Evaluation of the tolerability of zoledronic acid preparations for parenteral administration

Introduction. From the perspective of evidence-based medicine, bisphosphonates (BP) represented by several drugs with various routes of administration and dosing regimens have been recognized as the gold standard for the treatment of osteoporosis (OP). Generic BPs are widely used for the treatment of OP due to the availability and optimal balance of cost and effectiveness.

The aim is to compare the tolerability of the generic zoledronic acid 5 mg (Osteostatics) and the original zoledronic acid 5 mg (Aclasta).

Materials and methods. A total of 54 women aged 56–65 years with postmenopausal OP were enrolled in the study and divided into two groups: 28 patients (Group 1) received intravenous infusions of Osteostatics 5 mg, 26 (Group 2) received Aclasta. Patients in both groups received concomitant therapy with calcium carbonate (1000 mg once a day) and vitamin D (2000 IU once a day). Adverse event data were collected within a week.

Results. Among side effects, it was fever that occurred most often: 57.1% in patients receiving Osteostatics (Group 1), and 61.5% in patients receiving Aclasta (Group 2). Headache occurred in 53.5% and 50% of cases, respectively. Side effects such as arthralgia and flu-like syndrome were less common and accounted for 17.8% and 15.4% of cases. Nausea only occurred in 14.2% and 11.5%, myalgia in 42.8% and 38.4%, respectively. In most cases the side effects did not last for more than 48 hours. The frequency and severity of side effects were comparable in patients with comorbidities in both groups.

Conclusion. The tolerability of the generic zoledronic acid Osteostatix at a dose of 5 mg is comparable to the original drug Aklasta.

1. Lesnyak O.M., Baranova I.A., Belova K.Yu., Gladkova E.N., Evstigneeva L.P., Ershova O.B. et al. Osteoporosis in Russian Federation: epidemiology, socio-medical and economical aspects (review). Traumatology and Orthopedics of Russia. 2018;24(1):155–168. (In Russ.) https://doi.org/10.21823/2311-2905-2018-24-1-155-168.

2. Brown J.P. Long-term treatment of postmenopausal osteoporosis. Endocrinol Metab (Seoul). 2021;36(3):544–552. https://doi.org/10.3803/EnM.2021.301.

3. Xu L.H., Adams-Huet B., Poindexter J.R., Maalouf N.M. Determinants of change in bone mineral density and fracture risk during bisphosphonate holiday. Osteoporos Int. 2016;27(5):1701–1708. https://doi.org/10.1007/s00198-015-3447-9.

4. Porter J.L., Varacallo M. Osteoporosis. Treasure Island (FL): StatPearls Publishing; 2022. Available at: https://www.ncbi.nlm.nih.gov/books/NBK441901.

5. Ran S.Y., Yu Q., Chen Y., Lin S.Q. Prevention of postmenopausal osteoporosis in Chinese women: A 5-year, double-blind, randomized, parallel placebo controlled study. Climacteric. 2017;20(4):391–396. https://doi.org/10.1080/13697137.2017.1325459.

6. Heidari M.E. Letter to the Editor about the article “A systematic review and meta-analysis of the effect of bisphosphonate drug holidays on bone mineral density and osteoporotic fracture risk”. Osteoporos Int. 2019;30(11):2355. https://doi.org/10.1007/s00198-019-05113-4.

7. Nayak S., Greenspan S.L. A systematic review and meta-analysis of the effect of bisphosphonate drug holidays on bone mineral density and osteoporotic fracture risk. Osteoporos Int. 2019;30(4):705–720. https://doi.org/10.1007/s00198-018-4791-3.

8. Jagpal A., Saag K.G. How to use bisphosphonates safely and optimally. Rheumatology (Oxford). 2018;57(11):1875–1876. https://doi.org/10.1093/rheumatology/kex384.

9. Moro Álvarez M.J., Neyro J.L., Castañeda S. Vacaciones terapéuticas en osteoporosis: estrategia en el tratamiento a largo plazo con bifosfonatos. Med Clin (Barc). 2016;146(1):24–29. https://doi.org/10.1016/j.medcli.2015.03.017.

10. Black D.M., Rosen C.J. Clinical practice. Postmenopausal osteoporosis. N Engl J Med. 2016;374(3):254–262. https://doi.org/10.1056/NEJMcp1513724.

11. Rizzoli R. Bisphosphonates for post-menopausal osteoporosis: are they all the same? QJM. 2011;104(4):281–300. https://doi.org/10.1093/qjmed/hcq259.

12. Cosman F., de Beur S.J., LeBoff M.S., Lewiecki E.M., Tanner B., Randall S., Lindsay R. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014;25(10):2359–2381. https://doi.org/10.1007/s00198-014-2794-2.

13. Svedboum A., Hernlund E., Ivergård M., Compston J., Cooper C., Stenmark J. et al. Osteoporosis in the European Union: a compendium of countryspecific reports. Arch Osteoporos. 2013;8(1):137. https://doi.org/10.1007/s11657-013-0137-0.

14. Dennison E.M., Cooper C., Kanis J.A., Bruyère O., Silverman S., McCloskey E. et al. Fracture risk following intermission of osteoporosis therapy. Osteoporos Int. 2019;30(9):1733–1743. https://doi.org/10.1007/s00198-019-05002-w.

15. Kannus P., Sievänen H., Palvanen M., Järvinen T., Parkkari J. Prevention of falls and consequent injuries in elderly people. Lancet. 2005;366(9500): 1885–1893. https://doi.org/10.1016/S0140-6736(05)67604-0.

16. Grima D.T., Papaioannou A., Airia P., Ioannidis G., Adachi J.D. Adverse events, bone mineral density and discontinuation associated with generic alendronate among postmenopausal women previously tolerant of brand alendronate: a retrospective cohort study. BMC Musculoskelet Disord. 2010;11:68. https://doi.org/10.1186/1471-2474-11-68.

17. Ström O., Landfeldt E. The association between automatic generic substitution and treatment persistence with oral bisphosphonates. Osteoporos Int. 2012;23(8):2201–2209. https://doi.org/10.1007/s00198-011-1850-4.

18. Green J.R., Müller K., Jaeggi K.A. Preclinical pharmacology of CGP 42’446, a new, potent, heterocyclic bisphosphonate compound. J Bone Miner Res. 1994;9(5):745–751. https://doi.org/10.1002/jbmr.5650090521.

19. Morin S., Lix L.M., Azimaee M., Metge C., Caetano P., Leslie W.D. Mortality rates after incident non-traumatic fractures in older men and women. Osteoporos Int. 2011;22(9):2439–2448. https://doi.org/10.1007/s00198-010-1480-2.

20. Compston J., Cooper A., Cooper C., Gittoes N., Gregson C., Harvey N. et al. UK clinical guideline for the prevention and treatment of osteoporosis. Arch Osteoporos. 2017;12(1):43. https://doi.org/10.1007/s11657-017-0324-5.

21. Black D.M., Rosen C.J. Postmenopausal osteoporosis. N Engl J Med. 2016;374(21):2096–2097. https://doi.org/10.1056/NEJMc1602599.

22. Jiang S.Y., Kaufman D.J., Chien B.Y., Longoria M., Shachter R., Bishop J.A. Prophylactic fixation can be cost-effective in preventing a contralateral bisphosphonate-associated femur fracture. Clin Orthop Relat Res. 2019;477(3):480–490. https://doi.org/10.1097/CORR.0000000000000545.

23. Black D.M., Delmas P.D., Eastell R., Reid I.R., Boonen S., Cauley J.A. et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356(18):1809–1822. https://doi.org/10.1056/NEJMoa067312.

24. Fuzzell L.N., Richards M.J., Fraenkel L., Stark S.L., Politi M.C. What information can the lay public find about osteoporosis treatment? A descriptive study coding the content and quality of bisphosphonate information on the internet. Osteoporos Int. 2019;30(11):2299–2310. https://doi.org/10.1007/s00198-019-05008-4.

25. Park-Wyllie L.Y., Mamdani M.M., Juurlink D.N., Hawker G.A., Gunraj N., Austin P.C. et al. Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA. 2011;305(8):783–789. https://doi.org/10.1001/jama.2011.190.

26. Gedmintas L., Solomon D.H., Kim S.C. Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: a systematic review and meta-analysis. J Bone Miner Res. 2013;28(8):1729–1737. https://doi.org/10.1002/jbmr.1893.

27. Shoback D., Rosen C.J., Black D.M., Cheung A.M., Murad M.H., Eastell R. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society Guideline update. J Clin Endocrinol Metab. 2020;105(3):dgaa048. https://doi.org/10.1210/clinem/dgaa048.

28. Eastell R., Walsh J.S., Watts N.B., Siris E. Bisphosphonates for postmenopausal osteoporosis. Bone. 2011;49(1):82–88. https://doi.org/10.1016/j.bone.2011.02.011.

29. Yong E.L., Logan S. Menopausal osteoporosis: screening, prevention and treatment. Singapore Med J. 2021;62(4):159–166. https://doi.org/10.11622/smedj.2021036.

30. Horikawa A., Miyakoshi N., Hongo M., Kasukawa Y., Shimada Y., Kodama H., Sano A. The effects of trends in osteoporosis treatment on the incidence of fractures. J Osteoporos. 2021:5517247. https://doi.org/10.1155/2021/5517247.

31. Wysowski D.K., Greene P. Trends in osteoporosis treatment with oral and intravenous bisphosphonates in the United States, 2002–2012. Bone. 2013;57(2):423–428. https://doi.org/10.1016/j.bone.2013.09.008.

32. Chen L.X., Zhou Z.R., Li Y.L., Ning G.Z., Zhang T.S., Zhang D., Feng S.Q. Comparison of bone mineral density in lumbar spine and fracture rate among eight drugs in treatments of osteoporosis in men: a network meta-analysis. PLoS ONE. 2015;10(5):e0128032. https://doi.org/10.1371/journal.pone.0128032 .