Lecture 39 + 40: cant make me Flashcards
Note about serum Ca2+
-50% ionized (DIFFUSABLE)
-10% complexed (DIFFUSABLE)
-40% protein bound
-total Ca+: 10mg/dL
-diffusable Ca+: ~5mg/dL
Body distribution of calcium
-99% in bone and teeth
-1% in ECF and cytoplasm
Calcium state in bone
-crystalline form
-hydroxyapatite (Ca10(PO4)6(OH)2
Osteoblasts
-bone forming cells
-inc Ca and PO4 from plasma INTO bone
Osteoclasts
-bone resorption cells
-RELEASE Ca+ and PO4 into PLASMA
Osteocytes
-release factors that regulate osteoblast/clast activity
Osteocytes are stimulated by
-mechanical force detected by cell process that extend into canaliculi forming a network involving ACTIN and CONNEXIN 43 connection channels
positive regulators of osteoblasts/neg of osteoclasts
-sense inc load
-inc BMD
-osteonectin
-Nitric oxide
-Dentin Matrix Protein 1
negative regulators of osteoblasts/postitive regulators of osteoCLASTS
-sense dec in load
-dec BMD
-sclerostin
-DKK-1
-RANKL
Regulation of Ca homeostasis by
hormone
-Parathyroid Hormone (PTH)
Parathyroid hormone (PTH)
-peptide hormone secreted from parathyroid gland
-84aa cleaved from 115aa
-aa 1-34 have full activity
-deletion of aa 1 and 2 eliminates activity
PTH effect on calcium
-inc Ca in ECF (PLASMA!)
PTH mech of action
-inc Ca reabsorption from collecting tubules (kidney)(ECaC1/TrpV5)
-inc Ca reabsorption from bone (inc osteoCLAST # and activity)
-inc PO4 loss in urine
-inc 1,25(OH2) D3 production by kidney
PTH secretion triggered by
2 things
-low serum Ca++ levels
-low levels of CSR (GPCR that binds Ca++)
First step of Vitamin D synthesis
-7-dehyrocholesterol (Provitamin D) to Cholecalciferol (Vitamin D3) by UV irradition of skin
Cholecalciferol
-Vitamin D3
-can be obtained in diet or by exposure to sunlight
Vitamin D3 fate
-transport to liver
-then to kidmey
Vitamin D binding protein
-transports vitamin D3 to liver
-adds OH to the top branch
=25 hydryoxyvitamin D3
25 hydroxyvitamin D3 transport to kidney
-1-a-hydroxylase (if PTH present)
-24-hydroxylase (normal Ca and PO4 levels)
1-a-hydroxylase
-converts 25OH-vitamin D3 to 1,25diOH vitamin D3 calcitriol
-kidney
-only if PTH is present (low Ca and PO4)
-24hydroxylase if no PTH
-adds OH under CH2 on bottom ring
24-hydroxylase
-25-OHvitamin D3 to 24,25 diOH vitamin D3
-secalciferol
-if no PHT present/Ca and PO4 levels ok
-inactive form
-adds OH to top branch
1,25 Dihydroxy Vitamin D3
-Calcitriol
-active form of vit D
-1-a-hydroxylase in kidney
Actions of Vitamin D
-inc Ca and PO4 absorption from small intestine
-inc reABsorption
-indirect effect on calbindins and vitamin D binding protein
-feedback inhibition of PTH
How does Vit D inc Ca and PO4 absorption from small intestine?
-direct, rapid effect on brush border of intestinal mucosal cells
-ECaC2/TrpV6
Absorption of Ca++ from intestine
-Ca2+ enters cell via TrpV6 on brush border
-exists in cell bound to calbindin-D9k
-released from cell by Ca2+ ATP-ase (requires ATP)
Vit D3 upregulates
-TrpV6
-calbindin
-Ca2+ATPase
-also NPt2b which enhances PO4 absorption
Fibroblast Growth Factor 23 (FGF23)
-32kDa protein
-STIMULATES PO4 excretion (supress Npt2a and c)
-INHIBITS PTH secretion
-INHIBITS 1,25(OH)2D3 synthesis (=less P absorption by intestine)
FGF23 secreted by
-osteocytes and osteoBLAsts
-in response to elevated serum PHOSPHATE
FGF23 Auto/paracrine effect on osteoctyes
-inhibits bone mineralization
High levels of FGF23 correlate w
-poor prognosis in pts w CKD on dialysis
Protease-resistant mutant of FGF23
-causes autosomal dominant hypophosphatemic rickets
-excreting too much phosphate
Inhibitors of PTH secretion
-1,25-(OH)2 Vit D3
-FGF23
-High Ca2+
Calcitonin
-negative regulator of serum Ca++
-secreted by C-cells in thyroid gland
-32aa peptide
Calcitonin actions
-INHIBIT osteoCLASTs
-INCREASE Ca++ and PO4 excretion in urine
Calcitonin stimulated by
high serum Ca++
Paget’s Disease
-uncontrolled osteoCLASTIC bone resorption and secondary bone formation that is poorly organized
Paget’s Disease characteristics
-bone pain
-bone deformities
-loss of hearing, HYPERcalcemia
-may be caused by slowly acting virus
Osteoporosis
-shift in bone balance toward resorption
-more osteoCLASTs
-spontaneous or minimal trauma fractures
-hip, vertebrae ribs
causes of osteoporosis
-postmenopause: dec in estrogen levels dec bone mass
-age related dec in osteoBLAST activity
Vertebral complications of osteoporosis
-fragility fracture
-pain
-height loss
-kyphosis
-activity limitations
-restrictive lung disease
-psychological symptoms
Risk factors for osteoporosis
-physical INactivity
-age
-low Ca++ intake in early years
-long term glucocorticoid therapy
Hypercalcemia symptoms
-CNS
-depression
-coma
Hypercalcemia causes
-Hyperparathyroidism (more PTH)
-malignant tumors (some produce peptide w PTH activity)
HYPOcalcemia symptoms
-neuromuscular disturbances
-paresthesias
-tetany
-muscle cramps
HYPOcalcemia causes
-HYPOparathyroidism
-vit D deficiency
Vit D deficiency in children
-can cause weight bearing bone deformities
Vitamin D preparations
-Cholecalciferol Vit D3 (OTC)
-Calcifediol 25 OH Vit D3 (Calderol) (liver disease)
-Calcitriol 1,25OH2 Vit D3 (Rocaltrol) (kidney disease)
-Ergocalciferol (Vit D2) from UV radiated yeast
Vitamin D preparations mech of action
-inc Ca++ and PO4 absorption from gut
-inc Ca++ and PO4 reabsorption in renal tubules
Drugs to treat osteoporosis
-Vit D supplement first
1. Bisphosphonates/Denosumab
2. Ibandronate
3. Raloxifene
4. Calcitonin
Drugs to treat osteoporosis in HIGH fracture risk
3
-teriparatide/abaloparatide
-romosozumab
Vitamin D for osteoporosis treatment
-vitamin D (800-1000 IU)
-Ca++ (>1200mg)
-daily
-slight reduction in fracture risk
-supplement w osteoporosis therapy
Vitamin D use in Hypocalcemia/Hypoparathyroidism
-Vit D and Ca++
-with rPTH
Vitamin D treatment in hyperparathyroidism 2’ to CKD
-analogs suppress PTH
Vitamin D overdose
-Ca++ deposits in kidney and soft tissues
-Hypercalcemia = coma and death
Bisphosphonates
-first line therapy for osteoporosis
-inorganic pyrophosphoric acid
-nitrogen side chain
-inhibits bone resorption
Bisphosphonates action
-reduce formation and dissolution of hydroxyapatit crystals
-accumulates in bone as part of matrix (50% of dose)
-disrupt cytoskeleton
-induce apoptosis
-inhibit farnesyl-PP synthesis of osteoCLASTS
Bisphosphonate dosing precautions
-10% absorbed orally
-take w water 30 min before breakfast
Bisphosphonate problems
-may lead to HYPOcalcemia (supplement w Ca++ and vit D)
-esophagitis, nausea, heart burn
-necrosis of the jaw
-atypical femur fractures
Bisphosphonates approved for Paget’s and cancer (not osteoporosis)
-Pamidronate
-Etindronate
Bisphosphonates approved for osteoporosis
-Zoledronate (IV/year)
-Alendronate (oral)
-Risendronate (oral)
-Ibandronate (IV or oral) (doesn’t prevent hip fractures)
importance of N-side chain in bisphosphonates
-inhibts farnesyl pyrophosphate synthase
-disrupts prenylation of proteins in osteoCLASTS
=Rac and Ras cannot get to membrane to start signal
-apoptosis of osteoclast
-Lys and Thy
Farnesyl
-allows proteins to be held at membrane
-allows Ras and Rac to signal to osteoCLAST
Teriparatide (Froteo)
-aa 1-34 of PTH produced in E. coli
-treat osteoporosis in patients with HIGH RISK of fracture
Abaloparatide (Tymlos)
-aa 1-34 of PTHeP produced syntheticallly
-treat osteoporosis in HIGH risk patients
TeriPARAtide and AbaloPARAtide dosing
-inject SQ qd (20/80ug) w oral Ca++ and Vit D
-better stimulation of osteoBLASTs this way
TeriPARAtide and AbaloPARAtide problems
-potential for HYPERcalcemia
-but rare
-only drug w this side effect
Teriparatide (Forteo) mech of action
-interacts with PTH1 receptor
-dosing can affect stimulation of osteoclasts or blasts
PTH1 recptor
-GPCR
-Gs and adenylyl cyclase
-Gq/PLC
-expressed on osteoblasts and kidney cells
Differentiation of Osteoclasts
-Osteoblast secretes RANKL
-RANKL binds to receptors on osteoclast precursor
-regulated by OPG (osteoprotegerin) binding excess
Intermittent teriparatide dosing
-dec osteoblast apoptosis
=more osteoblasts
-inc BMD
continuous teriparatide dosing
-inc RANKL
-dec OPG
=inc osteoCLASTs
-inc serum Ca++
=HYPERcalcemia
Pros of Teriparatide over Bisphosphates
-may be more effective at PREVENTING fractures
-builds bone mass at higher rate
-may allow better bone healing after fracture
Cons of teriparatide
-must be injected daily
-not recommended beyond 2 years
-black box warning for bone cancer
Teriparatide black box warning
-bone cancer
-dont use more than 2 years
Denosumab (Prolia)
-mAb against RANKL
=prevents osteoCLAST differentiation
Denosumab (Prolia) dosing
-inject SC every 6 months
-must take 1000mg Ca++ and 400 IU vit D daily
Denosumab (prolia) risks
-Hypocalcemia (must treat underlying hypocalcemia first)
-inc risk of fracture upon discontinuation
Romosozumab (Evenity)
-treat HIGH RISK pts
-mAB aginst sclerostin
Romosozumab (Evenity) dosing
-inject SC monthly for 12 months
-w Ca/VitD supplementation
Sclerostin
-dec osteoBLASTS
-inc osteoCLASTS
Sclerostin secretion increases with
-unloading
-after menopause
Romosozumab (evenity) problems
-MACE (not used in pts w MI or stroke in last year)
-hypersensitivity
-hypocalcemia
-osteonecrosis
-atypical fractures
Sclerostin mech
-binds LRP 5/6
=inhibits Wnt signaling
-GSK3 complex displaced from Wnt
=phosphorylates B-cantenin
-B-cantenin (required for osteoblast diff) degraded
Estrogens and SERMs
-prevention of postmenopausal bone resorption
-inc activity of osteoblasts
-maybe dec activity of osteoclasts
SERM drugs
-Raloxifene (evista)
-Bazedoxifene + conjugated estrgogens (Duavee)
Raloxifene and Bazedoxifene action
-ANTAgonists in breast, uterus, brain (hot flashes)
-AGONISTs in bone and liver
Raloxifene and Bazedoxifene risk
-blood clots
Salmon Calcitonin (Miacalcin)
-nasal spray/inj
-dec osteoclast activity
-blocks renal reabsorption of PO4 and Ca++
-not drug of choice
-not great to treat hypercalcemia (loses efficacy quickly)
salmon calcitonin clinical use
-Paget’s disease
-hypercalcemia 2’ to malignancy
-postmenopausal osteoporosis (alt to ERT)
salmon calcitonin side effects
-uticaria
-hand swelling
-nausea
-hypersensitivity reactions
-risk of malignancies w long-term use
-hypocalcemia
Cinacalcet (Sensipar)
-treat 2’ HYPERparathyroidism
-dec serum levels of PTH and Ca++
Cinacalcet (sensipar) dose
-oral
-30mg BID initial
Common causes of hyperparathyroidism
-CKD with dialysis (loss of 1,25OHVitD3 production)
-parathyroid carcinoma
Cinacalcet (Sensipar) mech
-binds to calcium-sensing receptor (CSR) (GPCR) to inc sensitivity to Ca++
=inhibits release of PTH
-dec PTH and Ca++
Cinacalcet (Sensipar) risk
-HYPOcalcemia
-seizures
-adynamic bone disease
CSR in CKD w dialysis
-less responsive to Ca++
-also elevated PO4 can lock CSR in inactive state
Etelcalcetide (Parsabiv)
-treat 2’ hyperparathyroidism
-PAM of CSR to inhibit PTH release
-dec PTH and Ca++
-big ass molecule
Etelcalcetide (parsabiv)
-hypocalcemia
-adynamic bone disease
-worsening HF
-upper GI bleeding
Etelcalcetide (parsabiv) dose
-IV 5mg 3x/week initial
Vit D analog drugs
-Zemplar
-HectorolV
Vit D analogs
-IV or oral
-inhibit secretion of PTH w less effect on serum Ca++ than vit D3
Zemplar
-Vit D analog
-2’ hyperparathyroidism in CKD stage 3-4
-CKd w dialysis
-1-4mcg 3x/week IV or oral
Hectorol
-Vit D analog
-2’ hyperparathyroidism in CKD w dialysis
-prodrug 25 hydroxylation by CYP27 in liver
-4mcg/week. IV or oral
CKD often results in
-loss of phosphate excretion in response to PTH and FGF23
-Hyperphosphatemia
-Calcific Uremic Arteriolopathy risk
Calcific Uremic Arteriolopathy
-Ca++ combine w PO4 and precipitate in tissues
-calification
Phosphate binder
-complex w dietary PO4
-prevent absorption from GI
-treat hyperphosphatemia in CKD w dialysis
Phosphate binder drugs
-Lanthanum Carbonate (Fosrenol)
-Sevelamer (Renagel, Renvela)
Lanthum Carbonate (Fosrenol)
-phosphate binder
-treat hyperphosphatemia in CKD w dialysis
-forms insoluble LaPO4 salts in GI tract
-dec serum PO4 AND Ca!!
Sevelamer (Renagel, Renvela)
-phosphate binder
-treat hyperphosphatemia in CKD w dialysis
-contains amine
-binds PO4 in GI tract
-dec ONLY PO4
Which phosphate binder only decreases PO4
Sevelamer
Which phosphate binders dec PO4 AND Ca++
Lanthum Carbonate
