Pharmacotherapy: Osteoporosis Diagnosis and Management

Bone Functions

• Provides structural support
• Protects organs
• Supports marrow development and storage of blood cells
• Stores minerals (Ca, Mg, PO4)

Bone Composition

• Osteoid (non-mineral, organic part of bone matrix): made of collagen and non-collagenous proteins
• Minerals (hydroxyapatite, Ca, and PO4): provides stiffness and strength
• Osteoblasts (bone forming cells): synthesize and secrete organic matrix, regulate mineralization
• Osteocytes and lining cells: communicate with bone cells, formerly osteoblasts that become incorporated into bone matrix or cover the surface as lining cells
• Osteoclasts (bone resorbing cells): adhere to bone, remove it by acidification and proteolytic digestion

Bone Remodeling

• Resorption and formation: osteoclasts remove bone, osteoblasts synthesize new bone matrix
• Osteoclast cell signaling:
  • RANKL (Receptor activator of nuclear factor kappa β ligand): stimulates progenitor cell differentiation to osteoclast
  • Estrogen: inhibits RANKL release, stimulates osteoclast apoptosis
  • Calcitonin: inhibits RANKL release, decreases osteoclast bone resorption
• Osteoblast cell signaling:
  • Parathyroid hormone (PTH) and Parathyroid-related protein (PTHrP): stimulate osteoblast differentiation and activity
  • Osteoprotegerin (OPG): binds to RANKL, stopping bone resorption

Calcium Homeostasis

• Calcium absorption: usually 30-35%, decreased with low vitamin D (10-15%)
• PTH release: stimulated by low calcium, increases osteoclast bone resorption
• Calcitonin: inhibits RANKL release, decreases osteoclast bone resorption

Osteoporosis

• Reduced bone strength and deterioration of bone tissue, increasing risk of fractures
• Most common fractures: hip, spine, wrist, and shoulder
• WHO definition: bone density < 2.5 SD below the mean for young healthy adults of the same sex (T-score of -2.5)

Clinical Assessment for Osteoporosis

• Identify risk factors
• Assess for signs of undiagnosed vertebral fracture(s)
• Risk factors:
  • Previous fracture after age 40
  • Glucocorticoids (> 3 months in the last year; prednisone dose ≥ 5 mg daily)
  • Secondary osteoporosis
  • Parent fractured hip
  • Current smoking
  • Alcohol ≥ 3 drinks/day
  • Body Mass Index < 20 kg/m²
• Recommended dietary intake:
  • Calcium-rich foods (milk products, fortified beverages, canned salmon)
  • Vitamin D-rich foods (fatty fish, fortified foods, eggs)
  • Protein-rich foods (beef, pork, chicken, fish, eggs, milk products, legumes, beans, nuts, seeds)

Exercise and Fall Prevention

• Balance and functional training, with or without resistance training can prevent falls and fractures
• Resistance and impact exercise may improve BMD
• Exercise improves physical functioning or QoL
• Balance exercises: shifting body weight, reacting to balance upset, reducing base of support
• Functional exercises: exercises that improve ability to perform daily tasks or activities
• Resistance exercises: work against resistance (e.g., squats, lunges, push-ups)

Pharmacotherapy Options

• Anti-resorptive agents:
  • Bisphosphonates (alendronate, risedronate, zoledronic acid)
  • RANKL monoclonal antibody (denosumab)
  • Selective estrogen receptor modulator (raloxifene)
• Anabolic agents:
  • Parathyroid hormone analog (teriparatide)
  • Sclerostin inhibitor (romosozumab)

Approach to Pharmacotherapy

• Bisphosphonates: first-line therapy for most people
• Denosumab: second-line option for those with contraindications or intolerance to bisphosphonates
• Anabolic therapy: for select patients with recent severe vertebral fracture or ≥ 2 vertebral fractures and T-score ≤ -2.5
• Raloxifene: last resort for postmenopausal females who are not at high risk of VTE### Contraindications and Intolerance
• Individuals who cannot take or choose not to take other suggested therapies may consider alternative treatments.

Treatment Duration - Bisphosphonates

• Initial treatment duration: 3-6 years.
• 6-year treatment duration for individuals with a history of hip, vertebral, or multiple non-vertebral fractures, or new/ongoing risk factors for accelerated bone loss.
• Assess adherence and tolerance to therapy.
• Inadequate response or ongoing concerns: extend or switch therapy, seek consultant advice.
• Stop therapy (drug holiday) and reassess after 3 years, or earlier if necessary.

Treatment Duration - Denosumab

• Long-term uninterrupted therapy with 6-month injections is recommended.
• Delaying injections by more than 1 month increases the risk of rapid bone loss and vertebral fractures.
• Therapy duration may be assessed after 6-10 years, with transition to alternative therapy if stopping.

Treatment Duration – Anabolic Therapies

• Teriparatide: daily subcut injections for up to 24 months.
• Romosuzumab: monthly subcut injections for up to 12 months.
• Consultation with an expert is required, and therapy may depend on affordability and feasibility.

Monitoring

• BMD may be repeated at a shorter interval if secondary causes of OP, new fracture, or new clinical risk factors associated with rapid bone loss are present.

Pharmacotherapy Workup

• Use risk assessment tools to determine patient's risk for fractures.
• Consider secondary drug-induced causes, nonpharmacological and pharmacological interventions.

Calcium and Vitamin D

• Calcium benefits and risks include recommending 500-700 mg/day through diet and supplementation, considering type of calcium salt and elemental Ca2+.
• Vitamin D recommendations include considering patient's 25-OH-Vit D level.

Pharmacotherapy Considerations

• Indications, common/rare side effects, contraindications, drug interactions, dosage, and administration issues should be considered.
• Effectiveness, cost, safety, convenience, frequency, and patient adherence to pharmacotherapy should be evaluated.

Summary

• Identification of OP fracture risk factors is key.
• Risk assessment tools include FRAX and CAROC.
• Investigations include biochemical and radiographic measures like BMD, spine X-ray, and VFA.
• Benefit of pharmacotherapy increases with risk.
• Bisphosphonates are first-line therapy for most, with initial duration of 3-6 years.
• Denosumab is an alternative therapy requiring long-term commitment.
• Anabolic agents are for select high-risk patients, with accessibility and feasibility limitations.
• Raloxifene is a last option for females not at high risk for VTE.
• Regular monitoring of therapy is necessary, with reassessment of BMD and fracture risk in 3 years or earlier if necessary.

Calcium and Vitamin D

• Recommended dietary allowance for calcium: 1000 mg/day for men and women aged 51-70 years, 1200 mg/day for men and women over 70 years old
• Recommended dietary allowance for vitamin D: 600 IU/day for men and women aged 51-70 years, 800 IU/day for men and women over 70 years old
• Health Canada recommends 400 IU/day of vitamin D for adults over 50 years old, in addition to dietary sources

Exercise for Fracture Prevention

• Balance and functional training with or without resistance training can prevent falls and may prevent fractures
• Resistance and impact exercise may improve bone mineral density (BMD)
• Exercise may improve physical functioning or quality of life
• Examples of balance exercises: shifting body weight to the limits of stability, reacting to things that upset one's balance, maintaining balance while moving
• Examples of functional exercises: chair stands for sit-to-stand ability, stair-climbing to train for hiking
• Examples of resistance exercises: squats, lunges, push-ups

Nonpharmacologic Interventions

• Balanced diet with a "foods first" approach
• Individualized approach may be needed, consult a dietitian
• If receiving pharmacotherapy, individualize calcium and vitamin D intake

OHIP Coverage of 25-OH Vit D Testing

• Coverage for individuals with malabsorption syndromes, osteopenia, osteoporosis, rickets, renal diseases, and medications affecting vitamin D metabolism

Risk-Based Pharmacotherapy

• Indications for pharmacotherapy: previous hip or spine fracture, or ≥ 2 fragility fracture events
• Pharmacotherapy options: anti-resorptive (bisphosphonates, RANKL monoclonal antibody, SERM) and anabolic (parathyroid hormone analog, sclerostin inhibitor) agents
• Safety and adherence issues: risks of atypical femur fracture and osteonecrosis of the jaw with long-term bisphosphonate use, bone loss and vertebral fracture risk with delayed denosumab dosing or discontinuation

Approach to Pharmacotherapy

• Bisphosphonates: first-line therapy for most people, assess adherence and tolerance
• Denosumab: second-line option, assess contraindications or substantial intolerance to, or barriers to bisphosphonates
• Anabolic agents: upfront therapy for select higher-risk patients, accessibility and feasibility may limit use
• Raloxifene: last option for women, not for individuals at high risk for venous thromboembolism

Pharmacotherapy Considerations

• Indications, efficacy, safety, cost, convenience, and patient adherence to pharmacotherapy
• Monitoring for side effects, contraindications, and drug interactions
• Initial duration of pharmacotherapy: 3-6 years, reassess to resume or stop therapy

Summary

• Identification of osteoporosis fracture risk factors is key
• Risk assessment tools: FRAX, CAROC
• Investigations: biochemical, radiographic (BMD, spine X-ray, vertebral fracture assessment)
• Bisphosphonates: first-line therapy for most, initial duration 3-6 years
• Denosumab: alternative therapy, uninterrupted long-term commitment to treatment
• Anabolic agents: upfront therapy for select higher-risk patients
• Raloxifene: last option for women
• Monitoring of therapy: regularly assess adherence, tolerability, and new risk factors