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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 11  |  Issue : 1  |  Page : 49-52

Effect of daily teriparatide for delayed union of fracture neck of the femur


1 Department of Orthopaedics, SCB Medical College, Cuttack, Odisha, India
2 Department of Orthopaedics, FM Medical College, Balasore, Odisha, India

Date of Web Publication19-Aug-2019

Correspondence Address:
Dr. Nirmal Chandra Mohapatra
Department of Orthopaedics, FM Medical College, Balasore, Odisha
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jotr.jotr_16_19

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  Abstract 


Background: Delayed union and nonunion of fracture neck of the femur remains a therapeutic challenge to orthopedic surgeons worldwide which is why this fracture is aptly named as unsolved fracture. Hip joint preservation surgery always remains the primary criteria in fracture neck of the femur in physiologically young patients. However, the outcome is not always satisfactory due to many factors, delayed presentation being one of them. This case series was conducted to determine and establish the role of recombinant teriparatide in fracture healing in delayed union of fracture neck of the femur. Materials and Methods: The study was done on nine cases (six males and three females) of delayed union of fracture neck of the femur with a previous history of some surgical interventions. All cases of delayed union were diagnosed by clinically and radiologically and undergone all routine blood investigations. All were administered 20 μg of teriparatide (recombinant parathormone) subcutaneous injection daily for a period of 3–5 months. Results: Eight patients who were evaluated clinically and radiologically showed satisfactory union and one case showed nonunion. One patient showed mild allergic reaction. Conclusion: This study showed that daily administration of teriparatide accelerates fracture healing in delayed union. It also enhances fracture healing throughout the period of bone remodeling phase. It also emphasizes the safety of teriparatide.

Keywords: Delayed union, neck of femur, teriparatide


How to cite this article:
Mishra JK, Mohapatra NC, Kar BK. Effect of daily teriparatide for delayed union of fracture neck of the femur. J Orthop Traumatol Rehabil 2019;11:49-52

How to cite this URL:
Mishra JK, Mohapatra NC, Kar BK. Effect of daily teriparatide for delayed union of fracture neck of the femur. J Orthop Traumatol Rehabil [serial online] 2019 [cited 2019 Nov 22];11:49-52. Available from: http://www.jotr.in/text.asp?2019/11/1/49/264716




  Introduction Top


Fracture neck of the femur occurs in all the age groups, but the treatment in physiologically young group of patients remains a challenge for orthopedic surgeons. In young patients, internal fixation is always preferred for the preservation of normal head of femur.[1] Although majority of fractures have an exceptional quality to heal, approximately 10%–30% of fractures can land up in nonunion and delayed union.[1],[2],[3] In Indian scenario, many patients present late due to ignorance, poverty, fear of surgery, or bone-setting therapy, which complicates the treatment and may contribute to the abovementioned complications. Delayed union presents a treatment challenge with the need for surgical intervention, prolonged hospitalization, and economic burden. There are wide ranges of treatment for delayed union from the use of bone graft or bone graft substitutes with revision surgery and use of biological agents such as bone matrix proteins (BMPs),[4] vascular endothelial growth factor, prostaglandin E, placenta growth factor, and fibroblast growth factor-2. All these procedures are invasive in nature and their use limited by increased morbidity due to prolonged hospitalisation, postoperative complications and extra financial burden. Despite improved surgical techniques, the high prevalence of delayed unions has directed research efforts toward the development of novel and affordable nonsurgical treatments to increase bone formation and accelerate fracture repair. Hence, there is a great need for and significant interest in the identification of anabolic agents that can be administered systemically.

Teriparatide (TPTD) (parathyroid hormone [PTH 1–34]) is an approved anabolic drug for the treatment of delayed union and nonunion with a proven efficacy in stimulating bone formation.[5],[6],[7],[8],[9],[10] TPTD stimulates bone formation, improving some macro- and microarchitectural characteristics of bone, and it has a potential to accelerate fracture callus formation and remodeling during bone repair.[11],[12] TPTD is the first Food and Drug Administration-approved agent for the treatment of osteoporosis that stimulates new bone formation. There is an increasing evidence, suggesting that daily intermittent administration of TPTD accelerates fracture healing in delayed union and nonunion of the humerus, radius, femur, sternum, etc.[5],[6],[7],[8],[9],[10] However, there are few reported studies on teriparatide accelerating fracture healing in delayed union of fracture neck of the femur.[10]


  Materials and Methods Top


This is a prospective study to evaluate the effect of TPTD treatment on delayed union of fracture neck of the femur. The average follow-up period was 1 year (10–20 months). Informed consent from patients was taken as per local hospital regulations. Nine patients (six males and three females) who were clinically and radiologically proven of delayed union of fracture neck of the femur were included in the study [Table 1]. All the patients were within physiological age group of 28–54 years having radiological sign of a radiolucent line through the fracture site and widening of the fracture gap. Those patients with sclerotic margins, overt nonunion, complete absorption of neck of femur, infected nonunion, and avascular necrosis were excluded from the study. Similarly, patients with pathological fracture and increased serum calcium and alkaline phosphatase and a history of addiction to alcohol and nicotine were excluded from the study.
Table 1: Detail of patients treated with Teriparatide

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Procedure

All patients underwent detail clinical & laboratory evaluation to rule out infection & co-morbidities. Clinical evaluations such as tenderness and inability to bear weight on the affected limb were recorded. Radiological evaluation included X-ray in two planes and computed tomography in a few cases.

All patients received subcutaneous injection of TPTD 20 μg daily in anterior aspect of thigh, abdomen, or forearm for minimum 3–5 months. All patients were given elemental calcium of 1 g daily along with Vitamin D 400 IU with a gap of at least 8–10 h of injection and advised to use braces, crutches, and walker for mobilization along with regular checkup once in a month. Evaluation of efficacy was based on the clinical parameters such as reduction of pain which was measured by visual analog scale (VAS), improvement of joint function which was measured by ability to bear weight without limp in the affected limb, and normal range of motion and strength. Radiologically, treatment efficacy was evaluated by fracture union as observed by crossing of trabeculae.

In the complete course of therapy, patients were carefully monitored and assessed for any adverse effects such as nausea, vomiting, headache, dizziness, and any local allergic reaction and serious complications such as fainting, unusual tiredness, or mental/mood changes (such as confusion).


  Results Top


A total of nine patients (six males and three females) with a mean age of 43 years (range from 28 to 54 years) and delayed union of fracture neck of the femur treated by TPTD were evaluated. The mean duration of presentation of delayed union was found to be 11.7 ± 3.0 weeks. We reviewed fracture history in details with previous orthopedic surgical procedures for each subject, history of smoking, date and duration of delayed union diagnosis, radiograph reports, and physical examination of the affected limb. Our primary endpoints were radiographic evidence of fracture union or crossing of trabeculae through fracture line and ability to bear weight without limp on the affected limb.

All nine patients were administered 20 μg of TPTD daily injection by subcutaneous route. The mean duration of treatment of TPTD started was 11.1 ± 3.0 weeks. The mean duration of TPTD injection treatment was 15.3 ± 3.9 weeks whereas the minimum duration was 12 weeks and maximum 20 weeks.

Patients were evaluated clinically by ability to bear weight without pain, decreasing tenderness at fracture site & improved hip function. Reduction in pain is also an important indicator for evaluating the fracture healing by VAS score. While the pretherapy VAS score was 8.3 ± 0.67, the posttherapy score reduced to 2.2 ± 0.91, which amounts to a 61% reduction. The efficacy of TPTD was also analyzed using serial radiographs to assess for callus formation, bony bridging, and reduction of fracture line and complete bony union. The mean time to fracture union after starting TPTD varied widely across different types of fracture, but in our study, the mean duration was approximately 15.3 ± 3.9 weeks. TPTD treatment was well tolerated and induced radiologic evidence of fracture healing in eight patients, and one patient could not respond to TPTD and developed nonunion. In our study, one patient experienced mild side effect of local allergic reaction from TPTD administration. No other significant severe adverse effects were observed to cause discontinuation of TPTD.


  Discussion Top


Fracture healing is a continuous cascade process that includes multiple signaling pathways and is regulated by both local and systemic factors. However, any abnormality within this cascade process leads to impair healing, leading to delayed union and nonunion. Factors causing delayed union can be biological, mechanical, or both. TPTD facilitates fracture healing by a number of mechanisms, which includes promoting proliferation and differentiation of mesenchymal stem cell, chondroprogenitors and osteoprogenitors, chondrocyte maturation, production of BMPs, and formation of osteoclasts. It also promotes the early callus formation and callus remodeling by stimulating matrix proteins for the bones and formation of osteoclasts.[11],[12],[13],[14] The Wnt/beta-catenin signaling pathway which regulates the type II and X collagen involved in determining the size of the callus is also promoted and enhanced by the administration of TPTD. Most of the current literatures on the effect of TPTD in primary, delayed, and nonunion observe a positive outcome in enhancing the time to clinical and radiological union.[5],[8],[10]

Previous studies showed that administration of daily TPTD increases bone formation and improves bone microarchitecture and structure that may be helpful during bone repair. Clinical trials in postmenopausal females demonstrated improved healing of distal radius fractures and pelvic ring injuries with daily TPTD and even promoted spinal fusion for surgery in spondylolisthesis.[14] On the other hand, there are only clinical case reports of 1–3 patients that describe the use of PTH for the management of fracture nonunion. Tachiri et al reported accelerated fracture healing in two cases of metatarsal fracture,[5] Rubery etall in three patients of odontoid fracture delayed union,[9] and Oteo-Alvarez in one case of atropic nonunion of humerus following use of teriparatide.[10] Lee et al. showed that TPTD could be an alternative to surgical intervention in nonunion. They used TPTD in three patients of nonunion of the femur even after the initial surgical intervention where fracture healing occurred.[13] Oteo-Álvaro and Marín reported a case of atrophic nonunion after humeral shaft fracture in a patient with severe psychiatric disorders that advised against hospital admission and surgery.[7] There have been few reports of trial of TPTD in fracture neck of the femur. Bhandari et al. did a prospective, double-blind, placebo-controlled, multicenter trial and found no difference in fracture union or revision surgery between the two groups.[15] Although there were no between-group differences in measures of pain control, a greater proportion of patients treated with TPTD were able to ambulate without worsening or regained prefracture ambulatory status at 12 months. Thus, the effect of TPTD on fracture healing remains uncertain. Therefore, TPTD remains a treatment option for elderly patients with low trauma hip fractures who are at high risk for subsequent fractures. Our case series shows that TPTD at a dose of 20 μg/day facilitated early clinical and radiologic improvement of chronic delayed union fractures of neck of the femur, with complete healing over 3–5 months. In this series, most patients had undergone previous operation with cannulated hip screw and dynamic hip screw [Figure 1]. Eight out of nine of the TPTD-treated patients showed an improvement in fracture healing which was evaluated by clinically and radiologically [Figure 2].
Figure 1: (a) Eight weeks postsurgery shows nonunion. (b) Eight weeks postinjection teriparatide shows fracture union in progress. (c) Four months after teriparatide injection shows good union

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Figure 2: (a) Two months postoperative shows screw backout and delayed union. (b) Two months after starting teriparatide shows healing in progress. (c and d) Four months after teriparatide shows good union

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The present study has some limitations. As a case series comprising small number of cases, our report represents an observational study that reports data from a subject group without a comparison population. The lack of controls makes any case series prone to bias. This series also did not allow us to address the optimal timing, dose, or form of PTH to enhance fracture healing.

However, this study describes the outcome of a novel treatment which can be used to focus studies with stronger designs and more number of cases in a fracture which poses important and significant orthopedic challenge.


  Conclusion Top


Delayed union of fracture neck of the femur treated with daily administration of TPTD (20 μg) showed acceleration of fracture healing proven by clinically and radiologically. TPTD is a relatively safe drug with minimal adverse effects and economical compared to other options of fracture healing such as bone grafting and second surgery. Teriparatide enhances fracture healing by stimulating exuberant callus formation and has constant positive anabolic effect throughout the period of remodeling in fracture healing. Moreover it is less invasive and provides better patient compliance. However, studies across this field are not much and some more clinical studies are needed to determine the usefulness of TPTD and the clinical indications for the use of TPTD in the treatment of fracture healing.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Pauyo T, Drager J, Albers A, Harvey EJ. Management of femoral neck fractures in the young patient: A critical analysis review. World J Orthop 2014;5:204-17.  Back to cited text no. 1
    
2.
Haidukewych GJ, Rothwell WS, Jacofsky DJ, Torchia ME, Berry DJ. Operative treatment of femoral neck fractures in patients between the ages of fifteen and fifty years. J Bone Joint Surg Am 2004;86-A:1711-6.  Back to cited text no. 2
    
3.
Parker MJ, Raghavan R, Gurusamy K. Incidence of fracture-healing complications after femoral neck fractures. Clin Orthop Relat Res 2007;458:175-9.  Back to cited text no. 3
    
4.
Kamiya N. The role of BMPs in bone anabolism and their potential targets SOST and DKK1. Curr Mol Pharmacol 2012;5:153-63.  Back to cited text no. 4
    
5.
Tachiiri H, Okuda Y, Yamasaki T, Kusakabe T. Weekly teriparatide administration for the treatment of delayed union: A report of two cases. Arch Osteoporos 2014;9:179.  Back to cited text no. 5
    
6.
Borges JL, Freitas A, Bilezikian JP. Accelerated fracture healing with teriparatide. Arq Bras Endocrinol Metabol 2013;57:153-6.  Back to cited text no. 6
    
7.
Oteo-Alvaro A, Moreno E, Atrophy humeral shaft nonunion treated with Teriparatide (rh PTH 1-34): A case report. J Shoulder Elbow Surg 2010;19:e22-e28.  Back to cited text no. 7
    
8.
Ochi K, Ikari K, Naomi A, Momohara S. Administration of teriparatide treatment for a challenging case of nonunion of periprosthetic fracture after total knee arthroplasty. Arch Osteoporos 2013;8:159.  Back to cited text no. 8
    
9.
Rubery PT, Bukata SV. Teriparatide may accelerate healing in delayed unions of type III odontoid fractures: A report of 3 cases. J Spinal Disord Tech 2010;23:151-5.  Back to cited text no. 9
    
10.
Chintamaneni S, Finzel K, Gruber BL. Successful treatment of sternal fracture nonunion with teriparatide. Osteoporos Int 2010;21:1059-63.  Back to cited text no. 10
    
11.
Lindsay R, Zhou H, Cosman F, Nieves J, Dempster DW, Hodsman AB, et al. Effects of a one-month treatment with PTH(1-34) on bone formation on cancellous, endocortical, and periosteal surfaces of the human ilium. J Bone Miner Res 2007;22:495-502.  Back to cited text no. 11
    
12.
Jiang Y, Zhao JJ, Mitlak BH, Wang O, Genant HK, Eriksen EF. Recombinant human parathyroid hormone (1-34) [teriparatide] improves both cortical and cancellous bone structure. J Bone Miner Res 2003;18:1932-41.  Back to cited text no. 12
    
13.
Lee YK, Ha YC, Koo KH. Teriparatide, a nonsurgical solution for femoral nonunion? A report of three cases. Osteoporos Int 2012;23:2897-900.  Back to cited text no. 13
    
14.
Aspenberg P, Genant HK, Johansson T, Nino AJ, See K, Krohn K, et al. 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 2010;25:404-14.  Back to cited text no. 14
    
15.
Bhandari M, Jin L, See K, Burge R, Gilchrist N, Witvrouw R, et al. Does teriparatide improve femoral neck fracture healing: Results from a randomized placebo-controlled trial. Clin Orthop Relat Res 2016;474:1234-44.  Back to cited text no. 15
    


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