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Endogenous tissue engineering: PTH therapy for skeletal repair

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Abstract

Based on its proven anabolic effects on bone in osteoporosis patients, recombinant parathyroid hormone (PTH1-34) has been evaluated as a potential therapy for skeletal repair. In animals, the effect of PTH1-34 has been investigated in various skeletal repair models such as fractures, allografting, spinal arthrodesis and distraction osteogenesis. These studies have demonstrated that intermittent PTH1-34 treatment enhances and accelerates the skeletal repair process via a number of mechanisms, which include effects on mesenchymal stem cells, angiogenesis, chondrogenesis, bone formation and resorption. Furthermore, PTH1-34 has been shown to enhance bone repair in challenged animal models of aging, inflammatory arthritis and glucocorticoid-induced bone loss. This pre-clinical success has led to off-label clinical use and a number of case reports documenting PTH1-34 treatment of delayed-unions and non-unions have been published. Although a recently completed phase 2 clinical trial of PTH1-34 treatment of patients with radius fracture has failed to achieve its primary outcome, largely because of effective healing in the placebo group, several secondary outcomes are statistically significant, highlighting important issues concerning the appropriate patient population for PTH1-34 therapy in skeletal repair. Here, we review our current knowledge of the effects of PTH1-34 therapy for bone healing, enumerate several critical unresolved issues (e.g., appropriate dosing regimen and indications) and discuss the long-term potential of this drug as an adjuvant for endogenous tissue engineering.

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References

  • Abe Y, Takahata M, Ito M, Irie K, Abumi K, Minami A (2007) Enhancement of graft bone healing by intermittent administration of human parathyroid hormone (1–34) in a rat spinal arthrodesis model. Bone 41:775–785

    Article  PubMed  CAS  Google Scholar 

  • Aleksyniene R, Thomsen JS, Eckardt H, Bundgaard KG, Lind M, Hvid I (2009) Parathyroid hormone PTH(1–34) increases the volume, mineral content, and mechanical properties of regenerated mineralizing tissue after distraction osteogenesis in rabbits. Acta Orthop 80:716–723

    Article  PubMed  Google Scholar 

  • Alkhiary YM, Gerstenfeld LC, Krall E, Westmore M, Sato M, Mitlak BH, Einhorn TA (2005) Enhancement of experimental fracture-healing by systemic administration of recombinant human parathyroid hormone (PTH 1–34). J Bone Joint Surg Am 87:731–741

    Article  PubMed  Google Scholar 

  • Andreassen TT, Cacciafesta V (2004) Intermittent parathyroid hormone treatment enhances guided bone regeneration in rat calvarial bone defects. J Craniofac Surg 15:424–429

    Article  PubMed  Google Scholar 

  • Andreassen TT, Ejersted C, Oxlund H (1999) Intermittent parathyroid hormone (1–34) treatment increases callus formation and mechanical strength of healing rat fractures. J Bone Miner Res 14:960–968

    Article  PubMed  CAS  Google Scholar 

  • Andreassen TT, Fledelius C, Ejersted C, Oxlund H (2001) Increases in callus formation and mechanical strength of healing fractures in old rats treated with parathyroid hormone. Acta Orthop Scand 72:304–307

    Article  PubMed  CAS  Google Scholar 

  • Andreassen TT, Willick GE, Morley P, Whitfield JF (2004) Treatment with parathyroid hormone hPTH(1–34), hPTH(1–31), and monocyclic hPTH(1–31) enhances fracture strength and callus amount after withdrawal fracture strength and callus mechanical quality continue to increase. Calcif Tissue Int 74:351–356

    Article  PubMed  CAS  Google Scholar 

  • Arrighi I, Mark S, Alvisi M, Rechenberg B von, Hubbell JA, Schense JC (2009) Bone healing induced by local delivery of an engineered parathyroid hormone prodrug. Biomaterials 30:1763–1771

    Article  PubMed  CAS  Google Scholar 

  • Aspenberg P, Johansson T (2010) Teriparatide improves early callus formation in distal radial fractures. Acta Orthop 81:234–236

    Article  PubMed  Google Scholar 

  • Aspenberg P, Genant HK, Johansson T, Nino AJ, See K, Krohn K, Garcia-Hernandez PA, Recknor CP, Einhorn TA, Dalsky GP, Mitlak BH, Fierlinger A, Lakshmanan MC (2009) Teriparatide for acceleration of fracture repair in humans: a prospective, randomized, double-blind study of 102 postmenopausal women with distal radial fractures. J Bone Miner Res 25:404–414

    Article  Google Scholar 

  • Awad HA, Zhang X, Reynolds DG, Guldberg RE, O'Keefe RJ, Schwarz EM (2007) Recent advances in gene delivery for structural bone allografts. Tissue Eng 13:1973–1985

    Article  PubMed  CAS  Google Scholar 

  • Bikle DD, Sakata T, Leary C, Elalieh H, Ginzinger D, Rosen CJ, Beamer W, Majumdar S, Halloran BP (2002) Insulin-like growth factor I is required for the anabolic actions of parathyroid hormone on mouse bone. J Bone Miner Res 17:1570–1578

    Article  PubMed  CAS  Google Scholar 

  • Bostrom MP, Gamradt SC, Asnis P, Vickery BH, Hill E, Avnur Z, Waters RV (2000) Parathyroid hormone-related protein analog RS-66271 is an effective therapy for impaired bone healing in rabbits on corticosteroid therapy. Bone 26:437–442

    Article  PubMed  CAS  Google Scholar 

  • Bukata SV, Puzas JE (2010) Orthopedic uses of teriparatide. Curr Osteoporos Rep 8:28–33

    Article  PubMed  Google Scholar 

  • Canalis E, Centrella M, Burch W, McCarthy TL (1989) Insulin-like growth factor I mediates selective anabolic effects of parathyroid hormone in bone cultures. J Clin Invest 83:60–65

    Article  PubMed  CAS  Google Scholar 

  • Chavassieux P, Asser Karsdal M, Segovia-Silvestre T, Neutzsky-Wulff AV, Chapurlat R, Boivin G, Delmas PD (2008) Mechanisms of the anabolic effects of teriparatide on bone: insight from the treatment of a patient with pycnodysostosis. J Bone Miner Res 23:1076–1083

    Article  PubMed  CAS  Google Scholar 

  • Einhorn TA (2003) Clinical applications of recombinant human BMPs: early experience and future development. J Bone Joint Surg Am 85-A (Suppl 3):82–88

    PubMed  Google Scholar 

  • Harada S, Rodan GA (2003) Control of osteoblast function and regulation of bone mass. Nature 423:349–355

    Article  PubMed  CAS  Google Scholar 

  • Jacobson JA, Yanoso-Scholl L, Reynolds DG, Dadali T, Bradica G, Bukata S, Puzas EJ, Zuscik MJ, Rosier R, O'Keefe RJ, Schwarz EM, Awad HA (2010) Teriparatide therapy and beta-tricalcium phosphate enhance scaffold reconstruction of mouse femoral defects. Tissue Eng A 17:389–398

    Article  Google Scholar 

  • Jilka RL (2007) Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone 40:1434–1446

    Article  PubMed  CAS  Google Scholar 

  • Jilka RL, Weinstein RS, Bellido T, Roberson P, Parfitt AM, Manolagas SC (1999) Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J Clin Invest 104:439–446

    Article  PubMed  CAS  Google Scholar 

  • Jung RE, Cochran DL, Domken O, Seibl R, Jones AA, Buser D, Hammerle CH (2007) The effect of matrix bound parathyroid hormone on bone regeneration. Clin Oral Implants Res 18:319–325

    Article  PubMed  Google Scholar 

  • Kaback LA, Soung do Y, Naik A, Geneau G, Schwarz EM, Rosier RN, O'Keefe RJ, Drissi H (2008) Teriparatide (1–34 human PTH) regulation of osterix during fracture repair. J Cell Biochem 105:219–226

    Article  PubMed  CAS  Google Scholar 

  • Kakar S, Einhorn TA, Vora S, Miara LJ, Hon G, Wigner NA, Toben D, Jacobsen KA, Al-Sebaei MO, Song M, Trackman PC, Morgan EF, Gerstenfeld LC, Barnes GL (2007) Enhanced chondrogenesis and Wnt signaling in PTH-treated fractures. J Bone Miner Res 22:1903–1912

    Article  PubMed  CAS  Google Scholar 

  • Kim HW, Jahng JS (1999) Effect of intermittent administration of parathyroid hormone on fracture healing in ovariectomized rats. Iowa Orthop J 19:71–77

    PubMed  CAS  Google Scholar 

  • Komatsu DE, Brune KA, Liu H, Schmidt AL, Han B, Zeng QQ, Yang X, Nunes JS, Lu Y, Geiser AG, Ma YL, Wolos JA, Westmore MS, Sato M (2009) Longitudinal in vivo analysis of the region-specific efficacy of parathyroid hormone in a rat cortical defect model. Endocrinology 150:1570–1579

    Article  PubMed  CAS  Google Scholar 

  • Komatsubara S, Mori S, Mashiba T, Nonaka K, Seki A, Akiyama T, Miyamoto K, Cao Y, Manabe T, Norimatsu H (2005) Human parathyroid hormone (1–34) accelerates the fracture healing process of woven to lamellar bone replacement and new cortical shell formation in rat femora. Bone 36:678–687

    Article  PubMed  CAS  Google Scholar 

  • Lawrence JP, Ennis F, White AP, Magit D, Polzhofer G, Drespe I, Troiano NW, Grauer JN (2006) Effect of daily parathyroid hormone (1–34) on lumbar fusion in a rat model. Spine J 6:385–390

    Article  PubMed  Google Scholar 

  • Lehman RA Jr, Dmitriev AE, Cardoso MJ, Helgeson MD, Christensen CL, Raymond JW, Eckel TT, Riew KD (2010) Effect of teriparatide [rhPTH(1,34)] and calcitonin on intertransverse process fusion in a rabbit model. Spine (Phila Pa 1976) 35:146–152

    Article  Google Scholar 

  • Li G, White G, Connolly C, Marsh D (2002) Cell proliferation and apoptosis during fracture healing. J Bone Miner Res 17:791–799

    Article  PubMed  Google Scholar 

  • Manabe T, Mori S, Mashiba T, Kaji Y, Iwata K, Komatsubara S, Seki A, Sun YX, Yamamoto T (2007) Human parathyroid hormone (1–34) accelerates natural fracture healing process in the femoral osteotomy model of cynomolgus monkeys. Bone 40:1475–1482

    Article  PubMed  CAS  Google Scholar 

  • McClung MR, San Martin J, Miller PD, Civitelli R, Bandeira F, Omizo M, Donley DW, Dalsky GP, Eriksen EF (2005) Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass. Arch Intern Med 165:1762–1768

    Article  PubMed  CAS  Google Scholar 

  • Miyakoshi N, Kasukawa Y, Linkhart TA, Baylink DJ, Mohan S (2001) Evidence that anabolic effects of PTH on bone require IGF-I in growing mice. Endocrinology 142:4349–4356

    Article  PubMed  CAS  Google Scholar 

  • Nakajima A, Shimoji N, Shiomi K, Shimizu S, Moriya H, Einhorn TA, Yamazaki M (2002) Mechanisms for the enhancement of fracture healing in rats treated with intermittent low-dose human parathyroid hormone (1–34). J Bone Miner Res 17:2038–2047

    Article  PubMed  CAS  Google Scholar 

  • Nakazawa T, Nakajima A, Shiomi K, Moriya H, Einhorn TA, Yamazaki M (2005) Effects of low-dose, intermittent treatment with recombinant human parathyroid hormone (1–34) on chondrogenesis in a model of experimental fracture healing. Bone 37:711–719

    Article  PubMed  CAS  Google Scholar 

  • Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH (2001) Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:1434–1441

    Article  PubMed  CAS  Google Scholar 

  • Nozaka K, Miyakoshi N, Kasukawa Y, Maekawa S, Noguchi H, Shimada Y (2008) Intermittent administration of human parathyroid hormone enhances bone formation and union at the site of cancellous bone osteotomy in normal and ovariectomized rats. Bone 42:90–97

    Article  PubMed  CAS  Google Scholar 

  • O'Loughlin PF, Cunningham ME, Bukata SV, Tomin E, Poynton AR, Doty SB, Sama AA, Lane JM (2009) Parathyroid hormone (1–34) augments spinal fusion, fusion mass volume, and fusion mass quality in a rabbit spinal fusion model. Spine (Phila Pa 1976) 34:121–130

    Article  Google Scholar 

  • Okazaki K, Jingushi S, Ikenoue T, Urabe K, Sakai H, Iwamoto Y (2003) Expression of parathyroid hormone-related peptide and insulin-like growth factor I during rat fracture healing. J Orthop Res 21:511–520

    Article  PubMed  CAS  Google Scholar 

  • Oteo-Alvaro A, Moreno E (2010) Atrophic humeral shaft nonunion treated with teriparatide (rh PTH 1–34): a case report. J Shoulder Elbow Surg 19:e22–28

    Article  PubMed  Google Scholar 

  • Redlich K, Gortz B, Hayer S, Zwerina J, Doerr N, Kostenuik P, Bergmeister H, Kollias G, Steiner G, Smolen JS, Schett G (2004) Repair of local bone erosions and reversal of systemic bone loss upon therapy with anti-tumor necrosis factor in combination with osteoprotegerin or parathyroid hormone in tumor necrosis factor-mediated arthritis. Am J Pathol 164:543–555

    Article  PubMed  CAS  Google Scholar 

  • Reynolds DG, Shaikh S, Papuga MO, Lerner AL, O'Keefe RJ, Schwarz EM, Awad HA (2009) muCT-based measurement of cortical bone graft-to-host union. J Bone Miner Res 24:899–907

    Article  PubMed  Google Scholar 

  • Reynolds DG, Takahata M, Lerner AL, O'Keefe RJ, Schwarz EM, Awad HA (2011) Teriparatide therapy enhances devitalized femoral allograft osseointegration and biomechanics in a murine model. Bone 48:562-570

    Article  PubMed  CAS  Google Scholar 

  • Rubery PT, Bukata SV (2010) Teriparatide may accelerate healing in delayed unions of type III odontoid fractures: a report of 3 cases. J Spinal Disord Tech 23:151–155

    Article  PubMed  Google Scholar 

  • Seebach C, Skripitz R, Andreassen TT, Aspenberg P (2004) Intermittent parathyroid hormone (1–34) enhances mechanical strength and density of new bone after distraction osteogenesis in rats. J Orthop Res 22:472–478

    Article  PubMed  CAS  Google Scholar 

  • Skripitz R, Andreassen TT, Aspenberg P (2000) Parathyroid hormone (1–34) increases the density of rat cancellous bone in a bone chamber. A dose-response study. J Bone Joint Surg Br 82:138–141

    Article  PubMed  CAS  Google Scholar 

  • Yao W, Cheng Z, Pham A, Busse C, Zimmermann EA, Ritchie RO, Lane NE (2008) Glucocorticoid-induced bone loss in mice can be reversed by the actions of parathyroid hormone and risedronate on different pathways for bone formation and mineralization. Arthritis Rheum 58:3485–3497

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. The Center for Musculoskeletal Research, University of Rochester, 665, 601 Elmwood Avenue, Rochester, NY 14642, USA

    Masahiko Takahata, Hani A. Awad, Regis J. O’Keefe, Susan V. Bukata & Edward M. Schwarz

  2. Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA

    Hani A. Awad & Edward M. Schwarz

  3. Department of Orthopaedics, University of Rochester, Rochester, NY, USA

    Hani A. Awad, Regis J. O’Keefe, Susan V. Bukata & Edward M. Schwarz

Authors
  1. Masahiko Takahata
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  2. Hani A. Awad
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  3. Regis J. O’Keefe
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  4. Susan V. Bukata
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  5. Edward M. Schwarz
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Corresponding author

Correspondence to Edward M. Schwarz.

Additional information

This work was funded in part by grants from the Aircast Foundation and grants from the National Institutes of Health (AR056696, AR054041, DE019902).

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Takahata, M., Awad, H.A., O’Keefe, R.J. et al. Endogenous tissue engineering: PTH therapy for skeletal repair. Cell Tissue Res 347, 545–552 (2012). https://doi.org/10.1007/s00441-011-1188-4

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  • DOI: https://doi.org/10.1007/s00441-011-1188-4

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