There are three hormones that may influence calcium and phosphate utilisation and bone homeostasis.  One of these, released from the parathyroid gland, is parathyroid hormone (parathormone, PTH).  The second is vitamin D, which is formed in the skin and metabolised to active hormones in the liver and kidney.  The third, calcitonin, is released from the thyroid gland.  Since these hormones control serum levels of calcium and phosphate, they not only impact bone homeostasis but also control the availability of these ions body wide, thus contributing to cell function (particularly nerve, muscle, and secretory cells) and hæmatopoiesis and hæmastasis.

Parathormone (PTH)
This polypeptide hormone is released from the parathyroid gland in response to changes in plasma levels of calcium.  If free (ionised) levels of calcium decline, PTH is released.  NOTE that bound calcium (i.e. calcium phosphate or calcium complexed with plasma proteins such as albumin) does not cause the release of PTH.  Free calcium interacts with a calcium sensor (putatively identified as G_q-type coupled receptor), which regulates the release of PTH.  Calcium binding to this sensor reduces both intracellular cAMP and protein kinase C activity.  Hypocalcæmic states will increase protein kinase C activity, cAMP, and subsequent synthesis and release of PTH.

Mechanism of Action
The exact mechanisms of action of PTH are not fully known.  There is a specific receptor for PTH and it is believed that at least some of its actions are mediated by cAMP acting as a second messenger.  Other actions are thought to be independent of this signal transduction system.

Physiologic and Pharmacodynamic Effects

Bone -- High doses of PTH will increase the number and activity of osteoclasts, resulting in bone resorption (breakdown).  This effect may be secondary to PTH-induced stimulation of osteoblasts (bone forming cells) which then stimulates osteoclastic activity.  Osteoblast activity resulting from PTH action has been linked with intracellular increases in both cAMP and calcium.  Despite the activity of osteoblasts, the net effect of high dose PTH is bone resorption and loss of calcium to the serum.  At low doses, PTH may stimulate bone formation (osteoblast action alone) and no calcium is lost.

Kidney -- PTH increases calcium and magnesium reabsorption and decreases the reabsorption of phosphate, amino acids, bicarbonate, sodium, chloride, and sulphate.  PTH will also cause the formation of the calcitriol form of vitamin D (see below).

Intestine -- PTH increases the absorption of dietary calcium and phosphate.  This action is secondary to vitamin D formation and activity.

The net effect of PTH on these systems is to increase serum calcium and decrease serum phosphate levels.

Once formed, vitamin D is bound to vitamin D binding globulin, one of the large family of alpha-globulins that serve as carrier proteins in the plasma.  Since vitamin D is one of the fat soluble vitamins, excess is stored in adipose tissue.  Dietary vitamin D, primarily from fortified milk or plant sources, undergoes similar hepatic and renal metabolism to products whose physiologic function is identical to endogenous vitamin D.  Any of these precursor of vitamin D may be used therapeutically.

Mechanism of Action -- The exact mechanism of action of vitamin D is unknown.  It is assumed that since it is a steroid, it would act via a typical nuclear receptor, modifying gene transcription and resulting in increased protein synthesis.  It is known that vitamin D will increase the synthesis of calcium binding protein, presumably by this mechanism.  However, vitamin D also increases calcium transport across cellular and mitochondrial membranes by a mechanism that is not dependent upon gene activation.

Physiologic and Pharmacodynamic Effects

Bone -- Vitamin D (calcitriol) will increase bone resorption, thus increasing the loss of bone calcium and phosphorus to the serum.

Kidney -- Vitamin D (calcitriol) increases calcium and phosphorus reabsorption passively, by decreasing their secretion.

Intestine -- Vitamin D (calcitriol) will increase the intestinal absorption of dietary calcium and phosphorus.

The net effect of the calcitriol form of vitamin D (the predominant form in adults) is to increase serum levels of both calcium and phosphorus.

Vitamin D may also be involved with PTH release, insulin secretion, cytokine production, and cell proliferation.
 

Vitamin D Analogues -- In addition to the naturally occurring forms of vitamin D, some analogues are used.
25-dihydrovitamin D (calcifediol) -- this analogue possesses the pharmacodynamic response that would be analogous to secalcifediol, that is increased bone formation.  Calcifediol is used more than the endogenous form secalcifediol in clinical situations.

Paricalcitol -- a vitamin D analogue that is administered intravenously for the treatment of secondary hyperparathyroidism.  It is a derivative of calcitriol that reduces PTH synthesis/release but does not appreciably alter circulating calcium levels.

Dihydrotachysterol (DHT) -- the older, standard vitamin D supplement.  It is more efficacious in bone resorption than calcitriol and does not require renal activation for its pharmacologic effects.

Calcipotriene (calcipotriol) -- This vitamin D analogue is used in the treatment of chronic, severe psoriasis.  Its mechanism of action in psoriasis is not known.  It does possess affinity, but very little efficacy, for the calcitriol receptors.

Other Vitamin D analogues

Ergocalciferol -- may be administered orally or parenterally (intravenous or intramuscular) -- requires renal activation to the active form.

Calcifediol -- the 25-hydroxy from of cholecalciferol, also requiring renal activation, is available for oral administration.

Calcitriol -- the 1,25 dihydroxy from of cholecalciferol may be administered orally or parenterally.  It is given in the active form (does not require renal bioactivation).  The FDA recently approved a generic form of the brand name drug Rocaltrol® of 1,25 dihydroxycholecalciferol.  This has met all bioavailability and therapeutic equivalency tests as set forth by the FDA.
 

These vitamin D analogues are used in the prevention and treatment of rickets, osteomalacia, and hyper- or hypo-parathyroidism, dependent upon the specific form of vitamin D used.

Mechanism of Action -- The exact mechanism of action of calcitonin is not know.  Calcitonin acts at specific receptors on the osteoclasts to inhibit bone resorption.  It is believed that at least some of its effects are mediated through cAMP as a second messenger system.

Physiologic and Pharmacodynamic Effects -- In general, the effects of calcitonin are opposite those of PTH and vitamin D.

Bone -- Calcitonin decreases osteoclastic activity in bone to decrease calcium and phosphate loss (inhibits bone-derived increases in circulating calcium and phosphate).

Kidney -- Calcitonin will enhance renal loss of calcium and phosphorus by inhibiting their reabsorption.  It also reduces the reabsorption of sodium, potassium, and magnesium

Other effects -- Calcitonin also decreases gastric acid and gastrin secretion and increases the secretion of sodium, potassium, chloride, and water into the intestine.  The exact role of calcitonin with respect to these effects is not known.
 

Calcitonin is used therapeutically in the treatment of hypercalcæmia, Paget's disease, and osteroporosis.

Biphosphonates -- Etidronate, Pamidronate, Alendronate, Risedronate, Tiludronate, Zoledronic acid

Mechanism of Action -- the exact mechanism of these drugs is not known.  Some drugs in the class (etidronate, tiludronate) are metabolised to an analogue of ATP which then inhibits ATP-dependent osteoclastic cell processes.  Others (alendronate) are know to inhibit cholesterol-dependent steps involved in protein synthesis required for osteoclastic activity.

Pharmacodynamic Effect -- Regardless of the exact mechansim, these drugs will decrease bone loss by inhibiting bone resorption.  This action may be mediated by decreased formation and dissolution of hydroxyapatite crystals, by inhibition of osteoclasts.  The overall effect of biphosphonates is to slow bone resporption and thus lower circulating calcium.

Adverse Effects -- These agents are poorly absorbed (<10%) and must be taken on an empty stomach.  However, they may produce GI side effects (these are severe enough with pamidronate that it is not administered orally).

Therapeutic Uses -- The biphosphonates are effective in the treatment of Paget's disease, osteoporosis, and hypercalcæmia.

Mechanism of Action -- Plicamycin is an antineoplastic antibiotic that decreases protein synthesis.  Its mechanism of action that accounts for efficacy in bone loss is not known, but is presumed to be mediated by decreased protein synthesis.

Pharmacodynamic Effect -- Plicamycin reduces bone resorption, thus increasing bone density.

Adverse Effects -- At high doses, typical anti-neoplastic effects may be seen. The dose used in the following conditions is approximately 1/10 the antineoplastic dose, which limits the adverse effects.

Therapeutic Uses -- Paget's disease and hypercalcæmia

Mechanism of Action -- In the prevention of dental caries, fluoride stabilises hydroxyapatite crystals.  The cellular mechanism of action of fluoride in increasing bone density is not known.  However, it is known that fluoride induces osteoblastic mitogenesis.  Moreover, it is ineffective unless the patient also takes calcium supplements.

Pharmacodynamic Effect -- Fluoride with calcium supplementation will increase bone mineral density and volume.

Adverse Effects -- Nausea, vomiting, GI blood loss, arthralgia, arthritis.  These side effects may be decreased with lower doses and by taking with food.

Acute Fluoride Toxicity -- Severe GI effects, cardiovascular collapse, respiratory failure

Chronic Fluoride Toxicity -- Thickened bone cortex and  vertebral thickening, which may cause a "crippling" fluorosis, caused by an extension of the pharmacologic effects.

Aluminium hydroxide -- antacids containing aluminium hydroxides may be used to lower levels of phosphates in patients with hyperphosphatæmia.  These agents bind to phosphates, removing their influence on bone homeostasis and allowing their excretion.

Sevelamer hydrochloride -- This agent, recently approved by the FDA, is a polymeric phosphate binding agent that binds to intestinal phosphates preventing the absorption/re-absorption.  It is approved for the treatment of hyperphosphatæmia in end stage renal disease.

Hypercalcæmia -- Treatment may include one of the following:  saline diuresis, biphosphonates, calcitonin, gallium nitrate (this agent decreases bone resorption and may produce nephrotoxicity), plicamycin, phosphate, and glucocorticoids.

Hypocalcæmia -- Treatment generally consists of calcium supplementation with vitamin D to increase its absorption.

Hyperphosphotæmia -- This condition often occurs in patients with renal failure.  It is usually treated with aluminium hydroxide antacids which bind to dietary phosphates, inhibiting the absorption.

Rickets -- Vitamin D deficiency, usually treated with supplementation.  The deficiency may represent specific deficiencies in the metabolic pathway, which pre-determines the specific form of vitamin D that needs to be supplemented.

Chronic Renal Failure -- As noted above, phosphate retention may occur with renal failure.  Other problems associated with kidney failure include reduced vitamin D formation, so that secondary effects of renal failure present as a reduction in free calcium (bound by excess phosphates), reduced calcium absorption, and hyperparathyroidism.

Paget's Disease -- This disease is characterised by uncontrolled osteoclastic bone resorption.  Its etiology is unknown but may involve a slow virus.  Treatment is designed to inhibit bone resorption, thus reducing bone loss and increasing bone density.

END MATERIAL FOR TEST 4