Teriparatide for Treating Delayed Union and Nonunion Fractures: A Systematic Review

Delayed or non-healing fractures occur in approximately 5–10% of cases and are associated with significant morbidity and healthcare burden. Many current treatments are surgical and carry risks such as infection and prolonged hospitalization, underscoring the need for conservative options to stimulate bone union. Parathyroid hormone (PTH), particularly in intermittent dosing, exerts anabolic effects on bone. Teriparatide (PTH 1-34) is a synthetic analog used for osteoporosis that may enhance fracture healing by stimulating osteoblasts, reducing osteoblast apoptosis, accelerating chondrocyte recruitment and differentiation during endochondral ossification, and increasing callus formation and mechanical strength at fracture sites. The research question addressed by this review is whether teriparatide improves healing outcomes in delayed unions and nonunions across various bones and treatment contexts, and whether it does so safely.

Basic science indicates intermittent PTH (1-34) increases callus formation and mechanical strength and prevents osteoblast apoptosis, supporting an anabolic mechanism relevant to fracture repair. Prior clinical work has documented teriparatide’s efficacy in osteoporosis and suggested potential benefits in fracture healing, though earlier reviews largely focused on osteoporosis. Reports include case studies and small series showing improved radiographic and clinical union across fracture types (e.g., femur, sacrum, odontoid, sternal), with common dosing at 20 µg daily and some weekly regimens (e.g., 56.5 µg). Evidence before this review was mixed in randomized settings but generally favorable in observational and case-based reports.

This systematic review followed PRISMA guidelines. Inclusion criteria: adult patients (>16 years) with delayed union or nonunion of any bone (long, flat, short, or irregular) regardless of initial fracture management (surgical or conservative). Intervention: teriparatide via any route, dose, and frequency (typically subcutaneous daily 20 µg or weekly regimens). Outcomes: fracture healing (clinical and/or radiographic) and adverse effects. Study designs: case reports, case series, retrospective and prospective studies. Information sources: PubMed and Google Scholar; searches conducted September 10, 2022 and September 25, 2022. Search terms used combinations of: “teriparatide,” “parathyroid hormone,” “PTH analogs,” “delayed union,” “nonunion,” and “fracture healing,” with Boolean operators AND/OR. A total of 504 records were identified; after screening, 32 articles met inclusion criteria. Language limited to English. Data extracted included study design, sample size, intervention details (dose, frequency, route, duration), fracture diagnosis, healing outcomes, time to union, and adverse events.

• Thirty-two studies were included: 19 case reports, 5 case series, 2 retrospective studies, and 6 prospective studies, totaling 572 participants across both sexes and a variety of fracture types.
• Overall, teriparatide was generally effective in promoting union in delayed unions and nonunions with minimal reported adverse effects. Prospective studies (6 total):
• Five of six showed positive effects. Almirol et al.: teriparatide increased tibial cortical area and thickness vs placebo by 8 weeks. Aspenberg et al.: 20 µg daily significantly reduced median time to radiographic healing vs placebo; 40 µg did not show benefit and had mild nausea in one patient. Bhandari et al.: mixed results noted in the review, with no reduction in revision surgery and no clear radiographic improvement vs placebo at 12 months despite 84% union in the teriparatide group. Saraf et al.: shorter healing time vs placebo in delayed unions. Kastirr et al.: 30/32 patients achieved stable consolidation and full weight-bearing without pain after 4.1 ± 1.5 months of treatment; mean time from initial fracture to PTH start was 24.3 ± 17.8 months. Kim et al. (2018): no difference vs placebo in intertrochanteric fractures with short-term weekly dosing. Retrospective studies (2 total):
• Huang et al. (2015): teriparatide group had shorter mean union time (11.2 ± 1.6 vs 14.3 ± 2.8 weeks), less lag screw sliding (2.2 ± 1.4 vs 9.6 ± 5.3 mm; p<0.001), less femoral shortening, and less varus collapse.
• Kim et al. (2019): mean time to healing 12.1 ± 6.4 weeks with teriparatide vs 14.8 ± 7.1 weeks with placebo; fewer postoperative complications with teriparatide. Case reports/series:
• Multiple reports across fracture locations (e.g., femoral shaft, distal femur, odontoid, sternal, sacral, acetabular, periprosthetic, humeral shaft) documented clinical and radiographic unions with daily 20 µg teriparatide for durations ranging from weeks to months, and some with weekly dosing (56.5 µg). Examples: Baillieul et al. (sacral stress fracture) showed CT-remodeling and symptom resolution by 6 months; Ochi et al. achieved union of a periprosthetic knee fracture nonunion after weekly teriparatide for 6 months; Kastirr et al. case achieved consolidation and full weight-bearing after 8 weeks of 20 µg/day; Yu and Guo reported union in femoral nonunion after 9 months of 20 µg/day without side effects. Safety:
• Adverse effects were rare and generally mild (e.g., mild nausea in one patient in Aspenberg et al.). The review reported no significant negative side effects during follow-up across included studies.

The findings support that teriparatide can promote healing in delayed unions and nonunions and may offer a safe, conservative alternative to reoperation, which carries infection and other surgical risks. Positive effects likely stem from teriparatide’s anabolic actions, including enhanced osteoblast survival and activity, accelerated endochondral ossification, and increased callus formation and mechanical strength. While most prospective and observational data favor benefit, one randomized study with short-term weekly dosing showed no improvement, indicating that dose and regimen (daily 20 µg vs weekly dosing) and fracture context may influence outcomes. The consistent clinical unions in case-based literature and improved radiographic/mechanical metrics in nonrandomized studies suggest clinical relevance across varied fracture types. However, heterogeneity in study designs, dosing schedules, and endpoints, along with limited high-quality randomized evidence, temper definitive conclusions. Further research into molecular mechanisms and optimal dosing regimens is warranted to clarify patient selection and maximize efficacy.

This systematic review synthesizes case reports, case series, and retrospective and prospective studies evaluating teriparatide for delayed union and nonunion. Existing evidence indicates teriparatide can enhance callus formation and accelerate fracture healing in many such cases, with a favorable safety profile. As a conservative modality, teriparatide may reduce reliance on surgical interventions. Future work should include more high-quality prospective randomized trials to define optimal dosing, treatment duration, fracture types most likely to benefit, and mechanistic underpinnings of its anabolic effects in fracture repair.

The review was limited to English-language publications. The majority of included studies were case reports and case series, with only a small number of randomized controlled trials, limiting the strength of evidence. Additional limitations include variability in dosing regimens, treatment durations, fracture types, and outcome measures across studies, and the lack of detailed mechanistic data within clinical contexts.