Efficacy and Safety of Teriparatide in Improving Fracture Healing and Callus Formation: A Systematic Review

Fracture nonunion remains a great challenge for orthopedic surgeons. Some bone fractures don't heal promptly, resulting in delayed unions and nonunions, and there is a need for an additional surgical procedure. Previous research has shown that teriparatide, a type of synthetic parathyroid hormone, can promote the formation of callus and lead to healing in individuals with delayed or non-healing bone fractures. Limited systematic reviews exist that examine the use of teriparatide in cases of delayed healing or non-healing bone fractures, which have their limitations. In this review, we overcome those limitations by including prospective studies, retrospective studies, case reports, and case series together. A systematic search of the literature was conducted in both PubMed and Google Scholar up to September of the year 2022. The studies included in our research included adult patients (over the age of 16) diagnosed with delayed union or nonunion of any bone in the body (flat bone, long bone, short bone, or irregular bone). The studies were limited to those written in English. The outcomes that were tracked and recorded include the healing of the fracture and any negative side effects or adverse events. The initial search yielded 504 abstracts and titles. After reviewing these, 32 articles were selected for further analysis, which included 19 case reports, five case series, two retrospective studies, and six prospective studies. Studies included daily (20 micrograms) or weekly (56.5 micrograms) subcutaneous administration of teriparatide. The duration of follow-up for these studies varied from three to 24 months. Based on the available research, it appears that administering teriparatide subcutaneously is a safe treatment option for delayed healing and non-healing bone fractures, with very few to no reported negative side effects. Using teriparatide for induction of callus formation and treating delayed and nonunions is highly safe and effective.


Introduction And Background
About five to ten percent of bone fractures do not heal as they are expected to in the time interval they are normally supposed to heal [1,2]. This can lead to delayed healing or non-healing bone fractures, which require additional hospital treatment and can cause significant physical, mental, and financial difficulties for patients. Despite advances in treatment methods, many of the current options are surgical in nature and involve reopening the fracture site and risking post-operative infections, prolonging hospital stay, and other surgical complications. Therefore, there is a need for a more conservative treatment modality that can stimulate fracture unions with minimal intervention and minimal adverse effects.
Parathyroid glands located in the posterior region of the thyroid gland secrete the parathyroid hormone, which is also called parathormone. Parathormone is one of the key regulators of calcium homeostasis and the metabolism of calcium in the body. Although the parathyroid hormone is thought to stimulate the function of osteoclasts ("bone-eating cells"), causing bone resorption and bone loss, bone loss is observed only to be in hyperparathyroidism, which results in higher levels of circulating parathormone.
Intermittent administration of the parathyroid hormone (PTH) has been shown to increase bone mass due to 1,2 3, 4 5 6 5 its anabolic effects dominating the catabolic effects [3]. Teriparatide, a synthetic PTH analog, which contains the first 34 residues of parathyroid hormone (PTH 1-34), is often used for treating osteoporosis. Teriparatide is considered to be the most potent of osteoporosis therapies due to its marked anabolic effects [4]. The existing basic science data suggest teriparatide accelerates chondrocyte recruitment and differentiation, which are essential processes in early enchondral ossification [5,6].
Numerous clinical studies have reported the efficacy of teriparatide in promoting fracture healing. Teriparatide works by stimulating osteoblasts and reducing osteoblast apoptosis, resulting in an increased osteoblast life span [7]. Teriparatide also works by increasing callus formation and improving the mechanical strength of bone at the fracture site [8]. Most reviews in this area focus on osteoporosis; the present review is the most recent and systematic on teriparatide and its effect on bone healing [9].

Review Methods
This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines [10].

Participants
The studies that we analyzed in our research included adult patients (over the age of 16) diagnosed with delayed union or nonunion of any bone in the body (long bone, flat bone, short bone, or irregular bone) or treatment modality used for initial fracture treatment (surgical or conservative).

Interventions
The interventions studied included the administration of teriparatide via any route of administration (but generally by subcutaneous route) at any dose and frequency.

Outcomes
The outcomes measured and recorded were the healing of the fracture and any negative side effects or adverse events.

Study Characteristics
All types of study designs, such as case reports, case series, and retrospective and prospective studies, were included in the research.

Information sources
Our study utilized a systematic literature search with PubMed and Google Scholar to gather relevant articles. The first search was performed on September 10, 2022. The second search was conducted on September 25, 2022.

Search strategy
A combination of the following free words and Medical Subject Headings (MeSH) terms were used: "teriparatide", "parathyroid hormone", "PTH analogs", "delayed union", "nonunion", and "fracture healing". Boolean operators, including "AND" and "OR" were used. A systematic search of the literature was conducted in both PubMed and Google Scholar up to September 2022.

Literature Search
A total of 504 publications were retrieved based on our search criteria. Of these, 472 were excluded during the screening process, and 32 articles were finally included. To further illustrate the selected articles used, the PRISMA flowchart shows the process in more detail ( Figure 1) [10].

Study Characteristics
Out of the 32 articles reviewed, we identified 19 case reports, five case series, two retrospective studies, and six prospective studies. The number of participants in each study ranged from one to 159. In total, 572 participants were included in this review. The participants included both males and females. Table 3 shows the study characteristics of this systematic review.

Author(s)
Year of publication    Table 5 shows the diagnosis of patients included in the respective articles.

Discussion
Currently, teriparatide has been widely proven to be effective in treating osteoporosis. However, there is an ongoing debate over whether teriparatide can improve fracture healing. This is not the first systematic review to examine the effect of teriparatide on fracture healing [9]. Fracture nonunion and delayed unions are devastating complications resulting from impaired bone healing. These conditions are characterized by pain and functional limitations, often resulting in decreased quality of life. Patients often respond differently to treatment for nonunions, making this condition very difficult to treat. A comparison between the results of all the considered studies has been described in Table 6.
In addition to six prospective studies and two retrospective investigations, this evaluation includes 32 research, primarily case reports and case series. In conclusion, teriparatide was found to be effective in treating nonunion without any negative side effects during the follow-up period, indicating that using it to treat nonunion is safe. However, the specific ways in which it promotes healing in patients with delayed union and nonunion have yet to be fully understood. Therefore, future research that examines the molecular processes underlying teriparatide's anabolic actions is necessary. From the case reports considered in this review, we found that the subjects with delayed and nonunions had achieved clinical union. Most of the interventions in these case studies included daily administration of 20 mcg of teriparatide, which suggests that teriparatide, when administered continuously, may also have anabolic effects on improving fracture healing.
A case series by Coppola et al. reported that teriparatide was effective in treating four cases of nonunions after open reduction and internal fixation of lower limb fractures. The patients had sufficient bone growth at the site of the nonunion, and they achieved both clinical and radiographic union. This study adds to the growing body of evidence that suggests teriparatide may be effective in the treatment of nonunions of lower limb fractures [2].
Similarly, a case study by Yu et al. treated a 45-year-old male with a nonunion of a femoral fracture using teriparatide for nine months. The patient received a daily dose of 20 mcg of teriparatide, and the treatment resulted in a fracture union. Additionally, there were no reported side effects. This case adds to the evidence that teriparatide may be effective in treating nonunion of femoral fractures with a good safety profile [3].

Prospective Studies
A total of six prospective studies were included in this review article, and five out of six showed a positive result. A prospective study done by Almirol et al. showed a positive result. The teriparatide-treated group showed a greater tibia cortical area and thickness compared to the placebo-treated group as early as eight weeks of treatment [11]. Another study done by Aspenberg et al. also showed a positive result, with a clinically approved dose of 20 µg of teriparatide significantly reducing the median time required for healing compared with placebo treatment. The study found that a 20 µg dose of teriparatide had a positive effect on healing, while a 40 µg dose did not. Additionally, the 20 µg dose was found to have a highly significant impact on reducing the median time to healing compared to a placebo [12]. Bhandari et al. also conducted a prospective study which yielded a positive result [14].
A prospective study done by Kim et al. 2018, showed a negative result. The study found no difference between the two groups in terms of radiographic fracture healing at the final follow-up. The conclusion of the study was that based on the patients studied, short-term use of teriparatide did not reduce pain, improve radiographic signs of fracture healing, or decrease the rate of postoperative complications compared to a placebo in patients with intertrochanteric fractures [24].
A prospective study done by Saraf et al. showed a positive result. The study found that for delayed union fractures, the use of teriparatide was associated with a shorter healing time compared to the group treated with a placebo [36]. Another prospective study done by Kastirr et al. also showed a positive result after an average of 4.1 ± 1.5 (two to six) months after PTH treatment. The study found that 30 out of 32 patients who were treated with teriparatide for delayed union fractures experienced a stable bone consolidation at the nonunion site and were able to regain full weight-bearing capacity of the affected limb without experiencing pain. The mean time between the initial fracture and the PTH treatment was 24.3 ± 17.8 months [23].

Retrospective Studies
We included two retrospective studies in this review, both of which showed significant positive results by showing faster healing rates and lesser complication rates. The first retrospective study, done by Huang et al. (2015), showed that the mean union time was longer (14.3 ± 2.8 weeks versus 11.2 ± 1.6 weeks), the sliding of the lag screw was greater (9.6 ± 5.3 mm versus 2.2 ± 1.4 mm, p<0.001), there was more femoral shortening, and the study found that varus collapse was more severe in hips that did not receive teriparatide treatment compared to hips that were treated with teriparatide. The main conclusion of the study is that teriparatide improves the healing of fractures, reduces surgical and healing complications, and leads to better clinical outcomes at three and six months after surgery in elderly patients with unstable pertrochanteric fractures.
The second retrospective study, done by Kim (2019), showed that the mean time to fracture healing postoperatively was 14.8 weeks (SD 7.1) and 12.1 weeks (SD 6.4) in the placebo group and teriparatide group, respectively. The frequency of patients reporting postoperative complications was also markedly reduced in the teriparatide-treated groups. The overall conclusion is that short-term daily teriparatide used for osteoporosis treatment improved radiographic fracture healing of a hip fracture and reduced complication rates.

Case Reports and Series
According to Johansson's study, there were no improvements in radiographic signs of healing or clinical improvement in the group treated with short-term (four weeks) daily teriparatide (20 μg/day) in proximal humerus fractures. However, Baillieul et al. reported that when a three-month-old delayed union was started on daily treatment by teriparatide (20 micrograms per day, subcutaneous injection), after six months of treatment, the patient was asymptomatic and on CT, signs of bone re-mineralization were described [13].
Ochi et al. also reported a case of a 74-year-old woman with nonunion of a periprosthetic fracture after total knee arthroplasty, in whom bone union could not be achieved even after she underwent internal fixation and bone grafting twice; however, successful bone fusion was achieved after simple once-weekly administration of teriparatide for six months [31]. In a case series described by Saraf et al. done on 20 patients with fractures, all patients in the study were given 20 µg of teriparatide injections daily. The duration of treatment varied between two to four months, depending on the type of fracture and the time required for radiographic evidence of union. The study found that fractures treated with 20 µg of teriparatide showed early signs of union with significant callus formation, a decrease in the time required for radiographic union, and early rehabilitation of patients in all three groups [36].
Tsa and Hu reported a case of a 60-year-old woman with a right femoral shaft fracture who immediately underwent closed reduction and internal fixation surgery with intramedullary nailing showed no signs of healing for six months, and her condition was diagnosed as atrophic nonunion. Subsequently, teriparatide 20 micrograms/day was administered for six months subcutaneously, and a complete union was observed at the fracture site six months after discontinuing teriparatide [39]. Kastirr et al. also reported on a patient with a fracture in the lower leg that had not yet consolidated after seven months. After receiving therapy with 20 µg of teriparatide per day for eight weeks, the fracture had consolidated, and the patient was able to regain full weight-bearing capacity of the leg without experiencing pain and without any reported side effects. These cases suggest that teriparatide may be effective in promoting the healing of fractures that have not yet consolidated, and further research is needed to establish the efficacy and safety of teriparatide in these cases [22].
Matsumoto described a case report of the successful use of teriparatide to treat delayed union of a spine fracture in a patient with DISH without surgical intervention. The patient, a 70-year-old man, was treated with teriparatide and achieved union in two months without experiencing any adverse events. Six months after starting teriparatide, additional bone formation was observed, and the patient's lumbar instability had resolved [28]. Fukuda et al. also reported a 74-year-old female patient with atypical femoral fracture delayed unions, showing a union of bilateral femurs after three months of weekly once administration of teriparatide [17]. Chintamaneni S reported a case of the first successful use of teriparatide in the healing of a sternal nonunion fracture [16]. Many other case reports and case series have described the successful use of teriparatide in improving callus formation and healing fracture delayed union and nonunions, with no reported side effects [30][31][32][33][34][35][36][37][38][39][40][41]. These studies suggest that teriparatide may be effective in promoting the healing of fractures that have not yet consolidated, and further research is needed to establish the efficacy and safety of teriparatide in these cases.

Limitations
Our systematic review has limitations as we only used articles in English. This study contains case studies and case series as a majority, and only five randomized controlled trials were included. More prospective studies are needed to strengthen the evidence of teriparatide's efficacy in delayed treatment and nonunion.

Conclusions
By examining the various outcomes of teriparatide use, the current review intends to evaluate the effectiveness and safety of teriparatide in delayed union and nonunion, and its overall impact on fracture healing and callus formation. This systematic review has taken into consideration case studies, case series, and retrospective and prospective studies.
Existing evidence demonstrates that teriparatide may help in improving callus formation and promote fracture healing in cases of delayed union and nonunion. The use of this drug is highly suggested, as it is safe and highly effective when compared to surgical approaches risking postoperative infections and many other complications. Many more prospective studies are needed to strengthen the evidence regarding the efficacy of teriparatide in this regard.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.