THE ASSOCIATION OF ALBUMINURIA WITH FRACTURE RISK
Main Article Content
Abstract
Background: Large blood vessel atherosclerotic cardiovascular disease is associated with hip fracture risk. Here we summarize studies on the association of microvascular disease with hip fracture risk. We further assess whether the risk of hip fractures with microvascular disease is through reduced trabecular bone density or through markers of endothelial dysfunction.
Methods: We used albuminuria (>30 mg albumin/gram creatinine) as a marker of microvascular disease. Albuminuria is associated with microvascular disorders of the heart, lungs, eyes, skin, and brain. It is present in 30-40% of adults >70 years, the age at which hip fractures occur.
Results: In an observational study of the elderly, a doubling of albuminuria was associated with a hazard ratio (HR) of 1.12 (95 % CI, 1.001-1.25) for hip fractures among women. In a blood pressure study, macroalbuminuria (>299 mg/gram) had an adjusted HR of 2.01 (1.21, 2.15). In a population study of 360,000 people, the HRs for hip fractures were 1.30 (1.02-1.65) for microalbuminuria (30-299 mg/gram) and 1.58 (1.07-2.35) for macroalbuminuria. In a population study of 2.7 million people, macroalbuminuria had an increased odds ratio of hip fracture (odds ratio 1.37 [1.28, 1.47]). Despite these findings, volumetric trabecular bone density was not significantly reduced in association with albuminuria levels nor with markers of endothelial dysfunction.
Conclusions: Microvascular disease, as detected by albuminuria, is independently associated with hip fracture risk. However, this association is not through reduced trabecular bone density nor through endothelial dysfunction. Other mechanisms of fracture risk need to be explored.
Keywords:
bone density, albuminuria, fracture risk, microcirculation
Article Details
How to Cite
BARZILAY, Joshua I et al.
THE ASSOCIATION OF ALBUMINURIA WITH FRACTURE RISK.
Medical Research Archives, [S.l.], v. 13, n. 4, apr. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6473>. Date accessed: 15 may 2025.
doi: https://doi.org/10.18103/mra.v13i4.6473.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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2. Barzilay JI, Buzkova P, Djoussé L, Ix J Kizer J, Cauley J, Matthan N, Lichtenstein AH, Mukamal KJ. Serum Non-Esterified Fatty Acid Levels and Hip Fracture Risk in Older Adults: The Cardiovascular Health Study. Osteoporos Int 2021; 32(9):1745-1751. doi: 10.1007/s00198-021-05897-4
3. Barzilay J, Buzkova P, Cauley JA, Robbins JA, Fink HA, Mukamal KJ. The associations of subclinical atherosclerotic cardiovascular disease with hip fracture risk and bone mineral density in elderly adults; the Cardiovascular Health Study. Osteoporos Int 2018; 29(10): 2219-2230. doi: 10.100 7/s00198-018-4611-9
4. Stein PK, Buzkova P, Fink HA, Robbins JA, Mukamal KJ, Cauley JA, Carbone L, Elam R, McMillan DW, Valderrabano R, Barzilay JI. Cardiovascular Autonomic Nervous System Function and Hip Fracture Risk: The Cardiovascular Health Study. Arch Osteoporos 2021 Oct 31; 16(1):163. doi: 10.1007/s1 1657-021-01028-y
5. Robbins JA, Buzkova P, Barzilay JI, Cauley JA, Fink HA, Carbone LD, Chen Z, Stein PK, Elam R, Sheets K, Mukamal KJ. Mortality following hip fracture in older adults with and without coronary heart disease: The Cardiovascular Health Study Am J Med 2023: 136 (8): 789-795. doi: 10.1016/j.amjm ed.2023.03.036
6. Carbone L, Buzkova P, Fink HA, Lee JS, Chen Z, Ahmed A, Parashar S, Robbins JA. Hip fractures and heart failure: findings from the Cardiovascular Health Study. Eur Heart J 2010; 3 (1): 77-84. doi.org/10.1093/eurheartj/ehp345
7. Gross PM, Heistad DD, Marcus ML. Neurohumoral regulation of blood flow to bones and marrow. Am J Physiol. 1979;237:H440–H448. doi: 10.1152/ajpheart.1979.237.4.H440.
8. McCarthy I. The physiology of bone blood flow: a review. Bone Joint Surg Am 2006; 88 Suppl 3: 4-9. doi: 10.2106/JBJS.F.00890.
9. Prisby RD. Bone marrow microvasculature. Compr Physiol 2020; 10 (3): 1009- 1046. doi: 10.100 2/cphy.c190009.
10. Laroche M, Ludot I, Thiechart M. Study of the intraosseous vessels of the femoral head in patients with fractures of the femoral neck or osteoarthritis of the hip. Osteoporos Int 1995; 5: 213-217. doi: 10.1007/BF01774009
11. Griffith JF, Yeung DKW, Tsang PH. Compromised bone marrow perfusion in osteoporosis. J Bone Miner Res. 2008; 23(7): 1068-75. doi: 10.1359/jbmr.080233.
12. Aguirre J, Buttery L, O'Shaughnessy M, et al. Endothelial nitric oxide synthase gene-deficient mice demonstrate marked retardation in postnatal bone formation, reduced bone volume, and defects in osteoblast maturation and activity. Am J Pathol. 2001;158(1):247-57. doi: 10.1016/S0002-9440(10)63963-6.
13. Ramasamy SK, Kusumbe AP, Schiller M, et al. Blood flow controls bone vascular function and osteogenesis Nat Commun. 2016 Dec 6:7:13601. doi: 10.1038/ncomms13601.
14. Sheets KM, Buzkova P, Chen Z, et al. Association of covert brain infarcts and white matter hyperintensities with risk of hip fracture in older adults: the Cardiovascular Health Study. Osteoporos Int. 2023;34(1):91-99. doi: 10.1007/s0 0198-022-06565-x
15. Pallister I, Gosling P, Alpar K, Bradley S. Prediction of posttraumatic adult respiratory distress syndrome by albumin excretion rate eight hours after admission. J Trauma. 1997;42(6):1056-61. doi: 10.1097/00005373-199706000-00012.
16. Kopf S, Groener JB, Kender Z, et al. Breathlessness and Restrictive Lung Disease: An Important Diabetes-Related Feature in Patients with Type 2 Diabetes. Respiration. 2018;96(1):29-40. doi: 10.1159/000488909.
17. Steegh FMEG, Keijbeck AA, de Hoogt PA, et al. Capillary rarefaction: a missing link in renal and cardiovascular disease? Angiogenesis. 2024; 27(1):23-35. doi: 10.1007/s10456-023-09883-8.
18. Martens RJH, Houben AJHM, Kooman JP, et al. Microvascular endothelial dysfunction is associated with albuminuria: the Maastricht Study. J Hypertens. 2018;36(5):1178-1187. doi: 10.1097/H JH.0000000000001674
19. Li J, Zhang W, Zhao L, et al. Positive correlation between hypertensive retinopathy and albuminuria in hypertensive adults. BMC Ophthalmol. 2023;23 (1):66. doi: 10.1186/s12886-023-02807-6.
20. von Scholten BJ, Hasbak P, Christensen TE. Cardiac (82)Rb PET/CT for fast and non-invasive assessment of microvascular function and structure in asymptomatic patients with type 2 diabetes. Diabetologia 2016; 59(2):371-8. doi: 10.1007/s00125-015-3799-x.
21. Barzilay JI, Bůžková,P, Chen Z, et al. Albuminuria is associated with hip fracture risk in older adults: the cardiovascular health study. Osteoporos Int. 2013;24(12):2993-3000. doi: 10.100 7/s00198-013-2389-3.
22. Barzilay JI, Gao P, Clase CM, et al. Albuminuria and rapid loss of GFR and risk of new hip and pelvic fractures. Clin J Am Soc Nephrol. 2013;8(2):233-240. doi: 10.2215/CJN.06640712
23. Kim SH, Yi SW, Yi JJ, Kim YM, Won YJ. Chronic Kidney Disease Increases the Risk of Hip Fracture: A Prospective Cohort Study in Korean Adults. J Bone Miner Res. 2020;35(7):1313-1321. doi: 10.1002/jbmr.3997.
24. Cooke-Hubley SM, Senior P, Bello AK, Wiebe N, Klarenbach S. Degree of Albuminuria is Associated with Increased Risk of Fragility Fractures Independent of Estimated GFR. Kidney Int Rep. 2023;8(11):2315-2325. doi: 10.1016/j.ekir.2023.08.016.
25. Bůžková P, Barzilay JI, Fink HA, Robbins JA, Cauley JA, Fitzpatrick AL. Ratio of urine albumin to creatinine attenuates the association of dementia with hip fracture risk. J Clin Endocrinol Metab. 2014;99(11):4116-4123. doi: 10.1210/jc.2014-2409.
26. Johannesdottir F, Tedtsen T, Cooke LM, et al. Microvascular disease and early diabetes onset are associated with deficits in femoral neck bone density and structure among older adults with longstanding type 1 diabetes. J Bone Miner Res. 2024 Sep 26;39(10):1454-1463. doi: 10.1093/jbm r/zjae134.
27. Goldshtein I, Nguyen AM, dePapp AE, et al. Epidemiology and correlates of osteoporotic fractures among type 2 diabetic patients. Arch Osteopor 2018 Mar 3; 13 (1): 15. Doi: 10.1007/116 57-018-0432-x.
28. Barzilay JI, Peterson D, Cushman M, et al. The relationship of cardiovascular risk factors to microalbuminuria in older adults with or without diabetes mellitus or hypertension: The Cardiovascular Health Study. Am J Kid Dis 2004; 44: 25 - 34. doi: 10.1053/j.ajkd.2004.03.022.
29. Garg AX, Kiberd BA, Clark WF, Haynes RB, Clase CM. Albuminuria and renal insufficiency prevalence guides population screening: results from the NHANES III. Kidney Int. 2002; 61(6):2165-75. doi: 10.1046/j.1523-1755.2002.00356.x.
30. Gimbrone MA Jr, García-Cardeña G (2016) Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res 2016: 118(4):620–636. doi.org/10.1161/CIRCRESAHA.115.306301
31. Prisby RD. Mechanical, hormonal and metabolic influences on blood vessels, blood flow and bone. J Endocrinol. 2017;235(3): R77-R100. doi: 10.1530/JOE-16-0666.
32. Watson EC, Adams RH. Biology of bone: the vasculature of the skeletal system. Cold Spring Harb Perspect Med. 2018; 8(7):a031559. doi: 10.110 1/cshperspect.a031559.
33. Prasad M, Reriani M, Khosla S, et al. Coronary microvascular endothelial dysfunction is an independent predictor of development of osteoporosis in postmenopausal women. Vasc Health Risk Manag 2014:10:533-8. doi: 10.2147/VH RM.S63580. eCollection 2014.
34. Barzilay JI, Buzkova P, Bielinski SJ, et al. The association of microvascular disease and endothelial dysfunction with vertebral trabecular bone mineral density: The MESA study. Osteoporos Int. 2024;35 (9):1595-1604. doi: 10.1007/s00198-024-07152-y.
35. Barzilay JI, Buzkova P, Fink HA, et al. Systemic markers of microvascular disease and bone mineral density older in adults: The cardiovascular health study. Osteoporos Int. 2016;27(11):3217-3225. doi: 10.1007/s00198-016-3649-9.
36. Jørgensen L, Jenssen T, Ahmed L, Bjornerem A, Joakimsen R, Jacobsen BK. Albuminuria and risk of nonvertebral fractures. Arch Intern Med. 2007; 167:1379–1385. doi: 10.1001/archinte.167.13.1379.
37. Shanbhogue VV, Hansen S, Frost M, et al. Compromised cortical bone compartment in type 2 diabetes mellitus patients with microvascular disease. Eur J Endocrinol. 2016; 174(2):115-24. doi: 10.1530/EJE-15-0860.
38. Samelson EJ, Broe KE, Xu H, et al. Cortical and trabecular bone microarchitecture as an independent predictor of incident fracture risk in older women and men in the Bone Microarchitecture International Consortium (BoMIC): a prospective study. Lancet Diabetes Endocrinol. 2019;7(1):34-43. doi: 10.1016/S2213-8587(18)30308-5.
2. Barzilay JI, Buzkova P, Djoussé L, Ix J Kizer J, Cauley J, Matthan N, Lichtenstein AH, Mukamal KJ. Serum Non-Esterified Fatty Acid Levels and Hip Fracture Risk in Older Adults: The Cardiovascular Health Study. Osteoporos Int 2021; 32(9):1745-1751. doi: 10.1007/s00198-021-05897-4
3. Barzilay J, Buzkova P, Cauley JA, Robbins JA, Fink HA, Mukamal KJ. The associations of subclinical atherosclerotic cardiovascular disease with hip fracture risk and bone mineral density in elderly adults; the Cardiovascular Health Study. Osteoporos Int 2018; 29(10): 2219-2230. doi: 10.100 7/s00198-018-4611-9
4. Stein PK, Buzkova P, Fink HA, Robbins JA, Mukamal KJ, Cauley JA, Carbone L, Elam R, McMillan DW, Valderrabano R, Barzilay JI. Cardiovascular Autonomic Nervous System Function and Hip Fracture Risk: The Cardiovascular Health Study. Arch Osteoporos 2021 Oct 31; 16(1):163. doi: 10.1007/s1 1657-021-01028-y
5. Robbins JA, Buzkova P, Barzilay JI, Cauley JA, Fink HA, Carbone LD, Chen Z, Stein PK, Elam R, Sheets K, Mukamal KJ. Mortality following hip fracture in older adults with and without coronary heart disease: The Cardiovascular Health Study Am J Med 2023: 136 (8): 789-795. doi: 10.1016/j.amjm ed.2023.03.036
6. Carbone L, Buzkova P, Fink HA, Lee JS, Chen Z, Ahmed A, Parashar S, Robbins JA. Hip fractures and heart failure: findings from the Cardiovascular Health Study. Eur Heart J 2010; 3 (1): 77-84. doi.org/10.1093/eurheartj/ehp345
7. Gross PM, Heistad DD, Marcus ML. Neurohumoral regulation of blood flow to bones and marrow. Am J Physiol. 1979;237:H440–H448. doi: 10.1152/ajpheart.1979.237.4.H440.
8. McCarthy I. The physiology of bone blood flow: a review. Bone Joint Surg Am 2006; 88 Suppl 3: 4-9. doi: 10.2106/JBJS.F.00890.
9. Prisby RD. Bone marrow microvasculature. Compr Physiol 2020; 10 (3): 1009- 1046. doi: 10.100 2/cphy.c190009.
10. Laroche M, Ludot I, Thiechart M. Study of the intraosseous vessels of the femoral head in patients with fractures of the femoral neck or osteoarthritis of the hip. Osteoporos Int 1995; 5: 213-217. doi: 10.1007/BF01774009
11. Griffith JF, Yeung DKW, Tsang PH. Compromised bone marrow perfusion in osteoporosis. J Bone Miner Res. 2008; 23(7): 1068-75. doi: 10.1359/jbmr.080233.
12. Aguirre J, Buttery L, O'Shaughnessy M, et al. Endothelial nitric oxide synthase gene-deficient mice demonstrate marked retardation in postnatal bone formation, reduced bone volume, and defects in osteoblast maturation and activity. Am J Pathol. 2001;158(1):247-57. doi: 10.1016/S0002-9440(10)63963-6.
13. Ramasamy SK, Kusumbe AP, Schiller M, et al. Blood flow controls bone vascular function and osteogenesis Nat Commun. 2016 Dec 6:7:13601. doi: 10.1038/ncomms13601.
14. Sheets KM, Buzkova P, Chen Z, et al. Association of covert brain infarcts and white matter hyperintensities with risk of hip fracture in older adults: the Cardiovascular Health Study. Osteoporos Int. 2023;34(1):91-99. doi: 10.1007/s0 0198-022-06565-x
15. Pallister I, Gosling P, Alpar K, Bradley S. Prediction of posttraumatic adult respiratory distress syndrome by albumin excretion rate eight hours after admission. J Trauma. 1997;42(6):1056-61. doi: 10.1097/00005373-199706000-00012.
16. Kopf S, Groener JB, Kender Z, et al. Breathlessness and Restrictive Lung Disease: An Important Diabetes-Related Feature in Patients with Type 2 Diabetes. Respiration. 2018;96(1):29-40. doi: 10.1159/000488909.
17. Steegh FMEG, Keijbeck AA, de Hoogt PA, et al. Capillary rarefaction: a missing link in renal and cardiovascular disease? Angiogenesis. 2024; 27(1):23-35. doi: 10.1007/s10456-023-09883-8.
18. Martens RJH, Houben AJHM, Kooman JP, et al. Microvascular endothelial dysfunction is associated with albuminuria: the Maastricht Study. J Hypertens. 2018;36(5):1178-1187. doi: 10.1097/H JH.0000000000001674
19. Li J, Zhang W, Zhao L, et al. Positive correlation between hypertensive retinopathy and albuminuria in hypertensive adults. BMC Ophthalmol. 2023;23 (1):66. doi: 10.1186/s12886-023-02807-6.
20. von Scholten BJ, Hasbak P, Christensen TE. Cardiac (82)Rb PET/CT for fast and non-invasive assessment of microvascular function and structure in asymptomatic patients with type 2 diabetes. Diabetologia 2016; 59(2):371-8. doi: 10.1007/s00125-015-3799-x.
21. Barzilay JI, Bůžková,P, Chen Z, et al. Albuminuria is associated with hip fracture risk in older adults: the cardiovascular health study. Osteoporos Int. 2013;24(12):2993-3000. doi: 10.100 7/s00198-013-2389-3.
22. Barzilay JI, Gao P, Clase CM, et al. Albuminuria and rapid loss of GFR and risk of new hip and pelvic fractures. Clin J Am Soc Nephrol. 2013;8(2):233-240. doi: 10.2215/CJN.06640712
23. Kim SH, Yi SW, Yi JJ, Kim YM, Won YJ. Chronic Kidney Disease Increases the Risk of Hip Fracture: A Prospective Cohort Study in Korean Adults. J Bone Miner Res. 2020;35(7):1313-1321. doi: 10.1002/jbmr.3997.
24. Cooke-Hubley SM, Senior P, Bello AK, Wiebe N, Klarenbach S. Degree of Albuminuria is Associated with Increased Risk of Fragility Fractures Independent of Estimated GFR. Kidney Int Rep. 2023;8(11):2315-2325. doi: 10.1016/j.ekir.2023.08.016.
25. Bůžková P, Barzilay JI, Fink HA, Robbins JA, Cauley JA, Fitzpatrick AL. Ratio of urine albumin to creatinine attenuates the association of dementia with hip fracture risk. J Clin Endocrinol Metab. 2014;99(11):4116-4123. doi: 10.1210/jc.2014-2409.
26. Johannesdottir F, Tedtsen T, Cooke LM, et al. Microvascular disease and early diabetes onset are associated with deficits in femoral neck bone density and structure among older adults with longstanding type 1 diabetes. J Bone Miner Res. 2024 Sep 26;39(10):1454-1463. doi: 10.1093/jbm r/zjae134.
27. Goldshtein I, Nguyen AM, dePapp AE, et al. Epidemiology and correlates of osteoporotic fractures among type 2 diabetic patients. Arch Osteopor 2018 Mar 3; 13 (1): 15. Doi: 10.1007/116 57-018-0432-x.
28. Barzilay JI, Peterson D, Cushman M, et al. The relationship of cardiovascular risk factors to microalbuminuria in older adults with or without diabetes mellitus or hypertension: The Cardiovascular Health Study. Am J Kid Dis 2004; 44: 25 - 34. doi: 10.1053/j.ajkd.2004.03.022.
29. Garg AX, Kiberd BA, Clark WF, Haynes RB, Clase CM. Albuminuria and renal insufficiency prevalence guides population screening: results from the NHANES III. Kidney Int. 2002; 61(6):2165-75. doi: 10.1046/j.1523-1755.2002.00356.x.
30. Gimbrone MA Jr, García-Cardeña G (2016) Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res 2016: 118(4):620–636. doi.org/10.1161/CIRCRESAHA.115.306301
31. Prisby RD. Mechanical, hormonal and metabolic influences on blood vessels, blood flow and bone. J Endocrinol. 2017;235(3): R77-R100. doi: 10.1530/JOE-16-0666.
32. Watson EC, Adams RH. Biology of bone: the vasculature of the skeletal system. Cold Spring Harb Perspect Med. 2018; 8(7):a031559. doi: 10.110 1/cshperspect.a031559.
33. Prasad M, Reriani M, Khosla S, et al. Coronary microvascular endothelial dysfunction is an independent predictor of development of osteoporosis in postmenopausal women. Vasc Health Risk Manag 2014:10:533-8. doi: 10.2147/VH RM.S63580. eCollection 2014.
34. Barzilay JI, Buzkova P, Bielinski SJ, et al. The association of microvascular disease and endothelial dysfunction with vertebral trabecular bone mineral density: The MESA study. Osteoporos Int. 2024;35 (9):1595-1604. doi: 10.1007/s00198-024-07152-y.
35. Barzilay JI, Buzkova P, Fink HA, et al. Systemic markers of microvascular disease and bone mineral density older in adults: The cardiovascular health study. Osteoporos Int. 2016;27(11):3217-3225. doi: 10.1007/s00198-016-3649-9.
36. Jørgensen L, Jenssen T, Ahmed L, Bjornerem A, Joakimsen R, Jacobsen BK. Albuminuria and risk of nonvertebral fractures. Arch Intern Med. 2007; 167:1379–1385. doi: 10.1001/archinte.167.13.1379.
37. Shanbhogue VV, Hansen S, Frost M, et al. Compromised cortical bone compartment in type 2 diabetes mellitus patients with microvascular disease. Eur J Endocrinol. 2016; 174(2):115-24. doi: 10.1530/EJE-15-0860.
38. Samelson EJ, Broe KE, Xu H, et al. Cortical and trabecular bone microarchitecture as an independent predictor of incident fracture risk in older women and men in the Bone Microarchitecture International Consortium (BoMIC): a prospective study. Lancet Diabetes Endocrinol. 2019;7(1):34-43. doi: 10.1016/S2213-8587(18)30308-5.