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zoledronate (Zometa, Reclast)

Indications: - hypercalcemia of malignancy (treatment of choice) [20] - osteoporosis (quarterly-yearly)* - secondary prevention of hip fracture [9] - increase in bone mineral density at the lumbar spine & femoral neck [13] - osteolytic bone lesions of multiple myeloma [16] - Paget's disease of bone [5] * yearly IV zoledronate generally approved by Medicare only if contraindications to oral bisphosphates (dysphagia, esophageal stricture, GERD requiring daily PPI) [20] Contraindications: - creatinine clearance < 35 ml/min - renal failure or worsening renal function* - radiographic evidence of tooth abscess [25] - vitamin D deficiency (osteoporosis) * see notes Benefit/risk: - 1 dose of IV zoledronate in frail elderly women in nursing homes or assisted living with osteoporosis [18] - improves bone mineral density - non-significant increase in bone fractures & mortality - lowers risk for fragility fractures in postmenopausal women with osteopenia ((22 vs 39 per 1000 person-years) [23] - NNT: 15 women for 6 years to prevent one fragility fracture - zoledronate every other year reduced overall fractures in elderly women, but not hip fractures [23] Dosage: 1) 0.25-5 mg IV, given over 15 minutes 2) osteoporosis: 4-5 mg/year divided quarterly to yearly a) duration of therapy 3 years for most patients [15] b) reassess fracture risk after 3 years* c) risk of vertebral fracture may be diminished with therapy continued longer than 3 years [15] 3) Paget's disease: 5 mg IV once, every 6 months? [5] * dental examination prior to administration * correct vitamin D deficiency prior to administration for osteoporosis * risk for subsequent osteoporotic fracture during the following 3 years is low if Z score > -2.5, no recent fracture & no more than 1 risk factor [17] Pharmacokinetics: - eliminated in the urine Dosage adjustment in renal failure: - monitor serum creatinine before each dose [3] - measure serum cystatin C/creatine ratio if frailty/sarcopenia (not directly affected by muscle mass) eGFR Dosage > 60 mL/min 4.0 mg 55-60 mL/min 3.5 mg 40-49 mL/min 3.3 mg 35-39 mL/min 3.0 mg Adverse effects: 1) nausea 2) myalgia 3) fever 4) osteonecrosis of the jaw* 5) serious atrial fibrillation (1%) [8] 6) reports of acute renal failure [12,14] 7) transient hypocalcemia may occur, treat vitamin D deficiency 8) pyrexia & myalgias may occur after the 1st dose, but does not usually recur [26] *dental consultation - no active oral infection - biannual dental care for - teeth cleaning - minizing periodontal inflammation - addressing caries - endodontic care for non restorable teeth Mechanism of action: 1) inhibits bone resorption 2) may reduce bone pain & fractures in patients with bone metastases 3) more effective than pamidronate 4) as effective as residronate [11] 5) diminishes risk of hip fractures, vertebral fractures & other factures [19] Notes: - cost $1000/dose 2007 - GRS9 describes 69 yo man with weight loss of 9 kg due to lung cancer with hypercalcemia of malignancy, serum creatinine of 1.9 mg/dL, no weight given; if his weight was 60 kg (132 lbs) calculated creatinine clearance would be 31 mL/min & zoledronate would be contraindicated according to the standard above; yet zoledronate was recommended (GRS9) [20]

Interactions

drug interactions drug adverse effects of bisphosphonates

Related

hypercalcemia

General

bisphosphonate

Database Correlations

PUBCHEM correlations

References

  1. Prescriber's Letter 8(9):53 2001
  2. Journal Watch 22(7):53, 2002 Reid et al, N Engl J Med 346:653, 2002
  3. FDA Safteywatch http://www.fda.gov/medwatch/SAFETY/2005/safety05.htm#Zometa
  4. FDA Safteywatch http://www.fda.gov/medwatch/SAFETY/2005/safety05.htm#zometa2
  5. Reid IR et al, Comparison of a single infusion of zoledronic acid with risedronate for Paget's disease. N Engl J Med 2005 Sep 1; 353:898-908 PMID: 16135834
  6. Prescriber's Letter 14(6): 2007 New Developments With Bisphosphonate Therapy Detail-Document#: 230613 (subscription needed) http://www.prescribersletter.com
  7. Prescriber's Letter 14(9): 2007 Once-yearly Osteoporosis Treatment and Other Bisphosphonate Developments PATIENT HANDOUT: Bisphosphonates and Jaw Bone Damage INFORMATION FOR DENTISTS: American Dental Association recommendations for patients taking oral bisphosphonates RECLAST FOR OSTEOPOROSIS Detail-Document#: 230902 (subscription needed) http://www.prescribersletter.com
  8. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR; HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007 May 3;356(18):1809-22. PMID: 17476007
  9. Lyles KW et al, Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007 357:[ePub] http://dx.doi.org/10.1056/NEJMoa74941 PMID: 17878149
  10. Prescriber's Letter 14(11): 2007 Zoledronic Acid (Reclast) After an Initial Hip Fracture Detail-Document#: 231114 (subscription needed) http://www.prescribersletter.com
  11. Reid DM et al, Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomised controlled trial Lancet 2009 373:1253-1263, 11 April 2009 PMID: 19362675
  12. FDA Drug Safety Newsletter - Volume 2, Number 2, 2009 http://www.fda.gov/Drugs/DrugSafety/DrugSafetyNewsletter/ucm167843.htm
  13. McClung M et al. Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: A randomized controlled trial. Obstet Gynecol 2009 Nov; 114:999. PMID: 20168099
  14. FDA MedWatch 09/01/11 Reclast (zoledronic acid): Drug Safety Communication - New Contraindication and Updated Warning on Kidney Impairment http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm270464.htm
  15. Whitaker M et al Bisphosphonates for Osteoporosis - Where Do We Go from Here? N Engl J Med 2012 May 9, PMID: 22571168 http://www.nejm.org/doi/full/10.1056/NEJMp1202619 - Black DM et al Continuing Bisphosphonate Treatment for Osteoporosis - For Whom and for How Long? N Engl J Med 2012 May 9, PMID: 22571169 http://www.nejm.org/doi/full/10.1056/NEJMp1202623
  16. Deprecated Reference
  17. Cosman F et al. Reassessment of fracture risk in women after 3 years of treatment with zoledronic acid: When is it reasonable to discontinue treatment? J Clin Endocrinol Metab 2014 Dec; 99:4546 PMID: 25215556
  18. Greenspan SL et al Efficacy and Safety of Single-Dose Zoledronic Acid for Osteoporosis in Frail Elderly WomenA Randomized Clinical Trial. JAMA Intern Med. Published online April 13, 2015 PMID: 25867538 http://archinte.jamanetwork.com/article.aspx?articleid=2247163 - Lindsay R Osteoporosis Treatment and Fracture Outcomes. JAMA Intern Med. Published online April 13, 2015 PMID: 25866943 http://archinte.jamanetwork.com/article.aspx?articleid=2247159
  19. Reid IR Efficacy, effectiveness and side effects of medications used to prevent fractures. J Intern Med. 2015 Jun;277(6):690-706 PMID: 25495429
  20. Geriatric Review Syllabus, 9th edition (GRS9) Medinal-Walpole A, Pacala JT, Porter JF (eds) American Geriatrics Society, 2016
  21. Maricic M. Intravenous zoledronic acid: what are the indications for male osteoporosis? Curr Osteoporos Rep. 2010 Mar;8(1):4-9. PMID: 20425084
  22. Maricic M. The role of zoledronic acid in the management of osteoporosis. Clin Rheumatol. 2010 Oct;29(10):1079-84. Review. PMID: 20544246
  23. Reid IR, Horne AM, Mihov B et al Fracture Prevention with Zoledronate in Older Women with Osteopenia. N Engl J Med 2018;379:2407-2416. Oct 1, 2018 Not indexed in PubMed. Published Online. https://www.nejm.org/doi/full/10.1056/NEJMoa1808082 - Rosen CJ A Not-So-New Treatment for Old Bones. N Engl J Med. Oct 1, 2018 PMID: 30273092 DOI: Free full text https://www.nejm.org/doi/full/10.1056/NEJMe1812434
  24. Kaur U, Chakrabarti SS, Gambhir IS. Zoledronate Induced Hypocalcemia and Hypophosphatemia in Osteoporosis: A Cause of Concern. Curr Drug Saf. 2016;11(3):267-9. PMID: 27113952
  25. Geriatric Review Syllabus, 10th edition (GRS10) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2019
  26. Medical Knowledge Self Assessment Program (MKSAP) 19 American College of Physicians, Philadelphia 2022
  27. An JN, Kim JK, Lee HS, Kim SG, Kim HJ, Song YR. Serum cystatin C to creatinine ratio is associated with sarcopenia in non-dialysis-dependent chronic kidney disease. Kidney Res Clin Pract. 2022 Sep;41(5):580-590. PMID: 35791742 PMCID: PMC9576455 Free PMC article.