Bone Disorder Drugs Flashcards
Basic Bone Physiology:
- Bone is a living, dynamic tissue exposed to continuous remodelling.
- Osteoblasts form bone
- Osteoclasts break down bone.
What is Osteoporosis?
- The most common bone disorder
- Characterized by a loss of bone mineral density (BMD) and increased fracture risk.
- Tends to be associated with aging, but can occur in relatively young individuals.
Bisphosphonates (Zoledronic Acid)
- Promote apoptosis of osteoclasts
- Inhibit the Mevalonate pathway, which inhibits generation of prenylated proteins. Prenylated proteins promote osteoclast function and promote apoptosis.
Other uses:
- Used to treat Hypercalcemia (inhibit bone resorption, which reduces the release of Ca2+ into the blood)
- Bisphosphonates concentrate in the bone and can remain attached in bone for several months. Osteoclast activity (release of acid) releases BP’s slowly over time, which osteoclasts lead to their own demise.
- Can take weeks (one formulation of Zoledronic Acid administered IV once a year)
- Most bisphosphonates are administered orally; Zoledronic acid is administered IV
-Low oral bioavailability
-Food and minerals like Ca2+ reduce absorption
-Should be taken on an empty stomach, however, BP’s are irritating to the GI tract.
(Can induce abdominal pain, nausea, vomiting and diarrhea)
Adverse Effects of Zoledronic Acid (Bisphosphonates):
Main serious safety issue is esophageal damage
–>May be due to a direct effect, or due to increased acid production.
-A patient should remain upright for at least 30 minutes after taking.
-GI upset is common
-Some bisphosphonates somehow interfere with normal turnover of bone in the jaw
(a key risk factor is previous dental extraction)
–>Some bisphosphonates are anti- angiogenic, so may also inhibit repair mechanisms.
Estrogens:
- Hormone Therapy
- Estrogens promote bone growth (inhibit osteoclasts and may promote osteocyte survival)
- -Estrogens decline with age (as does bone health)
Estrogens have both positive and negative effects in the body.
Negative effects of Estrogens in the body:
- Increased risk of certain cancers.
- Increased risk of thrombosis
Raloxifene:
- A SERMS (Selective Estrogen Response Modifiers)
- Acts as an estrogen agonist in the bone (inhibits resorption)
Adverse Effects: Flushing (due to vasodilation), leg cramps and in serious but rare cases, thrombosis
Denosumab:
Receptor Activator of Nuclear factor Kappa-B Ligand (RANKL):
- Binds to the RANK receptor which prevents RANKL binding- thus inhibiting osteoclast activity.
- Type of monoclonal antibody (administered by injection)
Adverse Effects:
- May increase risk of infection
- RANKL plays a role in the immune system
- Osteonecrosis of the jaw
Calcitonin:
-Inhibits osteoclast activity by activating a G protein coupled receptor
-Decreases bone reabsorption
-In turn, decrease blood calcium
(Therefore, can also be used to treat hypercalcemia)
–>Receptor desensitization can also occur over time- reducing the efficacy of calcitonin
-Administered via injection
-Most commonly given for pain from osteoporotic fractures.
AE:
- Nausea and Hives
- Serious but Rare AE: Cancer
- Calcitonin nasal spray was taken off the market over cancer concerns.
Teriparatide:
Human recombinant parathyroid hormone (PTH)
- High levels of PTH stimulates osteoclasts.
- Low, intermittent PTH stimulates osteoblasts.
- Intermittent use permits increased osteoblast numbers and prevent osteoblast apoptosis.
- Administered as a SC injection.
AE:
-Cramping & Hypercalcemia
Osteosarcoma & Teriparatide’s effect:
Cancer- promotes growth of immature bone.
- Teriparatide promotes bone formation
- ->Animal studies show a link to osteosarcoma.
- Treatment duration limited to 18 months!
Ca2+ Supplements:
- Calcium Carbonate
- Calcium Citrate
- ->Carbonate has a higher Ca2+ content than citrate.
Adverse Effects of Ca2+ Supplements:
- GI (Constipation*)
- Hypercalcemia
- Renal Stones
What is the impact of Ca2+ supplements in Elderly versus a Younger Population?
Early: Contributes to bone growth
Elderly: Reduces bone turnover
(NO evidence that Ca2+ prevents fractures)
Vitamin D:
To improve Calcium Absorption
-Natural sources of Vitamin D include Sunshine, Dairy and Fish.
*Elderly are at an increased risk of deficiency due to reduced time outdoors.
Adverse Effects:
- GI (Nausea & Constipation)
- Hypercalcemia
Differen Vitamin D Supplements:
Ergocalcierfol: Vitamin D2
Cholecalciferol: Vitamin D3
–Synthetic form: Calcitriol
