Zoledronate Slows Weight Loss and Maintains Fat Mass in Osteopenic Older Women: Secondary Analysis of a Randomized Controlled Trial


Studies in mice have suggested that osteocalcin plays an important role in glucose and fat metabolism. Since anti-resorptive drugs reduce circulating levels of osteocalcin they might be associated with increased fat mass and an increased risk of diabetes. Positive changes in body weight have been found in trials of alendronate and denosumab, but no significant effect in a previous trial of zoledronate. Whether those weight differences were in fat or lean mass is unknown. There were no effects of anti-resorptive treatments on fasting glucose concentrations or incidence of diabetes in those three studies. We have used our recent trial comparing zoledronate and placebo over 6 years in 2000 older osteopenic women to re-examine these questions. Both treatment groups lost body weight during the study (placebo 1.65 kg, zoledronate 1.05 kg), and this was significantly greater in the placebo group (P = 0.01). Both groups lost lean mass, and this loss was marginally (0.17 kg) but significantly (P = 0.02) greater in those receiving zoledronate. The placebo group had a mean loss of fat mass of 0.63 kg but there was no change in fat mass in the zoledronate group (between-groups comparison, P = 0.007). In the placebo group, there were 20 new diagnoses of diabetes, and in the zoledronate group, 19 (P = 0.87). Zoledronate prevented age-related loss of fat mass in these late postmenopausal women. The present study is the first to document a significant effect of zoledronate treatment on body weight, confirming results previously found with alendronate and denosumab. It also demonstrates that this is principally an effect to maintain fat mass rather than influencing lean mass, raising an important physiological question as to how anti-resorptive drugs have this effect on intermediary metabolism. It is possible that this anti-catabolic action contributes to the beneficial effects of anti-resorptive drugs on bone and longevity.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 199

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2
Fig. 3


  1. 1.

    Ferron M, Hinoi E, Karsenty G, Ducy P (2008) Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci USA 105:5266–5270

  2. 2.

    Ferron M, Wei JW, Yoshizawa T, Del Fattore A, DePinho RA, Teti A, Ducy P, Karsenty G (2010) Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell 142:296–308

  3. 3.

    Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Mee PJ, McKee MD, Jung DY, Zhang Z, Kim JK, Mauvais-Jarvis F, Ducy P, Karsenty G (2007) Endocrine regulation of energy metabolism by the skeleton. Cell 130:456–469

  4. 4.

    Schafer AL, Sellmeyer DE, Schwartz AV, Rosen CJ, Vittinghoff E, Palermo L, Bilezikian JP, Shoback DM, Black DM (2011) Change in undercarboxylated osteocalcin is associated with changes in body weight, fat mass, and adiponectin: parathyroid hormone (1–84) or alendronate therapy in postmenopausal women with osteoporosis (the PaTH Study). J Clin Endocrinol Metab 96:E1982–E1989

  5. 5.

    Grey A, Bolland MJ, Wattie D, Horne A, Gamble G, Reid IR (2009) The antiresorptive effects of a single dose of zoledronate persist for two years: a randomized, placebo-controlled trial in osteopenic postmenopausal women. J Clin Endocrinol Metab 94:538–544

  6. 6.

    Schwartz AV, Schafer AL, Grey A, Vittinghoff E, Palermo L, Lui L-YL, Wallace RB, Cummings SR, Black DM, Bauer DC, Reid IR (2013) Effects of antiresorptive therapies on glucose metabolism: Results from the FIT, HORIZON-PFT and FREEDOM trials. J Bone Mineral Res. 28:1348–1354

  7. 7.

    Harsløf T, Sikjær T, Sørensen L, Pedersen SB, Mosekilde L, Langdahl BL, Rejnmark L (2015) The effect of treatment with PTH on undercarboxylated osteocalcin and energy metabolism in hypoparathyroidism. J Clin Endocrinol Metab. 100:2758–2762

  8. 8.

    Reid IR, Horne AM, Mihov B, Stewart A, Garratt E, Wong S, Wiessing KR, Bolland MJ, Bastin S, Gamble GD (2018) Fracture prevention with zoledronate in older women with osteopenia. N Engl J Med 379:2407–2416

  9. 9.

    Nickerson BS, Tinsley GM, Esco MR (2019) Validity of field and laboratory three-compartment models in healthy adults. Med Sci Sports Exerc. 51:1032–1039

  10. 10.

    Yang S, Leslie WD, Morin SN, Majumdar SR, Lix LM (2016) Antiresorptive therapy and newly diagnosed diabetes in women: a historical cohort study. Diabetes Obes Metab 18:875–881

  11. 11.

    Toulis KA, Nirantharakumar K, Ryan R, Marshall T, Hemming K (2015) Bisphosphonates and glucose homeostasis: a population-based, retrospective cohort study. J Clin Endocrinol Metab 100:1933–1940

  12. 12.

    Vestergaard P (2011) Risk of newly diagnosed type 2 diabetes is reduced in users of alendronate. Calcif Tissue Int. 89:265–270

  13. 13.

    Lambert LJ, Challa AK, Niu A, Zhou L, Tucholski J, Johnson MS, Nagy TR, Eberhardt AW, Estep PN, Kesterson RA, Grams JM (2016) Increased trabecular bone and improved biomechanics in an osteocalcin-null rat model created by CRISPR/Cas9 technology. Dis Models Mech 9:1169

  14. 14.

    Catalano A, Morabito N, Basile G, Brancatelli S, Cucinotta D, Lasco A (2013) Zoledronic acid acutely increases sclerostin serum levels in women with postmenopausal osteoporosis. J Clin Endocrinol Metab 98:1911–1915

  15. 15.

    Anastasilakis AD, Polyzos SA, Gkiomisi A, Bisbinas I, Gerou S, Makras P (2013) Comparative effect of zoledronic acid versus denosumab on serum sclerostin and dickkopf-1 levels of naive postmenopausal women with low bone mass: a randomized, head-to-head clinical trial. J Clin Endocrinol Metab 98:3206–3212

  16. 16.

    Muschitz C, Kocijan R, Pahr D, Patsch JM, Amrein K, Misof BM, Kaider A, Resch H, Pietschmann P (2015) Ibandronate increases sclerostin levels and bone strength in male patients with idiopathic osteoporosis. Calcif Tissue Int 96:477–489

  17. 17.

    Gatti D, Viapiana O, Adami S, Idolazzi L, Fracassi E, Rossini M (2012) Bisphosphonate treatment of postmenopausal osteoporosis is associated with a dose dependent increase in serum sclerostin. Bone 50:739–742

  18. 18.

    Kim SP, Da H, Li Z, Kushwaha P, Beil C, Mei L, Xiong WC, Wolfgang MJ, Clemens TL, Riddle RC (2019) Lrp4 expression by adipocytes and osteoblasts differentially impacts sclerostin's endocrine effects on body composition and glucose metabolism. J Biol Chem. 294:6899–6911

  19. 19.

    Kim SP, Frey JL, Li Z, Kushwaha P, Zoch ML, Tomlinson RE, Da H, Aja S, Noh HL, Kim JK, Hussain MA, Thorek DLJ, Wolfgang MJ, Riddle RC (2017) Sclerostin influences body composition by regulating catabolic and anabolic metabolism in adipocytes. Proc Natl Acad Sci USA 114:E11238–E11247

  20. 20.

    Reid IR, Ames RW, Evans MC, Sharpe SJ, Gamble GD (1994) Determinants of the rate of bone loss in normal postmenopausal women. J Clin Endocrinol Metab 79:950–954

  21. 21.

    Johansson H, Kanis JA, Odén A, McCloskey E, Chapurlat RD, Christiansen C, Cummings SR, Diez-Perez A, Eisman JA, Fujiwara S, Glüer CC, Goltzman D, Hans D, Khaw KT, Krieg MA, Kröger H, Lacroix AZ, Lau E, Leslie WD, Mellström D, Melton Iii LJ, O'Neill TW, Pasco JA, Prior JC, Reid DM, Rivadeneira F, Van Staa T, Yoshimura N, Carola ZM (2014) A meta-analysis of the association of fracture risk and body mass index in women. J Bone Miner Res 29:223–233

  22. 22.

    Crandall CJ, Yildiz VO, Wactawski-Wende J, Johnson KC, Chen Z, Going SB, Wright NC, Cauley JA (2015) Postmenopausal weight change and incidence of fracture: post hoc findings from Women's Health Initiative Observational Study and Clinical Trials. BMJ 350:25

  23. 23.

    Wedick NM, Barrett-Connor E, Knoke JD, Wingard DL (2002) The relationship between weight loss and all-cause mortality in older men and women with and without diabetes mellitus: the Rancho Bernardo study. J Amer Geriatr Soc 50:1810–1815

  24. 24.

    Modig K, Erdefelt A, Mellner C, Cederholm T, Talbäck M, Hedström M (2019) "Obesity paradox" holds true for patients with hip fracture: a registry-based cohort study. J Bone Joint Surg Am 101:888–895

  25. 25.

    Zhang T, Lary CW, Zullo AR, Lee Y, Daiello L, Kiel DP, Berry SD (2019) Post-hip fracture mortality in nursing home residents by obesity status. J Am Geriatr Soc (in press)

Download references


The authors are grateful to Leanne Purvis for her contributions to trial organization and conduct.

Author information

Correspondence to Ian R. Reid.

Ethics declarations

Conflict of interest

This trial was funded by grants from the Health Research Council of New Zealand. Trial medication was supplied by Novartis. Dr Reid has received honoraria and/or research grants from Amgen, Merck, Lilly and Novartis. Anne M. Horne, Borislav Mihov, Angela Stewart, Sonja Bastin, and Gregory D. Gamble have nothing to disclose.

Human and Animal Rights and Informed Consent

The trial was approved by the regional Health and Disability Ethics Committee, and all participants provided written informed consent.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Reid, I.R., Horne, A.M., Mihov, B. et al. Zoledronate Slows Weight Loss and Maintains Fat Mass in Osteopenic Older Women: Secondary Analysis of a Randomized Controlled Trial. Calcif Tissue Int (2020) doi:10.1007/s00223-019-00653-7

Download citation


  • Bisphosphonates
  • Weight
  • Fat mass
  • Lean mass
  • Osteoporosis