Clinical trial NCT01971931: Prospective Evaluation of Biomarkers Variability in Knee Prosthetic Surgery
Official title: Prospective Evaluation of Biomarkers Variability in Knee Prosthetic Surgery
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Knee Osteoarthritis
Lead sponsor: University of Milan
Sponsor class: OTHER
First posted: 2013-10-30
Enrollment: 40
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients undergoing TKR surgery.

Brief summary: Bone quality is an important factor influencing the outcome of total knee replacement (TKR) surgery. Therefore, assessing bone quality preoperatively could help the surgeon in the choice of the most appropriate prosthetic implant.

The primary goal of this study is to measure serum and tissue levels of some proteins involved in bone remodelling.

Detailed description: Aseptic implant loosening after TKR causes knee pain, reduces knee function and may require revision surgery.

Several proteins have been identified, which are involved in bone metabolism and remodelling; variations in serum levels of some of these proteins after TKR loosening have also been described.

However, preoperative identification of risk factors for aseptic loosening remains a challenge.

An observational study is conducted to evaluate how levels of the following serum biomarkers vary after TKR:

* osteoprotegerin (OPG)
* receptor activator of nuclear factor kappa-B (RANK)
* receptor activator of nuclear factor kappa-B ligand (RANK-L)
* sclerostin
* cathepsin K

To avoid bias caused by inflammatory states, C reactive protein (CRP), interleukin 1 (IL-1), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α) levels and erythrocyte sedimentation rate (ESR) will be measured.

Secondary goals are to evaluate the mRNA expression of OPG, RANK-L, cathepsin K and sclerostin on tibial bone biopsies and to study if changes in serum biomarkers levels after surgery are associated with:

* clinical outcomes
* periprosthetic bone density
* variation of two bone reabsorption markers, the postoperative change of which has already been described in details: type 1 collagen cross-linked C-terminal telopeptide (CTP1) and type 1 procollagen N-terminal telopeptide (P1NP).

One day before surgery, after having signed informed consent, patients will undergo a vertebral and femoral dual-energy X-ray absorptiometry (DEXA) scan and blood samples will be collected.

During surgery a tibial biopsy will be collected. Between 4 and 7 days postoperatively and 3, 6 and 12 months after surgery patients will again undergo periprosthetic DEXA scans and blood samples will be collected.

Eligibility criteria: Inclusion Criteria:

* Age \> 40, \<80
* Indication for TKR
* Surgical indication for PFC Sigma®, posterior stabilized, mobile bearing TKR
* Patients signed written informed consent

Exclusion Criteria:

* Age \> 80, \< 40
* TKR revision surgery
* Fixed knee deformities greater than 15° in varus, valgus, flexion or tibial slope.
* Knee ankylosis
* Paget's disease
* Hyperparathyroidism
* Patient treated with: bisphosphonates, strontium ranelate, selective estrogen receptor modulators for osteoporosis, calcitonin, denosumab.
* Informed consent not accepted
* Serious comorbidity
* Active infections
* Pregnant or breastfeeding women

Primary outcomes:
measure: Change in biomarkers serum level after surgery
timeFrame: One day before surgery; 3 months after surgery and 12 months after surgery
Secondary outcomes:
measure: Change in periprosthetic bone density after surgery
timeFrame: 3, 6, 12 months after surgery
measure: Biomarkers mRNA expression
timeFrame: Baseline
Other outcomes:
measure: Change in knee function score after surgery
timeFrame: One day before surgery; 3, 6, 12 months after surgery
measure: Change in knee pain scale after surgery
timeFrame: One day before surgery; 3, 6, 12 months after surgery
Locations:
city: San Donato Milanese
country: Italy
facility: Policlinico San Donato (Istituto di Ricovero e Cura a Carattere Scientifico)
state: Milano
Study officials:
affiliation: Istituto Ortopedico Galeazzi IRCCS, Milano, Italy
name: Emanuela Galliera, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Policlinico San Donato IRCCS, San Donato Milanese, Italy
name: Randelli Pietro, MD
role: STUDY_DIRECTOR
affiliation: Policlinico San Donato IRCCS, San Donato Milanese, Italy
name: Corsi Romanelli M. Massimiliano, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Vega D, Maalouf NM, Sakhaee K. CLINICAL Review #: the role of receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/osteoprotegerin: clinical implications. J Clin Endocrinol Metab. 2007 Dec;92(12):4514-21. doi: 10.1210/jc.2007-0646. Epub 2007 Sep 25.
citation: Colombini A, Lombardi G, Galliera E, Dogliotti G, Randelli P, Meerssemann A, Mineo G, Cabitza P, Corsi MM. Plasma and drainage fluid levels of soluble receptor activator of nuclear factor-kB (sRANK), soluble receptor activator of nuclear factor-kB ligand (sRANKL) and osteoprotegerin (OPG) during proximal humerus fracture healing. Int Orthop. 2011 May;35(5):777-82. doi: 10.1007/s00264-010-1088-3. Epub 2010 Jul 11.
citation: Rogers A, Eastell R. Circulating osteoprotegerin and receptor activator for nuclear factor kappaB ligand: clinical utility in metabolic bone disease assessment. J Clin Endocrinol Metab. 2005 Nov;90(11):6323-31. doi: 10.1210/jc.2005-0794. Epub 2005 Aug 16.
citation: Ryd L, Albrektsson BE, Carlsson L, Dansgard F, Herberts P, Lindstrand A, Regner L, Toksvig-Larsen S. Roentgen stereophotogrammetric analysis as a predictor of mechanical loosening of knee prostheses. J Bone Joint Surg Br. 1995 May;77(3):377-83.
citation: Li MG, Thorsen K, Nilsson KG. Increased bone turnover as reflected by biochemical markers in patients with potentially unstable fixation of the tibial component. Arch Orthop Trauma Surg. 2004 Jul;124(6):404-9. doi: 10.1007/s00402-004-0695-0. Epub 2004 May 20.
citation: Li MG, Nilsson KG. The effect of the preoperative bone quality on the fixation of the tibial component in total knee arthroplasty. J Arthroplasty. 2000 Sep;15(6):744-53. doi: 10.1054/arth.2000.6617.
citation: Mertens MT, Singh JA. Biomarkers in arthroplasty: a systematic review. Open Orthop J. 2011 Mar 16;5:92-105. doi: 10.2174/1874325001105010092.
citation: Kenanidis EI, Potoupnis ME, Papavasillioul KA, Sayegh FE, Petsatodis GE, Kapetanos GA. Serum levels of bone turnover markers following total joint arthroplasty. J Orthop Surg (Hong Kong). 2010 Dec;18(3):290-5. doi: 10.1177/230949901001800307.
citation: Pijls BG, Valstar ER, Nouta KA, Plevier JW, Fiocco M, Middeldorp S, Nelissen RG. Early migration of tibial components is associated with late revision: a systematic review and meta-analysis of 21,000 knee arthroplasties. Acta Orthop. 2012 Dec;83(6):614-24. doi: 10.3109/17453674.2012.747052. Epub 2012 Nov 9.
citation: van Loon CJ, Oyen WJ, de Waal Malefijt MC, Verdonschot N. Distal femoral bone mineral density after total knee arthroplasty: a comparison with general bone mineral density. Arch Orthop Trauma Surg. 2001 May;121(5):282-5. doi: 10.1007/s004020000232.
citation: Minoda Y, Ikebuchi M, Kobayashi A, Iwaki H, Inori F, Nakamura H. A cemented mobile-bearing total knee replacement prevents periprosthetic loss of bone mineral density around the femoral component: a matched cohort study. J Bone Joint Surg Br. 2010 Jun;92(6):794-8. doi: 10.1302/0301-620X.92B6.23159.
citation: Soininvaara TA, Harju KA, Miettinen HJ, Kroger HP. Periprosthetic bone mineral density changes after unicondylar knee arthroplasty. Knee. 2013 Mar;20(2):120-7. doi: 10.1016/j.knee.2012.10.004. Epub 2012 Nov 13.
citation: Cucchi D, Menon A, Galliera E, Messina C, Zanini B, Marazzi MG, Massaccesi L, Compagnoni R, Corsi Romanelli MM, Randelli P. A Prospective Assessment of Periprosthetic Bone Mineral Density and Osteoimmunological Biomarkers Variations After Total Knee Replacement Surgery. J Clin Densitom. 2019 Jan-Mar;22(1):86-95. doi: 10.1016/j.jocd.2018.05.039. Epub 2018 May 26.