REVIEW
Treatment with vitamin D3 and/or vitamin K2
for postmenopausal osteoporosis
Jun Iwamoto, Tsuyoshi Takeda and Shoichi Ichimura1
Department of Sports Medicine, School of Medicine, Keio University, 1Department of Orthopaedic Surgery
Kyorin University School of Medicine, Tokyo, Japan(Received for publication on January 29, 2003)

Abstract. It is established in Japan that treatment with 1a-hydroxyvitamin D3 (alfacalcidol) slightly
reduces bone turnover, sustains lumbar bone mineral density (BMD), and prevents osteoporotic
vertebral fractures in postmenopausal women with osteoporosis, while vitamin K2 (menatetrenone)enhances g-carboxylation of bone glutamic acid residues and secretion of osteocalcin, sustains lumbar
BMD, and prevents osteoporotic fractures in patients with osteoporosis. Available evidence suggeststhat the effect of vitamin K2 on mineralization by human periosteal osteoblasts is enhanced in thepresence of 1,25 dihydroxyvitamin D3 in vitro. The effect of vitamin K2 on BMD in ovariectomized rats
is affected by the plasma 25-hydroxyvitamin D3 level in vivo, and is signiﬁcant only when rats are fed adiet containing vitamin D3 . Based on this line of evidence, combined treatment with alfacalcidol andmenatetrenone for osteoporosis is surmised to be more effective than treatment with menatetrenone
alone, and may have anabolic effects on osteoporotic bone. This combined treatment may increasebone formation as well as bone resorption over the mild anti-resorptive effect of alfacalcidol itself, andshows the greatest effect on lumbar BMD or the incidence of vertebral fractures in studies in which themean age and years since menopause of subjects were low and the degree of osteoporosis was mild.
It may be effective for mild postmenopausal osteoporosis in which age-related deterioration of trabecular bone properties remains below the threshold for vertebral fractures, even if bone resorption isincreased and trabecular bone has deteriorated. (Keio J Med 52 (3): 147–150, September 2003)
Key words: vitamin D3 , vitamin K2 , postmenopausal osteoporosis, bone formation, bone resorption

Introduction
One a-hydroxyvitamin D3 (alfacalcidol) and vitamin
K2 (menatetrenone) are widely used for the treatmentof osteoporosis in Japan. It is established that treatment with alfacalcidol slightly reduces bone turnover,sustains lumbar bone mineral density (BMD), andprevents osteoporotic vertebral fractures in postmenopausal women with osteoporosis.1 It is also reported
that treatment with active vitamin D metabolites including alfacalcidol or calcitriol with or without calcium
supplementation is effective in preventing hip fractures in elderly women.2,3 On the other hand, menatetrenone enhances g-carboxylation of bone glutamic
acid (Glu) residues and secretion of osteocalcin, sustains lumbar BMD, and prevents osteoporotic fracturesin patients with osteoporosis.4 It has been suggested

that vitamin K insufﬁciency might contribute to osteoporotic fractures.5,6The effect of vitamin K2 on bone formation andresorption is not yet established. Vitamin K2 is a cofactor of g-carboxylase, which converts the Glu residue
to a g-carboxyglutamic acid (Gla) residue in osteocalcin molecules, and is essential for g-carboxylationof osteocalcin.7,8 Available evidence suggests that vitamin K2 enhances osteocalcin accumulation in the extracellular matrix of osteoblasts in vitro.9 Osteocalcin
knockout mice develop hyperostosis,10 suggesting that
Gla-containing osteocalcin promotes normal bone mineralization. Although the role of osteocalcin in bonemineralization remains obscure, it may regulate thegrowth of hydroxyapatite crystals.11
In regard to the interaction between vitamin K2 andvitamin D3 , the effect of menatetrenone on mineral-

Reprint requests to: Dr. Jun Iwamoto, Department of Sports Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku,
Tokyo 160-8582, Japan, e-mail: jiwamoto@sc.itc.keio.ac.jp
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ization by human periosteal osteoblasts is enhanced in
the presence of 1,25 dihydroxyvitamin D3 in vitro.12
The effect of menatetrenone on femoral BMD in
ovariectomized rats is affected by the plasma 25hydroxyvitamin D3 level in vivo, and is signiﬁcant only
when rats are fed a diet containing vitamin D3 .13 The
effect of menatetrenone on lumbar BMD is greater inosteoporotic patients with higher serum levels of 1,25and 24,25-dihydroxyvitamin D3 and 25-hydroxyvitamin
D3 .14 This line of evidence allows us to surmise that the
efﬁcacy of combined treatment with alfacalcidol andmenatetrenone for osteoporosis may be greater thanthat of treatment with menatetrenone alone, and may
have beneﬁcial anabolic effects on osteoporotic bone.
However, the results of this combined treatment forpostmenopausal osteoporosis have not always been
consistent. This paper discusses the effect of treatment
with alfacalcidol and/or menatetrenone for postmenopausal osteoporosis.
Treatment with Alfacalcidol or Menatetrenone for
Postmenopausal Osteoporosis
Preclinical studies
Alfacalcidol causes dose-dependent suppression ofbone resorption, and yet maintains or even stimulatesbone formation, as reﬂected in increases in the serum
osteocalcin level and the bone formation rate at bothtrabecular and cortical sites in ovariectomized rats.15
Alfacalcidol can also prevent ovariectomy-induced deterioration of trabecular bone microarchitecture.16 On
the other hand, the effect of menatetrenone on boneloss induced by ovariectomy in rats remains controversial. Some studies show that menatetrenone prevents
early bone loss through the inhibition of bone resorption,17 and protects against the loss of trabecular bonevolume and its connectivity in ovariectomized rats.18
Another study shows that menatetrenone does not reduce the ovariectomy-associated increase in bone turnover or decline in distal femoral BMD.19 Thus, the effect of menatetrenone on bone loss and bone formation
and resorption in ovariectomized rats is not established.
However, there is some evidence indicating that menatetrenone retards the increase in bone turnover inorchidectomized rats and ameliorates the increase inbone resorption and decrease in bone formation in sciatic neurectomized rats.20 Because the doses of alfacalcidol and menatetrenone used in these studies arepharmacologic, not physiologic, it is not known whether
these results are applicable to humans.
Clinical studies
It is established that treatment with alfacalcidol
slightly reduces bone turnover, sustains lumbar BMD,

Iwamoto J, et al: Vitamin D and vitamin K for osteoporosis

and prevents osteoporotic vertebral fractures in postmenopausal women with osteoporosis.1 Calcitriol also
reduces bone turnover in postmenopausal women,
which is partly a consequence of the enhanced intestinal
absorption of calcium and suppressed serum parathyroid hormone level.21 The increase in serum 25hydroxyvitamin D level and decrease in serum parathyroid hormone level by treatment with active vitamin
D3 may be greater in patients with a lower baseline
serum 25-hydroxyvitamin D level.22 Calcitriol with calcium supplementation is effective in preventing hip
fractures in elderly women.2 On the other hand, treatment with menatetrenone enhances g-carboxylationof bone Glu residues and secretion of osteocalcin, sustains lumbar BMD, and prevents osteoporotic fracturesin patients with osteoporosis.4 The effect of menatetrenone on lumbar BMD may be greater in early postmenopausal (e 5 years after menopause) women thanin late (> 5 years after menopause) postmenopausal
women.23 Serum undercarboxylated osteocalcin may reﬂect the low activity of vitamin K, and a higher incidenceof femoral neck fractures is observed in patients withhigher levels of undercarboxylated osteocalcin.5,24,25
The reason that despite no signiﬁcant increase in BMD,
both drugs individually prevent osteoporotic fractures
including vertebral fractures remains uncertain. Bonestrength is primarily determined not only by BMD, butalso by bone microarchitecture, skeletal mineralization,
microdamage, etc. Thus, both drugs may individually
have the potential at least to improve deterioration ofbone architecture as shown in preclinical studies using
animals, resulting in improvement of the deteriorationof bone strength and subsequent osteoporotic fractures.
Combined Treatment with Alfacalcidol and
Menatetrenone for Postmenopausal Osteoporosis
Preclinical studies
No evidence has been reported concerning the therapeutic effect of combined administration of vitamin D3
and vitamin K2 on bone mass in animals with established osteoporosis induced by ovariectomy. However,a few studies have demonstrated a preventative effectof this combined treatment on bone mass in ovariectomized rats. Matsunaga et al.26 and Hara et al.27 demonstrated that combined treatment of alfacalcidol andmenatetrenone was more effective for loss of bonemass and/or bone properties in ovariectomized rats.
Although these two studies did not clarify the mechanism of the positive effect of this combined treatment
on ovariectomy-induced osteoporosis, these results may
support the synergistic effect of combined treatment
with alfacalcidol and menatetrenone on bone loss in theearly phase of estrogen deﬁciency after the menopause.

Keio J Med 2003; 52 (3): 147–150

Clinical studies
A few well-controlled studies have demonstrated
the effect of combined treatment with alfacalcidol andmenatetrenone on postmenopausal osteoporosis.28–30
Ushiroyama et al.28 reported that in early postmenopausal women with osteopenia/osteoporosis31,32 (meanage: 52.8–54.1 years), treatment with alfacalcidol or
menatetrenone sustained lumbar BMD over 2 years,
while this combined treatment increased serum cterminal peptide of type I procollagen (PICP) level aswell as urinary pyridinoline level and tended to increaseosteocalcin level from baseline, resulting in a signiﬁcant
increase in lumbar BMD by 4.92%. We also reported
that in late postmenopausal women (mean age: 64.0
years), treatment with alfacalcidol or menatetrenone
sustained lumbar BMD over 2 years, while this combined treatment signiﬁcantly increased lumbar BMD by
1.35% with a signiﬁcantly greater increase than either
treatment with alfacalcidol or menatetrenone alone.29
On the other hand, Kobayashi et al.30 reported thatin elderly patients with osteoporosis, combined treatment with alfacalcidol and menatetrenone over 2 years
increased urinary deoxypyridinoline level, resulting ina decrease in lumbar BMD and an increase in theincidence of vertebral fractures, while treatment withalfacalcidol increased lumbar BMD with a signiﬁcantly
greater increase than combined treatment, and treatment with menatetrenone decreased it by a similar degree to combined treatment.
Thus, the results of combined treatment with alfacalcidol and menatetrenone for postmenopausal osteoporosis are not always consistent. However, it appears
that this combined treatment had the greatest effecton lumbar BMD or the incidence of vertebral fracturesin studies in which the mean age and years sincemenopause of subjects were low and the degree ofosteoporosis was mild. The effects of combined treatment with alfacalcidol and menatetrenone on bonemass appear to be greater than those of either treatment with alfacalcidol or menatetrenone alone in early
postmenopausal women with mild osteoporosis rather
than in late postmenopausal women with establishedosteoporosis. Curiously, the effect of this combined
treatment in postmenopausal women with osteoporosis
seems to be anabolic despite the mild anti-resorptive
effect of alfacalcidol itself. The effect of menatetrenone
on bone formation may become signiﬁcant in the presence of alfacalcidol.
The reason why combined treatment with alfacalcidol and menatetrenone had the greatest effect on lumbar BMD or the incidence of vertebral fractures inthe studies in which the mean age and years sincemenopause of subjects were low and the degree ofosteoporosis subjects had was mild, remains uncertain.

149

The difference between early postmenopausal womenwith mild osteoporosis and late postmenopausal womenwith established osteoporosis lies in deterioration of trabecular bone architecture and properties, because as
trabecular thickness and trabecular number decrease,trabecular spacing increases, and trabecular bone volume and network deteriorate with age in postmenopausal women, and these factors play an important rolein the determination of trabecular bone properties.33
Therefore, age and severity of osteoporosis may inﬂuence the effect of anabolic agents on postmenopausal
osteoporosis because they also increase bone resorption. Thin trabeculae due to aging and/or severe osteoporosis are easily perforated by increased bone resorption caused by combined treatment with alfacalcidoland menatetrenone despite increased bone formation,
resulting in deterioration of the trabecular bone volume
and trabecular network and an increased risk ofvertebral fractures. In early postmenopausal womenwith osteopenia/osteoporosis, on the other hand, eventhough increased bone resorption caused by this combined treatment erodes thick trabeculae, trabecularbone volume and trabecular bone properties may remain below the threshold for vertebral fractures. Then,
increased bone formation can increase trabecular bonevolume without the occurrence of vertebral fractures.
Thus, combined treatment with alfacalcidol and menatetrenone may be effective for mild postmenopausal
osteoporosis in which the age-related deterioration ofbone properties remains below the threshold for theoccurrence of vertebral fractures, even if bone resorption is increased and trabecular bone has deteriorated.
Conclusion
Treatment with 1a-hydroxyvitamin D3 (alfacalcidol)slightly reduces bone turnover, sustains lumbar BMD,
and prevents osteoporotic vertebral fractures in postmenopausal women with osteoporosis, while vitamin K2(menatetrenone) enhances g-carboxylation of bone Glu
residues and secretion of osteocalcin, sustains lumbar
BMD, and prevents osteoporotic fractures in patientswith osteoporosis. Combined treatment with alfacalcidol and menatetrenone may increase bone formation as
well as bone resorption over the mild anti-resorptive
effect of alfacalcidol itself, and shows the greatest effecton lumbar BMD in studies in which the mean age andyears since menopause of subjects were low and thedegree of osteoporosis was mild. It may be effective for
mild postmenopausal osteoporosis in which age-related
deterioration of trabecular bone properties remains
below the threshold for vertebral fractures, even if bone
resorption is increased and trabecular bone has deteriorated.

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Iwamoto J, et al: Vitamin D and vitamin K for osteoporosis

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