Presentation on theme: "Calcium Homeostasis: Parathyroid Hormone, Calcitonin and Vitamin D3"— Presentation transcript:
1 Calcium Homeostasis: Parathyroid Hormone, Calcitonin and Vitamin D3
2 Physiological Importance of Calcium Ca salts in bone provide structural integrity of the skeleton.Ca is the most abundant mineral in the body.The amount of Ca is balance among intake, storage, and excretion.This balance is controlled by transfer of Ca among 3 organs: intestine, bone, kidneys.Ca ions in extracellular and cellular fluids is essential to normal function of a host of biochemical processesNeuoromuscular excitability and signal transductionBlood coagulationHormonal secretionEnzymatic regulationNeuron excitation
3 Intake of Calcium About 1000 mg of Ca is ingested per day. About 200 mg of this is absorbed into the body.Absorption occurs in the small intestine, and requires vitamin D (stay tuned....)
4 Storage of CalciumThe primary site of storage is our bones (about 1000 grams).Some calcium is stored within cells (endoplasmic reticulum and mitochondria).Bone is produced by osteoblast cells which produce collagen, which is then mineralized by calcium and phosphate (hydroxyapatite).Bone is remineralized (broken down) by osteoclasts, which secrete acid, causing the release of calcium and phosphate into the bloodstream.There is constant exchange of calcium between bone and blood.
5 Excretion of CalciumThe major site of Ca excretion in the body is the kidneys.The rate of Ca loss and reabsorption at the kidney can be regulated.Regulation of absorption, storage, and excretion of Ca results in maintenance of calcium homeostasis.
6 Regulation of [Calcium] The important role that calcium plays in so many processes dictates that its concentration, both extracellularly and intracellularly, be maintained within a very narrow range.This is achieved by an elaborate system of controls
7 Regulation of Intracellular [Calcium] Control of cellular Ca homeostasis is as carefully maintained as in extracellular fluids[Ca2+]cyt is approximately 1/1000th of extracellular concentrationStored in mitochondria and ER“pump-leak” transport systems control [Ca2+]cytCalcium leaks into cytosolic compartment and is actively pumped into storage sites in organelles to shift it away from cytosolic pools.
9 Extracellular Calcium When extracellular calcium falls below normal, the nervous system becomes progressively more excitable because of increase permeability of neuronal membranes to sodium.Hyperexcitability causes tetanic contractionsHypercalcemic tetany [Ca2+]cyt
10 Extracellular Calcium Three definable fractions of calcium in serum:Ionized calcium 50%Protein-bound calcium 40%90% bound to albuminRemainder bound to globulinsCalcium complexed to serum constituents 10%Citrate and phosphate
11 Extracellular Calcium Binding of calcium to albumin is pH dependentAcute alkalosis increases calcium binding to protein and decreases ionized calciumPatients who develop acute respiratory alkalosis have increased neural excitability and are prone to seizures due to low ionized calcium in the extracellular fluid which results in increased permeability to sodium ions
12 Calcium and Phosphorous Ca is tightly regulated with P in the body.P is an essential mineral necessary for ATP, cAMP 2nd messenger systems, and other roles
14 Calcium in Blood and Bone Ca2+ normally ranges from mg/dL in the plasma.The active free ionized Ca2+ is only about 48% 46% is bound to protein in a non-diffusible state while 6% is complexed to salt.Only free, ionized Ca2+ is biologically active.
16 Phosphorous in Blood and Bone PO4 normal plasma concentration is mg/dL. 87% is diffusible, with 35% complexed to different ions and 52% ionized.13% is in a non-diffusible protein bound state % is found in bone.The rest is in ATP, cAMP, and proteins
17 Calcium and Bone99% of Ca is found in the bone. Most is found in hydroxyapatite crystals. Very little Ca2+ can be released from the bone– though it is the major reservoir of Ca2+ in the body.
18 Structure of BonesHaversian canals within lamellae
19 Calcium Turnover in Bones 80% of bone is mass consists of cortical bone– for example: dense concentric layers of appendicular skeleton (long bones)20% of bone mass consists of trabecular bone– bridges of bone spicules of the axial skeleton (skull, ribs, vertebrae, pelvis)Trabecular bone has 5 X greater surface area, though comprises lesser mass.Because of greater accessibility trabecular bone is more important to calcium turnover
20 Bones99% of the Calcium in our bodies is found in our bones which serve as a reservoir for Ca2+ storage.10% of total adult bone mass turns over each year during remodeling processDuring growth rate of bone formation exceeds resporption and skeletal mass increases.Linear growth occurs at epiphyseal plates.Increase in width occurs at periosteumOnce adult bone mass is achieved equal rates of formation and resorption maintain bone mass until age of about 30 years when rate of resportion begins to exceed formation and bone mass slowly decreases.
21 Types of Bone CellsThere are 3 major types of bone cells: Osteoblasts are the differentiated bone forming cells and secrete bone matrix on which Ca2+ and PO43- precipitate.Osteocytes, the mature bone cells are enclosed in bone matrix.Osteoclasts is a large multinucleated cell derived from monocytes whose function is to resorb bone. Inorganic bone is composed of hydroxyapatite and organic matrix is composed primarily of collagen.
22 Bone Formation Active osteoblasts synthesize and extrude collagen Collagen fibrils form arrays of an organic matrix called the osetoid.Calcium phosphate is deposited in the osteoid and becomes mineralizedMineralization is combination of CaPO4, OH-, and H3CO3– hydroxyapatite.
23 Mineralization Requires adequate Calcium and phosphate Dependent on Vitamin DAlkaline phosphatase and osteocalcin play roles in bone formationTheir plasma levels are indicators of osteoblast activity.
24 CanaliculiWithin each bone unit is a minute fluid-containing channel called the canaliculi.Canaliculi traverse the mineralized bone.Interior osteocytes remain connected to surface cells via syncytial cell processes.This process permits transfer of calcium from enormous surface area of the interior to extracellular fluid.
26 Control of Bone Formation and Resorption Bone resorption of Ca2+ by two mechanims: osteocytic osteolysis is a rapid and transient effect and osteoclasitc resorption which is slow and sustained.Both are stimulated by PTH. CaPO4 precipitates out of solution id its solubility is exceeded. The solubility is defined by the equilibrium equation: Ksp = [Ca2+]3[PO43-]2.In the absence of hormonal regulation plasma Ca2+ is maintained at 6-7 mg/dL by this equilibrium.
27 Osteocytic Osteolysis Transfer of calcium from canaliculi to extracellular fluid via activity of osteocytes.Does not decrease bone mass.Removes calcium from most recently formed crystalsHappens quickly.
28 Bone ResorptionDoes not merely extract calcium, it destroys entire matrix of bone and diminishes bone mass.Cell responsible for resorption is the osteoclast.
29 Bone RemodelingEndocrine signals to resting osteoblasts generate paracrine signals to osteoclasts and precursors.Osteoclasts resorb and area of mineralized bone.Local macrophages clean up debris.Process reverses when osteoblasts and precursors are recruited to site and generate new matrix.New matrix is minearilzed.New bone replaces previously resorbed bone.
31 Calcium, Bones and Osteoporosis The total bone mass of humans peaks at years of age.Men have more bone mass than women.A gradual decline occurs in both genders with aging, but women undergo an accelerated loss of bone due to increased resorption during perimenopause.Bone resorption exceeds formation.
32 Calcium, Bones and Osteoporosis Reduced bone density and mass: osteoporosisSusceptibility to fracture.Earlier in life for women than men but eventually both genders succumb.Reduced risk:Calcium in the diethabitual exerciseavoidance of smoking and alcohol intakeavoid drinking carbonated soft drinks
33 Vertebrae of 40- vs. 92-year-old women Note the marked loss of trabeculae with preservation of cortex.
35 Hormonal Control of Ca2+ Three principal hormones regulate Ca2+ and three organs that function in Ca2+ homeostasis.Parathyroid hormone (PTH), 1,25-dihydroxy Vitamin D3 (Vitamin D3), and Calcitonin, regulate Ca2+ resorption, reabsorption, absorption and excretion from the bone, kidney and intestine. In addition, many other hormones effect bone formation and resorption.
36 Vitamin DVitamin D, after its activation to the hormone 1,25-dihydroxy Vitamin D3 is a principal regulator of Ca2+.Vitamin D increases Ca2+ absorption from the intestine and Ca2+ resorption from the bone .
37 Synthesis of Vitamin D Humans acquire vitamin D from two sources. Vitamin D is produced in the skin by ultraviolet radiation and ingested in the diet.Vitamin D is not a classic hormone because it is not produce and secreted by an endocrine “gland.” Nor is it a true “vitamin” since it can be synthesized de novo.Vitamin D is a true hormone that acts on distant target cells to evoke responses after binding to high affinity receptors
38 Synthesis of Vitamin DVitamin D3 synthesis occurs in keratinocytes in the skin.7-dehydrocholesterol is photoconverted to previtamin D3, then spontaneously converts to vitamin D3.Previtamin D3 will become degraded by over exposure to UV light and thus is not overproduced.Also 1,25-dihydroxy-D (the end product of vitamin D synthesis) feeds back to inhibit its production.
39 Synthesis of Vitamin DPTH stimulates vitamin D synthesis. In the winter or if exposure to sunlight is limited (indoor jobs!), then dietary vitamin D is essential.Vitamin D itself is inactive, it requires modification to the active metabolite, 1,25-dihydroxy-D.The first hydroxylation reaction takes place in the liver yielding 25-hydroxy D.Then 25-hydroxy D is transported to the kidney where the second hydroxylation reaction takes place.
40 Synthesis of Vitamin DThe mitochondrial P450 enzyme 1a-hydroxylase converts it to 1,25-dihydroxy-D, the most potent metabolite of Vitamin D.The 1a-hydroxylase enzyme is the point of regulation of D synthesis.Feedback regulation by 1,25-dihydroxy D inhibits this enzyme.PTH stimulates 1a-hydroxylase and increases 1,25-dihydroxy D.
41 Synthesis of Vitamin D25-OH-D3 is also hydroxylated in the 24 position which inactivates it.If excess 1,25-(OH)2-D is produced, it can also by 24-hydroxylated to remove it.Phosphate inhibits 1a-hydroxylase and decreased levels of PO4 stimulate 1a-hydroxylase activity
42 Regulation of Vitamin D Metabolism PTH increases 1-hydroxylase activity, increasing production of active form.This increases calcium absorption from the intestines, increases calcium release from bone, and decreases loss of calcium through the kidney.As a result, PTH secretion decreases, decreasing 1-hydroxylase activity (negative feedback).Low phosphate concentrations also increase 1-hydroxylase activity (vitamin D increases phosphate reabsorption from the urine).
43 Regulation of Vitamin D by PTH and Phosphate Levels 1-hydroxylase25-hydroxycholecalciferol1,25-dihydroxycholecalciferolincrease phosphate resorptionLow phosphate
45 Vitamin DVitamin D is a lipid soluble hormone that binds to a typical nuclear receptor, analogous to steroid hormones.Because it is lipid soluble, it travels in the blood bound to hydroxylated a-globulin.There are many target genes for Vitamin D.
47 Vitamin D actionThe main action of 1,25-(OH)2-D is to stimulate absorption of Ca2+ from the intestine.1,25-(OH)2-D induces the production of calcium binding proteins which sequester Ca2+, buffer high Ca2+ concentrations that arise during initial absorption and allow Ca2+ to be absorbed against a high Ca2+ gradient
48 Vitamin D promotes intestinal calcium absorption Vitamin D acts via steroid hormone like receptor to increase transcriptional and translational activityOne gene product is calcium-binding protein (CaBP)CaBP facilitates calcium uptake by intestinal cells
49 Clinical correlate Vitamin D-dependent rickets type II Mutation in 1,25-(OH)2-D receptorDisorder characterized by impaired intestinal calcium absorptionResults in rickets or osteomalacia despite increased levels of 1,25-(OH)2-D in circulation
50 Vitamin D Actions on Bones Another important target for 1,25-(OH)2-D is the bone.Osteoblasts, but not osteoclasts have vitamin D receptors.1,25-(OH)2-D acts on osteoblasts which produce a paracrine signal that activates osteoclasts to resorb Ca++ from the bone matrix.1,25-(OH)2-D also stimulates osteocytic osteolysis.
51 Vitamin D and BonesProper bone formation is stimulated by 1,25-(OH)2-D.In its absence, excess osteoid accumulates from lack of 1,25-(OH)2-D repression of osteoblastic collagen synthesis.Inadequate supply of vitamin D results in rickets, a disease of bone deformation
52 Parathyroid HormonePTH is synthesized and secreted by the parathyroid gland which lie posterior to the thyroid glands.The blood supply to the parathyroid glands is from the thyroid arteries.The Chief Cells in the parathyroid gland are the principal site of PTH synthesis.It is THE MAJOR of Ca homeostasis in humans.
54 Synthesis of PTH PTH is translated as a pre-prohormone. Cleavage of leader and pro-sequences yield a biologically active peptide of 84 aa.Cleavage of C-terminal end yields a biologically inactive peptide.
55 Regulation of PTH The dominant regulator of PTH is plasma Ca2+. Secretion of PTH is inversely related to [Ca2+].Maximum secretion of PTH occurs at plasma Ca2+ below 3.5 mg/dL.At Ca2+ above 5.5 mg/dL, PTH secretion is maximally inhibited.
57 Regulation of PTHPTH secretion responds to small alterations in plasma Ca2+ within seconds.A unique calcium receptor within the parathyroid cell plasma membrane senses changes in the extracellular fluid concentration of Ca2+.This is a typical G-protein coupled receptor that activates phospholipase C and inhibits adenylate cyclase—result is increase in intracellular Ca2+ via generation of inositol phosphates and decrease in cAMP which prevents exocytosis of PTH from secretory granules.
58 Regulation of PTH When Ca2+ falls, cAMP rises and PTH is secreted. 1,25-(OH)2-D inhibits PTH gene expression, providing another level of feedback control of PTH.Despite close connection between Ca2+ and PO4, no direct control of PTH is exerted by phosphate levels.
60 PTH actionThe overall action of PTH is to increase plasma Ca2+ levels and decrease plasma phosphate levels.PTH acts directly on the bones to stimulate Ca2+ resorption and kidney to stimulate Ca2+ reabsorption in the distal tubule of the kidney and to inhibit reabosorptioin of phosphate (thereby stimulating its excretion).PTH also acts indirectly on intestine by stimulating 1,25-(OH)2-D synthesis.
62 Actions of PTH: BonePTH acts to increase degradation of bone (release of calcium).- causes osteoblasts to release cytokines, which stimulate osteoclast activity- stimulates bone stem cells to develop into osteoclasts- net result: increased release of calcium from bone- effects on bone are dependent upon presence of vitamin D
63 Actions of PTH: KidneyPTH acts on the kidney to increase the reabsorption of calcium (decreased excretion).Also get increased excretion of phosphate (other component of bone mineralization), and decreased excretion of hydrogen ions (more acidic environment favors dimineralization of bone)ALSO, get increased production of the active metabolite of vitamin D3 (required for calcium absorption from the small intestine, bone demineralization).NET RESULT: increased plasma calcium levels
65 Mechanism of Action of PTH PTH binds to a G protein-coupled receptor.Binding of PTH to its receptor activates 2 signaling pathways:- increased cyclic AMP- increased phospholipase CActivation of PKA appears to be sufficient to decrease bone mineralizationBoth PKA and PKC activity appear to be required for increased resorption of calcium by the kidneys
66 Regulation of PTH Secretion PTH is released in response to changes in plasma calcium levels.- Low calcium results in high PTH release.- High calcium results in low PTH release.PTH cells contain a receptor for calcium, coupled to a G protein.Result of calcium binding: increased phospholipase C, decreased cyclic AMP.Low calcium results in higher cAMP, PTH release.Also, vitamin D inhibits PTH release (negative feedback).
69 PTH-Related PeptideHas high degree of homology to PTH, but is not from the same gene.Can activate the PTH receptor.In certain cancer patients with high PTH-related peptide levels, this peptide causes hypercalcemia.But, its normal physiological role is not clear.- mammary gland development/lactation?- kidney glomerular function?- growth and development?
70 Primary Hyperparathyroidism Calcium homeostatic loss due to excessive PTH secretionDue to excess PTH secreted from adenomatous or hyperplastic parathyroid tissueHypercalcemia results from combined effects of PTH-induced bone resorption, intestinal calcium absorption and renal tubular reabsorptionPathophysiology related to both PTH excess and concomitant excessive production of 1,25-(OH)2-D.
71 Hypercalcemia of Malignancy Underlying cause is generally excessive bone resorption by one of three mechanisms1,25-(OH)2-D synthesis by lymphomasLocal osteolytic hypercalcemia20% of all hypercalcemia of malignancyHumoral hypercalcemia of malignancyOver-expression of PTH-related protein (PTHrP)
72 PTHrPThree forms of PTHrP identified, all about twice the size of native PTHMarked structural homology with PTHPTHrP and PTH bind to the same receptorPTHrP reproduce full spectrum of PTH activities
73 PTH receptor defectRare disease known as Jansen’s metaphyseal chondrodysplasiaCharacterized by hypercalcemia, hypophosphotemia, short-limbed dwarfismDue to activating mutation of PTH receptorRescue of PTH receptor knock-out with targeted expression of “Jansen’s transgene”
74 HypoparathyroidismHypocalcemia occurs when there is inadequate response of the Vitamin D-PTH axis to hypocalcemic stimuliHypocalcemia is often multifactorialHypocalcemia is invariably associated with hypoparathyroidismBihormonal—concomitant decrease in 1,25-(OH)2-D
75 Hypoparathyroidism PTH-deficient hypoparathyroidism Reduced or absent synthesis of PTHOften due to inadvertent removal of excessive parathyroid tissue during thyroid or parathyroid surgeryPTH-ineffective hypoparathyroidismSynthesis of biologically inactive PTH
76 Pseudohypoparathyroidism PTH-resistant hypoparathyroidismDue to defect in PTH receptor-adenylate cyclase complexMutation in Gas subunitPatients are also resistant to TSH, glucagon and gonadotropins
79 Calcitonin Calcitonin acts to decrease plasma Ca2+ levels. While PTH and vitamin D act to increase plasma Ca2+-- only calcitonin causes a decrease in plasma Ca2+.Calcitonin is synthesized and secreted by the parafollicular cells of the thyroid gland.They are distinct from thyroid follicular cells by their large size, pale cytoplasm, and small secretory granules.
80 CalcitoninThe major stimulus of calcitonin secretion is a rise in plasma Ca2+ levelsCalcitonin is a physiological antagonist to PTH with regard to Ca2+ homeostasis
81 Calcitonin The target cell for calcitonin is the osteoclast. Calcitonin acts via increased cAMP concentrations to inhibit osteoclast motility and cell shape and inactivates them.The major effect of calcitonin administration is a rapid fall in Ca2+ caused by inhibition of bone resorption.
82 Actions of CalcitoninThe major action of calcitonin is on bone metabolism.Calcitonin inhibits activity of osteoclasts, resulting in decreased bone resorption (and decreased plasma Ca levels).calcitonin(-)osteoclasts: destroy bone torelease CaDecreasedresorption
83 CalcitoninRole of calcitonin in normal Ca2+ control is not understood—may be more important in control of bone remodeling.Used clinically in treatment of hypercalcelmia and in certain bone diseases in which sustained reduction of osteoclastic resorption is therapeutically advantageous.Chronic excess of calcitonin does not produce hypocalcemia and removal of parafollicular cells does not cause hypercalcemia. PTH and Vitamin D3 regulation dominate.May be more important in regulating bone remodeling than in Ca2+ homeostasis.
84 Regulation of Calcitonin Release Calcitonin release is stimulated by increased circulating plasma calcium levels.Calcitonin release is also caused by the gastrointestinal hormones gastrin and cholecystokinin (CCK), whose levels increase during digestion of food.Food (w/ Ca?)gastrin, CCKincreasedcalcitonindecreased boneresorption
85 What is the Role of Calcitonin in Humans? Removal of the thyroid gland has no effect on plasma Ca levels!Excessive calcitonin release does not affect bone metabolism!Other mechanisms are more important in regulating calcium metabolism (i.e., PTH and vitamin D).
86 Calcitonin Gene-Related Peptide (CGRP) The calcitonin gene produces several products due to alternative splicing of the RNA.CGRP is an alternative product of the calcitonin gene.CGRP does NOT bind to the calcitonin receptor.CGRP is expressed in thyroid, heart, lungs, GI tract, and nervous tissue.It is believed to function as a neurotransmitter, not as a regulator of Ca.
87 Other Factors Influencing Bone and Calcium Metabolism Estrogens and Androgens: both stimulate bone formation during childhood and puberty.Estrogen inhibits PTH-stimulated bone resorption.Estrogen increases calcitonin levelsOsteoblasts have estrogen receptors, respond to estrogen with bone growth.Postmenopausal women (low estrogen) have an increased incidence of osteoporosis and bone fractures.
88 Findings of NIH Consensus Panel on Osteoporosis The National Institutes of Health has concluded the following:Adequate calcium and vitamin D intake are crucial to develop optimal peak bone mass and to preserve bone mass throughout life.Factors contributing to low calcium intakes are restriction of dairy products, a generally low level of fruit and vegetable consumption, and a high intake of low calcium beverages such as sodas.
89 Influences of Growth Hormone Normal GH levels are required for skeletal growth.GH increases intestinal calcium absorption and renal phosphate resorption.Insufficient GH prevents normal bone production.Excessive GH results in bone abnormalities (acceleration of bone formation AND resorption).
90 Effects of Glucocorticoids Normal levels of glucocorticoids (cortisol) are necessary for skeletal growth.Excess glucocorticoid levels decrease renal calcium reabsorption, interfere with intestinal calcium absorption, and stimulate PTH secretion.High glucocorticoid levels also interfere with growth hormone production and action, and gonadal steroid production.Net Result: rapid osteoporosis (bone loss).
91 Influence of Thyroid Hormones Thyroid hormones are important in skeletal growth during infancy and childhood (direct effects on osteoblasts).Hypothyroidism leads to decreased bone growth.Hyperthyroidism can lead to increased bone loss, suppression of PTH, decreased vitamin D metabolism, decreased calcium absorption. Leads to osteoporosis.
92 Effects of DietIncreasing dietary intake of Ca may prevent osteoporosis in postmenopausal women.Excessive Na intake in diet can impair renal Ca reabsorption, resulting in lower blood Ca and increased PTH release. Normally, PTH results in increased absorption of Ca from the GI tract (via vitamin D). But in aging women, vitamin D production decreases, so Ca isn’t absorbed, and PTH instead causes increased bone loss.High protein diet may cause loss of Ca from bone, due to acidic environment resulting from protein metabolism and decreased reabsorption at the kidney.
93 Nutrition and CalciumHeaney RP, Refferty K Am J. Clin Nutr :343-7Excess calciuria associated with consumption of carbonated beverages is confined to caffeinated beverages.Acidulant type (phosphoric vs. citric acid) has no acute effect.The skeletal effects of carbonated beverage consumption are due primarily to milk displacement.
94 Nutrition and Calcium See Nutrition 2000 Vol 16 (7/8) in particular: Calvo MS “Dietary considerations to prevent loss of bone and renal function”“overall trend in food consumption in the US is to drink less milk and more carbonated soft drinks.”“High phosphorus intake relative to low calcium intake”Changes in calcium homeostasis and PTH regulation that promote bone loss in children and post-menopausal women.High sodium associated with fast-food consumption competes for renal reabsorption of calcium and PTH secretion.
95 Nutrition and Calcium See Nutrition 2000 Vol 16 (7/8) in particular: Harland BF “Caffeine and Nutrition”Caffeine is most popular drug consumed world-wide.75% comes from coffeeDeleterious effects associated with pregnancy and osteoporosis.Low birth-rate and spontaneous abortion with excessive consumptionFor every 6 oz cup of coffee consumed there was a net loss of 4.6 mg of calciumHowever, if you add milk to your coffee, you can replace the calcium that is lost.
96 Effects of soft drinksIntake of carbonated beverages has been associated with increased excretion and loss of calcium25 years ago teenagers drank twice as much milk as soda pop. Today they drink more than twice as much soda pop as milk.Another significant consideration is obesity and increased risk for diabetes.For complete consideration of ill effects of soft drinks on health and environment see:
97 Excessive sodium intake Excessive intake of Na may cause renal hypercalciuria by impairing Ca reabsorption resulting in compensatory increase in PTH secretion.Stimulation of intestinal Ca absorption by PTH-induced 1,25-(OH)2-D production compensates for excessive Ca excretionPost-menopausal women at greater risk for bone loss due to excessive Na intake due to impaired vitamin D synthesis which accompanies estrogen deficiency.
98 Effects of ExerciseBone cells respond to pressure gradients in laying down bone.Lack of weight-bearing exercise decreases bone formation, while increased exercise helps form bone.Increased bone resorption during immobilization mayresult in hypercalcemia
99 Exercise and CalciumNormal bone function requires weight-bearing exerciseTotal bed-rest causes bone loss and negative calcium balanceMajor impediment to long-term space travel
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