Skip to main content

Advertisement

SpringerLink
Log in

Effects of teriparatide and low-intensity aerobic exercise on osteopenia in type 2 diabetes mellitus rats

  • Original Article
  • Published:
Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Introduction

In patients with type 2 diabetes mellitus (T2DM), bone fragility increases fracture risk. Teriparatide (TPTD) improves bone strength, and exercise therapy suppresses blood glucose levels in T2DM. In this study, the combined effects of TPTD and exercise therapy on trabecular and cortical bone were examined in advanced T2DM model rats.

Materials and methods

Thirty-week-old Otsuka Long–Evans Tokushima Fatty rats were divided into four groups (n = 9–10 in each group at two time points): Cont group (vehicle-treated control), TPTD group (TPTD 30 μg/kg injected subcutaneously, 3 times/week), Exe group (treadmill exercise, 10 m/min, 60 min/day, 5 times/week), and Comb group (TPTD-treated and treadmill exercise combined). Five and 10 weeks after treatment, bone mineral density (BMD), bone strength, and bone micro-architecture were measured.

Results

TPTD and combined treatment significantly increased BMDs of the lumbar spine and femur compared to the Cont group (p < 0.05 to p < 0.01). In the three-point bending test of the femur, only combined treatment increased the maximum load at 5 weeks compared with the Cont and Exe groups (p < 0.01). In the compression test of the distal femoral metaphysis, both TPTD and combined treatment increased the trabecular bone strength compared with the Cont and Exe groups (p < 0.05 to p < 0.01). Although TPTD and combined treatment improved the micro-architecture of trabecular bone (p < 0.05 to p < 0.01), only combined treatment improved the micro-structures of cortical bone from 5 weeks of treatment (p < 0.05 to p < 0.01).

Conclusion

The combination of TPTD and treadmill exercise increased BMD and trabecular and cortical bone strength of the femur with improved micro-architecture in T2DM model rats.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. IDF Diabetes Atlas 9th edition 2019. https://www.diabetesatlas.org/en/. Accessed 8 May 2021

  2. Vestergaard P (2007) Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes—a meta-analysis. Osteoporos Int 18:427–444

    Article  CAS  Google Scholar 

  3. Janghorbani M, Van Dam RM, Willett WC, Hu FB (2007) Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol 166:495–505

    Article  Google Scholar 

  4. Wang J, You W, Jing Z, Wang R, Fu Z, Wang Y (2016) Increased risk of vertebral fracture in patients with diabetes: a meta-analysis of cohort studies. Int Orthop 40:1299–1307

    Article  Google Scholar 

  5. Bliuc D (2009) Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women. JAMA 301:513

    Article  CAS  Google Scholar 

  6. Center JR, Nguyen TV, Schneider D, Sambrock PN, Eisman JA (1999) Mortality after all major types of osteoporotic fracture in men and women: an observational study. Lancet 353:878–882

    Article  CAS  Google Scholar 

  7. Borrelli J Jr, Pape C, Hak D, Hsu J, Lin S, Giannoudis P, Lane J (2012) Physiological challenges of bone repair. J Orthop Trauma 26:708–711

    Article  Google Scholar 

  8. Cauley JA, Blackwell T, Zmuda JM, Fullman RL, Ensrud KE, Stone KL, Barrett-Connor E, Orwoll ES, Osteoporotic Fractures in Men Study (2010) Correlates of trabecular and cortical volumetric bone mineral density at the femoral neck and lumbar spine: the osteoporotic fractures in men study (MrOS). J Bone Miner Res 25:1958–1971

    Article  Google Scholar 

  9. Farr JN, Khosla S (2016) Determinants of bone strength and quality in diabetes mellitus in humans. Bone 82:28–34

    Article  CAS  Google Scholar 

  10. Nakamura T, Sugimoto T, Nakano T, Kishimoto H, Ito M, Fukunaga M, Hagino H, Sone T, Yoshikawa H, Nishizawa Y, Fujita T, Shiraki M (2012) Randomized Teriparatide [human parathyroid hormone (PTH) 1–34] Once-Weekly Efficacy Research (TOWER) trial for examining the reduction in new vertebral fractures in subjects with primary osteoporosis and high fracture risk. J Clin Endocrinol Metab 97:3097–3106

    Article  CAS  Google Scholar 

  11. Garnero P, Bauer DC, Mareau E, Bilezikian JP, Greenspan SL, Rosen C, Black D (2008) Effects of PTH and alendronate on type I collagen isomerization in postmenopausal women with osteoporosis: the PaTH study. J Bone Miner Res 23:1442–1448

    Article  CAS  Google Scholar 

  12. Kelley GA, Kelley KS (2007) Effects of aerobic exercise on lipids and lipoproteins in adults with type 2 diabetes: a meta-analysis of randomized-controlled trials. Public Health 121:643–655

    Article  CAS  Google Scholar 

  13. Umpierre D (2011) Physical activity advice only or structured exercise training and association with HbA 1c levels in type 2 diabetes: a systematic review and meta-analysis. JAMA 305:1790

    Article  CAS  Google Scholar 

  14. Bonaiuti D, Shea B, Iovine R, Negrini S, Robinson V, Kemper HC, Wells G, Tugwell P, Cranney A (2002) Exercise for preventing and treating osteoporosis in postmenopausal women. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD000333

    Article  PubMed  Google Scholar 

  15. Wallace BA, Cumming RG (2000) Systematic review of randomized trials of the effect of exercise on bone mass in pre- and postmenopausal women. Calcif Tissue Int 67:10–18

    Article  CAS  Google Scholar 

  16. Papaioannou A, Adachi JD, Winegard K, Ferko N, Parkinson W, Cook RJ, Webber C, McCartney N (2003) Efficacy of home-based exercise for improving quality of life among elderly women with symptomatic osteoporosis-related vertebral fractures. Osteoporos Int 14:677–682

    Article  CAS  Google Scholar 

  17. Sakamoto K, Endo N, Harada A, Sakada T, Tsushita K, Kita K, Hagino H, Sakai A, Yamamoto N, Okamoto T, Liu M, Kokaze A, Suzuki H (2013) Why not use your own body weight to prevent falls? A randomized, controlled trial of balance therapy to prevent falls and fractures for elderly people who can stand on one leg for ≤ 15s. J Orthop Sci 18:110–120

    Article  Google Scholar 

  18. Hamann C, Picke AK, Campbell GM, Balyura M, Rauner M, Bernhardt R, Huber G, Morlock MM, Günther KP, Bornstein SR, Glüer CC, Ludwig B, Hofbauer LC (2014) Effects of parathyroid hormone on bone mass, bone strength, and bone regeneration in male rats with type 2 diabetes mellitus. Endocrinology 155:1197–1206

    Article  Google Scholar 

  19. Sato C, Miyakoshi N, Kasukawa Y, Nozaka K, Tsuchie H, Nagahata I, Yuasa Y, Abe K, Saito H, Shoji R, Shimada Y (2021) Teriparatide and exercise improve bone, skeletal muscle, and fat parameters in ovariectomized and tail-suspended rats. J Bone Miner Metab 39:385–395

    Article  CAS  Google Scholar 

  20. Roberts MD, Santner TJ, Hart RT (2009) Local bone formation due to combined mechanical loading and intermittent hPTH-(1–34) treatment and its correlation to mechanical signal distributions. J Biomech 42:2431–2438

    Article  CAS  Google Scholar 

  21. Li J, Duncan RL, Burr DB, Gattone VH, Turner CH (2003) Parathyroid hormone enhances mechanically induced bone formation, possibly involving l-type voltage-sensitive calcium channels. Endocrinology 144:1226–1233

    Article  CAS  Google Scholar 

  22. Jepsen DB, Ryg J, Hansen S, Jørgensen NR, Gram J, Masud T (2019) The combined effect of parathyroid hormone (1–34) and whole-body vibration exercise in the treatment of postmenopausal OSteoporosis (PaVOS study): a randomized controlled trial. Osteoporos Int 30:1827–1836

    Article  CAS  Google Scholar 

  23. Kinoshita H, Miyakoshi N, Kasukawa Y, Sakai S, Shiraishi A, Segawa T, Ohuchi K, Fujii M, Sato C, Shimada Y (2016) Effects of eldecalcitol on bone and skeletal muscles in glucocorticoid-treated rats. J Bone Miner Metab 34:171–178

    Article  CAS  Google Scholar 

  24. Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M, Natori T (1992) Spontaneous long-term hyperglycemic rat with diabetic complications: Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes 41:1422–1428

    Article  CAS  Google Scholar 

  25. Takakura A, Lee JW, Hirano K, Isogai Y, Ishizuya T, Takao-Kawabata R, Iimura T (2017) Administration frequency as well as dosage of PTH are associated with development of cortical porosity in ovariectomized rats. Bone Res 5:1–14

    Article  Google Scholar 

  26. Akagawa M, Miyakoshi N, Kasukawa Y, Ono Y, Yuasa Y, Nagahata I, Sato C, Tsuchie H, Nagasawa H, Hongo M, Shimada Y (2018) Effects of activated vitamin D, alfacalcidol, and low-intensity aerobic exercise on osteopenia and muscle atrophy in type 2 diabetes mellitus model rats. PLoS ONE 13:e0204857

    Article  Google Scholar 

  27. Kawano T, Miyakoshi N, Kasukawa Y, Hongo M, Tsuchie H, Sato C, Fujii M, Suzuki M, Akagawa M, Ono Y, Yuasa Y, Nagahata I, Shimada Y (2017) Effects of combined therapy of alendronate and low-intensity pulsed ultrasound on metaphyseal bone repair after osteotomy in the proximal tibia of glucocorticoid-induced osteopenia rats. Osteoporos Sarcopenia 3:185–191

    Article  Google Scholar 

  28. Miyakoshi N, Fujii M, Kasukawa Y, Shimada Y (2019) Impact of vitamin C on teriparatide treatment in the improvement of bone mineral density, strength, and quality in vitamin C-deficient rats. J Bone Miner Metab 37:411–418

    Article  CAS  Google Scholar 

  29. Jepsen KJ, Silva MJ, Vashishth D, Guo XE, van der Meulen MC (2015) Establishing biomechanical mechanisms in mouse models: practical guidelines for systematically evaluating phenotypic changes in the diaphyses of long bones. J Bone Miner Res 30:951–966

    Article  Google Scholar 

  30. Kasukawa Y, Miyakoshi N, Itoi E, Tsuchida T, Tamura Y, Kudo T, Suzuki K, Seki A, Sato K (2004) Effects of h-PTH on cancellous bone mass, connectivity, and bone strength in ovariectomized rats with and without sciatic-neurectomy. J Orthop Res 22:457–464

    Article  CAS  Google Scholar 

  31. Murata K, Yano E (2002) Medical statistics for evidence-based medicine with SPBS user’s guide. Nankodo, Tokyo

    Google Scholar 

  32. Moustafa A, Sugiyama T, Prasad J, Zaman G, Gross TS, Lanyon LE, Price JS (2012) Mechanical loading-related changes in osteocyte sclerostin expression in mice are more closely associated with the subsequent osteogenic response than the peak strains engendered. Osteoporos Int 23:1225–1234

    Article  CAS  Google Scholar 

  33. Ortinau LC, Linden MA, Dirkes RK, Rector RS, Hinton PS (2017) Exercise initiated after the onset of insulin resistance improves trabecular microarchitecture and cortical bone biomechanics of the tibia in hyperphagic Otsuka Long Evans Tokushima Fatty rats. Bone 103:188–199

    Article  CAS  Google Scholar 

  34. Minematsu A, Hanaoka T, Takeshita D, Takada Y, Okuda S, Imagita H, Sakata S (2017) Long-term wheel-running can prevent deterioration of bone properties in diabetes mellitus model rats. J Musculoskelet Neuronal Interact 17:433–443

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Kimura S, Sasase T, Ohta T, Sato E, Matsushita M (2012) Parathyroid hormone (1–34) improves bone mineral density and glucose metabolism in spontaneously diabetic Torii-Lepr(fa) rats. J Vet Med Sci 74:103–105

    Article  CAS  Google Scholar 

  36. Nomura S, Kitami A, Takao-Kawabata R, Takakura A, Nakatsugawa M, Kono R, Maeno A, Tokuda A, Isogai Y, Ishizuya T, Utsunomiya H, Nakamura M (2019) Teriparatide improves bone and lipid metabolism in a male rat model of type 2 diabetes mellitus. Endocrinology 160:2339–2352

    Article  CAS  Google Scholar 

  37. Ohuchi K, Miyakoshi N, Kasukawa Y, Segawa T, Kinoshita H, Sato C, Fujii M, Shimada Y (2019) Effects of teriparatide on bone in autochthonous transgenic model mice for diabetes mellitus (Akita mice). Osteoporos Sarcopenia 5:109–115

    Article  Google Scholar 

  38. Suzuki K, Miyakoshi N, Tsuchida T, Kasukawa Y, Sato K, Itoi E (2003) Effects of combined treatment of insulin and human parathyroid hormone (1–34) on cancellous bone mass and structure in streptozotocin-induced diabetic rats. Bone 33:108–114

    Article  CAS  Google Scholar 

  39. Sugiyama T, Saxon LK, Zaman G, Moustafa A, Sunters A, Price JS, Lanyon LE (2008) Mechanical loading enhances the anabolic effects of intermittent parathyroid hormone (1–34) on trabecular and cortical bone in mice. Bone 43:238–248

    Article  CAS  Google Scholar 

  40. Gardinier JD, Mohamed F, Kohn DH (2015) PTH signaling during exercise contributes to bone adaptation. J Bone Miner Res 30:1053–1063

    Article  CAS  Google Scholar 

  41. Gardinier JD, Daly-Seiler C, Rostami N, Kundal S, Zhang C (2019) Loss of the PTH/PTHrP receptor along the osteoblast lineage limits the anabolic response to exercise. PLoS ONE 14:e0211076

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Asahi Kasei Pharma Corporation for providing TPTD and Ms. Kudo for her support of our experiments.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita, 010-8543, Japan

    Kazunobu Abe, Naohisa Miyakoshi, Yuji Kasukawa, Koji Nozaka, Hiroyuki Tsuchie, Chiaki Sato, Hikaru Saito, Ryo Shoji & Yoichi Shimada

Authors
  1. Kazunobu Abe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naohisa Miyakoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuji Kasukawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Koji Nozaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroyuki Tsuchie
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chiaki Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hikaru Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ryo Shoji
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yoichi Shimada
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KA: investigation, validation, visualization, and writing—original draft. NM: conceptualization, methodology, project administration, and writing—review & editing. YK: conceptualization, methodology, and writing—review and editing. KN: investigation and formal analysis. HT: investigation and formal analysis. CS: investigation. HS: investigation. RS: investigation. YS: conceptualization, funding acquisition, and supervision.

Corresponding author

Correspondence to Naohisa Miyakoshi.

Ethics declarations

Conflict of interest

Naohisa Miyakoshi has received payments for lectures from Asahi Kasei Pharma Corporation. The other authors declare that they have no conflicts of interest.

Ethical approval

The protocols for all animal experiments were approved in advance by the Animal Research Committee of our institute, and all subsequent animal experiments adhered to the “Guidelines for Animal Experimentation” of our university (approval number: a-1-3046).

Additional information

Publisher's Note

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

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abe, K., Miyakoshi, N., Kasukawa, Y. et al. Effects of teriparatide and low-intensity aerobic exercise on osteopenia in type 2 diabetes mellitus rats. J Bone Miner Metab 40, 229–239 (2022). https://doi.org/10.1007/s00774-021-01289-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00774-021-01289-0

Keywords

Search

Navigation