L19 Calcium and Osteoperosis Flashcards
Why is calcium homeostatis important?
How is it controlled?
Calcium homeostasis is very tightly controlled to maintain
[ionized Ca2+] in extracellular fluids, important for:
- Muscle contraction
- Cardiac function
- Neural signaling, remodeling
- Blood clotting
How is a shortfall in extracellular Ca2+ made up?
1) increasing absorption efficiency
2) withdrawing from the bank: the skeleton
Where is calcium absorbed?
What inhibits calcium absorption?
What regulates calcium absorption efficiency?
Calcium absorbed primarily (90%) in the small intestine
• 80% ileum, paracellular
• 5‐15% jejunum, paracellular
• 5‐10% duodenum, transcellular
• 10% in the colon, paracellular
Ca2+ absorption is inhibited by many of the same agents that inhibit iron absorption:
• Phytates (grains, legumes), polyphenols (tea, coffee), oxalate(spinach) can all chelate calcium and form insoluble complexes
Physiological needs regulate calcium absorption efficiency:
• Low calcium diet, growth, pregnancy, and lactation all increase efficiency in the enterocytes
Aging decreases efficiency of calcium absorption
What is paracellular absorption?
How can you tailor supplementation for maximizing paracellular absoprtion of calcium?
Paracellular Absorption
= between enterocytes, through tight junctions
Diffusion only; not dependent on other factors, like Vitamin D
Nonsaturable:
• Absorption is proportional to dietary Ca2+ levels and time
resident in intestine (food in ileum for the longest time)
Unregulated:
• Humans are unable to compensate for reduced Ca2+ by
physiologically increasing paracellular absorption
Supplements should be divided into 3 doses of
taken with meals for optimal absorption, maximizing use of
the paracellular pathway.
How does paracellular absorption happen in the colon?
Fermentation of prebiotics favor Ca2+ absorption in the colon
• Prebiotics are primarily nondigestible oligosaccharides (NDOs),
e.g., soluble fiber, that stimulate growth of intestinal bacteria
• NDO fermentation products (short‐chain FAs) lower colonic pH
Low pH increases the solubility of Ca2+ and thus its bioavailability via the paracellular route:
• Lower pH minimizes deprotonated phosphate (PO4
‐3) available to form insoluble calcium phosphate, Ca3(PO4)2
In cells and fluids, the body actively keeps Ca2+ and
phosphate separated!
What is transcellular absorption?
How is it done with calcium?
Transcellular Absorption = through enterocytes, primarily in duodenum
• Minor role when dietary calcium is high (20% of total)
• Significant role when dietary calcium is low (80% of total)
Vitamin D‐dependent active transport system
Saturable, expression regulated by 1,25(OH)2D3 (active vitamin D;calcitriol)
• Calcitriol binds vitamin D receptor (VDR), a transcription factor
• VDR‐calcitriol complex binds the vitamin D‐responsive
elements in nuclear DNA
• Controls the synthesis of apical membrane Ca2+ channels
(TRPV5/6), intracellular calbindin, plasma membrane Ca2+
ATPase (PMCA1b), and Na+/Ca2+ exchanger (NCX1)
What are the steps of transcellular absorption of calcium?
(1) Apical entry of calcium through epithelial Ca2+ channels
TRPV5 and TRPV6
• TRPV6 most abundant in intestine, TRPV5 in kidney
• Transport down steep concentration gradient
(2) Cytosolic diffusion bound to calbindins
• Bind Ca2+ at cell surface and prevent its use in signaling
and prevent precipitation with phosphate
(3) Extrusion across the basolateral membranes by the plasma membrane Ca2+‐ATPase (PMCA1b) and the Na+/Ca2+ exchanger (NCX1).
• Active transport to the circulation
What is vitamin D?
Vitamin D3 (cholecalciferol): most active form • Food sources very limited to fatty fish, and fortified milk, cereals • Made in the skin from 7‐dehydrocholesterol via nonenzymatic reaction catalyzed by UVB light
– Sunscreen (SPF 8) reduces vitamin D3 production by 90%
– Dark complexion decreases production
– “Vitamin” D is a misnomer: only a vitamin when lacking
exposure to sunlight; is actually a prohormone/hormone
• Vitamin D2 (ergocalciferol) found in plants/plankton but only has one‐third activity of D3
– Check form of vitamin D in multivitamins to ensure full activity
Explain vitamin D biosynthesis?
Vitamin D has no biological activity until modified. After synthesis in skin, vitamin D must be hydroxylated to an active form in a 2‐ step process:
1) In liver, to calcidiol: 25(OH)D3 , through the actions of at least two 25‐hydroxylase enzymes, at least one appearing
mitochondrial
2) In kidney, to calcitriol: 1,25(OH)2D3, via 25(OH)D3‐1α‐
hydroxylase
• Mitochondrial enzyme
How is vitamin D involved in calcium regulation?
1,25(OH)2D3 (calcitriol) increases intestinal
absorption of dietary Ca2+
This is the rationale for co‐supplementation
of vitamin D and Ca2+: transcriptional
upregulation of the calcium import machinery
Calcitriol also suppresses production of parathyroid hormone (PTH), so long as homeostasis is maintained…
How does parathyroid hormone contribute to calcium regulation?
1) Decreasing plasma [Ca2+] increases PTH
production (parathyroid has Ca2+ receptors)
2) PTH activates renal 25‐(OH)D3 1‐alpha‐hydroxylase
• Increases renal Vitamin D activation
3) PTH and 1,25(OH)2D3 then synergistically:
a) Enhance renal reabsorption of Ca2+
b) Mobilize Ca2+ stores from bone
• Can lead to weakening of bone
Summarize calcium homeostasis.
Decreasing plasma Ca2+ stimulates PTH production:
• PTH increases vitamin D activation, increasing intestinal
absorption and kidney reabsorption
• If plasma levels respond, PTH production decreases
• If plasma levels don’t respond, PTH continues to increase
vitamin D and both together increase mobilization of
stores (bone)
• Increased (overcorrected) plasma Ca2+ stimulates thyroid
gland to release calcitonin, which blocks bone Ca2+
mobilization and regulates vitamin D for noncalcemic needs
How does dietary NaCl affect calcium reabsorption?
What is Calciuria?
Dietary NaCl increases urinary calcium losses (calciuria)
• For every 2300 mg of dietary Na+ (~1 RDA), urine calcium
increases by 20 to 60 mg
• Sodium and calcium compete for the same reabsorption
mechanism
Calciuria due to Na+ is only a problem if calcium homeostasis is compromised
• Absorptive compensation (PTH, vitamin D) will occur
• However, e.g., middle‐aged women average only ~600 mg/day
• Loss of estrogen will compromise absorptive compensation
• Increasing PTH and decreasing Ca2+ will further compromise bone
Calciuria is only seen when using NaCl, not just Na+
• Sodium acetate or bicarb has no effect on urinary calcium
What effects does potassium citrate have on NaCl and urinary calcium?
Potassium citrate counteracts effect of NaCl on urinary calcium
• K+ and bicarbonate anion (from citrate) may act in distal
renal tubule to facilitate reabsorption of Ca2+ outcompeted
by Na+ in proximal tubule
• Fruits & vegetables are good source of potassium and
citrate and appear to protect bone health
What is osteoporosis?
Skeletal disorder characterized by a decrease in bone density and architectural deterioration which compromises bone strength
• Trabecular bone is most susceptible to demineralization and is especially abundant in vertebral bodies, femoral head, and wrist
• Bone is the calcium storage bank, and we make frequent
withdrawals after about age 35
How is osteoporosis diagnosed?
Must assess body’s calcium stores (bone):
Bone mineral density (BMD) in the spine, hip and wrist is quantified
(dual‐energy x‐ray absorptiometry (DXA) = gold standard; also Quantitative Ultrasound
(QUS), Quantitative Computer Tomography (QCT)
• Serum calcium does not reflect calcium stores
Normal BMD is defined as no lower than 1 standard deviation (SD) below mean BMD of young (30 yo) healthy adults (T score > ‐1)
• Osteopenia is BMD between 1 and 2.5 SD below mean (T
score ‐1 to ‐2.5)
• Osteoporosis is defined as T score < ‐2.5
What are the standards for the T-score?
Normal = T‐score of ‐1 or higher
Osteopenia = T‐score between ‐1 and ‐2.5 = Bone less dense only
Osteoporosis = T‐score ‐2.5 or lower = Bone less dense, more fragile
Severe Osteoporosis = T‐score ‐2.5 or lower and Hx of fragility fracture
What are signs of osteoporosis?
Osteoporosis causes vertebral bones to collapse
resulting in a perpetual “hunch” (Dowager’s hump)
A decrease of >1.5 inches from premenopausal
height is warning sign of osteoporosis
What are three major risk factors for osteoporosis?
- Aging
- Low peak BMD at age 30
- Menopause
Explain aging as a risk factor for osteoporosis.
Address senescence-related bone loss and sarcopenia.
Senescence‐related bone loss starts between 35 and 45 years of age
- Ca2+ absorption decreases with age
- Vitamin D synthesis decreases with age (skin thins)
- Skeletal reserves are tapped, decreasing BMD
- Decreasing BMD aggravated by decreased exercise
Sarcopenia (age‐related loss of muscle mass and strength)
acts synergistically with bone loss to increase risk of fractures
• Sedentary lifestyle predominantly effects Type II fibers; Type I fibers utilized more often in activities of daily living
• Breaking a fall requires rapid activation of Type II fibers;
disproportionate loss of these increases the likelihood of injury (bone fracture, e.g. hip fracture)
Explain low peak BMD at age 30 as a risk factor for osteoporosis.
Peak BMD is attained by age 30 and is most important
determinant of life‐long skeletal health
• Determinants of BMD approx equally divided between
genetics and lifestyle (nutrition and exercise)
• Prevention focuses on achieving the genetically‐programmed peak BMD
- Peak BMD in women:
- 90% of peak BMD at 17 years of age
- 99% at 26 years of age
• Peak BMD in men occurs ~1.5 years later
“Osteoporosis is a disease of teenagers that strikes after 60”
Explain menopause as a risk factor for osteoporosis.
Menopause – Loss of estrogen
Menopause results in 15% loss in bone over ~5 years
- Calcium supplementation alone fails to prevent this bone loss
- This one‐time bone loss increases the importance of achieving maximum peak BMD
Estrogen otherwise slows bone loss by:
- Transcriptional activation of Ca2+ import machinery in enterocyte
- Inhibiting osteoclasts
- Estrogen triggers buildup of calcium reserves in bone, from which calcium can be released during pregnancy and lactation
Increased bone mass is more pronounced in postmenopausal women treated with estrogen and calcium together than with women treated with calcium alone
