L8 Calcium & Bone Flashcards
Generic name for vitamin D
Calciferol
Generic name for vitamin D3
Cholecalciferol
Generic name for vitamin D2
Ergocalciferol
Generic name for 25-hydroxyvitamin D
Calcifediol
Generic name for 1,25(OH)₂D
Calcitriol
Clinical indications of Cholecalciferol and Ergocalciferol
- Vitamin D deficiency
- Vitamin D malabsorption
- Hypoparathyroidism
Clinical indications of Calcitriol
- Secondary hyperparathyroidism of CKD
- Hypoparathyroidism
- Hypophosphatemic rickets with decreased calcitriol levels
- Acute hypocalcaemia
- Pseudovitamin D-deficient rickets
- Hereditary vitamin D-resistant rickets
Do children or adults have higher 1,25(OH)₂D levels?
children
Main function of vitamin D metabolites
The regulation of calcium and phosphate homeostasis, which occurs in conjunction with PTH
Principle target tissues for regulation of calcium and phosphate homeostasis
Gut, kidney and bone
Major pathologic complication of vitamin D deficiency
Rickets (in children with open epiphyses) or osteomalacia (in adults), due to deficiency of the calcium and phosphate required for bone mineralisation
Which is the most biologically active vitamin D metabolite?
1,25(OH)₂D
Best-known cause of abnormal bone mineralisation
Vitamin D deficiency
Vitamin D permits osteoblasts to…
produce a bone matrix that can be mineralised and then allows them to mineralise that matrix normally
Many hypophosphatemic conditions result from excess circulating __. What is the result of this?
FGF23
Can both decrease 1-hydroxylase activity and renal phosphate reabsorption
What causes osteomalacia and rickets?
abnormal mineralisation of bone and cartilage
What is osteomalacia?
A bone defect occurring after the epiphyseal plates have closed (i.e. in adults)
Rickets occurs in __ bone.
growing
What occurs as a result of abnormal mineralisation in patients with rickets?
an enormous profusion of disorganised, non-mineralised, degenerating cartilage appears in the zone of provisional calcification, leading to widening of the epiphyseal plate with flaring or cupping and irregularity of the epiphyseal-metaphyseal junctions
What is the clinical term for obvious beaded swellings along the costochondrial junctions in patients with rickets?
Rachitic rosary
Why is defective mineralisation more difficult to observe in adults?
because once bone growth has ceased (closure of epiphyseal plates), the clinical evidence for defective mineralisation becomes more subtle
Causes of osteomalacia
- Disorders of the vitamin D endocrine system (most significant cause)
- Disorders of phosphate homeostasis
- Calcium deficiency
- Primary disorders of bone matrix
- Inhibitors of mineralisation
Treatment for vitamin D deficiency
Alfacalcidol, Dihydrotachysterol
- promote active transport of calcium & phosphate in GIT (increased reabsorption) & renal tubule (decreased excretion)
A single dose of vitamin D has biological effects for how long?
up to 6 months
What is the best understood target tissue response of 1,25(OH)₂D?
intestinal calcium transport
Calcium transport through the intestinal epithelium
- Entrance of calcium into cell from lumen across brush border membrane down a steep electrochemical gradient
- Passage through the cytosol
- Removal of calcium from cell against a steep electrochemical gradient at basolateral membrane
1,25(OH)₂D induces a change in the binding of calmodulin to __.
brush border myosin 1
(calmodulin-myosin 1 complex may provide a mechanism for removing calcium from the brush border)
Which calcium channel in the brush border membrane is induced by 1,25(OH)₂D? And what is the channel’s role?
TRPV6
- likely the major mechanism by which calcium enters the intestinal epithelial cell
What is required for calcium transport through the cytosol?
a vitamin D-inducible protein called calbindin (exists in either a 28kDa or 9kDa form)
Which pump removes calcium from the cell at the basolateral membrane?
Ca2+-ATPase (PMCA1b)
How is phosphate absorption from the intestine regulated?
via NaPi-IIb, whose levels are increased by 1,25(OH)₂D
Key feature of the defence against hypercalcemia
suppression of PTH secretion
- reduces bone resorption, renal production of 1,25(OH)₂D and intestinal calcium absorption
- increases urinary calcium losses
What is the only route of net calcium elimination in hypercalcemia?
kidney
What causes increased renal calcium excretion in hypercalcemia?
a combination of increased filtered load of calcium and PTH suppression
Nausea and vomiting in hypercalcemia may predispose to…
dehydration and renal azotaemia
What compromises calcium clearance, perpetuating the viscous cycle of hypercalcemia?
renal insufficiency
Only alternative to the renal route for calcium elimination from ECF in a hypercalcemic state?
deposition of calcium phosphate and other salts in bone and soft tissues
Disorders causing hypercalcemia
- Primary hyperparathyroidism (common)
- Malignancy-associated hypercalcemia
- Sarcoidosis and other granulomatous disorders
- Endocrinopathies e.g. thyrotoxicosis, adrenal insufficiency
- Thiazide diuretics
- Hypervitaminosis D and A
- Milk-alkali syndrome
- Miscellaneous conditions e.g.s immobilisation, acute renal failure
Mnemonic for primary hyperparathryoidism signs and symptoms
‘Stones, bones, abdominal groans, and psychic moans’
Ophthalmic condition associated with hypercalcemia
band keratopathy
Temporary hypercalcemia treatment
- Physiological saline (correct volume depletion and increase renal calcium excretion)
- Bisphosphonates e.g. Pamidronate, Zoledronic acid (inhibit bone resorption)
- Calcitonin (maintains calcium levels by suppressing PTH)
- Corticosteroids i.e. Prednisolone (reduce intestinal calcium absorption)
- Dialysis (in renal failure)
Long-term treatment for hypercalcemia
- Sodium cellulose phosphate (Calcisorb - binds calcium in gut) - for patients who over-absorb dietary calcium
- Inorganic phosphate (sodium acid phosphate)
Causes of hypocalcemia
- Hypoparathyroidism
- Resistance to PTH action
- Failure to produce 1,25(OH)₂D normally
- Resistance to 1,25(OH)₂D action
- Acute complexation or deposition of calcium
What are many of the complications of hypocalcemia treatment a result of?
the deposition of calcium in soft tissue
What ophthalmic condition is common in chronic hypocalcemia?
subcapsular cataract
Dermatological effects of hypocalcemia
dry and flaky skin, brittle nails
Treatment for hypocalcemia patients with tetany
intravenous calcium: calcium gluconate/calcium glucoheptate, with constant electrocardiographic monitoring
IV calcium can mimic and synergise with __ to have serious cardiac effects
digitalis
Treatment for acute hypocalcemia
oral calcium and a rapidly-acting preparation of vitamin D (e.g. calcitriol)
Chronic hypocalcemia treatment
- calcium carbonate/calcium citrate
- in patients with vitamin D deficiency: combined calcium with cholecalciferol
- in patients with hypoparathyroidism: Alfacalcidol or calcitriol
What is osteoporosis?
A condition of low bone mass and microarchitectural disruption that results in fractures with minimal trauma
Primary vs. secondary osteoporosis
Primary: reduced bone mass & fractures in postmenopausal women, or in older men & women due to age-related factors
Secondary: bone loss resulting from specific clinical disorders
Two types of endocrine treatment for osteoporosis
- Anabolic
- PTH-specific
- bone gain - Anti-resorptive
- maintain bone
Example of PTH-specific osteoporosis medication
Teriparatide
What drugs are considered anti-resorptive endocrine treatment?
- Bisphosphonates e.g. Alendronate (inhibits bone resorption)
- Calcitonin (suppresses PTH), Salcatonin (inhibits bone resorption)
- SERM e.g. Raloxifene (acts as an agonist at bone oestrogen receptors)
- HRT
- Vitamin D e.g. Ergocalciferol (D2)
How do SERMs work?
They act as agonists at bone & CVS oestrogen receptors, and as antagonists at oestrogen receptors in mammary tissue & uterus
How do excessive levels of glucocorticoids cause osteoporosis?
Physiologic levels of GCs: osteoblast differentiation
Excessive levels of GCs lead to decreased osteoblast differentiation and increased osteoclast action. GC therapy is associated with an appreciable risk of bone loss.
