187. Calcium/Parathyroid/Bone Pharmacology/Basic Science Flashcards
Pharmacokinetics:
- poor oral absorption (need w/o food)
- retained in bone
- renal excretion
- dosed once a week
Adverse effects:
- heartburn, esophageal irritation, esophagitis
- abdominal pain, diarrhea
- Osteonecrosis of the jaw and atypical femoral fractures are rare but serious side effects
Bisphosphanates
Functions of __:
- regulation of excitable tissues
- secretion
- coagulation
- enzymatic activity
- signal transduction
- formation and maintenance of the skeleton (structural role)
Calcium
Important for the maintenance of bone
Decreased __ at menopause accelerates bone loss
__ is antiresorptive and anabolic:
- inhibits production of RANKL and IL-6
- Increases production of osteoprotegerin
- causes apoptosis of osteoclasts
- decreases sclerostin, promoting bone formation
Estrogen
An __ pool provides buffering, acid-base balance
- minute-to-minute calcium that the body may need
- > 1% of calcium in bone
Exchangeable
Thin, cortex, largely trabecular, highly connected bony plates
Contain more marrow and fat
Trabecular bone has the highest activity
- turnover
- more likely for bone loss
Axial bones
251 AA protein produced by osteoblasts and osteocytes
- synthesis increased by calcitriol and phosphate
Inhibits renal calcitriol synthesis, phosphate reabsorption
Tumoral calcinosis results from mutations that inhibit __ secretion
Hypophosphatemic rickets results from mutations in a cleavage site require for __ inactivation
FGF-23
Normal serum calcium levels
8.5-10.4
Acts on the same receptor as PTH
Etiologic factor in the hypercalcemia of malignancy and in the osteolytic metastases of breast cancer
Effects on mammary glands, placenta, smooth muscle
Anabolic action on bone
PTHrP
Products used as markers of osteoblastic activity (3 of them)
Osteocalcin
Alk phos
Collagen peptide cleaved off during synthesis
Secrete H+ and proteolytic enzymes to eat away at old bone
Have a monocyte lineage
Stimulated by RANKL
Osteoclasts
Short term glucocorticoid treatment can reduce __ because glucocorticoids:
- decrease intestinal calcium absorption
- increase renal calcium excretion
Hypercalcemia
What accompanies calcium when being absorbed in the gut due to Vit D activity?
Phosphate
Human monoclonal antibody against RANKL
Inhibits osteoclast fusion, function, and survival
- antiresorptive
Increases bone mineral density and decreases fractures
Use:
- osteoporosis
- bone metastases from solid tumors
Adverse effects:
- hypocalcemia
- rashes
- osteonecrosis of the jaw
- risk of infections in individuals with weak immune systems
Denosumab
Type of SERM - selective estrogen response modulator
Interact with estrogen receptors in a tissue-specific manner
- largely antiresorptive
- anti-estrogenic effects on the mammary gland
Uses:
- prevent and treat postmenopausal osteoporosis
- reduces risk of breast cancer
Adverse effects:
- thromboses
- hot flashes
- don’t use if pregnant or wanna be
Raloxifene
Anabolic agent for the treatment of osteoporosis
- used the first 34 AAs of PTH
Administered by subcutaneous injection once daily
- get pulsatile effect of PTH
Teriparatide
32 AA peptide secreted by the C-cells of the thyroid gland
- secretion is stimulated by calcium
Acts on mature osteoclasts through GPCRs to inhibit bone resorption
Calcitonin
BP medication that actually decreases calcium excretion
- can be used to treat hypocalcemia
Thiazide diuretics
Calcium __ in the kidney is increased by:
- dietary protein
- glucocorticoids
Excretion
Major site of calcium storage in the body
Bone
Used to treat __:
- Loop diuretics
- Bisphosphonates
- Calcitonin
- Glucocorticoids
Hypercalcemia
Factors promoting osteoblast differentiation and activity:
- Wnt signaling
- What other 2 factors?
IGF-1 and BMP (bone morphogenic proteins)
Increases calcium absorption in the distal nephron
- 99% calcium reabsorbed
PTH
Major director of calcium absorption in the gut
Activated Vit D (1,25-(OH)2 Vit D)
Secrete Type I collagen, other matrix proteins, growth factors, and cytokines (including RANKL)
- osteocalcin
- Alk phos
Derived from pluripotent precursors that can also give rise to adipocytes, chondrocytes, and myocytes
Osteoblasts
Effects are produced through nuclear receptors
Stimulates intestinal calcium and phosphate absorption, resulting in bone mineralization
Suppresses PTH secretion
In excess, can cause hypercalcemia through
- excess calcium and phosphate intestinal absorption
- direct actions on osteoblasts to increase RANKL
Calcitriol
PTH action on bone:
- bone resorption results from __ exposure
- -> resorption is largely due to increased RANKL
- -> PTH increases RANKL
Continuous
Actions on kidney:
- increase calcium absorption
- decrease phosphate reabsorption
- stimulate 1alpha-hydroxylation of 25-OH Vit D to form 1,25-(OH)2 Vit D
Actions on intestine:
- indirectly mediated through the increase of 1,25-(OH)2 Vit D
PTH
3 major sites at which calcium is regulated
Intestine
Kidney
Bone
50% of calcium in the blood is __
- active states
- mediates biological responses
Ionized
Use is related to its effects on calcium and phosphate absorption
Treatment of nutritional rickets
In patients with osteoporosis, adequate __ is an important adjunct to other therapy
Vitamin D
Decreased calcium leads to..
Increased PTH secretion
Chronic glucocorticoid treatment can cause __ because glucocorticoids:
- decrease intestinal calcium absorption
- increase renal calcium excretion
- increase PTH secretion
- decrease gonadal steroids
- decrease protein synthesis in bone
Osteoporosis
Systemic condition in which osteoblastic activity cannot keep pace with accelerated osteoclastic activity, resulting in loss of mineral and matrix and increased susceptibility to fracture
- d/t menopause or estrogen loss in most cases
Osteoporosis
Largely compact cortical bone, with some trabecular regions
Long bones
Appendicular bones
Disorder in which local increased osteoclastic activity is followed by increased osteoblastic activity, resulting in abnormal bone
Paget’s Disease of Bone
As bone forms around osteoblasts, they become __
Comprise 90% of the cells of the bone
Sensors of mechanical load
Osteocytes
PTH action on bone:
- bone formation results from __ exposure
- -> decreased osteoblast apoptosis
- -> increased osteoblast differentiation
- -> suppression of sclerostin production
Intermittent
Used to treat __:
- Vitamin D
- Calcitriol
- Alphacalcidol
- Thiazide diuretics
All supplemented with calcium
Hypocalcemia
RANKL antagonist secreted by osteoblasts
Osteoprotegerin
Vitamin D analog that does not require 1-hydroxylation
Useful when 1-hydroxylase is deficiency
- renal disease
- VDRR
Alphacalcidol
What two factors increase phosphate excretion in the kidney?
FGF-23
PTH
Vitamin D analog that suppresses parathyroid hormone
Minimal effects on intestine
Useful for secondary hyperparathyroidism
- seen in renal disease
Paracalcitol
40% of calcium is protein bound
- of that, ~90% is bound with __
Albumin
Calcium __ through the intestine can result from:
- glucocorticoids which decrease calcium absorption
- mucosal and biliary secretion
- steatorrhea, diarrhea, and malabsorption syndromes
Loss
Osteocytes produce __ that inhibits Wnt signaling and osteoblast differentiation and maturation
Antagonists increase bone formation
Sclerostin
The final activation step of Vit D, 1-hydroxylation, occurs in the __
- stimulated by PTH
- stimulated by low serum phosphate
- tightly feedback regulated
Kidney
GPCR found in the parathyroids that is the site of negative feedback control from calcium levels in the blood
- increased calcium in blood is going to decrease PTH levels through this receptor
CaSR
A __ pool is regulated by cellular activity, affected by hormones, cytokines, growth factors, and drugs
- 99% of calcium in bone
Stable
Membrane-associated cytokine produced by osteoblasts and other cells
Acts on a receptor on osteoclasts and osteoclast precursors
Promotes fusion, differentiation, activity, and survival of osteoclasts
RANKL
In times of __calcemia there is dehydrations, renal stones, pain, weakness, confusion, and cardiac arrythmias
Hyper
Makes up 90% of the protein of the bone matrix (osteoid)
- osteoid + hydroxyapatite = mineralized matrix
Collagen
Analogs of pyrophosphate
- alendronate, risedronate, zoledronic acid, ibandronate
Accumulate in bone at sites of active resorption
Taken up by osteoclasts, inhibit their activity and survival
- antiresorptive
Prevent and treat osteoporosis
- ~50% decrease in fracture risk
Treatment of:
- bone metastases from breast and prostate cancer
- hypercalcemia
- Paget’s disease
Bisphosphonates
BP medication that increases calcium excretion
- can be used to treat hypercalcemia
Loop diuretics
Tight homeostatic control of calcium is a consequence of the feedback regulation between calcium and __
PTH
Site of hematopoiesis
Provides bone cell precursors
- formation of bone and remodeling
Cells produce cytokines that affect bone
Bone marrow
Calcimimetic that acts as an allosteric activator of the CaSR
- enhances the activity of the CaSR –> lowers the calcium concentration at which the parathyroid is suppressed
=> Decreased PTH secretion
Used to suppress excess PTH in hyperparathryoidism, parathyroid carcinoma
Orally effective, metabolized by CYPs, renally excreted
Side effects:
- hypocalcemia
- adynamic bone disease (if PTH is too low)
Cinacalcet
In times of __calcemia there is increased neuromuscular excitability
- experience tetany seizures, parasthesias
Hypo
Intestinal calcium __ is promoted by:
- facilitated diffusion throughout the small intestine
- Vit D-dependent transport of calcium and phosphate (major pathway)
Absorption
Metabolic roles of bone
Calcium homeostasis
Buffering
Teriparatide and Abaloparatide are examples of __ therapies used to treat osteoporosis
Anabolic
Vitamin D is converted to 25-OH Vit D in the __
Liver
