nach oben

European Journal of Trauma and Emergency Surgery

Erschienen in:

26.04.2019 | Original Article

Do antiosteoporotic drugs improve bone regeneration in vivo?

verfasst von: Maximilian Leiblein, Dirk Henrich, Florian Fervers, Kerstin Kontradowitz, Ingo Marzi, Caroline Seebach

Erschienen in: European Journal of Trauma and Emergency Surgery | Ausgabe 2/2020

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Treatment of complex fractures in the elderly is a challenge for operative reconstruction due to degraded bone structure. Early peri-operative bone anabolic treatment could improve new bone formation, avoid implant loosening and accelerate fracture healing.

Methods

To compare the osteoanabolic potential of different drugs after distraction osteogenesis, 168 female Sprague–Dawley rats underwent lengthening of the right femur using a monolateral external fixator. Animals were randomly divided into six groups: vehicle-injected group, PTH(1-34), raloxifen, strontium ranelate, alendronate and simvastatin. Histomorphometry, CT-scanning, DEXA- and biomechanical analysis were performed to evaluate new bone formation, callus volume, mineralisation and biomechanical strength. Expression of bone metabolic mediators and differentiation indicators of distracted and intact bone were examined by RT-PCR and western blot.

Results

Histological analysis showed significant increase of the bone mass after treatment with PTH(1-34), raloxifen and strontium ranelate (p = 0.02). Raloxifen increased bone mineral content (BMC) of the whole distracted femur significantly (p = 0.007). Callus volume was significantly larger in the PTH(1-34), raloxifen and simvastatin groups (p = 0.001) compared to control. Ultimate load of distracted new formed bone was increased in PTH(1-34) and raloxifen groups. It seems that PTH(1-34) and raloxifen have a stronger effect on bone where a repair response is activated. Strontium ranelate demonstrates similar effects to PTH regarding new bone formation but shows low values for mineralisation and biomechanical strength.

Conclusion

This study suggests that peri-operative treatment of complex and/or osteoporotic fractures with PTH(1-34) and raloxifen might be useful as a stimulator of bone formation and mineralisation to shorten the consolidation time in humans.

Matthis C, Weber U, O’Neill TW, Raspe H. Health impact associated with vertebral deformities: results from the European Vertebral Osteoporosis Study (EVOS). Osteoporos Int. 1998;8:364–72.PubMed

Morley JE. Falls—where do we stand? Mo Med. 2007;104:63–7.PubMed

Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int. 2006;17:1726–33.PubMed

Frost HM. Cybernetic aspects of bone modeling and remodeling, with special reference to osteoporosis and whole-bone strength. Am J Hum Biol. 2001;13:235–48 (John Wiley & Sons, Inc).PubMed

Lill CA, Gerlach UV, Eckhardt C, Goldhahn J, Schneider E. Bone changes due to glucocorticoid application in an ovariectomized animal model for fracture treatment in osteoporosis. Osteoporos Int. 2002;13:407–14.PubMed

Aspenberg P. Drugs and fracture repair. Acta Orthopaedica. Taylor & Francis. 2009;76:741–8.

Hegde V, Jo JE, Andreopoulou P, Lane JM. Effect of osteoporosis medications on fracture healing. Osteoporos Int Springer Lond. 2016;27:861–71.

Shevtsov VI. Professor G. A. Ilizarov’s contribution to the method of transosseous osteosynthesis. Bull Hosp Jt Dis. 1997;56:11–5.PubMed

Seebach C, Skripitz R, Andreassen TT, Aspenberg P. Intermittent parathyroid hormone (1-34) enhances mechanical strength and density of new bone after distraction osteogenesis in rats. J. Orthop. Res. 2004;22:472–8 (Wiley Subscription Services, Inc., A Wiley Company).PubMed

10.

Zacchetti G, Dayer R, Rizzoli R, Ammann P. Systemic treatment with strontium ranelate accelerates the filling of a bone defect and improves the material level properties of the healing bone. Biomed Res Int. Hindawi. 2014;2014(549785):10.

11.

Tarantino U, Saturnino L, Scialdoni A, Feola M, Liuni FM, Tempesta V, et al. Fracture healing in elderly patients: new challenges for antiosteoporotic drugs. Aging Clin Exp Res. 2013;25(Suppl 1):S105–8.PubMed

12.

Bukata SV. Systemic administration of pharmacological agents and bone repair: what can we expect. Injury. 2011;42:605–8.PubMed

13.

Saito M, Shiraishi A, Ito M, Sakai S, Hayakawa N, Mihara M, et al. Comparison of effects of alfacalcidol and alendronate on mechanical properties and bone collagen cross-links of callus in the fracture repair rat model. Bone. 2010;46:1170–9.PubMed

14.

Yamashita M, Otsuka F, Mukai T, Yamanaka R, Otani H, Matsumoto Y, et al. Simvastatin inhibits osteoclast differentiation induced by bone morphogenetic protein-2 and RANKL through regulating MAPK, AKT and Src signaling. Regul Pept. 2010;162:99–108.PubMed

15.

Féron J-M, Mauprivez R. Fracture repair: general aspects and influence of osteoporosis and anti-osteoporosis treatment. Injury. 2016;47(Suppl 1):S10–4.PubMed

16.

Skripitz R, Andreassen TT, Aspenberg P. Parathyroid hormone (1-34) increases the density of rat cancellous bone in a bone chamber. A dose-response study. J Bone Joint Surg Br. 2000;82:138–41.PubMed

17.

Einhorn TA, Gerstenfeld LC. Fracture healing: mechanisms and interventions. Nat Rev Rheumatol Nat Publish Group. 2015;11:45–54.

18.

Reginster JY, Seeman E, De Vernejoul MC, Adami S, Compston J, Phenekos C, et al. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: treatment of peripheral osteoporosis (TROPOS) study. J Clin Endocrinol Metab. 2005;90:2816–22.PubMed

19.

Canalis E, Hott M, Deloffre P, Tsouderos Y, Marie PJ. The divalent strontium salt S12911 enhances bone cell replication and bone formation in vitro. Bone. 1996;18:517–23.PubMed

20.

Takahashi N, Sasaki T, Tsouderos Y. Suda T (2003) S 12911-2 inhibits osteoclastic bone resorption in vitro. J. Bone Miner. Res. 2003;18:1082–7 (John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)).PubMed

21.

Cavalli L, Brandi ML. Targeted approaches in the treatment of osteoporosis: differential mechanism of action of denosumab and clinical utility. Ther Clin Risk Manag. Dove Press. 2012;8:253–66.

22.

Mundy GR. Cellular and molecular regulation of bone turnover. Bone. 1999;24:35S–8S.PubMed

23.

Skoglund B, Forslund C, Aspenberg P. Simvastatin improves fracture healing in mice. J. Bone Miner. Res. 2002;17:2004–8 (John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)).PubMed

24.

Moshiri A, Sharifi AM, Oryan A. Role of Simvastatin on fracture healing and osteoporosis: a systematic review on in vivo investigations. Clin Exp Pharmacol Physiol. 2016;43:659–84.PubMed

25.

Li X, Wang P, Xu X, Wang Y, Xia Y, Wang D. Simvastatin increases the activity of endothelial nitric oxide synthase via enhancing phosphorylation. J Huazhong Univ Sci Technol Med Sci. 2009;29:286–90.PubMed

26.

Matos MA, Tannuri U, Guarniero R. The effect of zoledronate during bone healing. J Orthop Traumatol Springer Int Publish. 2010;11:7–12.

27.

de Vieira J. S, Giovanini A, Görhinger I, Gonzaga CC, Costa-Casagrande TA, Deliberador TM (2017) Use of low-dose alendronate improves cranial bone repair and is associated with an increase of osteocalcin: an experimental study. J Oral Maxillofac Surg. 2017;75:1873–81.PubMed

28.

Kučukalić-Selimović E, Valjevac A, Hadžović-Džuvo A, Skopljak-Beganović A, Alimanovic-Alagić R, Brković A. Evaluation of bone remodelling parameters after 1 year treatment with alendronate in postmenopausal women with osteoporosis. Bosn J Basic Med Sci. 2011;11:41–5.PubMedPubMedCentral

29.

Soroush M, Khabbazi A, Malek Mahdavi A. Serum osteocalcin levels in postmenopausal osteoporotic women receiving alendronate. Rheumatology Research. Iran Rheumatol Assoc. 2018;3:83–9.

30.

Amanat N, McDonald M, Godfrey C, Bilston L, Little D. Optimal timing of a single dose of zoledronic acid to increase strength in rat fracture repair. J. Bone Miner. Res. 2007;22:867–76 (John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)).PubMed

31.

Kates SL, Ackert-Bicknell CL. How do bisphosphonates affect fracture healing? Injury. 2016;47(Suppl 1):S65–8.PubMedPubMedCentral

32.

McDonald MM, Dulai S, Godfrey C, Amanat N, Sztynda T, Little DG. Bolus or weekly zoledronic acid administration does not delay endochondral fracture repair but weekly dosing enhances delays in hard callus remodeling. Bone. 2008;43:653–62.PubMed

33.

Cao Y, Mori S, Mashiba T, Westmore MS, Ma L, Sato M, et al. Raloxifene, estrogen, and alendronate affect the processes of fracture repair differently in ovariectomized rats. J. Bone Miner. Res. 2002;17:2237–46 (John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)).PubMed

34.

Stuermer EK, Sehmisch S, Rack T, Wenda E, Seidlova-Wuttke D, Tezval M, et al. Estrogen and raloxifene improve metaphyseal fracture healing in the early phase of osteoporosis: A new fracture-healing model at the tibia in rat. Langenbecks Arch Surg. Springer Verlag. 2010;395:163–72.

35.

Spiro AS, Khadem S, Jeschke A, Marshall RP, Pogoda P, Ignatius A, et al. The SERM raloxifene improves diaphyseal fracture healing in mice. J Bone Miner Metab. 2013;31:629–36.PubMed

36.

Lobo MJ, Remesar X, Alemany M. Effect of chronic intravenous injection of steroid hormones on body weight and composition of female rats. Biochem Mol Biol Int. 1993;29:349–58.PubMed

37.

Gennari L. Lasofoxifene, a new selective estrogen receptor modulator for the treatment of osteoporosis and vaginal atrophy. Expert Opin Pharmacother. 2009;10:2209–20.PubMed

38.

Barrett-Connor E, Grady D, Sashegyi A, Anderson PW, Cox DA, Hoszowski K, et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: 4-year results from the MORE (multiple outcomes of raloxifene evaluation) randomized trial. JAMA. 2002;287:847–57.PubMed

39.

Fuchs RK, Allen MR, Condon KW, Reinwald S, Miller LM, McClenathan D, et al. Strontium ranelate does not stimulate bone formation in ovariectomized rats. Osteoporos Int. Springer Verlag. 2008;19:1331–41.

40.

Scaglione M, Fabbri L, Casella F, Guido G. Strontium ranelate as an adjuvant for fracture healing: clinical, radiological, and ultrasound findings in a randomized controlled study on wrist fractures. Osteoporos Int. 2016;27:211–8.PubMed

41.

Cebesoy O, Tutar E, Kose KC, Baltaci Y, Bagci C. Effect of strontium ranelate on fracture healing in rat tibia. Jt Bone Spine. 2007;74:590–3.

42.

Jonville-Bera A-P. Autret-Leca E [adverse drug reactions of strontium ranelate (Protelos(®) in France]. Presse Med. 2011;40:e453–62.PubMed

43.

Tao Z-S, Zhou W-S, Tu K-K, Huang Z-L, Zhou Q, Sun T, et al. The effects of combined human parathyroid hormone (1-34) and simvastatin treatment on osseous integration of hydroxyapatite-coated titanium implants in the femur of ovariectomized rats. Injury. 2015;46:2164–9.PubMed

44.

Skoglund B, Aspenberg P. Locally applied Simvastatin improves fracture healing in mice. BMC Musculoskelet Disord BioMed Cent. 2007;8:98.

45.

Ihedioha JI, Noel-Uneke OA, Ihedioha TE. Reference values for the serum lipid profile of albino rats (Rattus norvegicus) of varied ages and sexes. Comp Clin Pathol. 2011;22:93–9.

46.

Tsunori K. Effects of parathyroid hormone dosage and schedule on bone regeneration. J Oral Sci Nihon Univ Sch Dent. 2015;57:131–6.

47.

Andreassen TT, Ejersted C, Oxlund H. Intermittent parathyroid hormone (1-34) treatment increases callus formation and mechanical strength of healing rat fractures. J. Bone Miner. Res. 1999;14:960–8 (John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)).PubMed

48.

Holzer G, Majeska RJ, Lundy MW, Hartke JR, Einhorn TA. Parathyroid hormone enhances fracture healing: A preliminary report. Clin Orthop Relat Res. 1999;366:258–63.

49.

Barnes GL, Kakar S, Vora S, Morgan EF, Gerstenfeld LC, Einhorn TA. Stimulation of fracture-healing with systemic intermittent parathyroid hormone treatment. J Bone Joint Surg Am. 2008;90(Suppl 1):120–7.PubMed

50.

Ma Y, Jee WS, Yuan Z, Wei W, Chen H, Pun S, et al. Parathyroid hormone and mechanical usage have a synergistic effect in rat tibial diaphyseal cortical bone. J. Bone Miner. Res. 1999;14:439–48 (John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)).PubMed

51.

Skripitz R, Böhling S, Rüther W, Aspenberg P. Stimulation of implant fixation by parathyroid hormone (1-34)-A histomorphometric comparison of PMMA cement and stainless steel. J. Orthop. Res. 2005;23:1266–70 (Wiley Subscription Services, Inc., A Wiley Company).PubMed

52.

Casanova M, Herelle J, Thomas M, Softley R, Schindeler A, Little D, et al. Effect of combined treatment with zoledronic acid and parathyroid hormone on mouse bone callus structure and composition. Bone. 2016;92:70–8.PubMed

53.

Giner M, Rios MJ, Montoya MJ, Vázquez MA, Miranda C, Pérez-Cano R. Alendronate and raloxifene affect the osteoprotegerin/RANKL system in human osteoblast primary cultures from patients with osteoporosis and osteoarthritis. Eur J Pharmacol. 2011;650:682–7.PubMed

54.

Kim YH, Kim G-S, Jeong-Hwa B. Inhibitory action of bisphosphonates on bone resorption does not involve the regulation of RANKL and OPG expression. Exp Mol Med. 2002;34:145–51.PubMed

55.

Ben-awadh AN, Delgado-Calle J, Tu X, Kuhlenschmidt K, Allen MR, Plotkin LI, et al. Parathyroid hormone receptor signaling induces bone resorption in the adult skeleton by directly regulating the RANKL gene in osteocytes. Endocrinology. 2014;155:2797–809.PubMedPubMedCentral

56.

Kaji H, Kanatani M, Sugimoto T, Chihara K. Statins modulate the levels of osteoprotegerin/receptor activator of NFκB Ligand mRNA in mouse bone-cell cultures. Horm Metab Res. 2005;37:589–92 (Georg Thieme Verlag KG Stuttgart, New York).PubMed

57.

Findlay D, Chehade M, Tsangari H, Neale S, Hay S, Hopwood B, et al. Circulating RANKL is inversely related to RANKL mRNA levels in bone in osteoarthritic males. Arthritis Res Ther BioMed Cent. 2008;10:R2.

58.

Vogel C, Marcotte EM. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet Nat Publish Group. 2012;13:227–32.

59.

Maier T, Güell M, Serrano L. Correlation of mRNA and protein in complex biological samples. FEBS Lett. 2009;583:3966–73.PubMed

60.

Seebach C, Schultheiss J, Wilhelm K, Frank J, Henrich D. Comparison of six bone-graft substitutes regarding to cell seeding efficiency, metabolism and growth behaviour of human mesenchymal stem cells (MSC) in vitro. Injury. 2010;41:731–8.PubMed

Titel: Do antiosteoporotic drugs improve bone regeneration in vivo?
verfasst von: Maximilian Leiblein
Dirk Henrich
Florian Fervers
Kerstin Kontradowitz
Ingo Marzi
Caroline Seebach
Publikationsdatum: 26.04.2019
Verlag: Springer Berlin Heidelberg
Erschienen in: European Journal of Trauma and Emergency Surgery / Ausgabe 2/2020
Print ISSN: 1863-9933
Elektronische ISSN: 1863-9941
DOI: https://doi.org/10.1007/s00068-019-01144-y

Arthropedia

Grundlagenwissen der Arthroskopie und Gelenkchirurgie. Erweitert durch Fallbeispiele, Videos und Abbildungen.
» Jetzt entdecken

Neu im Fachgebiet Orthopädie und Unfallchirurgie

25.04.2024 | Hypertonie | Nachrichten

Update Orthopädie und Unfallchirurgie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Do antiosteoporotic drugs improve bone regeneration in vivo?

Abstract

Purpose

Methods

Results

Conclusion

Arthropedia

Neu im Fachgebiet Orthopädie und Unfallchirurgie

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Ärztliche Empathie hilft gegen Rückenschmerzen

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Vorsicht mit hohen NSAR-Dosen bei ankylosierender Spondylitis!

Update Orthopädie und Unfallchirurgie

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusion

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 2/2020

Evaluation of patients with surgically stabilized rib fractures by different scoring systems

Prehospital triage for mass casualty incidents using the META method for early surgical assessment: retrospective validation of a hospital trauma registry

Focus on bone healing: new strategies for improvement of bone healing

Effect of bone sialoprotein coating on progression of bone formation in a femoral defect model in rats

Suicidal fall from heights trauma: difficult management and poor results

Determination of the effective dose of bone marrow mononuclear cell therapy for bone healing in vivo

Arthropedia

Neu im Fachgebiet Orthopädie und Unfallchirurgie

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Ärztliche Empathie hilft gegen Rückenschmerzen

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Vorsicht mit hohen NSAR-Dosen bei ankylosierender Spondylitis!

Update Orthopädie und Unfallchirurgie