The importance of bones in preserving the integrity of the body's function and ingredients that help preserve bone mass

Nutrition, exercise and appropriate supplementation can help maintain better mobility and an active lifestyle in later years. In addition to calcium, vitamins D and K, there are many other ingredients that can help maintain bone health.

AUTHOR: Valerija Pandza, M.Pharm.

Bones and joints play a key role in the musculoskeletal system, a network that includes muscles, ligaments, tendons, and other connective tissue. It is well known that as a result of normal aging, changes occur in the musculoskeletal system that can lead to reduced mobility and pain, and thus to a reduced quality of life.

Bones not only give shape to the body and protect organs, but also produce red and white blood cells, act as a storehouse of minerals such as calcium and phosphorus, and help regulate acidity, i.e. the acidbase balance of the blood. Joints, simply put, are places where bones come together. Some allow movement, such as the knee joints, and others do not, such as the joints between the bones of the skull.

Bone health is determined by genetics and environmental factors. Throughout life, both intrinsic factors (eg, genetics and hormonal status) and extrinsic factors (eg, exercise and diet) continually influence bone modeling and remodeling. Remodeling occurs through a complex and carefully orchestrated interaction between bone resorption (bone breakdown) and bone deposition (bone formation). Bone mass, i.e. the amount of minerals in the bone, reflects the result of the interaction between these two processes.

Most bone mass is accrued early in life, reaching its peak at the age of 30. In later life, bone remodel­ing continues, but more bone mass is generally lost than gained. However, this does not mean that bone health cannot be improved at any age. In fact, it is estimated that most of an adult's skeleton is replaced every ten years, and lifestyle choices can change the strength and health of these "new" bones.

Bone health refers to their strength and structural quality. Their health is assessed by a doctor through a detailed medical history and physical examination that includes proven tools to identify risk factors. The findings of this assessment determine whether and how bone health will be measured. Bone mineral density (BMD) is the most common way of measuring bone health.

Bone health is influenced by nutrient intake, hormonal regulation, exercise and age, among other factors (Table 1).

Age-related bone loss

Decreased bone density, changes in cartilage and connective tissue, and altered muscle function can occur as part of the normal aging process. Changes in muscle functions are also seen as part of normal aging. Fortunately, a healthy diet, exercise and proper supplementation can help mintain better mobility and an active lifestyle well into later years.

Age ­related bone loss is often considered a predominantly female problem. However, it is important to emphasize that although osteoporosis rates are low in men, the prevalence of osteopenia (low bone density) in the femoral neck or lumbar spine in men also increases with age.

A study by Center et al. of 852 women and 635 men (60 years and older) without fractures, reported an age­related decrease in volumetric bone mineral density (vBMD) at the hip (Center et al. 2004).

As a result of the aging process, the bone deteriorates in composition, structure and function, which predisposes to osteoporosis. Osteoporosis is defined as a decrease in bone mass and bone micro­architecture, with an increased risk of fragility fractures. Because of the close relationship between the aging process of bone and the pathogenesis of osteoporosis, research on the mechanisms of age­related bone loss has increased significantly in recent years, including a combination of basic, clinical, observational, and translational studies.

Age­related bone loss is a complex and heterogeneous disease. A combination of genetic, hormonal, biochemical, and environmental factors underlie its pathophysiology. The result is a decline in bone quantity and quality that increases fracture risk in a progressive manner. The two most common forms of primary osteoporosis in the elderly are postmenopausal osteoporosis (type 1) and senile osteoporosis (type 2). The strong ability of estrogen to suppress the activity of osteoclasts in the resorption phase and to increase their apoptosis is lost with the reduction of estrogen in menopause. Older postmenopausal women probably have both etiologies.

Despite greater understanding of the mechanisms of these contributing factors through clinical and animal studies, more research is needed to determine the relative contributions of each of these factors in order to improve preventative and therapeutic options.1

Food supplements for preserving bone health

As we age, the health of our bones and joints becomes more and more important. In addition, after an injury, healing should be supported, and it is also necessary to act preventively against osteoporosis and arthritis, and to look for ways to stay healthy. Vitamins, minerals and other ingredients can play an important role in maintaining bone and joint health.

A recent study conducted by strategic consulting and market research firm, Blue Weave Consulting, revealed that the global bone and joint nutritional supplements market was worth USD 10.31 billion in 2021. The market is projected to grow at a CAGR of 9.2%, earning around USD 18.83 billion by the end of 2028. The key growth driver of the global bone and joint health supplements market is the increasing trend of dietary supplements among the elderly population. It is estimated that the bone and joint health nutritional supplements market will experience sig­ nificant revenue growth during the forecast period due to the aging of the baby boom population and the increase in harmful lifestyle habits. Moreover, the growing interest of consumers in an active life, the rise in disposable income and the spread of awareness about health are further significant drivers of the sector. However, high R&D investments and the high cost of clinical trials hinder market growth. 2

Ingredients in food supplements with proven effects on maintaining bone health

Many articles have been written and research done on the topic of the need for supplementation with calcium, vitamin D, vitamin K and other micronutrients to maintain bone health. However, there are many more ingredients that can help preserve bone health, and they deserve additional attention, which we will devote to them in the following text.

In addition to supplementation with useful ingredients, changes in some lifestyle habits that can be undertaken are also important. A balanced diet is certainly the basis of good health, including the maintenance of healthy bones. The best diet plan depends on the possible health problems that the person has. For example, a gluten­free diet can improve bone mass in people with celiac disease. 3

Exercise and movement in nature are essential in the context of maintaining bone health. Regular bone density screenings according to recommended guidelines and doctor's instructions are also important.

Vitamin C

Supplementation with vitamin C can help prevent osteoporosis by reducing oxidative stress and consequent bone resorption. Vitamin C is also an essential factor for the formation of collagen (an important component of the bone matrix). In addition, it potentiates the activity of vitamin E in cells, by supporting the regeneration of α­tocopherol from its oxidized form. Studies have proven the association of higher levels of vitamin C with higher bone density.

A double­blind study of 90 participants showed that supplementation with 1,000 mg of vitamin C and 400 IU of vitamin E was associated with higher bone mineral density after 12 months.4

Phytoestrogens

Phytoestrogens such as soy isoflavones, or resveratrol, have a structural similarity to estrogen and can bind to estrogen receptors and thus achieve a multitude of benefits that estrogen is otherwise responsible for. They have attracted interest as potential therapies for the bone health of postmenopausal women who lack estrogen.

Resveratrol

Resveratrol, a natural polyphenol found in red grapes and berries, can act as a phytoestrogen. A 2­year randomized, double­blind, placebo­controlled crossover trial called RESHAW (resveratrol for healthy aging in women) evaluated the effect of resveratrol (75 mg twice daily) on cognition, cerebrovascular function, bone health, cardiometabolic markers, and general well­being in women in postmenopause.

After 12 months of resveratrol supplementation, compared to placebo, positive effects on bone density in the lumbar spine (+0.016 ± 0.003 g/cm2) and femoral neck (+0.005 ± 0.002 g/cm2) were recorded, which, also compared to placebo, were accompanied by a 7.24% decrease in the level of collagen C­terminal telopeptide type 1, a marker of bone resorption.

An increase in mineral density in the femoral neck resulted in an improvement in T­score (+0.070 ± 0.018) and a decrease in the 10­year probability of a higher risk of hip fracture. The extent of improvement was greater in women with poor bone health biomarker status. Importantly, the improvement in femoral neck T-score as a result of taking resveratrol correlated with the improvement in perfusion. A subanalysis found that the bone-protective benefit of resvera trol was greater in participants who took both vita min D and calcium. In conclusion, regular supplementation with 75 mg of resveratrol twice a day has the potential to slow bone loss in the lumbar spine and femoral neck, common fracture sites in postmenopausal women without significant osteoporosis.5

It is important to note that the dose of 75 mg, whose effectiveness for bone health benefits was determined by this study, is as much as 80 times higher than the average daily intake of resveratrol through food and drink.

Genistein

Another phytoestrogen, the soy isoflavone genistein, has also been proven to benefit bone health in postmenopausal women.

A clinical trial of 389 women with postmenopausal osteopenia evaluated the effects of genistein at a dose of 56 mg per day (plus 400 IJ of vitamin D). A significant increase in BMD, compared to placebo, was found in the femoral neck (+0.023 g/cm2) and lumbar spine (+0.055 g/cm2) after 12 months of supplementation. BMD continued to increase in the second year of supplementation.

Participants took 2 tablets with a total of 54 mg genistein or placebo daily for 24 months. The tablets also contained vitamin D3 and calcium, also necessary for healthy bones, and the placebo contained no other active ingredients.

After 24 months, bone density was measured and several blood tests were performed to see if bone breakdown or formation had occurred. Since estrogens can make the lining of the uterus thicker and can lead to cancer, ultrasound tests were also used to measure the thickness of the lining of the uterus to see if genistein causes this side effect as well.

After 24 months, women who took genistein had a greater increase in bone mineral density than women taking a placebo. In addition, bone markers were more favorable in women taking genistein than in women taking placebo. Gastrointestinal side effects were more common in women taking genistein than in women taking placebo. The thickness of the uterine lining did not change in either group, suggesting that genistein may be safe to use in terms of uterine health.

The phytoestrogen genistein, when taken with vitamin D3 and calcium, was proven to have beneficial effects on bone health compared to vitamin D3 and calcium alone.6

Olive leaf extract - bone support from the Mediterranean

In addition to the Mediterranean diet, which has various positive effects on bone health, olive extract also has proven effects. Bonolive® is an olive leaf extract standardized to a high content of oleuropein, a powerful phytonutrient unique to the olive tree. In various studies, it has shown beneficial properties, especially in reducing the risks associated with menopause.

Bonolive® is a patent­protected innovation that can be seamlessly integrated into nutritional supplements, medical nutrition and functional beverages, with the aim of supporting the health of women during menopause. The health benefits of this extract have been evaluated in several clinical studies that have shown its positive effect on the health of bones, joints, the cardiovascular system as well as its strong antioxidant properties. Clinically proven to improve bone health. A randomized, double­blind, placebo­controlled study demonstrated that it has significant effects on bone-building cells (osteoblasts) and bone mineral density in postmenopausal women.7

Preclinical research has shown that compounds from olive (Oleaeuropaea) can protect against bone loss by increasing the activity of osteoblasts at the expense of adipocyte formation. The aim of this exploratory study was to get the first insight into the effect of taking olive extract on bone remodeling in postmenopausal women with osteopenia (reduced bone mass).

FIGURE 1 The gut­bone axis The gut-bone axis: pathways and factors starting from gut dysbiosis that determine bone metabolism alterations favoring osteoclasts. Abbreviations — SCFAs: short-chain fatty acids; PAMPs: pathogen­associated molecular patterns; D Cell: somatostatin­producing cells; T Cell: type of leukocyte that is an essential part of the immune system; OB: osteoblast; OC: osteoclast; RNK-L: receptor activator of nuclear factor-κB ligand; OPG: osteoprotegerin; VDR: vitamin D receptor; IGF-1: insulin-like growth factor one. Taken from: SireA, deSireR, CurciC, CastiglioneF, WahliW. Role of Dietary Supplements and Probiotics in Modulating Microbiotaand Bone Health: The Gut­Bone Axis. Cells.2022Feb21;11(4):743.doi:10.3390/cells11040743.PMID:35203401;PMCID:PMC8870226.

A double­blind, placebo­controlled study was conducted in which participants with osteopenia were randomly assigned to treatment or placebo groups. The study included 64 of them, with a T­score of mean bone mineral density (BMD) in the lumbar spine (L2­L4) between ­1.5 and ­2.5. During 12 months, they took 250 mg of olive extract and 1,000 mg of calcium (treatment) or 1,000 mg of calcium alone (placebo) daily. Primary endpoints consisted of assessment of bone remodeling markers. Secondary endpoints included BMD measurements and blood lipid profiles. After 12 months, levels of the pro-osteoblastic marker osteocalcin were found to be significantly increased in the treatment group compared to placebo. At the same time, BMD decreased in the placebo group, while it remained stable in the treatment group. In addition, improved lipid profiles were observed in the therapeutic group, with a significant reduction in total and LDL­cholesterol.7

This research study supports preclinical observations and warrants further research, as it shows that this specific olive polyphenol extract affects serum osteocalcin levels and can stabilize lumbar spine BMD. Moreover, improved blood lipid profiles suggest additional health benefits.

The link between gut health and bone health

The relationship between gut health and bone health - known as the gut-bone axis - is an emerging area of scientific research8 (Figure 1).

Today, altered intestinal homeostasis is being in­ vestigated as a potential additional risk factor for reduced bone health, and therefore as a new potential therapeutic target. Intestinal microflora affects osteoclast activity, regulating serum IGF­1 levels, and at the same time affects intestinal calcium absorption. It is therefore not surprising that gut dysbiosis affects bone health. In this context, it has been hypothesized that dietary supplements, prebiotics and probiotics contribute to the intestinal microecological balance, which is important for bone health.

There are a number of possible ways in which this can be connected. First, intestinal dysbiosis makes it difficult to absorb calcium in the intestines. In addition, several metabolites produced in the gut exert control over the cells responsible for bone repair. Finally, dysbiosis­induced intestinal permeability causes the release of inflammatory cytokines into the bloodstream, which can negatively affect BMD and other factors related to bone health.

Prebiotics and probiotics have been investigated for their ability to improve bone health through effects on the gut microbiome. Although more research is needed, some evidence suggests that probiotics may protect against BMD loss and may improve markers of bone turnover in postmenopausal women.

Modulation of gut microbiota by other means such as diet, synbiotics, postbiotics, antibiotics, and fecal microbiota transplantation is another way to influence the gut­bone axis and improve bone health.

The Mediterranean diet can have a beneficial ef

fect on reducing the risk of bone fractures due to the high content of fiber, fermented milk products and polyphenols that favorably change the composition of the intestinal microbiome (Figure 2).

FIGURE 2 Gut microbiota modulators Lifestyle intervention and supplementation that might reduce bone loss; these modulators might exert their therapeutic effects through different known biological pathways, such as OPG, RANK, and TRAF. Abbreviations — OPG: osteoprotegerin; RANK-L: receptor activator of nuclear factor-κB ligand; RANK: receptor activator of nuclear factor κB; TRAF: tumor necrosis factor receptor­associated factor. Taken from: deSire A, deSire R, Curci C, Castiglione F, Wahli W. Role of Dietary Supplements and Probiotics in Modulating Microbiota and Bone Health: The Gut­Bone Axis. Cells. 2022Feb21;11(4):743.doi:10.3390/cells11040743.PMID:35203401;PMCID:PMC8870226.

Prebiotics share the ability to be converted to shortchain fatty acids (SCFAs)—including acetate, propionate, and butyrate—by the microbiota, increasing their levels in the gut and serum, thereby lowering gut pH. In an acidic environment, most minerals such as magnesium and calcium become more soluble, so their absorption is increased. Butyrate also acts as a growth factor for enterocytes and colonocytes.

In addition, SCFAs produced from prebiotics regulate the number and function of regulatory T cells in the colon, thereby controlling inflammation and modulating the synthesis of IGF­1 involved in bone remodeling. Therefore, fructooligosaccharide supplementation may have beneficial effects on bone metabolism, although further research is needed to confirm these findings.

Probiotics and their use have a special place in research related to the maintenance of bone health. A new term ‘osteomicrobiology’ was introduced recently for the rapidly emerging research field of the role of the microbiota in bone health and disease. This research field is aimed to bridge the gaps between bone physiology, gastroenterology, immunology, and microbiology. There has been a rapid translation from experimental animal studies to ongoing clinical trials of the effect of certain probiotic treatments on bone health in postmenopausal women and the results from these studies will be informative to determine if the GM might be a novel therapeutic target for osteoporosis.9

The combination of three Lactobacilli under the commercial name Probi®osteo ­ is a probiotic concept for bone health. It is based on the combination of Lactiplantibacillus plantarum HEAL9 (HEAL9™), Lactiplantibacillus plantarum HEAL19 and Lacticaseibacillus paracasei 8700: 2. This combination is clinically documented in supporting bone health, helps maintain their density and mineral content, maintain a balance in the natural bone remodel, and can lead to stronger bones. It is ideal for capsules and packs in the stick, and for functional foods such as drinks and powder products.12

Its efficiency was proven in a study conducted in Sweden, aiming to determine if supplementation with a combination of three bacterial strains protect from the rapid loss of bone mass of the spine in healthy women in early postmenopause. This randomized, double­blind, placebo­controlled, multicenter trial, conducted on 249 women randomly arranged in a 1: 1 ratio in a placebo or control group. The control group took probiotic treatment of the said probiotic product consisting of three Lactobacillus strains (Lactobacillus paracasei DSM 13434, Lactobacillus plantarum DSM 15312 and Lactobacillus plantarum DSM 15313; 1x1010).

The primary outcome was the percentage of a change in lumbar spine bone mineral density (LS­BMD) after 12 months, compared to the initial value. The primary analysis was done in all participants both at baseline and at 12 months. In conclusion, the treatment of Lactobacillus reduced LS­BMD loss compared to placebo. Losing LS-BMD was significant in the placebo group, while the loss of bone mass was not observed in a group treated with Lactobacillus11

References:

1 Demontiero O, Vidal C, Duque G. Aging and bone loss: new insights for the clinician. Ther Adv Musculoskelet Dis. 2012 Apr;4(2):61­76. doi: 10.1177/1759720X11430858. PMID: 22870496; PMCID: PMC3383520.

2 Bone And Joint Health Supplements Market Size, Share & Trends Analysis Report By Product, By Formulation, By Consumer Group, By Sales Channel, By Region, And Segment Forecasts, 2022 ­ 2030

3 Mosca C, Thorsteinsdottir F, Abrahamsen B, Rumessen JJ, Händel MN. Newly Diagnosed Celiac Disease and Bone Health in Young Adults: A Systematic Literature Review. Calcif Tissue Int. 2022 Jun;110(6):641­648. doi: 10.1007/s00223­021­00938­w. Epub 2022 Jan 3. PMID: 34978602; PMCID: PMC8721639.

4 Ruiz­Ramos M, Vargas LA, Fortoul Van der Goes TI, Cervantes­Sandoval A, Mendoza­Nunez VM. Supplementation of ascorbic acid and alpha­tocopherol is useful to preventing bone loss linked to oxidative stress in elderly. J Nutr Health Aging. 2010 Jun;14(6):467­72. doi: 10.1007/s12603­010­0099­5. PMID: 20617290.

5 Wong RH, Thaung Zaw JJ, Xian CJ, Howe PR. Regular Supplementation With Resveratrol Improves Bone Mineral Density in Postmenopausal Women: A Randomized, Placebo­Controlled Trial. J Bone Miner Res. 2020 Nov;35(11):2121­2131. doi: 10.1002/ jbmr.4115. Epub 2020 Jul 14. PMID: 32564438; PMCID: PMC7689937.

6 Marini H, Minutoli L, Polito F, Bitto A, Altavilla D, Atteritano M, Gaudio A, Mazzaferro S, Frisina A, Frisina N, Lubrano C, Bonaiuto M, D'Anna R, Cannata ML, Corrado F, Adamo EB, Wilson S, Squadrito F. Effects of the phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women: a randomized trial. Ann Intern Med. 2007 Jun 19;146(12):839­47. doi: 10.7326/0003­4819­146­12­200706190­00005. PMID: 17577003. 7 https://www.bonolive.com

8 Filip R, Possemiers S, Heyerick A, Pinheiro I, Raszewski G, Davicco MJ, Coxam V. Twelve­month consumption of a polyphenol extract from olive (Olea europaea) in a double blind, randomized trial increases serum total osteocalcin levels and improves serum lipid profiles in postmenopausal women with osteopenia. J Nutr Health Aging. 2015 Jan;19(1):77­86. doi: 10.1007/s12603­0140480­x. PMID: 25560820.

9 Ohlsson C, Sjögren K. Osteomicrobiology: A New Cross­Disciplinary Research Field. Calcif Tissue Int. 2018 Apr;102(4):426­432. doi: 10.1007/s00223­017­0336­6. Epub 2017 Oct 27. PMID: 29079994; PMCID: PMC5851705.

10 de Sire A, de Sire R, Curci C, Castiglione F, Wahli W. Role of Dietary Supplements and Probiotics in Modulating Microbiota and Bone Health: The Gut­Bone Axis. Cells. 2022 Feb 21;11(4):743. doi: 10.3390/cells11040743. PMID: 35203401; PMCID: PMC8870226.

11 Per-Anders Jansson, Dan Curiac, Irini Lazou Ahrén, Fredrik Hansson, Titti Martinsson Niskanen, Klara Sjögren, Claes Ohlsson, Probiotic treatment using a mix of three Lactobacillus strains for lumbar spine bone loss in postmenopausal women: a randomised, double­blind, placebo­controlled, multicentre trial, The Lancet Rheumatology, Volume 1, Issue 3, 2019, e154 ­ e162

12 https://www.probi.com/solutions/probiotic­portfolio/probi­osteo/