Bone hormones - a complex web

Bone is a living tissue that not only mechanically supports the body and protects vital organs, but also produces blood cells, stores minerals, and impacts endocrine regulation, with skeletal muscle also being an important component of bone health, with age-related degradation of muscle mass being a continuous process.

So many factors contribute to reduced bone quality – aging for one (tell me about it 🙄), medications, menopause (tell me about it again 🙄), and let’s not forget an inflamed, disrupted gut, poor liver/kidney function, and IR. But did you also know that a complex network of regulatory hormones modulate and support the skeletal system and bone health? The body’s hormones operate within a web of interconnection impacted by many factors, ultimately affecting the balance, function and health of body systems, and the skeletal system is no exception; multiple hormones modulate and support bone health - even gelding our boys can affect their bone health as it changes their sex hormones for a lower sex drive, aka hypogonadism.

Responding to changes in blood calcium and phosphorous levels, these regulatory hormones affect the formation and turnover of bone throughout the life stages, which makes supporting the lifelong bone remodeling process, maintaining or influencing bone homeostasis, essential for optimal bone health.

• Parathyroid hormone (PTH) - this calcium-regulating hormone controls the level of calcium in the blood and stimulates both resorption and formation of bone.

• Calcitriol (1,25 dihydroxy vitamin D) - also a noted calcium-regulating hormone, calcitriol is produced from vitamin D and is required for calcium absorption.

• Calcitonin - calcitonin protects against excessive blood calcium levels during early life by inhibiting bone turnover and decreasing reabsorption.

• Sex hormones - estrogen is a key regulator of bone remodeling, with testosterone important for skeletal growth.

• Growth hormones - growth hormone and its production of the insulin-like growth factor (IGF-1) influences bone formation.

• Thyroid hormones - these hormones are required for skeletal maturation and influence adult bone maintenance.

• Cortisol - large amounts of this adrenal gland hormone block bone growth, with glucocorticoid-induced osteoporosis being the most common secondary cause of osteoporosis.

• Insulin - important for bone growth, insulin signalling regulates both bone formation and resorption.

• Leptin - this circulating hormone has direct and indirect influences on bone metabolism.

And then there's the mitochondria connection

The equine bone fragility syndrome (BFS) or silica-associated osteoporosis (SAO) is a chronic and progressive disorder of horses characterised by increased respiratory issues, exercise intolerance, skeletal deformation, lameness, stiffness, fractures, low bone mass and deterioration of bone tissue. Sarcopenia, aka muscle-wasting, is a progressive decline of muscle mass with loss of strength or physical performance, common in our senior horses that gradually results in overall weakness.

There’s now growing evidence indicating that both disorders share many common biological pathways – there’s even a newly identified age-related musculoskeletal syndrome termed 'osteosarcopenia', highlighting the pathologic connections between simultaneous bone and muscle disorders. It’s characterised by porous and fragile bone as well as low muscle mass and function, and can contribute to an increased risk of falls, fractures, and dare I say it, mortality.

So, it’s no surprise to learn that the body’s mitochondria play an essential role in the health of the bone-muscle unit. Mitochondrial function and quantity are important in the maintenance of osteoblasts and osteoclasts in bone and for optimal function of myocytes in muscle. A recent study focusing on mitochondrial performance suggests that mitochondrial dysfunction impairs bone formation (osteogenesis), increases osteoclast activity, and accelerates age-related bone loss.

Related to overall muscle aging, mitochondria are central regulators; specifically, the loss of mitochondrial integrity in myocytes has been recognised as a potential factor in age-related muscle degeneration.

Connecting Musculoskeletal & Mitochondrial Health

Senescence - the condition or process of deterioration with age; loss of a cell's power of division and growth.

Cellular senescence has been implicated in the progressive, age-related loss of function across various body tissues, including muscle and bone, and the quality of mitochondrial performance is a key component of senescence, with impaired energy metabolism and dysregulated mitochondrial homeostasis both contributing to the negative impact of senescence.

Which means … when we have sub-optimal mitochondrial quality and function, musculoskeletal health is negatively impacted:

• Mitochondrial bioenergetics regulate stem cells in bone homeostasis, indicating that compromised energy metabolism and oxidative stress contribute to age-related stem cell dysfunction in bone.

• Mitochondrial quality plays an important role in maintaining muscle health, with dysfunction linked to age-related muscle atrophy and sarcopenia.

Studies are now suggesting that specifically targeting mitochondrial health hold promise for improving musculoskeletal function during aging. A 2020 study also investigated the beneficial effect of the aforementioned butyrate on mitochondrial pathways and function, with results showing that butyrate promoted mitochondrial antioxidant enzymes and energy metabolism, preserved bone microstructure and calcium homeostasis, and activated bone metabolism, reversing bone loss. Yet more evidence as to why the cellulose fibre in stemmy hay is so crucial to provide the fibre necessary for the fermentation process of the hindgut and production of those all-important VFAs.

Lifestyle-based support

Lifestyle approaches can help restore hormonal balance - no surprise that an anti-inflammatory diet is a priority, hence avoiding ultra-processed feeds alongside stress management. In addition to a nutrient-dense diet, specific minerals and nutraceuticals help to positively impact bone density and quality - calcium and magnesium are vital, alongside vitamin D from the great outdoors, as it helps regulate the amount of calcium and phosphate in the body. Finally, ensuring the omega-3 EFAs are balanced to the levels in forage (all explained in our Linseed page).

Feeding the appropriate cellulose fibre (from hay) through the hindgut is crucial as well; as well as the hindgut biome producing the three volatile fatty acids – butyrate, acetate and proprionate – all naturally derived from the fibre fermentation that create the horse’s energy, compelling results from a 2020 animal study suggest that butyrate is required to stimulate bone formation and increase bone mass, highlighting the relationship between how maintaining a healthy gut microbiome optimises bone health.

And another No Surprise – exercise! Other studies have suggested that exercise increases levels of PGC-1alpha, which regulates mitochondrial biogenesis and reduces the loss of skeletal muscle mass through the PGC-1alpha/SIRT1 signaling pathway. In other words (and plainer English) exercise promotes the remodeling of muscle tissue. 😉 Apparently, endurance training is of particular benefit, as it improves energy metabolism, metabolic flexibility and muscle quality.

Additional therapies that may help enhance muscle strength include increasing quality protein - have a look at Agrobs’ MyoProtein Flakes or Simple Systems’ Sainfoin pellets – not alfalfa!

Finally, and somewhat ironically, the use of Corticosteroids – the very drugs that are frequently prescribed to treat lameness - carry bone health risks. Always better to follow an anti-inflammatory diet and support with phytonutrients.

References

1. Sarafrazi N, Wambogo EA, Shepherd JA. Osteoporosis or low bone mass in older adults: United States, 2017-2018. Centers for Disease Control and Prevention, National Center for Health Statistics. Published March 2021. Accessed May 17, 2021. https://www.cdc.gov/nchs/products/databriefs/db405.htm

2. Wiedmer P, Jung T, Castro JP, et al. Sarcopenia – molecular mechanisms and open questions. Ageing Res Rev. 2021;65:101200. doi:10.1016/j.arr.2020.101200

3. Reginster JY, Beaudart C, Buckinx F, Bruyère O. Osteoporosis and sarcopenia: two diseases or one? Curr Opin Clin Nutr Metab Care. 2016;19(1):31-36. doi:10.1097/MCO.0000000000000230

4. He C, He W, Hou J, et al. Bone and muscle crosstalk in aging. Front Cell Dev Biol. 2020;8:585644. doi:10.3389/fcell.2020.585644

5. Kirk B, Miller S, Zanker J, Duque G. A clinical guide to the pathophysiology, diagnosis and treatment of osteosarcopenia. Maturitas. 2020;140:27-33. doi:10.1016/j.maturitas.2020.05.012

6. Teng Z, Zhu Y, Teng Y, et al. The analysis of osteosarcopenia as a risk factor for fractures, mortality, and falls. Osteoporos Int. Published online April 20, 2021. doi:10.1007/s00198-021-05963-x

7. Wang S, Deng Z, Ma Y, et al. The role of autophagy and mitophagy in bone metabolic disorders. Int J Biol Sci. 2020;16(14):2675-2691. doi:10.7150/ijbs.46627

8. Ferri E, Marzetti E, Calvani R, Picca A, Cesari M, Arosio B. Role of age-related mitochondrial dysfunction in sarcopenia. Int J Mol Sci. 2020;21(15):5236. doi:10.3390/ijms21155236

9. Dobson PF, Dennis EP, Hipps D, et al. Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss. Sci Rep. 2020;10(1):11643. doi:10.1038/s41598-020-68566-2

10. Habiballa L, Salmonowicz H, Passos JF. Mitochondria and cellular senescence: implications for musculoskeletal ageing. Free Radic Biol Med. 2019;132:3-10. doi:10.1016/j.freeradbiomed.2018.10.417

11. Korolchuk VI, Miwa S, Carroll B, von Zglinicki T. Mitochondria in cell senescence: is mitophagy the weakest link? EBioMedicine. 2017;21:7-13. doi:10.1016/j.ebiom.2017.03.020

12. Zheng CX, Sui BD, Qiu XY, Hu CH, Jin Y. Mitochondrial regulation of stem cells in bone homeostasis. Trends Mol Med. 2020;26(1):89-104. doi:10.1016/j.molmed.2019.04.008

13. Tang X, Ma S, Li Y, et al. Evaluating the activity of sodium butyrate to prevent osteoporosis in rats by promoting osteal GSK-3?/Nrf2 signaling and mitochondrial function. J Agric Food Chem. 2020;68(24):6588-6603. doi:10.1021/acs.jafc.0c01820

14. Mankhong S, Kim S, Moon S, Kwak HB, Park DH, Kang JH. Experimental models of sarcopenia: bridging molecular mechanism and therapeutic strategy. Cells. 2020;9(6):1385. doi:10.3390/cells9061385

15. Malmir H, Saneei P, Larijani B, Esmaillzadeh A. Adherence to Mediterranean diet in relation to bone mineral density and risk of fracture: a systematic review and meta-analysis of observational studies. Eur J Nutr. 2018;57(6):2147-2160. doi:10.1007/s00394-017-1490-3

16. Hettchen M, von Stengel S, Kohl M, et al. Changes in menopausal risk factors in early postmenopausal osteopenic women after 13 months of high-intensity exercise: the randomized controlled ACTLIFE-RCT. Clin Interv Aging. 2021;16:83-96. doi:10.2147/CIA.S283177

17. Shen D, Zhang X, Li Z, Bai H, Chen L. Effects of omega-3 fatty acids on bone turnover markers in postmenopausal women: systematic review and meta-analysis. Climacteric. 2017;20(6):522-527. doi:10.1080/13697137.2017.1384952

18. Lambert MNT, Thybo CB, Lykkeboe S, et al. Combined bioavailable isoflavones and probiotics improve bone status and estrogen metabolism in postmenopausal osteopenic women: a randomized controlled trial. Am J Clin Nutr. 2017;106(3):909-920. doi:10.3945/ajcn.117.153353

19. Nilsson AG, Sundh D, Backhed F, Lorentzon M. Lactobacillus reuterireduces bone loss in older women with low bone mineral density: a randomized, placebo-controlled, double-blind, clinical trial. J Intern Med. 2018;284(3):307-317. doi:10.1111/joim.12805

20. Dent E, Morley JE, Cruz-Jentoft AJ, et al. International Clinical Practice Guidelines for Sarcopenia (ICFSR): screening, diagnosis and management. J Nutr Health Aging. 2018;22(10):1148-1161. doi:10.1007/s12603-018-1139-9

21. Barajas-Galindo DE, González Arnaiz E, Ferrero Vicente P, Ballesteros-Pomar MD. Effects of physical exercise in sarcopenia. A systematic review. Endocrinol Diabetes Nutr. 2021;68(3):159-169. doi:10.1016/j.endinu.2020.02.010

22. Granic A, Dismore L, Hurst C, Robinson SM, Sayer AA. Myoprotective whole foods, muscle health and sarcopenia: a systematic review of observational and intervention studies in older adults. Nutrients. 2020;12(8):2257. doi:10.3390/nu12082257

23. Gkekas NK, Anagnostis P, Paraschou V, et al. The effect of vitamin D plus protein supplementation on sarcopenia: a systematic review and meta-analysis of randomized controlled trials. Maturitas. 2021;145:56-63. doi:10.1016/j.maturitas.2021.01.002

24. Huang YH, Chiu WC, Hsu YP, Lo YL, Wang YH. Effects of omega-3 fatty acids on muscle mass, muscle strength and muscle performance among the elderly: a meta-analysis. Nutrients. 2020;12(12):3739. doi:10.3390/nu12123739

25. Lettieri-Barbato D, Cannata SM, Casagrande V, Ciriolo MR, Aquilano K. Time-controlled fasting prevents aging-like mitochondrial changes induced by persistent dietary fat overload in skeletal muscle. PLoS One. 2018;13(5):e0195912. doi:10.1371/journal.pone.0195912

26. Madkour MI, El-Serafi AT, Jahrami HA, et al. Ramadan diurnal intermittent fasting modulates SOD2, TFAM, Nrf2, and sirtuins (SIRT 1, SIRT3) gene expressions in subjects with overweight and obesity. Diabetes Res Clin Pract. 2019;155:107801. doi:10.1016/j.diabres.2019.107801

27. Memme JM, Erlich AT, Phukan G, Hood DA. Exercise and mitochondrial health. J Physiol. 2021;599(3):803-817. doi:10.1113/JP278853

28. Harper C, Gopalan V, Goh J. Exercise rescues mitochondrial coupling in aged skeletal muscle: a comparison of different modalities in preventing sarcopenia. J Transl Med. 2021;19(1):71. doi:10.1186/s12967-021-02737-1

1. Compston J. Glucocorticoid-induced osteoporosis: an update. Endocrine. 2018;61(1):7-16. doi:10.1007/s12020-018-1588-2

2. Mirza F, Canalis E. Management of endocrine disease: secondary osteoporosis: pathophysiology and management. Eur J Endocrinol. 2015;173(3):R131-R151. doi:10.1530/EJE-15-0118

3. Fraser LA, Adachi JD. Glucocorticoid-induced osteoporosis: treatment update and review. Ther Adv Musculoskelet Dis. 2009;1(2):71-85. doi:10.1177/1759720X09343729

4. Buckley L, Guyatt G, Fink HA, et al. 2017 American College of Rheumatology guideline for the prevention and treatment of glucocorticoid-induced osteoporosis [published correction appears in Arthritis Rheumatol. 2017;69(11):2246]. Arthritis Rheumatol. 2017 Aug;69(8):1521-1537. doi:10.1002/art.40137

5. Egeberg A, Schwarz P, Harsløf T, et al. Association of potent and very potent topical corticosteroids and the risk of osteoporosis and major osteoporotic fractures. JAMA Dermatol. Published online January 20, 2021. doi:10.1001/jamadermatol.2020.4968

6. Spada F, Barnes TM, Greive KA. Comparative safety and efficacy of topical mometasone furoate with other topical corticosteroids. Australas J Dermatol. 2018;59(3):e168-e174. doi:10.1111/ajd.12762

7. Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in the United States. J Am Acad Dermatol. 2014;70(3):512-516. doi:10.1016/j.jaad.2013.11.013

8. Drucker AM, Wang AR, Li WQ, Sevetson E, Block JK, Qureshi AA. The burden of atopic dermatitis: summary of a report for the National Eczema Association. J Invest Dermatol. 2017;137(1):26-30. doi:10.1016/j.jid.2016.07.012

9. Kim MJ, Kim SN, Lee YW, Choe YB, Ahn KJ. Vitamin D status and efficacy of vitamin D supplementation in atopic dermatitis: a systematic review and meta-analysis. Nutrients. 2016;8(12):789. doi:10.3390/nu8120789

10. Ford AR, Siegel M, Bagel J, et al. Dietary recommendations for adults with psoriasis or psoriatic arthritis from the medical board of the National Psoriasis Foundation: a systematic review. JAMA Dermatol. 2018;154(8):934-950. doi:10.1001/jamadermatol.2018.1412

11. Nosrati A, Afifi L, Danesh MJ, et al. Dietary modifications in atopic dermatitis: patient-reported outcomes. J Dermatolog Treat. 2017;28(6):523-538. doi:10.1080/09546634.2016.1278071

12. Vaughn AR, Foolad N, Maarouf M, Tran KA, Shi VY. Micronutrients in atopic dermatitis: a systematic review. J Altern Complement Med. 2019;25(6):567-577. doi:10.1089/acm.2018.0363

13. Navarro-López V, Martínez-Andrés A, Ramírez-Boscá A, et al. Efficacy and safety of oral administration of a mixture of probiotic strains in patients with psoriasis: a randomized controlled clinical trial. Acta Derm Venereol. 2019;99(12):1078-1084. doi:10.2340/00015555-3305

14. Ko SH, Chi CC, Yeh ML, Wang SH, Tsai YS, Hsu MY. Lifestyle changes for treating psoriasis. Cochrane Database Syst Rev. 2019;7(7):CD011972. doi:10.1002/14651858.CD011972.pub2

15. Gamret AC, Price A, Fertig RM, Lev-Tov H, Nichols AJ. Complementary and alternative medicine therapies for psoriasis: a systematic review. JAMA Dermatol. 2018;154(11):1330-1337. doi:10.1001/jamadermatol.2018.2972

16. Malmir H, Saneei P, Larijani B, Esmaillzadeh A. Adherence to Mediterranean diet in relation to bone mineral density and risk of fracture: a systematic review and meta-analysis of observational studies. Eur J Nutr. 2018;57(6):2147-2160. doi:10.1007/s00394-017-1490-3

17. Hettchen M, von Stengel S, Kohl M, et al. Changes in menopausal risk factors in early postmenopausal osteopenic women after 13 months of high-intensity exercise: the randomized controlled ACTLIFE-RCT. Clin Interv Aging. 2021;16:83-96. doi:10.2147/CIA.S283177

18. Shen D, Zhang X, Li Z, Bai H, Chen L. Effects of omega-3 fatty acids on bone turnover markers in postmenopausal women: systematic review and meta-analysis. Climacteric. 2017;20(6):522-527. doi:10.1080/13697137.2017.1384952

19. Lambert MNT, Thybo CB, Lykkeboe S, et al. Combined bioavailable isoflavones and probiotics improve bone status and estrogen metabolism in postmenopausal osteopenic women: a randomized controlled trial. Am J Clin Nutr. 2017;106(3):909-920. doi:10.3945/ajcn.117.153353

20. Nilsson AG, Sundh D, Bäckhed F, Lorentzon M. Lactobacillus reuteri reduces bone loss in older women with low bone mineral density: a randomized, placebo-controlled, double-blind, clinical trial. J Intern Med. 2018;284(3):307-317. doi:10.1111/joim.12805

Originally published 3.6.22