Evel Knievel (USA, b. Robert Craig Knievel), the pioneer of motorcycle long jumping exhibitions, had suffered 433 bone fractures by end of 1975. In the winter of 1976, he was seriously injured during a televised attempt to jump a tank full of sharks at the Chicago Amphitheater.[i] 

Most of us aren’t as prolific as that.

The United states, Canada and Europe alone spent $48 billion in treating osteoporosis related fractures although this number doesn’t count the economic burden due to loss in productivity. It is estimated that by 2050 ca 21 million hip fractures would occur globally which will be leading cause of premature death and disability.

A fracture is a breach in the structural continuity of the bone cortex, with a degree of injury to the surrounding soft tissues.[ii] Following the fracture, secondary healing begins, which consists of four steps:

1. Hematoma formation

2. Fibrocartilaginous callus formation

3. Bony callus formation

4. Bone remodeling

cal·lus

· MEDICINE

the bony healing tissue which forms around the ends of broken bone.

Failed or delayed healing can affect up to 10% of all fractures and can be due to various factors like comminution, infection, tumor, and disrupted vascular supply.

Primary bone healing is the reestablishment of the cortex without the formation of a callus. It occurs if a fracture is adequately "fixed" through reduction, immobilization, and rehabilitation. Secondary bone healing, as described above, occurs through the formation of a callus and subsequent remodeling.

By reducing and fixating, the clinician moves the two ends of the fracture into close apposition, which results in the minimal formation of granulation tissue and callus. 'Cutting cones' of osteoclasts cross the fracture site to the resorbed damaged bone, and 'forming zones' of osteoblasts lay down new bone.[iii]

Statistics

On average, every person will experience two broken bones over the course of a lifetime. Vertebral or spinal fractures are the most common fractures occurring in 30-50% of people over the age of 50 and result in significantly increased morbidity and mortality. Hip fractures, while occurring less frequently, are the most devastating fractures as 20% of those who suffer from a hip fraction die within 6 months.[iv]

In the US there are about 2 million fractures each year, including fractures in patients suffering from osteoporosis. The majority of these heal normally. However, some fractures are associated with a high risk of delayed union, non-union, and other complications due to risk factors such osteoporosis, diabetes and/or smoking. In fact, 5% to 15% of all fractures result in impaired healing or non-union. This number is likely to increase due to the increase in average lifespan expectancy in many countries and, hence, a sharp increase of fractures caused by osteoporosis and other risk factors such as diabetes and smoking is anticipated.

The costs associated with osteoporotic fractures are predicted to rise markedly in the next 40 years. In Europe, the total direct costs are estimated to increase from 36 billion EUR in 2005 to 77 billion EUR in 2050.

History

Humans have never been immune from injury, and doubtless the practice of bone-setting was not unfamiliar to our most primitive forebears.

The earliest examples of the active management of fractures in humans were discovered at Naga-ed-Der (about 100 miles north of Luxor in Egypt) by Professor G. Elliott Smith during the Hearst Egyptian expedition of the University of California in 1903. Two specimens were found of splinted extremities. One was an adolescent femur with a compound, comminuted midshaft fracture that had been splinted with four longitudinal wooden boards, each wrapped in linen bandages. A dressing pad containing blood pigment was also found at approximately the level of the fracture site. The victim is judged to have died shortly after injury, as the bones show no evidence whatsoever of any healing reaction.[v]

Naga ed Deir type. Hieroglyphic incisions and an offering scene. With original paint.

On this offering stele is seen the mayour Inheretnakht sitting as an old man in front of a well filled offering table. Above Inheretnakht is a list of the things he wishes to have access to in the tomb, namely (from right to left): a thousand of ceremonial jars with water, a thousand loaves of bread, a thousand jars of beer, a thousand oxen, a thousand fowl, a thousand gazelles and a thousand antelopes. Behind him stands his wife, Sehetepu, "whom he loves". Opposite stands the same Inheretnakht, but here as a young and strong man.

The second specimen was of open fractures of a forearm, treated by similar splints, but in this case a pad of blood-stained vegetable fiber (probably obtained from the date palm) was found adherent to the upper fragment of the ulna, evidently having been pushed into the wound to stanch bleeding. Again, death appears to have occurred before any bone healing reaction had started.

A and B, Specimen of a fracture of an adolescent femur from circa 300 bc , excavated at Naga-ed-Der in 1903. This injury was an open fracture, and the absence of any callus (arrow in A) indicates early death.

Quince Therapeutics

Despite the need for improvement in the treatment for fracture repair, methods for treating fractures have changed little in recent decades. Systemic delivery of fracture-homing bone anabolics holds great promise as a therapeutic strategy in this regard. Here we report the design of a fracture-targeted peptide comprised of a payload (Aboloparatide) that binds and activates the parathyroid hormone receptor (PTHR1) and is linked to a targeting ligand comprised of 20 D-glutamic acids (D-Glu20) that directs accumulation of the payload specifically at fracture sites.[vi]

While some fractures heal without major intervention, most require surgery, often including insertion of screws, rods or plates, or implantation of grafts.[vii]

This targeted delivery results in reduction of fracture healing times to <1/2 while creating repaired bones that are >2-fold stronger than saline-treated controls in mice. Moreover, this hydroxyapatite-targeted peptide can be administered without detectable toxicity to healthy tissues or modification of healthy bones in dogs. Additionally, since similar results are obtained upon treatment of osteoporotic and diabetic fractures in mice, and pain resolution is simultaneously accelerated by this approach, we conclude that this fracture-targeted anabolic peptide displays significant potential to revolutionize the treatment of bone fractures.[viii]

Abaloparatide

Recently, aboloparatide, a PTHrP analogue has been approved in the United States for the treatment of osteoporosis and is under review by the European authorities.[ix]

The complete sequence of the peptide is H-AVSEHQLLHDKGKSIQDLRRRELLEKLL-AibKLHTAEIRATSEVSPNS-OH.

Conclusion

Unless someone else picks this up, it will remain only potential. Quince apparently does not have any designs of furthering the development of the active agent themselves.

References

[i] https://www.guinnessworldrecords.com/world-records/most-broken-bones-in-a-lifetime#:~:text=Evel%20Knievel%20(USA%2C%20b.,sharks%20at%20the%20Chicago%20Ampitheater.

[ii] https://www.ncbi.nlm.nih.gov/books/NBK551678/

[iii] Marsell R, Einhorn TA. The biology of fracture healing. Injury. 2011 Jun;42(6):551-5.

[iv] https://www.osteo-pharma.com/bone-fracture-facts/#:~:text=In%20the%20US%20there%20are,majority%20of%20these%20heal%20normally.

[v] https://musculoskeletalkey.com/the-history-of-fracture-treatment/

[vi] Stewart A. Low, Jeffery J. Nielsen, Cheyanne M. Coakley, Mini Thomas, Ephraim U. Mbachu, Christopher L. Chen, Yava Jones-Hall, Madeleine I. Tremblay, Jonathan R. Hicks, Philip S. Low, An engineered dual function peptide to repair fractured bones, Journal of Controlled Release, Volume 350, 2022, Pages 688-697

[vii] D. Karataglis, S.I. Stavridis, G. Petsatodis, P. Papadopoulos, A. Christodoulou

New trends in fixation of proximal humeral fractures: a review

Injury, 42 (2011), pp. 330-338

[viii] https://www.sciencedirect.com/science/article/pii/S0168365922005429?via%3Dihub

[ix] https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/abaloparatide