The Cause-effect Relationship Between Bone Loss and Alzheimer's Disease Using Statistical Modeling

Overview

Journal Med Hypotheses

Specialty General Medicine

Date 2018 Dec 30

PMID 30593432

Citations 4

Authors

Natalia Loskutova

Amber S Watts

Jeffrey M Burns

Affiliations

Soon will be listed here.

Abstract

Background: Animal studies provide strong evidence that the CNS directly regulates bone remodeling through the actions of the hypothalamus via two distinct pathways, the neural (mediated by leptin) arm and neurohumoral (mediated by neurohormones and growth factors) arm. The impact of AD on central regulatory mechanisms of bone mass is not known.

Objectives: To test a model that assesses the relationship between hypothalamic atrophy and bone loss in Alzheimer's disease (AD) and potential mediation through neural (leptin) and neurohumoral (insulin-like growth factor -1, IGF-1) mechanisms.

Hypotheses: AD-related hypothalamic structural change alters neural and neurohumoral regulatory systems of bone remodeling and contributes to bone loss in early AD.

Design: A secondary data analysis of data obtained in a two-year longitudinal study with path analysis and longitudinal mediation modeling.

Participants: The data were collected as a part of the University of Kansas Brain Aging Project, a two-year observational study of 71 older adults with early stage AD and 69 non-demented controls.

Measurements: Demographic characteristics and measures of bone density, body composition, and hypothalamic volume, serum levels of leptin, growth hormone, and IGF-1 were collected.

Results: Hypothalamic atrophy and bone loss were observed in AD group and were associated. Data modeling suggests that bone loss may precede measurable changes in the brain. Leptin increased over two years in AD and the increase in leptin was associated with hypothalamic atrophy. However, changes in leptin or IGF-1 levels did not mediate the relationship between hypothalamic atrophy and bone loss.

Conclusions: This study extends previous findings by suggesting that bone loss in AD may be related to neurodegenerative changes (atrophy) in the hypothalamus. Further studies are needed to explore the role of brain atrophy and mediating mechanisms in bone loss. Further exploring temporal relationship between bone loss and AD may have an important diagnostic value.

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References

Washburn R, McAuley E, Katula J, Mihalko S, Boileau R . The physical activity scale for the elderly (PASE): evidence for validity. J Clin Epidemiol. 1999; 52(7):643-51. DOI: 10.1016/s0895-4356(99)00049-9. View

Raskind M, Peskind E, Holmes C, Goldstein D . Patterns of cerebrospinal fluid catechols support increased central noradrenergic responsiveness in aging and Alzheimer's disease. Biol Psychiatry. 1999; 46(6):756-65. DOI: 10.1016/s0006-3223(99)00008-6. View

Yaffe K, Browner W, Cauley J, Launer L, Harris T . Association between bone mineral density and cognitive decline in older women. J Am Geriatr Soc. 1999; 47(10):1176-82. DOI: 10.1111/j.1532-5415.1999.tb05196.x. View

Kirkland J, Tchkonia T, Pirtskhalava T, Han J, Karagiannides I . Adipogenesis and aging: does aging make fat go MAD?. Exp Gerontol. 2002; 37(6):757-67. DOI: 10.1016/s0531-5565(02)00014-1. View

Lui L, Stone K, Cauley J, Hillier T, Yaffe K . Bone loss predicts subsequent cognitive decline in older women: the study of osteoporotic fractures. J Am Geriatr Soc. 2003; 51(1):38-43. DOI: 10.1034/j.1601-5215.2002.51007.x. View

Harada S, Rodan G . Control of osteoblast function and regulation of bone mass. Nature. 2003; 423(6937):349-55. DOI: 10.1038/nature01660. View

Cock T, Auwerx J . Leptin: cutting the fat off the bone. Lancet. 2003; 362(9395):1572-4. DOI: 10.1016/S0140-6736(03)14747-2. View

Cole D, Maxwell S . Testing mediational models with longitudinal data: questions and tips in the use of structural equation modeling. J Abnorm Psychol. 2003; 112(4):558-77. DOI: 10.1037/0021-843X.112.4.558. View

Moerman E, Teng K, Lipschitz D, Lecka-Czernik B . Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: the role of PPAR-gamma2 transcription factor and TGF-beta/BMP signaling pathways. Aging Cell. 2004; 3(6):379-89. PMC: 1850101. DOI: 10.1111/j.1474-9728.2004.00127.x. View

10.

Tan Z, Seshadri S, Beiser A, Zhang Y, Felson D, Hannan M . Bone mineral density and the risk of Alzheimer disease. Arch Neurol. 2005; 62(1):107-11. DOI: 10.1001/archneur.62.1.107. View

11.

Broekhuizen R, Vernooy J, Schols A, Dentener M, Wouters E . Leptin as local inflammatory marker in COPD. Respir Med. 2005; 99(1):70-4. DOI: 10.1016/j.rmed.2004.03.029. View

12.

Takeda S . Central control of bone remodeling. Biochem Biophys Res Commun. 2005; 328(3):697-9. DOI: 10.1016/j.bbrc.2004.11.071. View

13.

Oh K, Lee W, Rhee E, Baek K, Yoon K, Kang M . The relationship between serum resistin, leptin, adiponectin, ghrelin levels and bone mineral density in middle-aged men. Clin Endocrinol (Oxf). 2005; 63(2):131-8. DOI: 10.1111/j.1365-2265.2005.02312.x. View

14.

Murray R, Adams J, Shalet S . A densitometric and morphometric analysis of the skeleton in adults with varying degrees of growth hormone deficiency. J Clin Endocrinol Metab. 2005; 91(2):432-8. DOI: 10.1210/jc.2005-0897. View

15.

Muthen B, Asparouhov T, Rebollo I . Advances in behavioral genetics modeling using Mplus: applications of factor mixture modeling to twin data. Twin Res Hum Genet. 2006; 9(3):313-24. DOI: 10.1375/183242706777591317. View

16.

Milewicz T, Krzysiek J, Janczak-Saif A, Sztefko K, Krzyczkowska-Sendrakowska M . Age, insulin, SHBG and sex steroids exert secondary influence on plasma leptin level in women. Endokrynol Pol. 2006; 56(6):883-90. View

17.

Carlo C, Tommaselli G, Di Spiezio Sardo A, Sammartino A, Attianese W, Gargano V . Longitudinal evaluation of serum leptin and bone mineral density in early postmenopausal women. Menopause. 2007; 14(3 Pt 1):450-4. DOI: 10.1097/01.gme.0000236936.28454.6a. View

18.

Martin A, David V, Malaval L, Lafage-Proust M, Vico L, Thomas T . Opposite effects of leptin on bone metabolism: a dose-dependent balance related to energy intake and insulin-like growth factor-I pathway. Endocrinology. 2007; 148(7):3419-25. DOI: 10.1210/en.2006-1541. View

19.

Peng X, Xie H, Zhao Q, Wu X, Sun Z, Liao E . Relationships between serum adiponectin, leptin, resistin, visfatin levels and bone mineral density, and bone biochemical markers in Chinese men. Clin Chim Acta. 2007; 387(1-2):31-5. DOI: 10.1016/j.cca.2007.08.012. View

20.

Maimoun L, Coste O, Puech A, Peruchon E, Jaussent A, Paris F . No negative impact of reduced leptin secretion on bone metabolism in male decathletes. Eur J Appl Physiol. 2007; 102(3):343-51. DOI: 10.1007/s00421-007-0592-7. View