Bisphosphonate Prior to Parathyroidectomy in Primary Hyperparathyroidism

Summary

This study is a randomized, double-blinded, placebo-controlled trial investigating the effects of zoledronic acid (ZOL) versus placebo in patients with primary hyperparathyroidism (PHPT) undergoing parathyroidectomy (PTX). PHPT is a common endocrine disorder associated with hypercalcemia, reduced bone mineral density (BMD), increased fracture risk, renal calcifications, and cardiovascular complications. While PTX remains the definitive treatment, the potential role of bisphosphonates in optimizing post-surgical outcomes remains unclear. This trial aims to evaluate whether a single infusion of ZOL prior to PTX impacts bone health, cardiovascular parameters, and renal function one year post-surgery. The primary endpoint is the change in areal bone mineral density (aBMD) at the lumbar spine one year after PTX. Secondary endpoints include changes in aBMD at other skeletal sites, volumetric BMD, bone microarchitecture, bone turnover markers, coronary artery calcium score, arterial stiffness, and renal calcifications. A total of 140 postmenopausal women and men over 50 years with PHPT and low BMD will be enrolled and randomized to receive either ZOL or placebo 2-4 weeks before PTX. Participants will undergo extensive imaging, biochemical analysis, and cardiovascular assessments at baseline and one year post-surgery. This study seeks to clarify whether ZOL improves post-surgical bone recovery or interferes with the natural bone remodeling process following PTX. Additionally, it will provide insight into the cardiovascular and renal effects of bisphosphonate therapy in PHPT patients. Findings may help guide treatment strategies for optimizing long-term skeletal and systemic health in this patient population.

Timeline

Start

2025-03-01

Primary completion

2028-02-01

Completion

2028-02-01

Publications

• Background Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O'Neal L, McLeod L, Delacqua G, Delacqua F, Kirby J, Duda SN; REDCap Consortium. The REDCap consortium: Building an international community of software platform partners. J Biomed Inform. 2019 Jul;95:103208. doi: 10.1016/j.jbi.2019.103208. Epub 2019 May 9.
• Background Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009 Apr;42(2):377-81. doi: 10.1016/j.jbi.2008.08.010. Epub 2008 Sep 30.
• Background Marchini GS, Faria KVM, Torricelli FCM, Monga M, Srougi M, Nahas WC, Mazzucchi E. Sporadic primary hyperparathyroidism and stone disease: a comprehensive metabolic evaluation before and after parathyroidectomy. BJU Int. 2018 Feb;121(2):281-288. doi: 10.1111/bju.14072. Epub 2017 Nov 28.
• Background Odvina CV, Sakhaee K, Heller HJ, Peterson RD, Poindexter JR, Padalino PK, Pak CY. Biochemical characterization of primary hyperparathyroidism with and without kidney stones. Urol Res. 2007 Jun;35(3):123-8. doi: 10.1007/s00240-007-0096-2. Epub 2007 May 3.
• Background Frokjaer VG, Mollerup CL. Primary hyperparathyroidism: renal calcium excretion in patients with and without renal stone sisease before and after parathyroidectomy. World J Surg. 2002 May;26(5):532-5. doi: 10.1007/s00268-001-0262-6. Epub 2002 Feb 19.
• Background Corbetta S, Baccarelli A, Aroldi A, Vicentini L, Fogazzi GB, Eller-Vainicher C, Ponticelli C, Beck-Peccoz P, Spada A. Risk factors associated to kidney stones in primary hyperparathyroidism. J Endocrinol Invest. 2005 Feb;28(2):122-8. doi: 10.1007/BF03345354.
• Background Deaconson TF, Wilson SD, Lemann J Jr. The effect of parathyroidectomy on the recurrence of nephrolithiasis. Surgery. 1987 Dec;102(6):910-3.
• Background Mollerup CL, Vestergaard P, Frokjaer VG, Mosekilde L, Christiansen P, Blichert-Toft M. Risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study. BMJ. 2002 Oct 12;325(7368):807. doi: 10.1136/bmj.325.7368.807.
• Background Mollerup CL, Lindewald H. Renal stones and primary hyperparathyroidism: natural history of renal stone disease after successful parathyroidectomy. World J Surg. 1999 Feb;23(2):173-5; discussion 176. doi: 10.1007/pl00013175.
• Background Cooperberg MR, Duh QY, Stackhouse GB, Stoller ML. Oral calcium supplementation associated with decreased likelihood of nephrolithiasis prior to surgery for hyperparathyroidism. Int J Urol. 2007 Dec;14(12):1113-5. doi: 10.1111/j.1442-2042.2007.01904.x.
• Background Moosgaard B, Vestergaard P, Heickendorff L, Melsen F, Christiansen P, Mosekilde L. Vitamin D status, seasonal variations, parathyroid adenoma weight and bone mineral density in primary hyperparathyroidism. Clin Endocrinol (Oxf). 2005 Nov;63(5):506-13. doi: 10.1111/j.1365-2265.2005.02371.x.
• Background Starup-Linde J, Waldhauer E, Rolighed L, Mosekilde L, Vestergaard P. Renal stones and calcifications in patients with primary hyperparathyroidism: associations with biochemical variables. Eur J Endocrinol. 2012 Jun;166(6):1093-100. doi: 10.1530/EJE-12-0032. Epub 2012 Apr 3.
• Background Ejlsmark-Svensson H, Bislev LS, Rolighed L, Sikjaer T, Rejnmark L. Predictors of Renal Function and Calcifications in Primary Hyperparathyroidism: A Nested Case-Control Study. J Clin Endocrinol Metab. 2018 Sep 1;103(9):3574-3583. doi: 10.1210/jc.2018-00923.
• Background Ejlsmark-Svensson H, Rolighed L, Rejnmark L. Effect of Parathyroidectomy on Cardiovascular Risk Factors in Primary Hyperparathyroidism: A Randomized Clinical Trial. J Clin Endocrinol Metab. 2019 Aug 1;104(8):3223-3232. doi: 10.1210/jc.2018-02456.
• Background Rosa J, Raska I Jr, Wichterle D, Petrak O, Strauch B, Somloova Z, Zelinka T, Holaj R, Widimsky J Jr. Pulse wave velocity in primary hyperparathyroidism and effect of surgical therapy. Hypertens Res. 2011 Mar;34(3):296-300. doi: 10.1038/hr.2010.232. Epub 2010 Nov 25.
• Background Schillaci G, Pucci G, Pirro M, Monacelli M, Scarponi AM, Manfredelli MR, Rondelli F, Avenia N, Mannarino E. Large-artery stiffness: a reversible marker of cardiovascular risk in primary hyperparathyroidism. Atherosclerosis. 2011 Sep;218(1):96-101. doi: 10.1016/j.atherosclerosis.2011.05.010. Epub 2011 May 18.
• Background Cansu GB, Yilmaz N, Ozdem S, Balci MK, Suleymanlar G, Arici C, Boz A, Sari R, Altunbas HA. Parathyroidectomy in asymptomatic primary hyperparathyroidism reduces carotid intima-media thickness and arterial stiffness. Clin Endocrinol (Oxf). 2016 Jan;84(1):39-47. doi: 10.1111/cen.12952. Epub 2015 Oct 12.
• Background Streeten EA, Munir K, Hines S, Mohamed A, Mangano C, Ryan KA, Post W. Coronary artery calcification in patients with primary hyperparathyroidism in comparison with control subjects from the multi-ethnic study of atherosclerosis. Endocr Pract. 2008 Mar;14(2):155-61. doi: 10.4158/EP.14.2.155.
• Background Koubaity O, Mandry D, Nguyen-Thi PL, Bihain F, Nomine-Criqui C, Demarquet L, Croise-Laurent V, Brunaud L. Coronary artery disease is more severe in patients with primary hyperparathyroidism. Surgery. 2020 Jan;167(1):149-154. doi: 10.1016/j.surg.2019.05.094. Epub 2019 Oct 24.
• Background Townsend RR. Arterial stiffness and chronic kidney disease: lessons from the Chronic Renal Insufficiency Cohort study. Curr Opin Nephrol Hypertens. 2015 Jan;24(1):47-53. doi: 10.1097/MNH.0000000000000086.
• Background Meyer M, Henzler T, Fink C, Vliegenthart R, Barraza JM Jr, Nance JW Jr, Apfaltrer P, Schoenberg SO, Wasser K. Impact of coronary calcium score on the prevalence of coronary artery stenosis on dual source CT coronary angiography in caucasian patients with an intermediate risk. Acad Radiol. 2012 Nov;19(11):1316-23. doi: 10.1016/j.acra.2012.06.006. Epub 2012 Aug 14.
• Background Rubin KH, Moller S, Choudhury A, Zorina O, Kalsekar S, Eriksen EF, Andersen M, Abrahamsen B. Cardiovascular and skeletal safety of zoledronic acid in osteoporosis observational, matched cohort study using Danish and Swedish health registries. Bone. 2020 May;134:115296. doi: 10.1016/j.bone.2020.115296. Epub 2020 Feb 22.
• Background Liu S, Tan Y, Huang W, Luo H, Pan B, Wu S. Cardiovascular safety of zoledronic acid in the treatment of primary osteoporosis: A meta-analysis and systematic review. Semin Arthritis Rheum. 2024 Feb;64:152304. doi: 10.1016/j.semarthrit.2023.152304. Epub 2023 Nov 8.
• Background Kranenburg G, Bartstra JW, Weijmans M, de Jong PA, Mali WP, Verhaar HJ, Visseren FLJ, Spiering W. Bisphosphonates for cardiovascular risk reduction: A systematic review and meta-analysis. Atherosclerosis. 2016 Sep;252:106-115. doi: 10.1016/j.atherosclerosis.2016.06.039. Epub 2016 Jun 24.
• Background Reid IR, Horne AM, Mihov B, Stewart A, Garratt E, Bastin S, Gamble GD. Effects of Zoledronate on Cancer, Cardiac Events, and Mortality in Osteopenic Older Women. J Bone Miner Res. 2020 Jan;35(1):20-27. doi: 10.1002/jbmr.3860. Epub 2019 Oct 11.
• Background Billington EO, Reid IR. Benefits of Bisphosphonate Therapy: Beyond the Skeleton. Curr Osteoporos Rep. 2020 Oct;18(5):587-596. doi: 10.1007/s11914-020-00612-4.
• Background Palmer M, Adami HO, Bergstrom R, Jakobsson S, Akerstrom G, Ljunghall S. Survival and renal function in untreated hypercalcaemia. Population-based cohort study with 14 years of follow-up. Lancet. 1987 Jan 10;1(8524):59-62. doi: 10.1016/s0140-6736(87)91906-4.
• Background Ogard CG, Engholm G, Almdal TP, Vestergaard H. Increased mortality in patients hospitalized with primary hyperparathyroidism during the period 1977-1993 in Denmark. World J Surg. 2004 Jan;28(1):108-11. doi: 10.1007/s00268-003-7046-0. Epub 2003 Dec 4.
• Background Hedback G, Tisell LE, Bengtsson BA, Hedman I, Oden A. Premature death in patients operated on for primary hyperparathyroidism. World J Surg. 1990 Nov-Dec;14(6):829-35; discussion 836. doi: 10.1007/BF01670531.
• Background Ryhanen EM, Koski AM, Loyttyniemi E, Valimaki MJ, Kiviniemi U, Schalin-Jantti C. Postoperative zoledronic acid for osteoporosis in primary hyperparathyroidism: a randomized placebo-controlled study. Eur J Endocrinol. 2021 Aug 27;185(4):515-524. doi: 10.1530/EJE-21-0322.
• Background Orr LE, Zhou H, Zhu CY, Haigh PI, Adams AL, Yeh MW. Skeletal effects of combined medical and surgical management of primary hyperparathyroidism. Surgery. 2020 Jan;167(1):144-148. doi: 10.1016/j.surg.2019.04.059. Epub 2019 Sep 30.
• Background Lee IT, Sheu WH, Tu ST, Kuo SW, Pei D. Bisphosphonate pretreatment attenuates hungry bone syndrome postoperatively in subjects with primary hyperparathyroidism. J Bone Miner Metab. 2006;24(3):255-8. doi: 10.1007/s00774-005-0680-x.
• Background Choe HJ, Koo BK, Yi KH, Kong SH, Kim JH, Shin CS, Chai JW, Kim SW. Skeletal effects of combined bisphosphonates treatment and parathyroidectomy in osteoporotic patients with primary hyperparathyroidism. J Bone Miner Metab. 2022 Mar;40(2):292-300. doi: 10.1007/s00774-021-01279-2. Epub 2021 Nov 10.
• Background Sankaran S, Gamble G, Bolland M, Reid IR, Grey A. Skeletal effects of interventions in mild primary hyperparathyroidism: a meta-analysis. J Clin Endocrinol Metab. 2010 Apr;95(4):1653-62. doi: 10.1210/jc.2009-2384. Epub 2010 Feb 3.
• Background Vestergaard P, Mollerup CL, Frokjaer VG, Christiansen PM, Blichert-Toft M, Mosekilde L. [Cohort study of fracture risk before and after surgery of primary hyperparathyroidism]. Ugeskr Laeger. 2001 Sep 3;163(36):4875-8. Danish.
• Background Rolighed L, Vestergaard P, Heickendorff L, Sikjaer T, Rejnmark L, Mosekilde L, Christiansen P. BMD improvements after operation for primary hyperparathyroidism. Langenbecks Arch Surg. 2013 Jan;398(1):113-20. doi: 10.1007/s00423-012-1026-5. Epub 2012 Nov 7.
• Background Melton LJ 3rd, Atkinson EJ, O'Fallon WM, Heath H 3rd. Risk of age-related fractures in patients with primary hyperparathyroidism. Arch Intern Med. 1992 Nov;152(11):2269-73.
• Background Lundstam K, Heck A, Godang K, Mollerup C, Baranowski M, Pernow Y, Aas T, Hessman O, Rosen T, Nordenstrom J, Jansson S, Hellstrom M, Bollerslev J; SIPH Study Group. Effect of Surgery Versus Observation: Skeletal 5-Year Outcomes in a Randomized Trial of Patients With Primary HPT (the SIPH Study). J Bone Miner Res. 2017 Sep;32(9):1907-1914. doi: 10.1002/jbmr.3177. Epub 2017 Jul 7.
• Background Khosla S, Melton LJ 3rd, Wermers RA, Crowson CS, O'Fallon Wm, Riggs Bl. Primary hyperparathyroidism and the risk of fracture: a population-based study. J Bone Miner Res. 1999 Oct;14(10):1700-7. doi: 10.1359/jbmr.1999.14.10.1700.
• Background Kenny AM, MacGillivray DC, Pilbeam CC, Crombie HD, Raisz LG. Fracture incidence in postmenopausal women with primary hyperparathyroidism. Surgery. 1995 Jul;118(1):109-14. doi: 10.1016/s0039-6060(05)80017-0.
• Background Ejlsmark-Svensson H, Rolighed L, Harslof T, Rejnmark L. Risk of fractures in primary hyperparathyroidism: a systematic review and meta-analysis. Osteoporos Int. 2021 Jun;32(6):1053-1060. doi: 10.1007/s00198-021-05822-9. Epub 2021 Feb 1.
• Background Christiansen P, Steiniche T, Brixen K, Hessov I, Melsen F, Heickendorff L, Mosekilde L. Primary hyperparathyroidism: effect of parathyroidectomy on regional bone mineral density in Danish patients: a three-year follow-up study. Bone. 1999 Nov;25(5):589-95. doi: 10.1016/s8756-3282(99)00207-0.
• Background Christiansen P, Steiniche T, Brixen K, Hessov I, Melsen F, Charles P, Mosekilde L. Primary hyperparathyroidism: biochemical markers and bone mineral density at multiple skeletal sites in Danish patients. Bone. 1997 Jul;21(1):93-9. doi: 10.1016/s8756-3282(97)00078-1.
• Background Fraser WD. Hyperparathyroidism. Lancet. 2009 Jul 11;374(9684):145-58. doi: 10.1016/S0140-6736(09)60507-9.
• Background Ejlsmark-Svensson H, Bislev LS, Lajlev S, Harslof T, Rolighed L, Sikjaer T, Rejnmark L. Prevalence and Risk of Vertebral Fractures in Primary Hyperparathyroidism: A Nested Case-Control Study. J Bone Miner Res. 2018 Sep;33(9):1657-1664. doi: 10.1002/jbmr.3461. Epub 2018 Jun 7.

Drugs

Indications