|Bone is a dynamic tissue that undergoes continual adaptation
during vertebrate life to attain and preserve skeletal size, shape,
and structural integrity and to regulate mineral homeostasis. Two
processes, remodeling and modeling, underpin development and
maintenance of the skeletal system . Bone modeling is responsible
for growth and mechanically induced adaptation of bone and requires
the processes of bone formation and bone removal (resorption). Bone
remodeling is responsible for removal and repair of damaged bone to
maintain integrity of the adult skeletal and mineral homeostasis. Bone
homeostasis, which maintains bone mass, is skillfully regulated through
osteoclasts, osteoblasts and osteocytes, which are major cells in bone
tissues. Bone homeostasis is regulated through various physiological
systems including many hormones and cytokines and immune systems,
and it is disturbed through various pathophysiological states that
induce osteoporosis. Aging induces a reduction in bone mass with a
decrease in osteoblastic bone formation and an increase in osteoclastic
bone resorption. Osteoporosis with its accompanying decrease in bone
mass is widely recognized as a major public health problem. The most
dramatic expression of the disease is represented by fractures of the
proximately femur, and the number of which increase as the population
ages [2,3]. Moreover, bone loss has been shown to stimulate in various
pathophysiologic states including inflammation, obesity, diabetes,
and cancer cell bone metastasis . Malnutrition or undernutrition is
often observed with increasing ages, and it appears to be more intense
in patients with hip fracture than in the general aging population .
The deficiency in both micronutrients and macronutrients appears to
be strongly implicated in the pathogenesis and consequences of hip
fracture in the osteoporotic elderly. This may generate the concept
that bone homeostasis is regulated through various nutritional and
food factors in maintaining bone health in long life. There is growing
evidence that nutritional and functional food factors have a role in the
prevention of bone loss with increasing age . Food life style may help
to prevent bone loss with aging. Chemical factors including vitamins
and minerals in food and plants, which regulate bone homeostasis, have
been to be notice. Recent studies have been shown that these factors
stimulate osteoblastic bone formation and suppress osteoclastic bone
resorption in osteoporosis animal models and human subjects ,
thereby increasing bone mass. Supplemental intake of ingredients plays
an important role in maintaining bone health and in the prevention of
bone loss. This may provide a new tool in the treatment of osteoporosis.
|Calcium, phosphorus and vitamin D, which are nutrients,
were noticed in maintaining bone health and in the prevention of
osteoporosis. Calcium and phosphorus are essential elements in
bone composition and are regulated through calcium-regulating
hormones including parathyroid hormone, 1, 25-dihydroxyvitamin D3
and calcitonin. Nutrient vitamin D3 is converted to hydroxyVitamin
D3 [25(OH)D3] in the liver and then 1,25-dihydroxyVitamin D3
[1,25(OH)2D3] in the kidney which are its active metabolite. These forms
are hormone recognized to play a critical function in bone metabolism.
This is evidenced by formation of poorly mineralized bone during
vitamin D3 deficiency leading to rickets in children and osteomalacia
in adults. This is largely a consequence of the necessity for vitamin D
to promote efficient calcium absorption in the small intestine. Any
decline in serum calcium concentrations due to inadequate calcium
absorption leads to a secondary hyperparathyroidism that catabolizes the skeleton to maintain a physiological level of calcium necessary for
normal cellular metabolism . Although vitamin D supplementation
is commonly used to combat osteoporosis, currently the optimal
dose of vitamin D required for fracture prevention is contentious.
While a minimum of 10 ng/mL of 25(OH)D3 is sufficient to prevent
rickets and osteomalacia , recent studies have demonstrated that
a minimum threshold 25(OH)D3 level of 29.7 ng/mL is necessary
for protection from fracture . However, there is a paucity of data
as to the optimal vitamin D concentration for fracture prevention
and to complicate matters it is now appreciated that vitamin D plays
a number of extra-skeletal roles including promotion of innate and
adaptive immune function, prevention of cancers, and prevention of
hypertension [8,9]. The doses of vitamin D needed to achieve these
extra-skeletal actions may be considerable higher than that needed
to effect its actions on the skeleton . Recent meta-analysis have
suggested that supplementation of greater than 400 IU of vitamin D
may reduce fractures , however the mechanism is unclear and may
be associated in part with decreased risk of falling as a consequence
of improved neuromuscular function . In a clinical study of
bedridden older patients with chronic secondary hyperparathyroidism,
low dose (400 IU/d) vitamin D supplementation led to a significant
increase in amino-terminal propeptide of type I procollagen, a marker
of in vivo bone formation. These gains were complete negated by high
dose (1200 IU/d) vitamin D supplementation, while indices of bone
resorption did not significantly change with either regimen . In
another study, wintertime vitamin D supplementation of healthy
men led to a significant dose-dependent decline in bone specific
alkaline phosphatase, a marker of in vivo mineralization . As
the vast majority of studies involve vitamin D supplementation in
the context of antiresorptive therapy, typically a bisphosphonate, it
becomes extremely difficult to assess and effects of vitamin D alone
on bone turnover given that antiresorptive agents themselves potently
suppress bone formation as a consequence of coupling. Furthermore,
the amelioration of secondary hyperparathyroidism by vitamin D
supplementation is often associated with a decline in bone turnover
. This may be a consequence of reduced parathyroid hormone
(PTH)-driven bone resorption leading to reduced bone formation
as a consequence of coupling. Vitamin D further appears to have
hallmarks of an anti-inflammatory agent as vitamin D deficiency
has been linked to a number of different inflammatory conditions
including inflammatory bowel disease and rheumatoid arthritis. In a
population-based prospective cohort, vitamin D intake was inversely
correlated with risk of rheumatoid arthritis , an inflammatory autoimmune disease. Furthermore, vitamin D insufficiency promotes
the development of autoimmunity in animal models of inflammatory
bowel disease .
|Vitamin K is known as a blood coagulative factor. There are
three types of vitamin K: vitamin K1 (phylloquinone), vitamin K2
(menaquinone), and vitamin K3 (menadione). Menaquinone-4 (MK-
4), with four isoprene units, not only enhances mineralization but also
increases amount of osteocalcin, which has a high affinity to calcium
and/or hydroxyapataite, in human osteoblasts. MK-4 has been shown
to inhibit bone resorption and inhibits bone loss in ovariectomized rats.
Menaquinone-7 (MK-7) with seven isoprene units is very abundant in
fermented soybean. Dietary vitamin K intake has beneficial effects on
bone. MK-7 has a stimulatory effect on osteoblastic bone formation due
to increasing protein synthesis including osteocalcin . Also, MK-7
has an inhibitory effect on osteoclastogenesis . Suppressive effects
of MK-7 on osteoclasts may be partly mediated through the pathway
of Ca2+- and cyclic AMP-dependent signaling. The actions of MK-7 on
osteoblasts and osteoclasts are accomplished by down regulating basal
and cytokine-induced the nuclear factor kappa B (NF-κB) activation,
by increasing IκB mRNA, in a γ-carboxylation-independent manner
. Vitamin K2 is a transcriptional regulator of bone-specific genes
that act through steroid and xenobiotic receptors (SXRs) to promote
expression of osteoblastic markers. The intake of dietary MK-7 has a
preventive effect on bone loss caused in ovariectomized rats, an animal
model for osteoporosis, in vivo. The intake of dietary MK-7 with
fermented soybean can stimulate γ-carboxylation of osteocalcin in
normal human subjects. Dietary MK-7 may be useful in the prevention
and treatment of osteoporosis. Intake of fermented soybean, which
largely containes MK-7, has been shown to have preventive effects on
bone fracture in Japan.
|Genistein is a functional food factor, which is largely contained in
soybeans and fermented soybeans. Genistein has been shown to have
a stimulatory effect on osteoblastic bone formation and a suppressive
effect on osteoclastic bone resorption, thereby increasing bone mass
[19,20]. Genistein has regulatory effects on protein synthesis and
gene expression, which are related to bone formation in osteoblastic
cells and bone resorption in osteoclastic cells. Genistein has been
shown to directly evoke apoptosis of mature osteoclastic cells. Oral
administration of genistein has been shown to prevent on bone loss in
ovariectomized rats, indicating a role in the prevention of osteoporosis.
Moreover, the intake genistein has been shown to have a restorative
effect on osteoporosis in human subjects, suggesting a role in the
treatment of bone loss [21,22]. Zinc plays a pivotal role as an essential
nutritional factor in the growth of animals and human. Bone growth
retardation is a common finding in various conditions associated
with dietary zinc deficiency. Bone zinc content has been shown to
decrease in aging, skeletal unloading and postmenopausal conditions,
suggesting its role in bone disorder.
|Zinc has been demonstrated to have stimulatory effects on
osteoblastic bone formation and mineralization due to stimulating
cellular protein synthesis and the gene expression of the transcription
factors runt-related transcription factor 2 (Runx 2), which is related
to differentiation into osteoblastic cells [23,24]. Moreover, zinc
has been shown to inhibit osteoclastic bone resorption due to
inhibiting osteoclast-like cell formation from bone marrow cells and
stimulating apoptotic cell death of mature osteoclasts [23,25]. Zinc
has a suppressive effect on the receptor activator of nuclear factor
(NF)-κB ligand (RANKL)-induced osteoclastogenesis. The intake
of zinc causes an increase in bone mass. Oral administration of zinc
compound has potent-restorative effects on bone loss under various pathophysiologic conditions including aging, skeletal unloading,
aluminium bone toxicity, calcium- and vitamin D-deficiency, adjuvant
arthritis, estrogen deficiency, diabetes, and fracture healing . Zinc
compounds may be designed as new supplementation factor in the
prevention and treatment of osteoporosis.
|Interestingly, the osteogenic effects of vitamin D3 [26-29], MK-7
[30,31] and genistein [32-38] have been found to be synergistically
enhanced with combination of zinc and also have potential
suppressive effects on osteoclastic bone resorption. Such effects may
be based on protein synthesis and gene expression, which are related
to osteoblastic bone formation and osteoclastic bone resorption. Oral
administration with combination of vitamin D3, MK-7, genistein and
zinc has been shown to have a synergistic-preventive effect on bone
loss in aged and ovariectomized rats, an animal model for osteoporosis.
Moreover, supplemental intake of their ingredient has potent effects
on osteoporosis in human subjects. Such combination of biomedical
food factors may be a potential useful tool in maintaining bone
health and in the prevention and treatment of osteoporosis in various
pathophysiological states. Anti-resorptive agents have long been the
preferred standard of care for the amelioration of bone loss. Although
in general anti-resorptive agents do an excellent job of preventing
additional bone loss, they do not allow for adequate regeneration
of lost bone mass. Drugs, which are used clinically in the treatment
of osteoporosis, are mainly based on the action of osteoclastic bone
resorption. An intensive effort has begun to identify or develop anabolic
agents capable of rebuilding lost bone mineral density. At present,
teriparatide, a fragment of human parathyroid hormone is the only
United State Food and Drug Administration (FDA) approved anabolic
agent currently available. This agent represents a significant leap
forward but as a biologic based agent its use is limited by high cost and
the need for daily injection. Furthermore, therapy is not recommended
for more than 2 years due to the potential for osteosarcoma. As a
consequence there is intense interest in the identification of additional
anabolic agents. Clinical compounds that stimulate bone formation are
under development. Supplements with chemically pure ingredients of
vitamin D3, MK-7, genistein and zinc, which have potential osteogenic
effects, will be expected to use as new drug for osteoporosis.
|Author Contribution and Disclosures
|The author contributed to the design and conduct of the study, collection,
analysis, and interpretation of data, and manuscript writing. Author has no conflicts
|The author was partly supported by Awards of the Mishima Kaiun Memorial
Foundation (Japan), the Senji Miyata Foundation (Japan), and the Japan Society
for Biomedical Research on Trace Elements.
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