Metabolic bone diseases are those that affect the balance between bone formation and bone resorption, among which osteoporosis is particularly prevalent. In an increasingly ageing society, osteoporosis has become a global phenomenon affecting some 200 million people worldwide, and is a major cause of morbidity and mortality. Specifically, it is estimated that around 33% of women and 20% of men over the age of 50 will suffer an osteoporotic fracture in their lifetime.1
Osteoporosis is a systemic skeletal disease characterised by a decrease in bone mass and deterioration of bone structure, resulting in increased bone fragility and an increased risk of fracture.2 This skeletal weakness causes bones to become more porous, fragile and brittle resulting in fractures from minimal or no trauma, especially in the hip, femoral head, wrist, thoracic and lumbar spine.
There are a lot of factors that affect the appearance of the disease, some of them unalterable such as genetic predisposition , sex, age, race and others modifiable such as poor eating habits (diets poor in calcium and vitamin D), unhealthy lifestyles (sedentary lifestyle, alcohol, tobacco) and the use of osteo-toxic drugs (corticosteroids). Another major contributor to the development of osteoporosis is hormonal factors (oestrogen and parathyroid hormone (PTH) levels).3
Bone remodelling is the physiological process that is responsible for the restructuring of bone, which is in continuous formation and destruction throughout life. There are three types of cells involved in the process of bone remodelling: osteoblasts (bone-forming), osteoclasts (responsible for destruction) and osteocytes (contribute to maintenance). When new bone is generated more slowly than the destruction of old bone, bone density decreases and osteoporosis appears. The RANK-RANKL-OPG system is involved in the regulation of this phenomenon. RANK (Receptor Activator of Nuclear Factor Kappa B) is a receptor present in the osteoclasts, to which RANKL (Receptor Activator of Nuclear Factor Kappa B Ligand), present in the osteoblast membrane, binds. As a consequence of this binding, the osteoclasts are activated, increasing their proliferation and decreasing their apoptosis. Osteoprotegerin (OPG) is a soluble osteoblastic receptor of the RANK family. Its ligand is RANKL, which is why its binding prevents osteoclast activation. Ultimately, it is the RANKL/OPG ratio that determines the amount of bone to be resorbed.4
Overexpression of various pro-inflammatory cytokines (IL-1, IL-6, etc.) and tumour necrosis factor (TNF) stimulate the expression of RANK and RANKL and inhibit OPG synthesis, making control of inflammatory diseases essential to improve bone health.5 However, the long-term use of corticosteroid drugs to treat inflammation has a detrimental outcome for bone health as these osteotoxic drugs stimulate the expression of RANK and RANLK, resulting in increased bone resorption to the detriment of new bone formation. A more natural and safer alternative to address inflammation is supplementation with DHA (Docosa-Hexaenoic Acid), which at appropriate doses and over prolonged periods of time is able to modulate the inflammatory process and bone metabolism. Omega-3 supplementation promotes bone formation and inhibits bone resorption, which leads to an increase in bone mineral density (BMD). On the other hand, the combination of aerobic physical exercise with DHA intake has an extra benefit on hormonal and other factors that regulate calcium levels in post-menopausal women.
The hormonal factors contributing to osteoporosis are the so-called calciotropic hormones, including PTH, calcitriol and calcitonin, and sex hormones (oestrogens and androgens). Oestrogen deficiency that occurs with menopause is directly related to a decrease in BMD.6 Oestrogens play an important role in suppressing RANKL-mediated differentiation of osteoclasts and activating bone formation by stimulating osteoblasts.7 Calcitriol, on the other hand, inhibits PTH secretion, which indirectly stimulates osteoclasts, and facilitates bone mineralisation.
Osteoporosis is a silent disease that does not manifest symptoms until bone loss is significant enough to cause fractures. For this reason, the best treatment for the disease is to prevent the loss of bone mass and thus achieve a reduction in the number of fragility fractures. As a generalised measure, there are lifestyle habits that can improve bone quality, such as a balanced diet rich in calcium and vitamin D, avoiding smoking and excessive alcohol consumption, as well as daily controlled exercise to prevent falls. Physical activity provides an increase in serum concentrations of bone formation markers, as well as a decrease in bone resorption markers. On the other hand, good nutrition is essential to maintain strong and healthy bones throughout life. Both men and women between 18 and 50 years of age should consume at least 1000 mg of elemental calcium per day. This daily amount should be increased to 1200-1500 mg/day in post-menopausal women, the elderly and for periods of increased requirement such as puberty, pregnancy and lactation. Adequate vitamin D intake is also essential for calcium metabolism. There are numerous studies with combined treatments of calcium and vitamin D3 which show that in order to reduce the risk of bone fractures it is not enough to take each of these nutrients individually, but that both work synergistically to curb osteoporosis and improve bone health.8,9
It is not only calcium and vitamin D that contribute to strong, healthy bones. There are several nutrients that in combination enhance their effect and contribute to improved bone health. Each of these is discussed below, with the aim of providing the most comprehensive formula possible to slow the progression of osteoporosis.
SANGO MARINE CORAL CALCIUM
Calcium is the most abundant mineral in our body and is involved in a multitude of biological functions. When dietary intake is low, the body is forced to draw on the reserves of connective tissue and bones, as calcium is the dominant element in these tissues. In general, it is preferable to optimise calcium intake through the diet, but in many cases intake is insufficient or poorly absorbed and supplementation is necessary. Attention must be paid to the source of calcium in many food supplements, as inorganic calcium is not directly assimilated, but must be metabolised and in this process a large part of it is degraded (up to 95%). Sango sea coral calcium from Japan is a natural source of calcium that is much more bioavailable than synthetic calcium, is rapidly absorbed in its entirety by the cells, does not cause constipation and does not give rise to harmful deposits that could later become kidney or gallstones. In addition to calcium, Sango marine coral provides magnesium, sodium, potassium and other minerals and trace elements essential for life. It also has the capacity to oxygenate and alkalinise the body’s liquids and tissues in a short period of time and, given its high antioxidant power, it helps to keep the immune system in optimum condition. For all these reasons, we consider Sango coral calcium to be the best form of organic calcium supply.
This is a highly prized mushroom in traditional medicine. For many years it has been used as a tonic for longevity, stamina and vitality, especially in China and Asian countries. Since the 1980s, many scientists have been attracted to it, publishing numerous studies demonstrating its beneficial health properties, including anti-tumour, hypoglycaemic, immunomodulatory, hepatoprotective, nephroprotective, anti-inflammatory and antioxidant effects.10 Studies have also demonstrated its ability to modulate steroidogenesis. The bioactive components present in cordyceps sinensis (cordycepin, polysaccharides, ergosterol and mannitol, among others) include its isoflavones “phytoestrogens” for the treatment of osteoporosis. Its application has been studied in ovariectomised rats to test its effect on osteoporosis due to oestrogen deficiency.11 The results of this study show that cordyceps sinensis has the capacity to regulate calcium metabolism, reduce bone resorption and promote the formation of new bone, helping its regeneration and the maintenance of bone density. This is of particular interest to post-menopausal women where oestrogen deficiency leads to excessive bone resorption.
Hormone replacement therapy (HRT) helps to relieve menopausal symptoms caused by a drop in oestrogen levels, but it has been found that in some cases it can carry serious health risks. A natural and effective alternative is the use of plant extracts rich in phytoestrogens, including soy isoflavones (Glycine max), genistein and daidzein. Administration of 54 mg/day of genistein has been shown to be as effective as HRT in reducing BMD loss in the femur and lumbar spine in post-menopausal women.12 Several mechanisms explain its mode of action, ranging from direct genomic effects mediated by estrogen receptors to inhibition of protein kinases and activation of tyrosine phosphatases. Suppression of bone resorption can occur by direct inhibition of osteoclast activity or by inhibition of osteoclastogenesis. The intestinal microbiota plays an important role in the activation of soy isoflavones, as metabolites (genistein and daidzein) which are much more bioavailable are released when digested by bacteria in the colon, facilitating their absorption through the intestinal epithelium. In addition, some bacteria in the microbiota produce equol from a second enzymatic metabolism of daidzein. Some studies indicate that equol is the isoflavone-derived compound with the highest oestrogenic activity.13
Studies have linked melatonin levels to good bone health. Melatonin has been shown to increase osteoblast proliferation, stimulate the formation of the mineralised matrix and promote the expression of type I collagen and other proteins of vital importance to bone (osteocalcin, alkaline phosphatase, osteopontin, among others). In turn, melatonin increases OPG levels and decreases the expression of RANK, preventing osteoclast differentiation. On the other hand, melatonin regulates bone metabolism through its interaction with calciotropic hormones.14
Another interesting property of melatonin is its high antioxidant power, capable of eliminating free radicals which contribute to the process of bone degradation.
LICORICE EXTRACT (Glycyrrhiza glabra) AND KOREAN GINSENG (Panax ginseng)
Studies have shown the effectiveness of growth hormone (GH) as a treatment for osteoporosis. In one of these studies, women suffering from osteoporosis were treated for 3 years with GH and it was found that their BMD increased with a consequent reduction in the number of fractures from 56% to 28% compared to the control group.15 However, given the enormous number of people suffering from osteoporosis and the cost of treatment, the applicability of recombinant GH is limited. A natural alternative to this therapy is found in plant extracts of liquorice and Korean ginseng. Both glycyrrhizin from the root of Glycyrrhiza glabra and gingenosides from Panax ginseng have been shown to be effective in animal studies in increasing GH levels.16,17 These active ingredients are thought to act on the secretagogue receptors of GH or by stimulating substances that induce the production of GH.
QUERCETIN AND RESVERATROL
Quercetin is a natural flavonoid found in onions and other vegetables. It has excellent antioxidant properties and beneficial effects in the prevention of various diseases, including osteoporosis. It has been shown to increase alkaline phosphatase activity in osteoblasts, as well as its ability to inhibit bone resorption.18 Other studies confirm its role in increasing bone density by elevating biomarkers of bone formation such as osteocalcin. On the other hand, resveratrol is a natural polyphenol present in grape skins and other fruits that has a high antioxidant power. In vitro studies and animal models demonstrate its potential action as an anti-osteoporotic agent. This compound increases the proliferation and differentiation of pre-osteoblasts in vitro.19 Its mechanism of action appears to be mediated by the activation of the deacetylase Sirt1, which increases the expression of Fox03a and Runx2 in pre-osteoblastic cells. Of particular note is a study carried out in obese and osteopenic patients, in which oral administration of resveratrol (1000 mg/day for 16 weeks) significantly increased bone mass, as well as the amount of bone alkaline phosphatase, compared to the placebo group.20
GRIFFONIA SIMPLICIFOLIA (5-THP)
Griffonia Simplicifolia is an African plant rich in 5-hydroxytryptophan. 5-HTP is a natural amino acid and chemical precursor and intermediate in the biosynthesis of the neuro-transmitters serotonin and melatonin from tryptophan. Studies indicate that this molecule stimulates the proliferation of bone marrow mesenchymal stem cells, leading to increased expression of osteocalcin and alkaline phosphatase. In addition, serotonin increases bone formation by decreasing sympathetic tone and in turn decreases bone resorption by inhibiting RANKL synthesis in osteoclasts.21
BAMBOO EXTRACT (SILICON)
Bamboo extract is a very interesting natural product due to its high silicon content, which has been shown to be useful as a therapeutic or preventive agent for osteoporosis. Two epidemiological studies have shown a relationship between dietary silicon intake and osteoporosis.22 Silicon has the ability to increase BMD in the hips of men and pre-menopausal women, while in post-menopausal women the effect was not as significant. This suggests that oestrogen levels may be important for silicon metabolism and may have synergistic activity in improving bone health.23
Betaine is involved in a number of cellular and biochemical processes, including its contribution to normal homocysteine metabolism. Studies show that high levels of homocysteine in the blood (hyperhomocysteinemia) are associated with increased cardiovascular and cerebrovascular risk. In addition, the accumulation of homocysteine in plasma is toxic to the skeletal system. Betaine increases the activity of several enzymes involved in the homocysteine/methionine cycle by decreasing homocysteine levels and increasing methionine levels. It is commonly used to treat homocystinuria. A clinical consequence of this disease is osteoporosis.24
There is a worldwide consensus on the need to maintain adequate levels of vitamin D3 to maintain good bone health. But in addition to this vitamin, there are others such as vitamin B6, K, A and C which also contribute to reducing the risk of osteoporosis. The role of each of these vitamins in bone metabolism is detailed below.
- Vitamin D3
Vitamin D3 is mainly obtained through the skin by exposure to the sun and by eating certain foods such as fatty fish (tuna, salmon and mackerel). However, these sources are often not sufficient and an extra supply is needed through supplementation. The recommended daily amount of vitamin D3 in healthy children is 400 IU. In the case of hypovitaminosis D and risk of childhood osteoporosis, the treatment dose could reach 2.000 IU and be maintained for 6 weeks. The absorption of calcium in the intestine is regulated by the level of vitamin D in plasma, being higher as the levels of this vitamin increase. In adults, there is some controversy in deciding what should be the adequate vitamin D3 intake to achieve plasma levels above 30 ng/ml. The IOF (International Osteoporosis Foundation) recommends supplementation between 800 and 1.000 IU/day to achieve these levels. On the other hand, studies show that this dose should be 10 times higher.25 Ideally, to adjust the correct dose for each individual, analytical monitoring of vitamin D levels in patients under treatment should be done in order to avoid possible intoxication.
- Vitamin B6
Pyridoxine is very important for the normal functioning of the nervous and immune systems, but its applicability in osteoporosis lies in its involvement in the proper functioning of the enzyme tryptophan hydroxylase, which is key in the metabolic pathway of tryptophan to give rise to the serotonin and melatonin mentioned above.26
- Vitamin K2
Vitamin K is involved in the regulation of calcium in the body. While preventing vascular and soft tissue calcifications, vitamin K also promotes the integration of calcium into bone. There are 3 vitamin K-dependent proteins in bone: osteocalcin (OC), matrix protein Gla and protein S. Vitamin K acts as a cofactor for D-carboxylase and is essential for gamma-carboxylation of osteocalcin. OC is synthesised by osteoblasts during the mineralisation phase of bone formation and is essential for the formation of hydroxyapatite crystals. In the absence of vitamin K, osteocalcin lacks structural integrity and is unable to bind to the mineral hydroxyapatite. Menaquinone-7 (vitamin K2) supplementation has been shown to result in carboxylation of osteocalcin, thus contributing to improved bone health.27
- Vitamin A y C
The main property of these vitamins lies in their high antioxidant power. A reduction in oxidative stress reduces the rate of bone loss, as free radicals are directly involved in bone resorption, favouring osteoclastogenesis and apoptosis of bone-forming cells. Therefore, the consumption of antioxidant vitamins can be very beneficial in combating osteoporosis and reducing the number of fractures.28
- Rodríguez García I, Rodríguez Pérez M. Epidemiología de la osteoporosis. An Med Inter. 2007; 24:2-6.
- NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis and Therapy. JAMA. 2001; 285:785-95.
- Neer, R.M.; Arnaud, C.D.; Zanchetta, J.R.; Prince, R.; Gaich, G.A.; Reginster, J.Y.; Hodsman, A.B.; Eriksen, E.F.; Ish-Shalom, S.; Genant, H.K.; et al. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. Engl. J. Med. 2001; 344, 1434–1441.
- Boyle W.J, Scott Simonet W, Lacey D.L. Osteoclast differentiation and activation. Nature.2003; 423:337-42.
- Krantz E. et al. Effect of growth hormone treatment on fractures and quality of life in postmenopausal osteoporosis: a 10-year follow-up study. J Clin Endocrinol Metab, 2015; 100: 3251–3259.
- Fink K, Clark B. Screening for osteoporosis in postmenopausal women. Am Fam Physician. 2004; 69:139-40.
- Zallone A. Direct and indirect estrogen actions on osteoblasts and osteoclasts. Ann N Y Acad Sci, 2006 ;1068: 173-9.
- Weaver, C.M et al. Calcium plus vitamin D supplementation and risk of fractures: an updated meta-analysis from the National Osteoporosis Foundation Osteoporos Int.2016;27(1):367-7.
- Paschalis E.P. Vitamin D and calcium supplementation for three years in postmenopausal osteoporosis significantly alters bone mineral and organic matrix quality. Bone.2017;95:41.
- Ugyen Choda. Medicinal Value of Cordyceps sinensis. translational biomedicine, 2017,8(4):132.
- Zhang et al. The effects of Cordyceps sinensis phytoestrogen on estrogen deficiency-induced osteoporosis in Ovariectomized ratsBMC Complementary and Alternative Medicine 2014, 14:484.
- Morabito N. et al. Effect of genistein and hormone-replacement therapy on bone loss in early postmenopausal women: a randomized double-blind placebo-controlled study. J Bone Miner Res, 2002; 17:1904–1912.
- Rafii F.The Role of Colonic Bacteria in the Metabolism of the Natural Isoflavone Daidzin to Equol. Metabolites.2015; 5: 56-73.
- Liu J., et al. Melatonin effects on hard tissues: bone and tooth. Int J Mol Sci. 2013; 10;14(5):10063-74.
- Krantz E. et al. Effect of growth hormone treatment on fractures and quality of life in postmenopausal osteoporosis: a 10-year follow-up study. J Clin Endocrinol Metab, 2015; 100: 3251–3259.
- Lee H.Y et al. Induction of growth hormone release by glycyrrhizae radix on rat. J Biochem Mol Biol. 2007;40(6):979-85.
- Yoshizato H. et al. Stimulation of Growth Pituitary and Brain by Hormone Gene Panax ginseng C. A. MEYER. Endocrine Journal, 1999, 46 (Suppl), S85-S88.
- Wong, R. W.K. and Rabie, A. B. M., Effect of quercetin on bone formation. Orthop. Res.; 2008, 26: 1061–1066.
- Mizutani K, Ikeda K, Kawai Y, Yamori Y. Resveratrol stimulates the proliferation and differentiation of osteoblastic MC3T3-E1 cells. Biochem Biophys Res Commun. 1998; 253:859-63.
- Ornstrup MJ, Harsløf T, Kjær TN, Langdahl BL, Pedersen SB. Resveratrol increases bone mineral density and bone alkaline phosphatase in obese men: a randomized placebo-controlled trial. J Clin Endocrinol Metab. 2014; 99:4720-9.
- Michalowska M. et al. New insights into tryptophan and its metabolites in the regulation of bone metabolism. J Physiol Pharmacol. 2015; 66(6):779-91.
- Jugdaohsingh, K. L. et al. Dietary silicon intake is positively associated with bone mineral density in men and premenopausal women of the Framingham Offspring cohort, Journal of Bone and Mineral Research, 2004; 19 (2), 297–307.
- M. Macdonald, et al. Dietary silicon intake is associated with bone mineral density in premenopausal women and postmenopausal women taking HRT, Journal of Bone and Mineral Research, 2005, 20, S393.
- Van Meurs J.B.J et al. Homocysteine levels and therisk of osteoporotic fracture. N Engl J Med. 2004; 350:2033-41.
- Veugelers, P.J. and Ekwaru, J.P. A Statistical Error in the Estimation of the Recommended Dietary Allowance for Vitamin D. Nutrients, 2014; 6, 4472-4475.
- Birdsall T.C. 5-Hydroxytryptophan: A Clinically-Effective Serotonin Precursor. Altern Med Rev; 1998; 3(4): 271-280
- Beulens J.W et al The role of menaquinones (vitamin K2) in human health. Br J Nutr. 2013; 110:1357-8.
- Sugiura M. et al. High Vitamin C Intake with High Serum β-Cryptoxanthin Associated with Lower Risk for Osteoporosis in Post-Menopausal Japanese Female Subjects: Mikkabi Cohort Study. J Nutr Sci Vitaminol, 2016; 62(3):185-91.