13 - Vitamin D Flashcards
What are the most important forms of vitamin D?
- Cholecalciferol (D3)
- Ergocalciferol (D2)
What is osteomalcia? What is another name for it?
- AKA rickets
- Softening of the bone caused by defective bone mineralization due to inadequate amount of phosphorus and calcium
Which vitamins does vitamin D enhance the intestinal absorption of?
Calcium, iron, magnesium, phosphorus, and zinc
What are some causes of vitamin D deficiency?
- Sunscreen, melanin, winter
- Medications and supplements (antiseizure drugs, glucocorticoids, rifampin, St John’s wort)
- Malabsorption (Crohn’s disease, Whipple’s disease, cystic fibrosis, celiac disease, liver disease)
- Hepatic or renal failure; nephrotic syndrome, obesity
What are some consequences of vitamin D deficiency?
- Infections (tuberculosis, influenza, upper respiratory tract infections)
- Schizophrenia, depression
- Lung disease
- Autoimmune diseases (type 1 diabetes, MS, Crohn’s disease, RA)
- Cancer (breast, colon, prostate, pancreatic)
- Muscle weakness, osteoporosis, osteoarthritis, rickets
What are the 3 types of pericyclic reactions?
1) Electrocyclic reactions - intramolecular reaction in which a pi bond is converted to sigma bond
2) Cycloaddition reaction - intermolecular reaction in which two pi-bond-containing molecules react to form a new cycle
3) Sigmatropic rearrangement - intramolecular reaction in which a sigma bond is broken, a new sigma bond is formed and pi bond is rearranged
How is vitamin D3 synthesized?
7-dehydrocholesterol (provitamin D3) is converted into previtamin D3 in the skin epidermis by sunlight 290-310 nm, which is then converted to cholecalciferol (vitamin D3) by heat (body temperature)
Blocking which UV rays would prevent the conversion of provitamin D3/D2 to previtamin D3/D2?
UVB
How is vitamin D3 activated?
- Cholecalciferol -> calcidiol -> 24,25-OH-vitamin D3 -> calcitetiol
- OR Cholecalciferol -> calcidiol -> calcitriol -> calcitetiol
What is significant about calcitriol?
Active form of vitamin D3 that binds to its nuclear receptor and triggers genomic effects
What are the effects of calcitriol binding to its receptor?
- Increased production of certain calcium transport proteins, insulin, parathyroid and thyroid hormones
- Decreased production of interleukin
When do calcitriol and parathyroid hormone work in concert?
To reduce urinary excretion of calcium and increase bone resorption
What is the overall goal of calcitriol?
Increase plasma Ca2+ levels
What can a long period of high calcitriol cause?
- Hypercalcemia
- Stones, bones, groans, thrones, chest tones, and psychiatric overtones (kidney and biliary stones; bone pain; groans from abdominal pain and N/V; increased urination and polyuria; cardiac rhythm; psychiatric disorders like depression)
How is vitamin D2 synthesized?
- Ergosterol (provitamin D2) from plants is converted to previtamin D2 in skin epidermis from sunlight 290-310 nm
- Previtamin D2 is converted to vitamin D2 (ergocalciferol) by heat
How is vitamin D2 activated?
Vitamin D2 -> 1,25-diOH-vitamin D2 by 25-hydroxylase in liver and 1 alpha-hydroxylase in kidney
What is the principle counterion of serum Ca2+?
HPO4-
What is the major reservoir of calcium in the body?
Bone crystal lattice – Ca10(PO4)6(OH)2
What regulates the unbound ions in serum?
Vitamin D, calcitonin, and parathyroid hormone
What is the homeostasis of calcium essential for?
- Bone growth and remodeling
- Muscle contraction
- Cardiac rhythm
- Neurotransmission
What do osteoblasts do?
- Stimulate bone formation by producing products required to form bone matrix and mineralization
- Mediated by cytokines, hormones, and growth factors
What do osteoclasts do?
- Stimulate bone resorption (destruction) by acidifying and dissolving bone minerals, and digesting bone collagen matrix
- Activated by cytokines, parathyroid hormone, and calcitriol
Where are osteocytes found? What are they activated by and what do they do?
- Found deep in bone matrix
- Activated by parathyroid hormone
- Mobilize calcium to bone surface
When is calcitonin secreted? What does it do?
- Secreted when serum calcium > 9 mg/dL
- Serves to oppose the effects of parathyroid hormone
- Inhibits osteoclast activity, leading to reduced bone resorption
- Stimulates urinary excretion of HPO4- and Ca2+ and stops intestinal absorption of Ca2+
When is parathyroid hormone secreted? What does it do?
- Secreted when serum Ca2+ < 9 mg/dL
- Activates production of calcitriol in kidneys, which helps regulate parathyroid hormone levels
- Works in concert w/ calcitriol to promote osteoclast activity, leading to bone resorption
- Decreases urinary excretion of Ca2+ and indirectly stimulates intestinal absorption of Ca2+
Are low or high levels of PTH preferred? Why?
Low levels seem to help achieve a balanced bone remodeling process
What are the therapeutic options for osteoporosis?
- Calcium
- Calcitonin and PTH
- Vitamin D
- Estrogen
- Biphosphonates
- Fluoride
- Cathepsin K inhibitors
- Exercise
How does estrogen inhibit bone loss?
- Activation of estrogen-specific receptors on osteoclasts may shorten their life span by blocking production of certain cytokines (thus reduces bone resorption)
- Promotes calcitonin production
- Enhances intestinal calcium uptake
What is the action of bisphosphonates?
Replaces pyrophosphate of hydroxyapatite in forming an interaction w/ Ca2+
What is the effect of bisphosphonates on osteoclasts?
- Inhibit osteoclast proliferation
- Decrease osteoclasts activity
- Reduce osteoclast life span
- Decrease # of sites along the bone surface where bone resorption occurs, reducing bone loss
Which drugs are bisphosphonates?
- Zoledronate
- Alendronate
- Risedronate
- Ibandronate
Bisphosphonates have selective uptake in areas of bone that ____
Are actively undergoing remodeling
How should bisphosphonates be taken?
In an upright position, on an empty stomach w/ a minimum amount of water
What is an adverse effect of oral bisphosphonates?
Inflammation and erosions of esophagus, leading to esophageal cancer
What is cathepsin K?
- Lysosomal cysteine protease involved in bone remodeling and resorption
- Expressed predominantly in osteoclasts
- Catabolizes bone and cartilage
Which drug is a cathepsin K inhibitor? How is it dosed?
Odanacatib; dosed once weekly
What is teriparatide used for?
To assist bone remodeling via activating osteoblasts more than osteoclasts
What is abaloparatide?
Parathyroid hormone-related protein
What is romosozumab used for?
- Humanized monoclonal antibody that targets sclerostin for tx of osteoporosis
- Sclerostin = glycoprotein produced by osteocytes and inhibits bone formation
