Flashcards in Bone Mineral Homeostasis Deck (66):
Functions of bone
Structural support and protection
What is the inorganic component of bone?
Bones are far from lifeless
Bones are continually remodeled:
Bone resorption (breakdown and release of minerals into the blood).
Calcium and Phosphate
Calcium: neurotransmitter release, muscle contraction, coagulation.
Phosphate: ATP, DNA, RNA, cellular signaling (kinase cascades), phospholipids.
1. Long bones
-Cortex: cortical bone forms a thick outer layer
-Medulla: trabecular bone and bone marrow.
2. Vertebral bone and in the neck/head of femur.
-Cortical bone forms a thinner layer surrounding a larger core of trabecular bone.
75% inorganic components!
-Crystalline calcium phosphate salts; primarily hydroxyapatite Ca5PO43OH
-99% of calcium in the body is stored in skeleton.
25% organic components!
-Cells: osteoblasts (BONE FORMATION), osteoclasts (BONE RESORPTION), and osetocyctes; bone lining cells.
-Osteoid: matrix consisting of primarily type 1 collagen fibers, other low-abundance proteins.
1. 300 mg dietary calcium is normally absorbed; 1000 mg average intake, the balance is excreted in feces and urine.
2. Calcium is absorbed in the small intestine; facilitated transport through the small intestine, Vitamin D dependent active transport (occurs mainly in the duodenum-first part).
3. Calcium absorption can be increased to as much as 600 mg per day by calcitriol (active form of Vitamin D).
Regulating bone remodeling
Osteoclasts (resorption): catabolic
Osteoblasts (formation): anabolic
Regulated by: hormones, mechanical forces, cytokines
-25% of trabecular bone is remodeled each year in adults.
-3% of cortical bone is remodeled each year.
-Pathologic conditions preferentially affect bones with high content of trabecular bone (femoral neck and vertebral bodies); the trabecular bone is like a giant net, in osteoporosis, the spaces in between the net get bigger).
-Physical or chemical signals recruit osteoclasts
-Osteoclasts excavate small cavities on the surface of bone:
The extend villus-like projections toward the bone surface.
The villi secrete proteolytic enzymes to digest organic matrix.
This creates an acidic microenvironment by producing organic acids like lactic acid, carbonic acid, and citric acid.
An H+-ATPase in the villi pumps protons on the bone surface and dissolves the hydroxyapatite.
This lasts about 3 weeks: cytokines and other factors are liberated from the matrix that stimulate osteoblast proliferation and activation.
Osteoblasts replace the osteoclasts in resorption cavity (lacuna).
They begin to refill the cavity with concentric layers (lamellae) of unmineralized organic matrix (osteoid).
This eventually becomes completely surrounded with matrix called osteocytes; osteocytes may act as mechanosensors in bone.
-This process takes about 3 months.
-Osteoblasts secrete faactors for mineralization:
Alkaline phosphatase: this hydrolyzes phosphate esters including pyrophosphate, which is an inhibitor of bone mineralization and increases the local concentration of inorganic phosphate; alkaline phosphatase promotes the crystallization of calcium phosphate salts to favor mineralization.
Calcium-binding proteins: increases the local concentration of calcium and facilitates hydroxyapatite formation (the main inorganic component of bone).
Hormonal control of bone remodeling
Calcium homeostasis is very careful regulated.
Phosphate homeostasis must also be regulated: plasma phosphate concentrations affect plasma calcium levels.
Primary mediators: parathyroid hormone (PTH), vitamin D, calcitonin.
Secondary mediators: glucocorticoids, thyroid hormone, gonadal steroids.
Parathyroid hormone (PTH)
Most important endocrine regulator of calcium homeostasis!!!
84 AA peptide hormone
Secreted by parathyroid glands.
Secretion of PTH is REGULATED BY PLASMA CALCIUM LEVELS:
-Calcium-sensing membrane receptors of chief cells in the parathyroid gland.
-G protein-coupeld receptors cause increased intracellular free calcium.
-Increased intracellular calcium levels decreases secretion of preformed PTH; corresponds to high plasma calcium concentrations.
-Decreased intracellular calcium levels increase secretion of preformed PTH; corresponds to low plasma calcium concentrations.
This is the OPPOSITE of most secretory systems.
-PTH acts on G protein coupled receptors.
-High levels of receptor in kidney and osteoblasts.
PTH2: activated by PTH but not PTHrp, expressed in brain, vascular endothelium, smooth muscle, GI endocrine cells, sperm, functional role is unknown.
PTH effects on the KIDNEY
-Most rapid physiologic effects of PTH
-Increases reabsorption of calcium; decreases urinary excretion of calcium.
-Decreases reabsorption of phosphate by the kidney; increases urinary excretion of phosphate.
THIS RAISES PLASMA CALCIUM AND DECREASES PLASMA PHOSPHATE.
PTH effects on BONE
Slower effect of PTH on bone
Stimulate cell surface PTH receptors on osteoblasts
-Increased expression of RANK ligand (RANKL); RANKL binds to RANK on osteoclast precursors, which promotes differentiation into mature osteoclasts.
-This liberates calcium and phosphate by osteoclast activity.
Raises plasma calcium concentrations.
Continuous osteoclasts (resorption) catabolic.
Intermittent osteoblasts (formation) anabolic.
PTH effects on GI
Effects on the GI tract are indirect
PTH stimulates the kidney to increase formation of 1,25-dihydroxy vitamin D (calcitrol)-hydroxylation takes place in the cells of the proximal tubule.
-CALCITROL increases calcium absorption in the small intestine.
Catabolic (bone resorptive) actions of PTH
-Continuous exposure to PTH:
incudes expression of osteoclast differentiation factors: RANKL on osteoblast precursors
induces expression of inhibitors of osteoblasts: IGFBP released from osteoblast precursors; reduces IGF-1, an osteoblast differentiation factor.
The net result is that osteoclasts outnumber osteoblasts and bone resorption overrides bone formation.
Anabolic (bone formation) actions of PTH
Intermittent brief (1-2 hr) exposure to PTH (once daily injection): promotes release of osteoblast differentiation factors: IGF-1 on osteoblasts
has anti-apoptotic effect on osteoblasts
net results is that osteoblasts outnumber osteoclasts and bone formation overrides bone resorption.
The body itself makes vitamin D when it is exposed to the sun.
Cheese, butter, margarine, fortified milk, fish, and fortified cereals are food sources of vitamin D.
-Produced in sufficient amounts by the body; not usually required in the diet under normal conditions.
-Applies to 2 related compounds:
1. Cholecalciferol (vitamin D3): synthesized in skin from 7-dehydrocholesterol, biosynthesis is stimulated by exposure of the skin to UV radiation.
2. Ergocalciferol (vitamin D2); produced by plants, present in many commercial preparations and the form added to milk.
Vitamin D2 and D3 have equal biological activities.
Vitamin D metabolism
ACTIVE FORM OF VITAMIN D: also called 1alpha,25-hydroxy vitamin D or 1,25(OH)2D
Vitamin D2 and D3 travel to the liver; stored or converted to calcifediol (25-hydroxy vitamin D, or 25(OH)D).
-There are 2 enzymatic hydroxylation steps to calcitrol; the second hydroxylation step is PTH-dependent in the proximal tubule of the kidney.
Vitamin D effects on GI
Calcitriol (active form of Vitamin D) increases the absorption of dietary calcium.
-Calcitriol acts in enterocytes to up-regulate expression of:
-Calcium uptake pump on luminal surface of enterocyte
-Calbindin (an intracellular Ca2+ binding protein)
-ATP-dependent Ca2+ pump that extrudes enterocytes Ca2+ into the capillaries.
Other vitamin D effects
-Calcitriol inhibits PTH synthesis and release in the parathyroid gland.
-Calcitriol increases osteoclast number and activity in bone.
-Calcitriol affects the distal tubule of the kidney; increases reabsorption of both calcium and phosphate.
-Macrophages can produce calcitriol-may act as a local suppressant of adaptive immune cells; the use of vitamin D in the treatment of psoriasis.
32 AA peptide
Produced and released by parafollicular C cells of the thyroid gland.
Calcitonin is released in response to hypercalcemia.
It binds directly to receptors on osteoclasts and inhibits the resorptive activity of the osteoclasts; decreases bone resorption and plasma calcium levels.
-In adults...only a weak effect of endogenous calcitonin on plasma calcium levels.
-thyroidectomy generally causes no significant changes in plasma calcium levels.
-Exogenous calcitonin is used in the treatment of osteoporosis.
-Decrease intestinal absorption and renal absorption of Ca+2
-Glucocorticoids effects on bone: inhibits osteoblast maturation and activity.
-Glucocorticoid use is not associated with hypocalcemia; there is a compensatory increase in PTH stimulated by the decrease in calcium.
-Prolonged administration of glucocorticoids causes iatrogenic (illness caused by medical exam or treatment) osteoporosis.
-Excess hormone increases bone turnover
Stimulates bone resorption more than bone formation.
Prolonged elevated levels cause osteopenia (reduced bone mass of lesser severity than osteoporosis).
Estrogens and Androgens...
-Exert inhibitory effects on osteoclastic activity; slow the rate of bone turnover and bone loss.
-Estrogens and androgens inhibit the production of cytokines by osteoblasts; IL-6 normally recruits and activates osteoclasts, so osteoclasts activity reduced.
-Estrogen has a pro-apoptotic effect on the osteoclasts and an anti-apoptotic effect on osteoblasts and osteocytes.
Bone regulates male fertility...
-Resorption exceeds bone formation.
Chronic kidney disease
-Decreased mineral absorption and secondary hyperparathyroidism.
Bone Mineral Density (BMD):
-Normal: one standard deviation of BMD in young adults.
-Ostopenia: 1-2.5 standard deviations below the mean.
-Osteoporosis: >2.5 standard deviations below the mean.
-Increased risk of fractures.
Senile osteoporosis (caused by aging and a deficiency in calcium levels).
-Peak bone mass achieved in young adulthood.
-Peak bone mass is determined by several factors: dietary calcium levels, hormonal state, physical activity levels, genetic factors.
-Gradual decline in bone mass during mid-late adult life; osteoblast-mediated bone formation decreases related to osteoclast activity.
-Average loss of 0.7% of bone mass per year.
-Treatment: Calcium, vitamin D
Postmenopausal Osteoporosis (primary osteoporosis)
-Begins in the first 3-5 years after menopause
Rapid loss in bone mass related to the marked decline in estrogen production.
Longer lifespan of osteoclasts in the absence of estrogen!!!
Increased apoptosis of osteocytes imparting the mechanosensory network.
-Within 25-35 years after menopause: 35% cortical bone mass loss is possible, 50% trabecular bone mass loss is possible.
-Treatment: biphosphonates, raloxifene (SERM), calcitonin, PTH.
Induced by systemic illness and medications:
-High doses of glucocorticoids
NEED TO TREAT THE UNDERLYING CAUSE!!!
Chronic Kidney Disease
-Slow loss of kidney function over time
-Effect on bone mainly through secondary hyperparathyroidism: decreased production of Vitamin D synthesis, hyperphophatemia due to impaired renal function.
-The net effect is increased bone resorption
Osteomalacia (decreased mineralization)
Osteitis fibrosa cystica (increased osteoclastic resorption with replacement by fibrous tissue).
Decreased excretion of phosphate leads to ostemalcia; treat with phosphate restriction.
Decreased production of 1,25(OH)2D leads to osteitis fibrous cystica; treat with active vitamin D, calcimimetics.
Effects of Low Vitamin D...
-Lead to inadequate intestinal absorption of calcium
-Secondary hyperparathyroidism: stimulates PTH synthesis and secretion
Vitamin D NORMALLY SUPPRESSES PTH TRANSCRIPTION..
Reduces calcium receptor synthesis in the chief cells: raises set point for calcium regulation, thus higher concentration of calcium required to suppress PTH secretion.
-Hyperparathyroidism can persist even with hypercalcemia.
Impaired renal function
Results from decreased renal excretion of phosphate
Exacerbates the hypocalcemia of chronic kidney disease
Alters the equilibrium for hydroxyapatite formation and a dissolution
Extravascular precipitates of calcium phosphate can also damage other tissues.
-Characterized by dense and hard bones.
-Formation of ectopic bones (pathologic deposition of calcium salts in tissues or bone growth in soft tissues).
-Benign form of Van Buchem Disease
-Genetically dominant, linked to the LRP5 gene (LDL receptor-related protein 5).
Inadequate sunlight or dietary
Leads to skeletal deformities in children.
Treat with vitamin D
Decreased vitamin D leads to osteomalacia in adults.
Vitmamin D resistant
Defect in renal reabsorption of phosphate and production of vitamin D
Treat with oral phosphate or calcitriol.
Type 1 vitamin D dependent
Decreaed production of 1,25(OH)2D
Treat with oral phosphate or calcitriol
Type 2 vitamin D dependent
Defective receptors for 1,25(OH)2D
Treat with high dose calcitriol.
Increased PTH=increased bone resorption=hypercalcemia= osteoporosis, nephrolithiasis, osteitis fibrous, cystic, depression
Treatment: surgical removal, calcimimetic agents (investigational)
Familial hypocalcuric hypercalcemia (FHH)
Mutation in Ca2+ sensing receptor
Decreased activity or absence of parathyroid gland=hypocalcemia and hyperphosphatemia
Tetany (intermittant muscular spams)
Treatment is calcium and vitamin D
Impaired response to PTH=hypocalcemia
Short stature, short metacarpals
Treat with calcium and vitamin D
Increased local bone turnover
Bone pain, hearing loss, high-output cardiac failure
Treat with biphosphonates and calcitonin.
-Bone resorption and bone formation are closely coupled; decreasing resorption will usually decrease formation!
Cause LITTLE NET GAIN in bone mass.
-Antiresorptive agents mainly used to prevent progressive bone loss.
Initial increases in BMD due to mineralization of resorption cavities during excessive resorption.
Later, increases in BMD are due to inhibited resorption.
Hormone replacement therapy...
Estrogen was one of the most commonly used drugs.
-Exert inhibitory effects on osteoclastic activity; slow the rate of bone turnover and bone loss.
-Administered cyclically with a progestational agent-reduces the risk of endometrial cancer.
-Relieves postmenopausal symptoms including hot flashes and vaginal dryness.
-Compliance is often a problem with HRT: vaginal bleeding and breast tenderness.
-HRT increases risks of: venous thromboembolism and breast cancer.
-Women's Health Initiative studies (>10,000 patients): concluded that the increased risks outweigh the potential benefits of HRT; risks of CV disease and breast cancer.
-If it is NECESSARY to use HRT: lowest dose, shortest duration.
SERMs: selective estrogen receptor modulators
Bind to the estrogen receptor (ER)
Nature of the effects in different tissues: may act as an estrogen agonist, may act as an estrogen antagonist.
The goal of SERM development is to retain the beneficial effects in one or more tissues and to eliminate the undesirable effects in other tissues.
-SERMs are promising agents for the prevention and treatment of postmenopausal osteoporosis.
-May be the preferred therapy for osteoporosis: women with breast cancer, women with family history of breast or endometrial cancer, women who wish to avoid adverse effects of HRT.
Estrogen receptor in the breast and uterine cell; the breast receptor not activated, but the uterine receptor is activated; therefore, you get no breast cell proliferation, but you do get uterine proliferation.
Estrogen agonist in bone
Estrogen antagonist in the endometrium and breast.
Approved for osteoporosis (prevention/treatment)
Increases bone mineral density
Decreases vertebral fracture risk.
NOT ASSOCIATED WITH BREAT OR ENDOMETRIAL CANCER; may reduce the risk of breast cancer.
Lowers LDL cholesterol levels; may prevent heart disease.
Increases the risk of venous thromboembolism.
Biphosphonates (BPs) are currently the most widely used class of antiresorptive drugs.
-Analogues of pyrophosphate; P-O-P bond has been replaced by a nonhydrolyzable P-C-P bond.
-BPs concentrate in bone and incorporated into matrix
-BPs decrease the solubility of hydroxyapatite.
-BPs have strong binding to bone due to high affinity for calcium phosphate.
-They remain in matrix until the bone is remodeled.
Dissolved mineral matrix by osteoclastic activity release BP molecules which are then internalized by osteoclasts.
Amino-bisphosphonates inhibit a step in the mevalonate pathway which ultimately leads osteoclast apoptosis.
-Mevalonate pathway is important for protein prenylation; farnesylation and geranylgeranylation.
Post-translational addition of lipids to intracellular signaling proteins like GTPases.
Leads to loss of a number of osteoclastic functions like H-ATPase activity.
Ultimately causes osteoclast apoptosis.
-Mevalonate pathway inhibition is limited to osteoclasts.
Acidic environment releases biphosphonates, osteoclasts take up BP and lose ruffled border=inactivated osteoclast.
-Alendronate, risedronate, pamidronate, and ibandronate; these contain an amino moiety, which greatly enhances their activity.
-Zoledronic acid; contains an imidazole side chain.
-Biphosphonates have low oral bioavailability; should be administered with substantial water.
-Oral Bps can cause local esophagitis and esophageal erosion.
Patients should remain in the upright position for 30 minutes after medication; they should then have a meal before lying down.
In clinical use >10 years and they appear safe, but concerns over long-term inhibition of bone turnover; could lead to hyper mineralization and structural changes; could adversely affect bone quality and strength.
-Patients with extensive dental disease and oral surgery may experience osteonecrosis of the jaw with potent amino-BPs.
-Patients with cancer-associated hypercalcemia; IV BPs may cause osteonecrosis.
Alendronate, risedronate, and ibandronate are approved for prevention and treatment
Increase spine and hip BMD in postmenopausal women with osteopenia and osteoporosis.
Decrease the risk of fractures.
Once-a-week formulations: alendronate and risedronate.
Ibandronate is available in a ONCE A MONTH formulation.
-Hypercalcemia and malignancy
Certain tumors produce PTHrP, which causes hypercalcemia same way as PTH.
IV pamidronate and zoledronate have been approved for treatment; they rapidly inhibit the accelerated bone resorption due to osteoclastic hyperactivity.
BPs decrease bone turnover rates in Paget's disease.
Decrease the characteristic progressive deformity, pain, and fractures.
-Calcitonin is used in conditions characterized by high osteoclastic activity: Paget's disease, Osteoporosis, hypercalcemia.
Intranasal calcitonin: retards vertebral bone loss, decreases the incidence of vertebral fractures.
-Patients unable or unwilling to take rolxifene or biphosphonates; calcitonin has lower efficacy.
-Salmon calcitonin: higher affinity for the human calcitonin receptor; longer half-life than human calcitonin.
Administered subcutaneously or as a nasal spray.
Drawback to long-term calcitonin administration: tachyphylaxis (rapidly diminishing response to successive doses of a drug, rendering it less effective) from desensitization of the receptor-signaling pathway.
Weak analgesic properties (effects on endorphins?).
Bone anabolic agents, for patients with large bone mass loss.
-Fluoride is a mitogen (a substance that induces or stimulates mitosis) for osteoblasts.
-Fluoride increases trabecular bone mass.
-Conversion of hydroxyapatite to fluoroapatite; fluoroapatitde is denser but more brittle.
-Fluoride effectiveness in preventing osteoporosis-related fractures remains uncertain.
Great public health achievement!
-84 AA peptide; N-terminal first 31-34 AA of PTH retain the important functional properties.
-Subcutaneous injection designed to be self-administered.
PTH (1-34); generic name teriparatide; approved for the treatment of osteoporosis in postmenopausal women and in men.
Other classes of agents...
For secondary hyperparathyroidism (chronic kidney disease)
-Drugs that lower plasma phosphate levels: oral phosphate binders, dietary phosphate restriction.
-Drugs that decrease PTH synthesis and secretion: vitamin D and analogues, calcimimetics (a drug that mimics the action of calcium on tissues).
For prevention and treatment of osteoporosis, rickets, and hypoparathyroidism: calcium, vitamin D.
Treating chronic kidney disease
-Oral phosphate binders; to treat hyperphosphatemia.
-Active vitamin D analogues to bypass the requirement for 1alpha-hydroxylase activity in the kidney.
-Calcimimetic cinacalcet (a drug that acts as a calcimimetic by allosteric activation of the calcium-sensing receptor that is expressed in various human organ tissues): adjusts the sensitivity of the calcium-sending receptor on the parathyroid chief cells.
Oral phosphate binders
Treat hyperphosphatemia in chronic kidney disease.
Precipitates with phosphate in GI tract and forms non absorbable complexes.
Effective at lowering plasma phosphate levels.
Significant long-term (over years) risk of aluminum toxicity.
-Aluminum is generally not used because of thee toxicities; exception: refractory hyperphosphatemia.
-Calcium carbonate and calcium acetate
Oral preparations given with meals
Bind to dietary phosphate and inhibit its absorption.
Requires high doses; can cause iatrogenic hypercalcemia and an increased risk of vascular calcifications.
Non absorbable cationic ion-exchange resin that binds intestinal phosphate; decreases absorption of dietary phosphate.
Sevelamer binds bile acids as well; leads to interruption of the enterohepatic circulation.
Leads to decreased cholesterol absorption.
Vitamin D and analogues
Impaired synthesis of 1alpha-vitamin D derivatives:main homeostatic disturbances leading to secondary hyperparathyroidism in chronic kidney disease.
-Active vitamin D increases dietary absorption of calcium; increase in plasma calcium suppresses PTH secretion by parathyroid gland chief cell
Vitamin D receptor on chuef cells suppresses PTH gene transcription.
These agents can produce hypercalcemia.
-Three active (1alpha-hydroxlated) vitamin D congeners are approved for treatment of secondary hyperparathyroidism:
1. Calcitriol (1,25(OH)2D3)
2. Paricalcitol (19-nor-1,25(OH)2D2)
3. Doxercalciferol (1alpha-(OH)D2)
Vitamin D analogues-Calcitrol
Dihydroxylated form of vitamin D3
Available in oral and IV forms: IV formulation may be more effective in patients on hemodialysis.
-Patients with chronic kidney disease: calcitriol should not be administered until hyperphosphatemia has been controlled.
Calcitriol can cause increased plasma levels of both calcium and phosphate.
Vitamin D analogs-Paricalcitol and Doxercalciferol
Synthetic analog of vitamin D; lowers plasma PTH levels without significantly raising plasma calcium levels.
1alpha-hydroxylated form of vitamin D2
-25-hydroxylated to the fully active 1,25-dihydroxy form in the liver.
Lowers PTH synthesis and secretion.
-Vitamin D and its analogues; lead to hypercalcemia/hyperphosphatemia
-Calcimimetics: modulate the calcium-sensing receptor; effective treatment for hyperparathyroidism; no hypercalcemia/hyperphosphatemia.
-Binds to the transmembrane region of the calcium-sensing receptor; increases receptor sensitivity to calcium.
Cincacalet-bound receptor is activated at lower calcium concentrations; PTH synthesis and secretion are suppressed at lower calcium concentrations.
-Approved uses: treatment of secondary hyperparathyroidism and treatment of hypercalcemia associated with parathyroid carcinoma.
-Preventative and therapeutic value
-Disorders: Vitamin D-dependent rickets, hypoparathyroidism.
-Severe cases of hypocalcemia; calcium can be administered IV.
-Prevention of osteoporosis
Administered orally as a calcium salt: reduces vertebral bone loss modestly in postmenopausal women, effects on fracture prevention are less clear in post menstrual women; Premenopausal use may maintain bone density above the critical fracture threshold.
-Calcium also can treat mild hypocalcemia; administered orally as a calcium salt.
-Calcium citrate: most readily absorbed form.
-Calcium carbonate: most widely used form (low cost, wide availability, and antacid properties)
-Calcium gluconate: less venous irritation than calcium chloride.