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HMS Homeostasis II > Parathyroids and Vitamin D > Flashcards

Parathyroids and Vitamin D Flashcards

1
Q

Distribution of body calcium

A
  • 99% in bone
  • Of the remaining 1%:
    • 40% is in extracellular fluid bound to albumin and other proteins and does not cross the filtration barrier within the glomerulus
    • 50% is in the free ionized form and does cross the filtration barrier within the glomerulus. This fraction is important for muscle function and is sensed by the calcium sensing receptor in the parathyroid.
    • 10% is complexed with serum anions (phosphate, sulfate, lactate, biarbonate, citrate). This fraction is metabolically inert.
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2
Q

Unlike total calcium, [Ca++] is unaffected by ___, but is affected by ___.

A

Unlike total calcium, [Ca++] is unaffected by albumin concentration, but is affected by acid-base balance

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3
Q

Acidemia and calcium

A

In acidemia, there is more H+ present in the blood that competes with Ca++ to bind to albumin. This leads to an increase in serum calcium.

The opposite is also true in alkalemia.

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4
Q

A large increase in these anions can markedly increase . . .

A

A large increase in these anions can markedly increase the complexed fraction of calcium and subsequently reduce [Ca++] enough to produce tetany

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5
Q

What measure of calcium homeostatsis is routinely measured in clinical medicine?

A

Total calcium

Note that changes in serum albumin concentration affect total serum calcium concentration without affecting the biologically active ionized fraction [Ca++], however changes in other anions may sequester calcium.

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6
Q

“Corrected” serum calcium

A

“corrected” serum calcium = measured serum calcium + 0.8 * (4.0 -measured serum albumin)

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7
Q

Calcium and phosphate circulate in serum at concentrations close to ___.

A

Calcium and phosphate circulate in serum at concentrations close to saturation.

Thus, a substantial increase in either calcium or phosphate can lead to precipitation of calcium phosphate salts in tissues and formation of kidney stones

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8
Q

PTH acts on the___, ___, and___ to regulate [Ca++].

A

PTH acts on the kidney (directly), bone (directly), and intestine (indirectly through activation of vitamin D) to regulate [Ca++].

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9
Q

How is bodily calcium level maintained (broadly)?

A

The kidnies reabsorb as much calcium as possible, but even still are unable to reabsorb ~2-5%. This is made up for by dietary intake and by releaseing calcium stored in bone hydroxyapatite.

When an individual is calcium-replete, the intestinal tract ceases to absorb calcium. When an individual has extra calcium, it is stored as hydroxyapatite in bone.

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10
Q

Parathyroid hormone

A
  • Synthesized and released by the chief cells of the parathyroids
  • Liver and kidney rapidly clear PTH (halflife ~2-4 minutes)
  • Released in response to Ca2+ levels sensed by the calcium-sensing receptor
  • Stimulates bone resorption, intestinal calcium absorption (via activation of 1-α-hydroxylase), and tubular reabsorption of calcium and phosphate
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11
Q

Short-term vs long-term calcium defense

A

The short-term defense against hypocalcemia relies on release of bone calcium and reabsorption of urinary calcium (predominantly from PTH action), while long-term defense relies on dietary calcium absorption (from both PTH and calcitriol) to replace obligatory losses

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12
Q

Calcium-sensing receptor and regulation of chief cell PTH secretion

A
  • Calcium-sensing receptor is a G protein coupled-receptor with exquisite sensitivity to plasma [Ca2+]
  • Unlike most cells, low intracellular [Ca2+] increases PTH release and high intracellular [Ca2+] suppresses secretion
  • A mild decrease in serum magnesium stimulates PTH while severe depletion of magnesium stores paradoxically paralyzes the secretion of PTH leading to reversible (functional) hypoparathyroidism and hypocalcemia (probably due to Mg2+’s role in ATPase activity)
  • PTH is also negatively regulated by calcitriol
  • Hyperphosphatemia stimulates PTH, but primarily via depleting calcium
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13
Q

PTH regulation summary

A
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14
Q

Renal calcium handling

A
  • 70% reabsorbed passively along w/ sodium in the proximal tubule
  • 20% reabsorbed in the thick ascending limb of the loop of Henle
  • 10% reasorbed in the distal convoluted tubule – this is the portion under PTH control
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15
Q

Actions of PTH in the nephron

A
  • Stimulates Ca2+ uptake in the DCT
  • Inhibits the type II-2Na+/PO42- in the PCT
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16
Q

Hyperparathyroidism, in its defense of free serum calcium, will often lead to ___.

A

Hyperparathyroidism, in its defense of free serum calcium, will often lead to hypophosphatemia

This is directly due to its effect on the type II-2Na+/PO42- cotransporter of the PCT, which largely sets the serum level of phosphate

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17
Q

Parathyroid hormone-related protein

A
  • Homologous to PTH
  • Activates PTH receptors in bone and kidney
  • Produced by a wide variety of fetal and adult tissues and acts locally at its site of production
    • Regulates Ca2+ delivery across placenta in utero
    • Secreted during lactation to increase calcium content of breast milk
  • Abberant production of PTHrP by tumors may cause hypercalcemia as a paraneoplasm.
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18
Q

Dietary forms of vitamin D

A

Vitamin D2 (called ergocalciferol)

Vitamin D3 (called cholecalciferol)

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19
Q

What biologic activity does vitamin D have?

A

None!

Only its downstream metabolites do, specifically calcitriol.

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20
Q

Endogenous cholecalciferol biosynthesis

A

Vitamin D3 is synthesized from 7-dehydrocholesterol in the keratinocytes of the skin.

Synthesis is stimulated by sunlight (ultraviolet radiation). A short exposure to sunlight causes prolonged release of vitamin D3 from exposed skin; however, prolonged exposure to sunlight does not produce toxic quantities of vitamin D3.

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21
Q

Vitamin-D binding protein

A

Binds up ergocalciferol and cholecalciferol and delivers them to the liver, where they are converted by 25-α-dehydrogenase to 25-hydroxycholecalciferol.

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22
Q

Regulation of 1-α-hydroxylase

A
  • Stimulated by PTH and hypophosphatemia
  • Inhitibted by hyperphosphatemia and FGF23
    • FGF23 is a growth factor derived from bone
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23
Q

24-α-hydroxylase

A

Enzyme present in the liver which converts 25-hydroxycholecalciferol to 24,25-dihydroxycholecalciferol, an inactive form of the molecule.

This enzyme is inhibited by PTH, enabling production of active calcitriol.

However, it is activated downstream by calcitriol itself, producing another regulatory negative-feedback loop.

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24
Q

Calcitriol

A
  • Regulates calcium and phosphate homeostasis in conjunction with PTH
  • Acts via the nuclear Vitamin D receptor to modulate transcription
  • Increases intestinal Ca2+ and PO42- absorption and increases osteoclast bone resorption
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25
Q

Calcitriol’s effects in bone

A
  • Acts in osteoblasts via the VDR and triggers production of RANKL
  • RANKL binds to RANK in osteoclasts and stimulates osteoclast differentiation and activity via NFκB
  • Osteoclasts release HCl and proteolytic enzymes to dissolve bone and matrix, resulting in bone resorption
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26
Q

Assessing for vitamin D deficiency

A

Serum 25(OH)D has a long half-life (3–4 weeks), while calcitriol has a short half-life (hours).

Therefore, 25(OH)D is used as the most valuable laboratory indicator of total body vitamin D status.

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27
Q

Calcitonin

A
  • Produced by the parafollicular or C cells in the thyroid
  • Role in human physiology not fully understood
  • It has a very minor role to inhibit osteoclast-mediated bone resorption, and therefore has a role in treatment of hypercalcemia.
  • However, patients who have removal of parafollicular C cells have no complications with calcium handling, so it cannot be THAT important.
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28
Q

Magnesium handling

A
  • Absorbed in the small intestine similarly to calcium
  • Passive renal reabsorption occurs in the ascending limb of the loop of Henle at the same sites as calcium reabsorption
  • Active transcellular absorption occurs mainly in the distal renal tubule.
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29
Q

Body stores of phosphate

A
  • 80% in bone
  • Of the remaining 20%:
    • 45% in skeletal muscle
    • 54.5% in viscera
    • 0.5% in ECF
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30
Q

In contrast to calcium, normal plasma phosphate concentrations . . .

A

In contrast to calcium, normal plasma phosphate concentrations vary considerably during life, being highest during phases of rapid growth.

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31
Q

FGF23

A
  • Secreted by osteoblasts and osteocytes
  • Inhibits phosphate reabsorption at the PCT
  • Inhibits 1-α-hydroxylase, decreasing calcitriol levels
  • Hyperphosphaturic conditions caused by raised FGF23 levels are not accompanied by the expected increase in calcitriol, but only act to lower blood phosphate levels
  • Rarely secreted as part of a paraneoplastic syndrome, resulting in phosphate wasting
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32
Q

Symptoms of hypercalcemia

A
33
Q

Approach to hypercalcemia

A
34
Q

Primary hyperparathyroidism

A
  • Most common cause of hypercalcemia
  • Caused by excessive PTH secretion from adenomatous or hyperplastic parathyroid glands (almost always benign)
  • Many cases asymptomatic
  • May suffer symptoms of hypercalcemia or osteopoenia
  • Present with high serum Ca2+, high PTH, and hypercalciuria
35
Q

Cinacalcet

A

CaSR agonist

Reduces secretion of PTH

36
Q

Familial hypocalciuric hypercalcemia

A
  • Autosomal dominant
  • Caused by inactivating mutations in CaSR
  • Parathyroids constantly secretes too much PTH
  • Appears similar to primary hyperparathyroidism (Ca2+ and PTH both high)
    • However, they differ in urinary calcium: Inactivating mutations of the CaSR in the kidney result in excessive renal calcium absorption and hypocalciuria
37
Q

Mechanisms by which malignancy can cause hypercalcemia

A
  1. Cancer within the bone (hematologic, myeloma, or metastatic) will result in a local immune response. Since immune cytokines (especially RANKL) have been coopted for the purpose of regulating osteoclasts, this will activate osteoclasts to resorb bone.
  2. Some cancers (particularly squamous tumors of the lung and head and neck) produce PTHrP that activates osteoblasts to produce RANKL, also activating osteoclasts.
  3. Some lymphomas have dysregulated 1-α​-hydroxylase activity, resulting in aberrant calcitriol production and vitamin D toxicity.
38
Q

Non-malignant, non-PTH-mediated causes of hypercalcemia

A
  • Prolonged immobilization
  • Thyrotoxicosis
  • Increased intestinal absorption (due to high dietary intake, so-called Milk Alkali Syndrome, or due to dietary vitamin D toxicity)
  • Granulomatous disease (via aberrant 1-α-hydroxylase activity)
  • Tumor lysis syndrome
39
Q

Most common causes of hypocalcemia

A
  • Deficiency of PTH
  • Resistance to PTH
  • Severe vitamin D deficiency
  • Calcitriol resistance
40
Q

Pseudohypoparathyroidism

A
  • Congenital syndrome of resistance to PTH
  • Characterized by subcutaneous deposition of calcium, short stature, and brachydactyly (short metacarpals) in the presence of a syndrome of hypoparathyroidism, but with normal or elevated PTH levels
  • Part of the Albright Hereditary Osteodystrophy Syndrome
41
Q

Hypovitaminosis D

A
  • When severe/prolonged, will lead to reactive/physiologic secondary hyperparathyroidism to restore normal calcium levels
  • In adults this will result in osteomalacia
  • In children this will lead to rickets
42
Q

Treating hypocalcemia

A
  • If the cause is vitamin D deficiency:
    • High doses of D2 and D3 and calcium supplementation
  • If the cause is hypoparathyroidism:
    • Patients must be treated with calcitriol (since PTH is required for conversion of D2 and D3 to calcitriol), along with calcium supplementation
    • Goal is to achieve low-normal calcium levels (since hypoparathyroidism is also associated with hypercalciuria and hyperphosphatemia)
    • May be treated with recombinant PTH as well
43
Q

Secondary hyperparathyroidism

A
  • Two causes:
  1. Prolonged or severe poor calcium intake or absorption (as from prolonged or severe vitamin D deficiency)
  2. Chronic kidney disease
44
Q

Mechanism of hyperparathyroidism in prolonged dietary calcium deficiency

A
  • Chronically elevated PTH in order to obtain a normal serum calcium
  • At the expense of hypophosphatemia from urinary loss, to preserve calcium
  • Usually also osteopoenia from chronic bone turnover
45
Q

Mechanism of hyperparathyroidism in CKD

A
  • There are multiple:
    • Retention of phosphate, which sequesters calcium
    • Decrease in 1-alpha-hydroxylase activity, resulting in decreased calcitriol and decreased GI absorption
    • Increase in FGF23, causing phosphaturia
    • Reduced expression of vitamin D receptors and CaSR
46
Q

Tertiary hyperparathyroidism

A
  • In patients with severe chronic kidney disease and secondary hyperparathyroidism, the physiologic response that leads to the elevated PTH will cause appropriate parathyroid gland hyperplasia
  • This can then result in autonomous and unregulated overproduction of PTH
  • Can be treated with surgical resection of the offending gland and often resolves after renal transplantion
47
Q

Laboratory evaluation in hypercalcemia (table)

A
48
Q

Cortical versus trabecular or cancellous bone

A
  • Cortical: Compact bone on the exterior of bony structures, comprising 80% of bone weight and providing strength and protection while serving as a calcium and phosphate reserviore for periods of dietary deficinecy.
  • Cancellous or trabecular:“Spongy” bone on the interior of bony structures, provide mechanical support to vertebrae, generally more metabolically active and serves as initial supply of calcium and phosphate when small amounts are needed.
49
Q

Mechanisms of skeletal bone development

A
  • Intramembranous:
    • Undifferentiated mesenchymal cells develop directly into osteoblasts
    • Involved in the formation of the flat bones, the clavicle, the pelvis, and the collar of long bones
  • Endochondral:
    • Two-stage process: first mesencyhmal cells differentiate into cartilage and form a cartilage scaffold, then this scaffold is ossified
    • Involved in the development of appendicular bone and long bones, vertebrae, etc
50
Q

Bone remodeling summary

A
51
Q

Haversian remodeling

A
  • Occurs in cortical bone
  • A tunneling process, with a leading edge of bone resorption, followed by osteoblastic new bone formation
  • Resorption period takes 21-30 days, formation period, 90-120 days
    *
52
Q

Imbalances in bone remodeling

A
  • Can lead to bone gain, bone loss, or bone fragility
  • When resorption wins out, osteoporosis occurs
  • Net gain of bone when resorption malfunctions leads to osteopetrosis
    • Counterintuitively, osteopetrosis is also associated with bone fragility because microscopic damage is not repaired by the typical resorptive/depositive process
53
Q

Things that affect the rate of bone remodeling

A
  • Growth (most rapid in the young)
  • Mechanical strain (bone responds to bearing weight)
  • Response to circulating factors:
    • PTH
    • Estrogen
    • Cytokines
54
Q

Osteoprotegrin

A
  • Soluble RANK decoy ligand
  • Prevents maturation of osteoclasts by competitive inhibition of RANKL
55
Q

Osteoclast differentiation

A
  • M-CSF drives MΦ program
  • RANKL drives MΦ differentiation into osteoclast precursors
  • Osteoclast precursors express syncytin and form giant cells with multiple nuclei
  • When an osteoclast begins active bone resorption, the bone remodeling cycle is initiated at that site and the osteoclast digs a pit (a lacuna)
  • Vacuoles containing acid and cathepsin K are pumped onto bone surface to resorb.
56
Q

Osteoclast resorption diagram

A
57
Q

Osteoblasts

A
  • Originate from fibroblasts (which also develop into chondrocytes and adipocytes)
  • Mature osteoblasts lay down osteoid (bone matirx) composed of 90% type I collagen
  • Build bone slower than osteoclasts remove bone
  • Bone formed rapidly by osteoblasts is more disorganized and appears “woven.” This occurs in primary spongiosa, fracture healing, and Paget’s disease
  • Alkaline phosphatase expressed on the osteoid surface to catalyze bone formation in cooperation with coordinated calcium and phosphate release by the osteoblast
  • Most osteoblasts die by apoptosis; the remainder either become lining cells covering quiescent bone surface, or are entombed in the lacunae of the mineralized matrix as osteocytes
58
Q

Osteogenesis imperfecta

A
  • Heritable syndrome caused by mutations in the genes encoding the pathway for type I collagen production
  • Increased bone fragility due to poor osteoid formation and subsequent mineralization
  • Present with fractures, blue sclerae (thin collagen layer is transparent) and hyperextensible joints
59
Q

Osteocytes

A
  • Derived from former osteoblasts
  • Plentiful and long-lived compared to blasts/clasts
  • Have radiating cytoplasmic processes that link to other osteocytes and osteoblasts to communicate through bone, functioning as signal-transmitters during remodeling
  • Tonically secrete sclerostin along these processes to inhibit bone formation​
  • When mechanical stress is sensed by osteocytes, they secrete growth factors and suppress sclerostin, resulting in bone formation
  • Microcracks in the vicinity of osteocytes induce osteocyte apoptosis and recruitment of osteoblasts to fill in the hole
60
Q

Summary of bone cell regulation

A
61
Q

Osteoporosis of chronic inflammation

A
  • IL-1 and TNF-α induce bone resorption
  • Also promote poor absorption
62
Q

Peak bone mass is achieved. . .

A

. . . in the third decade of life

From there on, bone is gradually lost

63
Q

Osteoporosis

A
  • Low bone strength with an increased risk of fractures
  • Risk factors: aging, calcium deficiency, vitamin D deficiency, hyperparathyroidism, genetic risk factors, hypogonadism (manifested as delayed menarche, amenorrhea, or menopause), generalized malnutrition, decreased physical activity, chronic inflammation, corticosteroid usage, low body weight, cigarette smoking, excessive alcohol intake, hyperthyroidism, Cushing syndrome, female biological sex
64
Q

Diagnosing osteoporosis

A
  • Diagnosed in the presence of a fragility fracture or low bone mineral density, defined by a low T score, less than -2.5.
  • Osteopoenia is a more mild form of osteoporosis, with a T score in the range of -1.0 to -2.5.
  • Bone mineral density is measured by dual-energy x-ray absorptiometry (DXA)
  • Density often measured in lumbar spine, but errors may be due to aortic calcifications or osteoarthritic changes. Measurement should be taken on intact, non-fractured bone
  • USPS and NOF recommend beginning screening in women at age 65, or at age 60 for those with multiple risk factors. No screening currently done for men.
65
Q

Treating osteoporosis

A
  • Should be offered to any man or post-menopausal woman over age 50 with BMD less than -2.5 on DXA or with history of fracture who qualifies based on a 10-year probability of hip fracture or major osteoporosis-related fracture of ≥3.0 or ≥20 percent
    • FRAX calculator may be usqed for the above
  • Treat underlying cause
  • Ensure adequate calcium intake daily (1000 – 1200 mg/day for those w/o absorption problems and not on diuresis), but not excessive
  • Ensure vitamin D level high enough to prevent secondary hyperparathyroidism, ~800 IU/day
  • Exercise at least 30 minutes, 3x/week
  • Calcitriol for patients w/ renal failure or poor 1-α-hydroxylase function
  • Estrogen/SERMs (post-menopausal women only)
  • Anti-resorptives (bisphosphonates, denosumab)
  • Recombinant PTH and PTHrP (injectable, protein medications)
  • Sclerostin inhibitors (Romosozumab)
66
Q

SERMs

A
  • Bind to estrogen receptors and have either agonist or antagonist activity, depending on the site
  • Raloxifene, tamoxifen, and bazedoxefine all agonize bone and prevent osteoporosis
  • All carry tisk of thrombosis and have not been shown to reduce risk of hip fracture
  • Unlike the other two, tamoxifen has agonist activity at the endometrium and a risk of hyperplasia or cancer
67
Q

Bisphosphonates

A
  • Includes alendronate and zoledronic acid
  • First-line medication for osteoporosis
  • Structure similar to pyrophosphate
  • Taken up by osteoclasts selectively and interfere with osteoclast metabolism, differentiation, and activity
  • Thus, they inhibit bone resorption
  • By reducing turnover, may lead to accumulation of microdamage, and so long-term treatment without ‘holiday’ leads to higher risk of atypical fractures
  • So, drugs should be taken w/ occasional scheduled breaks
  • Osteonecrosis of the jaw is a rare but serious side effect
68
Q

Denosumab

A
  • Binds to and sequesters RANKL
  • Prevents differentiation and maturation of osteoclasts
  • Similar to bisphosphonates, it minimizes bone resorption while permitting some bone formation to continue.
69
Q

Teriparatide and abaloparatide

A
  • Teriparatide = recombinant PTH, Abaloparatide = recombinant PTHrP
  • Given in pulsatile manner, which results in an anabolic effect
    • This is an important difference in function. If PTH is seen over a prolonged period, it results in bone resorption. But, if there is a BURST of PTH, this triggers bone formation.
    • Stimulate osteoblast function and are highly effective in preventing fractures in patients with osteoporosis
    • Should not be used in individuals at risk for osteosarcoma
      • Includes ​persons with Paget’s disease, history of bone metastases or radiation to the bone, or unexplained high alkaline phosphatase levels
70
Q

Sclerostin inhibitors

A
  • Romosozumab is a mAb that binds to and sequesters sclerostin
  • Sclerostin typically tonically inactivates osteoblasts by Wnt signaling
  • Without the above signaling, osteoblasts build bone
  • Also indirectly stimulates RANKL production, stimulating bone resorption
  • The result is a higher level of dynamic equilibrium, but ultimately favors bone formation
  • May be associated with an increased risk of heart attack and stroke
71
Q

Osteomalacia and Rickets

A
  • Caused by inadequate calcium (from poor dietary intake, severe and/or prolonged vitamin D deficiency, or malabsorption), phosphate, and/or alkaline phosphatase activity, leading to poor bone mineralization
  • Both present with low-normal urinary and serum calcium and phosphorus, elevated PTH, elevated alkaline phosphatase, bone pain and tenderness, muscle weakness, and fractures
  • Low BMD, but this is secondary and will improve with treatment of primary condition, so treatment for osteoporosis is inappropriate
  • Rickets is distinct in that it involves the growth plates as well, leading to a more serious presentation
72
Q

Paget’s Disease of Bone

A
  • also called osteitis deformans
  • Localized accelerated bone remodeling, leading to overgrowth of bone and impaired integrity at that site
  • Most frequently affects skull, long bones of lower extremity, spine, and pelvis
  • May result in anatomic syndromes (cranial neuropathy, for example), bone pain, or osteoarthritis
  • Elevated alkaline phosphatase, lytic/sclerotic lesions on X-ray
  • Treated with anti-resorptive medications, similar to osteoporosis
73
Q

Osteopetrosis

A
  • Systemic disease of relative excess of bone formation
  • May be due to increased osteoblast activity OR decreased osteoclast activity
  • Often caused by mutations in M-CSF or RANK/RANKL
  • Despite being sclerosed, bones lack integrity and are brittle due to poor architecture
  • May present with fractures, anatomic symptoms (cranial neuropathy, especially blindness/hearing loss, etc), or anemia/pancytopenia (from decreased volume available for hematopoiesis)
74
Q

Bone disorder summary (table)

A
75
Q

Hormones regulating calcium and phosphorus (diagram)

A
76
Q

Net effect of PTH vs calcitriol on calcium and phosphate

A

PTH: Increases calcium, decreases phosphate

Calcitriol: Increases calcium AND phosphate

77
Q

Vitamin D metabolism

A
78
Q

Summary of factors affecting osteoclast development

A
  • M-CSF is required
  • RANKL is required
    • Things that upregulate RANKL:
      • Calcitriol
      • PTH
      • IL-1
      • Prostaglandins
    • Osteoprotegerin is a decoy ligand that competitively inhibits RANKL
      • Estrogen upregulates OPG
79
Q

Thyroid hormone and calcium

A

Hyperthyroidism may increase calcium levels slightly as a result of increased bone turnover, but hypothyroidism does not affect calcium levels

HMS Homeostasis II (35 decks)

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