Воздействие предварительной терапии по замене эстрогена на клинические результаты после хирургической операции со скачком люмбара.

Introduction

Lumbar spinal fusion is a commonly performed surgery for the management of degenerative spine disorders including spinal stenosis, spondylolisthesis, and degenerative disc disease. 1 , 2 Previous research has documented the impact of multiple patient factors on clinical outcomes following lumbar spinal fusion surgery including age, bone quality, and multiple medical comorbidities. 3 , 4 Recently, sex-based differences in musculoskeletal physiology and bone health have gained increasing attention due to its influence on post-operative outcomes following spine surgery. 5 - 8

Estrogen plays a vital role in bone metabolism, collagen synthesis, and inflammatory modulation, which may influence fusion rates fusion following lumbar spine surgery. 9 - 12 Postmenopausal estrogen deficiency has been associated with decreased bone mineral density and impaired rates of osteointegration, which may contribute to suboptimal outcomes following lumbar spine fusion surgery. 13 - 15 Despite these associations, the impact of estrogen replacement therapy (ERT) on outcomes following lumbar spinal fusion remains inadequately characterized across large patient cohorts. 16 , 17

Thus, the objective of this study was to assess the association between pre-operative ERT and clinical outcomes following lumbar spinal fusion. Based on prior evidence, 13 - 15 we hypothesized that ERT use would be associated with reduced rates of pseudoarthrosis five years following lumbar spinal fusion compared with patients not receiving ERT.

Materials and Methods

This propensity score–matched, multi-institutional cohort study analyzed patients undergoing single- and multi-level posterior lumbar spinal fusion between January 1, 2004, and December 31, 2024. Data were obtained from the TriNetX Research Network (TriNetX LLC, Cambridge, MA), a federated electronic medical record platform that aggregates clinical data from over one-hundred participating healthcare organizations. The dataset includes inpatient, outpatient, emergency department, laboratory data, and medication histories. All data were extracted from the TriNetX Research Collaborative Network on November 2, 2025. TriNetX compiles real-time, patient-level information and does not rely on healthcare administrative claims or employment records. Historical records prior to the implementation of ICD-10 were mapped to their corresponding ICD-9 codes to maintain consistency. This study was exempt from Institutional Review Board (IRB) review due to the lack of identifiable patient information. This study also adhered to observational reporting standards for cohort studies from the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE).

Patients undergoing single-level lumbar spine fusion were identified using Current Procedural Terminology (CPT) codes 22533, 22612, 22558, 22630, and 22633 ( Table 1 ). Patients undergoing multi-level lumbar spine fusion were identified using corresponding CPT codes 22534, 22614, 22585, 22632, and 22634. The primary study cohort of interest was defined by utilization of ERT within one-year prior to the index procedure via the International Classification of Diseases (ICD) code Z79.890. Only female patients over the age of fifty years were included in the final study cohort. Patients with a history of spine osteomyelitis, neoplasms, ankylosing spondylitis, other infectious or inflammatory bone diseases, and previous lumbar spinal surgeries or pseudoarthrosis diagnoses were excluded ( Table 1 ). Table 1. Diagnosis and Procedure Codes Associated with the Study Design Category Characteristic Codes Pre-operative propensity matching Myocardial infarction I21.x, I22.x, I25.x Congestive heart failure I09.9, I11.0. I13.0, I13.2, I25.5, I42.0, I42.5-I42.9, I43.x, I50.x, Cardiac arrythmias I44.1-I44.3, I45.6, I45.9, I47.x - I49.x, R00.0, R00.1, R00.8, T82.1, Z45.0, Z95.0 Valvular disease A52.0, I05.x - I08.x, I09.1, I09.8, I34.x - I39.x, Q23.0 - Q23.3, Z95.2 - Z95.4 Pulmonary circulation disorders I26.x, I27.x, I28.0, I28.8, I28.9 Peripheral vascular disease I70.x, I71.x, I73.1, I73.8, I73.9, I77.1, I79.0, I79.2, K55.1, K55.8, K55.9, Z95.8, Z95.9 Hypertension, uncomplicated I10.x Hypertension, complicated I11.x - I13.x, I15.x Paralysis G04.1, G11.4, G80.1, G80.2, G81.x, G82.x, G83.0 - G83.4, G83.9 Cerebrovascular disease G45.x, G46.x, I60.x-I69.x Dementia F00.x -F03.x, F05.x, G30.x Other neurological disorders G10.x - G13.x, G20.x - G22.x, G25.4, G25.5, G31.2, G31.8, G31.9, G32.x, G35.x - G37.x, G40.x, G41.x, G93.1, G93.4, R47.0, R56.x Chronic pulmonary disease I27.8, I27.9, J40.x - J47.x, J60.x - J67.x, J68.4, J70.1, J70.3 Diabetes, uncomplicated E10.0, E10.1, E10.9, E11.0, E11.1, E11.9, E12.0, E12.1, E12.9, E13.0, E13.1, E13.9, E14.0, E14.1, E14.9 Diabetes, complicated E10.2 - E10.8, E11.2 - E11.8, E12.2 - E12.8, E13.2 - E13.8, E14.2 - E14.8 Hypothyroidism E00.x - E03.x, E89.0 Liver disease B18.x, I85.x, I86.4, I98.2, K70.x, K71.1, K71.3 - K71.5, K71.7, K72.x - K74.x, K76.0, K76.2 - K76.9, Z94.4 Peptic ulcer disease, excluding bleeding K25.7, K25.9, K26.7, K26.9, K27.7, K27.9, K28.7, K28.9 Rheumatoid arthritis, collagen vascular disease L94.0, L94.1, L94.3, M05., M06.x, M08.x, M12.0, M12.3, M30.x, M31.0 - M31.3, M32.x - M35.x, M45.x, M46.1, M46.8, M46.9 Renal disease N03.x, N05.x, N18.x, N19.x, Z49.x AIDS/HIV B20.x-B22.x, B24.x Lymphoma C81.x - C85.x, C88.x, C96.x, C90.0, C90.2 Metastatic cancer C77.x - C80.x Solid tumor without metastasis C00.x - C26.x, C30.x - C34.x, C37.x - C41.x, C43.x, C45.x - C58.x, C60.х - C76.x, C97.x Coagulopathy D65 - D68.x, D69.1, D69.3 - D69.6 Obesity E66.x Weight loss E40.x - E46.x, R63.4, R64 Fluid and electrolyte disorders E22.2, E86.x, E87.x Blood loss anemia D50.0 Deficiency anemia D50.8, D50.9, D51.x - D53.x Alcohol abuse F10, E52, G62.1, 142.6, K29.2, K70.0, K70.3, K70.9, T51.x, Z50.2, Z71.4, Z72.1 Drug abuse F11.x - F16.x, F18.x, F19.x, Z71.5, 272.2 Psychoses F20.x, F22.x-F25.x, F28.x, F29.x, F30.2, F31.2, F31.5 Depression F20.4, F31.3 - F31.5, F32.x, F33.x, F34.1, F41.2, F43.2 Inclusion criteria Arthrodesis, lateral extracavitary technique, including minimal discectomy to prepare interspace (other than for decompression); lumbar 22533 Arthrodesis, lateral extracavitary technique, including minimal discectomy to prepare interspace (other than for decompression); thoracic or lumbar, each additional vertebral segment (list separately in addition to code for primary procedure) 22534 Arthrodesis, posterior or posterolateral technique, single interspace; lumbar (with lateral transverse technique, when performed) 22612 Arthrodesis, posterior or posterolateral technique, single interspace; each additional interspace (list separately in addition to code for primary procedure) 22614 Arthrodesis, anterior interbody technique, including minimal discectomy to prepare interspace (other than for decompression); lumbar 22558 Arthrodesis, anterior interbody technique, including minimal discectomy to prepare interspace (other than for decompression); each additional interspace (list separately in addition to code for primary procedure) 22585 Arthrodesis, posterior interbody technique, including laminectomy and/or discectomy to prepare interspace (other than for decompression), single interspace, lumbar 22630 Arthrodesis, posterior interbody technique, including laminectomy and/or discectomy to prepare interspace (other than for decompression), single interspace, lumbar; each additional interspace (list separately in addition to code for primary procedure) 22632 Arthrodesis, combined posterior or posterolateral technique with posterior interbody technique including laminectomy and/or discectomy sufficient to prepare interspace (other than for decompression), single interspace, lumbar 22633 Arthrodesis, combined posterior or posterolateral technique with posterior interbody technique including laminectomy and/or discectomy sufficient to prepare interspace (other than for decompression), single interspace, lumbar; each additional interspace (list separately in addition to code for primary procedure) 22634 Estrogen replacement therapy Z79.890 Exclusion criteria Other inflammatory spondylopathies M46 Ankylosing spondylitis M45 Osteomyelitis M86 Malignant neoplasm of bone C41 Secondary neoplasm C79 Neoplasm of uncertain behavior of spinal cord D43.4 Benign neoplasm of spinal cord D33.4 Fracture lumbar spine S32 Pseudoarthrosis M96.0 Previous surgical history 22842, 22840, 63035, 63030, 63047, 22558, 22585,22586, 22630, 22632, 22633, 22634, 22612, 22614 Thirty-day outcomes Pulmonary embolism I26 Deep venous thrombosis I82.4, I82.6 All VTE I26, I82.4, I82.6 Post-operative bleeding L72.4, L72.6 Infection T81.4, T84.63 Dehiscence T81.3 Pneumonia J18 Sepsis A41.9 Urinary tract infection N39.0 Acute kidney injury N17 Myocardial infarction I21 Stroke I60, I61, I62, I63 Opioid utilization CN101, 1022256, 80362, 80363 Inpatient readmission 99234, 99235, 99236 Emergency department utilization 99281, 99282, 99283, 99284, 99285 Incision and drainage 22015, 10180 Transfusion 36430 One, two, five-year outcomes Fusion 22558, 22630, 22633, 22612, 22800, 22802, 22804, 22808, 22810, 22812, 22533 Decompression 63030, 63035, 63042, 63044, 63047, 63048 Other surgical procedures 22830, 22849, 22850, 22899 Pseudoarthrosis M96.0 Adjacent segment disease M96.1 All reoperation 22558, 22630, 22633, 22612, 22800, 22802, 22804, 22808, 22810, 22812, 22533, 63030, 63035, 63042, 63044, 63047, 63048, 22830, 22849, 22850, 22899 Codes include ICD-10 diagnosis and CPT procedure codes.

To reduce confounding between patients in the ERT and non-ERT cohorts, 1:1 propensity score matching was performed based on over 320 clinical variables including age, sex, race, body mass index, and other medical comorbidities (Table 1). Comorbidities were identified using ICD-10 codes derived from the Charlson and Elixhauser comorbidity indices including essential hypertension (ICD-10: I10), hyperlipidemia (ICD-10: E78.5), diabetes mellitus (ICD-10: E08-E13), ischemic heart disease (ICD-10: I20-I25), chronic obstructive pulmonary disease (ICD-10: J44.9), chronic kidney disease (ICD-10: N18), anemia (ICD-10: D64.9), long-term anticoagulant use (ICD-10: Z79.01), and tobacco use (ICD-10: Z72.0) (Table 1). Propensity scores were calculated using logistic regression and patients were matched using nearest-neighbor matching without replacement and application of a caliper width of 0.10. Post-match balancing was evaluated using standardized mean differences (SMDs) all of which were <0.10, indicating adequate covariate balance.

Perioperative and longitudinal outcomes were identified using ICD-10, SNOMED, and CPT codes, which were evaluated at 30 days, 1-, 2-, and 5-year intervals after the index surgery ( Table 1 ). The primary outcomes of interest were pre-defined as rates of pseudoarthrosis (ICD-10: M96.0), adjacent segment disease (ICD-10: M96.1), and all lumbar spine reoperation (CPT codes (22558, 22630, 22633, 22612, 22800, 22802, 22804, 22808, 22810, 22812, 63030, 63035, 63042, 63044, 63047, 63048, 22830, 22849, 22850, 22899). Outcomes of interest were compared between patients in the ERT and non-ERT cohorts. In compliance with TriNetX privacy protocols, outcome counts <10 were rounded up to 10 to protect patient confidentiality. Binary outcomes were analyzed using the measure of association function, while time-to-event data were evaluated via Kaplan–Meier survival analysis with log-rank testing. Continuous variables were presented as means ± standard deviations and compared with independent-samples t -tests. Categorical variables were expressed as counts and percentages, which were compared using Chi-squared or Fisher’s exact tests, as appropriate. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated. Patients with preexisting outcomes prior to the observation window were excluded from time-to-event analyses. A two-tailed P value <.05 was considered statistically significant.

Results

Study Cohorts

After 1:1 propensity score matching, there were 2268 patients included in the single-level lumbar fusion cohort and 2776 patients included in the multi-level lumbar fusion cohorts, which were evenly divided into ERT and non-ERT cohorts. There were no significant differences in demographics or comorbidities between patients in the ERT and non-ERT cohorts with the exception of essential hypertension and Native Hawaiian/Other Pacific Islander race in the single-level lumbar spine fusion cohort ( Table 2 ). Table 2. Demographic and Medical Co-morbidity Data Used for Propensity Matching Characteristic Number of patients (%) P SMD Number of patients (%) P SMD Single level lumbar fusion without ERT Single level lumbar fusion with ERT Multi-level lumbar fusion without ERT Multi-level lumbar fusion with ERT n 1134 1134 1388 1388 Age at index, mean 66.4 ± 10 66.1 ± 9 .448 0.032 67.5 ± 10 67.3 ± 9 .504 0.025 Body mass index 30.3 ± 7 30.3 ± 7 .995 <0.001 30.7 ± 7 30.3 ± 7 .307 0.039 Race White 1014 (89.4) 998 (88.0) .288 0.045 1204 (86.7) 1192 (85.9) .508 0.025 Black 56 (4.9) 70 (6.2) .199 0.054 111 (8.0) 123 (8.9) .412 0.031 Unknown 18 (1.6) 23 (2.0) .431 0.033 22 (1.6) 22 (1.6) 1.0 <0.001 Other 15 (1.3) 15 (1.3) 1.0 <0.001 24 (1.7) 21 (1.5) .652 0.017 Asian 27 (2.4) 23 (2.0) .567 0.024 22 (1.6) 24 (1.7) .766 0.011 American Indian or Alaska native ≤10 (0.9) ≤10 (0.9) 1.0 <0.001 ≤10 (0.7) ≤10 (0.7) 1.0 <0.001 Native Hawaiian or other Pacific 0 (0) ≤10 (0.9) .001 0.133 0 0 - - Essential hypertension 604 (53.3) 664 (58.6) .011 0.107 858 (61.8) 907 (65.4) .053 0.073 Hyperlipidemia 451 (39.8) 481 (42.4) .200 0.054 636 (45.8) 663 (47.8) .304 0.039 Diabetes mellitus 248 (21.9) 262 (23.1) .481 0.03 372 (26.8) 394 (28.4) .350 0.036 Chronic ischemic heart disease 150 (13.2) 154 (13.6) .805 0.010 262 (18.9) 263 (18.9) .961 0.002 Chronic obstructive pulmonary disease 108 (9.5) 110 (9.7) .887 0.006 157 (11.3) 163 (11.7) .721 0.014 Chronic kidney disease 115 (10.1) 120 (10.6) .730 0.015 173 (12.5) 192 (13.8) .286 0.041 Anemia 164 (14.5) 189 (16.7) .165 0.058 249 (17.9) 253 (18.2) .844 0.008 Long term anticoagulant use 108 (9.5) 103 (9.1) .718 0.015 143 (10.3) 151 (10.9) .622 0.019 Tobacco use 36 (3.2) 50 (4.4) .124 0.065 71 (5.1) 74 (5.3) .798 0.010 Statistical significance is noted in bold ( P < .05); ERT = estrogen replacement therapy; SMD = standard mean difference.

Thirty-Day Outcomes

Within the thirty-day postoperative period, significantly lower rates of emergency department (ED) utilization were observed in the non-ERT groups for both the single- (OR: 0.6, 95% CI: 0.4-0.9; P = .006) and multi- (OR: 0.8, 95% CI: 0.6-1.0; P < .001) level lumbar spine fusion cohorts. Significantly lower rates of postoperative blood transfusion were observed in the non-ERT group (OR: 0.3, 95% CI: 0.2-0.4; P < .001) among patients undergoing multi-level lumbar spine fusion. There were no significant differences in the rates of pulmonary embolism, postoperative bleeding, infection, dehiscence, pneumonia, sepsis, urinary tract infection, acute kidney injury, myocardial infarction, and cerebrovascular accident between patients in the ERT and non-ERT cohorts. Additionally, there were no differences in rates of inpatient readmission and incision and drainage between patients in the ERT and non-ERT cohorts ( Table 3 ). Table 3. Comparison of Thirty-Day Complication Rates Following Lumbar Spine Fusion Outcomes Number of patients (%) OR (95%CI) P Number of patients (%) OR (95%CI) P Single level lumbar fusion without ERT Single level lumbar fusion with ERT Multi-level lumbar fusion without ERT Multi-level lumbar fusion with ERT Pulmonary embolism ≤10 (0.9) ≤10 (0.9) 1.0 (0.4 - 2.4) 1.0 13 (0.9) 12 (0.9) 1.1 (0.5 - 2.4) .841 Deep venous thrombosis ≤10 (0.9) ≤10 (0.9) 1.0 (0.4 - 2.4) 1.0 32 (2.3) 18 (1.3) 1.8 (1.0 - 3.2) .046 Postoperative bleeding ≤10 (0.9) ≤10 (0.9) 1.0 (0.4 - 2.4) 1.0 ≤10 (0.7) ≤10 (0.7) 1.0 (0.4 - 2.4) 1.0 Infection ≤10 (0.9) ≤10 (0.9) 1.0 (0.4 - 2.4) 1.0 27 (2.0) 28 (2.0) 1.0 (0.6 - 1.6) .892 Dehiscence 15 (1.3) 17 (1.5) 0.9 (0.4 - 1.8) .722 30 (2.2) 28 (2.0) 1.1 (0.6 - 1.8) .791 Pneumonia ≤10 (0.9) ≤10 (0.9) 1.0 (0.4 - 2.4) 1.0 29 (2.1) 21 (1.5) 1.4 (0.8 - 2.5) .254 Sepsis ≤10 (0.9) ≤10 (0.9) 1.0 (0.4 - 2.4) 1.0 18 (1.3) 24 (1.7) 0.8 (0.4 - 1.4) .351 Urinary tract infection 21 (1.9) 28 (2.5) 0.8 (0.4 - 1.3) .312 70 (5.0) 65 (4.7) 1.1 (0.8 - 1.5) .659 Acute kidney injury 19 (1.7) 14 (1.2) 1.4 (0.7 - 2.7) .381 51 (3.7) 57 (4.1) 0.9 (0.6 - 1.3) .556 Myocardial infarction ≤10 (0.9) ≤10 (0.9) 1.0 (0.4 - 2.4) 1.0 16 (1.2) 15 (1.1) 1.1 (0.5 - 2.2) .857 Cerebrovascular accident ≤10 (0.9) ≤10 (0.9) 1.0 (0.4 - 2.4) 1.0 21 (1.5) 23 (1.7) 0.9 (0.5 - 1.7) .761 Inpatient readmission ≤10 (0.9) ≤10 (0.9) 1.0 (0.4 - 2.4) 1.0 ≤10 (0.7) ≤10 (0.7) 1.0 (0.4 - 2.4) 1.0 Emergency department utilization 55 (4.9) 87 (7.7) 0.6 (0.4 - 0.9) .006 114 (8.2) 145 (10.5) 0.8 (0.6 - 1.0) .043 Incision and drainage ≤10 (0.9) ≤10 (0.9) 1.0 (0.4 - 2.4) 1.0 20 (1.4) 16 (1.2) 1.3 (0.7 - 2.4) .502 Transfusion 13 (1.2) 18 (1.6) 0.7 (0.4 - 1.5) .366 34 (2.5) 111 (8.0) 0.3 (0.2 - 0.4) <.001 Statistical significance is noted in bold ( P < .05); ERT = estrogen replacement therapy.

One-Year Outcomes

Among patients undergoing single-level lumbar spine fusion, the non-ERT cohort demonstrated significantly higher rates of pseudoarthrosis (OR: 1.9, 95% CI: 1.3-2.7; P < .001) compared to the ERT cohort within the one-year postoperative period ( Table 4 ). There were no significant one-year differences in the rates of adjacent segment disease and lumbar spine reoperation including fusion, decompression, and other lumbar spine surgical procedures following single-level lumbar fusion by ERT status ( P > .05). Table 4. Comparison of One-Year Complication Rates Following Lumbar Spine Fusion Outcomes Number of patients (%) OR (95%CI) P Number of patients (%) OR (95%CI) P Single level lumbar fusion without ERT Single level lumbar fusion with ERT Multi-level lumbar fusion without ERT Multi-level lumbar fusion with ERT Lumbar spine reoperation 15 (1.3) 17 (1.5) 0.9 (0.4 - 1.8) 0.722 49 (3.2) 54 (3.5) 0.9 (0.6 - 1.3) .616 Lumbar spine fusion ≤10 (0.9) ≤10 (0.9) 1.0 (0.4 - 2.4) 1.0 23 (1.5) 31 (2.0) 0.7 (0.4 - 1.3) .272 Lumbar spine decompression 14 (1.2) ≤10 (0.9) 1.4 (0.6 - 3.2) .412 21 (1.4) 20 (1.3) 1.1 (0.6 - 2.0) .875 Other lumbar spine surgery ≤10 (0.9) ≤10 (0.9) 1.0 (0.4 - 2.4) 1.0 20 (1.3) 16 (1.0) 1.3 (0.7 - 2.4) .503 Pseudoarthrosis 80 (7.1) 44 (3.9) 1.9 (1.3 - 2.7) <.001 198 (12.9) 73 (4.8) 3.0 (2.3 - 3.9) <.001 Adjacent segment disease 57 (5.0) 59 (5.2) 1.0 (0.7 - 1.4) .849 88 (5.7) 109 (7.1) 0.8 (0.6 - 1.1) .122 Statistical significance is noted in bold ( P < .05); ERT = estrogen replacement therapy.

Among patients undergoing multi-level lumbar spine fusion, the non-ERT cohort demonstrated significantly higher rates of pseudoarthrosis (OR: 3.0, 95% CI: 2.3-3.9; P < .001) compared to the ERT cohort within the one-year postoperative period. There were no significant one-year differences in the rates of adjacent segment disease and lumbar spine reoperation including fusion, decompression, and other lumbar spine surgical procedures following multi-level lumbar fusion by ERT status ( P > .05).

Two-Year Outcomes

Among patients undergoing single-level lumbar fusion, the non-ERT cohort demonstrated significantly higher rates of pseudoarthrosis (OR: 1.9, 95% CI: 1.3-2.7; P < .001) compared to the ERT cohort during the two-year postoperative period ( Table 5 ). There were no significant two-year differences in the rates of lumbar spine reoperation including fusion, decompression, and other lumbar spine surgical procedures following single-level lumbar fusion by ERT status ( P > .05). Table 5. Comparison of Two-Year Complication Rates Following Lumbar Spine Fusion Outcomes Number of patients (%) OR (95%CI) P Number of patients (%) OR (95%CI) P Single level lumbar fusion without ERT Single level lumbar fusion with ERT Multi-level lumbar fusion without ERT Multi-level lumbar fusion with ERT Lumbar spine reoperation 27 (2.4) 32 (2.8) 0.8 (0.5 - 1.4) .510 71 (4.6) 70 (4.6) 1.0 (0.7 - 1.4) .931 Lumbar spine fusion ≤10 (0.9) ≤10 (0.9) 1.0 (0.4 - 2.4) 1.0 34 (2.2) 42 (2.7) 0.8 (0.5 - 1.3) .353 Lumbar spine decompression 20 (1.8) 23 (2.0) 0.9 (0.5 - 1.6) .644 30 (2.0) 29 (1.9) 1.0 (0.6 - 1.7) .895 Other lumbar spine surgery ≤10 (0.9) ≤10 (0.9) 1.0 (0.4 - 2.4) 1.0 30 (2.0) 18 (1.2) 1.7 (0.9 - 3.0) .081 Pseudoarthrosis 86 (7.6) 47 (4.2) 1.9 (1.3 - 2.7) <.001 212 (13.9) 87 (5.7) 2.7 (2.1 - 3.5) <.001 Adjacent segment disease 86 (7.6) 82 (7.2) 1.1 (0.8 - 1.4) .748 123 (8.0) 151 (9.8) 0.8 (0.6 - 1.0) .076 Statistical significance is noted in bold ( P < .05); ERT = estrogen replacement therapy.

Among patients undergoing multi-level lumbar fusion, the non-ERT cohort demonstrated significantly higher rates of pseudoarthrosis (OR: 2.7, 95% CI: 2.1-3.5; P < .001) compared to the ERT cohort during the two-year postoperative period. There were no significant two-year differences in the rates of lumbar spine reoperation including fusion, decompression, and other lumbar spine surgical procedures following multi-level lumbar fusion by ERT status ( P > .05).

Five-Year Outcomes

At five years, patients in the non-ERT cohort demonstrated significantly higher rates of pseudoarthrosis (OR: 2.0, 95% CI: 1.4-2.8; P < .001) following single-level lumbar spine fusion ( Figure 1 ). There were no significant five-year differences in the rates of lumbar spine reoperation including fusion, decompression, and other lumbar spine surgical procedures following single-level lumbar fusion by ERT status ( P > .05, Table 6 ). Figure 1. Survival analysis for pseudoarthrosis diagnosis following single-level lumbar spine fusion Y -axis demonstrates the percentage of patients without pseudoarthrosis and x -axis demonstrates the number of days since the index surgery; ERT = Estrogen replacement therapy Table 6. Comparison of Five-Year Complication Rates Following Lumbar Spine Fusion Outcomes Number of patients (%) OR (95%CI) P Number of patients (%) OR (95%CI) P Single level lumbar fusion without ERT Single level lumbar fusion with ERT Multi-level lumbar fusion without ERT Multi-level lumbar fusion with ERT Lumbar spine reoperation 44 (3.9) 43 (3.8) 1.0 (0.7 - 1.6) .913 96 (6.2) 93 (6.1) 1.0 (0.8 - 1.4) .822 Lumbar spine fusion 16 (1.4) 16 (1.4) 1.0 (0.5 - 2.0) 1.0 52 (3.4) 57 (3.7) 0.9 (0.6 - 1.3) .626 Lumbar spine decompression 32 (2.8) 28 (2.5) 1.2 (0.7 - 1.9) .601 49 (3.2) 43 (2.8) 1.1 (0.8 - 1.7) .525 Other lumbar spine surgery ≤10 (0.9) ≤10 (0.9) 1.0 (0.4 - 2.4) 1.0 32 (2.1) 22 (1.4) 1.5 (0.9 - 2.5) .170 Pseudoarthrosis 97 (8.6) 52 (4.6) 2.0 (1.4 - 2.8) <.001 226 (14.7) 97 (6.3) 2.6 (2.0 - 3.3) <.001 Adjacent segment disease 123 (10.9) 103 (9.1) 1.2 (0.9 - 1.6) .161 176 (11.4) 184 (12.0) 1.0 (0.8 - 1.2) .654 Statistical significance is noted in bold ( P < .05); ERT = estrogen replacement therapy.

At 5 years, patients in the non-ERT cohort demonstrated significantly higher rates of pseudoarthrosis (OR: 2.6, 95% CI: 2.0-3.3; P < .001) following multi-level lumbar spine fusion ( Figure 2 ). There were no significant five-year differences in the rates of lumbar spine reoperation including fusion, decompression, and other lumbar spine surgical procedures following multi-level lumbar fusion by ERT status ( P > .05). Figure 2. Survival analysis for pseudoarthrosis diagnosis following multi-level lumbar spine fusion Y -axis demonstrates the percentage of patients without pseudoarthrosis and x -axis demonstrates the number of days since the index surgery; ERT = Estrogen replacement therapy

Discussion

Patients with pre-operative exposure to ERT demonstrated lower rates of pseudoarthrosis at five years following lumbar spinal fusion. However, there were similar rates of adjacent segment disease and lumbar spine reoperation between the two cohorts at 5 years. This study also demonstrated that pre-operative exposure to ERT was not associated with increased rates of thirty-day medical complications including cerebrovascular accident and venous thromboembolic events. However, pre-operative exposure to ERT was associated with higher rates of ED utilization, which may suggest the need for greater healthcare resource allocation during the early post-operative period. Collectively, these results confirmed our hypothesis that ERT use would be associated with lower rates of pseudoarthrosis following lumbar spinal fusion. Results from this study can be used to enhance patient counseling and risk stratification prior to lumbar spinal fusion.

The literature suggests that ERT has a biologically plausible and potentially beneficial influence on lumbar spinal fusion outcomes through its effect on inflammatory modulation and bone metabolism. 18 - 20 Estrogen deficiency is associated with increased bone resorption, reduced osteoblastic activity, and poor bone quality, which may compromise fusion mass formation and increase the risk of pseudoarthrosis in postmenopausal patients. 21 By mitigating these processes, ERT may enhance fusion biology, increase bone mineral density, and support hardware stability. 22 , 23 However, clinical evidence suggests that lumbar spine fusion rates can be influenced by patient age, baseline bone density, comorbidities, smoking status, and the use of adjunctive osteobiologics. 24 , 25 Importantly, potential benefits of pre-operative ERT exposure must be weighed against the known systemic risks of ERT including thromboembolic and cardiovascular events, which limit its routine use in post-menopausal women undergoing spine fusion surgery. 26 While ERT may contribute to a favorable biological environment for lumbar spine fusion in estrogen-deficient patients, it should be considered as part of a broader, individualized strategy for bone health optimization. 27

Prior studies have also highlighted potential risks and medical complications associated with pre-operative ERT exposure following surgery due to the pro-thrombotic nature of estrogen. 28 Venous thromboembolic events are feared complications following elective spine surgery, which vary between 0.2% and 13.6% depending on several patient factors. 29 Spine surgeons must balance the increased risk of venous thromboembolic events following surgery with the increased risk of post-operative bleeding events associated with prophylactic anticoagulation following lumbar spine fusion. 30 There are currently no widely accepted guidelines to inform spine surgeons on the use of chemoprophylaxis for venous thromboembolic events following lumbar spine surgery. 31 , 32 Prior studies have demonstrated that preoperative ERT is associated with increased risks of deep vein thrombosis and pulmonary embolism following spine surgery. 26 However, studies in the arthroplasty literature demonstrate lower rates of thromboembolic events among patients with ERT exposure after total joint arthroplasty, which highlights the risk dependency on the type of surgery. 33 In the present study, pre-operative ERT exposure was not associated with increased risks of deep vein thrombosis, pulmonary embolism, myocardial infarction, or cerebral vascular incidents following lumbar spinal fusion.

However, patients with pre-operative ERT exposure demonstrated higher rates of emergency department utilization following lumbar spine fusion, which may indicate a need for greater healthcare resource allocation during the early post-operative period for pain, anxiety, and other related factors. Spine surgeons should recognize this association and develop strategies to mitigate this risk following surgery including enhanced post-operative pain management protocols, earlier scheduled post-operative visits, and better-informed patient-specific counseling. The similar rates of medical complications observed between patients with and without pre-operative ERT exposure demonstrate the relative safety of ERT following lumbar spine fusion surgery.

Recent spine surgery literature has emphasized the importance of perioperative bone health optimization prior to lumbar spine fusion. 5 , 6 There are over 54 million patients in the United States alone that have osteoporosis, which is defined as having a bone mineral density that is 2.5 standard deviations below the average for a sex and race-matched cohort. 7 In the future, with the ease of measuring Hounsfield units on routine computerized tomography scans, the prevalence of osteoporosis is expected to increase significantly. 20 Prior studies in the spine surgery literature have demonstrated the difficulty of instrumentation and fusion among patients with osteoporosis, which can contribute to higher rates of pseudoarthrosis and proximal junctional failure. 4 , 6 , 8 Preoperative management of osteoporosis remains essential to mitigate the risk of these complications and enhance clinical outcomes after lumbar spine fusion. 18 , 19 Patients undergoing lumbar spine fusion should receive routine mineral supplementation in the form of calcium and vitamin D. 20 Patients with low bone mineral density including post-menopausal female patients should also be considered for anti-resorptive therapies like bisphosphonate or anabolic agents including ERT or parathyroid hormone. 21 In our study, rates of lumbar spine reoperation were similar between the two cohorts following lumbar spinal fusion despite lower rates of pseudoarthrosis observed in the ERT cohort. This suggests the presence of other etiologies for reoperation following lumbar spine fusion including symptom recurrence. Collectively, the best available evidence suggests that post-menopausal women present unique perioperative risks during lumbar spine fusion, which should be addressed through appropriate medical management prior to surgery. 22 - 25

There were several limitations to this study. While broad and inclusive across many healthcare organizations, electronic medical record data in TriNetX has coding limitations including a lack of certain clinical variables. For example, radiographic data, functional status, and patient reported outcome measures were not available. Rates of pseudoarthrosis were determined from recorded diagnostic codes as radiographic data were unavailable. Furthermore, biometric data including bone mineral density assessments were not unavailable in the electronic medical record. Inclusion of these data in future investigations can allow for an objective assessment of the impact of ERT on bone mineral density. Additionally, the reasons for increased emergency department utilization observed among patients on ERT could not be determined from the electronic medical record data due to a lack of associated diagnoses. The quality of electronic medical record data relies on the healthcare provider to input clinical endpoints accurately and consistently. Furthermore, the retrospective nature of this study limited the study findings to associations between variables. Future prospective studies are needed to validate these associations. The specific regimens for ERT exposure prior to lumbar spinal fusion were not detailed in TriNetX including dosing, administration, and duration. The magnitude and route of ERT administration may impact the bone metabolic profile and potential risk for medical complications following lumbar spine fusion. Underlying medical reasons for estrogen deficiency likely varied between study participants although all were post-menopausal women. While propensity score matching allowed for the creation of similar study cohorts with shared demographics and medical comorbidities, there was likely residual confounding from unaccounted variables. For example, additional institutional variables including surgeon experience, institutional volume, and surgical technique were unaccounted for in this study, which are known modulators of clinical outcomes following lumbar spine fusion. The purpose of this study, however, was to determine the association between pre-operative ERT exposure and rates of pseudoarthrosis, reoperation, and other medical complications following lumbar spine fusion.

In conclusion, pre-operative ERT exposure was associated with lower rates of pseudoarthrosis following lumbar spine fusion. Patients with pre-operative ERT exposure did not demonstrate higher rates of thirty-day medical complications after lumbar spine fusion. However, pre-operative ERT exposure was associated with higher rates of ED utilization following lumbar spine fusion. At 5 years, patients with pre-operative ERT exposure had similar rates of lumbar spine reoperation compared to patients without ERT exposure. Overall, results from this study highlight the relative safety of pre-operative ERT exposure prior to lumbar spine fusion surgery and a potential benefit with lower rates of pseudoarthrosis. Collectively, these findings suggest that pre-operative ERT exposure may enhance bone biology and fusion following lumbar spine fusion. Ultimately, insights from this study can enhance patient risk stratification and informed decision-making prior to lumbar spine fusion surgery.

Author Contributions: J.S.: Project conceptualization, data collection, data analysis, manuscript composition, manuscript revisions.

R.J.F.: data collection, data analysis, manuscript composition, manuscript revisions.

R.A.R.: project conceptualization, manuscript composition, manuscript revisions.

C.A.R.: Project conceptualization, data analysis, manuscript composition, manuscript revisions.

Funding: The authors received no financial support for the research, authorship, and/or publication of this article.

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

IRB Approval: This study received review exemption based on the policies of the Institutional Review Board.

ORCID iD

Jason Silvestre https://orcid.org/0000-0002-5831-0760

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