Drugs Affecting Mineral Homeostasis and Bone

What are the 3 major causes of hypocalcemia?

1. Hypoparathyroidism

2. Vitamin D deficiency

3. Chronic kidney disease

What are the 2 common oral formulations for calcium supplements?

1. Calcium carbonate

2. Calcium citrate

What is the most widely used calcium supplement?

calcium carbonate

T/F: Calcium carbonate requires gastric acid for its absorption, so it is less effective when taking PPIs.

True

Which oral calcium supplement is the most readily absorbable?

calcium citrate

The use of calcium supplements may decrease the absorption of what 4 drugs?

1. tetracyclines (eg doxycycline)

2. quinolone antibiotics (eg levofloxacin)

3. levothyroxine

4. bisphosphonates

What are the major signs of hypercalcemia?

1. Fatigue

2. muscle weakness

3. hyporeflexia

4. depression

5. diffuse abdominal pain

6. constipation

What are 4 common causes of hypercalcemia?

1. Many forms of cancer

2. Hyperparathyroidism

3. Excessive vitamin D intake

4. High doses of calcium with milk or antacid (milk-alkali syndrome)

What are 3 common treatments for hypercalcemia?

1. IV saline and loop diuretics (eg furosemide/Lasix)

2. Bisphosphonates, Denosumab (discuss later)

3. Glucocorticoids (eg prednisone)

The production of Vitamin D3 precursor requires (UVA/UVB).

UVB

What are 5 factors that increase the risk of a vitamin D deficiency?

1. Poor sunlight exposure

2. Dark skin

3. Advanced renal or liver disease

4. Intestinal disease

5. Some anticonvulsant therapy (phenytoin)

How does anticonvulsant therapy lead to a vitamin D deficiency?

the medications increase the catabolism of vitamin D into inactive metabolites.

What are the clinical effects of a prolonged, severe vitamin D deficiency? (4)

1. Decreased calcium and phosphorus

2. secondary hyperparathyroidism

3. Bone demineralization

4. osteomalacia or rickets

What are some signs/symptoms of vitamin D deficiency? (4)

1. Bone pain

2. muscle weakness

3. tetany

4. skeletal deformities (leg bowing common in children)

What are 2 vitamin D supplements?

1. cholecalciferol

2. ergocalciferol

(Osteoblasts/Osteoclasts) are inhibited by "anabolic" therapies. (Osteoblasts/Osteoclasts) are inhibited by "antiresorptive" therapies.

Osteoblasts, Osteoclasts

T/F: Osteocytes are not affected by any drugs.

True

What is the major physiologic function of PTH?

maintain normal serum Ca (Ca2+) when low

What is the dual action of PTH?

Chronic PTH stimulations leads to increased bone resorption and increased serum Ca. Intermittent PTH leads to an increase in bone formation.

PTH therapies are an example of (anabolic/antiresorptive) agents used to treat osteoporosis.

anabolic

What is the major mechanism of PTH therapies (osteoporosis)?

the intermittent exposure to PTH will increase bone formation via increased osteoblast activity

T/F: PTH therapies are frontline preventative therapies for osteoporosis.

False

When are PTH therapies used?

a therapy for high risk patients

T/F: You must follow PTH analog therapy with antiresorptive therapy or else bone loss will ensue.

True

What is an example of a PTH analog therapy?

Teriparatide

What is the main AE of Teriparatide?

hypercalcemia

Why do we limit the use of Teriparatide to two years?

there is a risk of osteosarcoma.

Which patients are contraindicated for treatment with Teriparatide?

1. Paget's disease

2. History of radiation to skeleton

3. History of bone metastases or skeletal malignancies

4. Other metabolic bone disorders

5. Hypercalcemia

6. Open bone growth plates

Sclerostin inhibiting medications are an example of an (anabolic/antiresorptive) therapy for osteoporosis.

anabolic and antiresorptive

What is an example of a Sclerostin inhibitor medication?

Romosozumab

What is the MoA of Romosozumab?

it is an Anti-sclerostin monoclonal antibody. since sclerostin decreases osteoblast activity and bone formation, Romosozumab increases osteoblast activity.

What are some AEs of Romosozumab? (4)

1. hypocalcemia

2. hypersensitivity reaction

3. low risk atypical femur fracture

4. osteonecrosis of jaw

What is the Box warning for Romosozumab?

May increase risk of MI, stroke, CV death

What is the 1st line treatment and prevention medication for osteoporosis?

Bisphosphonates

T/F: Bisphosphonates are only used to treat osteoporosis.

False

What 4 issues/diseases are treated using bisphosphonates other than osteoporosis?

1. Hypercalcemia of malignancy

2. Paget's disease

3. Skeletal related events in bone metastases

4. Bone loss due to antiestrogen or antiandrogen therapy

What are 3 examples of bisphosphonate drugs?

1. alendronate (Fosamax)

2. risedronate (Actonel)

3. zoledronic acid (Reclast

Bisphosphonates are (anabolic/antiresorptive) osteoporosis medications.

antiresorptive

What is the MoA of bisphosphonates?

They are analogs of pyrophosphate that bind Ca in hydroxyapatite in bone. They are incorporated into mineralized matrix. As osteoclast dissolves bone, bisphosphonate is released and taken up into osteoclast where it interferes with osteoclast function and promotes apoptosis

Once inside an osteoclast, how do bisphosphonates cause apoptosis? (3)

1. they inhibit the mevalonate pathway, specifically FPP synthase.

2. Thus, they decrease the synthesis of mature signaling molecules required for osteoclast formation, function, and survival.

3. The osteoclast, unable to survive, undergoes apoptosis.

T/F: Bisphosphonates have very poor oral availability.

True

T/F: To increase the bioavailability of oral bisphosphonates, you should take the pills after a full meal.

False

T/F: Divalent cations (like Ca, Mg, Fe) can interfere with the absorption of oral bisphosphonates.

True

Why should patients taking oral bisphosphonates maintain an upright position for 30 minutes after taking the medication?

the medication can cause esophagitis and esophageal erosion.

What are 7 AEs of bisphosphonates?

1. Esophageal ulcers, esophagitis, reflux

2. Osteonecrosis of the jaw

3. Ocular inflammation and uveitis

4. musculoskeletal pain

5. Hypocalcemia

6. Atypical femur fracture

7. renal impairment.

What is the proposed mechanism for Osteonecrosis of the jaw?

Maxilla and mandible are subjected to constant stress from masticatory forces so physiologic microdamage and micro fractures occur daily, but repair is hindered by drugs

What are some risk factors for bisphosphonate associated Osteonecrosis of the jaw? (4)

1. chronic disease states (cancer or diabetes mellitus)

2. history of smoking

3. glucocorticoid therapy

4. poor oral hygiene

What is the main dental recommendation for preventing bisphosphonate associated Osteonecrosis of the jaw?

Delay initiating bisphosphonate therapy until healing of jaw complete after invasive dental procedure if possible

What is Denosumab (Prolia)?

anti-RANKL monoclonal antibody

What is the MoA of Denosumab (Prolia)?

binds RANKL and prevents its activation of RANK receptor, leading to a decrease in bone resorption

What are some uses of Denosumab (Prolia)? (4)

1. High risk osteoporosis

2. bone metastases

3. hypercalcemia of malignancy

4. with anti-estrogen and anti-androgen cancer therapies

Denosumab is an example of an (anabolic/antiresorptive) osteoporosis therapy.

antiresorptive

What are 2 common AEs of Denosumab (Prolia)?

1. hypocalcemia

2. arthralgia

Why is estrogen not a frontline therapy for postmenopausal osteoporosis?

due to risk of breast CA in certain populations, stroke, venous thromboembolism