Time to consider fracture nonunion an orphan disease? An update into pathophysiology, epidemiology and therapeutic solutions

Abstract

Purpose: Fracture non-union (FNU) is a rare complication of bone fractures where healing does not occur without surgical intervention. This paper aims to summarize the current knowledge on FNUs from an orphan disease perspective, and to provide an overview of existing and some emerging treatment options.

Methods: Literature review.

Results: Epidemiological data on FNUs are limited and vary by population and methodology. While previously an overall estimate of 5-10% of nonunion of fractures has been reported, large epidemiological studies performed in Spain, Germany, Scotland and USA, reported that the prevalence of FNUs is less than 5 cases per 10.000 inhabitants justifying the criteria for an orphan designation. There are no approved pharmacological treatments for FNUs, highlighting the need for effective therapies. Current methods rely on mechanical stabilization of FNUs using various instrumentation with or without autologous bone grafting. Combining mechanical intervention and autologous bone grafting raises healing rates from 60-70% to more than 80%, but graft harvesting causes additional injury at the donor site. Lately, a novel drug, OSTEOGROW-C combining rhBMP6 with the patient's own blood coagulum as a carrier, augmented by synthetic ceramics for biomechanical support has been developed for the treatment of FNU. Results of preclinical studies suggested that OSTEOGROW-C is superior to other OSTEOGROW formulations and commercially available products.

Conclusion: Due to its low prevalence, FNU can be considered a rare disease. A novel drug, OSTEOGROW-C, represents a promising and safe therapeutic solution for inducing FNU healing.

Keywords: Autologous blood as BMP carrier; Bone graft; Fracture healing; Fracture nonunion; OSTEOGROW-C; RhBMP6.

Fig. 1

Time to healing/probability of union of tibial fractures (modified from [–50])

Fig. 2

Histopathology and diagnostics of normal fracture healing, DU and FNU. A long bone fracture normally heals via initial formation of the hematoma (1) which initiates endochondral bone formation and gradual fracture healing within 16 to 20 weeks (A). In DU (B) and FNU (C), there is no healing progress at week 12 and the two conditions cannot be differentiated by x rays; a bone biopsy (2) can, however, reveal a cartilage with ossifying un-mineralized bone spicules in DU (5) in contrast to fibrous tissue scar in FNU (6). At 20 weeks, the normal fracture is united (4), DU starts to heal (7), but FNU remains unchanged (8). At 36 weeks, DU unites (9,10) while FNU remains ununited (11,12)

Fig. 3

(A) Critical size ulna defect (white arrows) in rabbits treated with rhBMP7 on bovine collagen (Osigraft) vs. OSTEOGROW. Modified from [152]. (B) MicroCT cross-sections and (C) 3D reconstructions of tested formulations in ulnar CSD model in rabbit. Modified from [174]

Fig. 4

Compassionate use patients treated with OSTEOGROW-A. (A) Patient (63 y) with a tibial FNU was treated with OSTEOGROW-A 2,5 years following two unsuccessful previous treatments, including an autologous bone graft from the iliac crest. The intramedullary nail (not shown) was replaced with an internal plate, followed by implantation of OSTEOGROW-A (2 mg rhBMP6 in 10 mL ABC supplemented with allograft bone (2 g of 2–5 mm trabecular bone chips from a Bone bank, Vienna, Austria)). X-ray at 5 weeks after surgery (left) shows the fracture gap (red arrow), while at 16 weeks, a significant new bone formation between the bone ends is visible on lateral (LL) view (red arrow); white arrows on the lateral and anteroposterior (AP) view indicate a mineralized bridging callus. (B) A patient (33 y) with distal femoral FNU that lasted 2 years was treated with OSTEOGROW-A (2 mg rhBMP6 in ABC + 2 g trabecular bone allograft from a Bone bank, Vienna, Austria). The intramedullary nail was replaced by a plate and OSTEOGROW-A was implanted within and around the FNU (left). An x-ray healing progress was observed towards week 16 and advanced healing at 24 weeks

Fig. 5

Use of OSTEOGROW-C in patient with recalcitrant humerus bone FNU. (A) Preoperative X-ray showing the original nonunion in 2010. The patient (female, 57 y) was unsuccessfully re-operated five times. (B) The vascularized fibular graft failed following the 5th surgery. (C, D) In Jan 2023 the patient received OSTEOGROW-C (2 mg rhBMP6 in 10 mL ABCwith 10 cc of β-TCP ceramic particles) into 4 cm long humerus defect. (E) X-ray image after 12 weeks indicating that OSTEOGROW-C induced new bone formation in the defect (green arrows). (F) CT image after 20 weeks indicating bone consolidation and remodeling (green arrows)