Abstract
Summary
This prospective two-year study of patients on chronic dialysis measured changes in bone mineral density (BMD). Patients with higher baseline BMD and shorter dialysis vintage lost more bone. Treatment with anti-hypertensives acting on the central nervous system was protective against bone loss. Baseline serum levels of sclerostin and bone-specific alkaline phosphatase predicted bone loss.
Introduction
This prospective 2-year study of chronic kidney disease on dialysis (CKD-5D) patients assessed trabecular and cortical bone loss at the hip and spine and examined potential demographic, clinical, and serum biochemical predictors of bone loss.
Methods
Eighty-nine CKD-5D patients had baseline, year 1, and year 2 bone mineral density (BMD) measurements using dual X-ray absorptiometry (DXA) and quantitative computed tomography (QCT); concurrent blood samples were drawn and clinical variables recorded. No study treatments occurred.
Results
The 2-year total hip BMD change was − 5.9% by QCT and − 3.1% by DXA (p < 0.001). Spinal BMD was unchanged. QCT total hip cortical mass and volume decreased (− 7.3 and − 10.0%); trabecular volume increased by 5.9% (ps < 0.001). BMD changes did not vary with age, BMI, race, diabetes, smoking, or exercise. Patients with higher baseline BMD and shorter dialysis vintage lost more bone (p < 0.05). Vitamin D analogs and phosphate binders were not protective against bone loss; cinacalcet was protective by univariate but not by multivariable analysis. CNS-affecting antihypertensives were protective against loss of BMD, cortical mass, cortical volume (ps < 0.05) and trabecular mass (p = 0.007). These effects remained after adjustment. BSAP correlated with changes in BMD, cortical mass, and volume (p < 0.01) as did sclerostin (inversely).
Conclusions
There was severe cortical bone loss at the hip best recognized by QCT. Patients with shorter dialysis vintage and less pre-existing bone loss lost more bone, while treatment with CNS-acting antihypertensives was protective. BSAP and sclerostin were useful markers of bone loss.
Similar content being viewed by others
References
Malluche HH, Monier-Faugere MC (2006) Renal osteodystrophy: what’s in a name? Presentation of a clinically useful new model to interpret bone histologic findings. Clin Nephrol 65:235–242
Malluche HH, Mawad HW, Monier-Faugere MC (2011) Renal osteodystrophy in the first decade of the new millennium: analysis of 630 bone biopsies in black and white patients. J Bone Miner Res 26:1368–1376
Malluche HH, Ritz E, Lange HP, Kutschera L, Hodgson M, Seiffert U, Schoeppe W (1976) Bone histology in incipient and advanced renal failure. Kidney Int 9:355–362
Jadoul M, Albert JM, Akiba T, Akizawa T, Arab L, Bragg-Gresham JL, Mason N, Prutz KG, Young EW, Pisoni RL (2006) Incidence and risk factors for hip or other bone fractures among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study. Kidney Int 70:1358–1366
Tentori F, McCullough K, Kilpatrick RD, Bradbury BD, Robinson BM, Kerr PG, Pisoni RL (2014) High rates of death and hospitalization follow bone fracture among hemodialysis patients. Kidney Int 85:166–173
(2009) KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl 76:S1–130
Einhorn TA (1992) Bone strength: the bottom line. Calcif Tissue Int 51:333–339
Szulc P, Duboeuf F, Schott AM, Dargent-Molina P, Meunier PJ, Delmas PD (2006) Structural determinants of hip fracture in elderly women: re-analysis of the data from the EPIDOS study. Osteoporos Int 17:231–236
Nickolas TL, Stein EM, Dworakowski E et al (2013) Rapid cortical bone loss in patients with chronic kidney disease. J Bone Miner Res 28:1811–1820
Negri AL, Del Valle EE, Zanchetta MB, Nobaru M, Silveira F, Puddu M, Barone R, Bogado CE, Zanchetta JR (2012) Evaluation of bone microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT) in hemodialysis patients. Osteoporos Int 23:2543–2550
Lang T, LeBlanc A, Evans H, Lu Y, Genant H, Yu A (2004) Cortical and trabecular bone mineral loss from the spine and hip in long-duration spaceflight. J Bone Miner Res 19:1006–1012
Erlichman M, Holohan TV (1996) Bone densitometry: patients with end-stage renal disease. Health Technol Assess (Rockv) 1–27
Malluche HH, Arnala I, Faugere MC (1988) Values of noninvasive techniques in predicting bone histology. Ann Chir Gynaecol 77:246–250
Malluche HH, Davenport DL, Cantor T, Monier-Faugere MC (2014) Bone mineral density and serum biochemical predictors of bone loss in patients with CKD on dialysis. Clin J Am Soc Nephrol 9:1254–1262
Fishman WH (1990) Alkaline phosphatase isozymes: recent progress. Clin Biochem 23:99–104
Hale LV, Galvin RJ, Risteli J et al (2007) PINP: a serum biomarker of bone formation in the rat. Bone 40:1103–1109
Halleen JM, Alatalo SL, Suominen H, Cheng S, Janckila AJ, Vaananen HK (2000) Tartrate-resistant acid phosphatase 5b: a novel serum marker of bone resorption. J Bone Miner Res 15:1337–1345
Veverka V, Henry AJ, Slocombe PM et al (2009) Characterization of the structural features and interactions of sclerostin: molecular insight into a key regulator of Wnt-mediated bone formation. J Biol Chem 284:10890–10900
Winkler DG, Sutherland MK, Geoghegan JC et al (2003) Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 22:6267–6276
Kusu N, Laurikkala J, Imanishi M, Usui H, Konishi M, Miyake A, Thesleff I, Itoh N (2003) Sclerostin is a novel secreted osteoclast-derived bone morphogenetic protein antagonist with unique ligand specificity. J Biol Chem 278:24113–24117
Pinzone JJ, Hall BM, Thudi NK, Vonau M, Qiang YW, Rosol TJ, Shaughnessy JD Jr (2009) The role of Dickkopf-1 in bone development, homeostasis, and disease. Blood 113:517–525
Morvan F, Boulukos K, Clement-Lacroix P et al (2006) Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J Bone Miner Res 21:934–945
Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD (2006) Pathogenic role of Fgf23 in Hyp mice. Am J Physiol Endocrinol Metab 291:E38–E49
Vogeser M, Kyriatsoulis A, Huber E, Kobold U (2004) Candidate reference method for the quantification of circulating 25-hydroxyvitamin D3 by liquid chromatography-tandem mass spectrometry. Clin Chem 50:1415–1417
Hui SL, Slemenda CW, Johnston CC Jr (1988) Age and bone mass as predictors of fracture in a prospective study. J Clin Invest 81:1804–1809
Carvalho C, Magalhaes J, Neto R, Pereira L, Branco P, Adragao T, Frazao JM (2016) Cortical bone analysis in a predialysis population: a comparison with a dialysis population. J Bone Miner Metab
Malluche HH, Faugere MC (1986) Atlas of mineralized bone histology. Karger, New York
Gallagher JC, Riggs BL, Recker RR, Goldgar D (1989) The effect of calcitriol on patients with postmenopausal osteoporosis with special reference to fracture frequency. Proc Soc Exp Biol Med 191:287–292
Heaney RP, Gallagher JC, Johnston CC, Neer R, Parfitt AM, Whedon GD (1982) Calcium nutrition and bone health in the elderly. Am J Clin Nutr 36:986–1013
Ferreira A, Frazao JM, Monier-Faugere MC et al (2008) Effects of sevelamer hydrochloride and calcium carbonate on renal osteodystrophy in hemodialysis patients. J Am Soc Nephrol 19:405–412
Qunibi W, Muenz LR (2008) Progression of calcification in the Calcium Acetate Renagel Evaluation-2 (CARE-2) Study. Am J Kidney Dis 52:1022–1023 author reply 1023-1024
Fahrleitner-Pammer A, Herberth J, Browning SR, Obermayer-Pietsch B, Wirnsberger G, Holzer H, Dobnig H, Malluche HH (2008) Bone markers predict cardiovascular events in chronic kidney disease. J Bone Miner Res 23:1850–1858
Moe SM, Abdalla S, Chertow GM et al (2015) Effects of Cinacalcet on fracture events in patients receiving hemodialysis: the EVOLVE trial. J Am Soc Nephrol 26:1466–1475
Bonnet N, Beaupied H, Vico L, Dolleans E, Laroche N, Courteix D, Benhamou CL (2007) Combined effects of exercise and propranolol on bone tissue in ovariectomized rats. J Bone Miner Res 22:578–588
Ortuno MJ, Robinson ST, Subramanyam P, Paone R, Huang YY, Guo XE, Colecraft HM, Mann JJ, Ducy P (2016) Serotonin-reuptake inhibitors act centrally to cause bone loss in mice by counteracting a local anti-resorptive effect. Nat Med 22:1170–1179
Agacayak KS, Guven S, Koparal M, Gunes N, Atalay Y, Atilgan S (2014) Long-term effects of antihypertensive medications on bone mineral density in men older than 55 years. Clin Interv Aging 9:509–513
Yang S, Nguyen ND, Center JR, Eisman JA, Nguyen TV (2011) Association between beta-blocker use and fracture risk: the Dubbo Osteoporosis Epidemiology Study. Bone 48:451–455
Asaba Y, Ito M, Fumoto T, Watanabe K, Fukuhara R, Takeshita S, Nimura Y, Ishida J, Fukamizu A, Ikeda K (2009) Activation of renin-angiotensin system induces osteoporosis independently of hypertension. J Bone Miner Res 24:241–250
Ghosh M, Majumdar SR (2014) Antihypertensive medications, bone mineral density, and fractures: a review of old cardiac drugs that provides new insights into osteoporosis. Endocrine 46:397–405
Gu SS, Zhang Y, Li XL, Wu SY, Diao TY, Hai R, Deng HW (2012) Involvement of the skeletal renin-angiotensin system in age-related osteoporosis of ageing mice. Biosci Biotechnol Biochem 76:1367–1371
Shimizu H, Nakagami H, Osako MK, Hanayama R, Kunugiza Y, Kizawa T, Tomita T, Yoshikawa H, Ogihara T, Morishita R (2008) Angiotensin II accelerates osteoporosis by activating osteoclasts. FASEB J 22:2465–2475
Kaneko K, Ito M, Fumoto T, Fukuhara R, Ishida J, Fukamizu A, Ikeda K (2011) Physiological function of the angiotensin AT1a receptor in bone remodeling. J Bone Miner Res 26:2959–2966
Cejka D, Parada-Rodriguez D, Pichler S et al (2016) Only minor differences in renal osteodystrophy features between wild-type and sclerostin knockout mice with chronic kidney disease. Kidney Int 90:828–834
Cejka D, Herberth J, Branscum AJ, Fardo DW, Monier-Faugere MC, Diarra D, Haas M, Malluche HH (2011) Sclerostin and Dickkopf-1 in renal osteodystrophy. Clin J Am Soc Nephrol 6:877–882
Fang Y, Ginsberg C, Seifert M, Agapova O, Sugatani T, Register TC, Freedman BI, Monier-Faugere MC, Malluche H, Hruska KA (2014) CKD-induced wingless/integration1 inhibitors and phosphorus cause the CKD-mineral and bone disorder. J Am Soc Nephrol 25:1760–1773
Couttenye MM, D’Haese PC, Van Hoof VO, Lemoniatou E, Goodman W, Verpooten GA, De Broe ME (1996) Low serum levels of alkaline phosphatase of bone origin: a good marker of adynamic bone disease in haemodialysis patients. Nephrol Dial Transplant 11:1065–1072
Haarhaus M, Monier-Faugere MC, Magnusson P, Malluche HH (2015) Bone alkaline phosphatase isoforms in hemodialysis patients with low versus non-low bone turnover: a diagnostic test study. Am J Kidney Dis 66:99–105
Pifer TB, McCullough KP, Port FK, Goodkin DA, Maroni BJ, Held PJ, Young EW (2002) Mortality risk in hemodialysis patients and changes in nutritional indicators: DOPPS. Kidney Int 62:2238–2245
Acknowledgements
We thank the following colleagues for their support and making their patients available for our study: Dr. Nassair and colleagues of Nephrology Associates of Kentuckiana; Dr. Eleanor Lederer and colleagues of University of Louisville Division of Nephrology; Dr. Khalil Rahman and colleagues of Nephrology Associates of Lexington; Dr. Khalid Bhatti and Dr. Mahendra Patel of Nephrology Associates of Central Kentucky; Dr. Jyotin Chandarana, Dr. Rezkalla Butros, Dr. Ashutosh Lohe, Dr. Syed Hasni, and Dr. Harold Helton of Cumberland Nephrology; and Dr. Mostafa Amr of Central Kentucky Nephrology.
The authors would like to thank Kimberly McLaughlin and Nedda Hughes for their invaluable and knowledgeable work in patient enrollment and data collection. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Funding
This study was funded in part by the National Institutes of Health, Grant RO1 080770, and the Kentucky Nephrology Research Trust. The project was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR001998.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
None.
Rights and permissions
About this article
Cite this article
Malluche, H.H., Monier-Faugere, MC., Blomquist, G. et al. Two-year cortical and trabecular bone loss in CKD-5D: biochemical and clinical predictors. Osteoporos Int 29, 125–134 (2018). https://doi.org/10.1007/s00198-017-4228-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00198-017-4228-4