Bisphosphonate

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Contents 1 More Specific Terms 2 Introduction 3 Indications 4 Contraindications 5 Dosage 6 Pharmacokinetics 7 Monitor 8 Adverse-effects 9 Mechanism-of-action 10 Notes 11 More General Terms 12 References

More Specific Terms

• alendronate (Fosamax, Fosamax Plus D)
• clodronate; clodronic acid (Clodronsaeure, Clasteon, Bonefos, Loron)
• etidronate (Didronel)
• ibandronate; ibandronic acid (Boniva, Bondronat)
• pamidronate (Aredia)
• risedronate (Actonel)
• tiludronate (Skelid)
• zoledronate (Zometa, Reclast)

Introduction

• Group of compounds that bind to hydroxyapatite & inhibits osteoclast activity.

Indications

• osteoporosis

• post- menopausal women
• chronic glucocorticoid use, > 5 mg/day ( prednisone) for more than 3 months [8]
• androgen-deprivation therapy for prostate cancer

• excessive or disordered osteoclastic activity associated with

• Paget's disease of bone
• hypercalcemia

Contraindications

• (cautions)
• limit therapy to 3-5 years (saturation of benefit) [3,9]
• use with caution in premenopausal women [8]

Dosage

• separate from calcium supplement
• duration of therapy: 3-5 years for most patients [12,17]
• 5 years for alendronate, 3 years for zolendronate [17]*
• risk of vertebral fractures may be diminished with continuation of bisphosphonate therapy > 5 years [17]
• no data to support continued bisphosphonate therapy > 5 years for risk reduction of hip fracture [17]
  

• * bone loss after discontinuation of therapy may be greater for risedronate than alendronate or zolendronate [17]
• * no data to guide duration of ibandronate therapy

Pharmacokinetics

• poorly absorbed orally, 1-5% of oral dose

• food interferes with absorption

• plasma 1/2life of 1 hour
• eliminated in urine (80%)
• 20% of absorbed dose taken up by bone
• bisphosphonate may persist in bone for lifetime

Monitor

• routine monitoring of bone mineral density after initiating bisphosphonate therapy is costly & unwarranted [7]

Adverse-effects

• nausea/vomiting [15]
• erosive esophagitis
• ocular inflammation

• conjunctivitis, blurred vision, eye pain (uncommon)
• uveitis ( RR=1.45) & scleritis ( RR=1.51) [16]

• osteonecrosis of the jaw (especially IV administration) [2]
• inhibition of normal bone repair of microdamage that occurs during activities of daily living [3]
• long-term therapy may increase risk of minimal trauma fractures of the femur [9,10]
• severe joint pain [6]
• after 3-5 years of bisphosphonate therapy, risk may exceed benefit [12]*
  

• * American Board of Internal Medical appears to endorse long term bisphosphonate use, citing [14]
  

• drug adverse effects of bisphosphonates

Mechanism-of-action

• bind to hydroxyapatite & inhibits osteoclast activity
• reduces osteoclast number
• stimulates formation of osteoblast precursors
• 97% of patients show clinically beneficial increases in bone mineral density at the hip density after 3 years of treatment

Notes

• possible association with bisphosphonates & reduced risk of breast cancer [11]
• bisphosphonate use is associated with a lower rate of revision after hip arthroplasty & knee arthroplasty & longer implant survival [14]

More General Terms

• endocrine agent

References

1. Prescriber's Letter 10(5):26 2003
2. Prescriber's Letter 12(5): 2005 Bisphosphonate-associated Jaw Osteonecrosis Detail-Document#: [1] (subscription needed) [2]
   - Favia G et al. Osteonecrosis of the jaw correlated to bisphosphonate therapy in non-oncologic patients: Clinicopathological features of 24 patients. J Rheumatol 2009 Dec; 36:2780 [3] PMID: [4]
3. Journal Watch 25(9):69, 2005 Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab. 2005 Mar;90(3):1294-301. Epub 2004 Dec 14. PMID: [5]
   - Ott SM. Long-term safety of bisphosphonates. J Clin Endocrinol Metab. 2005 Mar;90(3):1897-9. PMID: [6]
4. UpToDate 13.3 [7]
5. Use of Bisphosphonates In Metabolic Bone Diseases [8]
6. FDA MedWatch [9]
7. Bell KJL Value of routine monitoring of bone mineral density after starting bisphosphonate treatment: secondary analysis of trial data BMJ 2009;338:b2266 [10]
8. Medical Knowledge Self Assessment Program (MKSAP) 15, American College of Physicians, Philadelphia 2009
9. Prescriber's Letter 16(12): 2009 Safety of Long-Term Bisphosphonate Therapy COMMENTARY: Safety of Long-Term Bisphosphonate Therapy GUIDELINES: Prevention and Treatment of Osteoporosis (NOF) GUIDELINES: Diagnosis and Treatment of Osteoporosis (ICSI) GUIDELINES: NAMS Position Statement on the Management of Osteoporosis in Postmenopausal Women GUIDELINES: Prevention and Treatment of Postmenopausal Osteoporosis (AACE) GUIDELINES: Menopause and Osteoporosis Update (Canadian) Detail-Document#: [11] (subscription needed) [12]
10. Capeci CM and Tejwani NC. Bilateral low-energy simultaneous or sequential femoral fractures in patients on long-term alendronate therapy. J Bone Joint Surg Am 2009 Nov; 91:2556. PMID: &dopt=Abstract
    - Lenart BA et al. Association of low-energy femoral fractures with prolonged bisphosphonate use: A case control study. Osteoporos Int 2009 Aug; 20:1353. PMID: [13]
11. Prescriber's Letter 17(1): 2010 Bisphosphonates and Breast Cancer Prevention Detail-Document#: [14] (subscription needed) [15]
12. Park-Wyllie LY Bisphosphonate Use and the Risk of Subtrochanteric or Femoral Shaft Fractures in Older Women JAMA. 2011;305(8):783-789 <PubMed> PMID: [16] <Internet> [17]
    - Prescriber's Letter 18(11): 2011 COMMENTARY: Safety of Long-Term Bisphosphonate Therapy PATIENT HANDOUT: What I Need to Know About My Bisphosphonate PATIENT HANDOUT SPANISH VERSION: Lo Que Necesito Saber Acerca De Mi Bifosfonato Detail-Document#: [18] (subscription needed) [19]
13. Prieto-Alhambra D et al. Association between bisphosphonate use and implant survival after primary total arthroplasty of the knee or hip: Population based retrospective cohort study. BMJ 2011 Dec 6; 343:d7222 PMID: [20]
14. Favus MJ. Bisphosphonates for osteoporosis. N Engl J Med 2010; 363:2027-2035. PMID: [21]
15. Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010
16. Etminan M et al Inflammatory ocular adverse events with the use of oral bisphosphonates: a retrospective cohort study CMAJ April 2, 2012 <PubMed> PMID: [22] <Internet> [23]
17. Whitaker M et al Bisphosphonates for Osteoporosis — Where Do We Go from Here? N Engl J Med 2012 May 9, <PubMed> PMID: [24] <Internet> [25]
    - Black DM et al Continuing Bisphosphonate Treatment for Osteoporosis — For Whom and for How Long? N Engl J Med 2012 May 9, <PubMed> PMID: [26] <Internet> [27]
18. National Guideline Clearinghouse
    - The use of bisphosphonates in men with hormone-refractory prostate cancer. (Practice Guidelines Initiative) ngc-guideline: [28]

bisphosphonate