Could Quatrefolic be a complementary option in compromised bone health?


Quatrefolic supplementation can help postmenopausal women to normalize Hcy, which contributes to bone health

Different nutrients such as the active folate 5-MTHF (vitamin B9) and the vitamin K2 as MK-7 (menaquinone-7) are known for their role in the development and maintenance of bone health, protecting from developing osteoporosis later in life.

The loss of bone mass, otherwise known as osteoporosis, mainly affects postmenopausal women due to a sharp decline in oestrogen, but many other contributing factors, such as genetic and metabolic disorders, lifestyle, environmental and inflammatory factors, could play a role.

Modifiable risk factors have been identified as of paramount importance and are being heavily researched as they can be adjusted or changed to reduce the risk of disease development. Among them, elevated homocysteine (Hcy) serum levels may represent a risk factor for compromised bone health and skeletal fractures. 1, 2, 3

Little is known, however, about the mechanistic role of Hcy in bone health. At this time there is strong epidemiological evidence, that is being further reinforced by genetic studies, showing an association between the common MTHFR polymorphism and the risk of osteoporosis. 3,4,5,6

High levels of circulating Hcy have been shown in in-vitro studies to cause collagen cross-linking impairment, as well as impacting osteoclast and osteoblast activity, leading to poor bone health and fragility fractures. 7

Folate, MTHFR Polymorphism and Bone Mineral Density in Hyperhomocysteinemia

The regulation of Hcy levels and the modulation of the inflammatory markers could represent additional therapeutic approaches not only for the protection of the cardiovascular system but also for bones, as suggested by recent research.

De Martinis et al.1 has positively investigated the association between hyperhomocysteinemia and low bone mineral density (BMD). Hyperhomocysteinemia was also associated with high inflammatory marker C-reactive protein levels and low vitamin D, vitamin B12 and folate levels in 252 post-menopausal women.

Hcy, inflammation, bone resorption markers, and prevalence of C677T polymorphism were higher, whereas vitamin D, B12, folate, and bone formation markers were lower in women with decreased BMD compared to those with normal BMD. Furthermore, 77% of women with low BMD presented with the C677T MTHFR polymorphism, while only 37% of women with normal BMD presented with the mutation.

Taken together, these results suggest an association between the C677T MTHFR polymorphism and elevated Hcy levels and inflammation, which may further influence osteoporosis onset.

Active Folate Quatrefolic also supports Bone Health

Quatrefolic supplementation can help postmenopausal women to normalize Hcy, which contributes to bone health, and provides a form of folate that is biologically active and not dependent on the metabolisation of the MTHFR enzyme.

Quatrefolic has been shown to lower and normalise homocysteine levels in a randomised clinical trial where hypertensive subjects at low cardiovascular risk received 400 µg/day for 2 months versus a conventional vitamin supplementation with highly dosed folic acid (5 mg/day).

Quatrefolic supplementation was more effective in reducing homocysteine serum level than folic acid, normalising homocysteine in 55.8% of cases, significantly higher than in the control. 8

Can Quatrefolic be reinforced by Vitamin K2?

Observational and intervention trials have widely demonstrated that Vitamin K2 in the form of menaquinone-7 (MK-7) is a vital nutrient for supporting bone health. Vitamin K2 as MK-7 is required for the activation/carboxylation of a specific protein – osteocalcin – which is one of the most abundant proteins in bone, synthetised by osteoblasts.

Since first reported, carboxylated osteocalcin (c-OC) levels were correlated with and have been used as a specific marker for bone formation. c-OC has a higher affinity for calcium and thus stimulates the formation of hydroxyapatite and bone mineralization. A meta-analysis published in 2015 showed that vitamin K2 as MK-7 plays a role in osteoporosis in postmenopausal women. Nineteen randomized controlled trials were included in the analysis. Subgroup analysis of postmenopausal women with osteoporosis revealed a significant improvement of vertebral BMD for both medium- and long-term results, favouring the Vitamin K2 group. There was a significant reduction in undercarboxylated osteocalcin while there was an osteocalcin increment.9

In 2013, Knapen et al. showed that a daily nutritional dose of MK-7 (180 mcg as MenaQ7) for three years demonstrated for the first time clinically statistically significant protection of the vertebra and the hip (femoral neck) against bone loss. In this study of 244 healthy post-menopausal women, the MenaQ7 group showed significantly decreased circulating uncarboxylated osteocalcin (ucOC), a well-established biomarker for bone and vitamin K status. After 3 years, both bone mineral content and bone mineral density, as well as bone strength, were statistically significantly better for the MK-7 group compared to the placebo group. 10

The postmenopausal period of women’s lives exposes them to important changes in bone structure, increasing their risk of osteoporosis, one of the main causes of disability and mortality in the elderly1. It is an age-related skeletal disease characterized by decreased bone mineral density (BMD) and bone structure deterioration resulting in an increased risk of fractures. The combination of Quatrefolic with Vitamin K2 as MK-7, such as MenaQ7 or vitaMK7, could be interesting and innovative to promote and protect women’s bone health. While the active folate Quatrefolic can contribute to their health through regulating and controlling healthy levels of Hcy, Vitamin K2 as MK-7 works to increase bone mineral density and promotes bone quality, protecting bone structure and metabolism associated. In this light Gnosis by Lesaffre is proud to highlight the great opportunity to combine its Quatrefolic brand with its MenaQ7 or vitaMK7 K2 brands to innovate the bone health market, providing advantages for its partners.


1. De Martinis M et al. Hyperhomocysteinemia is Associated with Inflammation, Bone Resorption, Vitamin B12 and Folate Deficiency and MTHFR C677T Polymorphism in Postmenopausal Women with Decreased Bone Mineral Density. Int J Environ Res Public Health. 2020

2. van Meurs JB et al. Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med. 2004

3. Kalimeri M, Leek F, Wang NX, et al. Folate and Vitamin B-12 Status Is Associated With Bone Mineral Density and Hip Strength of Postmenopausal Chinese-Singaporean Women. JBMR Plus. 2020

4. Wang P, Liu L, Lei SF. Causal effects of homocysteine levels on the changes of bone mineral density and risk for bone fracture: A two-sample mendelian randomization study. Clin Nutr. 2021

5. McLean RR et al. Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med. 2004

6. Tinelli C et al. Hyperhomocysteinemia as a Risk Factor and Potential Nutraceutical Target for Certain Pathologies. Front Nutr. 2019

7. Raghubeer S, Matsha TE. Methylenetetrahydrofolate (MTHFR), the One-Carbon Cycle, and Cardiovascular Risks. Nutrients. 2021

8. Mazza A et al. Nutraceutical approaches to homocysteine lowering in hypertensive subjects at low cardiovascular risk: a multicenter, randomized clinical trial. J Biol Regul Homeost Agents. 2016

9. Huang ZB et al. Does vitamin K2 play a role in the prevention and treatment of osteoporosis for postmenopausal women: a meta-analysis of randomized controlled trials. Osteoporos Int. 2015

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10. Knapen MH et al.Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int. 2013

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