Bone growth stimulation

Adjuncts in bone healing for Sports Medicine

The purpose of this article is to give a background of the bone healing adjuncts available and how to navigate the heterogenous and often biased literature on this topic.

Description:

There are 6 potential types of bone stimulation for use as adjunct to innate bone healing:

1) Low intensity Ultrasound (LIPUS)

2) Extracorporeal Shockwave

3) Electrostimulation (Direct current, capacity coupling, inductive coupling/pulsed electromagnetic fields)

4) Low Level Laser Therapy

5) Nutrition

6) Medication

Considerations for using these adjuncts and reviewing literature:

– Fracture type/bone injury: Fracture location, acute fracture v. chronic fracture, surgically fixated bone, non-union non surgical v. non-union surgical, stress fracture/reaction, bone edema, osteonecrosis

– Intervention: Location of application, dose, time applied, frequency of treatment, duration of treatment, Invasive v. non-invasive, cost of intervention ($3,195 – $5,495 CAD) (See resources section)

– Outcomes:  Patient reported outcomes (pain, function), radiographic measures of healing (xray v. CT)

Types of bone growth stimulation:

 

1) Low Intensity Pulsed Ultrasound (eg. Exogen, Osteotron, Orthofix AccelStim, Melmak)

Definition: Also known as low intensity pulsed ultrasound (LIPUS) – uses low intensity ultrasound waves, theoretically stimulating bone growth via micromotion in the area of bone exposed. (1,2)

Pros/Cons:  Noninvasive

Energy: 1.5MHz to 3MHz

Duration:  Application 20 min/day,  2-6 months (1)

Several individual studies report benefit in use for non-union fractures, however

Evidence: Cochrane review 2023 – finding that treatment “probably makes no difference to the number of bones that heal much later than we expect” (7)

Figure 1 – Exogen

Figure  2 – Osteotron

Figure 3 – Orthofix AccelStim

Figure 4 – Melmak

2) Extracorporeal Shockwave Therapy

Definition:  A treatment modality used to treat kidney stones (lithotripsy) and tendinopathies.   Shockwaves are pulses of pressure administered over small focal areas.  The concentrated shockwave is expressed as a energy flux density in mJ/mm2.  The shockwaves can be made by electromagnetic, electrohydraulic, piezoelectric or radial pulse sources.  The focused 3D administration of shockwave energy is proposed to affect tissue calcification as well as other local effects including hyperstimulation of nociceptors. (12)

Pros/Cons:  Non-invasive

Energy: Mean 0.4 – 0.62 mj/mm2, Pulses: 1500-6000 (8)

Duration: Mean 1-4 treatments

Evidence:  Limited evidence – meta-analysis suggest that it may reduce pain in short-term associated with fracture without significant effect on bone union.(8)

Another article reported better return to sport timeline for bone stress injuries with using ECSW at treatment, however it should be noted that 30% of the participants in that study had a bone stress injury at a different site within a year of treatment. (11)

3) Electrostimulation (EStim – 3 main types)

Definition:  Using electrical energy to stimulate bone to promote new bone growth. Rubinacci et al. demonstrated in 1988 that bone is formed under electronegative potentials and resorbed under electropositive potentials.  Below are the three types of electrostimulation and the typical dosages used. (2,3)

A) Direct current (eg. Osteogen, EBI Bone Healing System)  This technique involves surgical implantation of cathodes that are placed in direct contact with the injured bone.  The anode is typically attached to the skin.  The energy transfer is thought to stimulate osteogenesis through change in biochemical make up of the direct environment (decreased oxygen, increased pH and hydrogen peroxide). (1,2)

Pros/Cons:  Invasive – Requires direct contact with bone, carries risk of infection, skin irritation

Energy: Current 5-40 microamp

Evidence:  No randomized direct current trials

Figure 5 – Osteogen

B) Capacity Coupling (eg. Orthopak)

Definition:  In this technique, 2 electrodes are placed on the skin on either side of the fracture site.  Using an alternating current then creates an electrical field across the fracture site, theoretically stimulating bone growth. (1,2)

Pros/Cons:  Noninvasive – skin irritation from the electrode pads is possible (1)

Energy:  Electrical fields of 0.1-10mV/cm stimulate bone growth in vitro

Evidence:  A single randomized control trial by Scott and King, 1994 of 23 patients demonstrated that 55% nonunions healed compared to 8% placebo (4,5)

Figure 6 – Orthopak

C) Inductive coupling/pulsed electromagnetic fields (PEMF) (eg. CMF (Donjoy), Fintek, Physiostim)

Definition:  This technology involved creating an electromagnetic field at the fracture site.  The electrical force is varied through time and thought to mimic mechanical stress.  In vitro studies demonstrate osteogenesis resulting from PEMF. (1, 2)

Pros/Cons:  Noninvasive  – Non compliance may be the biggest issue because of the length of time manufactures recommend unit be attached to patient. (1)

Energy:  Magnetic fields from 0.1 to 20G, Electrical fields of 1 to 100mV/cm within bone

Duration:  Application 30min/d – to 20 h/d

Evidence:  Mollon et al. 2008 metanalysis (level 1) failed to show efficacy (6)

Figure 7 – CMF (Donjoy)

Figure 8 – Fintek

Figure 9 – Physiostim (Orthofix)

4) Low Level Laser Therapy (LLLT)/Photobiomodulation
Definition:  Low level laser therapy is a treatment that used to promote bone healing by influencing molecular pathways involved in bone generation and repair. It may be particularly useful in the early stages of the bone repair process and can be useful in treating inflammatory conditions like osteoarthritis.

Pros/Cons: Non-invasive

Energy:  5-100 mW,  power density 0.5-30 J/cm2, wavelength 500-1000 nm (13)

Duration: Irradiation time 3-1440s, repetition rate 1-60 (13)

Distance from sample 0-14 cm (13)

Evidence:  There are limited studies on humans, most of evidence is invitro or on rats.  There is some low-level evidence suggesting that it may have benefit and pain reduction and physical function, but there is no evidence that shows any significant differences observed in fracture healing (13).
Further high quality RCTs are needed to establish the effectiveness and safety of this modality in fracture treatment. This may prove challenging, as it is believed that effectiveness may be highly dependent on dosimetric parameters and a standardized protocol must be developed to optimize treatment outcomes. (14)

5) Nutrition

It is known that calcium and Vitamin D play an important role in bone health, osteoporosis management, and fracture prevention, but the role of Vitamin D and calcium supplementation in bone healing is more controversial. (15)
Research on this topic in human studies is generally inconclusive, but research in animal models shows a positive influence of Vitamin D on bone regeneration. More research needs to be completed to determine the precise role and effectiveness of calcium and Vitamin D supplementation. (16)  With athlete either suffering from stress fractures or repetitive fractures it may also benefit the athlete to have a nutritionist consultation to ensure dietary intake is sufficient for their level of activity.

6) Medications

There are several medications that have been considered as possible adjuvant medications for bone healing. A meta-analysis conducted in 2023 found that there was no convincing evidence for bisphosphonates, statins, monoclonal antibodies, statins, strontium ranelate, ibuprofen, calcium or vitamin D supplementation in bone healing.

Calcitonin:
There is some evidence to suggest that calcitonin may have a positive impact. (17)   Calcitonin is a hormone that inhibits osteoclasts. In studies investigating the impact of intranasal calcitonin (200 IU daily for 3 months) in patients with acute hip
fractures treated with internal fixation, and on bone healing following internal fixation of mandibular fractures, there were statistically significant improvements in bone fusion,
and pain and radiological bone healing, respectively. (18,19)

Teriparatide: Teriparatide is a parathyroid hormone analog. There are some studies that suggest that it enhances callus formation and mechanical strength in fractures (17).
There is evidence that has shown reduced time to union in observational studies in surgically managed intertrochanteric fractures. Conversely, there are other clinical
trials, including ones on postmenopausal women with distal radius fractures and proximal humerus fractures, that showed no significant improving time(20,21). A
randomized control trial (RETURN) is currently planned to study teriparatide in stress fracture healing in young adults(22).

Bisphosphonates: Studies in bisphosphonates show no significant effect on fracture healing time but increase the changes in BMD and reduce bone synthesis and
resorption markers. There may be benefit in the correct patient in using bisphosphonates after a fracture.(17,23)

Iloprost: Iloprost is a prostacyclin mimetic, and used to as a vasodilator. IV Iloprost infusions have been shown to have an impact on bone marrow edema syndrome in the
proximal femur in the areas of pain, improvement of function, and MRI-compared improvement of the amount of edema. This evidence is based on only 109 patients over
mostly retrospective analyses, and case reports, prospective studies, and not randomized clinical trials. (24)

PDE-5 Inhibitors: There is evidence to suggest that PDE-5 inhibitors influence bone union and bone regeneration in mouse models, but to date there is no research studying these medications in bone healing in humans. (25,26)

Summary:

There are several considerations to keep in mind when considering using bone stimulation for the athlete with a fracture.   When reviewing literature, keep in mind the specific fracture type and location of your athlete.   Consider the cost of the device or medication (in thousands of dollars) and who will cover it:  Insurance, athlete’s organization/club AND/or the athlete themselves.  If choosing a stimulator it is essential that the device be applied accurately to the surface anatomy overlying the fracture site.  Consider using a skin marker with xray to define the location, an alternative option would be using US if fracture is visible to confirm site of bone stimulator application.  Depending on fracture type, location follow up could be determined in weeks to months with follow up imaging options being either xray or CT.

Dr. Max Stone and Dr. Neil Dilworth (2024/7/2 – PR AF)

References:

1. Cook JJ, Summers NJ, Cook EA. Healing in the new millennium: bone stimulators: an overview of where we’ve been and where we may be heading. Clin Podiatr Med Surg. 2015 Jan;32(1):45-59. doi: 10.1016/j.cpm.2014.09.003. PMID: 25440417.
2. Kuzyk PR, Schemitsch EH. The science of electrical stimulation therapy for fracture healing. Indian J Orthop. 2009 Apr;43(2):127-31. doi: 10.4103/0019-5413.50846. PMID: 19838360; PMCID: PMC2762253.
3. Rubinacci A, Black J, Brighton CT, Friedenberg ZB. Changes in bioelectric potentials on bone associated with direct current stimulation of osteogenesis. J Orthop Res. 1988;6:335–45.
4. https://www.hmpgloballearningnetwork.com/site/podiatry/bone-stimulation-nonunions-what-evidence-reveals#:~:text=Currently%2C%20there%20are%20three%20main,extracorporeal%20shockwave%20therapy%20(ESWT).
5. Scott G., King JB. A prospective, double-blind trial of electrical capacitive coupling in the treatment of nonunion of long bones. J Bone Joint Surg. 1994; 76(6):820-826.
6. Mollon B, da Silva V, Busse JW, Einhorn TA, Bhandari M. Electrical stimulation for long-bone fracture-healing: a meta-analysis of randomized controlled trials. J Bone Joint Surg Am. 2008;90:2322–30
7. Searle HK, Lewis SR, Coyle C, Welch M, Griffin XL. Ultrasound and shockwave therapy for acute fractures in adults. Cochrane Database Syst Rev. 2023 Mar 3;3(3):CD008579. doi: 10.1002/14651858.CD008579.pub4. PMID: 36866917; PMCID: PMC9983300.
8. Garcia TA, de Andrade ALL, Von Keudell AG, Azevedo LP, Belangero WD. No dose response effect in shockwave therapy applied to bone conditions: a systematic review, meta-analysis and meta-regression. J Orthop. 2023 Nov 23;49:90-101. doi: 10.1016/j.jor.2023.11.016. PMID: 38094979; PMCID: PMC10714328.
9. Bhavsar MB, Han Z, DeCoster T, Leppik L, Costa Oliveira KM, Barker JH. Electrical stimulation-based bone fracture treatment, if it works so well why do not more surgeons use it? Eur J Trauma Emerg Surg. 2020 Apr;46(2):245-264. doi: 10.1007/s00068-019-01127-z. Epub 2019 Apr 6. PMID: 30955053.
10. Ebrahim S, Mollon B, Bance S, Busse JW, Bhandari M. Low-intensity pulsed ultrasonography versus electrical stimulation for fracture healing: a systematic review and network meta-analysis. Can J Surg. 2014 Jun;57(3):E105-18. doi: 10.1503/cjs.010113. Erratum in: Can J Surg. 2014 Oct;57(5):297. PMID: 24869616; PMCID: PMC4035413
11. Beling A, Saxena A, Hollander K, Tenforde AS. Outcomes Using Focused Shockwave for Treatment of Bone Stress Injury in Runners. Bioengineering (Basel). 2023 Jul 25;10(8):885. doi: 10.3390/bioengineering10080885. PMID: 37627770; PMCID: PMC10451564.
12. Speed C. A systematic review of shockwave therapies in soft tissue conditions: focusing on the evidence. Br J Sports Med. 2014 Nov;48(21):1538-42. doi: 10.1136/bjsports-2012-091961. Epub 2013 Aug 5. PMID: 23918444.
13. Berni, M. et al. The Role of Low-Level Laser Therapy in Bone Healing: Systematic Review. Int J Mol Sci 24, Preprint at https://doi.org/10.3390/ijms24087094 (2023)
14. Neto, F. C. J. et al. Effects of photobiomodulation in the treatment of fractures: a systematic review and meta-analysis of randomized clinical trials. Lasers Med Sci 35, 513–522 Preprint at https://doi.org/10.1007/s10103-019-02779-4 (2020)
15. Gorter, E. A., Hamdy, N. A. T., Appelman-Dijkstra, N. M. & Schipper, I. B. The role of vitamin D in human fracture healing: A systematic review of the literature. Bone 64, 288–297 Preprint at https://doi.org/10.1016/j.bone.2014.04.026 (2014)
16. Chiavarini, M., Naldini, G. & Fabiani, R. The Role of Diet in Osteoporotic Fracture Healing: a Systematic Review. Curr Osteoporos Rep 18, 138–147 Preprint at https://doi.org/10.1007/s11914-020-00573-8 (2020)
17. Migliorini, F. et al. Pharmacological agents for bone fracture healing: talking points from recent clinical trials. Expert Opin Investig Drugs 32, 855–865 Preprint at https://doi.org/10.1080/13543784.2023.2263352 (2023)
18. Huusko, T. M. et al. Randomized, double-blind, clinically controlled trial of intranasal calcitonin treatment in patients with hip fracture. Calcif Tissue Int 71, 478–484 (2002).
19. Roy, A. et al. Evaluation of the efficacy of salmon calcitonin nasal spray on bone healing following open reduction and internal fixation of mandibular fractures — A randomized controlled trial. Journal of Cranio-Maxillofacial Surgery 49, 1151–1157 (2021).
20. Aspenberg, P. et al. Teriparatide for acceleration of fracture repair in humans: A prospective, randomized, double-blind study of 102 postmenopausal women with distalradial fractures. Journal of Bone and Mineral Research 25, 404–414 (2010).
21. Johansson, T. PTH 1-34 (teriparatide) may not improve healing in proximal humerus fractures A randomized, controlled study of 40 patients. Acta Orthop 87, 79–82 (2016).
22. Carswell, A. T. et al. Teriparatide and stress fracture healing in young adults (RETURN – Research on Efficacy of Teriparatide Use in the Return of recruits to Normal duty): study protocol for a randomised controlled trial. Trials 22, 1–18 (2021).
23. Gao, Y. et al. The Effect of Bisphosphonates on Fracture Healing Time and Changes in Bone Mass Density: A Meta-Analysis. Front Endocrinol (Lausanne) 12, Preprint at https://doi.org/10.3389/fendo.2021.688269 (2021)
24. Zippelius, T. et al. The Use of Iloprost in the Treatment of Bone Marrow Edema Syndrome of the Proximal Femur: A Review and Meta-Analysis. J Pers Med 12, Preprint at https://doi.org/10.3390/jpm12111757 (2022)
25. Menger, M. M. et al. Sildenafil, a phosphodiesterase-5 inhibitor, stimulates angiogenesis and bone regeneration in an atrophic non-union model in mice. J Transl Med 21, (2023).
26. Toğral, G., Arikan, M., Korkusuz, P., Hesar, R. H. & Fatih Ekşioğlu, M. Positive effect of tadalafil, a phosphodiesterase-5 inhibitor, on fracture healing in rat femur. Eklem Hastaliklari ve Cerrahisi 26, 137–144 (2015).

 

Resources for Devices:

Online stores:

Orthomed.ca (Osteotron $3,900, Fintek $4,495, Orthofix spinal $5,995, CMF spinalogic $3,700, CMF $3,500, Physiostim $5,495)

Physiostore.ca (Donjoy CMF stilmulators $3,195 bone, $3,395 spine)

Orthohealth.ca (Osteotron IV)