Supplementation Materials

Supplementation materials:

Title: Hyponatremia and Osteoporosis: Reappraisal of a Novel Association

Journal Name: Osteoporosis International

Authors:

Farsad Afshinnia, MD: Division of nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan

Baskaran Sundaram, MBBS: Division of Radiology, Thomas Jefferson University, Philadelphia, Pennsylvania

Robert J Ackermann, BS, CNMT: Department of Nuclear Medicine/ Radiology, University of Michigan, Ann Arbor, Michigan

Ka Kit Wong, MBBS: Department of Nuclear Medicine/Radiology, University of Michigan, Ann Arbor, Michigan, and VA Ann Arbor Healthcare System, Ann Arbor, Michigan

Corresponding Author: Farsad Afshinnia MD

Email:

Supplement Table 1: List of comorbidities and their corresponding ICD9 codes used to search for identification of the known comorbidities

Comorbidities / ICD9 codes
Anorexia nervosa / 307.1
Bulimia / 307.51
Inflammatory arthridites / 714, 714.8, 714.81, 714.89, 714.9, 720, 720.8, 720.81, 720.89
Solid organ transplantation / E878, V42, V42.0, V42.1, V42.2, V42.3, V42.4, V42.6, V42.7, V42.8, V42.9
Malabsorption / 579, 579.8, 579.9
Osteomalacia / 268.2
Endometriosis / 617, 617.0, 617.1, 617.2, 617.3, 617.4, 617.5, 617.6, 617.7, 617.8, 617.9
Acromegaly / 253.0
Hyperparathyroidism / 252.0, 252.01, 252.02, 252.08, 588.81
Hyperthyroidism / 242, 242.1, 242.3, 242.9
Cushing syndrome / 255.0
Chronic alcoholism / 303, 303.9
Cirrhosis / 571, 571.0, 571.1, 571.2, 571.3, 571.4, 571.5, 571.6, 571.8, 571.9
Multiple myeloma / 203.0
Bariatric surgery / V45.86, V45.3, V45.89
Hip fracture / 733.14, 733.96, 820.0, 820.1, 820.2, 820.3
Spine fracture / 733.13, 805, 806

Supplement Table 2: List of class of medications searched in the clinical records of each patient

Medication class / Including
Calcium supplementation / Any form including Calcium Chloride, Calcium Carbonate, Calcium Acetate, Calcium Citrate
Vitamin D / Any form including synthetic analogues
Bisphosphonates / Alendronate, Etidronate, Ibandronate, Pamidronate, Risedronate, Zoledronic Acid
Thiazide diuretics / Hydrochlorothiazide, Chlorthalidone, Indapamide, Metolazone, Zaroxolyn, Methyclothiazide
Loop diuretics / Furosemide (Lasix), Bumetanide (Bumex), Torsemide (Demadex), Edecrin
Steroids / Cortisol, Cortisone, Prednisone, Prednisolone, Methylprednisolone, Dexamethasone, Betamethasone
Anti-consultants / Paraldehyde, Phenobarbital, Diazepam, Carbamazapine, Oxcarbazepine, Valproic acid, Divalproex, Topiramate, Gabapentin, Pregabalin, Phenytoin, Fosphenytoin, Levetiracetam, Ethosuximide, Acetazolamide, Lamotrigine
Anti-depressants / Citalopram (Celexa), Escitalopram (Lexapro, Cipralex), Paroxetine (Paxil, Seroxat), Fluoxetine (Prozac), Fluvoxamine (Luvox), Sertraline (Zoloft, Lustral), Mirtazapine (Remeron, Avanza, Zispin), Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Milnacipran (Ixel, Savella), Venlafaxine (Effexor), Levomilnacipran (Fetzima), Etoperidone (Axiomin, Etonin), Nefazodone (Serzone, Nefadar), Trazodone (Desyrel), Vilazodone (Viibryd), Vortioxetine (Brintellix), Bupropion (Wellbutrin, Zyban), Amitriptyline (Elavil, Endep), Amoxapine (Asendin), Clomipramine (Anafranil), Doxepin (Adapin, Sinequan), Imipramine (Tofranil), Trimipramine (Surmontil), Desipramine (Norpramin), Nortriptyline (Pamelor, Aventyl, Noritren), Protriptyline (Vivactil), Tianeptine (Stablon, Coaxil, Tatinol), Amineptine (Survector), Opipramol (Insidon, Pramolan, Ensidon, Oprimol), Isocarboxazid (Marplan), Phenelzine (Nardil), Selegiline (Eldepryl, Emsam), Tranylcypromine (Parnate), Moclobemide (Aurorix, Manerix), Pirlindole (Pirazidol)
Opiates / Codeine, Morphine, Hydrocodone, Hydromorphone, Oxycodone, Fentanyl, Propoxyphene, Methadone, Diphenoxylate, Loperamide
Androgen deprivation therapy / Leuprolide, Goserelin, Triptorelin, Histrelin, Degarelix, Flutamide, Bicalutamide, Nilutamide
Aromatase inhibitor therapy / Aminoglutethimide, Testolactone (Teslac), Anastrozole (Arimidex), Letrozole (Femara), Exemestane (Aromasin), Vorozole (Rivizor), Formestane (Lentaron), Fadrozole (Afema), 4-Hydroxyandrostenedione, 1,4,6-Androstatrien-3,17-dione (ATD), 4-Androstene-3,6,17-trione ("6-OXO"), Resveratrol, Nicotine, Myosmine, Zinc, Catechin, Chalcones, Apigenin, Eriodictyol, Isoliquiritigenin, Mangostin

Supplement Table 3: Odds ratio of osteoporosis by age and sodium categories in various models

Lumbar (Model 1):
n (% with Osteoporosis) / Odds Ratio / 95% Confidence Interval / P Value / Age-Sodium interaction P
Age <55 (N=7763) / <0.001
≤135 / 35 (24.0%) / 2.101 / 1.419 to 3.11 / <0.001
136-140 / 498 (12.5%) / 0.948 / 0.828 to 1.085 / 0.439
141-145 / 469 (13.0%) / 1 (Reference)
>145 / 3 (12.0%) / 0.909 / 0.271 to 3.048 / 0.877
Age 55-67 (N=8680)
≤135 / 51 (26.8%) / 1.53 / 1.102 to 2.124 / 0.011
136-140 / 588 (17.8%) / 0.905 / 0.808 to 1.013 / 0.082
141-145 / 989 (19.3%) / 1 (Reference)
>145 / 23 (28.8%) / 1.682 / 1.031 to 2.743 / 0.037
Age >67 (N=8341)
≤135 / 114 (31.1%) / 1.294 / 1.028 to 1.63 / 0.028
136-140 / 863 (25.9%) / 1.005 / 0.908 to 1.113 / 0.925
141-145 / 1185 (25.8%) / 1 (Reference)
>145 / 12 (21.8%) / 0.802 / 0.421 to 1.525 / 0.501
Lumbar (Model 2):
n (% with Osteoporosis) / Odds Ratio / 95% Confidence Interval / P Value / Age-Sodium interaction P
Age <55 (N=7763) / <0.001
≤135 / 35 (24.0%) / 1.989 / 1.339 to 2.957 / 0.001
136-140 / 498 (12.5%) / 0.951 / 0.83 to 1.09 / 0.472
141-145 / 469 (13.0%) / 1 (Reference)
>145 / 3 (12.0%) / 0.958 / 0.283 to 3.246 / 0.946
Age 55-67 (N=8680)
≤135 / 51 (26.8%) / 1.566 / 1.126 to 2.179 / 0.008
136-140 / 588 (17.8%) / 0.919 / 0.82 to 1.029 / 0.144
141-145 / 989 (19.3%) / 1 (Reference)
>145 / 23 (28.8%) / 1.697 / 1.039 to 2.772 / 0.035
Age >67 (N=8341)
≤135 / 114 (31.1%) / 1.206 / 0.952 to 1.528 / 0.121
136-140 / 863 (25.9%) / 1.017 / 0.917 to 1.129 / 0.748
141-145 / 1185 (25.8%) / 1 (Reference)
>145 / 12 (21.8%) / 0.796 / 0.416 to 1.522 / 0.489
Lumbar (Model 3):
n (% with Osteoporosis) / Odds Ratio / 95% Confidence Interval / P Value / Age-Sodium interaction P
Age <55 (N=7763) / 0.001
≤135 / 35 (24.0%) / 1.605 / 1.029 to 2.503 / 0.037
136-140 / 498 (12.5%) / 0.936 / 0.805 to 1.089 / 0.391
141-145 / 469 (13.0%) / 1 (Reference)
>145 / 3 (12.0%) / 0.462 / 0.06 to 3.58 / 0.46
Age 55-67 (N=8680)
≤135 / 51 (26.8%) / 1.509 / 1.051 to 2.166 / 0.026
136-140 / 588 (17.8%) / 0.885 / 0.777 to 1.009 / 0.068
141-145 / 989 (19.3%) / 1 (Reference)
>145 / 23 (28.8%) / 1.504 / 0.85 to 2.66 / 0.161
Age >67 (N=8341)
≤135 / 114 (31.1%) / 1.119 / 0.857 to 1.462 / 0.408
136-140 / 863 (25.9%) / 1.005 / 0.894 to 1.13 / 0.93
141-145 / 1185 (25.8%) / 1 (Reference)
>145 / 12 (21.8%) / 0.885 / 0.428 to 1.829 / 0.741
Femoral Neck (Model 1):
n (% with Osteoporosis) / Odds Ratio / 95% Confidence Interval / P Value / Age-Sodium interaction P
Age <55 (N=7763) / <0.001
≤135 / 18 (12.3%) / 3.206 / 1.907 to 5.391 / <0.001
136-140 / 195 (4.9%) / 1.169 / 0.941 to 1.453 / 0.159
141-145 / 151 (4.2%) / 1 (Reference)
>145 / 1 (4.0%) / 0.95 / 0.128 to 7.069 / 0.96
Age 55-67 (N=8680)
≤135 / 23 (12.1%) / 1.933 / 1.233 to 3.03 / 0.004
136-140 / 268 (8.1%) / 1.241 / 1.051 to 1.466 / 0.011
141-145 / 340 (6.7%) / 1 (Reference)
>145 / 5 (6.3%) / 0.936 / 0.376 to 2.329 / 0.886
Age >67 (N=8341)
≤135 / 96 (26.2%) / 1.586 / 1.242 to 2.025 / <0.001
136-140 / 661 (19.8%) / 1.109 / 0.99 to 1.242 / 0.075
141-145 / 838 (18.3%) / 1 (Reference)
>145 / 7 (12.7%) / 0.653 / 0.294 to 1.448 / 0.294
Femoral Neck (Model 2):
n (% with Osteoporosis) / Odds Ratio / 95% Confidence Interval / P Value / Age-Sodium interaction P
Age <55 (N=7763) / <0.001
≤135 / 18 (12.3%) / 2.805 / 1.647 to 4.777 / <0.001
136-140 / 195 (4.9%) / 1.168 / 0.937 to 1.456 / 0.167
141-145 / 151 (4.2%) / 1 (Reference)
>145 / 1 (4.0%) / 0.969 / 0.127 to 7.367 / 0.976
Age 55-67 (N=8680)
≤135 / 23 (12.1%) / 1.785 / 1.136 to 2.806 / 0.012
136-140 / 268 (8.1%) / 1.184 / 1.001 to 1.4 / 0.049
141-145 / 340 (6.7%) / 1 (Reference)
>145 / 5 (6.3%) / 0.973 / 0.39 to 2.424 / 0.953
Age >67 (N=8341)
≤135 / 96 (26.2%) / 1.266 / 0.981 to 1.633 / 0.07
136-140 / 661 (19.8%) / 1.037 / 0.922 to 1.166 / 0.547
141-145 / 838 (18.3%) / 1 (Reference)
>145 / 7 (12.7%) / 0.676 / 0.299 to 1.527 / 0.346
Neck (Model 3):
n (% with Osteoporosis) / Odds Ratio / 95% Confidence Interval / P Value / Age-Sodium interaction P
Age <55 (N=7763) / 0.015
≤135 / 18 (12.3%) / 1.897 / 1.038 to 3.469 / 0.037
136-140 / 195 (4.9%) / 1.168 / 0.918 to 1.486 / 0.206
141-145 / 151 (4.2%) / 1 (Reference)
>145 / 1 (4.0%) / 1.325 / 0.163 to 10.803 / 0.793
Age 55-67 (N=8680)
≤135 / 23 (12.1%) / 1.246 / 0.743 to 2.09 / 0.404
136-140 / 268 (8.1%) / 1.123 / 0.927 to 1.361 / 0.235
141-145 / 340 (6.7%) / 1 (Reference)
>145 / 5 (6.3%) / 0.608 / 0.184 to 2.013 / 0.415
Age >67 (N=8341)
≤135 / 96 (26.2%) / 1.154 / 0.868 to 1.536 / 0.325
136-140 / 661 (19.8%) / 1.03 / 0.904 to 1.174 / 0.653
141-145 / 838 (18.3%) / 1 (Reference)
>145 / 7 (12.7%) / 0.868 / 0.374 to 2.012 / 0.741
Total Hip (Model 1):
n (% with Osteoporosis) / Odds Ratio / 95% Confidence Interval / P Value / Age-Sodium interaction P
Age <55 (N=7763) / <0.001
≤135 / 19 (13.0%) / 4.018 / 2.406 to 6.713 / <0.001
136-140 / 172 (4.3%) / 1.208 / 0.957 to 1.524 / 0.112
141-145 / 129 (3.6%) / 1 (Reference)
>145 / 1 (4.0%) / 1.119 / 0.15 to 8.337 / 0.912
Age 55-67 (N=8680)
≤135 / 21 (11.1%) / 2.803 / 1.746 to 4.5 / <0.001
136-140 / 181 (5.5%) / 1.31 / 1.07 to 1.604 / 0.009
141-145 / 217 (4.2%) / 1 (Reference)
>145 / 2 (2.5%) / 0.578 / 0.141 to 2.369 / 0.447
Age >67 (N=8341)
≤135 / 84 (22.9%) / 2.254 / 1.738 to 2.922 / <0.001
136-140 / 461 (13.8%) / 1.22 / 1.068 to 1.394 / 0.003
141-145 / 534 (11.6%) / 1 (Reference)
>145 / 6 (10.9%) / 0.93 / 0.396 to 2.181 / 0.867
Total Hip (Model 2):
n (% with Osteoporosis) / Odds Ratio / 95% Confidence Interval / P Value / Age-Sodium interaction P
Age <55 (N=7763) / <0.001
≤135 / 19 (13.0%) / 3.485 / 2.066 to 5.881 / <0.001
136-140 / 172 (4.3%) / 1.148 / 0.908 to 1.453 / 0.249
141-145 / 129 (3.6%) / 1 (Reference)
>145 / 1 (4.0%) / 1.14 / 0.15 to 8.64 / 0.899
Age 55-67 (N=8680)
≤135 / 21 (11.1%) / 2.671 / 1.66 to 4.297 / <0.001
136-140 / 181 (5.5%) / 1.278 / 1.043 to 1.567 / 0.018
141-145 / 217 (4.2%) / 1 (Reference)
>145 / 2 (2.5%) / 0.589 / 0.144 to 2.413 / 0.462
Age >67 (N=8341)
≤135 / 84 (22.9%) / 1.831 / 1.392 to 2.407 / <0.001
136-140 / 461 (13.8%) / 1.171 / 1.02 to 1.345 / 0.025
141-145 / 534 (11.6%) / 1 (Reference)
>145 / 6 (10.9%) / 0.99 / 0.413 to 2.376 / 0.983
Total Hip (Model 3):
n (% with Osteoporosis) / Odds Ratio / 95% Confidence Interval / P Value / Age-Sodium interaction P
Age <55 (N=7763) / 0.002
≤135 / 19 (13.0%) / 2.464 / 1.362 to 4.458 / 0.003
136-140 / 172 (4.3%) / 1.124 / 0.87 to 1.452 / 0.371
141-145 / 129 (3.6%) / 1 (Reference)
>145 / 1 (4.0%) / 1.743 / 0.213 to 14.234 / 0.604
Age 55-67 (N=8680)
≤135 / 21 (11.1%) / 1.961 / 1.129 to 3.406 / 0.017
136-140 / 181 (5.5%) / 1.193 / 0.942 to 1.51 / 0.143
141-145 / 217 (4.2%) / 1 (Reference)
>145 / 2 (2.5%) / 0.32 / 0.043 to 2.397 / 0.267
Age >67 (N=8341)
≤135 / 84 (22.9%) / 1.547 / 1.13 to 2.118 / 0.006
136-140 / 461 (13.8%) / 1.17 / 1.001 to 1.367 / 0.049
141-145 / 534 (11.6%) / 1 (Reference)
>145 / 6 (10.9%) / 1.374 / 0.555 to 3.402 / 0.492

Model 1: Case mixed unadjusted model

Model 2: Adjusted for age, sex, and race

Model 3: Adjusted for model 2, plus BMI, serum albumin, calcium, glucose, medications, and comorbidities

Supplement Table 4:

Lumbar:
n (% with Osteoporosis) / Odds Ratio / 95% Confidence Interval / P Value / Age-HI interaction P
Age<55 (N=6740) / <0.001
≤3 / 924 (12.6%) / 1 (Reference)
4-19 / 24 (14.5%) / 0.933 / 0.582 to 1.494 / 0.772
20-104 / 31 (22.6%) / 1.417 / 0.89 to 2.258 / 0.142
≥105 / 26 (26.3%) / 1.693 / 1.023 to 2.803 / 0.041
Age 55-67 (N=7204)
≤3 / 1575 (19.0%) / 1 (Reference)
4-19 / 29 (20.9%) / 1.314 / 0.844 to 2.047 / 0.227
20-104 / 29 (21.5%) / 1.118 / 0.704 to 1.777 / 0.636
≥105 / 18 (14.4%) / 0.72 / 0.425 to 1.218 / 0.22
Age>67 (N=7193)
≤3 / 1981 (25.7%) / 1 (Reference)
4-19 / 41 (26.1%) / 1.053 / 0.708 to 1.564 / 0.8
20-104 / 56 (27.7%) / 1.015 / 0.716 to 1.44 / 0.932
≥105 / 96 (36.2%) / 1.526 / 1.142 to 2.038 / 0.004
Femoral Neck:
n (% with Osteoporosis) / Odds Ratio / 95% Confidence Interval / P Value / Age-HI interaction P
Age<55 (N=6740) / 0.029
≤3 / 309 (4.2%) / 1 (Reference)
4-19 / 22 (13.3%) / 1.879 / 1.1 to 3.212 / 0.021
20-104 / 18 (13.1%) / 1.64 / 0.904 to 2.976 / 0.103
≥105 / 16 (16.2%) / 2.019 / 1.076 to 3.789 / 0.029
Age 55-67 (N=7204)
≤3 / 581 (7.0%) / 1 (Reference)
4-19 / 25 (18.0%) / 1.703 / 1.033 to 2.809 / 0.037
20-104 / 18 (13.3%) / 0.791 / 0.439 to 1.425 / 0.435
≥105 / 12 (9.6%) / 0.836 / 0.439 to 1.592 / 0.586
Age>67 (N=7193)
≤3 / 1423 (18.4%) / 1 (Reference)
4-19 / 43 (27.4%) / 1.353 / 0.915 to 2.002 / 0.13
20-104 / 56 (27.7%) / 1.245 / 0.875 to 1.772 / 0.223
≥105 / 80 (30.2%) / 1.223 / 0.898 to 1.666 / 0.202
Total Hip:
n (% with Osteoporosis) / Odds Ratio / 95% Confidence Interval / P Value / Age-HI interaction P
Age<55 (N=6740) / 0.001
≤3 / 263 (3.6%) / 1 (Reference)
4-19 / 22 (13.3%) / 2.341 / 1.369 to 4.005 / 0.002
20-104 / 18 (13.1%) / 2.178 / 1.197 to 3.963 / 0.011
≥105 / 18 (18.2%) / 3.573 / 1.944 to 6.566 / <0.001
Age 55-67 (N=7204)
≤3 / 374 (4.5%) / 1 (Reference)
4-19 / 17 (12.2%) / 1.562 / 0.861 to 2.833 / 0.142
20-104 / 19 (14.1%) / 1.178 / 0.638 to 2.176 / 0.6
≥105 / 11 (8.8%) / 1.322 / 0.67 to 2.608 / 0.421
Age>67 (N=7193)
≤3 / 944 (12.2%) / 1 (Reference)
4-19 / 31 (19.7%) / 1.462 / 0.933 to 2.291 / 0.098
20-104 / 38 (18.8%) / 1.12 / 0.733 to 1.71 / 0.601
≥105 / 72 (27.2%) / 1.741 / 1.251 to 2.423 / 0.001

HI: Hyponatremia Interval