Archives of (2019) 14: 23 https://doi.org/10.1007/s11657-019-0572-7

REVIEW ARTICLE

Changes in femoral mineral density after total : a systematic review and meta-analysis

Joel M. Prince1 & James T. Bernatz1 & Neil Binkley2 & Matthew P. Abdel3 & Paul A. Anderson1

Received: 3 November 2018 /Accepted: 27 January 2019/Published online: 23 February 2019 # International Osteoporosis Foundation and National Osteoporosis Foundation 2019

Abstract Background Bone loss after total knee arthroplasty (TKA) may lead to periprosthetic fractures that are associated with significant costs (morbidity, economic, etc.) and pose a challenge to operative fixation. This meta-analysis quantifies the change in bone mineral density (BMD) of the distal after primary TKA. Methods A systematic review of six databases was performed by two independent reviewers. Studies that reported bone density after knee arthroplasty were identified and inclusion/exclusion criteria was applied. Data were extracted and analyzed using the Comprehensive Meta-Analysis Software. Results Fourteen studies were included in the analysis. The average decrease in BMD was 0.09 [0.05, 0.13], 0.14 [0.08, 0.20], 0.16 [0.10, 0.23], and 0.16 [0.12, 0.20] g/cm2 at 3, 6, 12, and 24 months, respectively, corresponding to a 9.3%, 13.2%, 15.8%, and 15.4% BMD loss. A high degree of heterogeneity existed between the studies (I2 > 90% at most time points). Conclusion In summary, there is a rapid and significant 15% decrease in BMD in the first 6 months after TKA that is sustained to 24 months. Better understanding regarding how perioperative optimization of bone health may affect BMD loss and the incidence of periprosthetic fracture is essential. Level of evidence Therapeutic Level II.

Keywords Bone mineral density . Bone loss . Femur . Total knee arthroplasty . Meta-analysis . Periprosthetic fracture

Introduction associated with high costs, prolonged length of stay, and poorer outcomes [2]. Major risk factors for fracture are older Currently over 7 million people in the USA have knee or hip age, female gender, and presence of osteoporosis which are arthroplasties [1], and unfortunately, there is a rise in common in those undergoing total knee arthroplasty (TKA) periprosthetic fractures. The majority of these cases are fragil- [3, 4]. A potential strategy to reduce periprosthetic fracture ity fractures which are difficult to manage surgically and are risk is to identify suboptimal bone status and provide appro- priate treatment if indicated [5]. Investigation performed at the University of Wisconsin, Madison, Approximately one quarter of patients with Wisconsin awaiting lower extremity arthroplasty have concomitant oste- oporosis as assessed by dual-energy x-ray absorptiometry * Paul A. Anderson (DXA) [6–8]. Several imaging modalities can quantify bone [email protected] mineral density (BMD) including dual photon absorptiometry (DPA), but DXA remains the gold standard providing accurate 1 Department of Orthopedics and Rehabilitation, University of Wisconsin School of Medicine and Public Health, UWMF and reproducible measurements with minimal radiation expo- Centennial Building, 1685 Highland Avenue, 6th Floor, sure [9]. DXA is also the ideal modality for measuring Madison, WI 53705, USA periprosthetic BMD as it is less by the metal implants unlike 2 University of Wisconsin Osteoporosis Clinical Research Program, other modalities, e.g., CT. However, DXA is rarely routinely Madison, WI 53705, USA performed in distal aspect of the femur prior to TKA, and 3 Department of Orthopedic , Mayo Clinic, 200 First Street standard methods to quantify BMD do not exist for the region. SW, Rochester, MN 65905-53705, USA In a patient population with a high baseline prevalence of 23 Page 2 of 11 Arch Osteoporos (2019) 14: 23 osteoporosis performing arthroplasty prior to bone quality op- The quality of each study was appraised using a modified timization may further increase the risk of postoperative version of the Downs and Black checklist, a methodology fractures. with high internal consistency (KR-20: 0.89) used to quantify In our experience, postoperative fragility fractures after study quality based on 27 mostly binary items [12]. With the TKA occur almost exclusively on the ipsilateral side. The exceptions of items 5 and 27, a score of 1 is awarded for an etiology of these fractures is likely multifactorial (e.g., altered answer of ‘yes’ whereas 0 represents ‘no’ or ‘unable to deter- gait mechanics increasing ipsilateral falls); however, these mine.’ Item 27 was modified to a binary answer: one point events may be related to post-surgical weight-bearing changes was awarded if a power calculation was present. The maxi- through an implant leading to decreased ipsilateral BMD. mum possible calculated score was 28. Previous studies with small sample sizes have reported a de- BMD measurements were extracted from text, figures crease in ipsilateral distal femur BMD ranging from 1 to 44% and tables, while ImageJ Software (NIH) was used to [10, 11]. However, there are no large studies that report results extract data points from digitized graphs [13]. If more from multiple patient populations, surgeons, and implant than one site of BMD was reported in the study, they were designs. categorized based on location on the distal femur: The senior author is associated with the American supracondylar or intracondylar. Supracondylar was de- Orthopaedic Association’s Own the Bone Program focused fined as being proximal to the superior aspect of the an- on addressing the fragility fracture epidemic by disseminating terior flange of the femoral component. Intracondylar was preventive measures aimed to reduce future fractures (e.g., defined as being distal to the superior aspect of the ante- counseling regarding nutrition, physical activity, and life- rior flange but within the confines of the implant. The style), bone active pharmacotherapy when indicated, and in- plane of imaging (coronal or sagittal) was also recorded. formed risk/benefit communication. DXA testing is important Subgroups within individual studies were pooled prior to after a fragility fracture; it is reasonable that preoperative analyzing the change in BMD at several time points: base- BMD screening and appropriate interventions could reduce line, 3 months, 6 months, 12 months, and greater than morbid periprosthetic fractures. Moreover, knowledge of 12 months. Only data from these exact time points were BMD change after arthroplasty may identify those patients included in the analysis as often times other time points who could benefit from bone active therapy and thereby re- were reported. Comprehensive Meta-Analysis Software duce periprosthetic fracture risk. (version 3) was used to calculate individual standardized We hypothesize that there is a significant decrease in BMD mean difference (Hedge’s g) statistics and the absolute after knee arthroplasty. This study is a systematic literature difference in means. A pooled Hedge’sgwascalculated review and meta-analysis devised to quantify the change in using random effects modeling weighting studies based BMD of the distal femur after primary TKA. on inverse variance. A percent change in BMD was cal- culated by comparing the difference in means to the base- line BMD. Standard deviation data was imputed for stud- Methods ies where it was not reported by inserting the pooled stan- dard deviation. A Pearson correlation coefficient was used A systematic review was independently performed by two for the pre-post correlation. Forest plots were constructed authors (JP and JB) querying PubMed, CINAHL, Cochrane, to include the calculated pooled effect sizes and 95% con- Scopus, Web of Science, and Google Scholar for articles pub- fidence intervals (CI). The Q-statistic and I2 were used to lished up until June 2017 (Fig. 1). Searches were conducted evaluate study heterogeneity. I2 values less than 25% sig- using the Medical Subject Headings (MeSH) ‘bone density’ nify low between-study variance and homogeneity of the and ‘arthroplasty, replacement, knee’ as defined by the studies while studies with I2 greater than 75% represent National Library of Medicine. The initial inclusion criterion high variance and heterogeneity. Significance was defined was studies reporting measurements of lower extremity BMD as a p value of less than 0.05. following primary knee arthroplasty. Upon a more thorough To calculate statistical changes over time, an artificial second review of these initially screened articles, those mea- variable based on Hedge’s g was calculated for each time suring BMD of the distal femur after TKA were included. point from baseline and compared using ANOVA. If a Exclusion criteria applied upon this second review included significant relationship was observed, the artificial vari- tibial and hip BMD reported without femoral measurements, able was compared between successive time points using revision total knee or unicompartmental arthroplasty, contra- Chi squared [14]. lateral knee pathology, patient populations with medical con- Publication bias was visually assessed with Funnel ditions altering bone density (e.g., inflammatory , can- plots. The Classic Fail-safe N, Orwin’sFail-safeN,and cer, chronic steroid use, etc.), computational studies, and bis- Duval and Tweedie’s Trim and Fill were utilized to quan- phosphonate use. tify the bias. For Orwin’s test, a trivial effect size was Arch Osteoporos (2019) 14: 23 Page 3 of 11 23

Fig. 1 Systematic review search strategy

defined as half of the calculated effect size, and the mean excluded as the absolute BMD could not be extracted. Details effect size of the missing studies was defined as the of the remaining studies included in the meta-analysis are smallest calculated effect size. We evaluated sources of shown in Table 1 (see Appendix for an in-depth summary of heterogeneity between the studies by performing a sensi- the studies) [10, 15–27]. Overall, BMD was reported for 547 tivity analysis at 12 months. This was done through single patients on the operative side. study deletion and moderator comparisons: pre-post cor- relation coefficient, use of cement, region of interest (ROI) measured, country, imaging modality, imaging Quality assessment of studies plane, and use of imputated data. Using the Downs and Black checklist, the range of calcu- lated quality index scores for the included studies was 10 Results to 20 with the mean quality score being 14.9 ± 3.4. While the Downs and Black checklist is validated for assessment Systematic review summary of both randomized and non-randomized studies, often points were not awarded for the several items addressing Nineteen studies were identified that measured distal femur randomization and blinding as most of the studies were BMD after primary TKA (Fig. 1). Five of these studies were longitudinal studies. 2 3 P a g e 4 o f 1 1

Table 1 Details of the remaining studies included in the meta-analysis

Study n Side Mean age (SD Mean BMI Males Time points Country Continent Implant(s) Modality Cement or range) (%)

Gazdzik 106 Operative 69.8 (± 9.37) 31.71 (± 4.84) 0.0 3, 6, and Poland Europe AGC II Biomet Merck PFC Sigma Johnson DXA + 12 months* & Johnson Scorpio type Stryker Järvenpää 69 Operative 67.7 (± 6.2) 29.8 (± 5) 17.4 3, 6, 12, 24, 48, and Finland Europe Duracon Nexgen AMK AGC DXA + 84 months Karbowski 12 Operative 70.5 (58–80) † 16.7 3 and 9 months Germany Europe PFC knee DXA † 12 Contralateral Liu 28 Operative 65.4 (54–78) Mean height 157 0.0 3,6,and Taiwan Asia Osteonics Whiteside DXA – 28 Contralateral (± 6 cm) 12 months Mean weight 64.6 (± 9.1 kg) Mau-Moeller 23 Operative 67.7 (± 8.3) 29.8 (± 2.4) 65.2 3 months Germany Europe Multigen Plus DXA † Minoda 56 Operative 72.9 (57–85) Mean height 150.7 21.4 3, 6, 12, 18, and Japan Asia NexGen LPS-flex; cemented fixed-bearing DXA + (135–172 cm) 24 months posterior-stabilized prosthesis, Zimmer; Mean weight 57.4 cemented mobile-bearing PFC Sigma RP posteriorly (33–79 kg) stabilized prosthesis, DePuy Petersen 8 Operative 70 (51–77) † 25.0 24 months Denmark Europe PCA Primary DPA – 1995 Petersen 29 Operative 70.9 (51–83) † 34.5 3, 6, and Denmark Europe PCA Modular, Modified PCA Modular, DPA – 1996 12 months and Duracon Saari 47 Operative 71.0 (50–82) † 27.7 12, 24, and Sweden Europe AMK DXA + 60 months Shibuki 22 Operative 76.0 (5.7) 24.9 (4.0) 9.1 3, 6, 12, and Japan Asia LCS Complete, DepuySynthes DXA – 24 months Soininvaara 69 Operative 67 (± 6.8) 29.5 (± 4.7) 29.0 3, 6, and Finland Europe Duracon, Nexgen, AMK DXA + 2004 12 months Soininvaara 16 Operative 66 (± 4.9) 29.5 (± 5.0) 31.3 6, 12, and Finland Europe Duracon modular (Howmedica Inc., Divsion of Pfizer), DXA + 2008 24 months Nexgen (Zimmer) and AMK (DePuy) – †

van Loon 12 Operative 62 (41 80) 33.3 3, 6, and Netherlands Europe Press Fit Condylar, Johnson & Johnson DXA + A r 12 months c h

Windisch 50 Operative 66 (58–83) † 26.0 3 and 6 months Germany Europe LCS-Knie Fa. DXA – O s t e o p o r o s ( 2 0 1 9 ) 1 4 : 2 3 Arch Osteoporos (2019) 14: 23 Page 5 of 11 23

Table 2 Baseline BMD observed between studies Study n ROI BMD

Mean [95% CI] SD

Operative leg Gazdzik 106 Supracondylar 0.674 [0.638, 0.710] 0.190 Järvenpää 69 Intracondylar and supracondylar 1.395 [1.353, 1.437] 0.179 Karbowski 12 Intracondylar 0.690 [0.558, 0.823]* 0.234* Liu 28 Intracondylar and supracondylar 0.746 [0.709, 0.783] 0.101 Mau-Moeller 23 Supracondylar 0.980 [0.935, 1.025] 0.110 Minoda 56 Distal femur 1.150 [1.104, 1.196] 0.175 Petersen 1995 8 Intracondylar 0.696 [0.592, 0.800] 0.149 Petersen 1996 29 Intracondylar 1.164 [1.090, 1.239] 0.205 Saari 47 Intracondylar and supracondylar 0.970 [0.899, 1.041] 0.249 Shibuki 22 Intracondylar and supracondylar 0.630 [0.583, 0.677] 0.112 Soininvaara 2004 69 Intracondylar and supracondylar 1.415 [1.372, 1.458] 0.184 Soininvaara 2008 16 Intracondylar and supracondylar 1.365 [1.288, 1.442] 0.158 van Loon 12 Intracondylar and supracondylar 0.950 [0.849, 1.050] 0.178 Windisch 50 Supracondylar 0.890 [0.801, 0.979]* 0.321* Overall 0.980 [0.818, 1.143] 0.310

Meta-analysis results Change in BMD

Baseline date The average decrease in BMD was 0.09 [0.05, 0.13], 0.14 [0.08, 0.20], 0.16 [0.10, 0.23], and 0.16 [0.12, 0.20] The overall mean baseline BMD was 0.989 g/cm2 [95% CI g/cm2 at 3, 6, 12, and 24 months, respectively. This 0.810, 1.167], Table 2. The standard deviation for the corresponded to a 9.3%, 13.2%, 15.8%, and 15.4% Windisch and Karbowski studies was imputed as the pooled BMD loss. Both Hedge’s g and the difference in means mean standard after excluding the Peterson studies which used are reported (Table 3) based on ROIs: distal femur com- DPA for BMD measurements. bined, intracondylar, and supracondylar. Heterogeneity

Table 3 Hedge’s g and the difference in means

Time point ROI Studies (n)Patients(n)Hedge’sg[CI] I2 Mean/difference in means [CI] Percent change (%) I2

Baseline Combined 12 510 ––0.989 [0.810, 1.167] 0 99.30 Supra 10 442 ––0.981 [0.793, 1.168] 0 99.02 Intra 8 275 ––1.052 [0.802, 1.302] 0 98.74 3 months Combined 11 476 − 0.382 [− 0.537, − 0.226] 96.25 − 0.089 [− 0.131, − 0.046] − 9.32 97.84 Supra 8 379 − 0.232 [− 0.280, − 0.184] 23.29 − 0.057 [− 0.074, − 0.040] − 5.98 65.92 Intra 7 241 − 0.541 [− 0.871, − 0.211] 97.18 − 0117 [− 0.186, − 0.047] − 11.68 97.88 6 months Combined 10 437 − 0.585 [− 0.807, − 0.363] 97.85 − 0.135 [− 0.195, − 0.076] − 13.19 98.93 Supra 8 352 − 0.365 [− 0.570, − 0.159] 95.04 − 0.097 [− 0.161, − 0.033] − 11.01 97.98 Intra 7 245 − 0.840 [− 1.195, − 0.485] 97.01 − 0.189 [− 0.245, − 0.134] − 16.93 95.78 12 months Combined 11 504 − 0.594 [− 0.790, − 0.397] 97.73 − 0.160 [− 0.225, − 0.096] − 15.75 99.13 Supra 9 419 − 0.423 [− 0.633, − 0.222] 95.70 − 0.129 [− 0.204, − 0.055] − 13.18 98.54 Intra 8 292 − 0.792 [− 1.149, − 0.434] 97.92 − 0.203 [− 0.296, − 0.111] − 18.43 98.72 24 months Combined 6 218 − 0.464 [− 0.624, − 0.304] 94.02 − 0.160 [− 0.204, − 0.115] − 15.42 94.36 Supra 4 154 − 0.591 [− 0.895, − 0.287] 93.99 − 0.186 [− 0.287, − 0.085] − 18.08 96.39 Intra 5 162 − 0.507 [− 0.834, − 0.181] 96.59 − 0.188 [− 0.307, − 0.070] − 17.88 97.69 23 Page 6 of 11 Arch Osteoporos (2019) 14: 23

Fig. 2 Forest plots of Hedge’sg for the absolute decrease in BMD at a 3 months, b 6 months, c 12 months, and d 24 months postoperatively. The size of the squares reflects the weight of the study, and the horizontal lines represent the 95% confidence interval. The diamond is the mean effect size

was large with the I2 statistic being greater than 90% for Publication Bias most of the time points. Forest plots of Hedge’sgforthe combined ROIs demonstrate a significant decrease in A representative funnel plot shown in Fig. 4 demonstrates BMD from baseline at each of the time points (Fig. 2a– that publication bias exists among the studies. There are d). Figure 3 displays the percentage decline from baseline several studies with smaller or larger effect sizes than in BMD. This was calculated from the difference between predicted, but they remain symmetric about the mean ef- the mean BMD at a particular time point and the baseline fect size despite the relative absence of smaller studies divided by the mean baseline BMD. It approaches an as- with larger standard errors. At 12 months, Duval and ymptote of approximately 15% loss by 2 years. A statis- Tweedie’s trim and fill revealed that only four trimmed tically significant decrease in BMD was observed in the studies to the left of the mean and 0 to the right of the combined, intracondylar, and supracondylar ROIs from mean were required to make the funnel plot symmetric. baseline to 24 months and at each time point (between With the four trimmed studies, the effect size increased to baseline and 3 months, 3 and 6 months, 6 and 12 months, − 0.797 [− 1.048, − 0.547] from − 0.594 [− 0.790, − and12and24months). 0.397]. The classic and Orwin’s fail-safe N tests resulted Arch Osteoporos (2019) 14: 23 Page 7 of 11 23

Fig. 2 continued.

3220 and 12 missing studies, respectively, required to significantly to the heterogeneity. Imaging modality was also change the effect size to nonsignificant. significant (p < 0.0001); however, only one study at 12 months was in the DPA group. Sensitivity analysis

To identify potential sources of heterogeneity, sensitivity anal- Discussion ysis was performed on the 12-month data. Several moderator variables did not significantly contribute to study heterogene- The prevalence of TKA in the US population has risen over ity. Low between study variance was seen when varying the several decades with 4.7 million individuals living with a pre-post correlation coefficient (p = 0.968), use of cement TKA in 2010 [1]. Increased demand among an aging popula- (p =0.164),country(p = 0.536), and imputed data (p = tion, greater implant longevity, and patients undergoing knee 0.176) in addition to single-study deletion. ROIs measured replacement at younger ages are all contributing factors to this (p < 0.0001) and imaging plane (p < 0.0001) contributed most rise. The incidence of periprosthetic fractures has also 23 Page 8 of 11 Arch Osteoporos (2019) 14: 23

Knowledge of postoperative BMD loss following arthroplasty might lead to improved protocols for preoperative bone health optimization aimed to reduce periprosthetic fracture [5]. Our meta-analysis found that a rapid and significant de- crease in BMD occurs after TKA that does not recover by 2 years. The observed 15% decrease occurs in the first 6 months after TKA (Fig. 3). The nadir in BMD is reached by 12 months and appears to be sustained to 24 months. Sensitivity analysis demonstrated a larger effect size in cemented compared to uncemented femoral components. Although the difference found was not statistically significant, it is consistent with previous finite-element computer model- ing predicting less bone loss of the distal femur with an uncemented femoral component, positing this as a potential protective factor for periprosthetic fractures [32]. The observed BMD decline is comparable to widely rec- ognized causes of Bacute rapid and severe bone loss [33]: stroke patients have 9% spine and hip bone loss after 1 year while renal transplant patients may have up to 18% spine and 4% hips bone loss annually. Unfortunately, these rapid bone loss disorders are associated with an increased risk of fracture. One meta-analysis evaluating commonly screened sites found that for every one standard deviation change in BMD (equiv- Fig. 3 Percent change in BMD of the femoral intracondylar (a) and alent to 10–12% change in BMD), the relative risk of fracture b supracondylar ( ) regions from baseline over 24 months postoperatively increased by 1.5–2.6% [34]. The exact clinical implication of postoperative femoral BMD decline is unknown, but the de- dramatically risen: noted to be 0.3–5.5% for primary TKA and crease in bone quality likely increases the risk of as high as 30% for revision arthroplasty [28, 29]. Abdel et al. periprosthetic fracture. In patients with low BMD preopera- reported a similar effect after total hip arthroplasty (THA): a tively (i.e., osteopenia), this 15% decrease may bring the ipsi- 3.5% 20-year cumulative risk of postoperative fracture after lateral leg into the range of osteoporotic BMD. However, if primary THA rising to a 11.4% 20-year cumulative risk after TKA patients are screened preoperatively for low BMD and revision THA [30, 31]. Implying a linkage to poor bone qual- their bone health is optimized prior to surgery, this may miti- ity, the risk of postoperative fracture was significantly higher gate the effects of the observed 15% BMD loss in the postop- in uncemented femoral stems and in females [30]. Although erative period [5]. bone status is a major consideration in revision arthroplasty, it Several investigations show promising results for this ap- is currently not commonly assessed in clinical practice when proach of preoperative optimization. A meta-analysis by Teng risk stratifying a candidate for primary arthroplasty surgery. et al. [35] demonstrated a 50% reduction in revision TKA

Fig. 4 Funnel plot of standard error by Hedge’sgforthechange in BMD at 12 months Arch Osteoporos (2019) 14: 23 Page 9 of 11 23 among patients with bisphosphonate use for at least 6 months known to affect BMD such as gender. We were also limited in prior to primary TKA. Fu et al. [36] published a large cohort drawing any meaningful conclusion about the effect of TKA study of osteoporotic patients with newly diagnosed osteoar- on BMD of the contralateral distal femur due to too few stud- thritis and found a 24–34% reduction in the requirement for ies reporting this data. TKA and a significant decrease in the amount of pain medi- Future research should focus on evaluating the contralateral cations consumed among bisphosphonate users. limb BMD change due to compensatory mechanics and Meta-analysis is a tool to investigate a given effect among weight-bearing. Examining the cause of postoperative femoral studies with similar methods. Heterogeneity, within and be- BMD loss and if the observed BMD loss is sustained beyond tween study variance, is measured using an I2 statistic. While 24 months is also of interest. The correlation between de- using random effects modeling, I2 was consistently greater creased postoperative femoral BMD to periprosthetic fracture than 90% in our review signifying a high degree of heteroge- risk is unknown. Additionally, further study is needed on the neity. Sensitivity analysis was performed to determine what effect of bisphosphonate use and other medications affecting variations in methodology and techniques most likely contrib- bone metabolism in the perioperative period, particularly on uted to this. Three factors were significant: ROI measured, the rate of periprosthetic fracture. The rate of periprosthetic imaging plane, and imaging modality. fracture in individuals preoperatively screened and treated for A limitation of this report is that there is no standard ROI osteoporosis in comparison to those who are not is another defined at which to measure distal femoral BMD following avenue of study. TKA. As such, to simplify analysis, ROIs were grouped into DXA measurements are only one aspect of determining a supracondylar or intracondylar measurements which likely patient’s fracture risk. Several other factors such as age, fall contributed to the heterogeneity observed. Unsurprisingly, risk, and prior fracture history help define the absolute fracture limb rotation can greatly affect the DXA precision and most risk for fragility fractures [42]. Periprosthetic fractures, with studies did not report methods to improve precision [37, 38]. arguably more associated morbidity, likely have analogous A coefficient of variation as high as 20% has been reported risk factors but may be affected by the type of prosthesis, with varying degrees of internal and external rotation with use of cement, and surgical placement and misadventures. supracondylar measures being least effected by rotation [38, This meta-analysis highlights the periprosthetic BMD loss 39]. Another contributor to heterogeneity within our study observed 2 years after TKA and calls to attention the need was the large variation in baseline BMD observed between for perioperative bone health optimization with continued studies (Table 2) which was likely in part due to differing postoperative evaluation. BMD measurement methods and patient populations. Data collected sooner postoperatively generally had higher base- Compliance with ethical standards lines. Studies with lower BMD baselines also appeared to have older populations with higher rates of osteopenia. Conflict of interest None. While these differing methods certainly affected the heteroge- neity observed among the studies, they should not confound Appendix the calculated effect sizes. Future studies should focus on de- veloping standardized methods and ROIs for DXA imaging of Summary of investigations extremities. Studies have evaluated strategies to improve re- producibility by mitigating rotation and flexion using soft Fourteen studies were included in the meta-analysis. Two of foam cast or braces [40, 41].Thesestrategiesneedtoberou- the first studies prospectively measuring BMD after TKA tinely applied to move this science forward. were by Petersen et al. [10, 15] using DPA. Petersen et al. We identified evidence of publication bias. The trim and fill [15] 1995 measured BMD in three areas of the distal femur analysis identified four theoretical missing studies in the ab- (anterior to the fixation lugs, proximally to the lugs and pos- sence of bias. The missing studies were left of the calculated teriorly to the lugs) 2 years after TKA in 8 patients. The 1996 mean and resulted in an increased effect size. Despite funnel Petersen et al. [10] study measured and compared the BMD at plot asymmetry, which could be due to random variation, the similar regions (behind the anterior flange of femoral compo- risk with the trim and fill analysis is that it could be adjusting nent and above the fixation lugs) for 29 patients at 1 year after for non-existent studies. implantation with different femoral components in hopes to There are several limitations to our meta-analysis. These reduce the previously observed loss in BMD. Another earlier include heterogeneity, unidentified bias, and confounding fac- study published, Liu et al. [16], was a case-control study mea- tors within individual studies, and only including studies from suring mostly supracondylar BMD bilaterally in 48 females, the databases searched. Many studies did not report patient comparing two different implants to age-matched controls. comorbidities, and few presented multivariable analysis eval- Several studies focused on quantifying supracondylar uating the effect of population characteristics, especially those BMD changes. Gazdzik et al. [17] is a prospective 23 Page 10 of 11 Arch Osteoporos (2019) 14: 23 longitudinal study that reported the BMD of an area proximal 2. Bozic KJ, Kamath AF, Ong K, Lau E, Kurtz S, Chan V, Vail TP, to the superior border of the femoral components in 106 post- Rubash H, Berry DJ (2015) Comparative epidemiology of revision arthroplasty: failed THA poses greater clinical and economic bur- menopausal females. In a similarly designed study, Mau- dens than failed TKA. Clin Orthop Relat Res 473:2131–2138. Moeller et al. [18] measured BMD three months postopera- https://doi.org/10.1007/s11999-014-4078-8 tively at the same femoral ROIs in 23 patients (65% male). 3. Singh JA, Jensen M, Lewallen D (2013) Predictors of periprosthetic – Windisch et al. [19] also measured supracondylar femur BMD fracture after total knee replacement. Acta Orthop 84:170 177. https://doi.org/10.3109/17453674.2013.788436 prospectively in 50 patients at several time points in the first 4. Canton G, Ratti C, Fattori R, Hoxhaj B, Murena L (2017) postoperative year. In the Minoda et al. [20]study,twenty- Periprosthetic knee fractures. A review of epidemiology, risk fac- eight patients with fixed-bearing TKA were matched with 28 tors, diagnosis, management and outcome. Acta Biomed 88:118– patients with mobile-bearing TKAs, and the BMD of the an- 128 5. Lin T, Yan S-G, Cai X-Z, Ying Z-M (2012) Bisphosphonates for terior, central and posterior distal femur ROIs (spanning periprosthetic bone loss after joint arthroplasty: a meta-analysis of metaphyseal and intracondylar regions) were measured for 14 randomized controlled trials. Osteoporos Int 23:1823–1834. 24 months. Van Loon et al. [21] studied the 1-year postoper- https://doi.org/10.1007/s00198-011-1797-5 ative changes in BMD of the femoral neck, lumbar spine, and 6. Labuda A, Papaioannou A, Pritchard J, Kennedy C, DeBeer J, Adachi JD (2008) Prevalence of osteoporosis in osteoarthritic pa- distal femur (distal anterior area of the femur behind the ante- tients undergoing Total hip or Total knee arthroplasty. Arch Phys rior flange and supracondylar area just superior to the anterior Med Rehabil 89:2373–2374. https://doi.org/10.1016/j.apmr.2008. flange of the femoral component). 06.007 Soininvaara et al. [22, 23] developed standardized 7. 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