Osteoporosis Pharmacology - Complete Guide

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SECTION 1: DEFINITION

• Katzung, p. 1226 | Lippincott Pharmacology, p. 887

Normal bone vs osteoporotic bone - comparison of trabecular architecture:

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SECTION 2: CLASSIFICATION / CAUSES

• Long-term glucocorticoids (most common drug cause)
• Antiandrogen therapy (e.g., prostate cancer treatment)
• Thyrotoxicosis, hyperparathyroidism
• Malabsorption syndromes
• Alcohol abuse and cigarette smoking
• Idiopathic

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SECTION 3: BONE REMODELING (Pathophysiology)

1. Osteoclasts - break down bone (resorption)
2. Osteoblasts - synthesize new bone (formation)
3. Hydroxyapatite crystals (calcium phosphate) are deposited during mineralization

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SECTION 4: DRUGS USED IN OSTEOPOROSIS

Classification of Anti-Osteoporosis Drugs

A. ANTIRESORPTIVE AGENTS (inhibit bone resorption)
   1. Bisphosphonates
   2. Denosumab (RANKL inhibitor)
   3. SERMs (Raloxifene)
   4. Estrogen / HRT
   5. Calcitonin

B. ANABOLIC AGENTS (stimulate bone formation)
   1. Teriparatide (PTH 1-34)
   2. Abaloparatide (PTHrP analog)
   3. Romosozumab (sclerostin inhibitor - dual action)

C. NON-PHARMACOLOGIC
   Calcium + Vitamin D supplementation

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SECTION 5: BISPHOSPHONATES

Drugs in Class

Antiresorptive Potency (Relative)

Mechanism of Action

Dosing Schedule

Administration Rules for Oral Bisphosphonates

• Take with 6-8 oz plain water ONLY
• Take at least 30 minutes (60 min for ibandronate) BEFORE any food, drink, or medications
• Remain upright (do not lie down) for at least 30 minutes after
• (Exception: risedronate delayed-release - taken AFTER breakfast)

Pharmacokinetics

• Oral bioavailability: <1% - poorly absorbed
• Food and other drugs significantly interfere with absorption
• Rapidly cleared from plasma by avid binding to hydroxyapatite in bone
• Once bound to bone, cleared over hours to years (long half-life in bone)
• Eliminated mainly via kidneys - avoid in severe renal impairment

Indications

1. Postmenopausal osteoporosis (first-line)
2. Osteoporosis in men
3. Glucocorticoid-induced osteoporosis
4. Paget disease of bone (higher doses)
5. Hypercalcemia of malignancy
6. Bone metastases (pamidronate, zoledronate)

Adverse Drug Reactions (ADRs)

1. GI upset - nausea, esophageal irritation, dyspepsia (especially alendronate - must stay upright after dosing)
2. Osteonecrosis of the Jaw (ONJ) - especially with IV bisphosphonates at high doses
3. Atypical femoral fractures - stress fractures of the subtrochanteric femur with long-term use (>5 years)
4. Flu-like symptoms - acute phase reaction with IV zoledronate (fever, myalgias, arthralgias)
5. Hypocalcemia - particularly with IV forms
6. Esophagitis / esophageal ulcers - if patient does not remain upright

Notes (Katzung)

• Side-by-side trials showed alendronate > calcitonin in efficacy
• Bisphosphonates protect against both hip and spine fractures
• BMD benefits plateau after a few years (unlike denosumab)
• A drug holiday is often recommended after 3-5 years in low-risk patients

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SECTION 6: DENOSUMAB (RANKL INHIBITOR)

Drug

Mechanism of Action

Dosing

• 60 mg subcutaneous injection every 6 months

Indications

1. Postmenopausal osteoporosis in women at high fracture risk
2. Osteoporosis in men
3. Glucocorticoid-induced osteoporosis
4. Hypercalcemia of malignancy (Xgeva formulation)
5. Prevention of skeletal-related events in multiple myeloma / bone metastases

Advantages Over Bisphosphonates

• No renal dose adjustment needed
• BMD continues to increase up to 10 years (unlike bisphosphonates which plateau after a couple of years)
• Alternative first-line agent, particularly at higher fracture risk

ADRs

• GI upset, bone pain
• Increased risk of infections (cellulitis, serious infections) - RANKL is also expressed on immune cells
• Dermatologic reactions (eczema, rash)
• Hypocalcemia
• Rarely: ONJ, atypical fractures (like bisphosphonates)

Critical Warning (Katzung)

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SECTION 7: TERIPARATIDE AND ABALOPARATIDE (ANABOLIC AGENTS)

Drugs

• Teriparatide (Forteo) - recombinant human PTH 1-34
• Abaloparatide (Tymlos) - analog of parathyroid hormone-related peptide (PTHrP)

Mechanism of Action

• Act as agonists at the parathyroid hormone receptor (PTH1R)
• Once-daily subcutaneous administration results in stimulation of osteoblastic activity and increased bone formation and bone strength
• When given intermittently (pulse dosing), the anabolic effect predominates over resorptive effect
• Note: PTH also activates bone resorption, but the net effect is anabolic with this dosing regimen

Dosing

Indications

• High fracture risk patients
• Patients who have failed or cannot tolerate other therapies
• Severe postmenopausal osteoporosis

Efficacy

• At least as great as bisphosphonates in preventing fractures
• Produces structurally normal new bone (unlike fluoride which produces abnormal bone)
• Effective for both vertebral and nonvertebral fractures

ADRs

1. Injection site reactions
2. Hypercalcemia (transient)
3. Orthostatic hypotension
4. Hyperuricemia (abaloparatide)
5. Osteosarcoma risk - increased in rats at high doses; contraindicated in patients at risk (Paget disease, prior radiation therapy to bone, unexplained elevations of alkaline phosphatase)

Contraindications

• History of Paget disease
• Prior skeletal radiation
• Unexplained elevated alkaline phosphatase
• Pre-existing hypercalcemia
• Pediatric patients (open epiphyses)

Important (Katzung + Lippincott)

• After completing 2-year course, an antiresorptive agent must be started to maintain BMD gained
• Cumulative lifetime use >2 years is NOT recommended

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SECTION 8: ROMOSOZUMAB (SCLEROSTIN INHIBITOR)

Drug

Mechanism of Action (DUAL - unique)

• Monoclonal antibody against sclerostin
• Sclerostin (produced by osteocytes) is an inhibitor of bone formation via the Wnt signaling pathway
• Romosozumab binds sclerostin → promotes osteoblast activity (anabolic) + decreases bone resorption (antiresorptive)
• The only agent with both effects simultaneously (Katzung Fig. 42-5 shows the highest BMD increase)

Dosing

• 210 mg SC injection monthly (2 injections of 105 mg to give full dose)
• Approved for 12 months only

Indications

• Postmenopausal osteoporosis at high fracture risk

ADRs

• Arthralgias, headache
• Injection site reactions
• Cardiovascular risk - small but significant increase in MI and stroke in clinical trials

Contraindications

• History of MI or stroke (black box warning)
• No renal dose adjustment required

After Therapy

• Must transition to an antiresorptive agent to maintain bone gained

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SECTION 9: SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)

Drugs

• Raloxifene (Evista) - available; first SERM approved for osteoporosis
• Bazedoxifene - used in Europe
• Tamoxifen - has bone effects but not approved for osteoporosis

Mechanism of Action

• SERMs are estrogen receptor modulators that act as estrogen agonists on bone (and lipid metabolism) but as estrogen antagonists on breast and endometrial tissue
• Raloxifene prevents the estrogen-deficiency-driven proliferation and activation of osteoclasts

Indications

• Prevention and treatment of postmenopausal osteoporosis (alternative agent)
• Reduces risk of invasive breast cancer (important added benefit)

Limitations vs Bisphosphonates

• Protects against vertebral fractures only - NOT hip or nonvertebral fractures
• Bisphosphonates, denosumab, and teriparatide all protect against both

ADRs

1. Hot flashes (leg cramps)
2. Venous thromboembolism (VTE) - same risk as estrogen; contraindicated if history of DVT/PE
3. Does NOT prevent hot flushes (may worsen them)
4. Does NOT increase risk of endometrial or breast cancer

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SECTION 10: ESTROGEN / HRT

Mechanism

Status

• Increases risk of breast cancer with continued use
• Increased risk of endometrial cancer (prevented if combined with progestin in women with uterus)
• Does NOT protect against heart disease and may increase risk
• Combined E+P increases risk of stroke and VTE

Current Role

• No longer routinely recommended as first-line for osteoporosis
• May be considered for women with severe menopausal symptoms who have contraindications or intolerance to first-line agents

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SECTION 11: CALCITONIN

Drug

Mechanism

• Peptide hormone secreted by thyroid parafollicular cells
• Binds directly to osteoclasts and inhibits their resorptive activity

Formulations

• Intranasal spray (most common for osteoporosis) - rhinitis is main ADR
• Subcutaneous / Intramuscular injection - injection site reactions

Indications

1. Treatment of osteoporosis in women at least 5 years postmenopausal (when other agents not tolerated)
2. Unique indication: relief of pain from osteoporotic vertebral fracture (analgesic property)
3. Paget disease
4. Hypercalcemia (acute)

ADRs

• Nasal: rhinitis, epistaxis
• Injectable: nausea, flushing, injection site reactions
• Increased risk of new malignancy with long-term use (limits use)

Limitations (Katzung + Lippincott)

• Less effective than bisphosphonates, denosumab, or teriparatide
• Reduces fractures only in the spine (not hip)
• Should only be used if other agents are inappropriate or not tolerated

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SECTION 12: CALCIUM AND VITAMIN D

Role

Calcium

Vitamin D

• Essential for intestinal calcium absorption and bone mineralization
• Vitamin D2 (ergocalciferol) or Vitamin D3 (cholecalciferol) used for supplementation
• 800 IU/day shown to improve bone density, reduce falls, and prevent fractures
• Calcitriol (1,25-(OH)₂D) and 1α(OH)D₃ analogs also used (not FDA-approved for osteoporosis in US)

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SECTION 13: INDICATIONS SUMMARY

Threshold for Pharmacologic Treatment (Lippincott, p. 891)

• Previous osteoporotic fracture, OR
• BMD T-score ≤ -2.5 (osteoporosis), OR
• Low bone mass (osteopenia) with high probability of future fractures (using FRAX tool)

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SECTION 14: BONE MINERAL DENSITY - TREATMENT EFFECTS

• Antiresorptives (bisphosphonates, denosumab, calcitonin, estrogen) - produce a transient rise, then plateau as both formation and resorption equalize
• Anabolics / dual agents (Vitamin D, PTH/teriparatide, strontium, romosozumab/anti-sclerostin) - continue to increase BMD throughout the treatment period, achieving greater gains
• No treatment - continued bone loss over time

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SECTION 15: SEQUENCE / COMBINATION THERAPY PRINCIPLES

1. Anabolic first, antiresorptive second - after teriparatide or abaloparatide, must follow with bisphosphonate/denosumab to preserve gains
2. Romosozumab (1 year) → then antiresorptive agent
3. Denosumab discontinuation → must switch to bisphosphonate (not just stop) to prevent rebound
4. Bisphosphonate holiday - after 3-5 years, low-risk patients may pause; residual drug in bone provides continued effect

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Quick ADR Summary Table

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