Bone metabolism Flashcards
Which bone minerals make up 40-60% of the weight of bone?
Hydroxyapatites (Ca10(PO4)6 (OH)2), carbonates, Phosphorus (HPO4), and Calcium (Ca2+)
In which forms calcium can be found in the body?
- Storage in the bones as hydroxyapatite
- Circulating in the plasma
~45% as free ionised calcium only this form is physiologically active.
~45% bound to proteins, mainly albumin
~10% complexed with anions (i.e citrate, sulfates, phosphates)
Normal range of plasma calcium concentration
Normal range is 1.3-1.5 mmol/L = 7-10 mg/dL
Vitamin D actions
Calcitriol is the active form (1,25-dihydroxyvitamin D)
Lipophilic hormone, it acts through an intracellular receptor. It binds to a cofactor and acts at the vitamin D-responsive element.
- upregulation of apical membrane calcium channels and calbindin protein that is required for the passage of intracellular calcium in the kidney and gut -> intestinal and renal calcium absorption
- On the osteoblasts, the RANK ligand and OPG increase -> increase bone mineralization
- It also acts on the parathyroid decreasing PTH expression.
-> elevation of plasma calcium and phosphorus
PTH
PTH is a polypeptide secreted by chief cells of the parathyroid glands. There is a pro-hormone and hormone.
PTH acts through a g protein-coupled receptor (mostly Gq): PTH1R which is present on osteoblasts but absent in osteoclasts
Stimulated by low calcium levels.
- acts directly on the bone and kidneys, increasing calcium resorption
- increases hydroxylation of vitamin D that in turn increases the number of calcium channels in the intestine and also the calcium reabsorption in the kidneys. There is a feedback loop through vitamin D receptors.
- increases resorption by osteoclasts, thereby increasing calcium release by bone.
-> elevation of plasma calcium and decrease in phosphorus
FGF23
- inhibits PTH
- secreted by osteocytes in response to elevated calcitriol and elevated K
- decreases the reabsorption
- increases excretion of phosphate
RANK-RANKL osteoprotegerin pathway
Osteoclast precursors have the RANK membrane bound receptor which is activated by the RANK ligand secreted by osteoblasts. The ligand is produced by the activated osteoblast cells following specific stimuli.
Osteoprotegerin (OPG) that is a decoy receptor always made by the osteoblast/osteocyte lineage that binds to RANKL acting as a scavenger of excess RANKL produced.
Bone functions
- Structural support and locomotion
- Protection of internal structures
- Reservoir for GFs and cytokines
- Environnement for hematopoiesis
Bone regeneration
When there is a micro-fracture, osteoclasts are activated. Osteoclasts activate the stem cell and osteoblast progenitors that differentiate and start to form new organic protein and matrix that is mineralised. Osteoblasts lay down collagen and mineral and secrete numerous molecules as semaphorin 3a that has a dual function in bone remodelling: it augments osteoblastic activity through Winglessintregration (WNT) signals but repels osteoclast precursors. In turn, osteoblasts, if required, further activate osteoblasts.
TGF beta and IGF1 are important for osteoblasts maturation.
Brain-bone connection
The sympathetic nervous system, especially noradrenaline, activates osteoblasts by the beta2 receptor.
If you use beta blockers that block beta1 and beta2, you can have an increase in bone mass and reduced fracture risk.
Many hormones act both from neuro and adeno pituitary that act on the bone. ACTH and GH are involved in the regulation of growth. There is also direct regulation of bone cells by pituitary, meaning that alerted regulation of pituitary hormones can affect bone homeostasis.
Hypoxia in bone remodelling
As a consequence of fracture, blood vessels in the bone rupture and cause the fracture site to become hypoxic. VEGF and PlGF expression stimulates the angiogenic response. Together with other cytokines, PlGF recruits inflammatory cells to clear cellular debris, and induces the proliferation of periosteal cells (a source of osteogenic cells). In the subsequent phases of soft and hard callus formation, PlGF contributes to the turnover of the cartilage matrix and remodelling of the newly formed woven bone by controlling osteoclast formation.
Glucocorticoids and osteoporosis
One of the adverse effects of glucocorticoids in therapy is osteoporosis.
Very high levels of cortisol can inhibit osteocytes, impair the production of RANKL, and the results are that you will have endochondral bone resorption (tip of the bone will decrease) and osteoporosis.
Calcium and/or Vitamin D supplementation
Calcium supplements are unlikely to lead to a clinically significant reduction in risk of fracture. On the other hand, a decrease in calcium level in blood will increase PTH and will increase the resorptive phase of bone.
Vitamin D supplementation is able to prevent fractures, especially in older patients.
Risk of drug-vitamin D interaction is high.
important drug interaction is with thiazide diuretics because they decrease calcium excretion, so it can further increase hypercalcemia (in elderly).
Bisphosphonates
Anti-resorptive drugs, they decrease bone resorption by promoting apoptosis of osteoclasts.
- Simple, non-nitrogenous (Etidronate, Tiludronate): binds to HA, once uptaken in osteoclasts accumulate and leads them to apoptosis. Analogue of IPP -> participate to the formation of a non funcitonal ATP.
- Potent. non-nitrogenous (Alendronate): inhibits Farnesyl pyrophosphate synthase, inhibiting cholesterol biosynthesis.
Side effects
PO: upper GI tract irritation (eosophagitis, esophageal ulcers, gastric irritation)
IV: osteonecrosis of the jaw, acute inflammatory response, hypocalcemia, atrial fibrillation (caused by hypocalcemia)
Adverse drug interactions: calcium supplements, anacids, aspirin, NSAIDs (?)
Oestrogen - bone
Oestrogen is useful to increase bone anabolism. In post-menopausal women, you can administer oestrogen to better bone homeostasis. The risk of fracture upon oestrogen replacement is reduced, but the risk of stroke and cancer increases a lot.
