Leo Toussaint

Background: Osteoporosis (OP) is a skeletal disease involving the degeneration of bone structure, strength, and density resulting in an increased risk of fractures.¹ OP affects over 12% of US adults over 50 and causes over 2 million fractures with a cost of up to $17 million annually.² Risk factors associated with OP include female sex, substance use, excessive alcohol use, family history, and some pre-existing conditions.² Current treatment includes bisphosphonates such as alendronate, however, these drugs have GI and nephrotoxic side effects as well as making some musculoskeletal issues worse and being contraindicated in some patient populations such as those with renal insufficiency.² Exercise as a prevention/treatment of OP is promising as it has been shown that it can improve bone mineral density (BMD) and reduce the risk of falls.^1-3 Vascular endothelial growth factor (VEGF) could also play a role in bone growth/repair as it has been shown to increase vascularization and mineralization of bone tissue.⁴ These findings are promising, as exercise (via VEGF) could prove to be an effective non-pharmacological way of treating OP with minimal side effects.

 Objective: In this narrative review, we looked at the molecular impacts of exercise and VEGF on the growth of bones as a potential therapy or treatment for osteoporosis patients.

Search Methods: An online database search of PubMed of articles published between the years 2018 and 2024 was conducted using keywords such as “bone angiogenesis”, “exercise”, “VEGF”, and “osteoporosis”.

Results: Studies have shown that exercise increases osteoblast activity, promotes quicker bone formation, increases cortical thickness, and improves overall physical performance and strength.^5-6 Patients who underwent open-reduction internal-fixation surgery and went through an exercise routine on top of the normal physical therapy were found to have higher levels of bone growth and osteoblast activity at earlier days than the control group undergoing physical therapy.⁵ Exercise in post-menopausal women increased BMD and overall physical strength without any adverse side effects or injuries.⁶ VEGF was also found to increase BMD and osteoblast activity post-surgery in animal studies.^4,7 In bone grafts in rabbits and mice it was found that VEGF-treated bone grafts had much denser tissue vasculature, more mineralization, more bone density, and a higher number of osteoblasts.^4,7 Lastly, there have been studies that have shown a connection between exercise and increased circulating VEGF.^8-9 In a mouse study it was shown that circulating VEGF increased in aged mice following an 8-month exercise plan and that tissue biopsies of the aged mice were comparable to young mouse tissues.⁸ In a human study, circulating VEGF increased in elderly individuals following one 30-45 minute exercise routine.⁹

Conclusions: Exercise is a potential therapeutic agent in the treatment of osteoporosis. Although recommending exercise is already in practice, the true benefits have not fully been uncovered yet. Bone healing and mineralization requires the formation of new blood vessels that bring nutrients to the deprived tissue. Vascular endothelial growth factor is known to promote blood vessel growth. Other studies found that long-term exercise plans can also increase bone density, help broken bones heal, improve the overall physical ability of patients, and increase VEGF. Further studies could investigate the potential of exercise and VEGF treatment being combined to help treat/prevent osteoporosis in patients suffering from very low bone mineral density or fractures caused by osteoporosis.

Works Cited:

1. Tong X, Chen X, Zhang S, et al. The Effect of Exercise on the Prevention of Osteoporosis and Bone Angiogenesis. Biomed Res Int. 2019;2019:8171897.
2. Ensrud KE, Crandall CJ. Osteoporosis. Ann Intern Med. 2024;177(1):ITC1-ITC16.
3. Zhang S, Huang X, Zhao X, et al. Effect of exercise on bone mineral density among patients with osteoporosis and osteopenia: A systematic review and network meta-analysis. J Clin Nurs. 2022;31(15-16):2100-2111.
4. Largo RD, Burger MG, Harschnitz O, et al. VEGF Over-Expression by Engineered BMSC Accelerates Functional Perfusion, Improving Tissue Density and In-Growth in Clinical-Size Osteogenic Grafts. Front Bioeng Biotechnol. 2020;8:755.
5. Taufik NH, Tulaar ABM, Moesbar N, Ganie RA. The Effect of Isometric Exercise Plantar Flexor on Osteoblast Activity Measured by Bone Specific Alkaline Phosphatase and Callus Formation in a Patient Post Open Reduction Internal Fixation with Non-articular Tibia Fracture. Open Access Maced J Med Sci. 2019;7(20):3409-3415.
6. Watson S, Weeks B, Weis L, Harding A, Horan S, Beck B. High-Intensity Resistance and Impact Training Improves Bone Mineral Density and Physical Function in Postmenopausal Women With Osteopenia and Osteoporosis: The LIFTMOR Randomized Controlled Trial. J Bone Miner Res. 2019;34(3):572.
7. Chen Q, Wang Z, Yang C, et al. High resolution intravital photoacoustic microscopy reveals VEGF-induced bone regeneration in mouse tibia. Bone. 2023;167:116631.
8. Pourheydar B, Biabanghard A, Azari R, Khalaji N, Chodari L. Exercise improves aging-related decreased angiogenesis through modulating VEGF-A, TSP-1 and p-NF-Ƙb protein levels in myocardiocytes. J Cardiovasc Thorac Res. 2020;12(2):129-135.
9. Luttrell MJ, Mardis BR, Bock JM, et al. Effect of Age and Acute Exercise on Circulating Angioregulatory Factors. J Aging Phys Act. 2021;29(3):423-430.
10. Wazzani R, Pallu S, Bourzac C, Ahmaïdi S, Portier H, Jaffré C. Physical Activity and Bone Vascularization: A Way to Explore in Bone Repair Context?. Life (Basel). 2021;11(8):783.
11. Ribatti D, d’Amati A. Bone angiocrine factors. Front Cell Dev Biol. 2023;11:1244372.