What are the basics of initiating bisphosphonates (e.g. alendronate, risedronate) therapy in a patient with osteoporosis, including initial evaluation, treatment duration, and potential red flags to monitor?

Starting Bisphosphonates: A Practical Guide

Initial Evaluation Before Starting Therapy

Before prescribing bisphosphonates, you must correct vitamin D deficiency, complete any pending dental work, and verify adequate renal function. 1

Pre-Treatment Laboratory Assessment

• Check serum calcium and 25-hydroxyvitamin D levels to rule out hypocalcemia (an absolute contraindication) and vitamin D deficiency, which attenuates bisphosphonate efficacy and increases hypocalcemia risk 1
• Assess creatinine clearance: alendronate is contraindicated if CrCl <35 mL/min; consider switching to denosumab if CrCl <60 mL/min [1, @13@]
• Target vitamin D level >32 ng/mL before initiating therapy 2

Essential Pre-Treatment Steps

• Complete all dental procedures before starting therapy to minimize osteonecrosis of the jaw (ONJ) risk, which increases with cumulative bisphosphonate exposure 1
• Screen for esophageal abnormalities (stricture, achalasia) which are absolute contraindications 3, 4
• Confirm patient can stand or sit upright for at least 30 minutes after dosing 3, 4

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Choosing the Right Bisphosphonate and Dosing

Oral bisphosphonates (alendronate 70 mg weekly or risedronate 35 mg weekly) are first-line therapy for most patients. 1, 5

Standard Dosing Regimens

• Alendronate: 70 mg once weekly 4
• Risedronate: 35 mg once weekly 3
• Zoledronic acid IV: Consider for patients with adherence concerns or GI intolerance 2

Critical Administration Instructions (Non-Negotiable)

For oral bisphosphonates 3, 4:

• Take in the morning with a full glass of water (6-8 ounces) on an empty stomach
• Remain upright (standing or sitting) for 30 minutes after taking the medication
• Do not eat, drink, or take other medications during this 30-minute period
• Never chew, cut, or crush tablets
• Risedronate delayed-release: Take immediately after breakfast (not fasting) to reduce abdominal pain risk 3

Common pitfall: Improper administration is a frequent cause of treatment failure and esophageal complications 1, 2

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Mandatory Concurrent Supplementation

All patients on bisphosphonates require calcium 1,000-1,200 mg/day and vitamin D 800-1,000 IU/day throughout treatment. 1, 2, 5

• Take calcium supplements, antacids, magnesium-based products, and iron preparations at a different time of day (not with bisphosphonate) as they interfere with absorption 3
• Maintain 25(OH)D levels >32 ng/mL 2

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Monitoring During Treatment

Initial Response Assessment

Perform DXA scan at baseline, then repeat at 1-2 years to assess treatment response. 2

Expected BMD changes 2:

• Lumbar spine: 5-8% increase over 2-3 years
• Total hip: 2-5% increase over 2-3 years
• If BMD is stable or improved at 1-2 years, consider less frequent monitoring 2

Critical Monitoring Point

Do NOT perform routine BMD monitoring during the initial 5-year treatment period after confirming initial response, as fracture reduction occurs even without BMD increases 1

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Standard Treatment Duration: The 5-Year Rule

The American College of Physicians strongly recommends 5 years as the standard treatment duration for oral bisphosphonates (3 years for IV zoledronic acid). 1

Why 5 Years?

• High-certainty evidence demonstrates fracture reduction through 5 years without significant adverse events 1
• Risk of atypical femoral fractures (AFF) begins increasing significantly after 5 years, escalating sharply beyond 8 years 1
• Benefits beyond 5 years are limited to vertebral fractures only, not hip or other non-vertebral fractures 1

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Reassessment at 5 Years: Who Continues, Who Stops?

After 5 years, reassess fracture risk to determine whether to continue therapy, take a drug holiday, or switch agents. 1

Continue Treatment Beyond 5 Years If:

High-risk features present 1, 6:

• Previous hip or vertebral fracture (especially during treatment)
• Multiple non-spine fractures
• Hip BMD T-score ≤ -2.5 despite treatment
• Age >80 years
• Ongoing glucocorticoid use (≥7.5 mg prednisone daily)
• Significant bone loss (≥10% per year) despite therapy

For high-risk patients: Continue up to 10 years for oral bisphosphonates or 6 years for IV zoledronic acid, with periodic re-evaluation 1, 6

Consider Drug Holiday (2-3 Years) If:

Low-risk features present 1:

• No fractures during treatment
• Hip BMD T-score > -2.5 after treatment
• Age <80 years
• No ongoing glucocorticoid use

During Drug Holiday

• Reassess fracture risk regularly 1
• Monitor for new fractures clinically 1
• Resume bisphosphonates if: new fracture occurs, fracture risk increases significantly, or BMD declines substantially 1

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Red Flags and Serious Adverse Events

Osteonecrosis of the Jaw (ONJ)

Incidence: <1 case per 100,000 person-years with osteoporosis dosing, but increases with duration beyond 5 years 1

Risk factors 1:

• Recent dental surgery or tooth extraction (most consistent risk factor)
• Longer treatment duration
• IV bisphosphonates (higher risk than oral)

Prevention: Complete all dental work before starting therapy 1

Atypical Femoral Fractures (AFF)

Incidence: 3.0-9.8 cases per 100,000 patient-years, increasing significantly after 5 years 1

Clinical presentation 1:

• Low-energy fractures in femoral shaft (subtrochanteric or diaphyseal)
• May present with prodromal thigh pain
• Risk of contralateral fracture is 25% if one AFF occurs

Action if AFF occurs: Stop bisphosphonates immediately to reduce contralateral fracture risk 1

Important context: Despite AFF risk, an estimated 162 osteoporosis-related fractures are prevented for every one AFF associated with bisphosphonate treatment 1

Esophageal Complications

Risk factors 1, 4:

• Lying down within 30 minutes of dosing
• Taking with insufficient water
• Pre-existing esophageal disorders

Symptoms requiring immediate evaluation: Dysphagia, odynophagia, retrosternal pain, new or worsening heartburn

Atrial Fibrillation

• Some trials suggest association, but insufficient evidence to establish causality 1
• USPSTF analysis found no clear evidence of association 1

Hypocalcemia

• Correct vitamin D deficiency before initiating therapy, especially IV bisphosphonates 1
• Ensure adequate calcium and vitamin D supplementation throughout treatment 1

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Special Situations and Pitfalls

Renal Impairment

• CrCl <35 mL/min: Alendronate contraindicated [1, @13@]
• CrCl <60 mL/min: Consider switching to denosumab (no renal dose adjustment needed) 1
• IV bisphosphonates require renal monitoring and dose adjustments 1

If Patient Misses a Dose

• Take one tablet the morning after remembering 3
• Return to original weekly schedule
• Never take two tablets on the same day 3

Asian Patients

• Up to 8 times higher risk for AFF (595 vs 109 per 100,000 person-years in White patients) 1
• Consider shorter treatment duration or earlier drug holiday

Critical Warning About Denosumab

Never discontinue denosumab without immediately transitioning to bisphosphonates within 6 months, as rebound vertebral fractures occur with denosumab discontinuation 1

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When Treatment Fails: Worsening T-Scores on Therapy

If BMD declines or fractures occur despite bisphosphonates, first verify proper administration technique, then consider switching to anabolic therapy. 1

Verify Adherence and Administration

• Confirm patient takes medication correctly (upright 30 minutes, full glass water, empty stomach) 1
• Ensure adequate calcium and vitamin D supplementation 1

Consider Anabolic Therapy If:

• Multiple vertebral fractures present 1
• Fracture occurred after ≥18 months of adequate bisphosphonate treatment 1
• T-score ≤ -3.0 with additional risk factors 1
• Significant bone loss (≥10% per year) despite therapy 1