A Combination Treatment of Raloxifene and Vitamin D Enhances Bone-to-Tendon Healing of the Rotator Cuff in a Rat Model

Abstract

Background:

Tearing and degeneration of the rotator cuff at the tendon-to-bone junction are common in adults aged ≥50 years. Few studies have reported on the relationship between estrogen and the rotator cuff enthesis. In addition to preventing bone loss, selective estrogen receptor modulators have been shown to improve tendon and muscle quality.

Purpose:

To evaluate the effects of raloxifene (RLX) and vitamin D on rotator cuff tendon-to-bone healing in a rat model.

Study Design:

Controlled laboratory study.

Methods:

A total of 29 female rats (58 shoulders) were assigned to 4 groups: (1) control group, (2) ovariectomy (OVX)–only group, (3) no RLX group (OVX and rotator cuff repair [RCR]), and (4) RLX group (OVX, RCR, and RLX). Rats that did not undergo rotator cuff tear (RCT) surgery were divided into the control and OVX-only groups according to OVX surgery. Rats that underwent RCT surgery and RCR were divided into the no RLX and RLX groups according to RLX and vitamin D administration. An estrogen-deficient state was induced by OVX at 12 weeks of age. Bone mineral density (BMD) and trabecular bone characteristics were measured by micro–computed tomography, and healing of the tendon-to-bone junction was evaluated by biomechanical testing, histomorphometry, and micro–magnetic resonance imaging (MRI).

Results:

The mean final body weight (BW; 461.6 ± 47.3 g) of the OVX-only group was significantly higher and BMD (0.25 ± 0.07 g/cm³) was significantly lower (P < .001) than the mean final BW (338.5 ± 35.1 g) and BMD (0.48 ± 0.05 g/cm³) of the control group. In contrast, the RLX group showed that the BW (369.6 ± 35.8 g) and BMD (0.41 ± 0.08 g/cm³) were not significantly different from the control group. The RLX group had a significantly higher histomorphometric total score (8.50 ± 1.05) than the no RLX group (4.83 ± 2.48). On biomechanical testing, the RLX group (29.7 ± 9.1 N) showed a significantly higher load to failure than the no RLX group (19.4 ± 8.8 N). On micro-MRI, the RLX group had a more homogeneous low signal and tendon continuity than the no RLX group.

Conclusion:

The combination treatment of RLX and vitamin D prevented a decrease in local BMD (greater tuberosity of the proximal humerus) and enhanced tendon-to-bone healing of the rotator cuff in a rat model.

Clinical Relevance:

This study induced an estrogen-deficient state similar to the human postmenopausal state and used drugs that are actually being prescribed in a clinical situation.

Keywords

tendon-to-bone healing rat rotator cuff raloxifene vitamin D cholecalciferol

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References

Camp

Elhassan

Dines

. Clinical faceoff. Irreparable rotator cuff tears in young, active patients: tendon transfer versus superior capsular reconstruction? Clin Orthop Relat Res. 2018;476(12):2313-2317.

Cho

Zhang

Pruznak

Kim

. Effect of tamoxifen on fatty degeneration and atrophy of rotator cuff muscles in chronic rotator cuff tear: an animal model study. J Orthop Res. 2015;33(12):1846-1853.

Denard

Brady

Adams

Tokish

Burkhart

. Preliminary results of arthroscopic superior capsule reconstruction with dermal allograft. Arthroscopy. 2018;34(1):93-99.

Ding

Wang

Hao

, et al. Vitamin D supplement improved testicular function in diabetic rats. Biochem Biophys Res Commun. 2016;473(1):161-167.

Dunn

Schackman

Walsh

, et al. Variation in orthopaedic surgeons’ perceptions about the indications for rotator cuff surgery. J Bone Joint Surg Am. 2005;87(9):1978-1984.

Feichtinger

Monforte

Keibl

, et al. Substantial biomechanical improvement by extracorporeal shockwave therapy after surgical repair of rodent chronic rotator cuff tears. Am J Sports Med. 2019;47(9):2158-2166.

Gomes-Filho

Wayama

Dornelles

RCM

, et al. Raloxifene modulates regulators of osteoclastogenesis and angiogenesis in an oestrogen deficiency periapical lesion model. Int Endod J. 2015;48(11):1059-1068.

Gorai

Tanaka

Hattori

Iwaoki

. Assessment of adherence to treatment of postmenopausal osteoporosis with raloxifene and/or alfacalcidol in postmenopausal Japanese women. J Bone Miner Metab. 2010;28(2):176-184.

Guo

Yue

Wang

, et al. Vitamin D supplement ameliorates hippocampal metabolism in diabetic rats. Biochem Biophys Res Commun. 2017;490(2):239-246.

10.

Idris

. Ovariectomy/orchidectomy in rodents. In: Helfrich

Ralston

, eds. Bone Research Protocols. Humana Press; 2012:545-551.

11.

Irie

Takahata

Majima

, et al. Effect of selective estrogen receptor modulator/raloxifene analogue on proliferation and collagen metabolism of tendon fibroblast. Connect Tissue Res. 2010;51(3):179-187.

12.

Kessler

Nissim

. Primary repair without immobilization of flexor tendon division within the digital sheath: an experimental and clinical study. Acta Orthop Scand. 1969;40(5):587-601.

13.

Lama

Santoro

Corrado

, et al. Extracorporeal shock waves alone or combined with raloxifene promote bone formation and suppress resorption in ovariectomized rats. PLoS One. 2017;12(2):e0171276.

14.

Lee

Kim

Shim

Jang

Lee

. Effective healing of chronic rotator cuff injury using recombinant bone morphogenetic protein-2 coated dermal patch in vivo. J Biomed Mater Res B Appl Biomater. 2017;105(7):1840-1846.

15.

Lipner

Shen

Cavinatto

, et al. In vivo evaluation of adipose-derived stromal cells delivered with a nanofiber scaffold for tendon-to-bone repair. Tissue Eng Part A. 2015;21(21-22):2766-2774.

16.

Liu

Cai

Zheng

. Skeletal site-specific response to ovariectomy in a rat model: change in bone density and microarchitecture. Clin Oral Implants Res. 2015;26(4):392-398.

17.

Maffulli

Longo

Franceschi

Rabitti

Denaro

. Movin and Bonar scores assess the same characteristics of tendon histology. Clin Orthop Relat Res. 2008;466(7):1605-1611.

18.

Masi

. Epidemiology of osteoporosis. Clin Cases Miner Bone Metab. 2008;5(1):11-13.

19.

Mihata

Lee

Fukunishi

, et al. Return to sports and physical work after arthroscopic superior capsule reconstruction among patients with irreparable rotator cuff tears. Am J Sports Med. 2018;46(5):1077-1083.

20.

Ohta

Hamaya

Taketsuna

Sowa

. Quality of life in Japanese women with postmenopausal osteoporosis treated with raloxifene and vitamin D: post hoc analysis of a postmarketing study. Curr Med Res Opin. 2015;31(1):85-94.

21.

Park

Lhee

Moon

Hwang

. Clinical and ultrasonographic outcomes of arthroscopic suture bridge repair for massive rotator cuff tear. Arthroscopy. 2013;29(2):280-289.

22.

Pennington

. The locking loop tendon suture. Plast Reconstr Surg. 1979;63(5):648-652.

23.

X-Y

Liu

D-D

, et al. Combined administration on You-Gui Yin and low-dose raloxifene partially attenuates the bone loss in ovariectomized mice through the proliferation and osteogenic differentiation of bone marrow stromal cells. Phytomedicine. 2019;53:286-293.

24.

Rey

Cervino

Rentero

Crespo

Alvaro

Casillas

. Raloxifene: mechanism of action, effects on bone tissue, and applicability in clinical traumatology practice. Open Orthop J. 2009;3:14-21.

25.

Sun

Kwak

Kholinne

Tan

Koh

Jeon

. Nonabsorbable suture knot on the tendon affects rotator cuff healing: a comparative study of the knots on tendon and bone in a rat model of rotator cuff tear. Am J Sports Med. 2019;47(12):2809-2815.

26.

Tanaka

Kanazawa

Gotoh

, et al. Effects of estrogen-deficient state on rotator cuff healing. Am J Sports Med. 2019;47(2):389-397.

27.

Tashjian

. Epidemiology, natural history, and indications for treatment of rotator cuff tears. Clin Sports Med. 2012;31(4):589-604.

28.

Weber

Kaschig

Erben

. 1 Alpha-hydroxyvitamin D2 and 1 alpha-hydroxyvitamin D3 have anabolic effects on cortical bone, but induce intracortical remodeling at toxic doses in ovariectomized rats. Bone. 2004;35(3):704-710.

29.

Yoo

Moon

, et al. Osteoporotic fracture: 2015 position statement of the Korean Society for Bone and Mineral Research. J Bone Metab. 2015;22(4):175-181.

30.

Yoo

Kim

. Association between vitamin D intake and bone mineral density in Koreans aged ≥50 years: analysis of the 2009 Korea National Health and Nutrition Examination Survey using a newly established vitamin D database. Nutr Res Pract. 2019;13(2):115-125.

31.

Yoon

Chung

Jung

, et al. Is a local administration of parathyroid hormone effective to tendon-to-bone healing in a rat rotator cuff repair model? J Orthop Res. 2020;38(1):82-91.

32.

Zhu

Tay

Callon

, et al. Overlay repair with a synthetic collagen scaffold improves the quality of healing in a rat rotator cuff repair model. J Shoulder Elbow Surg. 2019;28(5):949-958.

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