Bone Disorders Flashcards
Bone physiology
- is living, dynamic tissue, subject to continuous remodelling
- balance between osteoclasts and osteoblasts
Osteoclasts: break down bone
Osteoblasts: build up bone
Most common disorder involving bone
Osteoporosis
Osteoporosis characteristics
- loss of bone mineral density (BMD) and increased fracture risk
- tends to be associated with aging, but can occur in relatively young individuals
Drugs used to treat Osteoporosis
Drugs that inhibit Osteoclasts: anti-resorptive
Drugs that promote osteoblasts: anabolic
Drugs that inhibit osteoclasts (4)
- Bisphosphonates
- Hormone therapies
- RANKL inhibitors
- Calcitonin
Bisphosphonates example
Alendronate
Mechanism of Bisphosphonates
Promote apoptosis of osteoclasts
- inhibit mevalonate pathway
- this inhibits generation of prenylated proteins
- prenylated proteins promote osteoclasts function and promote apoptosis
- therefore BPs inhibit osteoclasts function and promote apoptosis
Other uses of BPs (Alendronate)
Hypercalcemia: inhibit bone reabsorption, reduces release of Calcium into the blood
BPs unusual distribution
Concentrate in bone: can remain attached to bone for several months, Osteoclasts activity (release of acids) releases BPs slowly over time, can take weekly: One formulation, zolendronic acid, administered IV once/year
Administration of BP’s
Most administered Orally
- low oral bioavailability, food and mineral like calcium reduce absorption
- take on empty stomach
Other than Zolendronic acid: intravenous infusion
BPs adverse effects
- irritating to the GI tract
- Nausea, vomiting, diarrhea
- abdominal pain
- Osteonecrosis of the jaw: bone become necrotic and exposed to the oral cavity, painful and increased risk of fracture
- key factor is a previous dental extraction
Main serious Issue with BPs
- Esophageal damage: may be due to direct irritant effect or increased acid production
- should remain upright for at least 30 minutes after taking
Hormone therapy
Estrogens promote bone
- inhibit osteoclasts
- may promote osteocytes survival
- this is why as estrogen levels decline with age, so does bone health
Negative effects of Estrogen
- increased risk to some cancers
- increased risk to thrombosis
Raloxifene
Acts as an estrogen agonist in bone
- inhibits reabsorption
Adverse effects of Raloxifene
Hot flashes
Leg cramps
Increases risk of thrombosis
Role of RANKL
Receptor Activator of Nuclear factor Kappa-B Ligand
- binds to the RANK receptor
- stimulates osteoclasts
RANKL inhibitor example
Denosumab
Denosumab mechanism
- binds to the RANK receptor, prevents RANKL binding
- inhibits osteoclasts activity
Denosumab characteristics
- monoclonal antibody
- administered by injection
RANKL inhibitors adverse effects
- may increase risk of infection: RANKL plays a role in the immune system
- Osteonecrosis of jaw: Mechanism unclear
Calcitonin mechanism
- inhibits osteoclasts activity by activating G-protein coupled receptor: decreases bone reabsorption, decrease calcium in blood
- therefore can also be used in treatment of hypercalcemia
- receptor desensitization can occur over time, reducing efficacy of Calcitonin
Calcitonin uses
More commonly for treating pain from osteoporotic fractures
Administered as an injection
Calcitonin adverse effects
- Nausea
- Hives
Serious: Cancer - Calcitonin nasal spray withdrawn from market over cancer concerns
Promoting bone formation drug example
Teriparatide
- human recombinant parathyroid hormone (PTH)
- high levels of PTH stimulates osteoclasts
- low intermittent PTH stimulates osteoblasts
Intermittent use Human recombinant parathyroid hormone
- increase osteoblasts numbers
- prevents osteoblasts apoptosis
Administration of teriparatide
Subcutaneous injection
Adverse effects of Teriparatide
Cramping
Hypercalcemia
Safety issue: Teriparatide promotes bone formation/osteoblasts
- animal studies show link to osteosarcoma
- treatment duration limited to 18 months
Calcium Supplements available
- Calcium carbonate (TUMS)
- Calcium citrate
- Carbonate has higher Calcium content than citrate
Adverse effects of calcium supplements
- Gastrointestinal: constipation
- excess intake can lead to problems: hypercalcemia, renal stones
Calcium supplements in certain stages of life
Early: contributes to bone growth
Elderly: reduces bone turnover
- no clear evidence that supplementation reduces fractures
Role of Vitamin D
Improves Calcium absorption
- Natural sources: Sunshine, dairy, fish
Elderly at increased risk of deficiency due to reduced time outdoors
Various forms of Vitamin D
Vitamin D2: Ergocalciferol
Vitamin D3: Cholecalciferol
- synthetic form: calciferol
Vitamin D adverse effects
Gastrointestinal: Nausea, constipation
Hypercalcemia
Drugs that reduce BMD
Tobacco (smoking)
Corticosteroids
- both promote osteoclasts activity
