PUBLICATIONS OF THE UNIVERSITY OF EASTERN FINLAND Dissertations in Health Sciences ANTTI JAROMA ASSESSMENT OF BONE AFTER TOTAL KNEE ARTHROPLASTY

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1 PUBLICATIONS OF THE UNIVERSITY OF EASTERN FINLAND Dissertations in Health Sciences ANTTI JAROMA ASSESSMENT OF BONE AFTER TOTAL KNEE ARTHROPLASTY

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3 ASSESSMENT OF BONE AFTER TOTAL KNEE ARTHROPLASTY

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5 Antti Jaroma ASSESSMENT OF BONE AFTER TOTAL KNEE ARTHROPLASTY To be presented with permission of the Faculty of Health Sciences, University of Eastern Finland for public examination in Kuopio University Hospital Auditorium I, Kuopio, on Friday, June 15 th 2018, at hours Publication of the University of Eastern Finland Dissertations in Health Sciences Number 466 Department of Orthopaedics, Traumatology and Hand Surgery, School of Medicine, Faculty of Health Sciences, University of Eastern Finland Kuopio 2018

6 Series Editors: Professor Tomi Laitinen, M.D., Ph.D. Institute of Clinical Medicine, Clinical Physiology and Nuclear Medicine Faculty of Health Sciences Professor Hannele Turunen, Ph.D. Department of Nursing Science Faculty of Health Sciences Professor Kai Kaarniranta, M.D., Ph.D. Institute of Clinical Medicine, Ophthalmology Faculty of Health Sciences Associate Professor (Tenure Track) Tarja Malm, Ph.D. A.I. Virtanen Institute for Molecular Sciences Faculty of Health Sciences Lecturer Veli-Pekka Ranta, Ph.D. (pharmacy) School of Pharmacy Faculty of Health Sciences Distributor: University of Eastern Finland Kuopio Campus Library P.O.Box 1627 FI Kuopio, Finland Grano Oy Jyväskylä, 2018 Distributor: University of Eastern Finland Kuopio Campus Library ISBN: (nid.) ISBN: (PDF) ISSNL: ISSN: ISSN: (PDF)

7 Author s address: Supervisors: Department of Orthopaedics, Traumatology and Hand Surgery, Kuopio University Hospital, Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences University of Eastern Finland KUOPIO FINLAND Tarja Soininvaara, M.D., Ph.D. School of Medicine, Faculty of Health Sciences University of Eastern Finland KUOPIO FINLAND Professor Heikki Kröger, M.D., Ph.D. Department of Orthopaedics, Traumatology and Hand Surgery, Department of Surgery, Kuopio University Hospital, Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences University of Eastern Finland KUOPIO FINLAND Reviewers: Docent Antti Eskelinen, M.D., Ph.D. Faculty of Medicine and Life Sciences University of Tampere TAMPERE FINLAND Docent Tuukka Niinimäki, M.D., Ph.D. Deparment of Orthopaedics and Traumatology Faculty of Medicine University of Oulu OULU FINLAND Opponent: Professor Hannu T Aro, M.D., Ph.D. Department of Orthopaedic Surgery and Traumatology University of Turku and Turku University Hospital TURKU FINLAND

8 To Aarne, Reeta, Ellinoora and Henna

9 Jaroma, Antti Assessment of Bone After Total Knee Arthroplasty University of Eastern Finland, Faculty of Health Sciences Publications of the University of Eastern Finland. Dissertation in Health Sciences; p. ISBN: (print) ISSNL: ISSN: ISBN: (PDF) ISSN: (PDF) ABSTRACT Background: Total knee arthroplasty (TKA) provides pain relief and improves function in patients with knee osteoarthrosis (OA). Dual X-ray Absorptiometry (DXA) allows us to detect periprosthetic bone mineral loss after implantation of the prosthesis and examine bone mineral density (BMD) changes of the neighboring joints (hips and contralateral knee) after TKA. Cone beam computed tomography (CBCT) is a promising new tool in evaluating quality of the periprosthetic bone environment and TKA component rotations. Subjects and Methods: Periprosthetic tibial BMD (n=86) and the effect of alendronate treatment on periprosthetic femoral and tibial BMD (n= 26) were followed up to seven years and BMD of the hips and contralateral knee (n=38) up to four years postoperatively. CBCT of TKA knees scheduled for revision knee arthroplasty (n=18) were conducted the day before surgery and assessed by an orthopedic surgeon and two musculoskeletal radiologists. Results: The mean baseline BMD of the medial metaphyseal region of interest (ROI) was higher in the preoperatively varus-aligned group than in the valgusaligned group (25%, p<0.001) and remained higher throughout the follow-up (23%, p<0.002 in 7 years). There was a significant decrease of mean periprosthetic BMDs of the medial metaphyseal ROIs in both preoperatively varus- and valgus-aligned knees (13%, p<0.001 and 12%, p=0.02 respectively). In the postoperative valgus subgroup of preoperatively varus-aligned knees, the decrease of BMD in medial metaphyseal ROI was greatest (24%, p<0.001 in 7 years). The alendronate group showed significantly higher BMD in the anterior metaphyseal ROI at 4 years p=0.002) and in the posterior metaphyseal ROI 2 years (p= 0.024). At the seven-year measurement, the alendronate group showed significantly higher BMD in the lateral metaphyseal tibial ROI (p=0.024). In the hip of the affected side, there were no significant changes of the BMDs in any measured ROIs throughout the four-years follow-up. In contralateral hip, there was a significant decrease of femoral neck (3.3%, p < 0.01) and total femoral (3.0%, p < 0.001) BMDs. In the contralateral knee, 7

10 there were significant BMD decreases up to four years in anterior metaphyseal (5.0%, p < 0.001), total femoral metaphyseal (3.6%, p < 0.001) and femoral diaphyseal (5.1%, p < 0.001) ROIs compared to baseline. The interobserver reliability for femoral component rotation was moderate. The overall ICC between the three investigators was 0.41 (95% confidence interval ). For tibial component, the ICC was 0.87 ( ) corresponding a very good interobserver reliability. The intraobserver reliabilities were good for femoral component (ICC=0.70, 95% CI ) and very good for tibial component (ICC=0.92, 95% CI ). The sensitivity and specificity for tibial component loosening were 97% and 85% respectively. Conclusions: Both DXA and CBCT allow assessment of the quality of periprosthetic bone after TKA. The decrease in BMD of the more loaded medial condyle in patients with OA of the medial compartment of the knee results in more balanced bone stock below the tibial tray. Bisphosphonate treatment together with calcium for one year following a TKA operation has a positive effect on BMD up to four years postoperatively. TKA did not increase the BMD values of the hips or the contralateral knee. However, it seemed to stabilize BMD of the hip on the affected side. CBCT scanning provides reliable and repeatable data for determining the rotation of femoral and tibial components, while also showing minor overestimation of tibial component loosening. National Library of Medicine Classification: QU 100, WE 141, WE 202, WE 874, WN 206 Medical Subject Headings: Absorptiometry, Photon; Arthroplasty, Replacement, Knee; Bone Density; Cone-Beam Computed Tomography; Osteoarthritis, Knee 8

11 Jaroma, Antti Luun tutkiminen polven tekonivelleikkauksen jälkeen Itä-Suomen yliopisto, Terveystieteiden tiedekunta Publications of the University of Eastern Finland. Dissertation in Health Sciences; s. ISBN: (nid.) ISSNL: ISSN: ISBN: (PDF) ISSN: (PDF) TIIVISTELMÄ Tutkimuksen tausta: Polven tekonivelleikkaus vähentää nivelrikkoa sairastavien potilaiden kipua ja parantaa heidän toimintakykyään. Leikkauksen jälkeen tekoniveltä lähellä oleva luukudos alkaa muovautua. Muovautumisen seurauksena syntyviä luuntiheyden muutoksia voidaan mitata ns. kaksienergiaisella röntgenabsorptiometrialla (Dual X-ray Absorptiometry, DXA). Menetelmä soveltuu vastaavasti myös muiden kantavien nivelten luuntiheyden muutosten mittaamiseen. Kartiokeilatietokonetomografia (KKTT) on uusi lupaava luun kuvantamiseen käytetty menetelmä ja sillä voi olla mahdollista kuvata myös tekoniveltä sekä sitä lähellä olevaa luukudosta. Aineisto ja menetelmät: Tutkimukseen rekrytoitiin 86 polven tekonivelleikkaukseen kutsuttua potilasta. Leikkauksen jälkeen potilaiden sääriluun yläosan tekoniveltä lähellä olevaa luuntiheyttä seurattiin seitsemän vuoden ajan. Tutkimuksen potilaista 38:lta mitattiin myös leikatun raajan lonkan alueen ja leikkaamattoman raajan lonkan sekä polven alueen luuntiheys neljän vuoden ajan leikkauksesta. Toisessa tutkimuksessa 26 potilasta satunnaistettiin saamaan alendronaatti- ja kalsiumhoitoa tai pelkästään kalsiumhoitoa vuoden ajan tekonivelleikkauksen jälkeen, ja heidän polven alueen tekoniveltä lähellä olevan luun tiheyttä seurattiin seitsemän vuoden ajan leikkauksesta. 18:lta potilaalta, jotka kutsuttiin polven tekonivelen uusintaleikkaukseen, kuvattiin leikattava polvi KKTT:lla. Ortopedian erikoislääkäri ja kaksi tuki- ja liikuntaelinradiologian erikoislääkäriä arvioivat otetut KKTT-kuvat. Tulokset: Tekoniveltä lähellä olevan sääriluun sisäyläosan luuntiheyden keskiarvo oli välittömästi leikkauksen jälkeen korkeampi niillä potilailla, joilla alaraaja oli ennen leikkausta ollut ns. varus-virheasennossa (polvi kääntyy keskiasennosta ulospäin), kuin potilailla, joilla alaraajan virheasento oli ennen leikkausta ns. valgus (keskiasennosta sisäänpäin) (25%, p<0,001). Mitattu ero säilyi tilastollisesti merkitsevänä koko seurannan ajan (23%, p<0,002 seitsemän vuotta leikkauksesta). Molempien ryhmien sääriluun yläsisäosan luuntiheyden keskiarvo laski seurantaaikana tilastollisesti merkitsevästi (13%, p<0,001 varus-potilailla ja 12%, p=0,02 val- 9

12 gus-potilailla). Potilaat, joilla alaraajan virheasento oli ennen leikkausta varussuuntainen, jaettiin edelleen alaryhmiin leikkauksen jälkeisen raajan mekaanisen akselin mukaan. Alaryhmässä, jossa leikkauksen jälkeinen alaraajan asento oli ylikorjaantunut valgus-virheasentoon, laski sääriluun yläsisäosan tekonivelen alla oleva luuntiheys kaikkein eniten (24%, p<0,001 seitsemän vuoden kohdalla). Reisiluun alaetuosan luuntiheyden keskiarvo oli tilastollisesti merkitsevästi korkeampi neljään vuoteen saakka leikkauksesta siinä potilasryhmässä, joka sai leikkauksen jälkeen alendronaatti- ja kalsiumhoitoa verrattuna pelkästään kalsiumhoitoa saaneeseen ryhmään (p=0,002). Vastaava ero nähtiin reisiluun alatakaosan luuntiheydessä kahteen vuoteen saakka leikkauksesta (p=0,024) ja sääriluun yläulkoosan luun tiheydessä seitsemän vuoden kohdalla (p=0,024). Leikatun raajan lonkan luuntiheys säilyi neljän vuoden seurannan aikana muuttumattomana, kun taas leikkaamattoman raajan lonkassa havaittiin tilastollisesti merkitsevä luuntiheyden väheneminen (3,3%, p < 0,01 reisiluun kaulassa ja 3,0%, p < 0,001 koko reisiluun yläosassa). Leikkaamattoman polven reisiluun alaosan luuntiheys väheni neljän vuoden seurannan aikana tilastollisesti merkitsevästi (etuosa 5,0%, p < 0,001, koko reisiluun alaosa 3,6%, p < 0,001 ja reisiluun varsi 5,1%, p < 0,001). Eri tutkijoiden tutkimustulosten keskinäinen luotettavuus osoittautui keskinkertaiseksi arvioitaessa polviproteesin reisikomponentin rotaatiota (ICC=0,41, 95% luottamusväli [CI] 0,12-0,69) ja erittäin hyväksi arvioitaessa säärikomponentin rotaatiota (ICC=0,87, 95% [CI] 0,74-0,94). Yhden tutkijan tutkimustulosten välinen luotettavuus osoittautui reisikomponentin rotaation osalta hyväksi (ICC=0,70, 95% [CI] 0,35-0,87) ja säärikomponentin osalta erittäin hyväksi (ICC=0,92, 95% [CI] 0,80-0,97). KKTT osoitti säärikomponentin irtoamisen 97%:n herkkyydellä (sensitiivisyys) ja 85%:n tarkkuudella (spesifisyys). Yhteenveto: Sekä DXA että KKTT soveltuvat menetelminä polviproteesia lähellä olevan luun laadun tutkimiseen. Ennen tekonivelleikkausta leikkausta suuremmalle mekaaniselle kuormitukselle joutuneen polven nivelrikkopotilaan sääriluun yläsisäosan luun tiheyden väheneminen aiheuttaa säärikomponentin alaisen luuntiheyden tasapainottumista. Polviproteesileikkausen jälkeisen vuodenmittaisen alendronaattihoidon voitiin havaita lisäävän proteesin viereistä luuntiheyttä, ja vaikutus oli havaittavissa luuntiheysmittauksin neljään vuoteen saakka leikkauksesta. Polven tekonivelleikkaus ei kyennyt lisäämään lonkkien tai leikkaamattoman polven luuntiheyttä, mutta se vakautti leikatun raajan puoleisen lonkan luuntiheyden. KKTT:n avulla voidaan luotettavasti ja toistettavasti määrittää tekonivelkomponenttien rotaatiot, mutta tutkimus voi yliarvioida säärikomponentin irtoamista. Yleinen suomalainen asiasanasto: kartiokeilatomografia; leikkaushoito; luuntiheys; nivelrikko; polvet; tekonivelet FinMeSH: Fotoniabsorptiotekniikka 10

13 ACKNOWLEDGEMENTS The present study was carried out at the Departments of Surgery, Clinical Physiology and Nuclear Medicine, Orthopaedics, Traumatology and Hand Surgery, and Radiology of Kuopio University Hospital. I owe my most sincere gratitude and respect to my supervisor Tarja Soininvaara, M.D., Ph.D. for introducing me to scientific research and providing me the opportunity to work under her guidance. I am also thankful for her basic work for collecting the data of the Knee DXA-study, which was the true foundation of this thesis. I truly admire your knowledge and expertise concerning the bone mineral density research. You were most supportive from the beginning of my research and quided me through the hard times. I always got a rapid response, no matter how busy you were in your own tasks. I am eternally thankful for my other supervisor, Professor Heikki Kröger for his guidance. You have the ablility to separate the wheat from the chaff and could repeatably support me by responding and solving my problems no matter how foolish they were or what time of the day it was. I wonder if you ever rest. Your enthusiasm towards research is something that keeps on arousing admiration and your skills and knowledge in the field of bone research are unparalleled. I warmly thank the experts of musculosceletal radiology, Lea Niemitukia, M.D. and Juha-Sampo Suomalainen M.D. for enabling the knee revision CBCT study of this thesis. Despite the haste of your own clinical work, you were ready to take these time consuming tasks of image interpretation and revising the manuscript. I am grateful that I had the opportunity to do the scientific work together with you. The combination of decades of experience with the ethusiasm of youth made you an unbeatable team. I want to thank Professor Jari Salo for introducing me the opportunity to carry out the knee revision CBCT study and even providing me funding to enable it. I respect your interest in the field of orthopaedic imaging technology while your primary expertice lies in the field of clinical orthopaedics. From the very beginning of the Knee DXA study, there were key persons to whom I own my gratitude. Professor Jukka Jurvelin, Ph.D., gave his technical and practical advice for providing the mathematical formula and basis of the study. Docent Hannu Miettinen, M.D., Ph.D., Head of the Department of Orthopaedics, Traumatology and Hand Surgery has also been a key person from the beginning of the study, already for two decades. He has also played the key role in enabling me to carry out the scientific work in the middle of hasty times in the joint replacement unit of our hospital. I owe my deepest gratitude to my official reviewers, Docent Antti Eskelinen, M.D., Ph.D. from University Hospital of Tampere and Docent Tuukka Niinimäki, 11

14 M.D., Ph.D. from University Hospital of Oulu for their constructive critisism and advice in the reviewing process of this thesis. I warmly thank the study personnel, Raija Kantanen R.N. and Eila Koski R.N. for their technical assistance in the beginning of the study, and Elina Jalava R.N. for your assistace throughout the period of my own scientific work. I also thank Merja Perankoski, Assistant head nurse, Department of Radiology for her assistance in the knee revision CBCT study. I owe my sincere thanks to biostatisticians Marja-Leena Lamidi and Tuomas Selander for their assistace in statistics, the field where a clinician is, more or less, lost without quidance. I express my special thanks to physicist Hanna Matikka for radiation dose calculations in the home sthrech of the knee revision CBCT study. I also thank Xiaoyu Tong, Ph.D. for his skills with images. I extent my gratitude to David Laaksonen, M.D., Ph.D. for his careful language revision of this thesis. I want to thank all the patients who participated in this study. I was very lucky to have magnificient colleagues in the beginning of my orthopaedic career in Central Hospital of Central Finland, Jyväskylä. I thank you all for believing in me and encouraging me when a was a novice. Especially I want to thank my first tutor Esa Anttila, M.D., orthopaedic surgeon and Docent Maija Pesola, M.D., Ph. D., Head of the Orthopaedics, for introducing me the first steps on the increadible path of joint replacement surgery. I sincerely thank all my present and former colleagues in the Department of Orthopaedics, Traumatology and Hand Surgery in Kuopio University Hospital. I owe my special gratitude to those joint replacement surgeons, who participated in data collection and operations of the patients in this study. Thank you for the music, Antti Joukainen, M.D., Ph.D., scientist, friend, colleague and musician of the best quality. Whatever you intend, you accomplish with the greatest enthusiasm, which keeps the others, me included, going on. My dearest regards to a very special group of colleagues, the Intimate Association of Licenced Medicians of Kuopio (KuLLI ry). You have given me the opportunity to leave all the troubles of the everyday life behind for a while every time we had had a chance to meet each other. You have designated me the meaning of the true friendship. I have had an opportunity to have a lasting friendship with a lovely female colleaque group of Viiteryhmä along with their families and especially their husbands. Together we have been living through the very busy years between the hard work and family life with support to each other. Especially I caress the many mutual, even though mostly cold and rainy midsummer memories. I owe my deepest thanks to my dear mother-in-law Marja-Leena Kärkkäinen and my father-in-law Teuvo Kärkkäinen in memoriam. I could not have imagined better parents-in-law than you have been to me. I also thank the families of Susanna and Lasse Hydén, Ulla and Jarno Paldanius and Jenni and Hannu Hautakoski. 12

15 I warmly thank the lifetime support of my sister Kerttuliisa Jaroma and my brothers Kustaa and Jussi Jaroma along with my brother-in-law Michael Slotte and sisters-in-law Jaana and Marianne Jaroma and your families. You sincerely are yourselves, which make you all very special persons to me. I express my deepest gratitude and respect to my dear father Heikki Jaroma, who has not only been a loving and caring parent, but also an excellent example as a doctor. Along with your talent and skill, your natural, humane confrontation with your patients has been a guideline to me in my work as a doctor. I warmly thank you Anneli Jaroma, not only for saving my father when the times where hard, but also for being a grandmother to my children. And my mother Marjatta, I know you are there, looking after me from the eternity. Now you can be so-o proud of me. Finally, I owe the deepest possible love to my family. Aarne, Reeta and Ellinoora, you are the rays of sunlight in my life. You make it all worthwhile. Henna, you mean everything to me. Thank you for your love as a wife and your understanding support as a colleague and a scientist. It has been a priviledge to have you by my side for the majority of my life. I am planning to grow old with you. I love you. This study was supported financially by Kuopio University Hospital EVO-grants, the State Research Fund of Finland, Carmen Knee Project, Kuopio University Hospital Research Foundation and the Vappu Uuspää Foundation. Kuopio, April 2018 Antti Jaroma 13

16 LIST OF THE ORIGINAL PUBLICATIONS This dissertation is based on the following original publications: I. Jaroma A, Soininvaara T, Kröger H: Periprosthetic tibial bone mineral density changes after total knee arthroplasty.acta Orthop Jun;87(3): doi: / Epub 2016 Apr 27. Erratum in: Acta Orthop Aug;87(4):x II. III. IV. Jaroma AV, Soininvaara TA, Kröger H: Effect of one-year postoperative alendronate treatment on periprosthetic bone after total knee arthroplasty. A seven-year randomised controlled trial of 26 patients. Bone Joint J Mar;97-B(3): Jaroma AV, Soininvaara TA, Kröger H: Changes in bone mineral density of the proximal femur and contralateral knee after total knee arthroplasty: a 4-year follow-up of 38 patients. Submitted Jaroma A, Suomalainen JS, Niemitukia L, Soininvaara T, Salo J, Kröger H: Imaging of symptomatic total knee arthroplasty with cone beam computed tomography. Acta Radiol Jan 1: [Epub ahead of print] The publications were adapted with the permission of the copyright owners. 14

17 CONTENTS ABSTRACT... 9 TIIVISTELMÄ ACKNOWLEDGEMENTS INTRODUCTION REVIEW OF THE LITERATURE Knee osteoarthrosis and total knee arthroplasty (TKA) Biomechanics Development of osteoarthrosis and effect on bone mineral density Total knee arthroplasty Bone mineral density measurement Dual energy X-ray absorptiometry (DXA) Bone mineral density changes after total knee arthroplasty Inhibitors of bone resorption bisphosphonates Symptomatic total knee arthroplasty Reasons for revisions and unsatisfied patients Clinical evaluation Computed tomography (CT) AIMS OF THE STUDY SUBJECTS AND METHODS Subjects and study design Bone mineral density measurements Imaging of the symptomatic or failed total knee arthroplasty Cone Beam Computed Tomography (CBCT) Assessment of the scans Patient follow-up Statistical methods RESULTS Medium-term periprosthetic tibial bone mineral changes after total knee arthroplasty (I) Medium-term effect of alendronate on periprosthetic bone mineral changes after total knee arthroplasty (II) Medium-term bone mineral density in the proximal femur and contralateral knee after unilateral total knee arthroplasty (III) Inter- and intraobserver reliability of Cone Beam Computed Tomography (CBCT) scan for symptomatic total knee arthroplasty (IV) DISCUSSION The relevance of the study The subjects Validity of the data

18 6.4 Periprosthetic medium-term tibial bone mineral changes after total knee arthroplasty: The effect of alignment Effect of one-year post-operative alendronate treatment on the medium-term periprosthetic bone changes Effect of total knee arthroplasty on hips and contralateral knee joints Cone beam computed tomography scan for symptomatic total knee arthroplasty Implications for the future research SUMMARY AND CONCLUSIONS REFERENCES ORIGINAL PUBLICATIONS 16

19 ABBREVIATIONS AGC Anatomical Graduated G.C. Geometric Center Component ICC Intraclass Coefficient AKS American Knee Correlation Society KUH Kuopio AMK Anatomic Modular University Hospital Knee MPR Multiplanar AORI Anderson Orthopaedic Reconstruction Institute MSCT Multi-Slice Computed AP Anteroposterior Tomography BMD Bone mineral density OA Osteoarthrosis BMI Body Mass Index OARSI Osteoarthritis BMU Basic Multicellular Research Society Unit International Ca Calcium PE Polyethylene CBCT Cone Beam Computed PROM Patient Reported Tomography Outcome Measures CT Computed PSI Patient Specific Tomography Instrumentation CV Coefficient of RSA Radiostereometric Variation Analysis DXA Dual X-ray ROI Region of Interest Absorptiometry SD Standard Deviation FAR Finnish Arthroplasty THA Total Hip Arthroplasty Register TKA Total Knee Arthroplasty 17

20 1 INTRODUCTION Total Knee Arthroplasty (TKA) provides pain relief and improves function in patients with knee osteoarthrosis (OA) (Skou, et al. 2015). It is also considered to be a cost-effective treatment with excellent long-term survival up to 96% after 15 years (Robertsson, et al. 2000, Dakin, et al. 2012). The durability of the prosthesis implants allows the aging and remodeling processes of the periprosthetic bone to take place. The bone mineral loss induced by the implants may also interfere with the success of the arthroplasty (Karbowski, et al. 1999, Sundfeldt, et al. 2006). Because the number of primary TKA procedures conducted worldwide is increasing (Niemelainen, et al. 2017, Inacio, et al. 2017), it becomes more important to understand the longterm changes of the periprosthetic bone. Plain knee radiographs are still a standard method in postoperative follow-up imaging of TKA. The alignment of the lower limb and prosthesis implant positioning as well as bone-to-cement interface can be quite well assessed. However, the quality of the periprosthetic bone may not be well defined by radiographs only (Ardran. 1951). The decrease of bone mineral density (BMD) after TKA operation is a well-defined phenomenon, that has been reported in several previous studies (Liu, et al. 1995, Petersen, et al. 1995, van Loon, et al. 2001, Soininvaara, et al. 2004a, Soininvaara, et al. 2004b). It is mainly caused by a stress-shielding phenomenon which unloads periprosthetic bone (Au, et al. 2007). There are also contributions from impaired mobility postoperatively and local tissue reactions to the trauma caused by the operation itself. BMD is believed to reflect the quality of the bone rather well. Poor bone quality may lead to early migration of the prosthetic implants, periprosthetic fractures and perhaps also aseptic loosening, although this has not been convincingly proven in published studies (Tagil, et al. 2003). Dual-energy X-ray absorptiometry (DXA) can be used for measuring periprosthetic BMD with minimal precision error and good reproducibility (Trevisan, et al. 1998, Soininvaara, et al. 2000). It allows us to detect periprosthetic bone mineral loss and thus may give us a better understanding of the long-term changes after implantation of the prosthesis. DXA also gives us an opportunity to examine BMD changes of the neighboring joints after TKA (hips and contralateral knee) (Soininvaara, et al. 2004c, Kim, et al. 2014). With this method, we can also monitor the effect of bone active drugs on periprosthetic bone tissue. The reasons behind symptomatic TKA are not always clear. The assessment of component rotations can be difficult with plain radiographs and it usually requires a computed tomography (CT) scan, scatter reduction software and correct understanding of the reference axes (Victor. 2009). The cone-beam computed tomography (CBCT) technique is widely used in periodontology, and a method of choice in dental implant imaging (Tyndall, et al. 2012, Aljehani. 2014). The development of dedi- 18

21 cated CBCT imaging systems for musculoskeletal extremities have opened new indications for the use of the equipment (Zbijewski, et al. 2011). The incidence of total knee arthroplasty operations is increasing and the proportion of patients with prosthesis implants is growing as the life expectancy of the population is increasing. The number of revision procedures and the financial burden of these complex surgical procedures are expected to also increase (Lavernia, et al. 2006, Barnett and Toms. 2012). Understanding of implant related changes in periprosthetic bone is important, since the clinical survival might also be associated with the quality of the bone environment (Levitz, et al. 1995, Trevisan, et al. 1998). The main purpose of this study was to quantify the medium- to long-term changes of periprosthetic bones and neighboring joints after TKA. Periprosthetic bone and components were also assessed by CBCT in patients with symptomatic TKA to validate the technique. 19

22 2 REVIEW OF THE LITERATURE 2.1 KNEE OSTEOARTHROSIS AND TOTAL KNEE ARTHRO- PLASTY (TKA) Biomechanics The knee joint is located between femur and tibia, which are the two longest bones of the human skeleton. It is the largest weight-bearing joint in human body. Therefore, there are high mechanical forces transferred through the joint especially during walking, kneeling and climbing stairs. The patella is responsible in transmitting the tensile force of the extensor apparatus across the knee. Gait analysis has shown that in normally aligned knees during walking, approximately 70% of the total load is transmitted through the medial compartment (Hurwitz, et al. 1998), causing 2.5- fold load to the medial joint surface compared with the lateral one (Baliunas, et al. 2002). The forces from the femoral condyles to the tibial plateau during normal walking have been estimated to be 2-4 times the body weight. At 45 degrees of knee flexion, the tensile force in the surface of patella reaches the maximum, which can be 7-8 times the body weight during deep knee bends such as kneeling (Taylor, et al. 2004). The lower limb mechanical axis is regarded as the most important biomechanical mechanism of the knee joint. The mechanical axis is a combination of the femoral and tibial axis. The femoral axis is measured from the center of the femoral head to the center of the knee joint. The tibial axis is measured from the center of the knee to the center of the ankle joint (or center of the talus). The angle between the femoral and tibial axis demonstrates the degree of the aberration from the straight mechanical axis. Varus alignment means that the mechanical axis deviates medially from the center of the knee and valgus alignment laterally, respectively (Figure 1). A proper mechanical axis is considered to provide optimal and equal loading conditions of the tibial condyles (Hvid, et al. 1988, Miyazaki, et al. 2002). A major purpose of the joint replacement surgery is to restore a normal axis, and a postoperative aberration of 3 degrees to valgus or varus is still considered to be acceptable. The varus malalignment caused by knee OA further increases the normally greater load of the medial tibial condyle. Valgus malalignment, on the other hand, diminishes the load-bearing forces of the medial condyle and more weight is transferred through the lateral compartment of the joint. Force-analysis calculations and dynamic analysis of forces around the knee during gait have also shown that the medial compartment bears the entire load in knees with varus malalignment, and that the lateral compartment bears increased load only in instances of more advanced valgus malalignment (Li and Nilsson. 2001). Deviation of alignment is also associat- 20

23 ed with the progression of knee OA (Sharma, et al. 2001, Felson, et al. 2005, Sharma. 2007, Eckstein, et al. 2009, Khamaisy, et al. 2015). Figure 1. Varus alignment (A) and valgus alignment (B) of the knee. (A) The lower limb mechanical axis is in 21 degrees of varus. (B) The lower limb mechanical axis is in 10 degrees of valgus. During the knee flexion, there is a complex pattern movement between the articular facets of the distal femur and proximal tibia. The medial condyle of the femur can be viewed as a sphere, which rotates to produce a combination of flexion, longitudinal rotation and minimal varus. There is only a minimal translation of approximately ±1,5mm between the medial femoral condyle and medial tibial facet. On the lateral side, there is a rolling and sliding movement, which allows a 15mm posterior translation of the lateral femoral condyle. As a consequence, the tibia rotates internally approximately 30 degrees between 10 and 120 degrees of flexion (Pinskerova, et al. 2000, Pinskerova, et al. 2003, Freeman and Pinskerova. 2003, Freeman and Pinskerova. 2005). The geometry of the distal femur and proximal tibia are intimately linked with the kinematics of the tibiofemoral and patellofemoral joints. Therefore, it is necessary to define the anatomical landmarks, especially in TKA surgery, since any misplacement will affect the loads and ligament tensions, leading to aberrant kinematics of the prosthesis (Victor. 2009). The generalized use of CT has given possibilities to assess the rotational alignments (Berger, et al. 1993). The rotation of the femur is typically determined by the angle comparing the surgical epicondylar axis with the posterior condylar axis, which is a line connecting the surfaces of the 21

24 medial and lateral posterior femoral condyles. The rotation from the posterior condylar angle is 0.3 (± 1.2 ) internal rotation for females and 3.5 (± 1.2 ) internal rotation for males relative to the surgical epicondylar axis, which connects the medial epicondylar sulcus with the lateral epicondyle (Berger, et al. 1993, Berger, et al. 1998, Victor. 2009). To assess the tibial rotation, the geometric center (G.C.) of the tibial plateau is located and axially transposed to the level of the tibial tubercle. The line connecting the tip of the tubercle to the G.S. is the tibial anatomic axis. The AP tibial axis is drawn perpendicular to the posterior surface of the tibia. The angle between tibial anatomic axis and AP tibial axis is then measured to determine the rotation. Normal rotation using this method is 18 (± 2.6 ) of internal rotation (Berger, et al. 1998) Development of osteoarthrosis and effect on bone mineral density Knee OA is a very common degenerative joint disease (Sharma. 2016). According to the Mini-Finland health survey, the prevalence of knee OA in the population over 30 years of age was 6.1% in men and 8.0% in women (Toivanen, et al. 2010). There are many known risk factors for incident knee OA: Female gender, aging, obesity, traumatic knee injury, physically demanding work and heredity (Toivanen, et al. 2010, Sharma. 2016). However, OA is not only a disease of the cartilage. It can be defined as a disorder characterized by cell stress and extracellular matrix degradation initiated by micro- and macro-injury that activates maladaptive repair responses including pro-inflammatory pathways of innate immunity (oarsi.org. 2015, Sharma. 2016). The disease manifests first as abnormal joint tissue metabolism followed by damage to the cartilage, bone remodeling, osteophyte formation, joint inflammation and loss of normal joint function. Nevertheless, the basic reason for OA remains unknown. There has been a continuous debate of the relationship between high BMD and OA. The Chingford study over 20 years ago suggested that small increases in BMD are present in middle aged women with early radiological OA of the hands, knees and lumbar spine (Hart, et al. 1994). The Framingham study 17 years ago suggested, that high BMD and BMD gain decreased the risk of progression of radiographic knee OA, but may be associated with an increased risk of incident knee OA (Zhang, et al. 2000). A more recent data suggests that higher BMD could even reduce the risk of radiological hip OA, while intermediate levels may increase the risk of symptomatic knee OA (Barbour, et al. 2017). However, there are studies suggesting, that OA could be associated with high BMD and high bone mass phenotype (Burger, et al. 1996, Hardcastle, et al. 2015), and OA and osteoporosis rarely develop simultaneously (Hannan, et al. 2000). In fact, there is evidence of an inverse relationship between these two disorders (Dequeker, et al. 2003, Multanen, et al. 2015), 22

25 which could be explained by differences in bone metabolism (Jiang, et al. 2008) or genetic factors (Logar, et al. 2007, Valdes and Spector. 2011) Total knee arthroplasty Total knee replacement is an established treatment method to reduce pain and disability caused by end-stage OA. In this indication, it has been proved to be more effective than non-surgical treatment in a recent randomized controlled trial (Skou, et al. 2015) with a good survivorship of 90% or more up to fifteen years of follow-up (Robertsson, et al. 2000, Roberts, et al. 2007, Niinimaki, et al. 2014). Whereas the studies from previous decades mostly measured surgeon-driven objective scales or survivorship data, the recent focus been more on patient-reported outcome measures (PROMs) (Ethgen, et al. 2004, Jones, et al. 2014). These studies reveal that the proportion of patients satisfied after undergoing primary TKA ranges from 81.8% in a register study of England and Wales (Baker, et al. 2007) with similar results in the Ontario Joint Replacement Registry (Bourne, et al. 2010), up to 90% in prospective study settings (Klit, et al. 2014, Parvizi, et al. 2014). However, the knees of many dissatisfied patients are not revised. The recent focus of TKA research has been on perioperative and implant-related factors. The influence of computerassisted navigation on the alignment of the prosthesis components and functional outcome measures has been a major topic, even though the clinical long-term benefits are still controversial (Burnett and Barrack. 2013, van der List, J P, et al. 2016). On the contrary, there is a evidence from register data showing that cross-linked polyethylene (PE) inserts have a statistically lower revision rate at 10 years than conventional PE inserts (Civinini, et al. 2017). Since it is assumed that PE wear is a major contributor to implant loosening following TKA, cross-linked PE inserts may reduce wear-related loosening (Civinini, et al. 2017). Nevertheless, clear evidence of better clinical outcome or longevity of one prosthesis design over the others is unconvincing (Jo, et al. 2014, Hofstede, et al. 2015, Jiang, et al. 2016), and any benefits of patient-specific (PSI) or gender-specific instrumentations have not yet been proven in clinical use (Xie, et al. 2014, Sassoon, et al. 2015). The importance of component positioning and alignment (coronal and rotational) for longevity of the prosthesis and patient satisfaction is quite incontrovertible (Gromov, et al. 2014). TKA operations are nowadays performed also on younger patients (even under 50 years of age) with satisfactory results and improvements in their quality of life at rates similar to those of older populations (Goh, et al. 2017). Because primary knee replacements are conducted in such patients with ever increasing life expectancy, it seems quite obvious that the revision burden will also increase, since these younger patients are more likely to outlive their implants than older patients (Lavernia, et al. 2006, Inacio, et al. 2017, Goh, et al. 2017). 23

26 The overall incidence of periprosthetic supracondylar femoral fractures ranges from 0.3% to 2.5% after primary TKA surgery (Parvizi, et al. 2008). Diverse general risk factors for femoral fractures proximal to the implant have been documented. These fractures have been associated with conditions that result in osteopenia of the distal part of the femur (Parvizi, et al. 2008, Hoffmann, et al. 2012). The importance of procedure-related notching of the distal femoral anterior cortex as a risk factor for periprosthetic fracture has been controversial. (Ritter, et al. 2005, Parvizi, et al. 2008, Gujarathi, et al. 2009). Tibial periprosthetic fractures are even less common. The incidence of periprosthetic tibial fractures following TKA was 0.4% for postoperative fractures in a study reported from the Mayo Clinic (Felix, et al. 1997). However, varus malalignment of the tibia and presence of component loosening, are thought to be potential risk factors for periprosthetic tibial fractures (Parvizi, et al. 2008). 2.2 BONE MINERAL DENSITY MEASUREMENT Dual energy X-ray absorptiometry (DXA) The alignment of the lower limb and implant positioning (size and varus/valgus - alignment of the components) and the changes in bone-to-cement interface are quite well assessed by knee radiographs, and this method is still a gold standard in postoperative follow-up imaging of TKA. However, the quality of the periprosthetic bone is not well defined by plain radiographs, since the decline must exceed 20-50% in order to be visualized (ARDRAN. 1951, Petersen, et al. 1995, Karbowski, et al. 1999). Dual energy X-ray absorptiometry (DXA) is an accurate and reproducible method for measuring BMD. It is the standard examination to diagnose osteoporosis and to predict osteoporotic fracture risk (Cummings, et al. 1993, Kanis. 1994, Marshall, et al. 1996, Stone, et al. 2003). DXA can also be used for measuring periprosthetic BMD, since it has minimal precision error, a low coefficient of variation and proven reproducibility (Kroger, et al. 1996, Soininvaara, et al. 2000). The commercial software algorithms permit measurements of BMD adjacent to metal implants (Liu, et al. 1995, Trevisan, et al. 1998, Karbowski, et al. 1999, Soininvaara, et al. 2000) Bone mineral density changes after total knee arthroplasty The TKA operation is known to cause remodeling of the periprosthetic bone by altering the mechanical load on the knee joint (Karbowski, et al. 1999); the operation influences the bony structure and changes the mineral density of the surrounding bone in an attempt to adapt to the modulated demands (Petersen, et al. 1995). The extent of bone remodeling depends on several patient-related and implant-related factors such as age, sex, medication, time of primary surgery, activity level, weight, 24

27 stem stiffness, stem diameter, porous coating and bone quality (Sundfeldt, et al. 2006). The balance between loading conditions and bone remodeling is called Wolff s Law: Every change in the form and function of a bone or of their function alone is followed by certain changes in their internal architecture, and equally definite secondary alteration in their external conformation, in accordance with mathematical laws (Wolff. 2010). It means that bone remodeling attempts to adapt the bone tissue depending on loading conditions. Bone remodeling involves the removal of old or damaged bone (bone resorption) and the subsequent replacement of new bone (bone formation) (Parfitt. 1994). The process is carried out by an independent functional and anatomic structure known as the basic multicellular unit (BMU). Bone remodeling involves many mechanical and biochemical factors regulating the bone forming cells - the osteoblasts, and the cells responsible for resorption of the bone - the osteoclasts (Frost. 1969, Parfitt. 2002). A normal remodeling process consists four major phases: the initiation of bone remodeling at a specific site, bone resorption, osteoblast function and mineralization of osteoid that leads to completion of bone remodeling (Martin and Seeman. 2007, Feng and McDonald. 2011). This bone renewal phase takes over 2 to 6 months and is more rapid in the trabecular than cortical bone. Trabecular bone is also the major site of bone remodeling (Feng and McDonald. 2011). This important physiological process can be derailed by a variety of factors, including menopauseassociated hormonal changes, age-related factors, changes in physical activity, drugs, and secondary diseases (Feng and McDonald. 2011). When the mechanical loads increase, bone remodeling results in the formation of stronger bone to replace old bone in order to adequately meet the increased demands (Wolff. 2010). Conversely, prolonged immobilization reflects a decrease in mechanical requirements, which results in an immobilization-induced osteoporosis (disuse osteoporosis) (Takata and Yasui. 2001). Several studies have demonstrated a decline in BMD in the periprosthetic bone of a well-functioning TKA (Liu, et al. 1995, Petersen, et al. 1996, van Loon, et al. 2001, Soininvaara, et al. 2004a). The main hazard for periprosthetic bone derives from the stress shielding phenomenon; load is partially transferred through the cement and prosthesis, which unloads periprosthetic bone (Au, et al. 2007). The metaphyseal bone also adapts to the changed loading after correction of any preoperative malalignment. Intraoperative trauma and postoperative immobilization are other factors affecting bone quality in the postoperative recovery period. The clinical longevity of implants partially depends on their osseointegration, which is influenced by the load, the characteristics of the implant and the bone-implant interface, and the quality and quantity of the surrounding bone (Cavalli and Brandi. 2014). 25

28 The remodeling process consists of four major distinct, but overlapping phases: Phase 1: initiation/activation of bone remodeling at a specific site. Phase 2: bone resorption Phase 3: osteoblast differentiation and function (osteoid synthesis). Phase 4: mineralization of osteoid and completion of bone remodeling. Figure 2. Bone remodeling. The femoral stress shielding may be derived by the shape of the component. The components of a modern TKA are cup-shaped which may protect the distal metaphyseal femoral bone from stresses below the anterior and posterior surfaces. This combined with the protection of the anterior flange of the prosthesis against the shear forces of the extensor apparatus transmitted by patella (7 times the body weight at 45 degrees of knee flexion) may be the explanation of the phenomenon (Van Lenthe, et al. 1997, Karbowski, et al. 1999, van Loon, et al. 2001). The shape of the tibial component of a commonly used non-constrained tibial prosthesis is more or less flat with a short stem. The stability of the component is thought to be dependent on the proximal metaphyseal bone of the tibia (Petersen, et al. 1995, Taylor, et al. 1998, Li and Nilsson. 2000a, Soininvaara, et al. 2004b). Malalignment of a tibial component causes abnormal load distribution. This may induce abnormal bone remodeling beneath the component, leading to insufficient supportive strength of the proximal tibial bone (Felix, et al. 1997, Thompson, et al. 2001). Furthermore, poor bone quality and low BMD may even contribute to migration of the component (Andersen, et al. 2017). 26

29 2.3 INHIBITORS OF BONE RESORPTION BISPHOSPHO- NATES Bisphosphonates are an effective and widely used medication in bone disorders when the inhibition of bone resorption is needed; osteoporosis is the most common indication (Cranney, et al. 2002, Wells, et al. 2008). Nonetheless, concerns have recently been raised about their safety in long-term use (Abrahamsen. 2010). Reports have appeared on harmful effects such as atypical femoral shaft fractures and osteonecrosis of the jaw, but their risks are still considered to be relatively low when balanced against the positive effects of the medication (Khosla, et al. 2012). The efficacy of alendronate was clearly highlighted in a Cochrane database analysis of the secondary prevention of all osteoporotic fractures and in the primary prevention of vertebral fractures (Wells, et al. 2008). The benefit of alendronate treatment after TKA has remained controversial, and only a few studies on this issue have been conducted. In one study, distal femoral bone BMD increased 10% at six months, and a significant BMD-preserving effect was maintained up to the three-year follow-up assessment (Wang, et al. 2003). However, there have also been contrasting results published, with alendronate showing no effect on periprosthetic BMD after TKA (Abu-Rajab. 2009). There are additional studies supporting the short-term bone-preserving effect of alendronate treatment after total hip arthroplasty (THA) (Venesmaa, et al. 2001, Yamaguchi, et al. 2004, Yamasaki, et al. 2007, Trevisan, et al. 2010, Iwamoto, et al. 2011). However, long-term studies are scarce (Tapaninen, et al. 2010). The preventive impact on possible prosthesis component migration is even more controversial. In one study there was a preventive effect (Hilding, et al. 2000), but it was not confirmed in another study (Hansson, et al. 2009). 2.4 SYMPTOMATIC TOTAL KNEE ARTHROPLASTY Reasons for revisions and unsatisfied patients Despite many advances in primary TKA surgical technique, patient selection, and implant design, studies that report postoperative patient satisfaction indicate rates of only 82% to 89% (Anderson, et al. 1996, Chesworth, et al. 2008, Bourne, et al. 2010). Patient satisfaction is an important outcome measure since there often is a discrepancy between the surgeon-driven objective scales and the patient reported outcome measures (Mantyselka, et al. 2001, Janse, et al. 2004, Noble, et al. 2006). The reasons for revision knee arthroplasty vary according to different national registries (Lygre, et al. 2011, Siqueira, et al. 2015), in part because the registries often fail to represent standardized definitions for the modes of failure. For example, pain is not included as a reason of revision in the Swedish registry, and instability is not recognized in the registry of New Zealand. The British registry does not include a sep- 27

30 arate category for patellofemoral complications (Siqueira, et al. 2015). Nevertheless, component loosening, infection, pain, patellofemoral problems, instability and polyethylene wear are often reported to be the most common reasons for revisions in register data (Finnish Arthroplasty Register, Sadoghi, et al. 2013, Siqueira, et al. 2015). Reasons for early failure (within the first 2 years after surgery) can be assumed to be primarily caused by the surgical procedure itself while late failures more likely are implant related (Graichen. 2014). The most prominent reason for early failure is infection (Mayle, et al. 2012). Other reasons include malpositioning of the components, instability and patellofemoral problems. For the late failure, aseptic implant loosening becomes more often the reason (Graichen. 2014). Although TKA carries a high survivorship, it is less clear whether it confers adequate functional benefits to patients and whether they are considered successful by the patients themselves. The patient-reported reasons for dissatisfaction differ from the ones for TKA revision. Patients who experienced more pain and functional impairment after TKA are less likely to be satisfied with the procedure, with pain being a stronger determinant than function (Robertsson, et al. 2000, Baker, et al. 2007). Patient expectation also plays a critical role in eventual outcome and satisfaction. Patients with higher expectations are more likely to be dissatisfied (Noble, et al. 2006, Parvizi, et al. 2014). Patient age is a more controversial determinant of satisfaction. Some studies indicate that younger age is a predominant factor for dissatisfaction (Noble, et al. 2006, Parvizi, et al. 2014), but results demonstrating that patients aged 50 years or younger having similar satisfactory rate to those of non agerestricted populations have also been reported (Goh, et al. 2017). Elderly patients were not more dissatisfied than others in a Swedish register data (Robertsson, et al. 2000), but a correlation for poorer satisfaction with advancing age has also been reported (Bourne, et al. 2010) Clinical evaluation The clinical evaluation of a symptomatic TKA requires a thorough history and physical examination. The primary symptom (pain, instability, swelling, stiffness) of the patient should be identified. The examination of the knee should evaluate an active and passive range of motion, varus and valgus stability in flexion and extension, stability in the sagittal plane at 60 and 90 degrees of flexion to assess for midflexion and flexion stability, manual strength testing, palpation for swelling or focal tenderness, and evaluation of patellofemoral stability and patellofemoral pain. The appropriate radiographs (full weight bearing knee projections and a mechanical axis evaluation) should also be assessed. Laboratory analysis specifically evaluating the inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), along with a synovial fluid aspirate evaluating the white blood cell count with differential and culture should be examined if any sing or suspicion of infection is 28

31 present. Advanced imaging modalities are sometimes helpful when the diagnosis remains unclear. There is a consensus in the literature that revision surgery should be performed only if the causative mechanism for failure is well understood (Fehring, et al. 2001, Dennis. 2007, Fehring, et al. 2008, Mandalia, et al. 2008, Toms, et al. 2009, Cercek, et al. 2015, McDowell, et al. 2016). During the last decade, specific diagnostic algorithms to guide the evaluation of symptomatic TKA have been developed (Hofmann, et al. 2011, Djahani, et al. 2013) Computed tomography (CT) TKA component malalignment problems in the axial plane (rotational alignment) are associated with limited and painful range of motion, patellofemoral joint mismatch, anterior knee pain, and even implant loosening or TKA failure leading to revision surgery (Berger, et al. 1998, Matsuda, et al. 2001, Bell, et al. 2014). The assessment of component rotation requires a CT scan, scatter reduction software and correct understanding of the reference axes (Victor. 2009). 2-D CT scan has been reported to have moderate to good intra- and inter-observer reliability (Konigsberg, et al. 2014). The recent literature shows a strong preference for enhancing the reliability with 3-D CT scans (De Valk, et al. 2016). Revision surgery for component malrotation detected by CT protocol has been reported to be as beneficial for the patient as a revision for the indication of aseptic loosening (Sternheim, et al. 2012). Cone beam computed tomography (CBCT) uses a single x-ray source and a flat panel detector. Multiple planar images are produced as the x-ray source and detector rotates around the studied object. A single rotational (210 ) sequence captures enough data for volumetric image construction, which reduces the radiation exposure significantly. The images are then mathematically reconstructed into a volumetric dataset with isotropic voxels. The technique is widely used in periodontology, and a method of choice in dental implant imaging (Tyndall, et al. 2012, Aljehani. 2014). The development of dedicated CBCT imaging systems for musculoskeletal extremities opens whole new indications for the use of this technology (Zbijewski, et al. 2011). The radiation dose is substantially lower than in conventional multislice computed tomography (MSCT) devices (Koivisto, et al. 2013) and can even be further lowered with a radiation shield developed for the equipment (Matikka and Viren. 2014). A study on the capability of CBCT in imaging the knee joint has had promising results (Kokkonen, et al. 2014). However, at the time of this thesis, there is only one previously published study on the -evaluation of component rotation using CBCT (Nardi, et al. 2017) and none concerning TKA component loosening. 29

32 3 AIMS OF THE STUDY The aims of the present study were: I. To explore the medium-term BMD changes in tibial periprosthetic bone after TKA, focusing on the effect of mechanical axis correction to decrease the periprosthetic BMD of the preoperatively more loaded tibial condyle. II. To investigate if one-year oral alendronate therapy supplemented with calcium could lead to improved BMD compared to treatment with calcium supplementation alone in a group of cemented primary TKA patients in a medium-term follow-up. III. To investigate the medium-term BMD changes of the contra- and ipsilateral hips and the contralateral knee after TKA. The hypothesis was that the operation can preserve or even increase the BMD of the neighboring joint bones. IV. To determine the possibilities of CBCT to examine the knee status after total knee arthroplasty and validate the technique in symptomatic TKA. To evaluate the rotation and loosening of the components as well as the osteolysis and quality of the periprosthetic bone. 30

33 4 SUBJECTS AND METHODS The following section gives a brief introduction of the subjects and methods, which are presented in detail in the original publications I-IV. 4.1 SUBJECTS AND STUDY DESIGN There were three different populations in the present study. The first three subgroups consisted of patients in the Knee DXA Study and the fourth subgroup of patients in the Verity Study at Kuopio University Hospital (KUH). The study protocols were approved by the local ethics committee (decision numbers 71/1997 and 54/2011, respectively). All patients gave written informed consent. All patients in the Knee DXA Study (subgroups described in original publications I-III, n = 112) underwent cemented TKA for OA. The patella was resurfaced in all patients. 121 TKAs with all 3 components cemented using standard techniques were conducted. The implants used were Duracon (Howmedica Inc., Rutherford, New Jersey, USA n = 67), Nexgen (Zimmer, Warsaw, Indiana, USA, n = 36), AMK (DePuy, Warsaw, Indiana, USA, n = 14) and AGC (Biomet Ltd, Bridgend, United Kingdom n = 4). All patients were operated upon by experienced orthopedic surgeons. A tourniquet was used for all patients except two. Antibiotic prophylaxis was provided with cefuroxime to except two patients, who received vancomycin. Full weight-bearing was allowed immediately after the operation in all patients. Continuous passive motion (CPM) devices were used for total of 40 patients. All patients received mechanical (medical compression stockings) and pharmacological thromboprophylaxis with warfarin (n = 3) or low molecular weight heparin (dalteparin n = 3, enoxaparin for the rest of the patients). The American Knee Society score (AKS) was used to clinically evaluate the knee status and function during daily activities preoperatively and at each follow-up visit 3 months and 1, 2, 4, and 7 years postoperatively. The patients were free of any diseases and medications known to influence bone mineral metabolism, which was also confirmed at every follow-up visit and appointment for BMD measurement throughout the follow-up period. All women had reached their physiological menopause. A long standing radiograph was taken both preoperatively and at each follow-up visit, to measure the tibiofemoral angle. In the first subgroup, 86 patients were recruited from the waiting list of the orthopedic department at Kuopio University Hospital between May 1997 and February The study material consisted of 91 knees with primary and 3 knees with posttraumatic OA (previous meniscectomy or anterior cruciate ligament rupture). Furthermore, in 1 knee, there was an aseptic bone necrosis of the lateral femoral condyle. Knees with previous fractures were excluded. TKAs with all 3 components 31

34 cemented included Duracon modular (Howmedica Inc. Rutherford, NJ/International division of Pfizer, n=50), NexGen (Zimmer, Warsaw, IN, USA, n=30), AMK prostheses (DePuy, Warsaw, IN, USA n=14) or AGC (Biomet Merck Limited, Bridgend, South Wales, UK, n=1) prostheses. To assess the effect of mechanical axis correction in the tibial BMD (original publication I), we divided these patients according to their preoperative long-standing radiographs into preoperative varus and valgus groups. The varus group was further divided into subgroups reflecting the postoperative radiological status (residual varus (over 3 degrees of varus), straight or overcorrection to valgus (over 3 degrees of valgus) axis). The second subgroup consisted of 26 patients, who were recruited from the Kuopio University Hospital Orthopedic Department between May 15 th, 1998 and March 16 th, All twenty-six patients were enrolled into the study, and were randomized into two treatment groups by study nurses with a closed envelope method. All orthopedic surgeons who either operated on or examined the patients during the follow-up were blinded to the allocation. Medication was initiated after surgery. Initially, fourteen patients received alendronate (Fosamax, Merck & Co., Inc., NJ, USA), at a dose of 10mg/day orally in the morning, and calcium carbonate (Calcichew, Nycomed Pharma, Nycomed Amesham, Oslo, Norway), at a dose of 500mg/day orally, in the afternoon or evening. The other group of twelve patients received only calcium carbonate at a dose of 500mg/day. Alendronate was swallowed on an empty stomach with a full glass of plain water. The patient flow of this study is described in detail in Figure 3. The third subgroup consisted of thirty-eight patients. Thirty-five of these patients had a knee with primary OA and two with posttraumatic OA (not including prior bone-affecting traumas, only open or arthroscopic meniscectomy). One patient had a bone necrosis of the lateral femoral condyle. In this study setting, joint replacements of the contralateral knee or either hip before the scheduled surgery or during the whole follow-up period of four years postoperatively, were exclusion criteria. 32

35 Figure 3. Patient flow chart in bisphosphonate and control groups in the first seven years following total knee arthroplasty (TKA; DXA, dual-energy X-ray absorptiometry). The baseline characteristics of the patients in these three subgroups, together with their American Knee Society (AKS) scores (Insall, et al. 1989), are presented in Table I. 33

36 Table I. General patient characteristics of the the subgroups I-III (mean and standard deviation as appropriate). Tibial BMD subgroup (I) Alendronate subgroup (II) Hips and contralateral knee BMD subgroup (III) Baseline characteristics Preoperative varus knees Preoperative valgus knees Alendronate + calcium Calcium No of patients No of knees operated Male/Female 23/52 1/19 4/8 5/9 * /31 Age years (SD) 68 (6.6) 67 (7.4) 66 (7.0) 68 (8.2) (6.7) Body mass index (SD) Preoperative AKS score (SD) 30 (4.5) 28 (5.5) 29.0 (3.8) 29.8 (3.6) (5.2) 93 (30.4) 100 (39.1) 106 (30.6) 97 (20.9) (37.2) *p-value between the alendronate + calcium and calcium groups. Chi squared test p-value between the alendronate + calcium and calcium groups. Unpaired t-test The fourth subgroup consisted of eighteen patients, 10 male and 8 female, who were scheduled for revision arthroplasty of primary knee prostheses. Seventeen revision procedures were performed at this subgroup between March 2012 and February There was a patellar component in six of these knees. The main indications for revision surgery were instability (7 out of 18 knees, 38.9%), suspicion of aseptic loosening (4 out of 18, 22.2%), and patellar luxation (2 out of 18, 11,1%). Other reasons were pain (1), stiffness (1), suspected polyethylene wear (1) and malalignment (1). In one of the patients suffering a patellar fracture, the revision operation was canceled. A revision of one or more components was performed for seven of the patients (41.2% of the operated knees). An exchange of the tibial polyethylene insert only was performed for five patients (29.4%). The other revision procedures were performed once each (3.8%). The baseline characteristics of these patients, together with their AKS scores, revision indications and final operations performed are presented in Table II. 34

37 Table II. General characteristics of the 17 revision knee arthroplasty patients. The number of patients for the different indications for revision, the mean age (standard deviation, SD), gender, mean American Knee Society (AKS) scores (SD) and final operations performed are presented. Indication N:o of patients Age mean (+SD) Male/ Female AKS mean (+SD) Operation Instability 7 61 (7.0) 5/2 116 (32.1) Polyethylene change n=5 plus patellar resurfacing n=1 Component revision n=1 Aseptic loosening 4 72 (8.1) 1/3 79 (37.4) Component revision Patellar luxation 2 68 (7.8) 2/0 97 (23.3) Medial patellofemoral ligament reconstruction n=1 Partial patellar resection plus polyethylene change n=1 Pain /0 125 Patellar resurfacing Stiffness /0 159 Debridement, polyethylene change, patellar reresurfacing n=1 Polyethylene wear /1 65 Component revision Malalignment /1 90 Component revision Total (9.8) 10/7 104 (35.1) n=17 35

38 4.2 BONE MINERAL DENSITY MEASUREMENTS Bone mineral density (BMD) was measured using a fan beam dual X-ray absorptiometry (Lunar Expert-XL Lunar Corp., Madison, WI, U.S.A.). The system was equipped with a high-resolution detector array on a rotatable C-arm gantry, coupled to an X-ray tube in fan beam geometry. Dual-energy imaging is achieved by filtration of the X-ray beam and the use of detector arrays sensitive to lower and higher energy X-rays (Lang, et al. 1997). The knees of the patients were scanned both in anteroposterior (ap) and lateral projections. The regions of interest (ROI) were both metaphyseal and diaphyseal. For each ap-scan, the patient lay supine and the leg was in a 15 degree of internal rotation strapped in a foot brace. For the lateral scan, the patient s knee was flexed 15 degrees the patient laying on his/her side. The locations of ROIs in the ap and lateral scans are presented in Figure 4A and 4B (Soininvaara, et al. 2000). The femoral neck, Ward s triangle, trochanter, shaft and total area were measured in the proximal femoral scans. (Figure 5). A Figure 4. The ROIs for BMD measurements by DXA in contralateral and prosthesis knee. (A) ap view: medial (1) and lateral (2). 36

39 B (B) lateral view: (3) tibial diaphyseal, (4) femoral diaphyseal, (5) metaphyseal anterior, (6) central, (7) posterior and (8) total metaphyseal (5+6+7). Figure 5. The ROIs for BMD measurements by DXA in the hip: neck (N), Ward s (W), trochanter (TR), shaft (S) and total femur (including all femoral ROIs). 37

40 The precision, expressed as the coefficient of variation for repeatedly measured BMD of the TKA knees was 3.1% in the femoral regions of interest (ROI) and 2.9% in the tibial ROIs. In the contralateral knees, it was 3.2% in the femur and 2.5% in the tibia (Soininvaara, et al. 2000). For the proximal femur, the CV% was 1.8% for the femoral neck, 2.0% for the greater trochanter, 2.6% for Ward s triangle and 0.9% for total proximal femur (Huuskonen, et al. 2002). BMD was analyzed using the software developed by the manufacturer. The software algorithm enabled analysis of BMD adjacent to metal implants. To minimize operator-related inaccuracies, no attempt was made to exclude a cement mantle from the analysis of the TKA-operated knees. Seven measurements were taken of the TKA-operated knees, the first within 1 week after the operation and the others 3 months, 6 months, and 1, 2, 4 and 7 years postoperatively. Four measurements were taken of the contralateral knees and both hips as described in the original publication III; the first within a week after the operation and the others 1, 2, 4 years postoperatively. Similar ROIs were used in the analysis of the both TKA- and contralateral knees. One experienced operator analyzed all scans. 4.3 IMAGING OF THE SYMPTOMATIC OR FAILED TOTAL KNEE ARTHROPLASTY Cone Beam Computed Tomography (CBCT) All patients were investigated by 2-D CBCT scanning (Planmed Verity, Helsinki Finland) in a sitting position with no weight bearing. The knee was fully extended in a leg holding rest. The scans were performed using tube voltage of 96 kv, tube current of 12 ma, and voxel size of µm 3. For rotational measurements multiplanar reconstructions (MPR) were done with an MPR tool (Sectra AB, Linköping, Sweden) into sagittal, coronal and axial slices. The slice thickness of MPRs was 2 mm with no gaps between slices. The intra- and interobserver evaluations of component rotations were performed according to the protocol described by Berger et al. (Berger, et al. 1993) (Figures 6 and 7). Prosthesis component loosening was assessed and periprosthetic bone defects were graded according to Anderson Orthopaedic Institute (AORI) and Clatworthy and Gross classifications (Qiu, et al. 2011). 38

41 Figure 6. Determination of femoral component rotation in an axial cone beam computed tomography (CBCT) image. Femoral component rotation was determined by the angle of the surgical epicondylar axis and the posterior condylar axis, which forms a line connecting the surfaces of the medial and lateral posterior condyles of the component. The component shown here is in 1.0 of internal rotation relative to the surgical epicondylar axis. A B C Figure 7. Determination of the tibial component rotation. (A) Axial cone beam computed tomography (CBCT) image through the proximal tibial plateau just distal to the tibial component. The geometric center of the tibia was determined. (B) Axial cone beam computed tomography (CBCT) image through the tip of the tibial tubercle. The geometric center was axially transposed at the level of the tibial tubercle. The line connecting the tip of the tubercle to the geometric center is the tibial anatomic axis. (C) Axial cone beam computed tomography (CBCT) image through the tibial component. The anteroposterior tibial component axis (T.C.A.) was drawn perpendicular to the posterior surface of the component. The angle between the tibial anatomic axis and the T.C.A. was measured to determine the rotation of the component. The tibial component shown here is in 24 of internal rotation. The normal rotation determined using this method is 18 (± 2.6 ) of internal rotation Assessment of the scans The CBCT scans were assessed by an orthopedic surgeon and two musculoskeletal radiologists. To determine the interobserver reliability, the latter two evaluators were blinded to any patient clinical data. The CBCT scans were also coded, thereby 39

42 avoiding any connection to the clinical data before the final data analysis. The clinical data of the patients was opened by the orthopedic surgeon only after the CBCT assessments. The CBCT scans were assessed twice by the orthopedic surgeon and once by each of the musculoskeletal radiologists. Intraobserver analysis of the CBCT scans was assessed by two evaluations performed by the orthopedic surgeon, with a minimum 3-month interval between evaluations. The mean values of the two intraobserver measurements of component rotation were used to assess the interobserver reliability between the three investigators. In case of categorical variables (aseptic loosening and bone defect classifications), the interobserver reliabilities were determined between the two musculoskeletal radiologists. 4.4 PATIENT FOLLOW-UP The AKS score was used to clinically evaluate the knee status and function during daily activities. The maximum AKS score value is 200, consisting of knee status (100) and functional score (100). It was assessed by an orthopedic surgeon preoperatively and again at each follow-up visit at 3 months and 1, 2, 4, and 7 years postoperatively in the subgroups I and II. For these patients, there was an extra postoperative appointment scheduled with a study nurse six months postoperatively. At this appointment, BMD was measured and overall rehabilitation was evaluated with a questionnaire. For the subgroup III, the follow-up visits with an ortopedic surgeon were 1, 2 and 4 years postoperatively. Both preoperatively and at each follow-up visit a long-standing radiograph was taken to measure the tibiofemoral angle necessary for AKS scoring. In the study described in the original publication IV, there was no scheduled follow-up, and the knee was evaluated only pre- and perioperatively. The revision TKA patients were followed-up according to normal routine appointments by the orthopedic surgeons outside the study. 4.5 STATISTICAL METHODS The statistical analysis was performed using SPSS software, versions 19 and 21 (SPSS Inc., Chicago, IL). Differences in the baseline characteristics of continuous variables between the groups were analyzed with the unpaired t-test. Differences related to sex distribution were tested with the Chi-square test. The differences between proximal femoral BMD values of the contra- and ipsilateral hips were analyzed with paired sample T-tests. A linear regression model was used to examine the associations between BMD data, body mass index (BMI), age, AKS and functional scores at all four measuring points. The association between BMD and the degree of knee arthrosis was determined by a univariate general linear model, and the comparison between the Ahlbäck classification by Scheffe s test. In this model, 40

43 BMD was a dependent variable and Ahlbäck s classification a fixed factor. A mixed model based on the linearly independent pairwise comparisons among the estimated marginal means was used as the statistical method for assessing the associations between the series of measurements as well as managing any missing data. The mixed model was used to assess the association of the AKS scores and BMD changes of measured ROIs at the determined time intervals. The BMD-differences between the Ahlbäck grades II to III and IV to V were also determined by mixed model. In the model syntax of the subgroup described in the original publication II, we used the alendronate and calcium groups as fixed effects and BMD measurements and AKS scores as random effects. All data analysed by mixed model were confirmed to be normally distributed by mixed model residual histograms. P- values less than 0.05 were considered significant. A post hoc power calculation was performed according to the same mixed model method used during data analysis in the study of the subgroup II. The interaction between mean BMD of total femoral metaphyseal ROI and time factor was analyzed. The power of the alendronate treatment effect was 0.83 in the per protocol and 0.81 in the intention to treat analyses, with the alpha level at To assess the intra- and interobserver reliabilities between the measured rotational angles and sizing of the prosthesis components in the analysis of the results described in the original publication IV, the intraclass coefficient correlations (ICC) values were calculated. An ICC value of 1 indicates perfect reliability, very good reliability, good reliability, is moderate and 0.4 or less is poor. The intra- and interobserver assessments of the categorical variable reliabilities (component loosening and bone defect classifications of the tibia) were determined by kappa (κ) with linear weighting. Sensitivity and specificity for component loosening were calculated. 41

44 5 RESULTS 5.1 MEDIUM-TERM PERIPROSTHETIC TIBIAL BONE MINERAL CHANGES AFTER TOTAL KNEE ARTHROPLASTY (I) The AKS scores improved in both preoperative varus and valgus groups from baseline to 1 year (mean improvements 87 and 50 points respectively, p<0.001). The AKS score was higher in the varus group from 3 months up to 7 years follow-up (pvalues between ). Two patients suffered periprosthetic femoral fractures, 1 between the 2 and 4 year measurements, and the other between the 4 and 7 years measurements, and were therefore not able to continue in the study. No tibial component failures were found during the follow-up. The mean baseline BMD of the medial metaphyseal ROI was higher in the preoperatively varus-aligned group than in the valgus-aligned group (25%, p<0.001). The difference remained statistically significant throughout the follow-up (13%- 18%, p= from 3 months to 4 years, 23%, p<0.002 at 7 years) (Figure 8). Figure 8. Mean BMD values of bone mineral density of preoperatively varus and valgusaligned knees. Medial tibial region of interest. 95% confidence intervals are shown. The mean periprosthetic BMD of preoperatively varus-aligned knees decreased in medial metaphyseal and diaphyseal ROIs during the first 3 months postoperatively (4.9% and 4.3%, p=0.003 and p=0.009 respectively). In the medial metaphyseal ROI the decline continued up to the 7-year measurement (13%, p<0.001 between baseline and 7 years, 7.5%, p<0.001 between 3 months and 7 years), whereas in the diaphysis, the BMD remained virtually unchanged from 3 months to 7 years (-0.9%, p=0.91). 42

45 There were no statistically significant changes in mean BMD values in the lateral metaphyseal ROI during the follow-up (Figure 9). *p value compared to baseline Figure 9. Percentage change of bone mineral density. Preoperatively varus-aligned knees. 95% confidence intervals are shown. The preoperatively varus-aligned knees were divided into 3 subgroups according to the postoperative lower limb mechanical axis. The BMD of the medial metaphyseal ROI decreased significantly in the subgroup where the mechanical alignment was adequately corrected and especially in the subgroup where the postoperative mechanical alignment was in valgus. The decrease was significant from 1 to 7 years compared to the baseline value in the postoperatively valgus-aligned subgroup (a 16% decrease, p=0.02 at the 1-year measurement and a 24% decrease, p<0.001 at 7 years). In the postoperatively straight-aligned subgroup the decrease was significant from 3 months (5.3%, p=0.03) to 7 years (14%, p<0.001). The mean tibial diaphyseal BMD decreased in postoperatively straight-aligned subgroup from 3 months to 7 years compared to the baseline values (2.6%, p=0.02 at 3 months, 6.1%, p<0.001 at 7 years). There were no significant differences measured during the follow-up in any of the measured ROIs within the postoperatively varus-aligned subgroup. The mean medial metaphyseal periprosthetic BMD was lower in the postoperative valgus subgroup at the 2 and 7-year measurements than in the postoperatively straight and varus-aligned subgroups (p-values between ). (Figure 10). 43

46 *p value within the subgroup, compared to baseline BMD measurement a =p value between the postoperatively varus and valgus-aligned knees b =p value between the postoperatively straight and valgus-aligned knees Figure 10. The subgroup analysis of the preoperatively varus-aligned knees: Percentage change and the behavior of bone mineral density in medial tibial region of interest according to the postoperative alignment. 95% confidence intervals are shown. In the medial metaphyseal ROI of the preoperatively valgus-aligned knees, there was a statistically significant decrease at 7 years compared to the baseline and 3-month measurements (12%, p=0.02 and 15%, p<0.001 respectively). In the diaphyseal ROI, the BMD decreased from baseline to 4 years measurement (5.6%, p=0.05). There were no significant changes in BMD values in the lateral metaphyseal ROI during the follow-up (Figure 11). 44

47 *p value compared to baseline Figure 11. Percentage change of bone mineral density. Preoperatively valgus-aligned knees. 95 % confidence intervals are shown. The BMD values of medial and lateral metaphyseal ROIs were significantly higher from the baseline throughout the follow-up in one out of the three main prosthesis models used (NexGen) compared with the other two (Duracon modular and AMK). The BMD decline in all prosthesis models was statistically significant up to seven years (p<0.001) in the medial metaphyseal but not in the lateral metaphyseal ROIs. The decrease after one year was 8% with the Duracon modular and 6% with NexGen. At the seven years follow-up, the results were 12% and 9%, respectively. The decrease patterns did not differ significantly from each other. The single AGC prosthesis was excluded from this analysis (Table III). 45

48 Table III. Mean periprosthetic metaphyseal tibial BMD (SE) values at 7 years follow-up. Comparison between different prosthesis models. Prosthesis model 0 months 3 months 6 months 1 year 2 years 4 years 7 years Duracon (n=50) 1.13 (0.03) 1.08 (0.04) 1.06 (0.04)** 1.04 (0.04)*** 1.01 (0.04)*** 1.03 (0.03)*** 0.99 (0.04)*** Medial metaphyseal Nexgen (n=30) 1.36 (0.04)a 1.32 (0.04)a 1.30 (0.05)a 1.28 (0.05)*,a 1.29 (0.04)a 1.25 (0.05)***,a 1.24 (0.05)***,a Medial metaphyseal AMK (n=14) Medial metaphyseal 1.18 (0.07)b 1.16 (0.07)b 1.08 (0.07)c 1.08 (0.07)b 1.10 (0.07)b 1.06 (0.07)*,b 0.97 (0.07)***,c Duracon (n=50) 1.16 (0.03) 1.17 (0.03) 1.18 (0.03) 1.18 (0.03) 1.14 (0.03) 1.15 (0.03) 1.12 (0.04) Lateral metaphyseal Nexgen (n=30) 1.55 (0.04)d 1.55 (0.04)d 1.58 (0.05)d 1.56 (0.04)d 1.54 (0.04)d 1.57 (0.04)d 1.59 (0.05)d Lateral metaphyseal AMK (n=14) Lateral metaphyseal 1.16 (0.06) 1.17 (0.06) 1.14 (0.06) 1.13 (0.06) 1.13 (0.07) 1.12 (0.07) 1.07 (0.07) *p<0,05 compared to baseline BMD value ** p<0,01 compared to baseline BMD value *** p<0,001 compared to baseline BMD value a = p<0,001 between Nexgen and Duracon b = p<0,05 between AMK and Nexgen c = p<0,01 between AMK and Nexgen d = p<0,001 between Nexgen and Duracon/AMK 46

49 5.2 MEDIUM-TERM EFFECT OF ALENDRONATE ON PERIPROSTHETIC BONE MINERAL CHANGES AFTER TO- TAL KNEE ARTHROPLASTY (II) The alendronate + calcium and calcium only (control) groups were similar at baseline, i.e. there were no significant differences in age, BMI, sex distribution, distribution of prosthesis models or AKS score between the groups (Table I). The AKS scores improved significantly in both groups from baseline to three months postoperatively (+63 points in alendronate + calcium and +81 points in calcium only groups, p <0.001). From two to seven years postoperatively, the total AKS score was significantly lower in the calcium group (p=0.045, p=0.040 and p=0.016 in 2, 4 and 7- year measurements, respectively). The function evaluation score was significantly lower in the calcium group from four to seven years (p=0.030 and p=0.015, respectively). The knee evaluation scores showed no statistical differences between the groups. The reason for the lower functional outcome was not related to the operated knee, but rather to unrelated reasons such as mental dementia, cardiac disease, back pain, or joint pain in the contralateral knee, which in turn caused these patients to have the lowest functional scores. In the alendronate group, the unrelated reasons played a smaller role, with one patient having a hemiparesis and one other deteriorating as a result of back pain. In the total femoral metaphyseal ROI, the alendronate group displayed significantly higher BMD at the 6 and 12-month follow-ups compared with the calcium only group (p=0.030 and p=0.009, respectively), but the difference did not remain significant after the 12-month follow-up. The alendronate group showed significantly higher BMD in the anterior metaphyseal ROI at the 3, 6 and 12-month follow-up and 4-year follow-up (p values from to 0.002) (Figure 12) and in the posterior metaphyseal ROI at the 1 and 2-year follow-ups (p values of and 0.024, respectively). At the 7-year measurements, no statistically significant differences remained between the groups in femoral ROIs. 47

50 Figure 12. Periprosthetic bone mineral density (BMD) (mean and standard error (SE)) in both alendronate and calcium and calcium only groups in the anterior femoral region of interest. *P-value between the treatment groups (mixed model). P-value within the treatment groups compared with baseline (mixed model) At the seven-year measurement, the alendronate group showed significantly higher BMD in the lateral metaphyseal tibial ROI (p=0.024) (Figure 13). No significant differences could be found between the groups in tibial medial metaphyseal or tibial diaphyseal BMD. The medial metaphyseal tibial BMD below the implant remained unchanged during the seven-year follow-up in both groups. Lateral metaphyseal tibial BMD increased in the alendronate-treated patients, and the change was statistically significant at the 6-month (9%), 12-month (7%) and 7-year (10%) time points (p=0.009, p=0.013, p=0.002, respectively). In the calcium group, there were no significant differences in the BMD changes of the lateral metaphyseal ROI (Figure 13). BMD values in the tibial diaphyseal ROI remained static in the alendronate group, whereas the calcium group displayed bone loss, which was significant at the sixmonth and four-year measurement points (p=0.015, p=0.003) 48

51 Figure 13. Periprosthetic bone mineral density (BMD) (mean and standard error (SE)) in both alendronate and calcium and calcium only groups in the lateral metaphyseal tibial region of interest. *P-value between the treatment groups (mixed model). P-value within the treatment group (mixed model). 5.3 MEDIUM-TERM BONE MINERAL DENSITY IN THE PROXI- MAL FEMUR AND CONTRALATERAL KNEE AFTER UNI- LATERAL TOTAL KNEE ARTHROPLASTY (III) The mean AKS score of the operated knee improved from the baseline value of 91 (SE 5.9) up to 170 (SE 6.0) at one year, and this improvement persisted until the end of the 4-year follow-up period (173 (SE 6.0) after 2 years and 164 (SE 6.1) after 4 years, p < in all time points). Similar improvement was found for the mean patient functional score of the operated knee. All the BMD values of the hip on the affected side were significantly lower than the values of the contralateral hip, and the difference remained significant throughout the follow-up. In the hip on the affected side, there were no significant changes of the BMDs in any measured ROIs throughout the four-years follow-up. In the contralateral hip, there was a significant decrease of femoral neck (3.3%, p < 0.01) trochanteric (3.6%, p < 0.01), femoral shaft (2.5%, p < 0.01) and total femoral (3.0%, p < 0.001) BMDs. The mean total BMDs of the femur on the affected side was higher than the age- and sex-matched public-based mean values (Kanis. 1994); the mean Z- scores were +0.2 SD to +0.3 SD throughout the follow-up. BMD decreased significantly in the anterior metaphyseal ROI during the 1-year follow-up (3.3%, p = 0.044), and the decrease continued up to 4 years (5.0%, p < 0.001). (Table IV). In the total femoral metaphyseal ROI, the decrease was also significant at the 1-year (1.7%, p = 0.031) and 4-year measurements (3.6%, p < 0.001) compared to baseline. (Table IV). In the femoral diaphyseal ROI, there was a significant BMD decrease at 2 years (2.9%, p = 0.036) and 4 years (5.1%, p < 0.001). (Table 49