Bone Physiology Flashcards
What are the calcium-regulating hormones?
Circulating calcium in the ECF is tightly controlled - this is what is measurable in labs
Normal reference range for total calcium is 2.2-2.6 umol/L
Largely regulated by two hormones:
- PTH
- 1,25(OH)2D (calcitriol - activated vitamin D)
Also regulate phosphate concentration (Ca and P never go up together, one will increase as the other decreases as part of a regulatory mechanism - in CKD or some other diseases this is disrupted)
Calcitonin has a proposed minor role in Ca homeostasis - bigger role in other mammals
Where is PTH produced?
There are four parathyroid glands in the body, each is roughly size of a grain of rice so they are very difficult to localise, but in gland hyperplasia (causes hyperparathyroidism) at least one gland increases to the size of a baked bean (not much easier to locate).
PTH is secreted by each of the parathyroid glands, specifically chief and oxyphil cells. PTH synthesised, stored and secreted by chief cells.
Concentration PTH in plasma determined by its synthesis and secretion by parathyroid glands. Metabolism and clearance determined by liver and kidneys.
What is the function of PTH?
PTH acts:
- directly on bone and kidney
- indirectly on intestine to regulate [Ca] and [PO4]
PTH exerts its influence by interacting with PTH/PTHrP receptors on plasma membrane of target cells. This initiates a cascade of intracellular events:
- Generation of cAMP
- Activation of kinases
- Phosphorylation of proteins
- Increased entry of calcium and intracellular calcium
- Stimulated phospholipase C activity
- Generation of DAG and PI activate enzyme transport systems
- Secretion of lysosomal enzymes
What forms of vitamin D are present and active in the body?
Several forms of Vitamin D (vitamers): D1 – D5
Two major forms are the parent molecules, known collectively as calciferol:
Vitamin D2 – Ergocalciferol
Vitamin D3 – Cholecalciferol
25(OH) Vitamin D
- Precursor to vit D = not active, but what is measured as
deficiency. - Calcidiol, Calcifediol, 25-hydroxycholecalciferol, 25-hydroxyvitamin D
1,25(OH)2D
- Hydroxylated to active form in kidney - kidney issues lead to little vit D
- 1,25-dihydroxycholecalciferol, 1,25-dihydroxyvitamin D, Calcitriol
Alphacalcidol
1-hydroxycholecalciferol
Vitamin D analogue with less of an effect on calcium than calcitriol
Calcichew D3 Forte
Vitamin D3 with calcium
How is vitamin D clinically measured and utilised?
Vitamin D:
Non-hydroxylated parent compounds, short t1/2= 24hrs, conc transient based on recent sun exposure and diet
Very liphophilic and difficult to measure
25(OH) Vitamin D, D2 and D3
Effectively a pre-cursor of active form of Vitamin D
t1/2= 3 weeks
Direct indicator of available Vitamin D
1,25(OH) Vitamin D
Active form, very short t1/2= 4hrs
Limited clinical utility as the stability is too low - still metabolises in the tubes
How is vitamin D involved in the endocrine system?
PTH senses low Ca through Ca sensory receptors.
Causes an increase in PTH which:
- acts directly on the kidney:
- activates vit D by increasing 1a hydroxylase activity leading to
increased active vit D
- this increases calcium resorption and decreased excretion in
the tubules
- acts directly on the bone
- causes a deminarlisation of the top layer of bone
- this releases Ca and P, both of which increases the serum
calcium concentrations. BUT but dont want both P and Ca to
increase at the same time, so PTH is phosphoturic - causes
increased P excretion in urine to maintain balance, and increased
absorption of Ca
- acts indirectly on the gut via activated vitamin D,
- hence if an earlier route to activate vit D is ineffective, this will
be too.
- Increased absorption of active vit D in gut increases calcium
and phosphate.
How does PTH have an effect in the kidneys?
Induces 25-OH Vit D-1α-hydroxylase which increases production of 1,25(OH)2D (active form) which stimulates intestinal absorption of calcium and phosphate
- Increases calcium reabsorption in the DCT - Decreases reabsorption of phosphate in PT
Inhibits Na+-H+ antiporter activity which favours a mild hyperchloremic metabolic acidosis in hyperparathyroid states
- High chloride and low bicarbonate
How does PTH have an effect in the bone?
Effects of PTH are complex as can stimulate bone resorption or bone formation depending on [PTH] and duration of exposure
Chronic exposure to high [PTH] leads to increased bone resorption
- PTH acts directly by altering the activity or number of osteoblasts and
indirectly on osteoclasts
- Bone resorption, a quick response is important for maintenance of
calcium homeostasis
- Delayed effects are important for extreme systemic needs and skeletal
homeostasis - inc number of osteoblasts to increase bone turnover
How is calcium homeostasis affected in Renal failure?
Fall in calcium:
↓ conversion 25(OH)D to 1,25(OH)D = no activation
Increase in phosphate:
Kidneys are not excreting excess
FGF23 role - research tool but early indicator of phosphate homeostasis
Increase in PTH:
Stimulated by low Ca (no activation, and no indirect effect on gut)
Continual stimulation of parathyroid glands leads to 2° hyperparathyroidism (gland takes over and becomes autonomous = no homeostasis)
Patients with end stage renal failure become hypercalcaemiac
Probably due to development of autonomous PTH secretion from prolonged hypocalcaemic stimulus
Such hypercalcaemia may manifest for the first time in a renal transplant patient who becomes able to metabolise vitamin D normally - 3° hyperparathyroidism
How does PTH cause Ca mobilisation?
Integration of direct and indirect effects of PTH lead to alterations in calcium and phosphate in serum and urine
PTH mobilisation of calcium is biphasic:
- A rapid phase involving existing cells
- Long term response dependent on proliferation of osteoclasts
In serum total and free calcium are increased, phosphate decreased
In urine, inorganic phosphate and cAMP are increased
Urinary calcium is usually increased as larger filtered load of calcium from bone resorption and intestinal reabsorption overrides increased tubular reabsorption of calcium
In absence of disease the increase in serum calcium reduces PTH secretion through negative feedback loop maintaining homeostasis
How does PTH affect Phosphate and Mg?
Despite PTH being important in control of phosphate secretion
Changes in phosphate do not directly affect secretion of PTH
Mild hypomagnasaemia stimulates PTH secretion
More severe hypomagnasaemia reduces PTH secretion as it is a Mg dependent process (requires Mg for activation)- cAMP and ATP pathways always have Mg cofactors
What are the functions of bone?
Support:
Framework of body supporting softer connective tissues and muscles
Protection:
Mechanical protection for internal organs
Assisting in movement:
Muscles attached to bones so when they contract bones will move
Mineral storage:
Calcium and phosphate reservoirs
Production of blood cells (haeopoetic system):
Bone marrow inside some long bones
Storage of energy:
With age, bone marrow changes from ‘red’ to ‘yellow’ and is predominantly adipose cells providing a chemical energy reserve
What are the different types of bones?
Long bones
- Greater length than width, shaft (diaphysis) with variable number
of endings, curved for strength
- Predominantly COMPACT bone with lesser amounts of marrow
and spongy bone - Bigger capacity but less weight
- e.g. femur, tibia, ulna and radius
Short bones:
- Roughly cube shaped with approximately equal length and width
- Thin layer of compact bone surrounding SPONGY interior - Absorbing
bones - i.e. jumping
- e.g. ankle and wrist bones
Flat bones:
- Thin structure providing mechanical protection and extensive surface
area for muscle attachment
- TWO parallel layers of COMPACT bone surrounding SPONGY interior
- e.g. cranial bones, sternum, shoulder blades
Irregular bones:
- Complicated shapes due to function they fulfil within body
- Thin layers of compact bone surrounding SPONGY interior
- e.g. vertebrae and some facial bones
Sesamoid bones:
- Develop in some tendons where there is considerable friction, tension
and physical stresses; quantity varies considerably person to person
- e.g. common to all are patellae (kneecaps)
What is the structure of bones?
Long bones grow from the ends and under normal circumstances stop growing in late teens or early 20’s - dictate height
Two main types of (lamellar) bone tissue:
- Compact
- Forms outer shell of bones consisting of very hard bones
arranged in concentric layers (Haversian systems)
- Accounts for 80% of total bone mass of adult- thin but very dense -
hence function - Cancellous (trabecular, spongy bone)
- Located beneath the compact bone
- Consists of a meshwork of bony trabeculae with many interconnecting
spaces containing bone marrow
- Accounts for remaining 20% of total bone mass but nearly 10x surface
area of compact bone
What are the different types of bone cells?
OsteoBlasts (Build bone):
- Produce collagen-based matrix which mineralises to form
‘osteoid’
- Become quiescent and flatten to become lining cells
- Respond to hormonal control to activate osteoclasts
OsteoCYCtes (‘cycle’ - transport minerals)
- Cells inside the bone which sense mechanical stress to initiate
remodelling
- Transports mineral into and out of bone
OsteoClasts (‘Consume’ minerals)
Dissolve bone by solubilising mineral - resorption = demineralise top layer
Effects change in bone structure
What is bone remodelling?
Process of resorption followed by replacement
Lifelong process - but different periods of activity
- In 1st year of life almost 100% of bone is replaced
- In adults approx 10% per year - but no change in overall shape
Little change in shape and occurs throughout life
- Regulates calcium homeostasis
- Repairs micro-damaged bones (everyday stress)
- Shapes and sculptures skeleton during growth
Imbalance leads to metabolic bone disorders
