Acta Neurochirurgica

, Volume 160, Issue 10, pp 1909–1916 | Cite as

Ketogenic diet delays spinal fusion and decreases bone mass in posterolateral lumbar spinal fusion: an in vivo rat model

  • Qi Liu
  • Xiaomeng Wang
  • Zucheng Huang
  • Junhao Liu
  • Jianyang Ding
  • Xiaolin Xu
  • Ganggang Kong
  • Xiuhua Wu
  • Zhou Yang
  • Qingan Zhu
Original Article - Spine - Other
Part of the following topical collections:
  1. Spine - Other



Ketogenic diet (KD), a low-carbohydrate-and-high-fat diet, causes a metabolic state of ketogenesis and has been used to treat drug-resistance epilepsy. Our recent studies showed KD neuroprotective after spinal cord injury and causing bone loss. Effects of KD on spinal fusion were still unknown. This study was aimed to evaluate effects of KD on spinal fusion in rats.


Thirty-two Sprague-Dawley rats were randomly divided into KD and standard diet (SD) groups. The KD group was fed with food of 1:4 carbohydrates to fat. All rats were subjected to L4/5 posterolateral lumbar spinal fusion. The blood ketone, and serum calcium, phosphorus, and insulin-like growth factor-1 (IGF-1) were measured, as well as the fusion rates, bone mass (BV), and bone mineral contents (BMC) of fusion sites were estimated at 4 and 8 weeks.


There was no significant difference in serum calcium or phosphorus levels between groups at 4 or 8 weeks. However, there was a significant increase of blood ketone (1.02 mmol/L vs 0.38 mmol/L at 4 weeks; 0.83 mmol/L vs 0.32 mmol/L, at 8 weeks) and decrease of serum IGF-1 (339.4 ng/mL vs 630.6 ng/mL at 4 weeks; 418.8 ng/mL vs 628.6 ng/mL, at 8 weeks) in the KD group compared with the SD group. The spinal fusion occurred less in the KD group (1/16 vs 6/16 at 4 weeks; 7/16 vs 10/16, at 8 weeks), particularly at 4 weeks after surgery. The BV and BMC were lower in the KD group than that in the SD group at 4 weeks, but not different between groups at 8 weeks.


This study demonstrated that KD delayed spinal fusion and decreased bone mass in posterolateral lumbar spinal fusion in rats.


Bone fusion Bone volume Ketogenic diet Posterolateral spinal fusion Rats 



QZ, QL, and XW designed the experiments. QL, XW, ZH, and JH conducted the animal experiments. QL wrote the manuscript. XW and GK completed the data analysis, and QZ revised the manuscript.


This study was supported by the National Natural Science Foundation of China (No. 81472084) and Natural Science Foundation of Guangdong (No. 2014A030313336).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.


  1. 1.
    Aloia JF, Vaswani A, Yeh JK, Ross PL, Flaster E, Dilmanian FA (1994) Calcium supplementation with and without hormone replacement therapy to prevent postmenopausal bone loss. Ann Intern Med 120:97–103CrossRefPubMedGoogle Scholar
  2. 2.
    Beier EE, Inzana JA, Sheu TJ, Shu L, Puzas JE, Mooney RA (2015) Effects of combined exposure to lead and high-fat diet on bone quality in juvenile male mice. Environ Health Perspect 123:935–943CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Bergqvist AG, Schall JI, Stallings VA, Zemel BS (2008) Progressive bone mineral content loss in children with intractable epilepsy treated with the ketogenic diet. Am J Clin Nutr 88:1678–1684CrossRefPubMedGoogle Scholar
  4. 4.
    Bielohuby M, Matsuura M, Herbach N, Kienzle E, Slawik M, Hoeflich A, Bidlingmaier M (2010) Short-term exposure to low-carbohydrate, high-fat diets induces low bone mineral density and reduces bone formation in rats. J Bone Miner Res 25:275–284CrossRefPubMedGoogle Scholar
  5. 5.
    Boden SD, Sumner DR (1995) Biologic factors affecting spinal fusion and bone regeneration. Spine 20:102S–112SCrossRefPubMedGoogle Scholar
  6. 6.
    Bourassa-Moreau E, Mac-Thiong JM, Li A, Ehrmann Feldman D, Gagnon DH, Thompson C, Parent S (2016) Do patients with complete spinal cord injury benefit from early surgical decompression? Analysis of neurological improvement in a prospective cohort study. J Neurotrauma 33:301–306CrossRefPubMedGoogle Scholar
  7. 7.
    Brown ML, Yukata K, Farnsworth CW, Chen DG, Awad H, Hilton MJ, O'Keefe RJ, Xing L, Mooney RA, Zuscik MJ (2014) Delayed fracture healing and increased callus adiposity in a C57BL/6J murine model of obesity-associated type 2 diabetes mellitus. PLoS One 9:e99656CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Cornish J, Callon KE, Reid IR (1996) Insulin increases histomorphometric indices of bone formation in vivo. Calcif Tissue Int 59:492–495CrossRefPubMedGoogle Scholar
  9. 9.
    Cumming RG, Nevitt MC (1997) Calcium for prevention of osteoporotic fractures in postmenopausal women. J Bone Miner Res 12:1321–1329CrossRefPubMedGoogle Scholar
  10. 10.
    Dedania J, Borzio R, Paglia D, Breitbart EA, Mitchell A, Vaidya S, Wey A, Mehta S, Benevenia J, O'Connor JP, Lin SS (2011) Role of local insulin augmentation upon allograft incorporation in a rat femoral defect model. J Orthop Res 29:92–99CrossRefPubMedGoogle Scholar
  11. 11.
    Delany AM, Pash JM, Canalis E (1994) Cellular and clinical perspectives on skeletal insulin-like growth factor I. J Cell Biochem 55:328–333CrossRefPubMedGoogle Scholar
  12. 12.
    Deyo RA, Mirza SK, Martin BI, Kreuter W, Goodman DC, Jarvik JG (2010) Trends, major medical complications, and charges associated with surgery for lumbar spinal stenosis in older adults. JAMA 303:1259–1265CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Fehlings MG, Vaccaro A, Wilson JR, Singh A, Cadotte D, Harrop JS, Aarabi B, Shaffrey C, Dvorak M, Fisher C, Arnold P, Massicotte EM, Lewis S, Rampersaud R (2012) Early versus delayed decompression for traumatic cervical spinal cord injury: results of the surgical timing in acute spinal cord injury study (STASCIS). PLoS One 7:e32037CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Flouzat-Lachaniette CH, Ghazanfari A, Bouthors C, Poignard A, Hernigou P, Allain J (2014) Bone union rate with recombinant human bone morphogenic protein-2 versus autologous iliac bone in PEEK cages for anterior lumbar interbody fusion. Int Orthop 38:2001–2007CrossRefPubMedGoogle Scholar
  15. 15.
    Ghogawala Z, Whitmore RG, Watters WC 3rd, Sharan A, Mummaneni PV, Dailey AT, Choudhri TF, Eck JC, Groff MW, Wang JC, Resnick DK, Dhall SS, Kaiser MG (2014) Guideline update for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 3: assessment of economic outcome. J Neurosurg Spine 21:14–22CrossRefPubMedGoogle Scholar
  16. 16.
    Giang G, Mobbs R, Phan S, Tran TM, Phan K (2017) Evaluating outcomes of stand-alone anterior lumbar interbody fusion: a systematic review. World Neurosurg 104:259–271CrossRefPubMedGoogle Scholar
  17. 17.
    Guizzardi S, Di Silvestre M, Scandroglio R, Ruggeri A, Savini R (1992) Implants of heterologous demineralized bone matrix for induction of posterior spinal fusion in rats. Spine 17:701–707CrossRefPubMedGoogle Scholar
  18. 18.
    Guo C, Zhou J, Wu X, Jiang H, Lu K, Chen J, Wu Z, Yu R, Liu J, Zhu Q (2014) A clinical trial of ketogenic diet in patients with acute spinal cord injury: safety and feasibility. Nan Fang Yi Ke Da Xue Xue Bao 34:571–575PubMedGoogle Scholar
  19. 19.
    Kim DH, Lee N, Shin DA, Yi S, Kim KN, Ha Y (2016) Matched comparison of fusion rates between hydroxyapatite demineralized bone matrix and autograft in lumbar interbody fusion. J Korean Neurosurg Soc 59:363–367CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Koerner JD, Yalamanchili P, Munoz W, Uko L, Chaudhary SB, Lin SS, Vives MJ (2013) The effects of local insulin application to lumbar spinal fusions in a rat model. Spine J 13:22–31CrossRefPubMedGoogle Scholar
  21. 21.
    Kong G, Huang Z, Ji W, Wang X, Liu J, Wu X, Huang Z, Li R, Zhu Q (2017) The ketone metabolite beta-Hydroxybutyrate attenuates oxidative stress in spinal cord injury by suppression of class I histone deacetylases. J Neurotrauma 34:2645–2655CrossRefPubMedGoogle Scholar
  22. 22.
    Kossoff EH, Pyzik PL, McGrogan JR, Vining EP, Freeman JM (2002) Efficacy of the ketogenic diet for infantile spasms. Pediatrics 109:780–783CrossRefPubMedGoogle Scholar
  23. 23.
    Langlois JA, Rosen CJ, Visser M, Hannan MT, Harris T, Wilson PW, Kiel DP (1998) Association between insulin-like growth factor I and bone mineral density in older women and men: the Framingham heart study. J Clin Endocrinol Metab 83:4257–4262PubMedGoogle Scholar
  24. 24.
    Lenke LG, Bridwell KH, Bullis D, Betz RR, Baldus C, Schoenecker PL (1992) Results of in situ fusion for isthmic spondylolisthesis. J Spinal Disord 5:433–442CrossRefPubMedGoogle Scholar
  25. 25.
    Lumawig JM, Yamazaki A, Watanabe K (2009) Dose-dependent inhibition of diclofenac sodium on posterior lumbar interbody fusion rates. Spine J 9:343–349CrossRefPubMedGoogle Scholar
  26. 26.
    Matkovic V, Heaney RP (1992) Calcium balance during human growth: evidence for threshold behavior. Am J Clin Nutr 55:992–996CrossRefPubMedGoogle Scholar
  27. 27.
    Paoli A, Bianco A, Damiani E, Bosco G (2014) Ketogenic diet in neuromuscular and neurodegenerative diseases. Biomed Res Int 2014:474296CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Park SY, Moon SH, Park MS, Oh KS, Lee HM (2005) The effects of ketorolac injected via patient controlled analgesia postoperatively on spinal fusion. Yonsei Med J 46:245–251CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Prins ML, Fujima LS, Hovda DA (2005) Age-dependent reduction of cortical contusion volume by ketones after traumatic brain injury. J Neurosci Res 82:413–420CrossRefPubMedGoogle Scholar
  30. 30.
    Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, Zhao W, Thiyagarajan M, MacGrogan D, Rodgers JT, Puigserver P, Sadoshima J, Deng H, Pedrini S, Gandy S, Sauve AA, Pasinetti GM (2006) Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem 281:21745–21754CrossRefPubMedGoogle Scholar
  31. 31.
    Rath N, Balain B (2017) Spinal cord injury—the role of surgical treatment for neurological improvement. J Clin Orthop Trauma 8:99–102CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Rey JC (2008) History of the treatment of scoliosis. Hist Sci Med 42:21–28PubMedGoogle Scholar
  33. 33.
    Scheller EL, Khoury B, Moller KL, Wee NK, Khandaker S, Kozloff KM, Abrishami SH, Zamarron BF, Singer K (2016) Changes in skeletal integrity and marrow adiposity during high-fat diet and after weight loss. Front Endocrinol 7:102CrossRefGoogle Scholar
  34. 34.
    Shu L, Beier E, Sheu T, Zhang H, Zuscik MJ, Puzas EJ, Boyce BF, Mooney RA, Xing L (2015) High-fat diet causes bone loss in young mice by promoting osteoclastogenesis through alteration of the bone marrow environment. Calcif Tissue Int 96:313–323CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Shuid AN, Mohamad S, Mohamed N, Fadzilah FM, Mokhtar SA, Abdullah S, Othman F, Suhaimi F, Muhammad N, Soelaiman IN (2010) Effects of calcium supplements on fracture healing in a rat osteoporotic model. J Orthop Res 28:1651–1656CrossRefPubMedGoogle Scholar
  36. 36.
    Spulber G, Spulber S, Hagenas L, Amark P, Dahlin M (2009) Growth dependence on insulin-like growth factor-1 during the ketogenic diet. Epilepsia 50:297–303CrossRefPubMedGoogle Scholar
  37. 37.
    Sroga GE, Wu PC, Vashishth D (2015) Insulin-like growth factor 1, glycation and bone fragility: implications for fracture resistance of bone. PLoS One 10:e117046Google Scholar
  38. 38.
    Streijger F, Lee JH, Duncan GJ, Ng MT, Assinck P, Bhatnagar T, Plunet WT, Tetzlaff W, Kwon BK (2014) Combinatorial treatment of acute spinal cord injury with ghrelin, ibuprofen, C16, and ketogenic diet does not result in improved histologic or functional outcome. J Neurosci Res 92:870–883CrossRefPubMedGoogle Scholar
  39. 39.
    Streijger F, Plunet WT, Lee JH, Liu J, Lam CK, Park S, Hilton BJ, Fransen BL, Matheson KA, Assinck P, Kwon BK, Tetzlaff W (2013) Ketogenic diet improves forelimb motor function after spinal cord injury in rodents. PLoS One 8:e78765CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Thompson C, Feldman DE, Mac-Thiong JM (2016) Surgical management of patients following traumatic spinal cord injury: identifying barriers to early surgery in a specialized spinal cord injury center. J Spinal Cord Med 41:142–148CrossRefPubMedGoogle Scholar
  41. 41.
    Tian L, Yu X (2017) Fat, sugar, and bone health: a complex relationship. Nutrients 9Google Scholar
  42. 42.
    Vandenput L, Sjogren K, Svensson J, Ohlsson C (2012) The role of IGF-1 for fracture risk in men. Front Endocrinol 3:51CrossRefGoogle Scholar
  43. 43.
    Wang X, Liu Q, Zhou J, Wu X, Zhu Q (2017) Beta hydroxybutyrate levels in serum and cerebrospinal fluid under ketone body metabolism in rats. Exp Anim 66:177–182CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Winesett SP, Bessone SK, Kossoff EH (2015) The ketogenic diet in pharmacoresistant childhood epilepsy. Expert Rev Neurother 15:621–628CrossRefPubMedGoogle Scholar
  45. 45.
    Wu X, Huang Z, Wang X, Fu Z, Liu J, Huang Z, Kong G, Xu X, Ding J, Zhu Q (2017) Ketogenic diet compromises both cancellous and cortical bone mass in mice. Calcif Tissue Int 101:412–421CrossRefPubMedGoogle Scholar
  46. 46.
    Yamanaka JS, Yanagihara GR, Carlos BL, Ramos J, Brancaleon BB, Macedo AP, Issa JPM, Shimano AC (2017) A high-fat diet can affect bone healing in growing rats. J Bone Miner MetabGoogle Scholar
  47. 47.
    Zengin A, Kropp B, Chevalier Y, Junnila R, Sustarsic E, Herbach N, Fanelli F, Mezzullo M, Milz S, Bidlingmaier M, Bielohuby M (2016) Low-carbohydrate, high-fat diets have sex-specific effects on bone health in rats. Eur J Nutr 55:2307–2320CrossRefPubMedGoogle Scholar
  48. 48.
    Zernicke RF, Salem GJ, Barnard RJ, Schramm E (1995) Long-term, high-fat-sucrose diet alters rat femoral neck and vertebral morphology, bone mineral content, and mechanical properties. Bone 16:25–31CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  • Qi Liu
    • 1
  • Xiaomeng Wang
    • 2
  • Zucheng Huang
    • 1
  • Junhao Liu
    • 1
  • Jianyang Ding
    • 1
  • Xiaolin Xu
    • 1
  • Ganggang Kong
    • 1
  • Xiuhua Wu
    • 1
  • Zhou Yang
    • 1
  • Qingan Zhu
    • 1
  1. 1.Department of Spinal Surgery, Nanfang HospitalSouthern Medical UniversityGuangzhouChina
  2. 2.Department of Spinal SurgeryLongyan Frist HospitalLongyanChina

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