Antiresorptive and Anabolic Drugs for Bone Disorders

Overview

Antiresorptive agents: Slow bone resorption, minimizing bone density loss.
Anabolic agents: Increase bone formation.
Goal: Prevent fractures and associated morbidity in individuals with low bone mineral density or a history of fractures.

Estrogen and Bone Mineral Density

Estrogen has a protective effect on bone mineral density.
Postmenopausal women are at high risk for osteoporosis due to reduced estrogen levels.
Estrogen's effects:
- Decreases osteoblast apoptosis.
- Inhibits sclerostin (produced by osteocytes).
- Increases OPG synthesis.
- Decreases RANK ligand production.
- Inhibits RANKL-induced differentiation of osteoclasts.
- Increases apoptosis of osteoclasts.
- Overall, decreases bone resorption.

Selective Estrogen Receptor Modulators (SERMs)

Newer non-hormonal agents that bind to the estrogen receptor.
Also referred to as estrogen receptor agonist/antagonist.
Example: Raloxifene (Evista).
Not a first-line therapy for osteoporosis.
May be used as an alternative to bisphosphonates, especially in women with breast cancer or a family history.

Mechanism of Action

Estrogen regulates gene expression, leading to tissue-specific effects.
Raloxifene binds with high affinity to the estrogen receptor, acting as both an agonist and antagonist.
- Agonist on bone and in cardiovascular tissue.
- Antagonist in mammary and uterine tissue.
In bone, inhibits osteoclasts to reduce bone resorption.

Raloxifene Details

As effective as tamoxifen in preventing estrogen receptor-positive breast cancer.
Administered orally, well-absorbed (60% absorbed, but only 2% bioavailability due to first-pass metabolism).
Half-life of 27-32 hours.

Adverse Effects

Fewer adverse effects than estrogen therapy due to tissue selectivity.
Increased risk of thromboembolic events (DVT, pulmonary embolism).
Avoid in women with active or a history of venous thromboembolic disease.

Denosumab (Prolia)

Fully humanized monoclonal antibody that is a RANK ligand antagonist.
Binds to soluble and membrane-bound RANK ligand.
Prevents RANK ligand-induced stimulation of osteoclast differentiation, activity, and survival.
Acts similarly to OPG, the RANK ligand decoy receptor produced by osteoblasts.
Indicated for:
- Postmenopausal osteoporosis (when bisphosphonates are not tolerated, refractory, or in renal failure).
- Prevention of fracture associated with glucocorticoid use.
- Bisphosphonate-refractory hypercalcemia.

Pharmacokinetics and Administration

Elimination half-life of 25-32 days.
Nonlinear, dose-dependent pharmacokinetics.
60mg dose administered subcutaneously every 6 months.
Well-tolerated with no gastrointestinal side effects (unlike bisphosphonates).
Effects on bone do not persist once treatment is stopped.

Adverse Effects

Rare: osteonecrosis of the jaw, hypocalcemia.
Teratogenic: should not be used during pregnancy.

Calcitonin (Salcatonin)

Secreted by C cells of the thyroid.
Binds to calcitonin receptors on osteoclasts, reducing their activity.
Inhibits calcium resorption in the kidney.
Net effect: reduces serum calcium levels.
Salcatonin: synthetic calcitonin derived from salmon.
- Higher affinity and potency than human calcitonin.
- Calcitonin receptor agonist.
Indicated for hypercalcemia (rarely Paget's disease).

Limitations

Not first-line for osteoporosis (weak agent).
Multiple routes of administration (subcutaneous, intramuscular, intravenous, intranasal).
Often used short-term due to increased risk of malignancies with long-term use.
Calcitonin resistance reported with prolonged use.

Calcimimetics (Cinacalcet/Sensipar)

Agonists that are allosteric modulators of calcium-sensing receptors on parathyroid cells.
Increase the sensitivity of calcium-sensing receptors to extracellular calcium.
Lower serum calcium concentration is required for suppression of parathyroid hormone synthesis and release.
Net effect: reduction of serum calcium levels.

Clinical Use

Indicated for hypercalcemia in parathyroid carcinoma and primary hyperparathyroidism (when parathyroidectomy is not an option).
Orally administered (1-4 times per day).
Low bioavailability increased with food (contrast to bisphosphonates).

Adverse Effects and Monitoring

Hypocalcemia (cramps, spasms, seizure).
Dose must be titrated slowly.
Serum calcium and parathyroid hormone levels must be carefully monitored.

Drug Interactions

Smoking accelerates clearance by inducing CYP1A2.
Dose adjustment needed if patient starts or stops smoking.

Anabolic Agents

Parathyroid Hormone Analogs (Teriparatide/Forteo)

At acute or lower doses, PTH promotes osteoblast activity (paradoxical behavior).
Anabolic window: bone formation is stimulated, followed by increased bone resorption.
Teriparatide: PTH analog (first 34 amino acids).

Indications and Contraindications

Indicated for:
- Severe osteoporosis (alternatives unsuitable or refractory).
- High risk of fracture.
- Corticosteroid-induced osteoporosis in patients at high risk of fracture.
Contraindicated in hyperparathyroidism, hypercalcemia, and Paget's disease.

Administration, Interactions and Adverse Effects

Half-life ~1 hour, small volume of distribution.
Administered subcutaneously once per day.
Reduces risk of vertebral and nonvertebral fractures.
Not used with bisphosphonates, but may be combined with denosumab.
Calcium and vitamin D supplementation recommended.
Infrequent side effect: hypercalcemia, myalgia.
Maximum treatment is 18 months (increased risk of multiple myeloma and osteosarcoma).

Oral Calcium Salts

Adjunctive therapy for dietary deficiencies, hypocalcemia, osteoporosis, rickets, and osteomalacia.
Recommended daily intake: 1200-1300 mg.
Various formulations available.
Orally administered, poorly absorbed.
Side effects: constipation, hypercalcemia, flatulence.
Calcium gluconate can be administered intravenously in an emergency.

Vitamin D Analogs

Prohormone used to treat deficiency states (insufficient dietary intake or lack of sunlight).
Used for osteoporosis, osteomalacia, and hypoparathyroidism.
Increases intestinal absorption and renal reabsorption of calcium.
Often taken with calcium supplements.

Administration and Adverse Effects

Generally given orally, well-absorbed; injectable forms are available.
Calcitriol (active form) and cholecalciferol (precursor form stored in the liver).
Cholecalciferol is more commonly used for osteoporosis. Calcitriol is rarely used for osteoporosis.
Cholecalciferol administration depends on normal kidney function (conversion to calcitriol).
Low risk of hypercalcemia at physiological doses.
Calcitriol has a rapid onset and short duration of action; used for hypocalcemia.
Shouldn't be taken with calcium supplements (risk of hypercalcemia).
Cholecalciferol and calcium are often taken together, including with antiresorptive agents (e.g., bisphosphonates).

Romosozumab (Evenity)

Recently approved in Australia.
Humanized monoclonal antibody that inhibits sclerostin.
Sclerostin is a negative regulator of bone formation, produced by mature osteocytes; binds to a protein complex on osteoblasts to inhibit their survival and proliferation, increases RANK ligand production.
Inhibition of sclerostin results in increased bone density in the lumbar spine and hip in men and women.
Indicated for the treatment of osteoporosis in individuals with a high risk of fracture.

Administration, Interactions and Contraindications

Half-life of 12.4 days.
Administered by subcutaneous injection every month for 12 months.
Serious adverse effects: hypocalcemia, osteonecrosis of the jaw, and cardiovascular events.
Contraindicated for those with a stroke or myocardial infarction in the past 12 months.
Patients should be adequately supplemented with calcium and vitamin D.
Effects do not persist on completion of treatment; patients should be transferred to an antiresorptive agent.

Summary of Drug Classes

Calcimimetics (Cinacalcet): Increase sensitivity of calcium-sensing receptors to suppress parathyroid hormone release.
RANK Ligand Inhibitors (Denosumab): Bind to RANK ligand to reduce activation of osteoclasts.
Calcitonin (Salcatonin): Bind to osteoclasts to inhibit their activity.
SERMs (Raloxifene): Act as an agonist on bone estrogen receptors to restore the protective effect of estrogen.
Bisphosphonates: Slow resorption by affecting osteoclast activity.
Parathyroid Hormone Analogs (Teriparatide): Promote osteoblast activity (short-term).
Calcium and Vitamin D: Increase the absorption of calcium to promote bone deposition.
Sclerostin Inhibitor (Romosozumab): Prevents the action of sclerostin as a negative regulator of bone formation.
Glucocorticoids: Increase rank ligand expression, thereby promoting osteoclast activity.