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Current Osteoporosis Reports

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Open Access 01-10-2019 | Diabetic Neuropathy | Bone and Diabetes (A Schwartz and P Vestergaard, Section Editors)

Peripheral Neuropathy as a Component of Skeletal Disease in Diabetes

Authors: Alec T. Beeve, Jennifer M. Brazill, Erica L. Scheller

Published in: Current Osteoporosis Reports | Issue 5/2019

Abstract

Purpose of Review

The goal of this review is to explore clinical associations between peripheral neuropathy and diabetic bone disease and to discuss how nerve dysfunction may contribute to dysregulation of bone metabolism, reduced bone quality, and fracture risk.

Recent Findings

Diabetic neuropathy can decrease peripheral sensation (sensory neuropathy), impair motor coordination (motor neuropathy), and increase postural hypotension (autonomic neuropathy). Together, this can impair overall balance and increase the risk for falls and fractures. In addition, the peripheral nervous system has the potential to regulate bone metabolism directly through the action of local neurotransmitters on bone cells and indirectly through neuroregulation of the skeletal vascular supply.

Summary

This review critically evaluates existing evidence for diabetic peripheral neuropathy as a risk factor or direct actor on bone disease. In addition, we address therapeutic and experimental considerations to guide patient care and future research evaluating the emerging relationship between diabetic neuropathy and bone health.

Brazill JM, Beeve AT, Craft CS, Ivanusic JJ, Scheller EL. Nerves in bone: evolving concepts in pain and anabolism. J Bone Miner Res. 2019.

Rajbhandari SM, Jenkins RC, Davies C, Tesfaye S. Charcot neuroarthropathy in diabetes mellitus. Diabetologia. 2002;45:1085–96.PubMed

Lecka-Czernik B, Fowlkes JL, editors. Diabetic bone disease. Cham: Springer International Publishing; 2016.

Starup-Linde J, Lykkeboe S, Gregersen S, Hauge E-M, Langdahl BL, Handberg A, et al. Differences in biochemical bone markers by diabetes type and the impact of glucose. Bone. 2016;83:149–55.PubMed

Vestergaard P. Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes--a meta-analysis. Osteoporos Int. 2007;18:427–44.PubMed

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

Shanbhogue VV, Hansen S, Frost M, Jørgensen NR, Hermann AP, Henriksen JE, et al. Bone geometry, volumetric density, microarchitecture, and estimated bone strength assessed by HR-pQCT in adult patients with type 1 diabetes mellitus. J Bone Miner Res. 2015;30:2188–99.PubMed

Starup-Linde J, Lykkeboe S, Gregersen S, Hauge E-M, Langdahl BL, Handberg A, et al. Bone structure and predictors of fracture in type 1 and type 2 diabetes. J Clin Endocrinol Metab. 2016;101:928–36.PubMed

•• Shah VN, Joshee P, Sippl R, Pyle L, Vigers T, Carpenter RD, et al. Type 1 diabetes onset at young age is associated with compromised bone quality. Bone. 2019;123:260–4 This article shows that compromised skeletal architecture in adults is linked to early development of T1D (age <20). With the recent realization that neuropathy is also prevalent in this younger age group, more work is needed to determine whether the nerve-bone axis is already impaired at an early age. PubMedPubMedCentral

10.

• Verroken C, Pieters W, Beddeleem L, Goemaere S, Zmierczak HG, Shadid S, et al. Cortical bone size deficit in adult patients with type 1 diabetes mellitus. J Clin Endocrinol Metab. 2017;102:2887–95 Demonstrates that adults with T1D have an endosteal deficit, leading to overall decreases in cortical bone. This implicates remodeling, in addition to modeling, in the pathogenesis of T1D-associated bone disease. PubMed

11.

Abdalrahaman N, McComb C, Foster JE, McLean J, Lindsay RS, McClure J, et al. Deficits in trabecular bone microarchitecture in young women with type 1 diabetes mellitus. J Bone Miner Res. 2015;30:1386–93.PubMed

12.

Moyer-Mileur LJ, Dixon SB, Quick JL, Askew EW, Murray MA. Bone mineral acquisition in adolescents with type 1 diabetes. J Pediatr. 2004;145:662–9.PubMed

13.

•• Maratova K, Soucek O, Matyskova J, Hlavka Z, Petruzelkova L, Obermannova B, et al. Muscle functions and bone strength are impaired in adolescents with type 1 diabetes. Bone. 2018;106:22–7 This is the first study to comprehensively evaluate both muscle strength and bone quality in young patients with T1D. The results emphasize likely relationships between muscle health and bone health in diabetes. PubMed

14.

Weber DR, Haynes K, Leonard MB, Willi SM, Denburg MR. Type 1 diabetes is associated with an increased risk of fracture across the life span: a population-based cohort study using The Health Improvement Network (THIN). Diabetes Care. 2015;38:1913–20.PubMedPubMedCentral

15.

Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet. 2005;365:1333–46.PubMed

16.

• Samelson EJ, Demissie S, Cupples LA, Zhang X, Xu H, Liu C-T, et al. Diabetes and deficits in cortical bone density, microarchitecture, and bone size: Framingham HR-pQCT study. J Bone Miner Res. 2018;33:54–62 The largest HR-pQCT-based analysis of bone microarchitecture in adult patients with T2D to date. PubMed

17.

Yu EW, Putman MS, Derrico N, Abrishamanian-Garcia G, Finkelstein JS, Bouxsein ML. Defects in cortical microarchitecture among African-American women with type 2 diabetes. Osteoporos Int. 2015;26:673–9.PubMed

18.

De Waard EAC, de Jong JJA, Koster A, Savelberg HHCM, van Geel TA, Houben AJHM, et al. The association between diabetes status, HbA1c, diabetes duration, microvascular disease, and bone quality of the distal radius and tibia as measured with high-resolution peripheral quantitative computed tomography-the Maastricht study. Osteoporos Int. 2018;29:2725–38.PubMedPubMedCentral

19.

Patsch JM, Rasul S, Huber FA, Leitner K, Thomas A, Kocijan R, et al. Similarities in trabecular hypertrophy with site-specific differences in cortical morphology between men and women with type 2 diabetes mellitus. PLoS One. 2017;12:e0174664.PubMedPubMedCentral

20.

•• Shanbhogue VV, Hansen S, Frost M, Jørgensen NR, Hermann AP, Henriksen JE, et al. Compromised cortical bone compartment in type 2 diabetes mellitus patients with microvascular disease. Eur J Endocrinol. 2016;174:115–24 This well-controlled study tests the relationship between microvascular complications, bone density and skeletal microarchitecture in patients with type 2 diabetes. This demonstrates that modest skeletal deficits are present in patients with both microvascular disease and diabetes, but not with diabetes alone. PubMed

21.

Burghardt AJ, Issever AS, Schwartz AV, Davis KA, Masharani U, Majumdar S, et al. High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bone microarchitecture in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2010;95:5045–55.PubMedPubMedCentral

22.

Shu A, Yin MT, Stein E, Cremers S, Dworakowski E, Ives R, et al. Bone structure and turnover in type 2 diabetes mellitus. Osteoporos Int. 2012;23:635–41.PubMed

23.

Farr JN, Drake MT, Amin S, Melton LJ, McCready LK, Khosla S. In vivo assessment of bone quality in postmenopausal women with type 2 diabetes. J Bone Miner Res. 2014;29:787–95.PubMed

24.

• Nilsson AG, Sundh D, Johansson L, Nilsson M, Mellström D, Rudäng R, et al. Type 2 diabetes mellitus is associated with better bone microarchitecture but lower bone material strength and poorer physical function in elderly women: a population-based study. J Bone Miner Res. 2017;32:1062–71 This study combines HR-pQCT with in vivo biomaterial testing (Osteoprobe) in older women with T2D. This reveals that despite favorable microarchitecture, bone material properties were impaired and may explain increased fracture risk in this population. PubMed

25.

Heilmeier U, Cheng K, Pasco C, Parrish R, Nirody J, Patsch JM, et al. Cortical bone laminar analysis reveals increased midcortical and periosteal porosity in type 2 diabetic postmenopausal women with history of fragility fractures compared to fracture-free diabetics. Osteoporos Int. 2016;27:2791–802.PubMedPubMedCentral

26.

Starr JF, Bandeira LC, Agarwal S, Shah AM, Nishiyama KK, Hu Y, et al. Robust trabecular microstructure in type 2 diabetes revealed by individual Trabecula segmentation analysis of HR-pQCT images. J Bone Miner Res. 2018;33:1665–75.PubMed

27.

Patsch JM, Burghardt AJ, Yap SP, Baum T, Schwartz AV, Joseph GB, et al. Increased cortical porosity in type 2 diabetic postmenopausal women with fragility fractures. J Bone Miner Res. 2013;28:313–24.PubMed

28.

Rubin MR. Skeletal fragility in diabetes. Ann N Y Acad Sci. 2017;1402:18–30.PubMed

29.

Napoli N, Chandran M, Pierroz DD, Abrahamsen B, Schwartz AV, Ferrari SL, et al. Mechanisms of diabetes mellitus-induced bone fragility. Nat Rev Endocrinol. 2017;13:208–19.PubMed

30.

Magaziner J, Simonsick EM, Kashner TM, Hebel JR, Kenzora JE. Survival experience of aged hip fracture patients. Am J Public Health. 1989;79:274–8.PubMedPubMedCentral

31.

Cooper C, Atkinson EJ, Jacobsen SJ, O’Fallon WM, Melton LJ. Population-based study of survival after osteoporotic fractures. Am J Epidemiol. 1993;137:1001–5.PubMed

32.

Haentjens P, Magaziner J, Colón-Emeric CS, Vanderschueren D, Milisen K, Velkeniers B, et al. Meta-analysis: excess mortality after hip fracture among older women and men. Ann Intern Med. 2010;152:380–90.PubMedPubMedCentral

33.

Gulcelik NE, Bayraktar M, Caglar O, Alpaslan M, Karakaya J. Mortality after hip fracture in diabetic patients. Exp Clin Endocrinol Diabetes. 2011;119:414–8.PubMed

34.

Wang H, Lü YW, Lan L, Zhang Q, Chen HL, Zhang GY, et al. Impact of diabetes on the prognosis of hip fracture: a cohort study in the Chinese population. Chin Med J. 2013;126:813–8.PubMed

35.

Pan HH, Li CY, Chen PC, Lee MD, Liang CY, Hou WH, et al. Contributions of diabetic macro-vascular complications and hip fracture to depression onset in elderly patients with diabetes: an 8-year population-based follow-up study. J Psychosom Res. 2012;73:180–4.PubMed

36.

Reistetter TA, Graham JE, Deutsch A, Markello SJ, Granger CV, Ottenbacher KJ. Diabetes comorbidity and age influence rehabilitation outcomes after hip fracture. Diabetes Care. 2011;34:1375–7.PubMedPubMedCentral

37.

Dubey A, Aharonoff GB, Zuckerman JD, Koval KJ. The effects of diabetes on outcome after hip fracture. Bull Hosp Jt Dis. 2000;59:94–8.PubMed

38.

Norris R, Parker M. Diabetes mellitus and hip fracture: a study of 5966 cases. Injury. 2011;42:1313–6.PubMed

39.

Litwak L, Goh S-Y, Hussein Z, Malek R, Prusty V, Khamseh ME. Prevalence of diabetes complications in people with type 2 diabetes mellitus and its association with baseline characteristics in the multinational A1chieve study. Diabetol Metab Syndr. 2013;5:57.PubMedPubMedCentral

40.

Pambianco G, Costacou T, Ellis D, Becker DJ, Klein R, Orchard TJ. The 30-year natural history of type 1 diabetes complications: the Pittsburgh epidemiology of diabetes complications study experience. Diabetes. 2006;55:1463–9.PubMed

41.

Løseth S, Mellgren SI, Jorde R, Lindal S, Stålberg E. Polyneuropathy in type 1 and type 2 diabetes: comparison of nerve conduction studies, thermal perception thresholds and intraepidermal nerve fibre densities. Diabetes Metab Res Rev. 2010;26:100–6.PubMed

42.

Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester diabetic neuropathy study. Neurology. 1993;43:817–24.PubMed

43.

•• Jaiswal M, Divers J, Dabelea D, Isom S, Bell RA, Martin CL, et al. Prevalence of and risk factors for diabetic peripheral neuropathy in youth with type 1 and type 2 diabetes: SEARCH for diabetes in youth study. Diabetes Care. 2017;40:1226–32 Unlike previous assumptions, this paper from the SEARCH cohort establishes diabetic neuropathy as a prevalent complication of both T1D and T2D youth. PubMedPubMedCentral

44.

Dabelea D, Stafford JM, Mayer-Davis EJ, D’Agostino R, Dolan L, Imperatore G, et al. Association of type 1 diabetes vs type 2 diabetes diagnosed during childhood and adolescence with complications during teenage years and young adulthood. JAMA. 2017;317:825–35.PubMedPubMedCentral

45.

Eppens MC, Craig ME, Cusumano J, Hing S, Chan AKF, Howard NJ, et al. Prevalence of diabetes complications in adolescents with type 2 compared with type 1 diabetes. Diabetes Care. 2006;29:1300–6.PubMed

46.

Callaghan BC, Cheng HT, Stables CL, Smith AL, Feldman EL. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol. 2012;11:521–34.PubMedPubMedCentral

47.

Vincent AM, Callaghan BC, Smith AL, Feldman EL. Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat Rev Neurol. 2011;7:573–83.PubMed

48.

Pop-Busui R, Boulton AJM, Feldman EL, Bril V, Freeman R, Malik RA, et al. Diabetic neuropathy: a position statement by the American diabetes association. Diabetes Care. 2017;40:136–54.PubMed

49.

Britland ST, Young RJ, Sharma AK, Clarke BF. Association of painful and painless diabetic polyneuropathy with different patterns of nerve fiber degeneration and regeneration. Diabetes. 1990;39:898–908.PubMed

50.

Sala D, Zorzano A. Differential control of muscle mass in type 1 and type 2 diabetes mellitus. Cell Mol Life Sci. 2015;72:3803–17.PubMed

51.

Biessels GJ, Bril V, Calcutt NA, Cameron NE, Cotter MA, Dobrowsky R, et al. Phenotyping animal models of diabetic neuropathy: a consensus statement of the diabetic neuropathy study group of the EASD (Neurodiab). J Peripher Nerv Syst. 2014;19:77–87.PubMedPubMedCentral

52.

Arnold R, Kwai N, Lin CS-Y, Poynten AM, Kiernan MC, Krishnan AV. Axonal dysfunction prior to neuropathy onset in type 1 diabetes. Diabetes Metab Res Rev. 2013;29:53–9.PubMed

53.

Sung J-Y, Tani J, Chang T-S, Lin CS-Y. Uncovering sensory axonal dysfunction in asymptomatic type 2 diabetic neuropathy. PLoS One. 2017;12:e0171223.PubMedPubMedCentral

54.

Misawa S, Sakurai K, Shibuya K, Isose S, Kanai K, Ogino J, et al. Neuropathic pain is associated with increased nodal persistent Na(+) currents in human diabetic neuropathy. J Peripher Nerv Syst. 2009;14:279–84.PubMed

55.

Malik RA, Tesfaye S, Newrick PG, Walker D, Rajbhandari SM, Siddique I, et al. Sural nerve pathology in diabetic patients with minimal but progressive neuropathy. Diabetologia. 2005;48:578–85.PubMed

56.

Lindberger M, Schröder HD, Schultzberg M, Kristensson K, Persson A, Ostman J, et al. Nerve fibre studies in skin biopsies in peripheral neuropathies. I. Immunohistochemical analysis of neuropeptides in diabetes mellitus. J Neurol Sci. 1989;93:289–96.PubMed

57.

Tesfaye S, Boulton AJM, Dyck PJ, Freeman R, Horowitz M, Kempler P, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010;33:2285–93.PubMedPubMedCentral

58.

Sima AA, Nathaniel V, Bril V, McEwen TA, Greene DA. Histopathological heterogeneity of neuropathy in insulin-dependent and non-insulin-dependent diabetes, and demonstration of axo-glial dysjunction in human diabetic neuropathy. J Clin Invest. 1988;81:349–64.PubMedPubMedCentral

59.

Vincent AM, Perrone L, Sullivan KA, Backus C, Sastry AM, Lastoskie C, et al. Receptor for advanced glycation end products activation injures primary sensory neurons via oxidative stress. Endocrinology. 2007;148:548–58.PubMed

60.

Duran-Jimenez B, Dobler D, Moffatt S, Rabbani N, Streuli CH, Thornalley PJ, et al. Advanced glycation end products in extracellular matrix proteins contribute to the failure of sensory nerve regeneration in diabetes. Diabetes. 2009;58:2893–903.PubMedPubMedCentral

61.

Almaguel FG, Liu J-W, Pacheco FJ, De Leon D, Casiano CA, De Leon M. Lipotoxicity-mediated cell dysfunction and death involve lysosomal membrane permeabilization and cathepsin L activity. Brain Res. 2010;1318:133–43.PubMed

62.

Tsintzas K, Chokkalingam K, Jewell K, Norton L, Macdonald IA, Constantin-Teodosiu D. Elevated free fatty acids attenuate the insulin-induced suppression of PDK4 gene expression in human skeletal muscle: potential role of intramuscular long-chain acyl-coenzyme A. J Clin Endocrinol Metab. 2007;92:3967–72.PubMed

63.

Vincent AM, Hayes JM, McLean LL, Vivekanandan-Giri A, Pennathur S, Feldman EL. Dyslipidemia-induced neuropathy in mice: the role of oxLDL/LOX-1. Diabetes. 2009;58:2376–85.PubMedPubMedCentral

64.

Tesfaye S, Harris N, Jakubowski JJ, Mody C, Wilson RM, Rennie IG, et al. Impaired blood flow and arterio-venous shunting in human diabetic neuropathy: a novel technique of nerve photography and fluorescein angiography. Diabetologia. 1993;36:1266–74.PubMed

65.

Wu G, Ringkamp M, Murinson BB, Pogatzki EM, Hartke TV, Weerahandi HM, et al. Degeneration of myelinated efferent fibers induces spontaneous activity in uninjured C-fiber afferents. J Neurosci. 2002;22:7746–53.PubMedPubMedCentral

66.

Eller-Vainicher C, Zhukouskaya VV, Tolkachev YV, Koritko SS, Cairoli E, Grossi E, et al. Low bone mineral density and its predictors in type 1 diabetic patients evaluated by the classic statistics and artificial neural network analysis. Diabetes Care. 2011;34:2186–91.PubMedPubMedCentral

67.

Kayath MJ, Dib SA, Vieira JG. Prevalence and magnitude of osteopenia associated with insulin-dependent diabetes mellitus. J Diabetes Complicat. 1994;8:97–104.

68.

Rix M, Andreassen H, Eskildsen P. Impact of peripheral neuropathy on bone density in patients with type 1 diabetes. Diabetes Care. 1999;22:827–31.PubMed

69.

Forst T, Pfützner A, Kann P, Schehler B, Lobmann R, Schäfer H, et al. Peripheral osteopenia in adult patients with insulin-dependent diabetes mellitus. Diabet Med. 1995;12:874–9.PubMed

70.

Hansen CS, Theilade S, Lajer M, Hansen TW, Rossing P. Cardiovascular autonomic neuropathy and bone metabolism in type 1 diabetes. Diabet Med. 2018;35:1596–604.PubMed

71.

Muñoz-Torres M, Jódar E, Escobar-Jiménez F, López-Ibarra PJ, Luna JD. Bone mineral density measured by dual X-ray absorptiometry in Spanish patients with insulin-dependent diabetes mellitus. Calcif Tissue Int. 1996;58:316–9.PubMed

72.

Miazgowski T, Pynka S, Noworyta-Zietara M, Krzyzanowska-Swiniarska B, Pikul R. Bone mineral density and hip structural analysis in type 1 diabetic men. Eur J Endocrinol. 2007;156:123–7.PubMed

73.

Miazgowski T, Czekalski S. A 2-year follow-up study on bone mineral density and markers of bone turnover in patients with long-standing insulin-dependent diabetes mellitus. Osteoporos Int. 1998;8:399–403.PubMed

74.

Singh DK, Winocour P, Summerhayes B, Kaniyur S, Viljoen A, Sivakumar G, et al. The foot in type 2 diabetes: is there a link between vascular calcification and bone mineral density? Diabetes Res Clin Pract. 2011;94:410–6.PubMed

75.

Maser RE, Stabley JN, Lenhard MJ, Provost-Craig MA. Autonomic nerve fiber function and bone mineral density in individuals with type 1 diabetes: a cross-sectional study. Diabetes Res Clin Pract. 2009;84:252–8.PubMed

76.

Strotmeyer ES, Cauley JA, Orchard TJ, Steenkiste AR, Dorman JS. Middle-aged premenopausal women with type 1 diabetes have lower bone mineral density and calcaneal quantitative ultrasound than nondiabetic women. Diabetes Care. 2006;29:306–11.PubMed

77.

Chakrabarty N, Sarkar P, Pal SK, Banerjee R, Sarkar RN, Debnath NB. A study of bone mineral density in diabetes mellitus in eastern India. J Indian Med Assoc. 2004;102:418 420, 422 passim.PubMed

78.

Piaggesi A, Rizzo L, Golia F, Costi D, Baccetti F, Ciaccio S, et al. Biochemical and ultrasound tests for early diagnosis of active neuro-osteoarthropathy (NOA) of the diabetic foot. Diabetes Res Clin Pract. 2002;58:1–9.PubMed

79.

Christensen TM, Bülow J, Simonsen L, Holstein PE, Svendsen OL. Bone mineral density in diabetes mellitus patients with and without a Charcot foot. Clin Physiol Funct Imaging. 2010;30:130–4.PubMed

80.

Rasul S, Ilhan A, Wagner L, Luger A, Kautzky-Willer A. Diabetic polyneuropathy relates to bone metabolism and markers of bone turnover in elderly patients with type 2 diabetes: greater effects in male patients. Gend Med. 2012;9:187–96.PubMed

81.

Cundy TF, Edmonds ME, Watkins PJ. Osteopenia and metatarsal fractures in diabetic neuropathy. Diabet Med. 1985;2:461–4.PubMed

82.

Barwick AL, Tessier JW, Janse de Jonge X, Chuter VH. Foot bone density in diabetes may be unaffected by the presence of neuropathy. J Diabetes Complicat. 2016;30:1087–92.

83.

•• Lee RH, Sloane R, Pieper C, Lyles KW, Adler RA, Van Houtven C, et al. Clinical fractures among older men with diabetes are mediated by diabetic complications. J Clin Endocrinol Metab. 2018;103:281–7 This well-powered study of 2,798,309 veterans, including 900,402 with diabetes, found that older male veterans with diabetes have a significant increase in risk of incident clinical fracture. Within this cohort peripheral neuropathy was identified as a significant mediating factor for diabetes-associated fracture. PubMed

84.

Miao J, Brismar K, Nyrén O, Ugarph-Morawski A, Ye W. Elevated hip fracture risk in type 1 diabetic patients: a population-based cohort study in Sweden. Diabetes Care. 2005;28:2850–5.PubMed

85.

Leanza G, Maddaloni E, Pitocco D, Conte C, Palermo A, Maurizi AR, et al. Risk factors for fragility fractures in type 1 diabetes. Bone. 2019;125:194–9.PubMed

86.

Kim J-H, Jung M-H, Lee J-M, Son H-S, Cha B-Y, Chang S-A. Diabetic peripheral neuropathy is highly associated with nontraumatic fractures in Korean patients with type 2 diabetes mellitus. Clin Endocrinol (Oxf). 2012;77:51–5.

87.

Vestergaard P, Rejnmark L, Mosekilde L. Diabetes and its complications and their relationship with risk of fractures in type 1 and 2 diabetes. Calcif Tissue Int. 2009;84:45–55.PubMed

88.

Wukich DK, Joseph A, Ryan M, Ramirez C, Irrgang JJ. Outcomes of ankle fractures in patients with uncomplicated versus complicated diabetes. Foot Ankle Int. 2011;32:120–30.PubMed

89.

Shibuya N, Humphers JM, Fluhman BL, Jupiter DC. Factors associated with nonunion, delayed union, and malunion in foot and ankle surgery in diabetic patients. J Foot Ankle Surg. 2013;52:207–11.PubMed

90.

Schwartz AV, Vittinghoff E, Sellmeyer DE, Feingold KR, de Rekeneire N, Strotmeyer ES, et al. Diabetes-related complications, glycemic control, and falls in older adults. Diabetes Care. 2008;31:391–6.PubMed

91.

Resnick HE, Vinik AI, Schwartz AV, Leveille SG, Brancati FL, Balfour J, et al. Independent effects of peripheral nerve dysfunction on lower-extremity physical function in old age: the Women’s Health and Aging study. Diabetes Care. 2000;23:1642–7.PubMed

92.

Kanazawa I, Takeno A, Tanaka K-I, Yamane Y, Sugimoto T. Osteoporosis and vertebral fracture are associated with deterioration of activities of daily living and quality of life in patients with type 2 diabetes mellitus. J Bone Miner Metab. 2018.

93.

Richardson JK, Hurvitz EA. Peripheral neuropathy: a true risk factor for falls. J Gerontol A Biol Sci Med Sci. 1995;50:M211–5.PubMed

94.

Rasmussen NH, Dal J. Falls and fractures in diabetes-more than bone fragility. Curr Osteoporos Rep. 2019;17:147–56.PubMed

95.

Avin KG, Bloomfield SA, Gross TS, Warden SJ. Biomechanical aspects of the muscle-bone interaction. Curr Osteoporos Rep. 2015;13:1–8.PubMedPubMedCentral

96.

Kaynak G, Birsel O, Güven MF, Oğüt T. An overview of the Charcot foot pathophysiology. Diabetic Foot Ankle. 2013;4.

97.

Gomes AA, Ackermann M, Ferreira JP, Orselli MIV, Sacco ICN. Muscle force distribution of the lower limbs during walking in diabetic individuals with and without polyneuropathy. J Neuroeng Rehabil. 2017;14:111.PubMedPubMedCentral

98.

Parasoglou P, Rao S, Slade JM. Declining skeletal muscle function in diabetic peripheral neuropathy. Clin Ther. 2017;39:1085–103.PubMedPubMedCentral

99.

D’Silva LJ, Lin J, Staecker H, Whitney SL, Kluding PM. Impact of diabetic complications on balance and falls: contribution of the vestibular system. Phys Ther. 2016;96:400–9.PubMed

100.

Van Oers RF, Ruimerman R, Tanck E, Hilbers PA, Huiskes R. A unified theory for osteonal and hemi-osteonal remodeling. Bone. 2008;42:250–9.PubMed

101.

Parfitt AM. Osteonal and hemi-osteonal remodeling: the spatial and temporal framework for signal traffic in adult human bone. J Cell Biochem. 1994;55:273–86.PubMed

102.

•• Sayilekshmy M, Hansen RB, Delaissé J-M, Rolighed L, Andersen TL, Heegaard A-M. Innervation is higher above bone remodeling surfaces and in cortical pores in human bone: lessons from patients with primary hyperparathyroidism. Sci Rep. 2019;9:5361 This is one of the first quantitative studies of nerve density in human bone. This work clearly demonstrates that nerves in bone are predominantly, if not exclusively, associated with the vasculature. In addition, neurovascular bundles were preferentially identified above remodeling surfaces, suggesting that local neurotransmitters may contribute to bone remodeling. PubMedPubMedCentral

103.

Starup-Linde J, Eriksen SA, Lykkeboe S, Handberg A, Vestergaard P. Biochemical markers of bone turnover in diabetes patients--a meta-analysis, and a methodological study on the effects of glucose on bone markers. Osteoporos Int. 2014;25:1697–708.PubMed

104.

Wang LH, Zhou SX, Li RC, Zheng LR, Zhu JH, Hu SJ, et al. Serum levels of calcitonin gene-related peptide and substance P are decreased in patients with diabetes mellitus and coronary artery disease. J Int Med Res. 2012;40:134–40.PubMed

105.

Christensen NJ. Catecholamines and diabetes mellitus. Diabetologia. 1979;16:211–24.PubMed

106.

Cryer PE, Silverberg AB, Santiago JV, Shah SD. Plasma catecholamines in diabetes. The syndromes of hypoadrenergic and hyperadrenergic postural hypotension. Am J Med. 1978;64:407–16.PubMed

107.

Kalaitzoglou E, Popescu I, Bunn RC, Fowlkes JL, Thrailkill KM. Effects of type 1 diabetes on osteoblasts, osteocytes, and osteoclasts. Curr Osteoporos Rep. 2016;14:310–9.PubMedPubMedCentral

108.

Parajuli A, Liu C, Li W, Gu X, Lai X, Pei S, et al. Bone’s responses to mechanical loading are impaired in type 1 diabetes. Bone. 2015;81:152–60.PubMedPubMedCentral

109.

Seref-Ferlengez Z, Suadicani SO, Thi MM. A new perspective on mechanisms governing skeletal complications in type 1 diabetes. Ann N Y Acad Sci. 2016;1383:67–79.PubMedPubMedCentral

110.

Sample SJ, Behan M, Smith L, Oldenhoff WE, Markel MD, Kalscheur VL, et al. Functional adaptation to loading of a single bone is neuronally regulated and involves multiple bones. J Bone Miner Res. 2008;23:1372–81.PubMedPubMedCentral

111.

Wu Q, Sample SJ, Baker TA, Thomas CF, Behan M, Muir P. Mechanical loading of a long bone induces plasticity in sensory input to the central nervous system. Neurosci Lett. 2009;463:254–7.PubMedPubMedCentral

112.

Lau YC, Qian X, Po KT, Li LM, Guo X. Electrical stimulation at the dorsal root ganglion preserves trabecular bone mass and microarchitecture of the tibia in hindlimb-unloaded rats. Osteoporos Int. 2015;26:481–8.PubMed

113.

Schwartz AV. Marrow fat and bone: review of clinical findings. Front Endocrinol (Lausanne). 2015;6:40.

114.

• Robles H, Park S, Joens MS, Fitzpatrick JAJ, Craft CS, Scheller EL. Characterization of the bone marrow adipocyte niche with three-dimensional electron microscopy. Bone. 2019;118:89–98 This unique, three-dimensional study of the bone marrow niche reveals that terminal autonomic nerve endings may be located at the interface of bone marrow adipocytes and osteoblasts, suggesting a novel role for the local nerve-fat-bone axis in bone turnover. PubMed

115.

Kee Z, Kodji X, Brain SD. The role of calcitonin gene related peptide (CGRP) in neurogenic vasodilation and its cardioprotective effects. Front Physiol. 2018;9:1249.PubMedPubMedCentral

116.

Ziche M, Morbidelli L, Pacini M, Geppetti P, Alessandri G, Maggi CA. Substance P stimulates neovascularization in vivo and proliferation of cultured endothelial cells. Microvasc Res. 1990;40:264–78.PubMed

117.

Mapp PI, McWilliams DF, Turley MJ, Hargin E, Walsh DA. A role for the sensory neuropeptide calcitonin gene-related peptide in endothelial cell proliferation in vivo. Br J Pharmacol. 2012;166:1261–71.PubMedPubMedCentral

118.

Brain SD, Williams TJ. Inflammatory oedema induced by synergism between calcitonin gene-related peptide (CGRP) and mediators of increased vascular permeability. Br J Pharmacol. 1985;86:855–60.PubMedPubMedCentral

119.

Edmonds ME, Clarke MB, Newton S, Barrett J, Watkins PJ. Increased uptake of bone radiopharmaceutical in diabetic neuropathy. Q J Med. 1985;57:843–55.PubMed

120.

Christensen TM, Simonsen L, Holstein PE, Svendsen OL, Bülow J. Sympathetic neuropathy in diabetes mellitus patients does not elicit Charcot osteoarthropathy. J Diabetes Complicat. 2011;25:320–4.

121.

Shapiro SA, Stansberry KB, Hill MA, Meyer MD, McNitt PM, Bhatt BA, et al. Normal blood flow response and vasomotion in the diabetic charcot foot. J Diabetes Complicat. 1998;12:147–53.

122.

Jaiswal M, Lauer A, Martin CL, Bell RA, Divers J, Dabelea D, et al. Peripheral neuropathy in adolescents and young adults with type 1 and type 2 diabetes from the SEARCH for diabetes in youth follow-up cohort: a pilot study. Diabetes Care. 2013;36:3903–8.PubMedPubMedCentral

123.

Khan A, Petropoulos IN, Ponirakis G, Menzies RA, Chidiac O, Pasquier J, et al. Corneal confocal microscopy detects severe small fiber neuropathy in diabetic patients with Charcot neuroarthropathy. J Diabetes Investig. 2018;9:1167–72.PubMedPubMedCentral

124.

Casellini CM, Parson HK, Richardson MS, Nevoret ML, Vinik AI. Sudoscan, a noninvasive tool for detecting diabetic small fiber neuropathy and autonomic dysfunction. Diabetes Technol Ther. 2013;15:948–53.PubMedPubMedCentral

125.

Albiero M, Poncina N, Tjwa M, Ciciliot S, Menegazzo L, Ceolotto G, et al. Diabetes causes bone marrow autonomic neuropathy and impairs stem cell mobilization via dysregulated p66Shc and Sirt1. Diabetes. 2014;63:1353–65.PubMed

126.

Busik JV, Tikhonenko M, Bhatwadekar A, Opreanu M, Yakubova N, Caballero S, et al. Diabetic retinopathy is associated with bone marrow neuropathy and a depressed peripheral clock. J Exp Med. 2009;206:2897–906.PubMedPubMedCentral

127.

Jeong JO, Kim MO, Kim H, Lee MY, Kim SW, Ii M, et al. Dual angiogenic and neurotrophic effects of bone marrow-derived endothelial progenitor cells on diabetic neuropathy. Circulation. 2009;119:699–708.PubMedPubMedCentral

Title: Peripheral Neuropathy as a Component of Skeletal Disease in Diabetes
Authors: Alec T. Beeve
Jennifer M. Brazill
Erica L. Scheller
Publication date: 01-10-2019
Publisher: Springer US
Keywords: Diabetic Neuropathy
Diabetic Neuropathy
Published in: Current Osteoporosis Reports / Issue 5/2019
Print ISSN: 1544-1873
Electronic ISSN: 1544-2241
DOI: https://doi.org/10.1007/s11914-019-00528-8

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Peripheral Neuropathy as a Component of Skeletal Disease in Diabetes

Abstract

Purpose of Review

Recent Findings

Summary

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose of Review

Recent Findings

Summary

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