Abaloparatide Before Total Knee Arthroplasty

Study Overview
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Brief Summary
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The investigator hypothesizes that treating osteoporotic patients with abaloparatide prior to and after total knee arthroplasty will significantly reduce the amount of bone loss.

Detailed Description
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In primary unilateral total knee arthroplasty patients, The investigator will examine the effect of daily abaloparatide therapy in clinical osteoporotic patients beginning 3 months pre-op and continued for a total of 15 months. This will be compared to osteopenic patients receiving no therapy as well as previously published values in untreated osteoporotic patients 12 months following Total Knee Arthroplasty (TKA).

Official Title
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An Open-Label Phase 2 Study of Abaloparatide to Mitigate Distal Femoral Bone Loss Following Total Knee Arthroplasty

Conditions
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Osteoporosis, Arthroplasties, Knee Replacement

Intervention / Treatment
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* Drug: Abaloparatide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Post-menopausal women and men age ge ≥ 55 years and scheduled to undergo primary TKA at the University of Wisconsin Total Joint Program. Osteoporosis, i.e., BMD T-score (using female reference data) ≤ -2.5 at the lumbar spine, femoral neck OR total hip or ≤ -1.1 with Vertebral Fracture Assessment confirmed vertebral fracture or history of low-trauma nonvertebral fracture in the past 5 years OR osteopenia, BMD T-score (using female reference data) -1.1 to -2.4 at the lumbar spine, femoral neck or total hip and no prior low-trauma fracture. Serum calcium (albumin-corrected), serum creatinine and Parathyroid(PTH) values all within the normal range and 25(OH)D > 10 ng/mL. Willing to supplement with daily calcium and/or vitamin D3 at protocol specified doses. Able to provide written informed consent. Exclusion Criteria Unevaluable distal femur BMD due to hardware or other artifacts. History of bone disorders (e.g., Paget's disease) other than osteoporosis. History of prior external beam or implant radiation therapy involving the skeleton other than radioiodine. History of chronic or recurrent renal, hepatic, pulmonary, allergic, cardiovascular, gastrointestinal, endocrine, central nervous system, hematologic or metabolic diseases, or immunologic, emotional and/or psychiatric disturbances that, in opinion of the principal investigator, would compromise study data validity. History of Cushing's disease, growth hormone deficiency or excess, hyperthyroidism, hypo- or hyperparathyroidism or malabsorptive syndromes within the past year. History of significantly impaired renal function (serum creatinine >2.0 mg/dL. If the serum creatinine is > 1.5 and ≤ 2.0 mg/dL, the calculated creatinine clearance (Cockcroft-Gault) must be ≥ 37 mL/min. History of nephrolithiasis or urolithiasis within the past five years. History of cancer in prior 5 years (basal cell or squamous skin cancer is permissible). History of osteosarcoma at any time. Patients known to be positive for Hepatitis B, Hepatitis C, HIV-1 or HIV-2. Known hypersensitivity to any of the test materials or related compounds. Prior treatment with PTH- or PTHrP-derived drugs, (ABL, teriparatide or PTH (1-84)). Prior treatment with intravenous bisphosphonates at any time or oral bisphosphonates within the past three years. Patients who had received a short course of oral bisphosphonate therapy (3 months or less) may be enrolled as long as the treatment occurred 6 or more months prior to enrollment. Treatment with fluoride or strontium in the past five years or prior treatment with bone-acting investigational agents at any time. Treatment with calcitonin the past 6 months or denosumab in the past 18 months. Treatment with anticonvulsants affecting vitamin D metabolism (phenobarbital, phenytoin, carbamazepine or primidone) or chronic heparin within the prior 6 months. Treatment with anabolic steroids or calcineurin inhibitors (cyclosporin, tacrolimus) Daily treatment with oral, intranasal or inhaled glucocorticoids in the prior 12 months. Exposure to any investigational drug within 12 months. Consumption of > 2 alcoholic drinks per day or use of illegal drugs within 12 months of screening. Not suitable for study participation due to other reasons at the investigators discretion.

Ages Eligible for Study
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Minimum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment group<br>Those with clinical osteoporosis who elect ABL treatment. ABL therapy will begin 3 months pre-TKA and continue for a total of 18 months. ABL will be administered by injection pen with dose of 80 mcg SC qDay. | Drug: Abaloparatide<br>* 18 month ABL treatment<br>* Other names: Tymlos;|
| No Intervention: Comparator group<br>Those with clinical osteopenia who receive no treatment. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Distal femoral Bone mineral density (BMD) at the 25% regions of interest (ROIs) | Bone mineral density change at the 25% ROI of the surgical leg | Baseline and 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Distal femoral BMD at the 15% and 60 %ROI | Bone mineral density change at the 15% and 60% ROI of the surgical leg | Baseline and 18 months | 
| Change in Femur cortical thickness at the 15%, 25% and 60% femur ROIs | Cortical thickness change at the 15% and 60% ROI of the surgical leg | Baseline and 18 months | 
| TBS assessment by TRIP at the 15%, 25% and 60% femur ROIs | Trabecular bone score (TBS) assessment by Texture Research Investigation (Platform (TRIP) software change at the 15%, 25% and 60% femur ROIs (TBS >1.350 is normal; TBS between 1.200 and 1.350 is indicative of partially degraded microarchitecture; and TBS<1.200 equals degraded microarchitecture) | 18 months | 
| Knee injury & Osteoarthritis Outcome Score (KOOS) JR | Patient reported knee function score. The KOOS, JR was developed from the original long version of the Knee injury and Osteoarthritis Outcome Score (KOOS) survey using Rasch analysis. The KOOS, JR contains 7 items from the original KOOS survey. Items are coded from 0 to 4, none to extreme respectively. KOOS, JR is scored by summing the raw response (range 0-28) and then converting it to an interval score (0-100). The interval score ranges from 0 to 100 where 0 represents total knee disability and 100 represents perfect knee health. | 18 months | 
| Change in Veterans RAND 12 (VR-12) Question Health Survey score | 12 Item Health Survey using patient's self assessment of their perspective of their health and ability to do daily functions. Scores are derived using an algorithm that is referenced to a metric centered at 50.0 where a zero score indicates the lowest level of health and 100 indicates the highest level of health. | Baseline and 18 months | 
| Forgotten Joint Survey(FJS) score | FJS-12 consists of 12 questions and is scored using a 5-point response format with the raw scores transformed onto a 0- to 100-point scale. High scores indicate good outcome, that is, a high degree of forgetting the joint in everyday life (forgotten joint phenomenon). | 18 months | 
| Change in body composition using bioelectrical impedance analysis of lean mass | Change in body composition using bioelectrical impedance analysis of lean mass. | Baseline and 18 months | 
| Change in body composition using bioelectrical impedance analysis of skeletal mass. | Change in body composition using bioelectrical impedance analysis of skeletal mass. | Baseline and 18 months | 
| Change in body composition using bioelectrical impedance analysis of fat mass. | Change in body composition using bioelectrical impedance analysis of fat mass. | Baseline and 18 months | 
| TKA complications: Number of participants needed revision surgery | TKA complications: Number of participants needed revision surgery | 18 months | 
| TKA complications: Number of participants had fracture | TKA complications: Number of participants had fracture | 18 months | 
| Precision Error on Knee Bone Density Measurement | Precision assessment in the field of bone densitometry is the process whereby the ability of the instrument and the technologist to reproduce similar results, given no real biologic change, is tested. The mathematical result of precision assessment is called the precision error. To achieve statistical power, the investigators will take duplicate knee bone density measurements on 30 participants at either their 6 month or 15 month visit. The standard deviation for each participant is calculated, then the root mean square standard deviation for the group is calculated. | up to 15 months |