Osteoporosis Drugs Flashcards
Osteoporosis:
“Osteo” = Bones and “Porosis” = Porous
INCREASE likelihood of a fracture
“a pediatric disease w/ geriatric consequences”
- Porous bones are weak and fracture easily.
- A major cause of disability in the elderly.
breakdown/resorption > formation
= REDUCED bone density
–> fracture
What are Bone Cells?
- OSTEOBLASTS secrete collagen matrix around themselves which calcifies
- Type 1 collagen + Ca2+ + PO42- → hydroxyapatite crystal
Osteocyte:
maintains bone tissue
Osteoblast:
forms bone matrix
Osteogenic cell:
stem cell
Osteoclast:
resorbs bone
What is bone remodelling?
Bone turnover: 100% per year for infants, 20% in adults
balance b/t blasts & clasts constantly
Bone __________ & ___________ are normally balanced.
resorption
reformation
What is Excessive Osteoclastic activity?
Excessive Osteoclastic activity and the same level of Osteoblastic activity leads to osteoporosis.
What is the diagnosis of Osteoporosis?
X-RAY
* Fragility fractures from minor trauma- sneezing, coughing, bending, etc.
BONE MINERAL DENSITY
* Assessed by dual X-ray Absorptiometry at hip & spine.
* >50% decrease in density = osteoporosis
* T score < -2.5
What is the risk factors for osteoporosis?
- Menopause (b/c no longer have monthly cycle of estrogen)
- Age (>50 yrs old)
- Drugs e.g. Glucocorticoids
- Stress
- Genetics
Parathyroid Hormone (PTH):
- Maintains blood calcium
↓ EC Ca2+
↑ PTH secretion
1. ↑ Ca2+ & Phosphorus Secretion in Blood
2. ↑ Ca2+ Reabsorption
↑ Phosphorus Excretion in Urine Activates 1a-Hydroxylase
3. ↑ Ca2+ & Phosphorus Reabsorption
What is Parathyroid Hormone (PTH)?
- Elevated PTH increases bone turnover and remodeling
- ACTIVATES osteoblasts (bone formation increases)
- But osteoblasts activate osteoclasts by induction of a membrane-bound protein ligand (RANKL)
- Indirectly increases both the NUMBERS and ACTIVITY of osteoclasts
What does Calcitonin do?
Comes from the Thyroid gland - opposite of PTH (when Ca2+ levels get too HIGH in body, we have more Calcitonin produced & its goal is to try to REDUCE Ca2+ in blood)
- Inhibits Ca2+ reabsorption in the kidney (excreted in the urine)
- Promotes deposition of Ca2+ into bones (inhibits osteoclasts & stimulates osteoblasts)
- Inhibits Ca2+ absorption by the intestines
- Lowers Ca2+ levels in blood
What is Estrogen & Testosterone?
- Sex hormones increase osteoblast activity, block osteoclast activation
- This becomes an issue with aging, particularly after menopause in women
- b/c don’t have estrogen needed to maintain bone
Glucocorticoids:
- ↓ Bone Formation
- ↓ Sex Hormone Secretion –>
↑ Bone Resorption - ↓ Ca2+ Absorption & ↓ Renal Ca2+ Reabsorption
–> ↓ Plasma Ca2+ –> ↑ PTH Secretion –> ↑ Remodeling
=> Osteoporosis
What are strategies for preventing or delaying
osteoporosis?
Stronger bones at age 16 to 25 decrease degree of osteoporosis in later life.
- Weight bearing exercise
- Cessation of smoking, limiting alcohol intake
- Avoiding drugs that increase bone loss, e.g. Glucocorticoids
- Diet containing Calcium and Vitamin D
What is Calcium?
- ~ 99% of body’s calcium in bones and teeth; 1% in blood, muscle and other tissues
- Age 18-50: 1000 mg/day
- Age 50+: 1200 mg/day
- 300 mg in each: 1 cup milk, 1 cup fortified orange juice, 3⁄4 cup yoghurt, cheese
- Adequate calcium and vitamin D intake VERY IMPORTANT ADJUNT with OP meds
What is Vitamin D?
Calcitriol (1, 25 OH-VIT D3) Bone Actions (systemically)
* ↑ Ca2+ and phosphate absorption from gut
* ↓ renal excretion of Ca2+ and phosphate
* ↑ bone turnover or remodeling (stimulates both bone formation and resorption)
- Deficiency can be due to poor diet or inadequate sunlight
- Age <50: 400-1000 IU/day
- Age>50: 800-2000 IU/day
What are strategies for managing osteoporosis?
Anti-resportives (prevent osteoclast activity)
What is Bisphosphonates
(Alendronate, Risendronate, Zoledronic acid) MOA?
- BIND DIRECTLY TO THE BONE (hydroxyapatite crystals)
- Taken up by osteoclasts during remodeling
*Inhibit osteoclast activity and bone resorption by
inhibiting the cholesterol synthesis pathway (2nd, 3rd gen)
- kill osteoclasts
What are the pharmacokinetics of Bisphosphonates?
Considered 1st line therapy for prevention and treatment of OP
What is the absorption of Bisphosphonates?
low and variable; <1% of an oral dose is absorbed;
- Must be taken first thing in a.m. with full glass of water only on empty stomach
- Beverages (especially milk, coffee, orange juice, and mineral water) and food reduce absorption by up to 60%, do not consume for at LEAST 30 min after dose
- Dairy-rich foods, antacids, calcium should ideally be taken 2 or 3 hours after med.
What is the half-life elimination of Bisphosphonates?
Varies from months to years; slowly released with process of bone turnover
▪Eliminated by kidneys
What is the dosing of Bisphosphonates?
Alendronate and risedronate once weekly; Zoledronic acid given intravenously once yearly
What are the adverse effects of Bisphosphonates?
▪ALL bisphosphonates may cause bone, joint &/or muscle pain
▪Oral- may cause GI related problems such as abdominal pain, acid reflux, nausea, esophagitis, ulcers
▪I.V.-Acute-phase reaction; FLU-LIKE sx’s such as fatigue, fever, chills; usually occurs 3 to 7 days following the infusion; reaction tends to lessen with subsequent infusions.
▪RARE risks with long term use: osteonecrosis of the jaw (ONJ) and atypical femur fractures (AFF)
What is Denosumab?
- Monoclonal antibody
- Prevents RANKL from binding to RANK receptor on osteoclasts in the circulation
- Inhibits development, activation, and survival of osteoclasts
- Dose: subcutaneously q 6 months
What are the hormone related medication strategies for managing osteoporosis?
- Teriparatide
- Calcitonin
- Estrogen (for post-menopausal women)
- Raloxifene
What is Teriparatide?
- Recombinant formulation of part of parathyroid hormone
- ANABOLIC ACTION: stimulates osteoblast activity (more than osteoclasts)
- Net effect is increased bone formation
- Indicated for SEVERE osteoporosis
- Administered subcutaneously (DAILY)
- Associated with an increased risk of cancer (osteocarcinoma)
- Expensive!
What is Calcitonin?
↓ osteoclastic bone resorption (↓ serum calcium)
- Can be used to treat osteoporosis
- Only WEAKLY BENEFICIAL (other drugs are better)
- Increased risk of CANCER
What is Estrogen (for post-menopausal women)?
- Not recommended for treatment of OP, but may provide some benefit when menopause symptoms are also severe
- Decreases bone resorption; reduces RANKL; increases OPG
Potential systemic effects:
* Increased risk of breast cancer with long term therapy; increased risk of stroke,
What is Raloxifene?
- Selective Estrogen Receptor Modulator
(partial estrogen agonist-antagonist) for OP in post- menopausal women (better) - Agonist on bone; ANTAGONIST AT BREAST & ENDOMETRIUM
- Decreases bone resorption, reduces RANKL
- Associated with RISK REDUCTION IN BREAST CANCER (therefore, better than Estrogen option) in postmenopausal women
- Other adverse events: hot flashes; leg cramps/muscle spasms, thrombosis (can increase risk of stroke)
Denosumab?
RANKL inhibitor
Raloxifene Estrogen?
reduce RANKL
Teriparatide?
PTH Analog - for bone formation
Calcitonin?
for reabsorption
Bisphosphonates?
bind to bone inhibit osteoclasts
for resorption
