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Calcium homeostasis and osteoporosis

CONTENTS

Calcium homeostasis
Bone homeostasis
Osteoporosis

CALCIUM HOMEOSTASIS AND OSTEOPOROSIS

Patrick Kennedy (http://www.pathophys.org/author/pkennedy/), Ashu Jain (http://www.pathophys.org/author/ajain/),
Ragini Srinivasan (http://www.pathophys.org/author/rsrinivasan/) and Sultan Chaudhry
(http://www.pathophys.org/author/sultan/)

Editors: Sultan Chaudhry and Eric Wong

Calcium homeostasis
N Engl J Med. (http://www.ncbi.nlm.nih.gov/pubmed/17634462#) 2007 Jul 19;357(3):266-81.
Clin J Am Soc Nephrol. (http://www.ncbi.nlm.nih.gov/pubmed/20089499#) 2010 Jan;5 Suppl 1:S23-30.
Clin Chem. (http://www.ncbi.nlm.nih.gov/pubmed/10430817#) 1999 Aug;45(8 Pt 2):1347-52.

Calcium is found primarily in bone (99%), blood and ECF.

The overall goal of calcium homestasis is to maintain biologically active ionized [Ca] within a narrow acceptable
range (1.1-1.4 mmol/L) in order for critical functions such as signal transduction, neuronal activation and muscle
contraction to work. These concentrations are tightly regulated by hormonal mechanisms to avoid acute and
chronic complications. 

Vitamin D synthesis, metabolism and actions

Ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) are found in plant and animal sources respectively and
absorbed via the intestines. (See figure 1 for activation details)
Inactivation occurs by further hydroxylation by vitamin D-24 hydroxylase, induced by 1,25(OH)2D itself, producing
calcitroic acid which is excreted in bile and urine.

End organ effects: Vitamin D works to correct hypocalcemia via several mechanisms including: (i) increased uptake
of calcium from the intestinal lumen, (ii) calcium reabsorption in the distal convoluted tubules (DCT) in nephrons,
(iii) stimulating osteoblasts to secrete RANKL, thereby activating osteoclasts to resorb bone to raise serum calcium
levels. 
Vitamin D also suppresses PTH production. 
(http://www.pathophys.org/osteoporosis/vitamind/)
Figure 1: Calcium homeostasis is a process controlled by chiefly by hormones vitamin D and PTH. Vitamin D enters
circulation via synthesis in the skin or intestinal absorption and is subsequently converted to its active form,
1,25(OH)2D via separate hydroxylation processes in the liver and kidneys. Both 25(OH)D and 1,25(OH)2D are regulated
by classical negative feedback. PTH acts to increase serum calcium by increasing active vitamin D and stimulating
bone remodeling. It is regulated primarily by serum calcium with some contribution from circulating vitamin D levels.

Parathyroid hormone synthesis, regulation and actions

Parathyroid hormone (PTH) is a protein hormone synthesized, processed and secreted by the parathyroid chief
cells in response to changes in serum ionized calcium levels. Drop in serum calcium levels trigger secretion of PTH
via reduced binding to the calcium sensing receptors (CaSR).  Furthermore, a rise in vitamin D levels suppress PTH
secretion. High phosphate levels also induce PTH secretion by lowering serum calcium and vitamin D levels. 
Parathyroid hormone actions: Major effects of PTH are mediated in kidneys and bone. 
 Renal effects
Increased calcium reabsorption: Stimulates calcium transport in the DCT and the thick ascending loop of henle
(TALH) through up-regulation of TRPV5 (calcium channel) and calbindin both directly and indirectly via rise in
vitamin D levels.
Increases phosphate excretion: Inhibits phosphate reabsorption in proximal and distal tubule through
endocytosis and proteolysis of sodium-phosphate co-transporters.
Increases vitamin D production:
Stimulates hydroxylation of vitamin D by rapidly inducing transcription of 1α-hydroxylase in the proximal
tubule
Inhibits transcription of 24-hydroxylase gene in proximal tubule increasing availability of active form of
vitamin D.
Bone effects
Stimulates bone resorption: Increases osteoclastic activity through upregulation of RANKL and downregulation
of OPG secretion by osteoblasts.
Increases bone formation: Bone formation increased indirectly via autocrine and paracrine pathways through
release of IGF-1, FGF-2 and amphiregulin from osteoblasts.

Calcitonin
Produced in the parafollicular cells of the thyroid gland, calcitonin acts to correct hypercalcemia by directly
opposing the effects of PTH by inhibiting intestinal absorption of calcium, inhibiting osteoclastic activity and
inhibiting reabsorption of calcium in the nephron.

Phosphate metabolism
Phosphate is readily absorbed in small intestine via active transport by sodium-phosphate cotransporters whose
activity is increased by vitamin D and an increased filtered load of PO42- and can be reduced by PTH which down
regulates apical expression of the cotransporter.

Bone homeostasis
Guyton Textbook of Medical Physiology, 11e, Ch. 79
Robbins Pathologic Basis of Disease, 7e, Ch. 26
Clin J Am Soc Nephrol. (http://www.ncbi.nlm.nih.gov/pubmed/18988698#) 2008 Nov;3 Suppl 3:S131-9.
Endocr Rev. (http://www.ncbi.nlm.nih.gov/pubmed/10782361#) 2000 Apr;21(2):115-37.

Table 1: Components of bone

Origin Cells Function

Mesenchymal Osteoblast Bone formation

Osteocyte Dormant osteoblast in bone matrix

Hematopoietic Osteoclasts Bone resorption

Osteoblast function
Mesenchymal stem cells within the periosteum, called the osteoprogenitor cells, can differentiate into osteoblasts,
following stimulation from the bone morphogenic protein.  Osteoblasts have a 3 month life span, then either
become osteocytes or bone surface-lining cells. Osteocytes are dormant osteoblasts embedded in the mineralized
bone.  
 Osteoblasts secrete the components of the bone matrix including collagen and proteoglycans.  Polymerized
collagen monomers give the bones their tensile strength and the tight binding with the bone salts gives the bone its
shear strength.  Proteoglycans play a role in bone salt deposition. 

Deposition of calcium and phosphate ions

Calcium and phosphate salts have an intrinsic attraction to the bone matrix through a mechanism that is not well
understood. They initially deposit as non-crystalline compounds and are subsequently converted to hydroxyapatite
[Ca10(PO4)6(OH)2], the main crystalline salt of the bone.  Hydroxyapatite functions to store ions and gives bone its
compressional strength.  Some of the hydroxyapatite remains in the in non-crystalline form to facilitate a rapid
resorption, when needed. 
Pyrophosphate is responsible for inhibiting hydroxyapatite precipitation in other tissues along with maintenance of
low physiologic concentrations of these ions. Osteoblasts inhibit pyrophosphate activity in the bone allowing
precipitation of these minerals.

Osteoclast (OC) function

Hematopoietic stem cells can differentiate into osteoclasts, monocytes, and macrophages, all of which express
tumour necrosis factor (TNF) receptors.
Increase bone resorption, in response to physiologic signals (see figure 2 for details)

Receptor activator for nuclear factor κB (RANK) and RANK ligand (RANKL)
The binding of RANKL to RANK stimulates osteoclast formation, differentiation, and activation (see figure 2 for
details).

Osteoprotegerin (OPG)
OPG is member of the TNF family of receptors that is released by several cell types, including osteoblasts, marrow
cells, and immune cells.
It inhibits the function of RANK by binding to RANKL and preventing its interaction with RANK.
(http://www.pathophys.org/osteoporosis/boneresorption/)
Figure 2: Bone resorption and the relationship between osteoblasts and osteoclasts.  RANK is expressed on the
osteoclasts, allowing signals from other cell types to affect their life cycle and activity. RANKL is expressed on marrow
cells and osteoblasts. The binding of RANKL to RANK stimulates osteoclast formation, differentiation, and activation.
Villous projections from an osteoclast form a ruffled border on the surface of bone, which increases the membrane
surface area. Podosomes and their associated linking proteins (e.g. osteopontin, meaning “bone bridge”) create an
adhesive ring around the ruffled border.  This creates a resorptive pit that is sealed off from the adjacent bone and from
the ECF, wherein reactions that facilitate resorption occur. Several acids (e.g. citric acid, lactic acid) are released from
the mitochondria and secretory vesicles. Hydrogen ions are also released through the actions of carbonic anhydrase
and vacuolar ATPase proton pumps.  This creates an acidic environment in the resorptive pit, which results in bone salt
dissolution. Proteolytic enzymes (e.g. cathepsin K) are released from lysosomes in the osteoclast. These enzymes
break-down the collagen bone matrix and are most active in an acidic environment. Materials within the resorptive pit
are phagocytosed and moved across the cell and released into the ECF, this results in an increase in ion concentration
in the blood. CaK = cathepsin K, CA = carbonic anhydrase. RANK = receptor activator for nuclear factor κB, RANKL =
RANK ligand. 

Osteoporosis
N Engl J Med 2003; 348:618-629
Williams Textbook of Endocrinology 12E
J Clin Invest. 2008 115:3318-3325
J Clin Invest. 2000 November 15; 106(10): 1203–1204.
Eur Spine J. 2003 12:S90-S96
Endocrine Reviews. 2000  21(2) 115-137
Overview of osteoporosis (OP)
Osteoporosis is a condition defined by decreased bone mineral density (BMD), resulting from increased bone
degradation, decreased bone deposition, or both.
Any factor that reduces BMD can contribute to or cause OP

Etiology and pathogenesis

Estrogen deficiency (post-menopausal state) and testosterone deficiency
Estrogen acts on multiple cells via estrogen receptor (ER) α, with a net result of increased BMD. Therefore, the
deficiency of estrogen increases bone resorption, caused by increased OC numbers (due to enhanced OC
formation and reduced OC apoptosis).
Bone cells do not have receptors for testosterone, rather its effect on bone is indirect through the local
aromatization to estrogen.
Insufficient calcium intake
Serum calcium is tightly regulated by vitamin D and PTH (described previously).
Insufficient calcium intake leads to secondary hyperparathyroidism, which increases the rate of bone
remodelling to maintain a normal serum calcium levels.
The imbalance between resorption and formation of bone leads to accelerated bone tissue loss.
Vitamin D deficiency
Certain populations are at increased risk of vitamin D deficiency, including obesity (due to decreased
bioavailability of Vit D),  individuals living far from the equator (reduced sun exposure) and the elderly (impaired
intestinal absorption and decreased cutaneous production of vitamin D)
Vitamin D insufficiency also leads to secondary hyperparathyroidism, and accelerated bone loss.
Physical activity
Active individuals impose strain on their skeletal system, resulting in microtrauma and appropriate bone
remodelling and strengthening.
Inactivity result in minimal strain and shift in bone remodelling toward osteoclast activity, leading to bone loss.
Smoking
Use of cigarettes is detrimental to bone health by multiple mechanisms:
Tobacco compounds have a direct toxic effect of osteoblasts.
Estrogen metabolism is altered, leading to earlier menopause.
Smokers are more likely to have poor exercise habits and a need for medications that may be detrimental
to bone health (e.g. glucocorticoids for lung disease).
Illnesses associated with OP
Certain gastrointestinal disease result in impaired absorption of bone minerals and vitamin D and therefore
contribute to OP (e.g. malnutrition, malabsorption syndromes (celiac and crohn’s disease), short gut
syndrome).
In hypogonadal states, there is decreased functional activity of the gonads and the positive effects of estrogen
on bone health is reduced (e.g. Turner’s syndrome, anorexia nervosa).
Endocrine disorders can  impair bone health through a variety of mechanisms (e.g. Cushing syndrome,
hyperparathyroidism)
Medications associated with OP
Glucocorticoids (e.g. prednisone) are the most common cause of medication-induced OP.  They  adversely
affect bone metabolism by multiple mechanisms:
Stimulation of osteoclast differentiation
Inhibition of osteoblast proliferation
Decrease in intestinal calcium absorption
Increase in  renal calcium reabsorption
Other immunosuppressants, such as cyclosporine, can also cause rapid bone loss through similar mechanisms
to glucocorticoids.
 Thyroid hormone directly stimulates bone resorption.  Endogenous thyrotoxicosis accelerates bone turnover
and is a significant risk factor for development of OP.
Aromatase inhibitors are used for the treatment of estrogen-dependent cancers of the breast and ovaries.
 They limit the synthesis of estrogen and can therefore lead to bone loss secondary to estrogen deficiency.

Clinical features
Patients with low BMD are usually asymptomatic until a fracture occurs.

Signs and symptoms Mechanism

Fracture (most commonly in mid-thoracic Loss of BMD (see above for pathogenesis) leads to weakening of
vertebrae, hip and wrist) the bone predisposing them to fractures with minor trauma. 

Kyphosis or dowager hump or loss of height Progressive vertebral compression fractures. 

Fragility fractures (defined as a fracture Consequence of the decrease in bone strength and disorganized
occurring due to a fall from standing height or bone remodelling. 
less)

Bone pain (hip, back, pelvic, radius) Usually secondary to fractures. 

Treatment
N Engl J Med 2010; 363:2027-2035
J Clin Endocrinol Metab. (http://www.ncbi.nlm.nih.gov/pubmed/21118827#) 2011 Jan;96(1):53-8.
Endocr Rev. (http://www.ncbi.nlm.nih.gov/pubmed/15769903#) 2005 Aug;26(5):688-703
Clin Interv Aging. 2007 March; 2(1): 55–64

Calcium and vitamin D

Circulating levels of both calcium and vitamin D tend to decrease with age due to decreased consumption,
impaired intestinal absorption and decreased cutaneous production of vitamin D.
Calcium supplementation of 1000 – 2000 mg/day is recommended, taken in doses of ≤ 600 mg to maximize
absorption, with no significant difference shown between different calcium supplementation formulations.
Vitamin D, by inducing synthesis and expression of calcium transporters in the intestine and kidneys, should be
supplemented in conjunction with calcium at a dose between 400 and 2000 IU/day.
Estrogen
Estrogen receptors are found on many cells involved in bone metabolism, with ERα primarily found in cortical
bone and ERβ in cancellous bone.
Net effect of increasing bone density by increasing OPG levels, inhibiting production of osteoclasts from
precursor cells and promoting osteoclast apoptosis.
However, controversy surrounds its use given potential increase in cardiovascular disease and breast cancer
and therefore appropriate patient selection must be employed when starting hormone replacement therapy.
Bisphosphonates
Bisphosphonates are analogues of pyrophosphates which are compounds naturally found in bone matrix and
act by specifically impairing the action of osteoclasts and inducing apoptosis of osteoclasts.
Bisphosphonates bind to hydroxyapatite binding sites and impair the ability of the osteoclasts to properly
adhere to the bony matrix thereby reducing osteoclastic bone resorption.
Emerging evidence suggests that bisphosphonates also prevents osteocyte and osteoblast apoptosis.
Alendronate, risendronate and ibandronate are approved for the prevention and treatment of osteoporosis.
Selective estrogen-receptor modulators (SERMs)
 SERMs alter the ratio of co-activator to co-repressor proteins in different cells and can thus act as either
agonists or antagonists of estrogen receptors (ER).
In bone, agonistic activity on ERα leads to a reduction in bone resorption.
Currently, two SERMs (tamoxifen and raloxifene) have been shown to be beneficial in the treatment of post-
menopausal osteoporosis.
Teriparatide
1-34 or 1-31 amino acid sequence of PTH (physiologically 1-84 AA).   
The first two amino acids are obligatory for biological activity, and it appears that the bone anabolic properties
are fully maintained by the foreshortened fragment (1–31).
Given intermittently, osteoblast activity is upregulated over osteoclastic activity. 
Lifestyle
Exercise can be effective in preventing bone loss and improving balance, coordination and strength, thereby
reducing risk of falls. Thirty minutes of weight-bearing exercise should be undertaken daily by patients who are
able to tolerate it.
Smoking cessation and minimizing alcohol consumption are also beneficial.
Reducing medications and minimizing dosages, especially glucocorticoids, should be considered.

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