Bone health superheroes: Magnesium, collagen, and vitamin K2

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Osteoporosis impacts 200 million women worldwide and affects an estimated 75 million people-men and women-just in Europe, the United States, and Japan, according to recent International Osteoporosis Foundation estimates.¹ Worldwide, osteoporosis is responsible for nearly nine million fractures every year. Nearly 25% of annual hip fractures occur in men. Hip fractures are a significant cause of mortality; in men, the overall mortality rate in the first 12 months following a hip fracture is approximately 20%. These sobering statistics highlight the need for men and women to consider interventions to support bone health throughout life.

While eating a healthy diet, getting enough weight-bearing exercise, and ensuring calcium and vitamin D adequacy are good first steps in a nutritional and lifestyle plan to stop or slow down bone loss, research suggests this may not be enough. Several other nutritional compounds are known to play a major role in supporting bone health, and combining these with traditional strategies may be necessary to optimize the building blocks the body needs for healthy bones. These emerging contenders include magnesium, collagen, and vitamin K2. Current research show all three hold significant promise as adjunct therapies to the mainstays of bone health nutrition. Because of the fundamental roles they play in maintaining and growing healthy bone, leaving them out may not be a wise option.

Magnesium: Vitamin D’s Best Friend

Magnesium is an essential mineral that acts as a critical cofactor for hundreds of biochemical reactions in the body. With respect to bone health specifically, its importance can’t be overstated. As the fourth most abundant mineral in the human body, nearly half of total body magnesium stores lie in bone tissue. Animal studies reliably show that a low-magnesium diet adversely affects bone strength, while human population-based studies repeatedly have found that dietary levels of magnesium are positively associated with bone mineral density.²

Magnesium may work in several ways to promote healthy bones. Laboratory studies have found that low extracellular levels of magnesium promote the production of osteoclasts in bone tissue, cells responsible for bone breakdown. At the same time, low magnesium levels interfere with the proliferation of osteoblasts, cells that build bone. Overall, this favors a decrease in bone strength. Laboratory and human studies further demonstrate that magnesium has a suppressive effect on parathyroid hormone (PTH) secretion in situations where serum calcium levels are marginally low, leading to a protective effect on bone by allowing calcium to remain in bone tissue where it’s necessary for enhanced bone strength.²

Evidence indicates that magnesium plays a crucial role in the activation and function of vitamin D. A recent review suggests that nearly all of the enzymes that metabolize vitamin D require magnesium as a cofactor.³ The relationship between magnesium and vitamin D is codependent. Vitamin D improves intestinal magnesium absorption, while magnesium is necessary as a cofactor for the vitamin D–binding protein. In addition, metabolism of vitamin D in the liver and kidneys into its active form requires magnesium. Thus, vitamin D is unable to effectively play its role in influencing the growth of bone tissue by regulating calcium and phosphate balance without the presence of magnesium.

In a recent two-year follow-up cohort study including 113,683 individuals in Japan undergoing hemodialysis, Yusuke Sakaguchi from Osaka University Graduate School of Medicine (Suita, Japan) and colleagues found that those with lower serum magnesium levels had a significantly higher risk of hip fractures than those with higher serum magnesium levels.² Each 1 mg/dl increase in magnesium level was associated with a 14.3% decrease in the risk of fracture. The researchers also found that magnesium levels mildly above the normal range (mild hypermagnesemia) were more beneficial in reducing fracture risk in this cohort, indicating additive benefits of higher magnesium levels. Previous research by the same group linked mild hypermagnesemia to improved survival in hemodialysis patients; it is possible that the reduction in hip fractures associated with elevated magnesium is a contributing factor to the enhanced survival rates.

Further evidence in support of the beneficial effects of magnesium comes from a cohort study including 156,575 men and women aged 39 to 72. Led by Alisa Welch from the University of East Anglia (Norwich, UK), investigators assessed measurements of muscle and bone health indicators from individuals that were a part of the UK Biobank cohort.⁴ These measurements were compared to dietary intake levels of magnesium. Clinically significant differences were found in grip strength, fat free mass, and bone mineral density in both men and women when assessed across quintiles of dietary magnesium intake. Specific to bone mineral density, higher magnesium intake led to greater bone mineral density measurements in men and women. While these benefits were more pronounced in men, the bone mineral density differences were also significantly higher in women with greater dietary magnesium intake, reinforcing the importance of magnesium for bone health.

Collagen Peptides: Structural Support for a Strong Foundation

Collagen is a vital structural protein for bone that forms the backbone of bone’s mechanical strength. It is made up of three polypeptide strands forming a unique triple helix where the amino acid glycine is in every third position. The other two amino acids most commonly represented in collagen are proline and hydroxyproline. As the most abundant protein in mammals, collagen represents 30% of total protein in the body, while in bone and other connective tissue it represents 80%. In bone, collagen is intertwined with minerals, including calcium apatite crystals. The minerals are responsible for the stiffness and rigidity of bone, and collagen provides skeletal toughness and defines its shape. Nearly 95% of collagen in bone is type I, while type II collagen is also present.⁵ Research suggests that type I collagen synthesis promotes osteoblast growth and enhances bone mineral density.⁶

The ability of bone to resist mechanical forces and fractures is dependent on both the quantity of bone tissue (i.e. the amount of mineralization) as well as the quality (i.e. the structural organization of the collagen backbone). Age-related changes can have a significant impact on the collagen framework, leading to reduced bone strength and elasticity, making bone more prone to fractures (such as in osteoporosis). One factor affecting collagen is estrogen deficiency, which decreases collagen maturation rate. Aging also increases the overall metabolism of collagen, leading to a fragile bone matrix. Research further suggests that the formation of advanced glycation end products (AGEs) in bone tissue occurs with aging, weakening the integrity of the collagen backbone.⁵ Interestingly, laboratory studies in pre-osteoblasts from mice show that collagen peptides from a bovine source were able to enhance the growth and proliferation of osteoblasts and encourage the formation of mineralized bone matrix, highlighting its bone-protective effects.⁷ These factors attest to the importance of replenishing collagen in addition to the key bone-supportive vitamins and minerals in order to maintain healthy bones.

Most supplemental collagen is in the hydrolyzed form. The terms hydrolyzed collagen, collagen hydrolysate, hydrolyzed gelatin, and collagen peptides are essentially synonymous. Hydrolyzed collagen taken orally is digested in the gut and crosses the intestinal barrier. Being relatively well-absorbed, it enters circulation and has been found in various research models to reach target tissues.⁵

While the number of human studies evaluating the use of collagen for bone health is small, the results of early studies are promising. A published systematic review conducted by Brazilian researchers including five human trials and three animal studies published between 1994 and 2014 concluded that supplementation with hydrolyzed collagen had a positive therapeutic role in conditions such as osteoporosis and osteoarthritis, with a dose of 8 grams daily shown to increase plasma glycine and proline concentrations, while 12 grams daily supported significant symptomatic improvement of osteoporosis and osteoarthritis.⁶

More recently, a clinical trial led by Daniel König from the University of Freiburg (Freiburg, Germany) assessed the effect of collagen supplementation on bone-health markers in postmenopausal women.⁸ In the 12-month, double-blind, placebo-controlled study, 131 women with an average age of 64 were randomized to supplement with 5 grams of specific collagen peptides-the Fortibone brand from Gelita AG (Eberbach, Germany)-or a maltodextrin placebo daily. The primary endpoint was a change in bone mineral density of the femoral neck and spine after 12 months. Plasma levels of the bone turnover markers amino-terminal propeptide of type I collagen (PINP) and C-telopeptide of type I collagen (CTX-I) were also assessed. The women were also encouraged to consume 500-800 mg of calcium supplements and 400-800 IU of vitamin D daily, although the intake of these supplements was not controlled.

At the end of the study, bone mineral density at the femoral neck and spine increased significantly versus placebo in the collagen group. PINP also increased significantly in the collagen group whereas CTX-I rose in the placebo group. This indicates that supplementation with specific collagen peptides by postmenopausal women for 12 months led to a favorable shift in bone mineral density and in bone-health markers, leading to increased bone formation and reduced degradation.

Vitamin K2: Keeping Calcium in the Bones

Vitamin K is one of the fat-soluble vitamins most well-known for its role as a cofactor in the blood coagulation process. Vitamin K occurs in two main forms. The form that has traditionally been a component of multivitamins is known as K1, or phylloquinone. This is the form commonly found in many fruits, vegetables, and oils. However, a second form known as K2, or menaquinone, also exists and is mainly synthesized by bacteria; certain menaquinones are found in specific foods, including fish, liver, milk, and eggs.⁹

The different menaquinones (MK) are designated by the number of isoprenoid units occurring on their side chains and occur in configurations between MK-2 and MK-13, with longer-chain forms having a greater half-life and bioactivity. As research into the effects of menaquinones progresses, this form of vitamin K is gaining importance. Specifically, menaquinones play a central role in bone and cardiovascular health because of their influence on calcium balance in the body. MK-4 to MK-10 have superior absorption in the human body and show greater activity than vitamin K1. Furthermore, K1 is mainly stored in the liver and plays a bigger part in coagulation while K2 is distributed throughout the body and has a greater systemic effect.⁹

Vitamin K2’s role in bone health stems from its function in activating several vitamin K2–dependent proteins through a process known as gamma-carboxylation, the most important of which are osteocalcin and matrix Gla protein (MGP).⁹ Osteocalcin is a calcium-binding protein produced by osteoblasts in bone tissue. When activated by K2, osteocalcin binds to calcium ions and hydroxyapatite crystals. This results in favorable effects on the organization of the extracellular bone matrix and an influence on the size and shape of hydroxyapatite crystals, promoting bone mineralization.¹⁰ MGP, on the other hand, exerts its effects in smooth muscle of blood vessels and in cartilage. As another calcium-binding protein, MGP inhibits the calcification of arteries and cartilage, delivering calcium from these areas to the bone, facilitating healthy bone formation. Adequate levels of K2, by playing a major role in activating these proteins, facilitate bone health.⁹

Human clinical trials using the most common supplement form of vitamin K2, known as MK-7, have recently shown promising results for promoting a protective effect on healthy bone. An earlier study led by Marjo Knapen from Maastricht University (Maastricht, The Netherlands) assessed the effect of supplementation with MK-7-the MenaQ7 brand from NattoPharma (Oslo, Norway)-over a three-year period in healthy postmenopausal women.¹⁰ In the placebo-controlled trial, 244 women received placebo or 180 mcg MK-7 daily. Dual-energy X-ray absorptiometry (DXA) assessments for bone mineral content and density of the femoral neck, hip, and lumbar spine were conducted at baseline and after one, two, and three years of supplementation. Serum levels of uncarboxylated and carboxylated osteocalcin were assessed to determine vitamin K2 status. At the end of the study period, MK-7 supplementation led to improved vitamin K status and decreased age-related declines in bone mineral content and density at the lumbar spine and femoral neck, but not at the hip, compared to placebo. Measures of bone strength were also improved by supplementation with MK-7 daily.

An additional study conducted by Sofie Rønn and colleagues from Aarhus University Hospital (Aarhus C, Denmark) investigated the role of MK-7 supplementation in preventing age-related degradation of trabecular bone at the tibia.¹¹ In the randomized, double-blind study, 148 postmenopausal women with osteopenia supplemented with 375 mcg of MK-7 or a placebo daily for 12 months. High-resolution computed tomography was used to assess bone microarchitecture, while DXA scans were conducted to evaluate bone mineral density. Uncarboxylated osteocalcin levels were also measured.

The results of the study showed that MK-7 supplementation maintained trabecular number in the tibia, while this decreased in the placebo group. Furthermore, trabecular spacing and thickness were unchanged with MK-7 supplements, while both significantly increased with placebo. Uncarboxylated osteocalcin levels also decreased with MK-7 significantly more than placebo. While bone mineral density showed no improvement, there was a pronounced protective effect against deterioration of bone microarchitecture with MK-7.

The Bone Health Toolbox

Given the number of people impacted by bone health issues such as osteoporosis, a paradigm shift in the thought process for nutritional intervention is needed. As fundamental as diet, exercise, calcium, and vitamin D are to prevent bone deterioration, a more holistic approach including other key nutritional cofactors for bone structure is likely to yield greater benefit across the lifespan. Adding critical cofactors, including magnesium, collagen, and vitamin K2, to current nutritional recommendations for bone health could go a long way towards helping to reduce the occurrence of osteoporosis and related disorders.
 

References:

1. Facts and Statistics. International Osteoporosis Foundation. www.iofbonehealth.org/facts-statistics. Accessed July 28, 2019.
2. Sakaguchi Y et al. “Magnesium and risk of hip fracture among patients undergoing hemodialysis.” Journal of the American Society of Nephrology, vol. 29, no. 3 (March 2018): 991-999
3. Uwitonze AM et al. “Role of magnesium in vitamin D activation and function.” The Journal of the American Osteopathic Association, vol. 118, no. 3 (March 1, 2018): 181-189
4. Welch AA et al. “Dietary magnesium may be protective for aging of bone and skeletal muscle in middle and younger older age men and women: cross-sectional findings from the UK Biobank Cohort.” Nutrients. Published online October 30, 2017.
5. Daneault A et al. “Biological effect of hydrolyzed collagen on bone metabolism.” Critical Reviews in Food Science and Nutrition, vol. 57, no. 9 (June 13, 2017): 1922-1937
6. Porfírio E et al. “Collagen supplementation as a complementary therapy for the prevention and treatment of osteoporosis and osteoarthritis: a systematic review.” Revista Brasileira de Geriatria e Gerontologia, vol. 19, no. 1 (January/February 2016)
7. Liu J et al. “Bovine collagen peptides compounds promote the proliferation and differentiation of MC3T3-E1 pre-osteoblasts.” PLoS One. Published online June 13, 2014.
8. König D et al. “Specific collagen peptides improve bone mineral density and bone markers in postmenopausal women-a randomized controlled study.” Nutrients. Published online January 16, 2018.
9. Akbari S et al. “Vitamin K and bone metabolism: a review of the latest evidence in preclinical studies.” BioMed Research International. Published online June 27, 2018.
10. Knapen MH et al. “Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women.” Osteoporosis International, vol. 24, no. 9 (September 2013): 2499-2507
11. Rønn SH et al. “Vitamin K2 (menaquinone-7) prevents age-related deterioration of trabecular bone microarchitecture at the tibia in postmenopausal women.” European Journal of Endocrinology, vol. 175, no. 6 (December 2016): 541-549