PDA II Osteoporosis

Normal blood Ca level

10 mg / 100 mL

2 hormones for Ca homeostasis

-PTH

-Calcitonin

PTH

-Parathyroid hormone

-Released from parathyroid gland

-Stimulus: falling blood Ca levels

3 effects of PTH

-Stimulates Ca release from bones

-Increases Ca uptake in kidneys

-Increases Ca uptake in intestines

-All work to increase blood Ca2+ levels

Calcitonin

-Released from thyroid gland

-Stimulus: rising blood Ca levels

2 effects of calcitonin

-Stimulates Ca deposition in bones

-Reduces Ca uptake in kidneys

-Both work to reduce blood Ca levels

Osteoporosis

-Porous bone

-A condition where bone resorption exceeds bone formation

-Low bone mineral density (BMD)

-Disrupted bone architecture

-Fracture with minimal trauma

Resorption

-The process of removing or digesting old bone tissue

-Getting rid of bone

Deposition

-The process in which new bone is laid down

3 treatment strategies

-Inhibit bone resorption: decrease osteoclasts (antiresorptive)

-Promote bone formation: increase osteoblasts (anabolic agents)

-Inhibit bone resorption and promote bone formation (combo agents)

2 types of antiresorptive agents

-Nutritional supplements (standard therapy)

-Prescription medications

2 types of nutritional supplements

-Calcium

-Vitamin D

Calcium medications

-Ca carbonate

-Ca citrate

-Ca phosphate

-Ca lactate

-Ca gluconate

Calcium Carbonate

-Commonly used due to higher ratio of Ca to total weight

-Requires an acidic environment for absorption

-Take with food (stimulate acid secretion) to improve absorption

Calcium carbonate drug interactions

-PPIs

-H2 blockers

-Antacids

-All decrease acid in the body (decrease absorption of calcium carbonate)

Calcium citrate

-Less dependent on acid secretion for absorption

-Useful in pts with achlorhydria, IBS, absorption disorders, or those on H2 blockers / PPIs

Achlorhydria

-Lack of hydrochloric acid in the stomach

Calcium citrate adverse effects

-GI disturbances

-Constipation

-Kidney stones (rare)

Vitamin D drugs

-Ergocalciferol (vitamin D2)

-Cholecalciferol (vitamin D3)

-Calcitriol (1,25-dihydroxyvitamin D3)

How does vitamin D relate to calcium?

-Intake from the sun and food

-25-hydroxylase in liver converts cholecalciferol and ergocalciferol into calcifediol

-1-hydroxylase in kidney convert calcifediol to calcitriol

-Calcitriol maintains calcium balance in the body

Vitamin D in combo with calcium

-Improves Ca absorption

-Improves bone mineral density

Vitamin D in pts with severe hepatic or renal disease

-Administer calcitriol

-Other forms can't be hydroxylated into active form in liver / kidney

Vitamin D adverse effects

-Hypercalcemia

-Hypercalciuria: nephrolithiasis (kidney stones)

5 classes of prescription medications

-Bisphosphonates

-RANK-L Antagonists

-Hormone replacement therapy

-Selective estrogen receptor modulators (SERMs)

-Calcitonin

Bisphosphonates (BPs) drugs

-Alendronate (oral)

-Risedronate (oral)

-Ibandronate (oral and IV)

-Zoledronate (IV)

-Pamidronate (IV)

BP MOA

-Analogs of pyrophosphate

-Bind to Ca and get incorporated into bone matrix and taken up by osteoclasts

-Within osteoclasts, BPs inhibit prenylation (attachment of certain lipids) to multiple proteins

-Decrease osteoclastic activity through apoptosis

-Increase bone density

BP absorption

-Poorly absorbed orally

-1-6% bioavailability

-Presence of food and beverages decreases oral bioavailability

-Must be given on an empty stomach or IV

BP half life / administration

-50% of the dose accumulates in bones and remains for months

-Long biologic half lives of up to 10 years

-Zoledronate: greatest bone absorption and longest bone retention (given as IV infusion yearly or q 2 years)

-Other BPs: administered daily, weekly, or monthly basis

-Excreted in the urine

BP clinical uses

-Mainstay agents to prevent and treat osteoporosis

-Post-menopausal and corticosteroid induced

Pamidronate clinical use

-Hypercalcemia (too much Ca in blood) that may occur in pts with some types of cancer

-Bone weakness or pain caused by myeloma or breast cancer that has spread to bones

Oral BP adverse effects

-Heartburn

-Dyspepsia

-Esophageal irritation and ulcer

-Osteonecrosis of jaw

-Take drug on empty stomach with a glassful of plain water and remain upright for 30 mins (60 mins for ibandronate)

IV BP adverse effects

-Flu like symptoms

-Musculoskeletal pain

-Injection site reactions

-Osteonecrosis of jaw

RANK ligand

-A natural ligand that acts on the receptor activator of nuclear factor kappa B (RANK) present on osteoblast precursor cells

-Stimulates differentiation into osteoclasts

-Bone resorption (releases Ca into blood)

-Pro-osteoclast

RANK-L antagonist drugs

-Prolia (denosumab): human monoclonal antibody to RANK-L

RANK-L antagonist MOA

-Inhibits binding of RANKL to RANK

-Decrease osteoclast formation

-Decrease bone resorption

RANK-L antagonist clinical use

-Post-menopausal osteoporosis

-SC injection q 6 months

RANK-L antagonist adverse effects

-Hypocalcemia

-Monitor pt's plasma calcium levels

-Boxed warning: increased risk for severe hypocalcemia in pts with advanced chronic kidney disease (CKD)

SERM drugs

-Raloxifene

-Bazedoxifene

SERMs

-Bind to estrogen receptors and produce tissue-selective effects on target organs

-Agonist: bone (useful in osteoporosis)

-Antagonist: breast and uterus (useful in breast cancer, no risk of endometrial cancer)

SERM MOA

-Inhibit osteoclast formation and recruitment (like estrogen)

-Modestly increase bone density and decrease vertebral fractures (not as effective as estrogen)

SERM advantage and clinical use

-Reduce risk of breast cancer in postmenopausal women and in women with a family history of breast cancer

-Prevent and treat osteoporosis

SERM adverse effects

-Hot flashes (anti-estrogen effects on the brain)

-Venous thromboembolism (estrogenic effects on liver)

Calcitonin drugs

-Fortical

-Miacalcin

Calcitonin MOA

-Inhibits osteoclastic bone resorption by converting active osteoclasts into resting stage

-Modest increase in bone mass

Synthetic calcitonin

-Human and salmon

-Salmon calcitonin: longer half life and 40x higher potency to human calcitonin receptor

Calcitonin clinical uses

-Intranasal spray or SC/IM injection for postmenopausal osteoporosis

-Least effective compared to other anti-resorptive drugs

Calcitonin adverse effects

-Nasal: rhinitis, epistaxis (nose bleeds)

-Injection: nausea, flushing, irritation

Anabolic agent drug class

-Parathyroid hormone (PTH) analogs

PTH analog drugs

-Teriparatide: recombinant human PTH fragment (rhPTH 1-34)

-Abaloparatide: recombinant human PTH-related peptide [rhPTHrP (1-34)]

PTH analogs

-Increase bone formation (bone mass and strength)

-Stimulate osteoblasts

-Does not just prevent bone loss (bone resorption)

PTH analog MOA

-Activate PTH1 receptors to increase osteoblast activity and number

-Increase bone mass and bone strength (opposite to PTH)

-Increase Ca absorption in GI tract and kidneys (same as PTH)

PTH analog clinical uses

-Reserved for men or women with severe osteoporosis and glucocorticoid induced osteoporosis

-Approved for only 2 years of use

-Given SC

PTH analog adverse effects

-Orthostatic hypotension

-Dizziness

-Transient hypercalcemia

-Encouraged to sit down for the first few doses to determine their response

PTH analog contraindication

-Pts at risk for osteosarcoma

-Pts with Paget disease of bone metastases/malignancies

Combination anabolic and antiresorptive agent drug class

-Sclerostin inhibitor

Sclerostin

-Inhibits osteoblasts and stimulates osteoclasts

Sclerostin inhibitor drug

-Evenity (romosozumab)

Sclerostin inhibitor MOA

-Humanized monoclonal antibody that inhibits sclerostin

-Increases bone formation and, to a lesser extent, decreases bone resorption

Sclerostin inhibitor clinical uses

-Postmenopausal women with severe osteoporosis and pts who are intolerant to or have failed other osteoporosis therapy

-Approved for only 1 year of use as anabolic effect wanes

-SC

Sclerostin inhibitor adverse effects

-Arthralgia

-Headache

-Injection site pain

-Hypocalcemia

Boxed warning for sclerostin inhibitor

-Stroke

-Heart attack

-Death from CV problems

Relative efficacy of anti-osteoporotic drugs

Romosozumab > teriparatide > denosumab > bisphosphonate > estrogen > raloxifene > calcitonin

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