Better Bones: Next-generation bone health ingredients give formulators more options

Nutritional OutlookNutritional Outlook Vol. 25 No. 8
Volume 25
Issue 8

Newer bone health ingredients are building on strong research.

Photo © Scipro -

Photo © Scipro -

Calcium has long dominated the bone health market, but new research on ingredients is opening doors to the next generation of supplements. Product formulators now have opportunities to create synergistic blends of ingredients like vitamins, botanicals, non-calcium minerals, collagen, and omega-3 fatty acids, all bolstered by credible research that’s ongoing.

Vitamins and Minerals: Not Your Grandmother’s Calcium

Vitamins and minerals like vitamin D and calcium remain popular bone health supplements. Today, vitamin D and calcium products are becoming more targeted and advanced, with new studies showing benefits when these ingredients are combined with others in synergistic blends.

Take vitamin K2. The vitamin K2 ingredient menaquinone-7 (MK-7) is an essential bone health ingredient that enables the body to better utilize calcium, explains Xavier Berger, global marketing manager for Gnosis by Lesaffre (France). When activated by menaquinone-7, osteocalcin binds to the calcium in the bone matrix where calcium is most needed. Menaquinone-7 also activates matrix Gla protein (MGP) to inhibit calcium deposition where it is not wanted: in arteries and soft tissues.

Vitamin K2 menaquinone-7 is a promising addition to calcium and vitamin D formulations for this reason. “Vitamin K2 is growing in more consumer-friendly applications like gummies and liquids,” Berger says. “It’s a core ingredient in bone health supplements, working synergistically with other bone-supporting nutrients like calcium and vitamin D. Menaquinone-7 should be paired with vitamin D3…the combination is clinically proven to have an effect on bone health.”

Natto-Derived Menaquinone Outperforms Synthetic Vitamin K1 in Trials

Natto is a Japanese food made from fermented soybeans that is rich in the naturally occurring vitamin K2 menaquinone-7 (MK-7). Both vitamin K1 and MK-7 have been found to slow bone loss and improve bone mineral density—but new research is showing that MK-7 may have an edge.

One set of four clinical trials5 compared the bioavailability, dose-response relationship, level of osteocalcin carboxylation, and interference with anticoagulants in response to vitamin K1 and MK-7 supplementation. While both ingredients induced osteocalcin carboxylation within three days, only MK-7 increased that effect over time; the effect of vitamin K1 plateaued only barely above placebo.

Calcium ingredients are also advancing in their own right. Vitamin and mineral suppliers, for instance, are improving ingredient bioavailability. Traditional calcium supplements have come under fire for poor absorption; calcium carbonate, the most commonly used form of calcium in years past, is falling out of favor as newer forms of calcium emerge.

“Calcium carbonate is made from rocks, which we are not evolved to consume,” explains Crawford Currie, MBBS, head of research and development at Hofseth BioCare (Norway). By contrast, “Calcium phosphate is derived from a living organism, which our bodies can more easily absorb and digest.”

One randomized, blinded crossover trial1 published in January 2022 examined the effects of Hofseth’s branded calcium collagen complex CalGo on serum calcium levels in 12 postmenopausal women. Subjects in Group A received four 500-mg CalGo capsules on day 1, took a blood test on day 2, and then were given four 250-mg calcium carbonate capsules on day 8 after a seven-day washout period. Subjects in Group B followed the same protocol but started on the calcium carbonate regimen first before later crossing over to the CalGo regimen. All subjects gave another blood sample on day 9.

The study, which Hofseth BioCare conducted, showed that CalGo increased calcium levels by 1.28% after 24 hours, while calcium carbonate did not change calcium levels. The authors concluded that CalGo is more bioavailable than calcium carbonate.

Currie, the study’s lead author, says CalGo is in fact six times more absorbable than calcium carbonate. Marine-sourced calcium-collagen complexes offer good bioavailability and a better safety profile than historical calcium supplements, he says.

Calcium Citrate Malate Boosts Bioavailability

While calcium is still an important bone health ingredient, newer forms of the mineral are demonstrating considerable advantages over the traditional calcium carbonate. Common calcium salts like calcium carbonate are poorly absorbed, especially in older consumers, says Eric Ciappio, PhD, RD, strategic development manager, nutrition science, Balchem (New Hampton, NY).

“Calcium carbonate requires stomach acid for optimal absorption and therefore should be taken with meals,” Ciappio says. “Furthermore, older consumers may face a condition known as achlorhydria, a lack of hydrochloric acid in the digestive secretions of the stomach. This condition affects up to 30% of adults over age 60.”

Calcium citrate malate (CCM), a newer form of calcium, offers more bioavailability without the need for high stomach acid concentrations, Ciappio says. He notes that CCM is ideal for non-pill formulations like functional beverages.

Bioavailability is a priority for many bone health ingredient suppliers. Other sources of calcium, like calcium malate or Lithothamnium calcareum, offer better absorption profiles than traditional calcium, says Thies Ripcke, director of business development, North America, Kappa Bioscience (Oslo, Norway). Vitamins D3 and K2 can offer synergistic benefits, he adds.

“Vitamin D3 can aid in the expression of calcium-binding proteins, but alone, can only express them in their inactive form,” Ripcke explains. “This leaves the body effectively unable to regulate the integration of calcium from the intestines.” An adequate intake of vitamin K2 can help ensure that vitamin K–dependent proteins (VKDPs) are effectively carboxylated, which in turn helps the body bind calcium to bones.

Kappa Bioscience is currently running a clinical trial investigating the effects of vitamin K2 supplementation on cardiovascular, metabolic, and bone health. The study is being conducted in partnership with Bispebjerg Hospital in Copenhagen, Denmark. This trial is investigating the effects of 333 mcg per day of Kappa’s branded vitamin K2 ingredient K2VITAL on bone health in 450 healthy participants. When complete, Ripcke claims, it will be the largest and most extensive bone health trial ever conducted on its chosen endpoints.

The fact is that today, consumers are increasingly looking for a more holistic approach to bone health, says Laurentia Guesman, business manager, food and supplement ingredients, AIDP (City of Industry, CA). This interest is responsible for consumers’ diversified interest in bone health ingredients.

AIDP’s branded KoACT, a patented collagen peptide and chelated calcium blend, drives collagen into the bones to improve bone strength. One randomized controlled trial2 examined the effects of KoACT on bone metabolism and bone mineral density loss in 39 postmenopausal women with osteopenia.

The subjects received either 5 g of KoACT containing 500 mg of calcium and 200 IU of vitamin D per day, or a control supplement containing only the calcium and vitamin D, for 12 months. Subjects were assessed for total body, lumbar, and hip bone mineral density, as well as blood biomarkers of bone loss, at baseline and after six and 12 months. After 12 months, the KoACT group had higher levels of bone-specific alkaline phosphatase and lower levels of sclerostin and tartrate-resistant acid phosphatase isoform TRAP5b than the control group, indicating a lower rate of bone mineral loss.

Botanicals Decrease Bone Loss from Osteoporosis

Osteoporosis primarily affects postmenopausal women, but research indicates that people who take glucocorticoid medications are also at increased risk of the disease.3 Doctors prescribe glucocorticoids to treat a number of inflammatory diseases, from rheumatoid arthritis to asthma. Thus, osteoporosis prevention is an important priority for a number of consumers.

Certain herbal ingredients may help prevent bone loss in menopausal women and others, especially with new technologies enabling superior absorption, says David Liu, PhD, chief technology officer for Chenland Nutritionals (Irvine, CA). Liu says Chenland recently developed a patent-pending co-grinding solvent-free (CGSF) production technology that can enhance the bioavailability of active ingredients. The company’s branded CuminUP60 curcumin (Curcuma longa) was the first ingredient in its portfolio developed with this technology.

Are Prebiotics the Next Big Thing in Bone Health?

The next major players in bone health could be today’s gut health supplements. Gut microbiota are believed to play a role in bone metabolism, says Silvi Siddhu, senior manager of global marketing and technical sales for nutraceuticals, Univar Solutions (Downers Grove, IL).

“Evidence implicates the crosstalk between the gut and bones (the gut-bone axis) in bone remodeling,” Siddhu says. “Emerging ingredients with osteogenic potential, like prebiotics, will provide a boost to the bone health category either as standalone ingredients or in combination with existing mainstream ingredients for maximum benefits.”

“In clinical studies, CuminUP60 has shown inhibitory effects on the process of osteoporosis. The mechanism of action is via modulation of densitometry indices and bone resorption markers,” Liu says. “The CGSF technology enhanced the curcumin’s bioavailability by a factor of 14.”

More recently, Chenland Nutritionals completed an animal study4 that examined the effect of the company’s branded EuBone solution, a blend of the herbal extracts eucommia, cuscuta, and drynaria (ECD) on glucocorticoid-induced osteoporosis.

In this study, 40 female Wistar rats were randomly assigned to one of five groups. The rats underwent a one-week adaptation period in the study facility, followed by an eight-week study period. The rats received either saline via injection and gavage, or 4.5 mg/kg of prednisolone hydride twice per week to induce osteoporosis. After this run-in period, the rats were assigned to one of four groups. The first group received a saline control compound, while the other groups received varying dosages of the ECD blend for eight weeks (90 mg/kg/day, 135 mg/kg/day, or 180 mg/kg/day).

The rats were weighed and had their body temperatures taken once per week. After eight weeks, the study authors collected overnight urine from the rats via a metabolic cage. The study authors then sacrificed the rats and collected blood samples.

The study authors found that EuBone administration mediated body weight loss and restored serum calcium and phosphorus levels. The ECD blend also restored bone marrow structure and preserved osteocalcin and CTX levels, indicating superior osteogenesis. Micro-CT scanning showed that glucocorticoid administration decreased bone volume, but medium and high doses of ECD reversed the glucocorticoid’s effects.

This study demonstrates EuBone’s ability to increase bone mineral density and upregulate bone formation gene expression, says Liu, who coauthored the study. Liu expects that more herbs and botanicals will undergo study for bone health applications in the near future.

New Ingredients Set the Stage

The bone health market is undergoing a transformation as innovative new ingredients gain clinical validation. While calcium remains dominant, newer minerals, vitamins, and botanicals are carving out market space thanks to the robust clinical studies fueling them. Synergistic blends are also gaining ground, incorporating newer ingredients like menaquinone-7 and collagen. As research and development activity continues, more bone health ingredients of various types will offer formulators additional flexibility.


  1. Currie C et al. “A randomized, blinded, calcium-carbonate controlled cross over study of serum calcium levels 24 hours after CalGo oral supplementation in post-menopausal women.” Biomedical Journal of Scientific & Technical Research. Published online January 26, 2022.
  2. Elam ML et al. “A calcium-collagen chelate dietary supplement attenuates bone loss in postmenopausal women with osteopenia: A randomized controlled trial.Journal of Medicinal Food, vol. 18, no. 3 (March 2015): 324-331
  3. Leder B et al. “Glucocorticoid-Induced Osteoporosis.” The Endocrine Society website. Updated January 24, 2022.
  4. Han J et al. “Eucommia, cuscuta, and drynaria extracts ameliorate glucocorticoid-induced osteoporosis by inhibiting osteoclastogenesis through PI3K/Akt pathway.” Frontiers in Pharmacology. Published online February 4, 2022.
  5. Schurgers LJ et al. “Vitamin K-containing dietary supplements: Comparison of synthetic vitamin K1 and natto-derived menaquinone-7.” Blood, vol. 109, no. 8 (April 15, 2007): 3279-3282
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