Bone resorption inhibitors

Bone resorption inhibitors are a class of pharmacologic agents that act to reduce bone loss by inhibiting the activity of osteoclasts—the primary cells responsible for bone breakdown. These drugs are essential in the management of metabolic bone disorders, including osteoporosis, Paget’s disease of bone, bone metastases, multiple myeloma-related bone disease, and hypercalcemia of malignancy. By reducing the rate of bone turnover, they help preserve bone density, reduce fracture risk, and improve skeletal integrity.

---

1. Mechanism of Action

Bone resorption inhibitors work by interrupting the bone remodeling process, specifically targeting osteoclast formation, function, or survival. Bone remodeling involves a balance between osteoclastic bone resorption and osteoblastic bone formation. In pathological states like osteoporosis or bone metastasis, this balance is skewed toward resorption. Bone resorption inhibitors work by:

• Inhibiting osteoclast recruitment

• Impairing osteoclast function

• Promoting osteoclast apoptosis

• Interfering with RANKL-mediated signaling

• Suppressing osteolytic cytokine activity

---

2. Classification of Bone Resorption Inhibitors

Bone resorption inhibitors include several pharmacological subclasses:

A. Bisphosphonates (antiresorptive agents)
B. RANKL inhibitors
C. Calcitonin
D. Selective Estrogen Receptor Modulators (SERMs)
E. Estrogen and Hormone Therapy (in specific indications)
F. Cathepsin K inhibitors (emerging agents)

---

3. Bisphosphonates

Mechanism:
Bisphosphonates bind to hydroxyapatite crystals in bone and are internalized by osteoclasts during resorption. They inhibit farnesyl pyrophosphate synthase (FPPS), an enzyme in the mevalonate pathway critical for osteoclast function and survival.

Drugs:

1. Alendronate – Fosamax

2. Risedronate – Actonel

3. Ibandronate – Boniva

4. Zoledronic acid – Reclast (osteoporosis), Zometa (oncology)

5. Etidronate – Didronel (less commonly used today)

6. Pamidronate – Aredia (primarily oncology)

Indications:

• Postmenopausal osteoporosis

• Glucocorticoid-induced osteoporosis

• Paget’s disease

• Hypercalcemia of malignancy

• Bone metastases (zoledronic acid and pamidronate)

Pharmacokinetics:

• Poor oral bioavailability (~1%)

• Must be taken on an empty stomach with water

• Renally excreted

• Long skeletal half-life

---

4. RANKL Inhibitors

Mechanism:
RANKL (Receptor Activator of Nuclear Factor κB Ligand) is essential for osteoclast development and activity. RANKL inhibitors block the interaction between RANKL and its receptor (RANK), preventing osteoclastogenesis.

Drug:

• Denosumab

  • Brand Names: Prolia (osteoporosis), Xgeva (oncology)

  • Fully human monoclonal antibody to RANKL

Indications:

• Postmenopausal osteoporosis (Prolia)

• Bone loss due to hormone therapy

• Bone metastases from solid tumors (Xgeva)

• Giant cell tumor of bone

• Hypercalcemia of malignancy

Pharmacokinetics:

• Subcutaneous administration every 6 months (Prolia)

• Half-life: ~25–30 days

• Not renally excreted

---

5. Calcitonin

Mechanism:
Calcitonin is a peptide hormone produced by the thyroid that inhibits osteoclast activity. Pharmacologic formulations are derived from salmon calcitonin, which has greater potency and a longer half-life than human calcitonin.

Drug:

• Calcitonin-salmon

  • Brand Names: Miacalcin, Fortical

  • Formulations: Nasal spray, subcutaneous, intramuscular

Indications:

• Paget’s disease

• Postmenopausal osteoporosis (third-line)

• Hypercalcemia of malignancy

Limitations:

• Less effective than bisphosphonates and denosumab

• Concerns about long-term malignancy risk

---

6. Selective Estrogen Receptor Modulators (SERMs)

Mechanism:
SERMs bind to estrogen receptors and act as agonists on bone while being antagonists on breast and uterine tissue. They reduce bone resorption by mimicking the effects of estrogen in skeletal tissue.

Drugs:

1. Raloxifene – Evista

2. Bazedoxifene – Used in combination with conjugated estrogens (Duavee)

Indications:

• Prevention and treatment of postmenopausal osteoporosis

• Breast cancer risk reduction (raloxifene)

Limitations:

• Not first-line for fracture prevention

• May increase risk of thromboembolic events

---

7. Hormone Replacement Therapy (HRT)

Mechanism:
Estrogen suppresses bone resorption through direct effects on osteoclasts and cytokine modulation. Combined estrogen-progestin therapy may be used for bone health in menopausal women.

Indications:

• Postmenopausal osteoporosis prevention (short-term, only when other treatments are inappropriate)

Risks:

• Cardiovascular events

• Breast cancer

• Stroke

• DVT

---

8. Cathepsin K Inhibitors (Emerging)

Mechanism:
Cathepsin K is a protease used by osteoclasts to degrade collagen in bone matrix. Inhibiting this enzyme reduces bone resorption.

Drug:

• Odanacatib – Development discontinued due to stroke risk

• Other agents under investigation

---

9. Clinical Indications of Bone Resorption Inhibitors

• Postmenopausal osteoporosis

• Osteoporosis in men

• Glucocorticoid-induced osteoporosis

• Paget’s disease of bone

• Bone metastases from solid tumors (e.g., breast, prostate, lung)

• Multiple myeloma bone disease

• Hypercalcemia of malignancy

• Giant cell tumor of bone

---

10. Adverse Effects

Bisphosphonates:

• Esophagitis (oral agents)

• Atypical femoral fractures (long-term use)

• Osteonecrosis of the jaw (ONJ)

• Hypocalcemia

• Flu-like symptoms (IV formulations)

Denosumab:

• Hypocalcemia (especially in renal impairment)

• ONJ

• Serious infections

• Skin reactions

• Rapid bone loss and rebound fractures upon discontinuation

Calcitonin:

• Rhinitis (nasal spray)

• Nausea, flushing

• Antibody formation

• Potential increased cancer risk (long-term use)

SERMs:

• Hot flashes

• Leg cramps

• Thromboembolism

• No protection for hip fractures

HRT:

• Stroke

• MI

• Breast cancer

• DVT/PE

---

11. Contraindications

Bisphosphonates:

• Esophageal disorders

• Inability to remain upright

• Hypocalcemia

• Severe renal impairment (eGFR <30–35 mL/min)

Denosumab:

• Hypocalcemia

• Pregnancy

• Hypersensitivity

Calcitonin:

• Known hypersensitivity

• Malignancy risk (nasal spray – long-term)

SERMs and HRT:

• Active or past thromboembolic disease

• Estrogen-dependent malignancies

• Hepatic impairment

• Pregnancy/lactation

---

12. Precautions

• Ensure adequate calcium and vitamin D intake

• Monitor renal function (especially with bisphosphonates)

• Perform dental examination before IV bisphosphonates or denosumab

• Discontinue use before invasive dental procedures (when applicable)

• Monitor for symptoms of atypical femoral fracture (e.g., thigh/groin pain)

---

13. Drug Interactions

Bisphosphonates:

• Reduced absorption with:

  • Calcium, magnesium, iron, antacids

  • Must be taken on empty stomach with plain water

• NSAIDs may increase GI irritation

Denosumab:

• Increased risk of hypocalcemia when used with:

  • Loop diuretics

  • Glucocorticoids

Calcitonin:

• Potential additive hypocalcemia with:

  • Bisphosphonates

  • Loop diuretics

SERMs:

• Increased thrombotic risk when combined with estrogen therapy

• May interfere with warfarin anticoagulation

---

14. Summary of Common Bone Resorption Inhibitors

Drug Class	Generic Name	Brand Name(s)	Route	Indications
Bisphosphonate	Alendronate	Fosamax	Oral	Osteoporosis, Paget’s disease
Bisphosphonate	Zoledronic acid	Reclast, Zometa	IV	Osteoporosis, bone metastases
RANKL Inhibitor	Denosumab	Prolia, Xgeva	SC	Osteoporosis, metastases, giant cell tumor
SERM	Raloxifene	Evista	Oral	Osteoporosis, breast cancer risk reduction
Calcitonin	Calcitonin-salmon	Miacalcin, Fortical	SC, nasal	Paget’s disease, hypercalcemia
HRT	Conjugated estrogens	Premarin	Oral, transdermal	Osteoporosis prevention (not first-line)