecalciferol) mediated by ultraviolet light. It is then activated by i) hydroxylated in the liver ii) hydroxylated in the PCT of kidney to calcitriol.
Where can inactive metabolites of vitamin D be stored?
Body fat, released in winter
What are the physiological actions of vitamin D calcitriol
Bone: Increases bone formation and mineralisation
Bone: Increased bone remodelling
GI tract: Increased calcium absorption
Kidney: Increased calcium and phosphate reabsorption
also important immune system, inflammation and impair progression of cancer
Causes of vit d deficiency
Poor nutritional (amount or absorption) Failure to synthesis - kidney/liver insufficiency, lack of UV light
How does vitamin D deficiency present in children
Rickets failure to minerlise endochondral bone
Deformity of limbs, soft skull ones, delayed clousre anterior fontanelle, harrison sulcus, thickening ankles/knees/wrists
Suffer bone pain, increased fracture, defects in tooth formation, muscle weakness
How does vitamin D deficiency present in adults
Osteomalacia failure to mineralise newly formed osteoid
XRAY: bones thin, perhaps looser zones
Where is calcitonin produced?
What effects does it cause?
Produced parafollicular cells in the thyroid gland in response to high calcium
What effect does calcitonin cause
Acts on kidney and bone but decreases amount of Ca.
Kidney: inhibits calcium & phosphate reabsorption
Bone: Shrinks osteoclasts
What is dietary absorption of phosphate like?
Good 80% absorbed
How is phosphate excreted?
From the kidney - CKD suffer hyperphosphataemia.
How does the levels of calcium concentration compare between mother and inutero fetus?
At what stage of the pregnancy does most accumulation of calcium occur?
Baby is relative hyperpercalamic 1.4 to 1.0.
In the 3rd trimester as this is when ossification occurs.
When can the fetus produce PTH. What are the concentrations like at birth.
12 weeks. But serum conc remains low until 2-3days postpartum, high calcitonin
What happens to the mothers levels of PTH, Vit D and calctionin
PTH normal/low
Vit D Increased
Calcitonin Increased
Increased gut absorption
What is the function of bone
Structure protection production of blood cells Attachment muscles, tendons and ligaments Storage (buffer) of mineral (ca po Mg)
What the 2 main components of bone?
Osteoid - a protein matrix 25% secreted by osteoblasts.
Mineral component - hydroxyapatite 65% - requires high amounts of caclium and phosphate
What is osteoid made from
Type 1 collegen 90%
Non collagenous protein
What are the 2 types of bone tissue?
Trabecular - spondy appearance
Cortical strong heavy outer layer
What are the 3 types of bone cells
Osteoclasts - reabsorb bone
Osteoblasts - bone production
Osteocyte - terminally differentiated osteoblasts trapped in bone - maintain contact withsurface by fluid filled canalicil.
What is the importance of bone remodelling
Good quality bone and structural integrity
What id the effect of oestrogen on the bone cells
- Inhibits osteoclast function and osteoclastgensis
- Promote osteoblast survival
Hence why menopause is linked to osteoporosis
What hormone deficiency causes 20% osteoporosis in men
Testosterone deficiency
How can you asses bone remodeeling and bone mineral density
XRAY/DEXA
Biochemical markers of bone turnover
How many women are at risk of osteoporotic fractures >50
1 in 2 (1 in 5 in men)
What causes osteoporosis on a cellular level
Osteoclast reabsorption exceeds osteoblast bone formation. In bone remodelling the resorption pits are not fully rested by the osteoblasts and micro fracture are not repaired effectively.
What advice can be offered to those with osteopenia
Increase Ca intake
Light weight bating exercise
Vt D
Stop smoking reduced ETOH
Who are DEXA scans offered to
Long term steroids Premature menupasuse Prolonged secondary amenorrhoea Hx fragility fracture radiological osteopenia vertebral defmorty Fix early severe osteoporosis
WHO diagnosis of osteopenia/osteoporis
Normal above -0.1
Osteopenia -1 to -2.5
Osteoporosis below -2.5
What 2 important factors determine risk of osteoporosis
Rate of bone loss (accelerated in menopause)
Peak bone mass obtained
How to manage osteoporosis
Maintain current BMD
Lifestyle/diet
Drug Tx (bisphosphonates, selective oestrogen receptor modulator, PTH and denosumab)
Early detected with DXA
prevent fractures
Minimise falls, good footwear/glasses/walking aids/muscle strength & balance
How much calcium a day does lactation require
280-400mg/day
Can pregnancy cause osteoporosis
Yes - pregnancy related osteoporosis, BF related osteoporosis
41% 3rd trimester
56% postpartum
presents same pain/loss of height/ vertebral fractures
difficult to assess as imaging contains radiation
Resolved 6 months after birth/weaning
Juvenile osteoporosis
Causes
effect on later life
Idiopathic
Underlying condition (RA, endocrine disorder)
Drugs (steroid)
Lifestyle
Lower peak bone mass, high risk of osteoporosis in later life
