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Teriparatide Administration Increases Periprosthetic Bone Mineral Density After Total Knee Arthroplasty: A Prospective Study
Accepted Manuscript Teriparatide administration increases periprosthetic bone mineral density after total 1 knee arthroplasty: A prospective study Tatsuya Suzuki, MD, Fumio Sukezaki, MD, PhD, Takashi Shibuki, MD, PhD, Yoichi Toyoshima, MD, PhD, Takashi Nagai, MD, PhD, Katsunori Inagaki, MD, PhD PII:
S0883-5403(17)30642-3
DOI:
10.1016/j.arth.2017.07.026
Reference:
YARTH 56006
To appear in:
The Journal of Arthroplasty
Received Date: 24 March 2017 Revised Date:
5 July 2017
Accepted Date: 17 July 2017
Please cite this article as: Suzuki T, Sukezaki F, Shibuki T, Toyoshima Y, Nagai T, Inagaki K, Teriparatide administration increases periprosthetic bone mineral density after total knee arthroplasty: A 1 prospective study , The Journal of Arthroplasty (2017), doi: 10.1016/j.arth.2017.07.026. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Teriparatide administration increases periprosthetic bone mineral density after total
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knee arthroplasty: A prospective study
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Short title: Teriparatide administration for bone mineral density after total knee arthroplasty
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Tatsuya Suzuki*, MD; Fumio Sukezaki, MD, PhD; Takashi Shibuki, MD, PhD;
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Yoichi Toyoshima, MD, PhD; Takashi Nagai, MD, PhD; Katsunori Inagaki,
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MD, PhD
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of
Orthopedic
Surgery,
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1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan
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Showa
University
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School
*Corresponding author:
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Tatsuya Suzuki, MD
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Department of Orthopedic Surgery, Showa University School of Medicine
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1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan
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Phone: +81-3-3784-8543
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Fax: +81-3-3784-9005
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E-mail: [email protected]
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Author e-mail addresses:
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Fumio Sukezaki: [email protected]
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Takashi Shibuki: [email protected]
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Yoichi Toyoshima: [email protected]
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Takashi Nagai: [email protected]
of
Medicine
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Katsunori Inagaki: [email protected]
27 Trial registration
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This study was retrospectively registered with University Hospital Medical Information
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Network’s Ethics committee with approval number 1498 on March 19, 2014. The clinical
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trial was registered on May 26, 2014.
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32 Ethical approval
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The study was approved by an ethical review board of the University Hospital Medical
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Information Network clinical trial registry with reference number: 14074.
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36 Patient consent
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Participants provided written informed consent to participate in the study and for publication
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of its results.
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Availability of data and material
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The datasets used and/or analyzed during the current study available from the corresponding
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author on reasonable request.
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Competing interests
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The authors declare that they have no competing interests.
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Funding
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This research did not receive any specific grant from funding agencies in the public,
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commercial, or not-for-profit sectors.
ACCEPTED MANUSCRIPT 1
Teriparatide administration increases periprosthetic bone mineral density after total
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knee arthroplasty: A prospective study1
3 Abstract
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Background: Teriparatide is a currently available therapeutic agent for osteoporosis.
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Previous studies have reported that teriparatide affects periprosthetic bone mineral density
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(BMD) after total knee arthroplasty (TKA). However, little agreement has been reached
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concerning the treatment of periprosthetic BMD after TKA with teriparatide. Moreover,
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BMD in the femoral and tibial sides of the joints together has never been examined. We
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investigated the efficacy of teriparatide to inhibit BMD loss in the femoral and tibial side and
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considered complications such as migration and periprosthetic fractures after TKA.
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Methods: Twenty-two knees in 17 patients were included in this study, and a control group
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of patients who underwent TKA was identified according to their medical records. Dual-
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energy x-ray absorptiometry was performed for different locations (the knee, hip, and lumbar
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spine), and regions of interest were measured to estimate BMD at initiation of the study as a
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baseline reference, followed by subsequent measurements at 6 and 12 months.
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Results: As a result of adjusting the difference between the BMDs of the two groups at
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initiation, there was a significant increase in R3 (posterior condyle) and R4 (lateral) at 6
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months. Furthermore, there was a significant increase in R2 (anterior condyle), R3 (posterior
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condyle), and R6 (tibial diaphysis) at 12 months. The study group had a higher adjusted mean
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BMD in all regions than did the control group at 6 and 12 months.
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Abbreviations
MDCT: multi-detector computed tomography; BMD: Bone mineral density; TKA: total knee arthroplasty; DXA: Dual-energy x-ray absorptiometry; BMI: Body mass index; ROI: Regions of interest; ANCOVA: analysis of covariance.
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Conclusion: Teriparatide may be a reasonable treatment option for osteoporotic patients to
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preserve or improve periprosthetic BMD after TKA.
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Keywords: bone mineral density; osteoporosis; teriparatide; total knee arthroplasty
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ACCEPTED MANUSCRIPT Introduction
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Total knee arthroplasty (TKA) is one of the most effective treatment options for knee
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osteoarthritis. Although it has a stable long-term clinical effect, several problems still exist,
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such as periprosthetic bone atrophy. Periprosthetic bone atrophy may cause aseptic loosening
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and fracture [1]. Aseptic loosening and osteolysis are the most common indications for
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revision surgery [2, 3]. Bone atrophy is related to stress shielding, immobilization, and tissue
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reaction to operative trauma.
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TKA changes the mechanical stress of the knee joint and causes bone remodeling [4]. The
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bone surrounding the TKA implant affects the mineral density and structure of the joint in
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order to adjust to the new alignment of the lower legs. The new alignment increases patient
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mobility; moreover, there is increased hip and lumbar spine loading [5]. Therefore, there is
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potential for an increase in bone mineral density (BMD) in the hip and spine [5, 6]. The
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metaphyseal bone also adapts to changed loading after correction of any preoperative
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malalignment [7]. In contrast, several studies have described a significant postoperative
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decrease in BMD adjacent to the implants after TKA [5, 8, 9].
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Previous studies have reported the effect of bisphosphonates on periprosthetic BMD after
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TKA [10-14]. A 6-month course of alendronate initially increased BMD at 6 and 12 months
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after TKA [11]. In addition, oral bisphosphonate users had a 59% reduced probability of
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requiring revision surgery [13]. Teriparatide is a therapeutic agent that increases the
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formation of new bone tissue and is effective for patients with a high risk of fractures [15].
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Previous studies have reported the effectiveness of teriparatide in artificial joints. Teriparatide
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and alendronate had equal efficacy for preventing BMD loss around the implant after total
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hip arthroplasty [16]. Additionally, a once-weekly dose of teriparatide after TKA promoted
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bone ingrowth, mostly in the medial aspect of the bone-prosthesis interface, which meant that
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teriparatide increased periprosthetic BMD in the medial regions of the tibial component after
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been little agreement concerning the treatment of periprosthetic BMD of the tibial component
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after TKA with teriparatide, and the femoral side has never been studied at all. Moreover,
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since TKA consists of both the femoral and tibial sides of the joint, it is better to evaluate
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BMD on both sides together. However, to our knowledge, this has never been examined.
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We hypothesized that the administration of teriparatide to patients who underwent TKA
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would prevent statistically significantly higher periprosthetic BMD loss on the femoral and
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tibial sides of the joint.
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80 Materials and Methods
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Between April 2014 and July 2015, patients who gave consent for participation in this study
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were prospectively evaluated pre-administration and after 6 and 12 months of teriparatide
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administration. We excluded patients who were contraindicated according to the package
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insert of teriparatide and who had undergone revision surgery. Using medical records, we
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identified a control group of patients who were evaluated in the same time period, based on
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the same exclusion criteria. The control group was matched with the study group based on
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age at the time of study initiation, sex, height, weight, body mass index (BMI), and period
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from surgery to study initiation (Table 1). The study group included 17 patients (22 knees)
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(all postmenopausal women) in whom TKA was performed to treat osteoarthritis of the varus
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knee and a control group of patients who were diagnosed as having osteoporosis but did not
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receive treatment. The diagnosis of osteoporosis was based on the presence of a fracture after
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minimal trauma or BMD less than 70%. The diagnosis was made in accordance with the 2011
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version of the guideline for precaution and treatment of osteoporosis issued by the Japanese
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Society for Bone and Mineral Research [18].
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All patients in the study received the same cementless implants (LCS complete, Depuy
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ACCEPTED MANUSCRIPT Synthes, Inc., Los Angeles, CA, USA), and the patella was not resurfaced. Eleven patients
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(14 knees) received a once-weekly teriparatide regimen (56.5 µg/week subcutaneous
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injection), and 6 patients (8 knees) received a daily teriparatide regimen (20 µg/day
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subcutaneous injection). Considering the patients’ condition and need for convenience, we
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asked them to select their preferred injection regimen.
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Periprosthetic BMD levels were measured at 0 months (study initiation) as a baseline
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reference, followed by measurements at 6 and 12 months, using dual-energy x-ray
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absorptiometry (DXA) (Hologic, Inc., Bedford, MA, USA). To obtain a coronal view, we
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placed the patient in the supine position on the scanning bed, with the patella in the front
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position and the knee extended. To obtain a sagittal view, we placed the patient in the lateral
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position, with the knee in extension. The scan commenced 15 cm distal to the inferior edge of
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the patella and lasted for 90 seconds (140-100 kV; 2.5 mA; 0.2 mGy; field of view: 22 cm [L]
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× 11 cm [W]). The periprosthetic zones were classified based on previous studies [5, 7, 19-
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21]. We decided the regions of interest (ROIs) by using the DXA measurement. The ROIs in
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the sagittal view of the knee joint were divided into the following areas: R1 (femoral
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diaphysis), at the height of the upper margin of the femoral component on the femoral axis;
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R2 (anterior condyle), the dorsal side of the femoral component at the height of the center of
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the patella; and R3 (posterior condyle), the intersecting point with the peg of the femoral
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component at the height of the center of the patella. The coronal view was divided into the
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following areas: R4 (lateral), the lateral side of the tibial component at the height of the
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center of the fibula head; R5 (medial), the medial side of the tibial component at the height of
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the center of the fibula head; and R6 (tibial diaphysis), the lower tip of the tibial component
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(Fig. 1).
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The lumbar spine BMD levels were measured in the standard anteroposterior direction from
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L2 to L4 using DXA. BMD of the proximal femur was also measured using DXA in a
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Differences in baseline characteristics of continuous variables between the groups were tested
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with an unpaired t-test. We used analysis of covariance (ANCOVA) in order to examine the
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significance of BMD in both groups for R1 to R6. We tallied the mean and standard deviation
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(SD) of BMD in the study group and control group at study initiation, and at 6 months and 12
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months. We defined the independent variable as BMD at 6 months and 12 months, the
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dependent variable as group (study and control), and the covariate as BMD at initiation. We
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examined the difference between adjusted mean BMD at 6 months and 12 months (adjusting
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the difference of BMD at initiation between the study and control groups). In a similar way,
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we used ANCOVA for the lumbar spine and proximal femur. All statistical analyses were
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performed with IBM SPSS Statistics version 24 for Windows (SPSS Inc., Chicago IL, USA).
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Significance was set at P < 0.05, with associated 95% confidence intervals. The study was
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approved by an ethical review board and was performed in accordance with the ethical
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principles of the Declaration of Helsinki.
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Results
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At baseline, the BMD in the lumbar spine of the control group, as seen on DXA, was higher
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than that in the study group. There was no other difference between the two groups (Table 1).
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No patient had implant loosening or periprosthetic fractures; all knees were in good
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alignment, and the components were in the correct position. We could not find radiolucent
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lines more than 1 mm after 12 months in either group.
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The average BMD at study initiation was higher in the control group than in the study group
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in all regions (R1 to 6) (Table 2A). The results of the ANCOVA analysis for the two groups
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are provided in Table 2B. As a result of adjusting the difference between the BMDs of the
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two groups at initiation, there was a significant increase in R3 (posterior condyle) and R4
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adjusted mean BMD than the control group. In addition, there was a significant increase in
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R2 (anterior condyle), R3 (posterior condyle), and R6 (tibial diaphysis) at 12 months (P =
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0.018, P = 0.030, and P = 0.020, respectively), and the study group had a significantly higher
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adjusted mean BMD than the control group. There was no significant difference in the other
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regions; however, the study group had a higher adjusted mean BMD than the control group in
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these regions (Fig. 2).
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The BMD in the lumbar spine and proximal femur at study initiation was higher in the
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control group than in the study group (Table 3A, B). As a result of adjusting the difference
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between the BMDs of the two groups at initiation, there was a significant increase in the
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lumbar spine at 6 months, and the study group had a higher adjusted mean BMD than the
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control group. There was no significant difference in the proximal femur (Fig. 3).
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159 Discussion
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We hypothesized that the administration of teriparatide to patients with TKA would prevent
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periprosthetic BMD loss in the femoral and tibial sides of the joint. We found that the
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administration of teriparatide to patients with TKA increased periprosthetic BMD, as opposed
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to continuous periprosthetic bone loss, after TKA without osteoporosis treatment.
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Previous studies of periprosthetic BMD loss after TKA have considered the influence of
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implants with a cement or cementless design [9, 20, 22], stem design [23-27], with or without
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a peg and screw [28], and rotating or fixed platform TKA [29]. In these studies, the follow-up
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period was 2 to 7 years; moreover, these studies did not administer osteoporosis medication
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and did not find an increase in periprosthetic BMD after TKA.
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TKA implants are made from raw materials such as cobalt-chromium, titanium, etc. Some
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studies have compared the outcomes of various implant materials in primary TKA [30, 31].
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shielding because of their high stiffness. We used DePuy implants made from cobalt-
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chromium. Periprosthetic BMD should decrease from the viewpoint of metal stiffness, but
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our study showed an increase in periprosthetic BMD. If we used implants with different
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metals in this study, we would have seen different results.
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BMD in all regions of the femoral component and in the region behind the anterior flange of
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the femoral component showed maximum reduction in some studies [5, 8, 9, 32]. In these
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studies, the follow-up period was 1 to 7 years, and periprosthetic BMD around the femoral
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component reduced from 57% to 22% [9]. Our study showed a significant increase in
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periprosthetic BMD on the femoral side, in R3 (posterior condyle) at 6 months, and in R2
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(anterior condyle) and R3 (posterior condyle) at 12 months; however, several studies have
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reported that there should be a significant decrease with time in R2 (anterior condyle) [5, 8,
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9]. We considered that teriparatide had a strong influence on periprosthetic BMD after TKA.
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Compared with the femoral side, the tibial side had a more complicated outcome. Several
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studies have described a significant decrease in periprosthetic BMD in the tibial side after
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TKA [20, 26, 32]. In these studies, the follow-up period was 2 to 7 years, and periprosthetic
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BMD around the tibial component decreased between 5% and 30% [26, 32]. Furthermore,
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other studies have shown an asymmetrical density decrease between the ROIs, a slight
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decrease in the lateral region, and a large decrease in the medial region [27, 34]. In contrast,
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Petersen et al. reported that the BMD increased significantly only in the lateral region of the
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tibial side [35]. Our study similarly showed a significant increase in periprosthetic BMD on
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the tibial side, and R4 (lateral) increased at 6 months. This was thought to be due to the
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influence of change in the loading axis, as indicated by these authors. Although our control
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group and previous studies showed a decrease with time in R5 (medial) and R6 (tibial
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diaphysis), in our study, BMD increased with time in the same regions. We believe that
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ACCEPTED MANUSCRIPT teriparatide had an influence in the femoral side, similar to the tibial side. In a report that
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described the use of teriparatide in an animal model, an implant was inserted into the
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proximal part of the tibia (likely TKA) of mice that had received teriparatide [36]. The bone
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volume fraction was 168% higher distal to the implant compared with the bone volume
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fractions in the same regions in the vehicle-treated mice. In a study on humans, Kaneko et al.
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reported that a once-weekly dose of teriparatide increased periprosthetic BMD in the medial
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regions of the tibial component after TKA, as seen on MDCT [17]. However, our study did
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not show any increase in bone density in the same region. We considered that this difference
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occurred for two reasons. The first is the difference in administration timing. The condition of
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the bone around the component was unstable immediately after the operation, because of the
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intramedullary guiding rod and impaction of the implant during insertion [21, 32]. Kaneko
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et.al. [17] started the administration immediately after the operation, but we administered
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medication to patients at more than 3 months after surgery, considering the osteogenic cycle
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(period: 3 months) [37]. The second difference is the insertion angle of the component.
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Kaneko et al. [17] inserted the tibial component with a slight varus angle, and our surgeon
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tried to insert the component in the neutral position. This difference of axial load may
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contribute to the differences in BMD [4]. Our study suggested that teriparatide widely
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increased periprosthetic BMD. Furthermore, this is the first study to evaluate the femur side
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with administration of teriparatide and to show the increase in periprosthetic BMD on both
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sides with the administration of teriparatide.
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A limitation of this study was that BMD changes were observed only on DXA. Therefore,
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any advantages of teriparatide for biological fixation of the bone and implant could not be
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assessed. Second, this study was based on clinical research, so we could not include controls
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that consisted of osteoporotic patients who were not on medication. A randomized, placebo-
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controlled trial is needed. A power of analysis was not performed to estimate the adequate
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investigation period. When the sample size is small, researchers should use the range and
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interquartile range. However, these values did not match the initial values of BMD in the
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clinical research setting. Therefore, we used analysis of covariance and SD. Finally,
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prosthetic migration and periprosthetic fracture may occur with a longer duration of follow-
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up.
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228 Conclusions
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Treatment with a 1-year course of teriparatide increased periprosthetic BMD in all regions of
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the femoral and tibial component after TKA in our study. Our findings suggest that
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teriparatide administration may be a reasonable option for osteoporotic patients to preserve or
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improve periprosthetic BMD after TKA. We recommend the administration of teriparatide to
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achieve better fixation in postmenopausal osteoporotic patients. However, the long-term
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efficacy of teriparatide after TKA remains unclear. Additional studies are required to
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determine whether further therapy after treatment with teriparatide will protect the knee over
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the long term.
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ACCEPTED MANUSCRIPT References
243
[1] Boden HS, Skoldenberg OG, Salemyr MO, Lundberg HJ, Adolphson PY. Continuous
244
bone loss around a tapered uncemented femoral stem: a long-term evaluation with DEXA.
245
Acta Orthop 2006;77:877–85.
246
[2] Sundfeldt M, Carlsson LV, Johansson CB, Thomsen P, Gretzer C. Aseptic loosening, not
247
only a question of wear: a review of different theories. Acta Orthop 2006;77:177–97.
248
[3] Dalury DF, Pomeroy DL, Gorab RS, Adams MJ. Why are total knee arthroplasties being
249
revised? J Arthroplasty 2013;28:120–1.
250
[4] Teichtahl AJ, Wluka AE, Wijethilake P, Wang Y, Ghasem-Zadeh A, Cicuttini FM. Wolff’s
251
law in action: a mechanism for early knee osteoarthritis. Arthritis Res Ther 2015;17:207.
252
[5] van Loon CJ, Oyen WJ, de Waal Malefijt MC, Verdonschot N. Distal femoral bone
253
mineral density after total knee arthroplasty: a comparison with general bone mineral density.
254
Arch Orthop Trauma Surg 2001;121:282–5.
255
[6] Ishii Y, Yagisawa K, Ikezawa Y. Changes in bone mineral density of the proximal femur
256
after total knee arthroplasty. J Arthroplasty 2000;15:519–22.
257
[7] Soininvaara TA, Miettinen HJ, Jurvelin JS, Suomalainen OT, Alhava EM, Kroger HP.
258
Periprosthetic femoral bone loss after total knee arthroplasty: 1-year follow-up study of 69
259
patients. Knee 2004;11:297–302.
260
[8] Petersen MM, Lauritzen JB, Pedersen JG, Lund B. Decreased bone density of the distal
261
femur after uncemented knee arthroplasty. A 1-year follow-up of 29 knees. Acta Orthop
262
Scand 1996;67:339–44.
263
[9] Seki T, Omori G, Koga Y, Suzuki Y, Ishii Y, Takahashi HE. Is bone density in the distal
264
femur affected by use of cement and by femoral component design in total knee arthroplasty?
265
J Orthop Sci 1999;4:180–6.
266
[10] Soininvaara TA, Jurvelin JS, Miettinen HJ, Suomalainen OT, Alhava EM, Kroger PJ.
AC C
EP
TE D
M AN U
SC
RI PT
242
11
ACCEPTED MANUSCRIPT Effect of alendronate on periprosthetic bone loss after total knee arthroplasty: a one-year,
268
randomized, controlled trial of 19 patients. Calcif Tissue Int 2002;71:472–7.
269
[11] Wang CJ, Wang JW, Ko JY, Weng LH, Huang CC. Three-year changes in bone mineral
270
density around the knee after a six-month course of oral alendronate following total knee
271
arthroplasty. A prospective, randomized study. J Bone Joint Surg Am 2006;88:267–72.
272
[12] Jaroma AV, Soininvaara TA, Kroger H. Effect of one-year post-operative alendronate
273
treatment on periprosthetic bone after total knee arthroplasty. A seven-year randomised
274
controlled trial of 26 patients. Bone Joint J 2015;97-B:337–45.
275
[13] Prieto-Alhambra D, Lalmohamed A, Abrahamsen B, Arden NK, de Boer A, Vestergarrd
276
P et al. Oral bisphosphonate use and total knee/hip implant survival: validation of results in
277
an external population-based cohort. Arthritis Rheumatol 2014;66:3233–40.
278
[14] Namba RS, Inacio MC, Cheetham TC, Dell RM, Paxton EW, Khatod MX. Lower total
279
knee arthroplasty revision risk associated with bisphosphonate use, even in patients with
280
normal bone density. J Arthroplasty 2016;31:537–41.
281
[15] Shiraki M, Ueda S, Sugimoto T, Kuroda T, Nakamura T. Treatment responses with once-
282
weekly teriparatide therapy for osteoporosis. Osteoporos Int 2016;27:3057–62.
283
[16] Kobayashi N, Inaba Y, Uchiyama M, Ike H, Kubota S, Saito T. Teriparatide versus
284
alendronate for the preservation of bone mineral density after total hip arthroplasty - a
285
randomized controlled trial. J Arthroplasty 2016;31:333–8.
286
[17] Kaneko T, Otani T, Kono N, Mochizuki Y, Mori T, Nango N et al. Weekly injection of
287
teriparatide for bone ingrowth after cementless total knee arthroplasty. J Orthop Surg (Hong
288
Kong) 2016;24:16–21.
289
[18] Orimo H, Nakamura T. Guideline for precaution and treatment of osteoporosis: 2011
290
update. J Bone Miner Res 2011;2:12–35.
291
[19] Soininvaara TA, Miettinen HJ, Jurvelin JS, Suomalainen OT, Alhava EM, Kroger HP.
AC C
EP
TE D
M AN U
SC
RI PT
267
12
ACCEPTED MANUSCRIPT Periprosthetic tibial bone mineral density changes after total knee arthroplasty: one-year
293
follow-up study of 69 patients. Acta Orthop Scand 2004;75:600–5.
294
[20] Jarvenpaa J, Soininvaara T, Kettunen J, Miettinen H, Kroger H. Changes in bone mineral
295
density of the distal femur after total knee arthroplasty: a 7-year DEXA follow-up comparing
296
results between obese and nonobese patients. Knee 2014;21:232–5.
297
[21] Shibuki T, Suzuki T, Sukezaki F, Toyoshima Y. Nagai T, Inagaki K et al. Periprothetic
298
bone mineral density changes after cementless total knee arthroplasty. Showa Univ J Med Sci
299
2016 28:155–61.
300
[22] Li MG, Nilsson KG. Changes in bone mineral density at the proximal tibia after total
301
knee arthroplasty: a 2-year follow-up of 28 knees using dual energy X-ray absorptiometry. J
302
Orthopaedic Res 2000;18:40–7.
303
[23] Abu-Rajab RB, Watson WS, Walker B, Roberts J, Gallacher SJ, Meek RM. Peri-
304
prosthetic bone mineral density after total knee arthroplasty. Cemented versus cementless
305
fixation. J Bone Joint Surg Br 2006;88:606–13.
306
[24] Cameron HU, Cameron G. Stress-relief osteoporosis of the anterior femoral condyles in
307
total knee replacement. A study of 185 patients. Orthop Rev 1987;16:449–56.
308
[25] Mintzer CM, Robertson DD, Rackemann S, Ewald FC, Scott RD, Spector M. Bone loss
309
in the distal anterior femur after total knee arthroplasty. Clin Orthop Relat Res 1999;260:135–
310
43.
311
[26] Lonner JH, Klotz M, Levitz C, Lotke PA. Changes in bone density after cemented total
312
knee arthroplasty: influence of stem design. J Arthroplasty 2001;16:107–11.
313
[27] Saari T, Uvehammer J, Carlsson L, Regner L, Karrholm J. Joint area constraint had no
314
influence on bone loss in proximal tibia 5 years after total knee replacement. J Orthop Res
315
2007;25:798–803.
316
[28] Hernandez-Vaquero D, Garcia-Sandoval MA, Fernandez-Carreira JM, Gava R. Influence
AC C
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TE D
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ACCEPTED MANUSCRIPT of the tibial stem design on bone density after cemented total knee arthroplasty: a prospective
318
seven-year follow-up study. Int Orthop 2008;32:47–51.
319
[29] Sumner DR, Turner TM, Dawson D, Rosenberg AG, Urban RM, Galante JO. Effect of
320
pegs and screws on bone ingrowth in cementless total knee arthroplasty. Clin Orthop Relat
321
Res 1994;309:150–5.
322
[30] Martin JR, Watts CD, Levy DL, Kim RH. Medial Tibial Stress Shielding: A Limitation
323
of Cobalt Chromium Tibial Baseplates. The Journal of arthroplasty 2017;32:558-562.
324
[31] Zhang QH, Cossey A, Tong J. Stress shielding in periprosthetic bone following a total
325
knee replacement: Effects of implant material, design and alignment. Medical engineering &
326
physics 2016;38:1481-1488.
327
[32]Munro JT, Pandit S, Walker CG, Clatworthy M, Pitto RP. Loss of tibial bone density in
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patients with rotating- or fixed-platform TKA. Clin Orthop Relat Res 2010;468:775–81.
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[33] Levitz CL, Lotke PA, Karp JS. Long-term changes in bone mineral density following
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total knee replacement. Clin Orthop Relat Res 1995;321:66–72.
331
[34] Regner LR, Carlsson LV, Karrholm JN, Hansson TH, Herberts PG, Swanpalmer J. Bone
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mineral and migratory patterns in uncemented total knee arthroplasties: a randomized 5-year
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follow-up study of 38 knees. Acta Orthop Scand 1999;70:603–8.
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[35] Petersen MM, Gehrchen PM, Ostgaard SE, Nielsen PK, Lund B. Effect of
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hydroxyapatite-coated tibial components on changes in bone mineral density of the proximal
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tibia after uncemented total knee arthroplasty: a prospective randomized study using dual-
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energy x-ray absorptiometry. J Arthroplasty 2005;20:516–20.
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[36] Yang X, Ricciardi BF, Dvorzhinskiy A, Brial C, Lane Z, Bhimani S et al. Intermittent
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parathyroid hormone enhances cancellous osseointegration of a novel murine tibial Implant. J
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Bone Joint Surg Am 2015;97:1074–83.
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Clin Biochem Rev 2005;26:97–122.
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ACCEPTED MANUSCRIPT Acknowledgement
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We thank Tetsuya Nemoto, MD PhD for his technical and statistical assistance.
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Figure legends
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Fig. 1 Radiograph showing the regions of interest in the sagittal and coronal view Radiograph showing the regions of interest used to measure bone mineral density with
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dual-energy x-ray absorptiometry in the sagittal and coronal views at pre-
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administration and 6 and 12 months post-administration. (a) sagittal view, (b) coronal
6
view
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Fig. 2 Comparison of patients with or without teriparatide in terms of bone mineral density in the six regions of interest
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Comparison of patients with or without teriparatide in terms of bone mineral density
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in the six regions of interest (R1 to 6): (a) R1 (femoral diaphysis), (b) R2 (anterior
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condyle), (c) R3 (posterior condyle), (d) R4 (lateral), (e) R5 (medial), and (f) R6
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(tibial diaphysis)
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Fig. 3 Comparison of patients with or without teriparatide in terms of bone mineral density in the lumbar and proximal femur
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Comparison of patients with or without teriparatide in terms of bone mineral density
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in the lumbar spine and proximal femur. (a) lumber spine, (b) proximal femur
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BMD: bone mineral density; SE: standard error; ANCOVA: analysis of covariance
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Tables
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Table 1. General baseline characteristics Description
Study group
Control
P-value
No. of patients
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No. of knees
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17
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Only female 78.9 (4.1)
79.1 (5.1)
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Age (years)
Only female
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Height (m) Weight (kg) 2
1.48 (6.1)
1.49 (3.9)
0.69
54.3 (8.3)
56.3 (5.7)
0.37
24.5 (3.4)
25.3 (2.3)
0.45
18.2 (15.8)
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0.87
Until administration or baseline
16.4 (13.0)
from operation (months)
Once-weekly
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11 patients (14 knees) 6 patients (8 knees)
BMI: body mass index. Values are presented as a mean ± standard deviation
ACCEPTED MANUSCRIPT Table 2A. Average and standard deviation of R1 to 6 Control group
Average (SD)
Average (SD)
0 month
0.553 (0.114)
0.669 (0.155)
6 months
0.563 (0.116)
0.645 (0.159)
12 months
0.550 (0.140)
0.609 (0.161)
0 month
0.505 (0.136)
0.569 (0.189)
6 months
0.520 (0.141)
0.531 (0.163)
12 months
0.526 (0.160)
0 month
0.776 (0.164)
0.802 (0.239)
6 months
0.832 (0.153)
0.758 (0.233)
12 months
0.833 (0.197)
0.708 (0.190)
0 month
0.642 (0.225)
0.665 (0.177)
6 months
0.659 (0.181)
0.609 (0.174)
12 months
0.662 (0.191)
0.615 (0.188)
0 month
0.558 (0.195)
0.608 (0.17)
6 months
0.564 (0.180)
0.601 (0.212)
12 months
0.575 (0.171)
0.578 (0.179)
0 month
0.578 (0.169)
0.752 (0.169)
6 months
0.623 (0.155)
0.742 (0.197)
12 months
0.642 (0.159)
0.709 (0.189)
R2
R3
R4
R6
6 7 8
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ROI
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0.514 (0.149)
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SD: standard deviation; ROI: regions of interest
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Table 2B. Adjusted mean and standard error with analysis of covariance of R1 to 6 Study group
Control group
Adjusted mean
Adjusted mean
ROI
P-value
R4
R5
R6
0.611
0.613 (0.016)
0.595 (0.016)
12 months
0.604 (0.018)
0.555 (0.018)
0.537
6 months
0.545 (0.019)
12 months
0.552 (0.018)
0 month
0.789
6 months
0.843 (0.019)
12 months
0.841 (0.030)
0 month
0.654
0.537
0.506 (0.019)
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0 month
0.445
0.073
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6 months
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R3
0.611
0.488 (0.018)
0.169
0.018*
0.789
0.747 (0.019)
0.001*
0.700 (0.030)
0.002*
0.654
6 months
0.668 (0.021)
0.601 (0.021)
0.028*
12 months
0.671 (0.023)
0.606 (0.023)
0.059
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R2
0 month
0 month
0.583
0.583
6 months
0.588 (0.016)
0.577 (0.016)
0.616
12 months
0.596 (0.019)
0.558 (0.019)
0.165
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(SE)
0 month
0.665
0.665
6 months
0.703 (0.020)
0.661 (0.020)
0.156
12 months
0.721 (0.020)
0.630 (0.020)
0.004*
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※covariate: BMD at initiation (0 month) * p<0.05
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SE: standard error; ROI: regions of interest; BMD: bone mineral density
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Average (SD)
Average (SD)
0 month
0.842 (0.137)
0.989 (0.189)
6 months
0.875 (0.134)
0.992 (0.200)
12 months
0.879 (0.142)
1.013 (0.232)
0 month
0.494 (0.052)
0.561 (0.082)
6 months
0.505 (0.059)
0.567 (0.078)
12 months
0.501 (0.060)
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Control group
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Lumbar spine
Study group
0.576 (0.077)
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Table 3B. Adjusted mean and SE by analysis of covariance of the lumbar spine and proximal
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femur Study group
Control group
Adjusted mean
Adjusted mean
(SE)
(SE)
0 month
0.916
0.916
6 months
0.949 (0.009)
0.918 (0.009)
0.021*
12 months
0.960 (0.014)
0.931 (0.014)
0.181
0 month
0.528
6 months
0.535 (0.007)
0.536 (0.007)
0.913
12 months
0.529 (0.008)
0.547 (0.008)
0.149
※covariate: BMD at initiation (0 month) * p<0.05
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SE: standard error; BMD: bone mineral density
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Proximal femur
0.528
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Lumbar spine
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P-value
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S0883-5403(17)30642-3
DOI:
10.1016/j.arth.2017.07.026
Reference:
YARTH 56006
To appear in:
The Journal of Arthroplasty
Received Date: 24 March 2017 Revised Date:
5 July 2017
Accepted Date: 17 July 2017
Please cite this article as: Suzuki T, Sukezaki F, Shibuki T, Toyoshima Y, Nagai T, Inagaki K, Teriparatide administration increases periprosthetic bone mineral density after total knee arthroplasty: A 1 prospective study , The Journal of Arthroplasty (2017), doi: 10.1016/j.arth.2017.07.026. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Teriparatide administration increases periprosthetic bone mineral density after total
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knee arthroplasty: A prospective study
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Short title: Teriparatide administration for bone mineral density after total knee arthroplasty
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Tatsuya Suzuki*, MD; Fumio Sukezaki, MD, PhD; Takashi Shibuki, MD, PhD;
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Yoichi Toyoshima, MD, PhD; Takashi Nagai, MD, PhD; Katsunori Inagaki,
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MD, PhD
9 Department
of
Orthopedic
Surgery,
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1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan
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Showa
University
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School
*Corresponding author:
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Tatsuya Suzuki, MD
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Department of Orthopedic Surgery, Showa University School of Medicine
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1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan
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Phone: +81-3-3784-8543
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Fax: +81-3-3784-9005
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E-mail: [email protected]
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Author e-mail addresses:
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Fumio Sukezaki: [email protected]
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Takashi Shibuki: [email protected]
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Yoichi Toyoshima: [email protected]
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Takashi Nagai: [email protected]
of
Medicine
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Katsunori Inagaki: [email protected]
27 Trial registration
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This study was retrospectively registered with University Hospital Medical Information
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Network’s Ethics committee with approval number 1498 on March 19, 2014. The clinical
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trial was registered on May 26, 2014.
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32 Ethical approval
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The study was approved by an ethical review board of the University Hospital Medical
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Information Network clinical trial registry with reference number: 14074.
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36 Patient consent
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Participants provided written informed consent to participate in the study and for publication
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of its results.
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Availability of data and material
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The datasets used and/or analyzed during the current study available from the corresponding
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author on reasonable request.
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Competing interests
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The authors declare that they have no competing interests.
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Funding
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This research did not receive any specific grant from funding agencies in the public,
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commercial, or not-for-profit sectors.
ACCEPTED MANUSCRIPT 1
Teriparatide administration increases periprosthetic bone mineral density after total
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knee arthroplasty: A prospective study1
3 Abstract
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Background: Teriparatide is a currently available therapeutic agent for osteoporosis.
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Previous studies have reported that teriparatide affects periprosthetic bone mineral density
7
(BMD) after total knee arthroplasty (TKA). However, little agreement has been reached
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concerning the treatment of periprosthetic BMD after TKA with teriparatide. Moreover,
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BMD in the femoral and tibial sides of the joints together has never been examined. We
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investigated the efficacy of teriparatide to inhibit BMD loss in the femoral and tibial side and
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considered complications such as migration and periprosthetic fractures after TKA.
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Methods: Twenty-two knees in 17 patients were included in this study, and a control group
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of patients who underwent TKA was identified according to their medical records. Dual-
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energy x-ray absorptiometry was performed for different locations (the knee, hip, and lumbar
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spine), and regions of interest were measured to estimate BMD at initiation of the study as a
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baseline reference, followed by subsequent measurements at 6 and 12 months.
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Results: As a result of adjusting the difference between the BMDs of the two groups at
18
initiation, there was a significant increase in R3 (posterior condyle) and R4 (lateral) at 6
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months. Furthermore, there was a significant increase in R2 (anterior condyle), R3 (posterior
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condyle), and R6 (tibial diaphysis) at 12 months. The study group had a higher adjusted mean
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BMD in all regions than did the control group at 6 and 12 months.
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1
Abbreviations
MDCT: multi-detector computed tomography; BMD: Bone mineral density; TKA: total knee arthroplasty; DXA: Dual-energy x-ray absorptiometry; BMI: Body mass index; ROI: Regions of interest; ANCOVA: analysis of covariance.
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Conclusion: Teriparatide may be a reasonable treatment option for osteoporotic patients to
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preserve or improve periprosthetic BMD after TKA.
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Keywords: bone mineral density; osteoporosis; teriparatide; total knee arthroplasty
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ACCEPTED MANUSCRIPT Introduction
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Total knee arthroplasty (TKA) is one of the most effective treatment options for knee
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osteoarthritis. Although it has a stable long-term clinical effect, several problems still exist,
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such as periprosthetic bone atrophy. Periprosthetic bone atrophy may cause aseptic loosening
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and fracture [1]. Aseptic loosening and osteolysis are the most common indications for
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revision surgery [2, 3]. Bone atrophy is related to stress shielding, immobilization, and tissue
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reaction to operative trauma.
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TKA changes the mechanical stress of the knee joint and causes bone remodeling [4]. The
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bone surrounding the TKA implant affects the mineral density and structure of the joint in
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order to adjust to the new alignment of the lower legs. The new alignment increases patient
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mobility; moreover, there is increased hip and lumbar spine loading [5]. Therefore, there is
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potential for an increase in bone mineral density (BMD) in the hip and spine [5, 6]. The
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metaphyseal bone also adapts to changed loading after correction of any preoperative
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malalignment [7]. In contrast, several studies have described a significant postoperative
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decrease in BMD adjacent to the implants after TKA [5, 8, 9].
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Previous studies have reported the effect of bisphosphonates on periprosthetic BMD after
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TKA [10-14]. A 6-month course of alendronate initially increased BMD at 6 and 12 months
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after TKA [11]. In addition, oral bisphosphonate users had a 59% reduced probability of
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requiring revision surgery [13]. Teriparatide is a therapeutic agent that increases the
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formation of new bone tissue and is effective for patients with a high risk of fractures [15].
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Previous studies have reported the effectiveness of teriparatide in artificial joints. Teriparatide
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and alendronate had equal efficacy for preventing BMD loss around the implant after total
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hip arthroplasty [16]. Additionally, a once-weekly dose of teriparatide after TKA promoted
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bone ingrowth, mostly in the medial aspect of the bone-prosthesis interface, which meant that
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teriparatide increased periprosthetic BMD in the medial regions of the tibial component after
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been little agreement concerning the treatment of periprosthetic BMD of the tibial component
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after TKA with teriparatide, and the femoral side has never been studied at all. Moreover,
75
since TKA consists of both the femoral and tibial sides of the joint, it is better to evaluate
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BMD on both sides together. However, to our knowledge, this has never been examined.
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We hypothesized that the administration of teriparatide to patients who underwent TKA
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would prevent statistically significantly higher periprosthetic BMD loss on the femoral and
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tibial sides of the joint.
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80 Materials and Methods
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Between April 2014 and July 2015, patients who gave consent for participation in this study
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were prospectively evaluated pre-administration and after 6 and 12 months of teriparatide
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administration. We excluded patients who were contraindicated according to the package
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insert of teriparatide and who had undergone revision surgery. Using medical records, we
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identified a control group of patients who were evaluated in the same time period, based on
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the same exclusion criteria. The control group was matched with the study group based on
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age at the time of study initiation, sex, height, weight, body mass index (BMI), and period
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from surgery to study initiation (Table 1). The study group included 17 patients (22 knees)
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(all postmenopausal women) in whom TKA was performed to treat osteoarthritis of the varus
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knee and a control group of patients who were diagnosed as having osteoporosis but did not
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receive treatment. The diagnosis of osteoporosis was based on the presence of a fracture after
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minimal trauma or BMD less than 70%. The diagnosis was made in accordance with the 2011
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version of the guideline for precaution and treatment of osteoporosis issued by the Japanese
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Society for Bone and Mineral Research [18].
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All patients in the study received the same cementless implants (LCS complete, Depuy
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ACCEPTED MANUSCRIPT Synthes, Inc., Los Angeles, CA, USA), and the patella was not resurfaced. Eleven patients
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(14 knees) received a once-weekly teriparatide regimen (56.5 µg/week subcutaneous
99
injection), and 6 patients (8 knees) received a daily teriparatide regimen (20 µg/day
100
subcutaneous injection). Considering the patients’ condition and need for convenience, we
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asked them to select their preferred injection regimen.
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Periprosthetic BMD levels were measured at 0 months (study initiation) as a baseline
103
reference, followed by measurements at 6 and 12 months, using dual-energy x-ray
104
absorptiometry (DXA) (Hologic, Inc., Bedford, MA, USA). To obtain a coronal view, we
105
placed the patient in the supine position on the scanning bed, with the patella in the front
106
position and the knee extended. To obtain a sagittal view, we placed the patient in the lateral
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position, with the knee in extension. The scan commenced 15 cm distal to the inferior edge of
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the patella and lasted for 90 seconds (140-100 kV; 2.5 mA; 0.2 mGy; field of view: 22 cm [L]
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× 11 cm [W]). The periprosthetic zones were classified based on previous studies [5, 7, 19-
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21]. We decided the regions of interest (ROIs) by using the DXA measurement. The ROIs in
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the sagittal view of the knee joint were divided into the following areas: R1 (femoral
112
diaphysis), at the height of the upper margin of the femoral component on the femoral axis;
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R2 (anterior condyle), the dorsal side of the femoral component at the height of the center of
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the patella; and R3 (posterior condyle), the intersecting point with the peg of the femoral
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component at the height of the center of the patella. The coronal view was divided into the
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following areas: R4 (lateral), the lateral side of the tibial component at the height of the
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center of the fibula head; R5 (medial), the medial side of the tibial component at the height of
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the center of the fibula head; and R6 (tibial diaphysis), the lower tip of the tibial component
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(Fig. 1).
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The lumbar spine BMD levels were measured in the standard anteroposterior direction from
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L2 to L4 using DXA. BMD of the proximal femur was also measured using DXA in a
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Differences in baseline characteristics of continuous variables between the groups were tested
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with an unpaired t-test. We used analysis of covariance (ANCOVA) in order to examine the
125
significance of BMD in both groups for R1 to R6. We tallied the mean and standard deviation
126
(SD) of BMD in the study group and control group at study initiation, and at 6 months and 12
127
months. We defined the independent variable as BMD at 6 months and 12 months, the
128
dependent variable as group (study and control), and the covariate as BMD at initiation. We
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examined the difference between adjusted mean BMD at 6 months and 12 months (adjusting
130
the difference of BMD at initiation between the study and control groups). In a similar way,
131
we used ANCOVA for the lumbar spine and proximal femur. All statistical analyses were
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performed with IBM SPSS Statistics version 24 for Windows (SPSS Inc., Chicago IL, USA).
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Significance was set at P < 0.05, with associated 95% confidence intervals. The study was
134
approved by an ethical review board and was performed in accordance with the ethical
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principles of the Declaration of Helsinki.
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Results
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At baseline, the BMD in the lumbar spine of the control group, as seen on DXA, was higher
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than that in the study group. There was no other difference between the two groups (Table 1).
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No patient had implant loosening or periprosthetic fractures; all knees were in good
141
alignment, and the components were in the correct position. We could not find radiolucent
142
lines more than 1 mm after 12 months in either group.
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The average BMD at study initiation was higher in the control group than in the study group
144
in all regions (R1 to 6) (Table 2A). The results of the ANCOVA analysis for the two groups
145
are provided in Table 2B. As a result of adjusting the difference between the BMDs of the
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two groups at initiation, there was a significant increase in R3 (posterior condyle) and R4
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148
adjusted mean BMD than the control group. In addition, there was a significant increase in
149
R2 (anterior condyle), R3 (posterior condyle), and R6 (tibial diaphysis) at 12 months (P =
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0.018, P = 0.030, and P = 0.020, respectively), and the study group had a significantly higher
151
adjusted mean BMD than the control group. There was no significant difference in the other
152
regions; however, the study group had a higher adjusted mean BMD than the control group in
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these regions (Fig. 2).
154
The BMD in the lumbar spine and proximal femur at study initiation was higher in the
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control group than in the study group (Table 3A, B). As a result of adjusting the difference
156
between the BMDs of the two groups at initiation, there was a significant increase in the
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lumbar spine at 6 months, and the study group had a higher adjusted mean BMD than the
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control group. There was no significant difference in the proximal femur (Fig. 3).
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159 Discussion
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We hypothesized that the administration of teriparatide to patients with TKA would prevent
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periprosthetic BMD loss in the femoral and tibial sides of the joint. We found that the
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administration of teriparatide to patients with TKA increased periprosthetic BMD, as opposed
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to continuous periprosthetic bone loss, after TKA without osteoporosis treatment.
165
Previous studies of periprosthetic BMD loss after TKA have considered the influence of
166
implants with a cement or cementless design [9, 20, 22], stem design [23-27], with or without
167
a peg and screw [28], and rotating or fixed platform TKA [29]. In these studies, the follow-up
168
period was 2 to 7 years; moreover, these studies did not administer osteoporosis medication
169
and did not find an increase in periprosthetic BMD after TKA.
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TKA implants are made from raw materials such as cobalt-chromium, titanium, etc. Some
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studies have compared the outcomes of various implant materials in primary TKA [30, 31].
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shielding because of their high stiffness. We used DePuy implants made from cobalt-
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chromium. Periprosthetic BMD should decrease from the viewpoint of metal stiffness, but
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our study showed an increase in periprosthetic BMD. If we used implants with different
176
metals in this study, we would have seen different results.
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BMD in all regions of the femoral component and in the region behind the anterior flange of
178
the femoral component showed maximum reduction in some studies [5, 8, 9, 32]. In these
179
studies, the follow-up period was 1 to 7 years, and periprosthetic BMD around the femoral
180
component reduced from 57% to 22% [9]. Our study showed a significant increase in
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periprosthetic BMD on the femoral side, in R3 (posterior condyle) at 6 months, and in R2
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(anterior condyle) and R3 (posterior condyle) at 12 months; however, several studies have
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reported that there should be a significant decrease with time in R2 (anterior condyle) [5, 8,
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9]. We considered that teriparatide had a strong influence on periprosthetic BMD after TKA.
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Compared with the femoral side, the tibial side had a more complicated outcome. Several
186
studies have described a significant decrease in periprosthetic BMD in the tibial side after
187
TKA [20, 26, 32]. In these studies, the follow-up period was 2 to 7 years, and periprosthetic
188
BMD around the tibial component decreased between 5% and 30% [26, 32]. Furthermore,
189
other studies have shown an asymmetrical density decrease between the ROIs, a slight
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decrease in the lateral region, and a large decrease in the medial region [27, 34]. In contrast,
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Petersen et al. reported that the BMD increased significantly only in the lateral region of the
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tibial side [35]. Our study similarly showed a significant increase in periprosthetic BMD on
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the tibial side, and R4 (lateral) increased at 6 months. This was thought to be due to the
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influence of change in the loading axis, as indicated by these authors. Although our control
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group and previous studies showed a decrease with time in R5 (medial) and R6 (tibial
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diaphysis), in our study, BMD increased with time in the same regions. We believe that
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ACCEPTED MANUSCRIPT teriparatide had an influence in the femoral side, similar to the tibial side. In a report that
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described the use of teriparatide in an animal model, an implant was inserted into the
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proximal part of the tibia (likely TKA) of mice that had received teriparatide [36]. The bone
200
volume fraction was 168% higher distal to the implant compared with the bone volume
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fractions in the same regions in the vehicle-treated mice. In a study on humans, Kaneko et al.
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reported that a once-weekly dose of teriparatide increased periprosthetic BMD in the medial
203
regions of the tibial component after TKA, as seen on MDCT [17]. However, our study did
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not show any increase in bone density in the same region. We considered that this difference
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occurred for two reasons. The first is the difference in administration timing. The condition of
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the bone around the component was unstable immediately after the operation, because of the
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intramedullary guiding rod and impaction of the implant during insertion [21, 32]. Kaneko
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et.al. [17] started the administration immediately after the operation, but we administered
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medication to patients at more than 3 months after surgery, considering the osteogenic cycle
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(period: 3 months) [37]. The second difference is the insertion angle of the component.
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Kaneko et al. [17] inserted the tibial component with a slight varus angle, and our surgeon
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tried to insert the component in the neutral position. This difference of axial load may
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contribute to the differences in BMD [4]. Our study suggested that teriparatide widely
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increased periprosthetic BMD. Furthermore, this is the first study to evaluate the femur side
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with administration of teriparatide and to show the increase in periprosthetic BMD on both
216
sides with the administration of teriparatide.
217
A limitation of this study was that BMD changes were observed only on DXA. Therefore,
218
any advantages of teriparatide for biological fixation of the bone and implant could not be
219
assessed. Second, this study was based on clinical research, so we could not include controls
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that consisted of osteoporotic patients who were not on medication. A randomized, placebo-
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controlled trial is needed. A power of analysis was not performed to estimate the adequate
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investigation period. When the sample size is small, researchers should use the range and
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interquartile range. However, these values did not match the initial values of BMD in the
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clinical research setting. Therefore, we used analysis of covariance and SD. Finally,
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prosthetic migration and periprosthetic fracture may occur with a longer duration of follow-
227
up.
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228 Conclusions
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Treatment with a 1-year course of teriparatide increased periprosthetic BMD in all regions of
231
the femoral and tibial component after TKA in our study. Our findings suggest that
232
teriparatide administration may be a reasonable option for osteoporotic patients to preserve or
233
improve periprosthetic BMD after TKA. We recommend the administration of teriparatide to
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achieve better fixation in postmenopausal osteoporotic patients. However, the long-term
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efficacy of teriparatide after TKA remains unclear. Additional studies are required to
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determine whether further therapy after treatment with teriparatide will protect the knee over
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the long term.
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ACCEPTED MANUSCRIPT References
243
[1] Boden HS, Skoldenberg OG, Salemyr MO, Lundberg HJ, Adolphson PY. Continuous
244
bone loss around a tapered uncemented femoral stem: a long-term evaluation with DEXA.
245
Acta Orthop 2006;77:877–85.
246
[2] Sundfeldt M, Carlsson LV, Johansson CB, Thomsen P, Gretzer C. Aseptic loosening, not
247
only a question of wear: a review of different theories. Acta Orthop 2006;77:177–97.
248
[3] Dalury DF, Pomeroy DL, Gorab RS, Adams MJ. Why are total knee arthroplasties being
249
revised? J Arthroplasty 2013;28:120–1.
250
[4] Teichtahl AJ, Wluka AE, Wijethilake P, Wang Y, Ghasem-Zadeh A, Cicuttini FM. Wolff’s
251
law in action: a mechanism for early knee osteoarthritis. Arthritis Res Ther 2015;17:207.
252
[5] van Loon CJ, Oyen WJ, de Waal Malefijt MC, Verdonschot N. Distal femoral bone
253
mineral density after total knee arthroplasty: a comparison with general bone mineral density.
254
Arch Orthop Trauma Surg 2001;121:282–5.
255
[6] Ishii Y, Yagisawa K, Ikezawa Y. Changes in bone mineral density of the proximal femur
256
after total knee arthroplasty. J Arthroplasty 2000;15:519–22.
257
[7] Soininvaara TA, Miettinen HJ, Jurvelin JS, Suomalainen OT, Alhava EM, Kroger HP.
258
Periprosthetic femoral bone loss after total knee arthroplasty: 1-year follow-up study of 69
259
patients. Knee 2004;11:297–302.
260
[8] Petersen MM, Lauritzen JB, Pedersen JG, Lund B. Decreased bone density of the distal
261
femur after uncemented knee arthroplasty. A 1-year follow-up of 29 knees. Acta Orthop
262
Scand 1996;67:339–44.
263
[9] Seki T, Omori G, Koga Y, Suzuki Y, Ishii Y, Takahashi HE. Is bone density in the distal
264
femur affected by use of cement and by femoral component design in total knee arthroplasty?
265
J Orthop Sci 1999;4:180–6.
266
[10] Soininvaara TA, Jurvelin JS, Miettinen HJ, Suomalainen OT, Alhava EM, Kroger PJ.
AC C
EP
TE D
M AN U
SC
RI PT
242
11
ACCEPTED MANUSCRIPT Effect of alendronate on periprosthetic bone loss after total knee arthroplasty: a one-year,
268
randomized, controlled trial of 19 patients. Calcif Tissue Int 2002;71:472–7.
269
[11] Wang CJ, Wang JW, Ko JY, Weng LH, Huang CC. Three-year changes in bone mineral
270
density around the knee after a six-month course of oral alendronate following total knee
271
arthroplasty. A prospective, randomized study. J Bone Joint Surg Am 2006;88:267–72.
272
[12] Jaroma AV, Soininvaara TA, Kroger H. Effect of one-year post-operative alendronate
273
treatment on periprosthetic bone after total knee arthroplasty. A seven-year randomised
274
controlled trial of 26 patients. Bone Joint J 2015;97-B:337–45.
275
[13] Prieto-Alhambra D, Lalmohamed A, Abrahamsen B, Arden NK, de Boer A, Vestergarrd
276
P et al. Oral bisphosphonate use and total knee/hip implant survival: validation of results in
277
an external population-based cohort. Arthritis Rheumatol 2014;66:3233–40.
278
[14] Namba RS, Inacio MC, Cheetham TC, Dell RM, Paxton EW, Khatod MX. Lower total
279
knee arthroplasty revision risk associated with bisphosphonate use, even in patients with
280
normal bone density. J Arthroplasty 2016;31:537–41.
281
[15] Shiraki M, Ueda S, Sugimoto T, Kuroda T, Nakamura T. Treatment responses with once-
282
weekly teriparatide therapy for osteoporosis. Osteoporos Int 2016;27:3057–62.
283
[16] Kobayashi N, Inaba Y, Uchiyama M, Ike H, Kubota S, Saito T. Teriparatide versus
284
alendronate for the preservation of bone mineral density after total hip arthroplasty - a
285
randomized controlled trial. J Arthroplasty 2016;31:333–8.
286
[17] Kaneko T, Otani T, Kono N, Mochizuki Y, Mori T, Nango N et al. Weekly injection of
287
teriparatide for bone ingrowth after cementless total knee arthroplasty. J Orthop Surg (Hong
288
Kong) 2016;24:16–21.
289
[18] Orimo H, Nakamura T. Guideline for precaution and treatment of osteoporosis: 2011
290
update. J Bone Miner Res 2011;2:12–35.
291
[19] Soininvaara TA, Miettinen HJ, Jurvelin JS, Suomalainen OT, Alhava EM, Kroger HP.
AC C
EP
TE D
M AN U
SC
RI PT
267
12
ACCEPTED MANUSCRIPT Periprosthetic tibial bone mineral density changes after total knee arthroplasty: one-year
293
follow-up study of 69 patients. Acta Orthop Scand 2004;75:600–5.
294
[20] Jarvenpaa J, Soininvaara T, Kettunen J, Miettinen H, Kroger H. Changes in bone mineral
295
density of the distal femur after total knee arthroplasty: a 7-year DEXA follow-up comparing
296
results between obese and nonobese patients. Knee 2014;21:232–5.
297
[21] Shibuki T, Suzuki T, Sukezaki F, Toyoshima Y. Nagai T, Inagaki K et al. Periprothetic
298
bone mineral density changes after cementless total knee arthroplasty. Showa Univ J Med Sci
299
2016 28:155–61.
300
[22] Li MG, Nilsson KG. Changes in bone mineral density at the proximal tibia after total
301
knee arthroplasty: a 2-year follow-up of 28 knees using dual energy X-ray absorptiometry. J
302
Orthopaedic Res 2000;18:40–7.
303
[23] Abu-Rajab RB, Watson WS, Walker B, Roberts J, Gallacher SJ, Meek RM. Peri-
304
prosthetic bone mineral density after total knee arthroplasty. Cemented versus cementless
305
fixation. J Bone Joint Surg Br 2006;88:606–13.
306
[24] Cameron HU, Cameron G. Stress-relief osteoporosis of the anterior femoral condyles in
307
total knee replacement. A study of 185 patients. Orthop Rev 1987;16:449–56.
308
[25] Mintzer CM, Robertson DD, Rackemann S, Ewald FC, Scott RD, Spector M. Bone loss
309
in the distal anterior femur after total knee arthroplasty. Clin Orthop Relat Res 1999;260:135–
310
43.
311
[26] Lonner JH, Klotz M, Levitz C, Lotke PA. Changes in bone density after cemented total
312
knee arthroplasty: influence of stem design. J Arthroplasty 2001;16:107–11.
313
[27] Saari T, Uvehammer J, Carlsson L, Regner L, Karrholm J. Joint area constraint had no
314
influence on bone loss in proximal tibia 5 years after total knee replacement. J Orthop Res
315
2007;25:798–803.
316
[28] Hernandez-Vaquero D, Garcia-Sandoval MA, Fernandez-Carreira JM, Gava R. Influence
AC C
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13
ACCEPTED MANUSCRIPT of the tibial stem design on bone density after cemented total knee arthroplasty: a prospective
318
seven-year follow-up study. Int Orthop 2008;32:47–51.
319
[29] Sumner DR, Turner TM, Dawson D, Rosenberg AG, Urban RM, Galante JO. Effect of
320
pegs and screws on bone ingrowth in cementless total knee arthroplasty. Clin Orthop Relat
321
Res 1994;309:150–5.
322
[30] Martin JR, Watts CD, Levy DL, Kim RH. Medial Tibial Stress Shielding: A Limitation
323
of Cobalt Chromium Tibial Baseplates. The Journal of arthroplasty 2017;32:558-562.
324
[31] Zhang QH, Cossey A, Tong J. Stress shielding in periprosthetic bone following a total
325
knee replacement: Effects of implant material, design and alignment. Medical engineering &
326
physics 2016;38:1481-1488.
327
[32]Munro JT, Pandit S, Walker CG, Clatworthy M, Pitto RP. Loss of tibial bone density in
328
patients with rotating- or fixed-platform TKA. Clin Orthop Relat Res 2010;468:775–81.
329
[33] Levitz CL, Lotke PA, Karp JS. Long-term changes in bone mineral density following
330
total knee replacement. Clin Orthop Relat Res 1995;321:66–72.
331
[34] Regner LR, Carlsson LV, Karrholm JN, Hansson TH, Herberts PG, Swanpalmer J. Bone
332
mineral and migratory patterns in uncemented total knee arthroplasties: a randomized 5-year
333
follow-up study of 38 knees. Acta Orthop Scand 1999;70:603–8.
334
[35] Petersen MM, Gehrchen PM, Ostgaard SE, Nielsen PK, Lund B. Effect of
335
hydroxyapatite-coated tibial components on changes in bone mineral density of the proximal
336
tibia after uncemented total knee arthroplasty: a prospective randomized study using dual-
337
energy x-ray absorptiometry. J Arthroplasty 2005;20:516–20.
338
[36] Yang X, Ricciardi BF, Dvorzhinskiy A, Brial C, Lane Z, Bhimani S et al. Intermittent
339
parathyroid hormone enhances cancellous osseointegration of a novel murine tibial Implant. J
340
Bone Joint Surg Am 2015;97:1074–83.
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ACCEPTED MANUSCRIPT [37] Seibel MJ. Biochemical markers of bone turnover: part I: biochemistry and variability.
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Clin Biochem Rev 2005;26:97–122.
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ACCEPTED MANUSCRIPT Acknowledgement
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We thank Tetsuya Nemoto, MD PhD for his technical and statistical assistance.
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Figure legends
2
Fig. 1 Radiograph showing the regions of interest in the sagittal and coronal view Radiograph showing the regions of interest used to measure bone mineral density with
4
dual-energy x-ray absorptiometry in the sagittal and coronal views at pre-
5
administration and 6 and 12 months post-administration. (a) sagittal view, (b) coronal
6
view
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Fig. 2 Comparison of patients with or without teriparatide in terms of bone mineral density in the six regions of interest
9
Comparison of patients with or without teriparatide in terms of bone mineral density
10
in the six regions of interest (R1 to 6): (a) R1 (femoral diaphysis), (b) R2 (anterior
11
condyle), (c) R3 (posterior condyle), (d) R4 (lateral), (e) R5 (medial), and (f) R6
12
(tibial diaphysis)
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Fig. 3 Comparison of patients with or without teriparatide in terms of bone mineral density in the lumbar and proximal femur
15
Comparison of patients with or without teriparatide in terms of bone mineral density
16
in the lumbar spine and proximal femur. (a) lumber spine, (b) proximal femur
17
BMD: bone mineral density; SE: standard error; ANCOVA: analysis of covariance
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Tables
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Table 1. General baseline characteristics Description
Study group
Control
P-value
No. of patients
17
No. of knees
22
17
22
Only female 78.9 (4.1)
79.1 (5.1)
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Age (years)
Only female
SC
Gender
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group
Height (m) Weight (kg) 2
1.48 (6.1)
1.49 (3.9)
0.69
54.3 (8.3)
56.3 (5.7)
0.37
24.5 (3.4)
25.3 (2.3)
0.45
18.2 (15.8)
0.69
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BMI (kg/m )
0.87
Until administration or baseline
16.4 (13.0)
from operation (months)
Once-weekly
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Teriparatide
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11 patients (14 knees) 6 patients (8 knees)
BMI: body mass index. Values are presented as a mean ± standard deviation
ACCEPTED MANUSCRIPT Table 2A. Average and standard deviation of R1 to 6 Control group
Average (SD)
Average (SD)
0 month
0.553 (0.114)
0.669 (0.155)
6 months
0.563 (0.116)
0.645 (0.159)
12 months
0.550 (0.140)
0.609 (0.161)
0 month
0.505 (0.136)
0.569 (0.189)
6 months
0.520 (0.141)
0.531 (0.163)
12 months
0.526 (0.160)
0 month
0.776 (0.164)
0.802 (0.239)
6 months
0.832 (0.153)
0.758 (0.233)
12 months
0.833 (0.197)
0.708 (0.190)
0 month
0.642 (0.225)
0.665 (0.177)
6 months
0.659 (0.181)
0.609 (0.174)
12 months
0.662 (0.191)
0.615 (0.188)
0 month
0.558 (0.195)
0.608 (0.17)
6 months
0.564 (0.180)
0.601 (0.212)
12 months
0.575 (0.171)
0.578 (0.179)
0 month
0.578 (0.169)
0.752 (0.169)
6 months
0.623 (0.155)
0.742 (0.197)
12 months
0.642 (0.159)
0.709 (0.189)
R2
R3
R4
R6
6 7 8
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ROI
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0.514 (0.149)
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SD: standard deviation; ROI: regions of interest
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Table 2B. Adjusted mean and standard error with analysis of covariance of R1 to 6 Study group
Control group
Adjusted mean
Adjusted mean
ROI
P-value
R4
R5
R6
0.611
0.613 (0.016)
0.595 (0.016)
12 months
0.604 (0.018)
0.555 (0.018)
0.537
6 months
0.545 (0.019)
12 months
0.552 (0.018)
0 month
0.789
6 months
0.843 (0.019)
12 months
0.841 (0.030)
0 month
0.654
0.537
0.506 (0.019)
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0 month
0.445
0.073
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6 months
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R3
0.611
0.488 (0.018)
0.169
0.018*
0.789
0.747 (0.019)
0.001*
0.700 (0.030)
0.002*
0.654
6 months
0.668 (0.021)
0.601 (0.021)
0.028*
12 months
0.671 (0.023)
0.606 (0.023)
0.059
EP
R2
0 month
0 month
0.583
0.583
6 months
0.588 (0.016)
0.577 (0.016)
0.616
12 months
0.596 (0.019)
0.558 (0.019)
0.165
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(SE)
RI PT
(SE)
0 month
0.665
0.665
6 months
0.703 (0.020)
0.661 (0.020)
0.156
12 months
0.721 (0.020)
0.630 (0.020)
0.004*
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※covariate: BMD at initiation (0 month) * p<0.05
11
SE: standard error; ROI: regions of interest; BMD: bone mineral density
ACCEPTED MANUSCRIPT Table 3A. Average and SD of the lumbar spine and proximal femur
13
Average (SD)
Average (SD)
0 month
0.842 (0.137)
0.989 (0.189)
6 months
0.875 (0.134)
0.992 (0.200)
12 months
0.879 (0.142)
1.013 (0.232)
0 month
0.494 (0.052)
0.561 (0.082)
6 months
0.505 (0.059)
0.567 (0.078)
12 months
0.501 (0.060)
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Proximal femur
Control group
SC
Lumbar spine
Study group
0.576 (0.077)
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SD: standard deviation
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Table 3B. Adjusted mean and SE by analysis of covariance of the lumbar spine and proximal
17
femur Study group
Control group
Adjusted mean
Adjusted mean
(SE)
(SE)
0 month
0.916
0.916
6 months
0.949 (0.009)
0.918 (0.009)
0.021*
12 months
0.960 (0.014)
0.931 (0.014)
0.181
0 month
0.528
6 months
0.535 (0.007)
0.536 (0.007)
0.913
12 months
0.529 (0.008)
0.547 (0.008)
0.149
※covariate: BMD at initiation (0 month) * p<0.05
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SE: standard error; BMD: bone mineral density
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20
SC
Proximal femur
0.528
M AN U
Lumbar spine
RI PT
P-value
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