July/August 2021

Nutrition: Bone Health and the Gut Microbiome
By Carrie Dennett, MPH, RDN, CD
Today’s Geriatric Medicine
Vol. 14 No. 4 P. 30

Can eating for a healthy gut also produce healthier bones?

The gut microbiota is a hot topic because of its possible associations with multiple areas of health—including bone health. Accumulating research suggests the gut microbiota is closely related to the regulation of bone metabolism, which could be significant, given that about 54 million Americans have low bone mass, placing them at increased risk of osteoporosis, according to the National Osteoporosis Foundation.1 

Osteoporosis occurs when the body loses too much bone, makes too little bone, or both. The National Osteoporosis Foundation estimates that 1 in 2 women and up to 1 in 4 men aged 50 and older will break a bone due to osteoporosis.1 Heredity, hormone levels, nutrition, and lifestyle all play a role in the development and progression of osteoporosis.1,2 It’s known that insufficient calcium in the diet can contribute to low bone mass, but so can poor absorption of the dietary calcium individuals do get. That’s why intestinal disorders that can cause malabsorption, including celiac disease and inflammatory bowel disease, increase osteoporosis risk. So does weight loss surgery and gastrectomy, procedures that remove part of the stomach, intestines, or both.1 

Mechanisms Connecting the Gut to Bone Health
A large body of research suggests that the gut microbiota may affect bone metabolism and the absorption of bone-related minerals, including calcium, which is primarily absorbed through the wall of the upper part of the small intestine. The gut microbiota is a diverse microbial community living in the gastrointestinal tract, especially the large intestine, primarily made up of bacteria, fungi, viruses, and protozoa.2 The gut microbiota produces metabolites that have effects on distant sites in the body, including the bones.3  

Osteoblasts originate from bone marrow and are responsible for forming bone tissue. Osteoclasts are bone cells that break down bone tissue. Recent research suggests that the gut microbiota is more likely to have an influence on osteoclasts. Researchers made such an association based on mouse models, indicating that the lack of a gut microbiome (as in germ-free mice) led to fewer osteoclasts and an increase in bone mass—though these findings don’t necessarily translate to humans.2 Conversely, some of the earliest evidence of a relationship between the gut microbiota and bone metabolism shows that bone loss in the lumbar (lower) spine and the femoral neck—the site of most hip fractures—was associated with intestinal bacterial overgrowth. This may be partly because bacterial overgrowth is also associated with malabsorption.4 

A 2020 study analyzed fecal samples of 48 osteoporosis patients and 48 healthy controls. They found that the osteoporosis patients had a significantly—and uncommonly—more diverse array of gut microbes, but also had significantly higher numbers of some microbes. The authors said this supports the view that excessive growth of intestinal bacteria leads to bone loss.5

Absorption of calcium, magnesium, and other minerals may be regulated by short-chain fatty acids (SCFAs) such as butyrate, acetate, and propionate, the main products of bacterial fermentation in the intestine, particularly in the large intestine.2 SCFAs can increase calcium absorption by reducing intestinal pH, making it more difficult for calcium to form nonabsorbable complexes with phosphates and oxalates.6 However, total SCFAs aren’t highly correlated with calcium absorption or bone health parameters, and lowered pH doesn’t always increase calcium absorption, so these may not be the only mechanisms.

Notably, butyrate is the preferred energy source of mucosal cells in the large intestine, so SCFAs may improve gut health, which may in turn promote bone health through other mechanisms.7 SCFAs, especially butyrate, also may indirectly stimulate formation of osteoblasts and inhibit formation of osteoclasts.2,3 SCFAs also help regulate the immune system, including triggering proliferation of regulatory T cells (Tregs). Tregs tend to accumulate on the endosteum, the lining of the internal cavity of long bones, and have the ability to activate osteoblasts and strongly inhibit osteoclasts.2,3 The effect of SCFAs on osteoblasts and osteoclasts has been observed generally, but there’s evidence from mouse studies that SCFAs prevent bone loss after removal of the ovaries, a procedure that usually triggers increased osteoclast formation. Human research is underway.3 

Effects of Prebiotics and Probiotics
People who eat plant-rich diets have higher levels of SCFAs, and research has shown that these diets are beneficial for bone health.3 Plant foods contain complex nondigestible carbohydrates, which are the preferred “food” of gut microbes. Prebiotics are selectively fermented ingredients, including certain fibers and carbohydrates that result in specific changes that benefit health. Prebiotic fiber, once it’s fermented, may indirectly improve calcium absorption by several mechanisms, including reducing intestinal pH, producing SCFAs, influencing signaling pathways that may regulate mineral absorption, modulating the gut microbiota, or modulating the immune system.8 

Prebiotic oligosaccharides and polysaccharides can support the activity and proliferation of beneficial bacteria, which in turn can increase secretion of SCFAs. This also can inhibit harmful bacteria, which may reduce inflammation.2 Dietary fructooligosaccharides, galactooligosaccharides, and other prebiotic fibers have been shown to increase calcium absorption during youth, at a time when building peak bone mass is important, in both humans and rats.8 Dietary fructooligosaccharides can increase the bioavailability of isoflavones, which are similar in structure to estrogen, and so may support healthy bones.2 Galactooligosaccharides, inulin, and resistant starch have been shown to promote mineral absorption.4 

Most studies involving participants of different ages—young, adult, and elderly—have found that prebiotic consumption increases calcium absorption, although research on the effects of prebiotics on mineral absorption and overall bone health in humans has yielded contradictory results, which may be due to a large variation in study design, including length of intervention, prebiotic dose, and age of participants. Studying the effects of prebiotics on bone health itself is more challenging due to the need to follow participants for long periods of time.6 

“The mechanisms still have not been elucidated,” says Connie Weaver, PhD, distinguished professor emerita in the department of nutrition science at Purdue University. “It’s likely several mechanisms are involved and different ones respond differently to different diets,” she says. “Prebiotics would favor fiber fermenters and production of SCFA. Polyphenolic-rich diets would stimulate genes in the endogenous antioxidant pathway, etc.”

What about use of probiotics, live microorganisms that provide health benefits when taken in adequate amounts, through food or supplements? A 2018 randomized, placebo-controlled double-blinded trial of 90 women aged 75 to 80 with low bone mineral density found that daily oral doses of Lactobacillus reuteri 6475 resulted in a significant reduction in loss of total bone mineral density after 12 months, compared with the control group.9 

A randomized clinical trial of patients with osteoporosis showed that consumption of kefir (fermented milk) for six months caused an increase in bone mineral density in men.10 Treatment for six months with Lactobacillus casei Shirota improved healing of fractures near the wrist in elderly men and women in another prospective, double-blinded, randomized placebo-controlled trial.11

Probiotics that increase the production of SCFAs, such as Lactobacillus rhamnosus GG, may act via a SCFA-Treg-bone formation pathway. Treatment with L rhamnosus GG has been shown to increase butyrate levels. There’s robust evidence that L rhamnosus GG and possibly all lactobacilli-containing probiotics can improve skeletal development in young animals, but this effect hasn’t been consistently observed with other probiotics.3 A 2020 review concluded the evidence suggesting that probiotics may improve bone health is compelling, although response is stronger in women and is more easily observable in people with high bone turnover, such as children, adolescents, or early postmenopausal women.12 

Recommendations for Clinicians
Development of osteoporosis treatment strategies targeting the gut microbiota may be promising and serve as a welcome alternative to current osteoporosis medications, which all have serious potential side effects.2 Increases in SCFA levels from prebiotic or probiotic supplementation may prove to be an inexpensive, safe, and effective intervention for preventing and treating osteoporosis.3

Encouraging intake of foods that contain prebiotic fiber—such as the onion family, dandelion greens, bananas, asparagus, artichokes, barley, wheat bran, oats, apples, and yacon and jicama roots—may be a smart strategy during times of peak bone growth during adolescence as well as in times of greater bone loss in older adults.6 Both calcium and dietary fiber have been identified in the 2020–2025 Dietary Guidelines for Americans as shortfall nutrients across the population.13

“Prebiotics have been shown to be effective when calcium intakes are low in various age groups for bone health even though we do not know the mechanism,” Weaver says. “I recommend them, especially for individuals who have inadequate calcium intakes.”

— Carrie Dennett, MPH, RDN, CD, is the nutrition columnist for The Seattle Times, owner of Nutrition By Carrie, and author of Healthy for Your Life: A Holistic Guide to Optimal Wellness. 

References
1. What is osteoporosis and what causes it? National Osteoporosis Foundation website. https://www.nof.org/patients/what-is-osteoporosis/

2. Li S, Mao Y, Zhou F, Yang H, Shi Q, Meng B. Gut microbiome and osteoporosis: a review. Bone Joint Res. 2020;9(8):524-530.

3. Zaiss MM, Jones RM, Schett G, Pacifici R. The gut-bone axis: how bacterial metabolites bridge the distance. J Clin Invest. 2019;129(8):3018-3028.

4. Chen YC, Greenbaum J, Shen H, Deng HW. Association between gut microbiota and bone health: potential mechanisms and prospective. J Clin Endocrinol Metab. 2017;102(10):3635-3646.

5. Xu Z, Xie Z, Sun J, et al. Gut microbiome reveals specific dysbiosis in primary osteoporosis. Front Cell Infect Microbiol. 2020;10:160.

6. Whisner CM, Weaver CM. Prebiotics and bone. Adv Exp Med Biol. 2017;1033:201-224.

7. Weaver CM. Diet, gut microbiome, and bone health. Curr Osteoporos Rep. 2015;13(2):125-130.

8. Wallace TC, Marzorati M, Spence L, Weaver CM, Williamson PS. New frontiers in fibers: innovative and emerging research on the gut microbiome and bone health. J Am Coll Nutr. 2017;36(3):218-222.

9. 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.

10. Tu MY, Chen HL, Tung YT, Kao CC, Hu FC, Chen CM. Short-term effects of kefir-fermented milk consumption on bone mineral density and bone metabolism in a randomized clinical trial of osteoporotic patients. PLoS One. 2015;10(12):e0144231.

11. Lei M, Hua LM, Wang DW. The effect of probiotic treatment on elderly patients with distal radius fracture: a prospective double-blind, placebo-controlled randomised clinical trial. Benef Microbes. 2016;7(5):631-637.

12. Rizzoli R, Biver E. Are probiotics the new calcium and vitamin D for bone health? Curr Osteoporos Rep. 2020;18(3):273-284.

13. US Department of Agriculture; Health and Human Services. Dietary Guidelines for Americans 2020–2025. https://www.dietaryguidelines.gov/sites/default/files/2020-12/Dietary_Guidelines_for_Americans_2020-2025.pdf. Published December 2020.