Download Pharmacology Ch 31 541-561 [4-20

Pharmacology Ch 31 541-561
Bone Mineral Homeostasis Pharmacology
-Osteoclasts and osteoblasts always remodel human skeleton in response to forces and factors
-PTH and vitamin D control bone metabolism to maintain extracellular calcium homeostasis
Structure of Bone – composed of 25% organic and 75% inorganic components
-organic includes osteoblasts, osteoclasts, osteocytes, bone lining cells, bone stromal cells,
osteoid (type 1 collagen)
-inorganic includes calcium phosphate salts (hydroxyapatite)
Mineral Balance – Ca is absorbed in small intestine by 2 mechanisms: (1) facilitated transport,
and (2) Calcitriol-dependent active transport; calcium homeostasis allows for 300mg/day
absorbed from small intestine, with lower intakes causing efficiency of absorption to increase
-Calcitriol, the active form of vitamin D, can increase absorption to 600mg/day
-absorption is balanced by renal excretion
Regulation of Bone Remodeling – osteoclasts resorb bone, osteoblasts form bone
-RANK ligand (RANKL) and M-CSF are both necessary to form osteoclasts; RANKL is synthesized
by osteoblasts, and binds to RANK, receptor on osteoclasts and precursors in bone marrow to
promote differentiation into mature osteoclasts
-RANKL can also bind osteoprotegerin (OPG) which is synthesized by osteoblasts and prevents
RANKL from interacting with RANK.
-deficiency of RANKL or RANK can cause osteopetrosis, deficiency of OPG causes osteoporosis
-human bone is continually resorbed and reformed (remodeling)
-remodeling is carried out by basic multicellular units consisting of osteoblasts and osteoclasts
-osteoclasts form a ring-like seal with bone surface and extend projections toward surface which
secrete lactic acid, carbonic acid, and citric acid, and use carbonic anhydrase to generate
protons and use H+ ATPase to pump them onto bone surface to cause acidic environment for
dissolution of hydroxyapatite
-demineralization of matrix exposes it to proteolysis by cathepsin K, collagenases and proteases
-blood levels of type I collagen indicative of total body bone resorption
-hydroxyapatite normally adsorbs various nonskeletal proteins including IGF-I and TGF-B
-demineralization exposes adorbed growth factors to proteolytic enzymes secreted by
osteoclasts, but some escape proteolysis and affect cellular activity of neighboring cells
-after 3 weeks of bone resorption, the cytokines/GF liberated from matrix stimulate osteoblasts
to replace osteoclasts in resorption cavity and refill the cavity with concentric layers (lamellae)
of unmineralized osteoid, and as they do this, hey secrete alkaline phosphatase to hydrolyze
phosphate esters to prevent inhibitors of bone mineralization and liberate inorganic phosphate
-as osteoblasts lay down matrix, they become completely surrounded and become osteocytes
-Osteocytes control balance between resorption and formation via sclerostin (protein that
inhibits bone formation)
-genetic defects in sclerostin cause increase in bone mass
Hormonal Control of Ca and PO4 – Ca essential for neurotransmitter release, muscle
contraction, and blood coagulation. Ca and PO4 are tightly regulated
-three main hormones, PTH, vitamin D, and FGF-23 mediate Ca and PO4 homeostasis in addition
to lesser hormones calcitonin, glucocorticoids, thyroid hormone, and gonadal steroids
Parathyroid Hormone – secretion of PTH is in response to plasma Ca levels from chief cells;
when bound by Ca, G protein receptors mediate increases in intracellular Ca, which decreases
PTH secretion
-high plamsma Ca suppresses PTH while low plasma stimulates PTH secretion
-PTH acts on 3 organs: kidney, bone, and GI tract; most rapid effect is increase reabsorption of
Ca and decrease PO4 reabsorption by kidney tubules
-PTH stimulates osteoblasts to increase OSTEOCLAST differentiation factor RANKL and decrease
expression of antagonist OPG, causing increased bone resorption to increase circulating Ca/PO4
-PTH also stimulates bone marrow to secrete IL-6 to stimulate osteoclast proliferation
-PTH raises plasma Ca by an indirect effect on intestine by increasing enzymatic conversion of
25-OHD3 to active 1,25OHD2 (vitamin D calcitriol) which takes place in proximal renal tubules
-calcitriol increases small intestine absorption of Ca and PO4
-although predominantly catabolic, PTH stimulates new bone formation by promoting
differentiation of osteoblast precursors to mature osteoblasts and enhancing osteoblast survival
Vitamin D – produced in the skin and is not required in the diet if sun exposure is present;
vitamin D applies to two compounds, cholecalciferol and ergocalciferol
-cholecalciferol – nonenzymatic vitamin D3 created when 7-dehydrocholesterol absorbs
a photon from UV light
-Ergocalciferol – vitamin D2 produced when ergosterol in plants absorbs photon
-both have equal biological effects and vitamin D refers to both of them
-vitamin D travels to the liver where it is stored or converted to califediol and then to calcitriol,
the final active form of vitamin D [1,25 (OH)2D]; second reaction occurs in proximal tubule of
kidney (PTH dependent) but not in intestine
-calcitriol’s primary effect is in small intestine where it increases absorption of dietary Ca by
acting on nuclear receptors in enterocyte to upregulate expression of brush border cell proteins
-calcitrol induces enterocyte expression of (1) Ca uptake pump on luminal surface of enterocyte,
(2) calbindin – an intracellular Ca-binding protein, (3) ATP-dependent Ca pump that extrudes Ca
into capillaries
-Calcitriol also binds to nuclear receptors on parathyroid cells to inhibit PTH synthesis and
release
-In bone, Calcitriol increases osteoclast number and activity resulting in bone resorption
-High blood levels of calcitriol increase bone formation
-in distal tubule of kidney, calcitriol increases reabsorption of both Ca and PO4
-in immune system, calcitriol production by macrophages suppresses adaptive immune cells
Fibroblast Growth Factor 23 (FGF-23) and Phosphatonins
-FGF-23 alters renal tubular Na-PO4 co-transporters to increase renal clearance of PO4
-FGF-23 also suppresses renal tubular vitamin D 1a-hydroxylase and INDUCES vitamin D 24hydroxylase to decrease renal secretion of 1,25-(OH)2D, to reduce active transport of Ca and
PO4 across intestines and increase PTH secretion
-phosphatonins – proteins with similar effects on renal tubular clearance like sFRP-4 and FGF-7
-FGF-23 is expressed by many cells including osteocytes, and increased osteocyte FGF-23
expression shows increased renal clearance of PO4, hypophosphatemia, or low vitamin D and
defective bone mineralization, suggesting that osteocytes are important FGF-23 secretors
-mutations in FGF-23 can produce autosomal dominant rickets (ADHR)
- X-linked rickets (XLH) caused by mutations in endopeptidase PHEX
Calcitonin – produced by parafollicular C cells of the thyroid gland in response to hypercalcemia
-binds directly to receptors on osteoclasts to inhibit resorptive activity of osteoclasts and
decreases bone resorption/Ca levels
-in adult humans, calcitonin has a weak effect on plasma Ca levels and elimination of calcitonin
does not have a significant change in plasma Ca levels, but calcitonin is useful in treatment of
hypercalcemia
Glucocorticoids – promote osteocyte/osteoblast apoptosis and inhibit osteoblast maturation
and osteoblast activity thereby decreasing bone formation and bone resorption
Thyroid Hormone – increases bone turnover by stimulating bone resorption more than bone
formation, high levels of thyroid hormone can cause bone loss
Estrogens and Androgens – inhibit osteoclastic activity and slow the rate of bone turnover and
inhibit production of RANKL by immune cells and production of IL-6
Osteoporosis – bone mass is reduced and internal bone architecture is degraded throughout
skeleton due to decreased bone formation, increased bone resorption, or both. Bones become
fragile and predisposed to fracture
-bone mineral density (aBMD) calculates mineral content of bone to assess osteoporosis, and
are expressed as standard deviations above or below mean for healthy young adults (T-score)
and age-matched people (Z score)
-normal aBMD is defined as values between +/- 1 standard
-osteopenia is defined as aBMD value of -1 to -2.5, and osteoporosis is <-2.5
-peak bone mass is achieved in young adulthood and is determined by dietary Ca, puberty age,
gonadal hormone status, physical activity
-once peak bone mass is attained, there is a very slow decline in bone mass during mid-late
adulthood resulting from imperfections in bone remodeling process
-osteoblast-mediated bone formation does not keep pace with osteoclast resorption
-with age, osteoblasts have reduced capacity to proliferate and synthesize matrix
-low estrogen in perimenopausal women lead to increased osteoclast activity and bone turnover
rate to cause imbalance toward bone resorption over formation and weaker weight-bearing
regions with thick trabeculae and porous spaces
-lack of estrogen increases apoptosis of osteoblasts and osteoclasts, screwing everything up
-in summary for postmenopausal women, increased osteoclast activity and larger resorption
cavities coupled with inadequate osteoblast activity and impairment of osteocyte
mechanosensory network for damage causes osteoporosis
-remodeling takes place greater in trabecular bone than in compact bone, and so axial bones are
more prone to osteoporotic fractures
-Secondary osteoporosis – caused by other systemic illnesses or medications, such as
thyrotoxicosis, hyperparathyroidism, glucocorticoids, smoking, alcohol, intestinal malabsorption,
cirrhosis, and bone marrow abnormalities
Chronic Kidney Disease – causes secondary hyperparathyroidism (increase resorption and
formation of bone), osteomalacia (excess unmineralized bone matrix), and osteitis fibrosa
cystica (increased osteoclastic resorption and osteoblastic formation of bone, and replacement
of hematopoietic cells by mone marrow stromal cells)
-hyperparathyroidism in chronic kidney disease stems from interplay of hyperphosphatemia,
increased blood FGF023, and decreased active vitamin D, and hypocalcemia
-inadequate active vitamin D leads to inadequate intestinal absorption of Ca, which stimulates
synthesis and secretion and suppresses degradation of PTH in parathyroid cells and causes
reduction in Ca receptor synthesis in chief cells of parathyroid to raise set-point for calcium
regulation
-this way, hyperparathyroidism can persist even under setting of hypercalcemia
-hyperphosphatemia, resulting from decreased renal excretion of phosphate, exacerbates
hypocalcemia of chronic kidney disease
-hyperphosphatemia induces hypocalcemia by altering equilibrium for hydroxyapatite
formation and dissolution and leads to formation of toxic CaPO4 precipitates in extracskeletal
tissues
-hyperphosphatemia also increases FGF-23 secretion, which decreases renal vitamin D secretion
Pharmacologic Classes and Agents – for osteoporosis, agents can be divided into (1) drugs that
inhibit bone resorption, and (2) drugs that can stimulate bone formation
Antiresorptive Agents – prevent or arrest bone loss by suppressing osteoclastic bone
resorption; hormone replacement therapy (HRT), selective estrogen receptor modulators,
bisphosphonates, RANKL antagonists, and calcitonin induce little increase in bone tissue
-increase is seen in first 12-18 months and represents filling of resorption cavity,
mineralization of new bone, and completion of mineralization
-Cathepsin K inhibitors suppress osteoclasts without suppressing bone resorption
Hormone Replacement Therapy – estrogens reduce bone resorption by suppressing
transcription of genes coding for RANKL and IL-6 that induce osteoclast proliferation
-also promotes apoptosis of osteoclasts while inhibiting apoptosis of osteoblasts
-side effects are vaginal bleeding and tenderness and risk of DVT or PE and risk of cancer
Selective Estrogen Receptor Modulators – group of compounds that bind estrogen receptor
and act as an agonist or antagonist
-goal of these is to have estrogen’s effect in certain tissue without negative effect of excessive
estrogen in the whole body
-Raloxifene is an estrogen agonist in bone, but an antagonist in endometrium and breast and
has been approved for prevention and treatment of osteoporosis since it increases density of
vertebral and nonvertibral bones and reduces risk of breast cancer
-raloxifene lowers –LDL cholesterol but increases risk of DVT and PE
-preferred treatment in women with breast cancer or familial history of breast cancer
Bisphosphonates – most widely used antiresorptive drugs, are analogues of pyrophosphate
-Alendronate, risedronate, ibandronate, pamidronate, and zoledronate
-oxygen atoms in phosphonate groups coordinate divalent cations like Ca, BP’s concentrate in
mineralized tissues where they are incorporated into mineral and remain unmetabolized and
active
-once bone is resorbed, acids secreted by osteoclasts dissociate bone mineral from BP, which is
excreted elsewhere or internalized by osteoclast
-inside osteoclasts, bisphosphonates block a step in mevalonate pathway which leads to
prenylation, covalent attachment of lipids to proteins, which inhibits osteoclast functions and
causes osteoclast apoptosis
-intravenous panidronate or zoledronate inhibits accelerated bone resorption caused by
osteoclast hyperactivity and are approved for hypercalcemia associated with malignancy, but
are ineffective at treating hypercalcemia caused by impaired renal secretion of calcium
-BPs also suppress bone resorption, arrest bone loss, and increase spine and hip BMD in women
and other people with hypogonadism
-oral BPs must be swalled in morning after an overnight fast due to poor intestinal absorption
with water and NO food, and to stand upright for 30-60 minutes due to local esophagitis
-aminobisphosphonates are used to treate Paget’s Disease of bone
Treatment of Hypercalcemia and Hypocalcemia – emergency treatment of hypercalcemia starts
with saline diuresis, then can be treated rapidly with calcitonin, or bisphosphonates if there is a
malignancy in bone marrow or metastatic to bone
-for hypocalcemia, use magnesium chloride
RANKL Antagonists –
Denosumab – synthetic fully humanized monoclonal antibody to RANKL that reduces osteoclast
numbers and bone resorption in humans and animal models of osteoporosis
-suppresses bone resorption, arrests bone loss, and increases spine/hip BMD
Calcitonin – binds to G protein on osteoclasts to decrease resorptive activity and treats
hypercalcemia, Paget’s disease of bone, and post-menopausal osteoporosis
-amino acid sequence for salmon (salmon calcitonin)
Bone Anabolic Agents – for patients who have already lost a large amount of bone mass
Fluoride – fluoride is a mitogen for osteoblasts and increases trabecular bone mass while
accelerating cortical bone loss
Parathyroid Hormone – elevated PTH leads to bone remodeling with more bone resorbed than
formed, which can cause weak and brittle bones, but INTERMITTENT exposure of bone cells to
PTH can INCREASE bone remodeling with more new bone formed than lost, so a once dailysubcutaneous injection increases bone anabolism, and continuous exposure favors catabolism
-recombinant, cut-short version of PTH called PTH (1-34) is in development and is called
teriparatide for its treatment of osteoporosis in post-menopausal women
Treatment of Secondary Hyperparathyroidism in Chronic Kidney Disease – three approaches to
preventing and modifying metabolic sequelae of chronic kidney disease:
1. Oral Phosphate Binders – increased plasma phosphate can complex with serum Ca to
decrease plasma Ca and cause hyperparathyroidism and precipitation of CaPO4 in peripheral
tissues
-Aluminum hydroxide – treats hyperphosphatemia because Al precipitates PO4 in GI
tract to form nonabsorbable complexes to lower plasma PO4 levels (Al is TOXIC)
-Calcium Carbonate and Calcium Acetate can control plasma phosphate by binding to
dietary PO4 and inhibiting its absorption, but can also cause iatrogenic hypercalcemia
-Sevelamer – nonabsorbable Ca ion-exchange resin that binds intestinal phosphate to
decrease absorption, but also binds bile acids to interrupt enterohepatic circulation and
decrease cholesterol absorption
2. Calcitriol – impaired synthesis of 1a-vitamin D derivatives is main homeostatic disturbance
leading to secondary hyperparathyroidism in chronic kidney disease, vitamin D is logical
replacement therapy
-3 active vitamin D congeners are approved for treatment of secondary hyperparathyroidism
-all of these bypass the need for 1a-hydroxylation in kidney and useful in treatment of bone
diseases that complicate renal failure
-active vitamin D increases dietary absorption of Ca to suppress secretion of PTH by chief cells
and directly bind chief cells to suppress PTH gene transcription
-Calcitriol – available in oral and intravenous forms, only use when hyperphosphatemia
is treated first
-Paricalcitol – synthetic analogue of vitamin D
-Doxercalciferol – 1a-hydroxylated form of vitamin D2 and made active in the liver.
Calcimimetics – agents that modulate activity of calcium-sensing receptors on chief cells to treat
hyperparathyroidism that do not cause unwanted effects (hypercalcemia and hyper
phosphatemia)
-Cinacalcet – binds to Ca-sensing receptor and increases its sensitivity to Ca, which
causes suppression of PTH synthesis since it takes less Ca to suppress PTH
-these effects interrupt pathophysiologic sequence of events leading from
chronic kidney disease to secondary hyperparathyroidism
Calcium – administered for hypocalcemic states associated with disorders such as vitamin Ddependent rickets and hypoparathyroidism; Calcium gluconate and CaCl are used
-to prevent osteoporosis or treat mild hypocalcemia, calcium citrate, calcium
carbonate, calcium phosphate, and calcium lactate are used
Inorganic Phosphate – administered as therapy for hypophosphatemia cuased by renal
phosphate wasting, intestinal PO4 malabsorption, rapid bone remineralization, sepsis, or other
disorders
Vitamin D – include cholecalciferol, ergocalciferol, calcifediol, and calitriol
-used in treatment of hypoparathyroidism, rickets, osteomalacia, osteoporosis, and chronic
kidney disease
-calcitriol is preferred because of its faster onset and offset
-for hypoparathyroidism, calcitriol is used to increase intestinal absorption of calcium
Summary – most important modulators of remodeling are PTH, calcitriol, and FGF-23