Basic and Clinical Pharmacology

42 AGENTS THAT AFFECT BONE MINERAL HOMEOSTASIS

ANITA Q. SANGALANG, MD, MHPEd, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

• Calcium and phosphorus PRINCIPAL HORMONAL REGULATORS OF BONE

• 2 major mineral constituents of bone MINERAL HOMEOSTASIS
• 2 most important minerals for general cellular • Parathyroid hormone (PTH)
function • Vitamin D
• Bone act as a storage reservoir of these • Fibroblast growth factor 23 (FGF 23)
minerals
• Parathyroid hormone (PTH)
• Calcium • 84 amino acid peptide precursor form
• Absorption (duodenum and upper jejunum) • Acts on membrane G-protein coupled
and secretion (ileum) receptors to increase cAMP in bone and renal
• Phosphorus tubular cells
• Absorption in the jejunum • Calcium sensitive protease in the gland
cleaves the hormone into fragments
• Renal excretion for both balances intestinal • Biologic activity resides in the amino terminal
absorption region
• Metabolic clearance is rapid occurring in the
liver and kidney
• Regulates calcium and phosphate flux cross
the cellular membrane
• Acts on the osteoblast (bone-forming) to
induce membrane-bound protein RANK
ligand (RANKL) that increases the activity
and number of osteoclasts responsible for
bone resorption
• Bone remodeling

• At high concentrations
• Increases blood calcium
• Decreases phosphorus
• Increases net bone resorption
• At lower physiologic concentrations
• Can increase net bone formation
• Teriparatide
• Recombinant PTH 1-34
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 • Treatment of osteoporosis • Mechanism of action
• In the kidney • Induction of a new protein synthesis
• Increases reabsorption of calcium and TRPV 6 (intestinal calcium channel)
magnesium • Modulation of calcium flux across brush
• Reduces reabsorption of phosphate, border of basolateral membrane
amino acids, HCO -, sodium, chloride,
3 • Calcitriol
and sulfate • Most potent
• Stimulates production of 1,25- • Calcipotriene (calcipotriol),
dihyroxyvitamin D (1,25[OH] ) 6
2D doxecalciferol, paricalcitol
• Synthetic analogs
• Vitamin D
• Derivative of 7-dehydrocholesterol • Fibroblast Growth Factor 23 (FGF 23)
• Formed in the skin under the influence of • Osteoblast and osteoclasts are primary sites
ultraviolet light of production
• Found in some food • Inhibits 1,25 (OH) 2D3 production and
• Commonly used as a nutritional additive in phosphate reabsorption in the kidney via
milk and in calcium supplements sodium phosphate co-transporter NaPi2a
• Cholecalciferol and 2c)
• Vitamin D , natural form
3

• Found in the diet • Interaction of PTH, FGF 23 and Vitamin D

• More potent • Net effect of PTH
• Ergocalciferol • To raise serum calcium and reduce
• Vitamin D plant-derived
2, serum phosphate

• Net effect of FGF 23

• To decrease serum phosphate
• Net effect of vitamin D
• To raise both

• Prohormone with active metabolites

• Liver
• 25-hydroxyvitamin D or calcifediol
• Kidney SECONDARY HORMONAL REGULATORS OF BONE
• 1, 25 dihydroxyvitamin D or calcitriol MINERAL HOMEOSTASIS
• 24, 25 dihydroxyvitamin D • Play modulatory roles
• Actions of Vitamin D • Calcitonin
• Increased intestinal calcium and • Glucocorticoids
phosphorus absorption • Estrogens
• Decreased renal excretion of these
substances • Calcitonin
• Net increased in blood levels of both • Peptide hormone secreted by the thyroid
minerals gland
• In the kidney • Decreases serum calcium and phosphate in
• PTH stimulates 1, 25 dihydroxyvitamin D the kidneys and bones
production • Decreases bone resorption
• FGF 23 inhibits production

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 • Bone formation is not impaired initially, but • Inhibition of calcium transport in the GI
ultimately it is reduced tract, metabolic changes in bone cells
• Used in conditions in which an acute like glycolysis, cell growth
reduction of serum calcium is needed • Cause gastric irritation except etidronate
• Paget’s disease • Oral bioavailability is low (<10 %)
• Hypercalcemia • Food impairs their absorption
• Treatment of osteoporosis • Take the drugs with large quantities of water
• Questionable whether long-term use to avoid situation that permit esophageal
prevents fractures reflux
• Human calcitonin is available • CI in decreased renal function, esophageal
• Salmon calcitonin motility disorder, peptic ulcer
• Selected for clinical use • Use IV pamidronate, zoledronate,
• Longer half-life ibandronate
• Greater potency • Chronic therapy
• Administered by injection or nasal spray • Slows the progress of postmenopausal
osteoporosis and reduces fractures
• Glucocorticoids • Etidronate, pamidronate
• Antagonizes vitamin D stimulated intestinal • Cause bone mineralization defects
calcium transport • Lose their effectiveness over 12 months
• By stimulating calcium renal excretion • Prevention or treatment of osteoporosis
• By blocking bone formation • Once weekly administration of relatively
• Common cause of osteoporosis in adults large dose
• Treatment of hypercalcemia in lymphomas • As efficacious as daily administration of
smaller dose
• Estrogens • Does not result in more toxicity
• Estrogens and selective estrogen receptor • Alendronate and risedronate
modulators (SERMs) • Block farnesyl pyrophoshate synthase
• Tamoxifen, raloxifene • Mevalonate pathway for osteoclast
• Prevent or delay bone loss in post survival
menopausal women • Cause fewer bone problems
• Reduces the bone-resorbing action of PTH • Effective for at least 5 years
• Leads to increase 1,25 (OH)2 D levels but no • Alendronate + HRT
direct effect on production • Further increases bone mass in
menopausal patients
NONHORMONAL AGENTS AFFECTING BONE
MINERAL HOMEOSTASIS • Denosumab
• Biphosphonates • Human monoclonal antibody that binds to
• Denosumab and prevents the action of RANKL
• Calcimimetics • Administered subcutaneously every 6
• Plicamycin months, which avoids GI side effects
• Thiazides • Increased risk of infection since a number of
• Fluoride cells in the immune system also express
• Strontium ranelate RANKL
• Risk of osteonecrosis of the jaw and
• Biphosphonates subtrochanteric fractures may be increased
• Alendronate, etidronate, pamidronate,
risedronate, tiludronate, ibandronate, and
zoledronate • Calcimimetics
• Short-chain analogs of pyrophosphate • Cinacalcet
• Reduce both the resorption and the formation • Activates the calcium sensing receptor (CaR)
of bone by an action on the basic which is most abundant in the parathyroid
hydroxyapatite crystal structure gland
• Greatest direct effects on osteoclasts • Blocks PTH secretion
• Other complex cellular effects
• Inhibition of vitamin D production • Plicamycin (mithramycin)
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 • Cytotoxic antibiotic
• Binds to DNA and interruption of DNA
directed RNA synthesis
• Reduces serum calcium and bone resorption
in Paget’s disease and hypercalcemia
• Risk of serious toxicity
• Thrombocytopenia, hemorrhage, hepatic
and renal damage)
• Short term treatment of serious
hypercalcemia
• Thiazide diuretics
• Reduces renal calcium excretion
• Increases the effectiveness of PTH in
stimulating reabsorption of calcium in the
renal tubules
• Fluoride
• Effective for prophylaxis for dental caries
• Appropriate concentrations of fluoride ion
in drinking water (0.5-1 ppm)
• Additive in toothpaste
• Accumulated by bones and teeth and
stabilize hydroxyapatite crystals
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• Increase resistance of teeth to dental
caries
• Does not explain new bone growth
• Fluoride without adequate calcium
supplementation causes osteomalacia
• Adverse effects like n/v, GI blood loss,
arthralgia and arthritis
• Strontium ranelate
• Organic ion, ranelic acid bound to two atoms
of strontium
• Blocks osteoclast differentiation, promoting
apoptosis and inhibiting bone resorption
• Increases bone formation markers and
inhibits bone resorption markers
• Used for osteoporosis
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