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Bone & Joint Research
Vol. 13, Issue 12 | Pages 741 - 749
6 Dec 2024
Blichfeldt-Eckhardt MR Varnum C Lauridsen JT Rasmussen LE Mortensen WCP Jensen HI Vaegter HB Lambertsen KL

Aims

Better prediction of outcome after total hip arthroplasty (THA) is warranted. Systemic inflammation and central neuroinflammation are possibly involved in progression of osteoarthritis and pain. We explored whether inflammatory biomarkers in blood and cerebrospinal fluid (CSF) were associated with clinical outcome, and baseline pain or disability, 12 months after THA.

Methods

A total of 50 patients from the Danish Pain Research Biobank (DANPAIN-Biobank) between January and June 2018 were included. Postoperative outcome was assessed as change in Oxford Hip Score (OHS) from baseline to 12 months after THA, pain was assessed on a numerical rating scale, and disability using the Pain Disability Index. Multiple regression models for each clinical outcome were included for biomarkers in blood and CSF, respectively, including age, sex, BMI, and Kellgren-Lawrence score.


The Bone & Joint Journal
Vol. 106-B, Issue 12 | Pages 1399 - 1407
1 Dec 2024
Fujii M Tanaka S Kawano S Ueno M Nagamine S Mawatari M

Aims

This study aimed to determine clinical outcomes; relationships between postoperative anterior, lateral, and posterior acetabular coverage and joint survival; and prognostic factors for joint survival after transposition osteotomy of the acetabulum (TOA).

Methods

Data from 616 patients (800 hips) with hip dysplasia who underwent TOA between November 1998 and December 2019 were reviewed. The median follow-up period was 8.9 years (IQR 5 to 14). A medical notes review was conducted to collect demographic data, complications, and modified Harris Hip Score (mHHS). Radiological indicators of acetabular coverage included lateral centre-edge angle (LCEA), anterior wall index (AWI), and posterior wall index (PWI). The cumulative probability of TOA failure (progression to Tönnis grade 3 or conversion to total hip arthroplasty) was estimated using the Kaplan-Meier product-limited method. A multivariate Cox proportional hazards model was used to identify predictors for failure.


The Bone & Joint Journal
Vol. 106-B, Issue 12 | Pages 1393 - 1398
1 Dec 2024
Morris WZ Haider S Hinds ST Podeszwa D Ellis H Osborne L Anable N Sucato D

Aims. There has been limited literature regarding outcomes of acetabular rim syndrome (ARS) with persistent acetabular os in the setting of acetabular dysplasia. The purpose of this study was to characterize a cohort of adolescent and young adult patients with ARS with persistent os and compare their radiological and clinical outcomes to patients with acetabular dysplasia without an os. Methods. We reviewed a prospective database of patients undergoing periacetabular osteotomy (PAO) for symptomatic acetabular dysplasia between January 1999 and December 2021 to identify hips with preoperative os acetabuli, defined as a closed triradiate cartilage but persistence of a superolateral os acetabulum. A total of 14 hips in 12 patients with persistent os acetabuli (ARS cohort) were compared to 50 randomly selected ‘control’ hips without persistent os acetabuli. Preoperative and postoperative radiographs were measured for markers of dysplasia: lateral centre-edge angle, anterior centre-edge angle, acetabular inclination, and migration index. Union of the os was determined in patients with ≥ six months’ follow-up. Patient-reported outcome measures (PROMs) included the University of California, Los Angeles (UCLA) activity score and modified Harris Hip Score (mHHS, maximum score 80) completed at one year postoperatively. Results. There was no significant difference between the ARS and control cohorts with regard to sex distribution (p = 0.270), age at surgery (p = 0.186), or BMI (p = 0.442). Preoperatively, the ARS cohort had more severe dysplasia, including lower lateral centre-edge angle (-9.3° (SD 12.5°) vs 7.6° (SD 10.7°); p < 0.001) and greater acetabular inclination (33.9° (SD 8.2°) vs 21.8° (SD 8.7°); p < 0.001). Postoperatively, 6/13 (46%) hips with ≥ six months of radiological follow up demonstrated union of the os. There was no difference between the ARS and control cohorts at one year in UCLA score (9.1 (SD 1.5) vs 8.2 (SD 1.9); p = 0.167) or mHHS (73.4 (SD 9.5) vs 69.9 (SD 8.8); p = 0.312). Conclusion. ARS with persistent acetabular os may occur in more severe dysplasia. Union occurs in 50% cases following corrective PAO. Cite this article: Bone Joint J 2024;106-B(12):1393–1398


Bone & Joint Research
Vol. 13, Issue 11 | Pages 673 - 681
22 Nov 2024
Yue C Xue Z Cheng Y Sun C Liu Y Xu B Guo J

Aims. Pain is the most frequent complaint associated with osteonecrosis of the femoral head (ONFH), but the factors contributing to such pain are poorly understood. This study explored diverse demographic, clinical, radiological, psychological, and neurophysiological factors for their potential contribution to pain in patients with ONFH. Methods. This cross-sectional study was carried out according to the “STrengthening the Reporting of OBservational studies in Epidemiology” statement. Data on 19 variables were collected at a single timepoint from 250 patients with ONFH who were treated at our medical centre between July and December 2023 using validated instruments or, in the case of hip pain, a numerical rating scale. Factors associated with pain severity were identified using hierarchical multifactor linear regression. Results. Regression identified the following characteristics as independently associated with higher pain score, after adjustment for potential confounders: Association Research Circulation Osseous classification stage IIIa or IIIb, bone marrow oedema, grade 3 joint effusion, as well as higher scores on pain catastrophizing, anxiety, and central sensitization. The final model explained 69.7% of observed variance in pain scores, of which clinical and radiological factors explained 37%, while psychological and neurophysiological factors explained 24% and demographic factors explained 8.7%. Conclusion. Multidimensional characteristics jointly contribute to the severity of pain associated with ONFH. These findings highlight the need to comprehensively identify potential contributors to pain, and to personalize management and treatment accordingly. Cite this article: Bone Joint Res 2024;13(11):673–681


Bone & Joint Open
Vol. 5, Issue 11 | Pages 971 - 976
5 Nov 2024
Baker G Hill J O'Neill F McChesney J Stevenson M Beverland D

Aims. In 2015, we published the results of our ceramic-on-metal (CoM) total hip arthroplasties (THAs) performed between October 2007 and July 2009 with a mean follow-up of 34 months (23 to 45) and a revision rate of 3.1%. The aim of this paper is to present the longer-term outcomes. Methods. A total of 264 patients were reviewed at a mean of 5.8 years (4.6 to 7.2) and 10.1 years (9.2 to 10.6) to determine revision rate, pain, outcome scores, radiological analysis, and blood ion levels. Those who were unwilling or unable to travel were contacted by telephone. Results. The all-cause revision rate at six years was 3.1% (eight THAs), increasing to 8.8% (18 THAs) at ten years. Of these, there were four and then seven bearing-related revisions at six and ten years, respectively. There was a statistically significant deterioration in the visual analogue scale pain score and Oxford Hip Score (OHS) between six and ten years. There were 18 CoM THAs in 17 patients who had a cobalt or chromium level over 4 ppb and ten CoM THAs in nine patients who had a cobalt or chromium level higher than 7 ppb with a statistically significant increase in chromium levels only between the two timepoints. Overall, 84 stems (39.1%) had significant radiolucent lines at ten years compared to 65 (25.5%) at six years. Conclusion. When compared to the original review, there has been a significant deterioration in pain score, OHS, radiograph appearance, and, most critically, survival has fallen to 91.2%, which does not meet the Orthopaedic Data Evaluation Panel (ODEP) 10 A* 95% threshold. Although this bearing is no longer on the market, 2.5% were bearing-related revisions, which have relevance to the discussion around modular dual-mobility implants that have a similar metal interface


Bone & Joint Open
Vol. 5, Issue 10 | Pages 825 - 831
3 Oct 2024
Afghanyar Y Afghanyar B Loweg L Drees P Gercek E Dargel J Rehbein P Kutzner KP

Aims. Limited implant survival due to aseptic cup loosening is most commonly responsible for revision total hip arthroplasty (THA). Advances in implant designs and materials have been crucial in addressing those challenges. Vitamin E-infused highly cross-linked polyethylene (VEPE) promises strong wear resistance, high oxidative stability, and superior mechanical strength. Although VEPE monoblock cups have shown good mid-term performance and excellent wear patterns, long-term results remain unclear. This study evaluated migration and wear patterns and clinical and radiological outcomes at a minimum of ten years’ follow-up. Methods. This prospective observational study investigated 101 cases of primary THA over a mean duration of 129 months (120 to 149). At last follow-up, 57 cases with complete clinical and radiological outcomes were evaluated. In all cases, the acetabular component comprised an uncemented titanium particle-coated VEPE monoblock cup. Patients were assessed clinically and radiologically using the Harris Hip Score, visual analogue scale (pain and satisfaction), and an anteroposterior radiograph. Cup migration and polyethylene wear were measured using Einzel-Bild-Röntgen-Analyze software. All complications and associated treatments were documented until final follow-up. Results. Clinical assessment showed persistent major improvement in all scores. On radiological assessment, only one case showed a lucent line (without symptoms). At last follow-up, wear and migration were below the critical thresholds. No cup-related revisions were needed, indicating an outstanding survival rate of 100%. Conclusion. Isoelastic VEPE cups offer high success rates and may prevent osteolysis, aseptic loosening, and the need for revision surgeries in the long term. However, longer follow-up is needed to validate our findings and confirm the advantages offered by this cup. Cite this article: Bone Jt Open 2024;5(10):825–831


Bone & Joint Open
Vol. 5, Issue 9 | Pages 776 - 784
19 Sep 2024
Gao J Chai N Wang T Han Z Chen J Lin G Wu Y Bi L

Aims

In order to release the contracture band completely without damaging normal tissues (such as the sciatic nerve) in the surgical treatment of gluteal muscle contracture (GMC), we tried to display the relationship between normal tissue and contracture bands by magnetic resonance neurography (MRN) images, and to predesign a minimally invasive surgery based on the MRN images in advance.

Methods

A total of 30 patients (60 hips) were included in this study. MRN scans of the pelvis were performed before surgery. The contracture band shape and external rotation angle (ERA) of the proximal femur were also analyzed. Then, the minimally invasive GMC releasing surgery was performed based on the images and measurements, and during the operation, incision lengths, surgery duration, intraoperative bleeding, and complications were recorded; the time of the first postoperative off-bed activity was also recorded. Furthermore, the patients’ clinical functions were evaluated by means of Hip Outcome Score (HOS) and Ye et al’s objective assessments, respectively.


The Bone & Joint Journal
Vol. 106-B, Issue 9 | Pages 898 - 906
1 Sep 2024
Kayani B Wazir MUK Mancino F Plastow R Haddad FS

Aims

The primary objective of this study was to develop a validated classification system for assessing iatrogenic bone trauma and soft-tissue injury during total hip arthroplasty (THA). The secondary objective was to compare macroscopic bone trauma and soft-tissues injury in conventional THA (CO THA) versus robotic arm-assisted THA (RO THA) using this classification system.

Methods

This study included 30 CO THAs versus 30 RO THAs performed by a single surgeon. Intraoperative photographs of the osseous acetabulum and periacetabular soft-tissues were obtained prior to implantation of the acetabular component, which were used to develop the proposed classification system. Interobserver and intraobserver variabilities of the proposed classification system were assessed.


Bone & Joint Open
Vol. 5, Issue 8 | Pages 671 - 680
14 Aug 2024
Fontalis A Zhao B Putzeys P Mancino F Zhang S Vanspauwen T Glod F Plastow R Mazomenos E Haddad FS

Aims

Precise implant positioning, tailored to individual spinopelvic biomechanics and phenotype, is paramount for stability in total hip arthroplasty (THA). Despite a few studies on instability prediction, there is a notable gap in research utilizing artificial intelligence (AI). The objective of our pilot study was to evaluate the feasibility of developing an AI algorithm tailored to individual spinopelvic mechanics and patient phenotype for predicting impingement.

Methods

This international, multicentre prospective cohort study across two centres encompassed 157 adults undergoing primary robotic arm-assisted THA. Impingement during specific flexion and extension stances was identified using the virtual range of motion (ROM) tool of the robotic software. The primary AI model, the Light Gradient-Boosting Machine (LGBM), used tabular data to predict impingement presence, direction (flexion or extension), and type. A secondary model integrating tabular data with plain anteroposterior pelvis radiographs was evaluated to assess for any potential enhancement in prediction accuracy.


The Bone & Joint Journal
Vol. 106-B, Issue 8 | Pages 775 - 782
1 Aug 2024
Wagner M Schaller L Endstrasser F Vavron P Braito M Schmaranzer E Schmaranzer F Brunner A

Aims. Hip arthroscopy has gained prominence as a primary surgical intervention for symptomatic femoroacetabular impingement (FAI). This study aimed to identify radiological features, and their combinations, that predict the outcome of hip arthroscopy for FAI. Methods. A prognostic cross-sectional cohort study was conducted involving patients from a single centre who underwent hip arthroscopy between January 2013 and April 2021. Radiological metrics measured on conventional radiographs and magnetic resonance arthrography were systematically assessed. The study analyzed the relationship between these metrics and complication rates, revision rates, and patient-reported outcomes. Results. Out of 810 identified hip arthroscopies, 359 hips were included in the study. Radiological risk factors associated with unsatisfactory outcomes after cam resection included a dysplastic posterior wall, Tönnis grade 2 or higher, and over-correction of the α angle. The presence of acetabular retroversion and dysplasia were also significant predictors for worse surgical outcomes. Notably, over-correction of both cam and pincer deformities resulted in poorer outcomes than under-correction. Conclusion. We recommend caution in performing hip arthroscopy in patients who have three positive acetabular retroversion signs. Acetabular dysplasia with a lateral centre-edge angle of less than 20° should not be treated with isolated hip arthroscopy. Acetabular rim-trimming should be avoided in patients with borderline dysplasia, and care should be taken to avoid over-correction of a cam deformity and/or pincer deformity. Cite this article: Bone Joint J 2024;106-B(8):775–782


The Bone & Joint Journal
Vol. 106-B, Issue 8 | Pages 783 - 791
1 Aug 2024
Tanaka S Fujii M Kawano S Ueno M Nagamine S Mawatari M

Aims

The aim of this study was to determine the clinical outcomes and factors contributing to failure of transposition osteotomy of the acetabulum (TOA), a type of spherical periacetabular osteotomy, for advanced osteoarthritis secondary to hip dysplasia.

Methods

We reviewed patients with Tönnis grade 2 osteoarthritis secondary to hip dysplasia who underwent TOA between November 1998 and December 2019. Patient demographic details, osteotomy-related complications, and the modified Harris Hip Score (mHHS) were obtained via medical notes review. Radiological indicators of hip dysplasia were assessed using preoperative and postoperative radiographs. The cumulative probability of TOA failure (progression to Tönnis grade 3 or conversion to total hip arthroplasty) was estimated using the Kaplan-Meier product-limited method. A multivariate Cox proportional hazards model was used to identify predictors of failure.


Bone & Joint Open
Vol. 5, Issue 6 | Pages 514 - 523
24 Jun 2024
Fishley W Nandra R Carluke I Partington PF Reed MR Kramer DJ Wilson MJ Hubble MJW Howell JR Whitehouse SL Petheram TG Kassam AM

Aims

In metal-on-metal (MoM) hip arthroplasties and resurfacings, mechanically induced corrosion can lead to elevated serum metal ions, a local inflammatory response, and formation of pseudotumours, ultimately requiring revision. The size and diametral clearance of anatomical (ADM) and modular (MDM) dual-mobility polyethylene bearings match those of Birmingham hip MoM components. If the acetabular component is satisfactorily positioned, well integrated into the bone, and has no surface damage, this presents the opportunity for revision with exchange of the metal head for ADM/MDM polyethylene bearings without removal of the acetabular component.

Methods

Between 2012 and 2020, across two centres, 94 patients underwent revision of Birmingham MoM hip arthroplasties or resurfacings. Mean age was 65.5 years (33 to 87). In 53 patients (56.4%), the acetabular component was retained and dual-mobility bearings were used (DM); in 41 (43.6%) the acetabulum was revised (AR). Patients underwent follow-up of minimum two-years (mean 4.6 (2.1 to 8.5) years).


Bone & Joint Research
Vol. 13, Issue 6 | Pages 294 - 305
17 Jun 2024
Yang P He W Yang W Jiang L Lin T Sun W Zhang Q Bai X Sun W Guo D

Aims

In this study, we aimed to visualize the spatial distribution characteristics of femoral head necrosis using a novel measurement method.

Methods

We retrospectively collected CT imaging data of 108 hips with non-traumatic osteonecrosis of the femoral head from 76 consecutive patients (mean age 34.3 years (SD 8.1), 56.58% male (n = 43)) in two clinical centres. The femoral head was divided into 288 standard units (based on the orientation of units within the femoral head, designated as N[Superior], S[Inferior], E[Anterior], and W[Posterior]) using a new measurement system called the longitude and latitude division system (LLDS). A computer-aided design (CAD) measurement tool was also developed to visualize the measurement of the spatial location of necrotic lesions in CT images. Two orthopaedic surgeons independently performed measurements, and the results were used to draw 2D and 3D heat maps of spatial distribution of necrotic lesions in the femoral head, and for statistical analysis.


Bone & Joint Open
Vol. 5, Issue 6 | Pages 479 - 488
6 Jun 2024
Paksoy A Meller S Schwotzer F Moroder P Trampuz A Imiolczyk J Perka C Hackl M Plachel F Akgün D

Aims

Current diagnostic tools are not always able to effectively identify periprosthetic joint infections (PJIs). Recent studies suggest that circulating microRNAs (miRNAs) undergo changes under pathological conditions such as infection. The aim of this study was to analyze miRNA expression in hip arthroplasty PJI patients.

Methods

This was a prospective pilot study, including 24 patients divided into three groups, with eight patients each undergoing revision of their hip arthroplasty due to aseptic reasons, and low- and high-grade PJI, respectively. The number of intraoperative samples and the incidence of positive cultures were recorded for each patient. Additionally, venous blood samples and periarticular tissue samples were collected from each patient to determine miRNA expressions between the groups. MiRNA screening was performed by small RNA-sequencing using the miRNA next generation sequencing (NGS) discovery (miND) pipeline.


The Bone & Joint Journal
Vol. 106-B, Issue 6 | Pages 540 - 547
1 Jun 2024
Nandra RS Elnahal WA Mayne A Brash L McBryde CW Treacy RBC

Aims

The Birmingham Hip Resurfacing (BHR) was introduced in 1997 to address the needs of young active patients using a historically proven large-diameter metal-on-metal (MoM) bearing. A single designer surgeon’s consecutive series of 130 patients (144 hips) was previously reported at five and ten years, reporting three and ten failures, respectively. The aim of this study was to extend the follow-up of this original cohort at 25 years.

Methods

The study extends the reporting on the first consecutive 144 resurfacing procedures in 130 patients for all indications. All operations were undertaken between August 1997 and May 1998. The mean age at operation was 52.1 years (SD 9.93; 17 to 76), and included 37 female patients (28.5%). Failure was defined as revision of either component for any reason. Kaplan-Meier survival analysis was performed. Routine follow-up with serum metal ion levels, radiographs, and Oxford Hip Scores (OHSs) was undertaken.


The Bone & Joint Journal
Vol. 106-B, Issue 6 | Pages 548 - 554
1 Jun 2024
Ohyama Y Minoda Y Masuda S Sugama R Ohta Y Nakamura H

Aims

The aim of this study was to compare the pattern of initial fixation and changes in periprosthetic bone mineral density (BMD) between patients who underwent total hip arthroplasty (THA) using a traditional fully hydroxyapatite (HA)-coated stem (T-HA group) and those with a newly introduced fully HA-coated stem (N-HA group).

Methods

The study included 36 patients with T-HA stems and 30 with N-HA stems. Dual-energy X-ray absorptiometry was used to measure the change in periprosthetic BMD, one and two years postoperatively. The 3D contact between the stem and femoral cortical bone was evaluated using a density-mapping system, and clinical assessment, including patient-reported outcome measurements, was recorded.


The Bone & Joint Journal
Vol. 106-B, Issue 6 | Pages 555 - 564
1 Jun 2024
Leal J Holland CT Cochrane NH Seyler TM Jiranek WA Wellman SS Bolognesi MP Ryan SP

Aims

This study aims to assess the relationship between history of pseudotumour formation secondary to metal-on-metal (MoM) implants and periprosthetic joint infection (PJI) rate, as well as establish ESR and CRP thresholds that are suggestive of infection in these patients. We hypothesized that patients with a pseudotumour were at increased risk of infection.

Methods

A total of 1,171 total hip arthroplasty (THA) patients with MoM articulations from August 2000 to March 2014 were retrospectively identified. Of those, 328 patients underwent metal artefact reduction sequence MRI and had minimum two years’ clinical follow-up, and met our inclusion criteria. Data collected included demographic details, surgical indication, laterality, implants used, history of pseudotumour, and their corresponding preoperative ESR (mm/hr) and CRP (mg/dl) levels. Multivariate logistic regression modelling was used to evaluate PJI and history of pseudotumour, and receiver operating characteristic curves were created to assess the diagnostic capabilities of ESR and CRP to determine the presence of infection in patients undergoing revision surgery.


Bone & Joint Open
Vol. 5, Issue 5 | Pages 394 - 400
15 May 2024
Nishi M Atsumi T Yoshikawa Y Okano I Nakanishi R Watanabe M Usui Y Kudo Y

Aims

The localization of necrotic areas has been reported to impact the prognosis and treatment strategy for osteonecrosis of the femoral head (ONFH). Anteroposterior localization of the necrotic area after a femoral neck fracture (FNF) has not been properly investigated. We hypothesize that the change of the weight loading direction on the femoral head due to residual posterior tilt caused by malunited FNF may affect the location of ONFH. We investigate the relationship between the posterior tilt angle (PTA) and anteroposterior localization of osteonecrosis using lateral hip radiographs.

Methods

Patients aged younger than 55 years diagnosed with ONFH after FNF were retrospectively reviewed. Overall, 65 hips (38 males and 27 females; mean age 32.6 years (SD 12.2)) met the inclusion criteria. Patients with stage 1 or 4 ONFH, as per the Association Research Circulation Osseous classification, were excluded. The ratios of anterior and posterior viable areas and necrotic areas of the femoral head to the articular surface were calculated by setting the femoral head centre as the reference point. The PTA was measured using Palm’s method. The association between the PTA and viable or necrotic areas of the femoral head was assessed using Spearman’s rank correlation analysis (median PTA 6.0° (interquartile range 3 to 11.5)).


The Bone & Joint Journal
Vol. 106-B, Issue 5 | Pages 435 - 441
1 May 2024
Angelomenos V Mohaddes M Kärrholm J Malchau H Shareghi B Itayem R

Aims

Refobacin Bone Cement R and Palacos R + G bone cement were introduced to replace the original cement Refobacin Palacos R in 2005. Both cements were assumed to behave in a biomechanically similar fashion to the original cement. The primary aim of this study was to compare the migration of a polished triple-tapered femoral stem fixed with either Refobacin Bone Cement R or Palacos R + G bone cement. Repeated radiostereometric analysis was used to measure migration of the femoral head centre. The secondary aims were evaluation of cement mantle, stem positioning, and patient-reported outcome measures.

Methods

Overall, 75 patients were included in the study and 71 were available at two years postoperatively. Prior to surgery, they were randomized to one of the three combinations studied: Palacos cement with use of the Optivac mixing system, Refobacin with use of the Optivac system, and Refobacin with use of the Optipac system. Cemented MS30 stems and cemented Exceed acetabular components were used in all hips. Postoperative radiographs were used to assess the quality of the cement mantle according to Barrack et al, and the position and migration of the femoral stem. Harris Hip Score, Oxford Hip Score, Forgotten Joint Score, and University of California, Los Angeles Activity Scale were collected.


Bone & Joint Research
Vol. 13, Issue 4 | Pages 184 - 192
18 Apr 2024
Morita A Iida Y Inaba Y Tezuka T Kobayashi N Choe H Ike H Kawakami E

Aims

This study was designed to develop a model for predicting bone mineral density (BMD) loss of the femur after total hip arthroplasty (THA) using artificial intelligence (AI), and to identify factors that influence the prediction. Additionally, we virtually examined the efficacy of administration of bisphosphonate for cases with severe BMD loss based on the predictive model.

Methods

The study included 538 joints that underwent primary THA. The patients were divided into groups using unsupervised time series clustering for five-year BMD loss of Gruen zone 7 postoperatively, and a machine-learning model to predict the BMD loss was developed. Additionally, the predictor for BMD loss was extracted using SHapley Additive exPlanations (SHAP). The patient-specific efficacy of bisphosphonate, which is the most important categorical predictor for BMD loss, was examined by calculating the change in predictive probability when hypothetically switching between the inclusion and exclusion of bisphosphonate.