Osteoporosis Flashcards
Calcium in the bone is
hydroxyapatite [Ca10(PO4)6(OH)2]
Osteoblasts
bone forming cells
Osteoclasts
bone resorption cells
Factors released by osteocytes that stimulates osteoblasts
prostaglandins, NO, dentin matrix protein-1
Factors released by osteocytes that stimulates osteoclasts
sclerostin; osteocalcin; MEPE (matrix extracellular phosphoglycoprotein)
What does parathyroid hormone (PTH) do?
- increased calcium reabsorption from CT
- increased calcium resorption from bone
- increased PO4 loss in urine
- increased 1,25(OH)2D3 production by kidney
PTH secretion is triggered by
low serum Ca2+ levels
First step of vitamin D synthesis
7-dehydrocholesterol -> (UV) -> cholecalciferol (D3)
Cholecalciferol can be obtained
in the diet or via exposure to sun light
Under which conditions is 25-hydyoxyvitamin D3 converted into 1,25 Dihydroxy vit D3 (calcitriol)?
low phosphorus and Ca2+
PTH
Under which conditions is 25-hydyoxyvitamin D3 converted into 24,25 Dihydroxy Vit D3 (secalciferol)?
normal phosphorus and calcium
What reaction does 1-alpha-hydroxylase catalyze?
25-hydyoxyvitamin D3 -> 1,25 Dihydroxy vit D3 (calcitriol)
What reaction does 24-hydroxylase catalyze?
25-hydyoxyvitamin D3 -> 24,25 Dihydroxy Vit D3 (secalciferol)
Actions of vitamin D
- increased calcium and PO4 absorption from small intestine
- increased calcium and PO4 reabsorption
- indirect (slow) effects on cells
- feedback inhibition of PTH (1,25(OH)2D
What is upregulated by Vitamin D3?
- TrpV6
- Calbindin-D9k
- Ca2+-ATPase
Which cells secrete calcitonin?
cells in the thyroid gland
What does calcitonin do?
negative regulator of serum calcium;
- inhibits osteoclastic bone resorption
- increases calcium and PO4 loss in the urine
What is calcitonin stimulated by?
high serum calcium levels
Describe postmenopausal osteoporosis.
decrease in estrogen levels causes a decrease in bone mass; shift in bone remodeling balance toward resorption; spontaneous or minimal trauma fractures
Describe osteoporosis related to aging.
caused by age-related decrease in osteoblast activity in both men and women
Vertebral complications of osteoporosis
fragility fractures; pain; height loss; kyphosis; activity limitations; restrictive lung disease; psychological symptoms
Risk factors for osteoporosis
Physical inactivity; age; low calcium intake in early years; long-term glucocorticoid therapy
Hyperparathyroidism
increased bone resorption and decreased calcium excretion
Hypercalcemia caused by malignant tumors
some tumors produce a peptide with PTH activity
CNS complications from hypercalcemia
depression and coma
Hypocalcemia can be caused by
hypoparathyroidism or vit. D deficiencies
Symptoms of hypocalcemia
causes neuromuscular disturbances, parasthesias, tetany, and muscle cramps
Rickets
Vitamin D deficieny; weight bearing bone deformities in children
Vitamin D preparations
Cholecalciferol Vit D3 (OTC)
Calcifediol 25(OH)Vit D3 (Calderol)
Calcitriol 1,25(OH)2VitD3 (Rocaltrol)
MOA of Vitamin D supplements
increased calcium and PO4 absorption from gut
increased calcium and PO4 reabsorption in renal tubules
Pagets disease
uncontrolled osteoclastic bone resorption and secondary bone formation
Symptoms of Pagets disease
- bone pain
- bone deformities
- loss of hearing, hypercalcemia
- may be caused by a slowly acting virus
How do loop diuretics affect serum Ca2+ levels?
increased calcium excretion
decreased driving force for uptake with inhibition of Na+/K+/2Cl- co-transporter
How do thiazides affect serum Ca2+ levels?
decreased calcium excretion
increased driving force for uptake with inhibition of Na/Cl transporter in the distal tubule
How do PPIs and H2 antagonists affect serum Ca2+ levels?
decreased acidity of stomach decreases calcium absorption (Omeprazole may inhibit bone resorption)
How do carbemazepine, isoniazid, theophylline and rifampin affect Ca2+ levels?
induction of Vit. D catabolic P450s
First line therapy for osteoporosis
Bisphosphonates
Bisphosphonates are analogs of what?
analogs of inorganic pyrophosphate
MOA of bisphosphonates
reduce formation and dissolution of hydroxyapatite crystals by accumulating in bone as part of the matrix; disrupt cytoskeleton, induce apoptosis, inhibit farnesyl-PP synthesis of osteoclasts
Adverse effects of bisphosphonates
NVD, musculoskeletal pain, osteonecrosis of the jaw, atypical femur fractures
What do bisphosphates do?
reduce formation and dissolution of hydroxyapatite crystals by accumulating in bone as part of the matrix; disrupt cytoskeleton, induce apoptosis, inhibit farnesyl-PP synthesis of osteoclasts
Bisphosphonates approved for osteoporosis (builds bone mass)
Zoledronate (Reclast)
Alendronate (Fosamax)
Risedronate (Actonel)
Ibandronate (Boniva)
MOA of bisphosphates
inhibition of farnesyl pyrophosphate synthase; disrupts prenylation of proteins in osteoclasts
Second line treatment for osteoporosis
Estrogens and SERMs
Calcitonin
Teriparatide (Forteo)
What do Estrogens and SERMs do?
- prevention and control of postmenopausal bone resorption
2. increases activity of osteoblasts, decreases activity of osteoclasts
Risks with Raloxifene
less cancer risk than estrogen, but risk for VTE and death from stroke
Estrogens and SERMs used 2nd line for osteoporosis
Estradiol and Raloxifene
Calcitonin formulations
Calcimar and Miacalcin (salmon)
Cibacalcin (human)
What does calcitonin treatment do?
decreased osteoclast activity, blocks renal reabsorption of PO4 and calcium
Clinical uses of calcitonin
Paget’s disease;
hypercalcemia secondary to malignancy;
Osteoporosis
Side effects of calcitonin
urticaria, hand swelling, nausea
What is Teriparatide (Forteo)?
amino acids 1-34 of parathyroid hormone produced in E. coli
What does Teriparatide do?
preferentially stimulates osteoblast activity
Clinical uses of Teriparatide
for treatment of osteoporosis in patients with a high risk of fracture
AEs of Teriparatide
orthostatic hypotension, hypercalcemia, arthralgias, allergic reactions
What does intermittent dosing of Teriparatide result in?
increased osteoblast number/function -> increased bone formation -> increased bone mass/strength
What does continuous dosing of Teriparatide result in?
increased osteoclast activity; increased bone resorption; increased serum calcium
Pros of Teriparatide compared to bisphosphonates
may be more effective in preventing fractures than bisphosphates; builds bone mass at a higher rate than bisphosphates; may allow better bone healing after fracture than bisphosphonates
Cons of Teriparatide compated to bisphosphonates
must be injected daily; not recommended beyond 2 years; black box warning required by FDA for risk of bone cancer
Denosumab (Prolia, Xgeva)
humanized monoclonal Ab against RANKL
MOA of Denosumab
binds to RANKL and prevents activation of RANK on osteoclast precursors, preventing differentiation of osteoclasts
Clinical use of Denosumab
for treatment of osteoporosis in postmenopausal women with a history of fractures, high risk of fractures or intolerance to bisphosphonates
What must Denosumab be taken with?
patients must take 1000 mg calcium and 400 IU Vit D daily
AEs of Denosumab
hypocalcemia, osteonecrosis of the jaw, atypical femur fractures, musculoskeletal pain, severe infections, skin reactions
Clinical use of Cinacalcet (Sensipar)
Primary hyperparthyroidism;
Parathyroid carcinoma;
Secondary HPT in CKD with dialysis
MOA of Cinacalcet (Sensipar)
binds to calcium-sensing receptor (a GPCR on PTH gland to inhibit release of PTH); allosteric regulator - causes receptor to be more sensitive to calcium
Cinacalcet (Sensipar) decreases
both serum PTH levels and serum calcium levels
Risks with Cinacalcet (Sensipar)
risk of hypocalcemia, seizures, adynamic bone disease
Analogs of Vitamin D
Zemplar and Hectorol
Calcific uremic arteriolopathy
Calcium can combine with (PO4)3- and precipitate in tissues - calcification
Phosphate binders
complex with dietary phosphate and prevent absorption from GI
Lanthanum Carbonate (Fosrenol)
forms insoluble LaPO4 salts in the GI tract; decreases serum (PO4)3- and calcium levels
Sevelamer (Renagel, Renvela)
Amine-containing polymer that binds (PO4)3- in the GI tract; decreases serum (PO4)3- levels selectively
