Abstract
Introduction
Fracture nonunion remains a great challenge for orthopaedic surgeons. Approximately 5–10% of bone fractures do not heal promptly, and require another surgical procedure. Previously, several small studies have found that teriparatide, a parathyroid hormone (PTH) analogue, has been found to induce union in those with delayed union and nonunion. However, to date, no systematic reviews regarding the use of teriparatide for delayed union and nonunion are available. The present review aims to investigate the safety and efficacy of teriparatide in delayed union and nonunion.
Methods
Systematic literature search was performed in PubMed, ScienceDirect, and Google Scholar until September 26, 2019. We included studies involving adult patients (age >16 years) diagnosed with delayed union or nonunion fracture regardless of location (long bone, short bone, flat bone or irregular bone). The language was restricted to English and Indonesian. Outcomes that were recorded were fracture union and adverse events.
Results
Initial search found 5416 abstract and titles. Of these, 20 articles consisting of 64 subjects were retrieved. Of these, 15 case reports, 4 case series, and one prospective study were included. All of the studies administered subcutaneous injection of teriparatide 20 μg/day with mean duration of 7.3 ± 1.5 weeks to 9.7 months. Sixty-one (95.3%) of 64 subjects developed complete union. The follow-up ranged from 3 to 24 months. No side effects occurred during the follow-up period.
Conclusions
Limited evidence demonstrates that daily subcutaneous injection of teriparatide 20 μg is a potential new safe treatment for delayed union and nonunion with no side effects. We highly suggest the use of such drug, as it is highly effective and safe. However, further clinical studies are required to investigate its safety and efficacy.
Keywords: Teriparatide, Parathyroid hormone, Nonunion, Delayed union
1. Introduction
As life expectancy increases worldwide, the incidence of fracture will be increased concomitantly. However, 5–10% of all fractures do not heal promptly.1,2 This may result in delayed union and nonunion, both of which remain a great challenge for orthopaedic surgeons. Moreover, they often cause considerable functional and socioeconomic problems for the patients.3,4 Despite advances in treatment, majority of the treatment modalities are associated with increased hospital length of stay, blood loss, pain, stiffness and other complications. Therefore, there is a need for another treatment method that could resolve this condition with minimal adverse effects.
Parathyroid hormone (PTH) is deemed as a key regulator of calcium metabolism in the body.4,5 Although hyperparathyroidism is associated with bone loss, intermittent administration of PTH has lead to increased bone mass, which may be due to the more dominant anabolic effects than the catabolic effects in PTH.6 Teriparatide, a synthetic PTH analogue containing the 1–34 amino acid (PTH 1–34) is often used for treating osteoporosis. In recent years, the efficacy of teriparatide in promoting fracture healing has been reported in numerous animal models7,8 and clinical studies.1, 2, 3,9, 10, 11, 12, 13, 14, 15, 16, 17, 18 This drug works by stimulating osteoblasts and reducing osteoblast apoptosis, increasing callus formation, improving mechanical strength,19 and resulting in increased osteoblast life span.20 Several case reports have shown that teriparatide could result in union in patients with nonunion.2,9,10 However, to date, there are no systematic reviews that investigate the use of teriparatide for delayed union and nonunion. The present review aims to investigate the safety and efficacy of delayed union and nonunion.
2. Methods
This systematic review is conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidance.21
2.1. Eligibility criteria
2.1.1. Participants
This systematic review included studies involving adult patients (age >16 years) diagnosed with delayed union or nonunion fracture regardless of location) long bone, short bone, flat bone or irregular bone) or treatment (operative or conservative).
2.1.2. Interventions
The intervention is teriparatide with any route, dose or frequency.
2.1.3. Outcomes
The outcomes included fracture union and adverse events.
2.1.4. Study characteristics
All study designs including clinical, prospective, retrospective, case series, and case reports were included in the study. Review articles, editorials and letters were excluded.
2.1.5. Information sources
We conducted systematic literature search at PubMed, ScienceDirect, and Google Scholar with no language restrictions. In addition, a manual search of all the bibliogrpahies of the retrieved articles and relative review were conducted to further identify potentially eligible trials. The first search was performed in January 12, 2019. The second and third searches were conducted in September 11 and 26, 2019, respectively.
2.1.6. Search strategy
A combination of both free words and MeSH terms were used: ‘teriparatide’, ‘parathyroid hormone’, ‘nonunion’, ‘osteoporotic’, ‘osteoporosis.’ Boolean operators including AND, OR, and NOT were used (Table 1).
Table 1.
Search strategy.
| Database | Search Strategy |
|---|---|
| PubMed | (teriparatide OR parathyroid hormone OR forteo OR PTH 1–34 oR rPTH 1–34) AND (nonunion OR delayed union) NOT (osteoporotic OR osteoporosis) |
| ScienceDirect | (teriparatide OR parathyroid hormone OR forteo OR PTH 1–34 oR rPTH 1–34) AND (nonunion OR delayed union) NOT (osteoporotic OR osteoporosis) |
| Google Scholar | (teriparatide OR forteo OR parathyroid hormone OR PTH 1–34) AND (nonunion OR non-union OR delayed union) |
2.1.7. Evidence quality appraisal
Quality of the included studies was appraised by using Oxford Centre for evidence-based medicine levels of evidence. Clinical evidence was grossly divided to five levels, ranging from I to V. Level Ia represents the highest quality evidence and V is the lowest.
3. Results
3.1. Literature search
A total 5441 publications were initially retrieved (Fig. 1). Of these, 5416 were excluded during abstract screening, and 20 articles were finally included.
Fig. 1.
Literature searching process.
3.2. Study characteristics
Of the 20 articles, there were 15 case reports, 4 case series, and one prospective study. Subjects ranged from 1 to 32. A total of 64 subjects were included in this review. Subjects consisted of 29 males and 35 females. Seven studies were conducted in Japan. The more detailed characteristics of the studies are listed in Table 2.
Table 2.
Characteristics of the included studies.
| author(s) | Year | Country | Study Design | Evidence level | Subjects | Mean Age | Male:Female |
|---|---|---|---|---|---|---|---|
| Kastirr et al.12 | 2018 | Germany | Prospective study | IIb | 32 | 55.1 ± 15.9 (22–83) | 15:17 |
| Pola et al.22 | 2017 | Italy | Case report | IV | 1 | 73 | 0:1 |
| Xiaofeng et al.3 | 2017 | China | Case report | IV | 1 | 44 | 1:0 |
| Yu et al.2 | 2017 | China | Case report | IV | 1 | 45 | 1:0 |
| Bednar17 | 2016 | Canada | Case report | IV | 1 | 70 | 0:1 |
| Kastirr et al.23 | 2016 | Germany | Case report | IV | 1 | 49 | 1:0 |
| Coppola et al.1 | 2015 | Italy | Case series | IV | 4 | 31.75 | 4:0 |
| Mancilla et al.18 | 2015 | USA | Case series | IV | 6 | 19 to 64 | 1:5 |
| Fukuda et al.26 | 2014 | Japan | Case report | IV | 1 | 74 | 0:1 |
| Matsumoto et al.24 | 2014 | Japan | Case report | IV | 1 | 70 | 1:0 |
| Nozaka et al.14 | 2014 | Japan | Case report | IV | 1 | 56 | 1:0 |
| Tachiiri et al.27 | 2014 | Japan | Case report | IV | 2 | 72 | 0:2 |
| Gianotti et al.25 | 2013 | Italy | Case report | IV | 1 | 80 | 0:1 |
| Mitani28 | 2013 | Japan | Case report | IV | 1 | 88 | 0:1 |
| Ochi et al.29 | 2013 | Japan | Case report | IV | 1 | 74 | 0:1 |
| Tamai et al.15 | 2013 | Japan | Case report | IV | 1 | 25 | 0:1 |
| Lee et al.9 | 2012 | South Korea | Case series | IV | 3 | 43.67 | 2:1 |
| Chintamaneni et al.16 | 2010 | USA | Case report | IV | 1 | 67 | 1:0 |
| Oteo-Alvaro et al.13 | 2010 | Spain | Case report | IV | 1 | 32 | 1:0 |
| Rubery et al.10 | 2010 | USA | Case series | IV | 3 | 85.67 | 0:3 |
3.3. Teriparatide
Fifteen studies1, 2, 3,9,10,12,13,15, 16, 17, 18,22, 23, 24, 25 administered daily injection of 20 μg teriparatide, and four26, 27, 28, 29 gave weekly 56.5 μg of teriparatide. The duration of treatment varied from 4 weeks to 9 months (Table 3).
Table 3.
Details of the treatment in the studies.
| Study | Intervention | Dose | Given daily/weekly | Route of administration | Duration of treatment |
|---|---|---|---|---|---|
| Kastirr et al.12 | Teriparatide | 20 μg | Daily | SC injection | 4–10 weeks |
| Pola et al.22 | Teriparatide | 20 μg | Daily | SC injection | 3 months |
| Xiaofeng et al.3 | Teriparatide | 20 μg | Daily | SC injection | 8 months |
| Yu et al.2 | Teriparatide | 20 μg | Daily | SC injection | 9 months |
| Bednar17 | Teriparatide | 20 μg | Daily | SC injection | 3 months |
| Kastirr et al.23 | Teriparatide | 20 μg | Daily | SC injection | 4 months |
| Coppola et al.1 | Teriparatide | 20 μg | Daily | SC injection | 5 (3–9) monthsa |
| Mancilla et al.18 | Teriparatide | 20 μg | Daily | SC injection | Discontinued at the time of radiographic evidence of fracture healing |
| Fukuda et al.26 | Teriparatide | 56.5 μg | Weekly | SC injection | 6 months |
| Matsumoto et al.24 | Teriparatide | 20 μg | Daily | SC injection | 6 months |
| Nozaka et al.14 | Teriparatide combined with LIPUS | Not stated | Not stated | Not stated | 6 months |
| Tachiiri et al.27 | Teriparatide | 56.5 μg | Weekly | SC injection | 4 months |
| Gianotti et al.25 | Teriparatide | 20 μg | Daily | SC injection | 3 months |
| Mitani28 | Teriparatide | 56.5 μg | Weekly | SC injection | 36 weeks |
| Ochi et al.29 | Teriparatide | 56.5 μg | Weekly | SC injection | 6 months |
| Tamai et al.15 | Teriparatide and alfacalcidol | 20 μg | Daily | SC injection | Not specified |
| Lee et al.9 | Teriparatide | 20 μg | Daily | SC injection | 3 months |
| Chintamaneni et al.16 | Teriparatide | 20 μg | Daily | SC injection | 9 months |
| Oteo-Alvaro et al.13 | Teriparatide | 20 μg | Daily | SC injection | 5 months |
| Rubery et al.10 | Teriparatide | 20 μg | Daily | SC injection | Not specified |
Presented as median (range).
3.4. Diagnosis
The diagnoses of the subjects are presented in Table 4.
Table 4.
Diagnosis of the subjects.
| Author(s) | Diagnosis |
|---|---|
| Kastirr et al.12 | Pilon tibial fracture nonunion (n = 16), distale crurale fracture nonunion (n = 2), femoral fracture nonunion (n = 8), metatarsale fracture nonunion (n = 1), distal humerus fracture nonunion (n = 1), olecranon fracture nonunion (n = 1), distal radius fracture nonunion (n = 1), |
| Pola et al.22 | Type II dens non-union fractures |
| Xiaofeng et al.3 | Tibial and femoral fracture nonunion |
| Yu et al.2 | Femoral shaft fracture nonunion |
| Bednar17 | Type III odontoid process fracture nonunion |
| Kastirr et al.23 | Aseptic delayed union of a distal lower leg fracture |
| Coppola et al.1 | Lower limb nonunions |
| Mancilla et al.18 | Femoral shaft (n = 2), tibial shaft (n = 2), tibial and femoral shaft (n = 1), subtrochanteric femur (n = 1) |
| Fukuda et al.26 | Delayed union of atypical subtrochanteric femur fracture |
| Matsumoto et al.24 | Delayed union of a lumbar vertebral fracture with diffuse idiopathic skeletal hyperostosis |
| Nozaka et al.14 | Femoral shaft fracture nonunion |
| Tachiiri et al.27 | Delayed union of fracture of the right foot |
| Gianotti et al.25 | Delayed union of femoral fracture |
| Mitani28 | Delayed union of femoral neck fracture |
| Ochi et al.29 | Nonunio of a periprosthetic fracture after total knee arthroplasty |
| Tamai et al.15 | Nonunion of an ankle fusion site, type 1 diabetes, severe osteoporosis, femoral shaft fracture |
| Lee et al.9 | Femoral nonunion |
| Chintamaneni et al.16 | Sternal nonunion |
| Oteo-Alvaro et al.13 | Atrophic humeral shaft nonunion |
| Rubery et al.10 | Type III odontoid fractures nonunion |
3.5. Union
In the present review, 61 of 64 (95.3%) subjects developed complete union, and the mean time to union ranged from 2 to 24 months. The mean time between initial fracture and teriparatide was 3–24.3 ± 17.8 months. The follow-up ranged from 3 to 24 months. No side effects occurred during the follow-up period (Table 5).
Table 5.
Results of Teriparatide treatment.
| Author(s) | Mean time between initial fracture and Teriparatide (months) | Treatment results | Mean time to union (months) | Side effects | Follow-up |
|---|---|---|---|---|---|
| Kastirr et al.12 | 24.3 ± 17.8 | Thirty patients experienced a stable osseous consolidation of the nonunion and regained full weight bearing capacity after a mean of 4.1 ± 1.5 (2–6) months of discontinuation. Two patients did not response after eight weeks of therapy. | 4.1 ± 1.5 (2–6) after discontinuation in 30 subjects | None | 4.1 ± 1.5 (2–6) months |
| Pola et al.22 | 6 | Final CT scan at 3 months of Teriparatide treatment demonstrated complete consolidation of the fracture | 3 | None | 3 months |
| Xiaofeng et al.3 | 11 | Complete fracture union after 12 months. | 12 | None | 12 months |
| Yu et al.2 | 25 | Complete union after 15 months of the discontinuation of teriparatide | 24 | None | 24 months |
| Bednar17 | 3 | Complete fracture-site healing after 6 months (3 months after discontinuing teriparatide therapy) | 6 | None | 6 months |
| Kastirr et al.23 | 7 | Bone bridges within the fracture gap were observed in 4 months after completion of therapy | 6 | None | 6 months |
| Coppola et al.1 | 9.5 | 1 subject developed complete union in 3 years, 3 subjects return to normal activity after 8–12 months (mean: 10 months) | 10 | None | 8 months to 5 years |
| Mancilla et al.18 | 12.83 | Complete union in 3–9 months in 5 of 6 patients. | 6.4 in 5 subjects | None | 3–9 months |
| Fukuda et al.26 | 5 | Complete union in 3 months | 3 | None | 6 months |
| Matsumoto et al.24 | Not reported | Complete union in 2 months | 2 | None | 6 months |
| Nozaka et al.14 | 6 | Bony union and full weight bearing was permitted after 6 months | 6 | None | 6 months |
| Tachiiri et al.27 | 4 | Complete union was achieved after 4 months of treatment | 4 | None | 4 months |
| Gianotti et al.25 | 7 | Complete union in 3 months | 3 | None | 3 months |
| Mitani28 | 13 | Complete union at 5 months | 5 | None | 5 months |
| Ochi et al.29 | 9 | New bone filling between the fracture gap after 5 months | 6 | None | 6 months |
| Tamai et al.15 | 3 | Complete healing of femoral shaft fracture in 12 weeks, complete healing of ankle in 12 weeks | 3 | None | 12 weeks |
| Lee et al.9 | 20 | Complete union achieved in 6–12 months (mean: 8.7 months) after discontinuation | 13.7 | None | 9–15 months |
| Chintamaneni et al.16 | Not reported | Complete fracture healing in 9 months | 9 | None | 9 months |
| Oteo-Alvaro et al.13 | 6 | Fracture healing was achieved in 5 months | 5 | None | 6 months |
| Rubery et al.10 | 4.67 | Two months after discontinuation, two months after discontinuation, four months after beginning teriparatide | 2.5 | None | 10 weeks to 4 months |
4. Discussion
Nonunion of a fracture is a devastating complication resulting from impaired bone healing.4,16 Such condition is characterised by pain and functional disability, which often leads to quality of life impairment.30 Patients often have various responses to the treatments of nonunion, making this condition a very difficult problem to treat. A second intervention is often necessary for treating such conditions; however, surgical procedures are often associated with numerous drawbacks such as prolonged hospital stay, expensive cost, etc. This suggests that a potential therapy that can treat nonunion with minimal adverse effects is urgently required.
Parathyroid hormone is an 84-amino acid secreted polypeptide and is one of the body’s most important calcium-regulating hormones. Although hyperparathyroidism is associated with bone loss, intermittent administration of PTH is known to increase bone mass, as the anabolic properties of PTH dominate its catabolic effects.4 Teriparatide, a PTH analogue, has been found to exert a catabolic effect on bone during daily administration; however, it gives an anabolic effect when intermittently administered. However in this review, we found that 53 (94.6%) of the subjects had achieved clinical union, although all studies administered teriparatide daily, not intermittently. This suggests that teriparatide may also give an anabolic effect when continuously administered. Coppola et al.31 found teriparatide was effective for treating nonunions in four cases after open fixation of lower limb fractures. The subjects had adequate bone callus in the site of nonunion, and they obtained clinical and radiographic union. Yu et al.2 administered teriparatide for 9 months to a 45-year-old male with femoral fracture nonunion. The drug was given once-daily with a dose of 20 μg per day. Moreover, there were no side effects.
PTH plays an important role in bone remodeling; it modulates the microenvironment of bone marrow and regulates osteogenic signaling pathways.2 In the present review, we found that 61 (95.3%) of 64 subjects, with mean time of initial fracture to teriparatide treatment ranging from 3 to 24.3 ± 17.8 months, developed complete union during the follow-up ranged from 3 to 24 months. Fifteen studies administered teriparatide 20 μg daily, while four studies gave weekly injection of 56.5 μg teriparatide. This is in line with previous studies investigating the effect of teriparatide in fracture healing. Bukata et al.32 administered 20 μg of teriparatide once-daily to patients with fractures of the spine or other extremities. Regardless of the fracture site, 141 subjects reported pain resolution at the fracture site within 12 weeks of starting teriparatide, and the rate of union was 93%. Aspenberg et al.33 investigated the effect of placebo compared with teriparatide administered in doses of 20 and 40 μg given daily to a population of female subjects with distal radius fractures. The median time to the first radiographic evidence of healing was 9.1, 7.4, and 8.84 weeks in the placebo group and groups treated with 20 μg and 40 μg of teriparatide, respectively. The mechanism behind this union might be explained below. The anabolic effect of teriparatide is attributable to the stimulation of osteoblasts, thus improving the bone architecture.34,35 It also accelerates fracture healing by improving the biomechanical properties of the fracture callus and by increasing endochondral ossification and bone remodeling in animal models.36 Nakajima et al.37 studied the molecular mechanism on how PTH improves fracture healing. They found that rats treated with PTH had earlier periosteal callus formation with more proliferating mesenchymal osteoprogenitor cells. PTH also resulted in the up-regulation of gene markers associated with osteoblast differentiation. Other studies have also suggested a role for PTH in endochondral bone healing, with increased cartilage volume and elevation of early markers of chondrogenic differentiation (such as Sox9) after administration of PTH.38,39 Other studies have reported that the anabolic effects of PTH on bone formation are mediated by IGF-1, which stimulates the proliferation and differentiation. Moreover, this factor also increases collagen synthesis.40, 41, 42, 43
This is the first systematic review of teriparatide in treating delayed union and non-union. This review included thirteen studies consisting of mostly case reports and series. In addition to its effectiveness in treating nonunion, there were no side effects occurred during the follow-up period, which suggests that teriparatide could safely be used for treating nonunion. Moreover, mechanisms by which teriparatide improves fracture healing in patients with delayed union and nonunion remains unclear. Therefore, further studies that investigate the molecular mechanisms regarding the anabolic effects of teriparatide are warranted in the future.
One limitation of this study is the data that were comprised of observational studies, which are prone to result in both systematic and random error.44 Therefore, we suggest that more randomised controlled trials are required to overcome the limitation of our study.
5. Conclusions
Existing evidence demonstrate that teriparatide may be a potential new treatment for delayed union and nonunion. We highly suggest the use of such drug, as it is highly effective and safe. However, these studies are limited by their few number of subjects and lack of controls. Further clinical studies are required to investigate the safety and efficacy of teriparatide for treating delayed union and nonunion.
Declaration of competing interest
None declared.
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