I remember my great-grandmother’s hands. So capable, big and warm, covered in freckles, ready to comfort, unbending the clawed rigidity to softly wipe my tears.

I remember her powerful, beautiful mind, endless with patience, tirelessly reading my favorite story over and over from a tattered book. I remember her, trapped in a creaky body, moving slowly around the kitchen in a sort of graceful dance with pain, cooking, cleaning, all the while humming, singing to herself.

In that time and space, to my child eyes, she seemed timeless and invincible. Now all I have are the sweetest memories of her. And the photographs of her looking so lovely and so fragile. She was one of the lucky ones – no falls, no breaks, no fractures. Instead, she quietly, silently, withered, shrank onto herself, rounded back and all.

Estrogen helps keep our bones healthy and strong. In menopause, when estrogen levels are very low, its protective effects on bone tissue are lost, predisposing women to fractures and disability. Postmenopausal osteoporosis is an estrogen deficiency-induced metabolic bone disease, characterized by reduced bone strength, increased bone loss and extensive structural destruction. Until a fracture event happens, osteoporosis silently devours bone tissues without any apparent symptoms. After a fracture, pain, malformation, and dysfunction can all contribute to the high morbidity of the disease. The National Osteoporosis Foundation estimates 10 million Americans over the age of 50 live with osteoporosis.

Major research efforts have been focused on understanding osteoporosis pathology. May is osteoporosis prevention month and is a good time to share what’s new in the frontier of science that addresses bone health.

Estrogen Works Directly on Bone Tissue to Elicit Protective Effects

Scientists have long known that estrogen works directly on estrogen receptors located within bone tissue to elicit its protective effects. Exciting new research is now beginning to explore the endocrine landscape of estrogen’s actions, illuminating new, previously unexplored, relationships between estrogen and the microbiome, and the impact these interactions have on bone health.

The Importance of a Diverse Microbiome

Surely the microorganisms that we host in our gastrointestinal tract are important for digestive health – they break down complex carbohydrates to improve energy extraction from food, produce vitamins and minerals, aid in digestion and absorption, and ferment dietary fibers. Turns out that these tiny microbial passengers residing in our digestive tract are also very important for bone health. Recent studies help illuminate the relationship between the intestinal microbiota and bone health, suggesting that the microbiome may serve as a potential therapeutic target for osteoporosis [1].

A diverse microbiome ensures that calcium and vitamin D – the dominant mineral and vitamin in bone formation and integrity – are absorbed adequately. These microbes also help safeguard the gut barrier to maintain its integrity. The integrity of the gut epithelial barrier is critical for regulating nutrient, electrolyte, and water absorption, and preventing the entry of pathogenic microorganisms and cytokines that are detrimental to bone health, from the gut into the rest of the body.

Additionally, a healthy microbiome can favorably shift the host’s immunity, where “osteoimmunity” [2] can protect from “immunoporosis [3].” Germ-free animals have decreased osteoclast precursor cells in the bone marrow, an effect that was counteracted by the introduction of gut microbiota from mice raised in a conventional environment [3]. The authors concluded that the increase in bone mass following colonization of gut bugs into germ free animals was associated with the reduction in the expression of pro-inflammatory cytokines.

What About Estrogen?

Estrogen engages the microbiome in an interplay geared to prevent the loss, and promote growth and proliferation, of beneficial bacteria [4]. Yes, estrogen is key to maintaining the diversity of our gut bugs! Research shows that animals treated with estrogen have significantly higher microbial diversity than controls [5].

And Now for That Estrogen-Microbiome-Bone Connection

Loss of estrogen is associated with unfavorable changes in the microflora, weakening of the gut barrier’s integrity, increased intestinal permeability, decreased calcium absorption, and increased inflammatory response [5] [6]. In menopause when estrogen is low, not only are estrogen’s direct protective effects on bone tissue lost (not enough estrogen to active its receptors on bone tissue), but also its indirect effects, via compromised microbial ecosystems and diminishing gastrointestinal health [7]. All of these consequences of estrogen deficiency compromise bone health.

Bone Loss is an Estrogen & a Gut Problem

Gut microbes regulate the systemic immune response critical for bone homeostasis. Occurrence of dysbiosis, when the gut bacterial population is askew, is sufficient to aggravate intestinal pathologies related to the immune system. When the immune system is triggered in the absence of estrogen’s potent anti-inflammatory effects, bone health — already compromised by the lack of estrogen — may suffer additional consequences due to detrimental changes in gut health. Importantly, the inflammatory response from gastrointestinal inflammation and dysbiosis, which estrogen protects against, can lead to an immune cascade that can hinder vitamin D receptor expression and activity, wounding not only the immune system but hindering the skeleton’s ability to retain its calcium.

Relevance to Patients

Overall, a balanced hormonal clinical picture is important for maintaining healthy bones. In addition, therapeutic approaches to preserve the integrity of the gut would offer a promising therapy to prevent estrogen depletion-induced bone loss. Estrogen therapy (if not contraindicated) together with probiotics may be worth considering for patients approaching menopause to maintain estrogen and bone health. 

Related Resources

• Blog: Estrogen: The Link Between Microbiome, Menopause & Metabolic Health
• Blog: Menopause - Is it All in Your Head? 
• Blog: What is Estrogen Dominance?

References 

[1]  Xu X, et al. Intestinal microbiota: a potential target for the treatment of postmenopausal osteoporosis. Bone Res 5 2017;5:17046.

[2]  Crotti TN, et al. Osteoimmunology: Major and costimulatory pathway expression associated with chronic inflammatory induced bone loss. J Immunol Res 2015;2015:281287.

[3]  Srivastava RK, et al. Immunoporosis: Immunology of osteoporosis - role of T cells. Front Immunol. 2018;9:657.

[4]  Chen KL, et al. Estrogen and microbiota crosstalk: should we pay attention? Trends Endocrinol Metab 2016;27:752-755.

[5]  Baker JM, et al. Estrogen-gut microbiome axis: Physiological and clinical implications. Maturitas 2017;103:45-53.

[6]  Braniste V, et al. Oestradiol decreases colonic permeability through oestrogen receptor beta-mediated up-regulation of occludin and junctional adhesion molecule-A in epithelial cells. J Physiol. 2009;587(Pt 13):3317-28.

[7]  Jones RM, et al. Osteomicrobiology: The influence of gut microbiota on bone in health and disease. Bone. 2017 Apr 27. [Epub ahead of print]