56: Parathyroid Hormone Flashcards
Describe the economy and basic mechanisms of calcium and phosphate homeostasis in the body.
There is about 1 Kg of Ca in the body; 99% is in the skeleton; Only about 1 % is in the ECF and muscles; 0.1% resides in the plasma (extracellular), half of which is ionized. It is this ionized Ca concentration that is tightly regulated by homeostatic mechanisms involving PTH.
Also, under acidic (acidemia) conditions, albumin in plasma can bind less Ca2+, leading to a true increase in ionized Ca. In, alkalemia, albumin binds more calcium.
Calcium Economy: The classical basic scheme of maintaining calcium balance in the body each day involves the interaction of three main organ systems: The digestive system (small Intestine particularly), where calcium enters the system, the kidneys (Renal tubules) and the bone (Skeleton) .MNEMONIC: easy to remember as the same place our taxes are regulated –the IRS.
a) over 80% of the ingested daily calcium is excreted into the feces
b) The enormous role of the kidneys is in filtering 10X the average daily intake and recapturing all but about 175 mg or so.
c) The role of bone as a repository and buffer of calcium is an active one with a daily turnover under normal conditions of about 280 mg in adults.
d) If dietary intake of calcium is low (or absorption is poor) the kidneys can compensate by increasing re-absorption of filtered Ca+2. In the long run, however, (or when the kidneys aren’t functioning well) the bone reservoir will bear the brunt by increasing bone ‘resorption’, causing a net loss of bone mass and density, and in the more extreme –osteoporosis.
The generally accepted classical mechanisms in normal calcium homeostasis revolve around 2 key hormonal (endocrine) regulators -parathyroid hormone (PTH) and vitamin D. In addition, we can list phosphate (PO4) as well as the binding of PO4 to calcium will reduce the ionized calcium level (and vice-versa) and it tends to ‘buffer’ the calcium concentration.
Calcitonin:
This hormone is produced by the thyroid gland. It is a potent inhibitor of bone resorption and salmon derived calcitonin was previously used as a treatment for osteoporosis.
Bone resorption is the process by which osteoclasts break down bone and release the minerals, resulting in a transfer of calcium from bone to blood .
Explain the actions and principal targets of parathyroid hormone and vitamin-D.
Parathyroid hormone PTH is a peptide hormone that is released when calcium concentration is lower than set point.
The calcium sensing receptor (seen in the following slide) is a G-protein coupled receptor with a signaling cascade involving, curiously enough, intracellular Ca+2 binding/release from the ER that controls the release and synthesis of PTH.
Secretion of parathyroid hormone is regulated only by changes in extracellular calcium concentration. Increases in the secretion rate are stimulated by decreases in extracellular calcium ion concentration–not by calcitonin or PTH-releasing hormone from the hypothalamus.
PTH has two targets:
Target 1 (primary): Kidney (rapid); it increases Calcium re-absoption @ the distal tuble & increases the synthsis of 1,25 (OH)2 D3 (active form) synthesis. It decreases phosphate concentration by reducing reabsorption @ the proximal tubule & increases excretion. The concentration of parathyroid hormone strongly regulates the absorption of calcium ion from the renal tubular fluid. A reduction in PTH concentration reduces calcium reabsorption and increases the rate of calcium excretion in the urine. Administration of parathyroid hormone causes rapid loss of phosphates in the urine, owing to the hormone’s ability to diminish proximal tubular reabsorption of phosphate ions.
Target 2: Bone cells (slow); osteoclastic resorption via receptors on osteoblasts. It increases calcium and phosphate in the ECF & plasma, it increases osteocytic osteolysis (rapid). This process slows to low levels as PTH and calcium return to normal.
The major effect of PTH is by controlling a portion of the the re-absorption of calcium by the kidney distal tubules, into the extracellular fluid and plasma. 60 % of daily calcium re-absorption occurs in the proximal tubule (active tranport) and 9 % in the distal tubule ( active transport), and the rest is by passive diffusion in most other locations. It is the 9% in the distal convoluted tubule that is actually controlled by the PTH concentration.
An increase in PTH will ‘re-capture’ more calcium ions. To bring up the [Ca+2] in the plasma. If Ca2+ in the plasma becomes too high, then PTH release is reduced below ambient and kidney re-absorption is reduced, allowing more Ca to enter the urine.
PO4 re-absorption in the proximal tubule is REDUCED when plasma PTH is increased. This reduces the serum [ PO4 ]. Phosphate re-absorption is increased when PTH decreases.
An increase in PTH due to low plasma Ca2+ only would ultimately* result in BOTH Ca and PO4 increases in plasma, due to increased bone resorption and Ca and PO4 absorption in the small intestine. But this increase in PO4 is not needed or desirable. Fortunately, the same increase in PTH at the same time reduces PO4 re-absorption in the proximal kidney tubules sufficient to correct this and keep PO4 more or less at normal* level—HENCE NET = ONLY CALCIUM INCREASES.
Vitamin D:
The concentration of the active form of vitamin D, 1,25 (OH)2 D3 (mnemonic A1 steak sauce—A = active & 1 - 1,25), is increased when plasma calcium drops. Vitamin D production is stimulated by increased plasma PTH releases through several mechanisms (not though that since vitamin D is a product of PTH, them vitamin D can negatively feed back & reduce PTH production).
Vitamin D has 2 Targets in calcium homeostasis:
Target 1: intestine—It increases Calcium AND Phosphate absorption in 24-48 hrs
Target 2: Bone—Stimulates osteoclastic resorption via receptors on osteoblasts & increases calcium AND phosphate. The stimulated osteoclasts actively resorb bone, liberating Ca+2 and PO4 from the mineral.
Vitamin D assists the transport of [Ca +2] during the re-absorption process in the distal convoluted tubules of the kidney.
Active vitamin D (1,25(OH)2D) also tends to reduce the production of PTH in the parathyroid gland, acting as a ‘buffer’ to the effect of low [Ca] (negative feedback).
Vitamin D synthesis:
The primary source of vitamin D precursors are cholesterol derivatives generated in the skin and and are converted by sunlight (UV) to cholicalciferol (vitamin D3) which migrates into the bloodstream.
Cholicalciferol is converted in the liver to 25-OH-cholicalciferal (25 hydroxy-vitamin D3) where is can be stored for a while and released slowly. This pre-cursor is not active in the intestine and bone. It is also the molecule that is typically measured in the plasma to indicate the adequacy of vitamin D level.
Finally, the active form of vitamin D (1-25 dihydroxy vitamin D3) or calcitriol, is formed in the KIDNEY by the action of the enzyme 1-alpha-hydroxylase on the circulating 25-OH-vitamin D3 and is enhanced by the action of PTH. Thus a low [Ca++] would lead to increased PTH and then to more conversion of vitamin D into its active form.
It is noteworthy that there are extra-renal sources of 1-alpha-hydroxylase that can produce some calcitriol too. Redundancy.
skin cholesterol-> cholicalciferol by UV -> 25-OH-cholicalciferal by liver -> 1-25 dihydroxy kidney by 1-alpha-hydroxylase enhanced by PTH.
Briefly describe how these factors affect bone remodeling and skeletal health?
The osteoBlasts generally line the bone surfaces and when actively synthesizing become rounder and develop lots of endoplasmic reticulum. The precursor molecules of collagen (triple alpha helices) are synthesized within the cell and then exported by means of attached telopeptides.
Outside the membrane, these ‘tropocollagen’ molecules further polymerize in a sort of ‘crystalline-like’ orderly arrangement to form long ‘fibrils’ with characteristic lateral banding seen on the electron microscope. Between the layer of osteoblasts and the mineralizing matrix is called ‘osteoid’ and the thickness of this not-yet mineralized collagen is a measure of the state of health of the skeleton and the availability of Ca and PO4.
OsteoBlasts also do most of the signaling in bone, although the osteocyte (which matures from the osteoBlast) also seems to be important in sensing mechanical loading and generating remodeling responses to it. OsteoBlasts have receptors for PTH, Vitamin D, estrogen, and many paracrine factors and growth factors. They signal osteoClasts to mature and activate to resorb bone.
Bone Mineral is about 65% by weight of bone substance. The rest is collagen (~22 %), fluid (~10%) and 1-2 % non-collagenous proteins and cells.
Approx. formula for bone mineral, microcrystalline hydroxylapatite (HA): Ca10(OH)2(PO4)6 with Mg2+, CO32-, and other trace constituents. Once seeded, the crystals begin to coalesce and accumulate within and around the new collagen fibrils until after several weeks the newly formed area because fully mineralized with about 65% by weight of mineral and the structure will be rigid and very strong under compression and tensile loading.
BONE REMODELING (turnover):
Despite bones rigid structure and strength, bone is constantly remodeling to one extent or another, and has the ability to self repair. The remodeling rate can accelerate or decline in response to a plasma calcium deficiency (mediated by PTH, & Vitamin D) injury, immobilization and a series of metabolic and hormonal changes and diseases. The rate varies by location as well as age. The spinal vertebrae and other trabecular areas of the skeleton can rapidly lose or gain bone whereas the cortex in the tibia is more stable. This is partly an effect of the much larger surface area to volume ratio in the trabecular bone. Growing bone in a child or adolescent, of course, is constantly reshaping and extending. At basal adult rates, It has been estimated that half the entire skeleton is replaced every 10 years.
The ability to dissolve bone in an organized fashion is the responsibility of the osteoclast, a multi-nucleated large cell derived from the monocytes of the blood or marrow. They secrete acidic molecules to dissolve the mineral, and proteases to digest and phagocytize the collagen matrix. Mature osteoclasts do not divide but must develop from mononuclear precursors. They do not last for more that a few days as others mature and take their place.
Another important signaling in bone remodeling has more recently been described: the RANK-L/OPG system. OsteoClast maturation and final activation to perform its task of resorbing bone appears to be greatly enhanced by a cytokine from the osteoBlast lineage cells called RANK-L which binds to receptors on the osteoClast precursors called RANK (receptor activator of NF-kappa-beta). The osteoblasts release of RANK-L is stimulated endocrine factors (e.g., PTH and 1,25 dihydroxy- Vitamin D3) and other systemic hormones and growth factors, as well as several paracrine factors.
In response to other stimuli, the osteobBlastic cells can also produce a soluble substance known as OPG (osteoprotegerin) that specifically binds to the RANK-L sites and competitively inhibits the binding of RANK-L and therefore inhibits the production and activation of osteoClasts. Therefore OPG slows down bone resorption. So the rate of bone resorption in the remodeling sequence appears to be controlled by the OPG/RANK-L ratio. Pharmaceutical companies have exploited this to develop OPG analogs that can be used to limit bone loss in a targeted fashion and therefore treat osteoporosis.
Regulators of bone remodeling:
PTH & Vitamin D increase resorption
Estrogen reduces resorption, so when it is low in menopause, resorption is increased. Estogen increases the rate of deposition and decreases the rate of absorption of bone.
Calcitonin inhibits osteoclasts & tones down calcium in kids. The role of calcitonin in adult bone remodeling is uncertain.
Glucocorticoids inhibit intestinal calcium absorption
Growth hormones like IGF & TGF beta stimulate bone formation
Mechanical loading of bone locally promotes bone accrual & maintenance. Of particular interest is the way bone appears to sense its mechanical loading environment and respond by regulated formation and resorption so as to adapt its structure and size to keep stresses in a moderate range.
Mechanical loading regulate bone mass and shape:
Increased loading tends to stimulate bone formation and repair, while decreased loading or immobilization tends to favor bone resorption over time. Currently, the osteocyte and its connected canaliculae seem to be the most sensitive elements in the response to mechanical loading and reduce the expression of sclerostin, an inhibitor of bone formation mediator when bone loading is weak.
Explain some clinical disturbances involving parathyroid hormone, calcium and
phosphorus using using these principles.
See slide on pg. 88 for general symptoms of calcium imbalance (not high yeild).
Thre is a situation in which the plasma [Ca+2] is stabilized at a high concentration (~ 11.5 mg/dl) in a rare, curious condition known as familial hypercalcemic hypocalcuria (FHH). In this exceptional case, the set point is raised, urine calcium excretion is low and the individuals are otherwise generally healthy and symptom free.
Clinical correlation: Rickets.
A chronic deficiency of vitamin D and/or the dietary deficiency of calcium or phosphorus during early development leads to disturbances in developing bone formation. These disturbances are a result of poor mineralization due to a lack of sufficient calcium and results in weakened and mechanically distorted (bowed) long bones and is also typified by large and abnormal growth plates (epiphyses) on x-ray. This is nutritional rickets in children.
In adults, a similar problem with mineralization leads to poor quality bone formed during remodeling and is called osteomalacia
Primary Hyperparathyroidism:
When a parathyroid gland nodule (adenoma) is out of control, secreting excess PTH, causing kidneys to increase Ca re-absorption, increasing serum Ca, and excrete more PO4.
High PTH also increases bone resorption liberating even more Ca into the ECF and increasing the alkaline phoshphatase, a marker for bone turnover.
Urinary Ca2+ excretion is high because the chronically high serum Ca will eventually increase Ca excretion despite the PTH.
Note the very high PTH, which we expect would occur when the serum Ca is LOW, not high! The parathyroid gland is not functioning correctly.
The treatment is surgical removal of the offending parathyroid nodule/ adenoma.
Humoral Hypercalcemia of Malignancy.
Serum Ca is high due to the release of PTH-related peptide (PTH-rp) by lung tumor cells. PTH-rp activates the same receptors as PTH and caused serum Ca2+ to increase from bone resorption and re-absorption in the kidney and PO4 loss. The actual PTH itself was low as it was inhibited by the high serum Ca. The alkaline phosphatase was high because the PTH-rp also activates receptors on osteoblasts causing increased bone turnover. The normal serum albumin reassures us that the high total Ca is NOT due to Ca bound up to the to excess albumin, but is really due to elevated ionized Ca2+.
Secondary hyperparathyroidism = hypocalcemia due to low vitamin D
Hypoparathyroidism = low calcium due to surgical or genetic damage to parathyroid
Pseudohypoparathyroidism = low calcium due to genetic defect in G protein coupled receptor in PTH receptor in the kidney.
Familial hypocalciuric hypercalcemia = genetic defect in calcium sensor which increases calcium reabsorption since damaged sensor senses low calcium.
Clinical Correlation: Osteoporosis and its relation to calcium homeostasis and bone physiology.
The simple definition is that ‘osteoporosis is a loss of bone mass associated with fracture’. More specifically, bone tissue is lost in either trabecular or cortical bone area, or both, by the osteoclastic resorption mechanisms described previously.
Loss at trabecular sites is most common and tends to occur first (more surface area). Spicules or walls of trabecular become thinner and less numerous or separated and the apparent density is reduced. In osteoporosis, cortical bone also becomes thinner and sometimes more porous (i.e., resorption canals widen and do not refill well). Danger occurs when the strength of the bone drops below the easily fractured level.
If substantial bone is lost, but not enough to be in danger of fracture, this is strictly called ‘osteopenia’, which is also used to refer to bone loss in a general way.
Important for endocrine physiology, the loss or erosion of bone is related to an excess of bone resorption in comparison to new bone formation. The chronic lack of availability of Ca, vitamin D, estrogen or an an excess production of PTH can lead to osteoporosis over time, as can immobilization and lack of suitable mechanical loading. Poor kidney function, long-term administration of glucocorticoids are also causes. All these would be in addition to a slight annual loss with aging. The treatments consist of replacing deficient nutrients, loading exercise, or drugs designed to reduce osteoclastic resorption (e.g., bisphosphonates) or stimulate osteoblastic bone formation (e.g., pulsed dosing of PTH analogs).
Distinguish between osteoporosis where bone tissue is actually lost, and osteomalacia in which the bone tissue is relatively unchanged in amount, but is poorly mineralized.
