Osteoporosis Pharmacology Flashcards
1
Q
Regulation of Plasma Calcium Levels
A
- Coordination of multiple organs
- Kidney, bone, parathyroid glands, GI tract, thyroid glands
2
Q
Plasma Calcium Levels
A
- Maintained at ~10 ng/dL
- Calcitonin and PTH utilized to help maintain these levels
3
Q
PTH stimulates…
A
- Ca+ release from bone
- Ca+ reuptake from urine
- Ca+ upake from intestine via active Bitamin D3 (1,25 dihydroxy-vitamin D3)
4
Q
Calcitonin inhibits
A
- Ca+ release from bone
- Ca+ reuptake from urine
5
Q
Active D3
A
- multi-step generation process
- Can be synthesized from cholesterol after its exposure to sunlight or from dietary intake of D3 (fish, meat, supplements)
- Liver and kidney utilized in conversion to active form
- 25-hydroxy-vitamin D3 is what is tested to monitor levels
6
Q
Bone Remodeling
A
- Continuous process with synthesis by osteoblasts and destruction by osteoclasts
- Gives bone mature structure and maintains normal blood calcium levels
7
Q
Osteoclasts
A
- Resorbs bones
- Creates acidic micro-environment
- Contains lysosomal enzymes
8
Q
Acidic Micro-environment
A
- Sealing zone
- Ruffled border (increase SA)
- Vacuolar-type hydrogen pump
9
Q
Osteoporosis
A
- Clasts > blasts
- Loss of bone mineral density (BMD)
- Increased risk of fragility fractures
10
Q
Risk Factors for Osteoporosis
A
- Older age
- Female
- Small stature
- Low sex hormones - menopause
- Chronic glucocorticoid therapy
11
Q
Osteoporosis Lifestyle Risks
A
- Smoking
- Alcohol abuse
- Inadequate physical activity
- Diet (low Ca+, vitamin D intake)
12
Q
Osteoporosis most common in…
A
- Postmenopausal women
- Low estrogen levels and increased osteoclast activity
13
Q
Estrogen is
A
Protective!!
Deficiency:
- Increased bone remodeling
- Increased bone resportion - increased osteoclast differentiation
- Decreased bone formation - increased apoptosis of osteoblasts
14
Q
Glucocorticoids
A
- Decreased osteoblast numbers and survivability
- Risk of fragility fractures depends on steroid dose and duration
15
Q
Diseases treated with Glucocorticoids
A
Autoimmune Diseases
- Rheumatoid arthritis
- Lupus
- IBS
16
Q
Bisphosphonates (BP)
A
- Binds to hydroxyapatite (bone matrix)
- Release during resportion
- Absorbed into osteoclasts and inhibits their activity and survivability
- First line therapy
17
Q
BP Mechanisms
A
- Inhibit farnesyl pyrophosphate synthade
- Inhibit transfer of prenyl group to protein
- Disrupts osteoclast ruffle border
- Inhibits generation of H+
- Disrupts sealing zone
18
Q
BP Examples
A
- Alendronate (Fosamax) - oral, once a week
- Ibandronate (Boniva) - oral, once a month
- Risedronate (Actonel) - oral, once a day/week/or month
- Zoledronic acid (Reclast) - IV, once every 1-2 years
19
Q
BP PK
A
- Poorly absorbed orally
- 70% excreted by kidney
- 30% binds to bone
- T1/2 in bone is 10 years
20
Q
BP SE/CI
A
- Heartburn, esophageal/stomach inflammation
- Jaw osteonecrosis (rare)
- Low trauma, atypical femur fractures (rare)
- CI: GFR < 30 mL/min
21
Q
BP Duration of Therapy
A
- Low Risk of Fracture: 2-3 years
- Mild Risk of Fracture: 2-5 years
- Moderate Risk of Fracture: 3-5 years
- High Risk of Fracture: Up to 10 years
- *Follow-up with a drug holiday**
22
Q
Low Risk of Fracture
A
- BMD < -2.0
- No risk factors
- Low BTMs
23
Q
Mild Risk of Fracture
A
- BMD >= -2.0 but =< 2.5
- Stable over the treatment
- Family history of hip fracture
24
Q
Moderate Risk of Fracture
A
- BMD: initially >= -2.5 with improvement but still >= -2.0
- No prior hip or spine fracture
25
High Risk of Fracture
- BMD >= -2.5
- History of a recent hip or spine fracture
- Ongoing high-dose glucocorticoid therapy
- High BTMs
26
Denosumab
- Prolia
- First line therapy
- Monoclonal antibody that binds to RANKL
- Decrease in osteoclast differentiation and survival
- Approved for postmenopausal women with high risk of fracture
27
Prolia PK
- SQ injection every 6 mo- 1 year
- T1/2 - 25 days
- Ensure adequate Ca+/Vitamin D3 intake
28
Prolia SE
- Joint/muscle pain
- Low osteonecrosis (rare)
- Low trauma, atypical femur fractures (rare)
29
Estrogen Therapies for Osteoporosis
- Premarin - conjugated estrogens
- Raloxifene - SERM
- Duavee - estrogen + estrogen agonist/antagonist
30
Estrogen Therapy MoA
- Increase OPG
- Inhibit RANK
- Inhibit osteoclasts
31
Premarin Limitations
- Increased risk of MI, stroke
- Increased risk of breast cancer
- Increased risk of DVT
32
Raloxifene Limitations
- Fewer SE
| - Can worsen VM symptoms
33
Calcitonin MoA
- Inhibits osteoclast activity
| - Directly binds to receptors
34
Calcitonin Limitations
-Poor efficacy compared to BP
35
PTH Analogs
- Teriparatide
| - Abaloparatide
36
PTH Analog MoA
- Transient stimulation of osteoblasts
| - Stimulation of bone formation
37
PTH Analog Limitations
- Expensive
| - $7 K annually
38
PTH
- initiates bone remodeling
- Release Ca+ from bone through induction of RANKL
- Stimulate bone formation when given as intermittent, non-sustained preparations
39
PTH Analog PK
- Route: SQ
- Frequency: daily
- T1/2 - 60 minutes
40
PTH Analog SE
- Nausea
- Leg cramps
- Headaches
- Dizziness
41
PTH Analog Precautions
- Patients at risk of osteosarcoma
| - Limit use to no more than 2 years
