Bone health: the role of micronutrients
Susan A New
Centre for Nutrition and Food Safety, University of Surrey, Guildford, UK
Development and maintenance of skeletal health is essential since the resultant
effect of poor bone health is an increased risk of osteoporotic fracture. Osteoporosis is currently a major public health problem and with predicted demographic changes, its future health and economic impact is likely to be phenomenal. Adult bone health is predominantly governed by two factors: (i) maximum
attainment of peak bone mass; and (ii) rate of bone loss which occurs with
ageing. Both aspects are determined by a combination of endogenous and
exogenous factors and, although genetic influences are believed to account for
up to three-quarters of the variation in bone mass, there is still room for the
modifiable factors (including nutrition) to play an important role. There is now
good evidence to show that calcium is important not only to peak bone mass
development but also in reducing bone loss in women who are greater than 5
years postmenopause. Vitamin D and calcium (and possibly vitamin K) are vital to
fracture prevention in the elderly. Our knowledge of the influence of other
micronutrients on bone health remains limited and further research is required to
establish the essential ingredients for optimum bone health.
Correspondence to:
Dr Susan A New, Centre
for Nutrition and Food
Safety, School of
Biological Sciences,
University of Surrey,
Guildford GU2 5XH, UK
Predisposition to poor bone health will result in an increased risk of
fracture and hence the clinical diagnosis of osteoporosis. This term was
first described1 in France around 1820 as 'porous bone' and is now
considered a disorder in which there is a diminution of bone mass without
detectable changes in the ratio of mineralized to non-mineralised matrix2.
Since 1991, osteoporosis has been defined as: 'a disorder characterised by
increased skeletal fragility due to decreased bone mass and to microarchitectural deterioration of bony tissue'.
This newer definition shifts the focus of attention from reduced bone
mass to that of bone fragility and, hence, reflects the growing recognition
that bone weakness is related to poor structural quality as well as
decreased bone mass3. An illustration of 'normal' and 'osteoporotic' bone
is shown in Figure 1.
The clinical significance of osteoporosis is related to the fractures which
occur, affecting in particular the proximal femur (hip fractures), the spine
(vertebral crush fractures) and the distal radius (Colles fracture). It is
estimated that about 1.66 million hip fractures occurred world-wide in
British Medical Bulletin 1999; 55 (No 3)- 619-633
© The British Council 1999
Micronutrients in health and disease
HEALTHY BONE
OSTEOPOROTIC BONE
Fig. 1 Comparison of enlargement of normal hearthy bone as in a woman of 35 years with
bone in a woman over 60 years with severe osteoporosis. Reproduced with permission from
the National Osteoporosis Society, UK.
1990 and lifetime risks are 17.5% in women and 6.0% in men with
approximately 70,000 hip fractures occurring in British women each
year4. Osteoporosis is clearly a major public health problem with annual
costs to the UK National Health Service estimated at nearly £750 million
for women alone and around £942 million if the costs of treating male
fractures are included5. Furthermore, the future health and economic
impacts of osteoporosis will be phenomenal when it is considered that by
the year 2030, elderly people are predicted to account for one in four of
the adult UK population with a projection of the rise in the number of
fractures from 1.66 million in 1990 to 6.26 million by the year 2050 2 .
Two mechanisms principally determine adult bone health: (i) the
maximum attainment of peak bone mass (PBM) which is achieved during
growth; and (ii) the rate of bone loss with advancing age. Both mechanisms
are believed to be determined by a combination of endogenous and exogenous factors, namely: genetic, endocrine, mechanical and nutrition, with
extensive interactions between them. Studies of bone mass in monozygotic
and dizygotic twins6 and in mother-daughter pairs7, together with the
findings of an association between polymorphisms of the vitamin D
receptor gene8, oestrogen receptor gene9 and collagen I a 1 gene10 and bone
mass provide strong evidence that the genetic factors account for up to
three-quarters of the variation in bone mass. However, there is still room
for the modifiable factors (including nutrition) to play a vital role in bone
health.
This chapter will focus on the importance of micronutrients to bone
health by examining our current knowledge on the relationship between
nutrition and bone mass within the three key stages of skeletal health,
namely: (i) in the development of maximum peak bone mass; (ii) in the
reduction of perimenopausal and postmenopausal bone loss; and (iii) in the
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British Medical Bulletin 1999; 55 (No. 3)
Bone health: the role of micronutrients
risk of fracture. Attention will focus on calcium, since most studies have
concentrated on this nutrient but consideration will also be given to the role
of other micronutrients including: vitamin D, magnesium, phosphorus, the
trace elements (zinc, copper and manganese), vitamin C, vitamin K and
potassium. The chapter will conclude with a summary of the clinical
relevance of these nutrients and indications of areas for further research.
Role of micronutrients to peak bone mass attainment
Calcium
The important minerals within bone are calcium, phosphate and
magnesium with approximately 1 kg of calcium being contained within
the adult skeleton as a complex crystalline material with phosphate in
the form of hydroxyapatite 11 . It is important to understand that the
skeleton is not just a repository for calcium but has a mechanical as well
as biochemical function. Furthermore, in trying to understand the
importance of nutrition to bone health, it should be emphasised that the
skeleton is not inert but is being continually removed and replaced by
the actions of the cells within it and that these cells are controlled by a
number of mechanical and hormonal factors12.
The importance of calcium to peak bone mass attainment was first
highlighted by the work of Boyd Orr in the 1920s, who showed that
children provided with milk grew taller than those without a milk supplement 1314 . A formal assessment of their bone health was, of course, not
available. Although the importance of dietary calcium to PBM attainment
has been highlighted by a number of cross-sectional studies15"20, it was not
until 1992 that the first 3 year, double blind, placebo-controlled trial on
the effect of calcium supplementation on bone mineral density in children
was undertaken. A total of 45 pairs of identical twins (22 prepubertal and
23 postpubertal), with one twin serving as a control for the other were
studied. The calcium supplement enhanced the rate of increase in bone
mineral density in the prepubertal group 21 .
Other calcium supplementation studies have since followed, each
showing that an increased calcium intake is associated with higher bone
mineral status of approximately 1-5% (particularly in prepubertal
children) depending on the skeletal site and with the greatest impact in the
early months of the supplementation period22"24. The importance of
calcium to PBM development has been further highlighted by supplementation trials using calcium enriched foods25 and dairy products26. The
first British study was published in 1997 and using milk as the supplementation source; PBM was enhanced in the milk group 27 . Although there
is some concern that the effects may, in part, be influenced by increased
British Medical Bulletin 1999; 55 (No. 3)
621
Micronutrients in health and disease
cereal consumption in the milk group28, the interesting observation of
raised insulin-like growth factor I (IGF1) levels in this group may point to
a stimulation of periosteal bone apposition. The resultant effect would be
a slightly larger skeletal envelope in the milk group. Other possible
explanations point to an IGF-1 response to changes in intake of other
nutrients in the milk supplemented group, namely protein and energy29.
Studies are now required to see if the effect on bone mass is greatest in milk
or in a calcium supplementation alone. Furthermore, while several of the
calcium supplementation studies have shown that the benefits are lost once
supplements are stopped, the milk and calcium enriched food studies have
both shown that the effect persists one year after stopping treatment25.
Other micronutrients
Virtually all published studies on nutrition and PBM attainment have
focused on calcium which explains why our knowledge of the
relationship between nutrition and bone health is still largely undefined.
A diet which is low in calcium is also likely to be low in a large number
of other micronutrients, all of which have plausible mechanisms for a
role in maintaining skeletal health, but until recently have received very
little scientific attention30'31.
Recent evidence suggests that dietary phosphorus has an important
and positive role to play in the development of PBM32. As phosphate,
this nutrient makes up roughly half the weight of bone mineral and,
therefore, must be present in adequate amounts in the diet to mineralise
and maintain the skeleton. As it is available in relatively adequate
amounts in the diet, attention has tended to focus on excessive amounts
being harmful to bone health and the characteristics of a low calcium to
phosphorus ratio. There is some evidence that increased phosphorus
intake depresses ionised calcium leading to an increase in parathyroid
hormone and, hence, a rise in the rate of bone resorption33. However,
most studies have failed to show a deleterious long-term effect on bone
health34.
Results from the largest reported cross-sectional study to date on
nutrition and bone mass investigating 1000 healthy UK premenopausal
women suggest that high, long-term intakes of nutrients found in
abundance in fruit and vegetables (namely magnesium, potassium, fibre
and vitamin C) may be important to bone health35. In this study, women
in the lowest quartile of energy-adjusted intakes of these nutrients were
found to have significantly lower bone mass, independent of important
confounding factors including weight, height, smoking and socioeconomic class (Figs 2 and 3). A significant difference in bone mass was
also found in those women who reported consuming a low intake of
622
British Medical Bulletin 1999, 55 (No. 3)
Bone health: the role of micronutrients
Fig. 2 Increase in LS
BMD (mean ± SEM)
with quartiles of
energy adjusted
magnesium intake.
F-test for linearity
(P < 0.004) ANOVA
(P<0.01) ANCOVA
(P < 0.02). Adjusted
for age, weight,
height, physical
activity, smoking and
social status. Data
from New et aP5.
LJ J I I
2
3
Quartiles of Mg Intake
1.086
1.075
Fig. 3 Increase in LS
BMD (mean ± SEM)
with quartiles of
energy adjusted
potassium intake.
F-test for linearity
(P < 0.005) ANOVA
(P < 0.007) ANCOVA
(P < 0.06). Adjusted
for age, weight,
height physical
activity, smoking and
social status. Data
from New et a/35.
|
\06S
Q
.055
m
irt
n
i i
Ti i! 1i
i i
2
3
Quartiles of K Intake
i
fruit during their childhood and early adulthood. Further support is
provided by a second study in the same population group (but different
women) which found bone resorption to be higher in those women
consuming low intakes of the same nutrients36. As noted by Wachman
and Bernstein, the skeleton is not only a labile reservoir of calcium
responsive to the mechanisms which maintain ionic calcium, but it is
also a reservoir of alkaline salts of calcium, which in turn provide a
source of labile base37. This base can be mobilised to react to both blood
pH and plasma bicarbonate concentrations. The failure to maintain
acid-base homeostasis in adults has been proposed as the mechanism
behind the progressive decline in bone mass seen with age, and that such
bone loss may be attributable to the life-long mobilisation of skeletal
British Medical Bulletin 1999; 55 (No. 3)
623
Micronutrients in health and disease
salts to balance the endogenous acid generated from foods which are
acid producing, such as meat. This theory may help to explain why some
studies have shown a difference in bone mass in vegetarians compared
to omnivores. Furthermore, findings by Sebastian et al (1994) that
supplementation of potassium bicarbonate was found to improve
calcium and phosphorus balance, reduced bone resorption and increase
the rate of bone formation in postmenopausal women lends further
support to this hypothesis38.
There is very little documented evidence for the effect of other
micronutrients on PBM development and this is certainly an area which
requires further research. Of major concern is the growing evidence that
nutrient intakes, (in particular calcium and iron) and physical activity
levels are declining in British adolescents39'40, while smoking habits and
alcohol intake are on the increase41. The long-term implications of these
trends are not favourable to adult bone health and, hence, more research
to target the 'at risk' groups are required.
Role of micronutrients in reducing peri- and
postmenopausal bone loss
Calcium
Following attainment of PBM, a gradual loss of bone occurs with
ageing. Before the menopause, the amount lost is very small but it then
increases to approximately 1-2% per annum over the next 5-10 years.
These respective changes in bone mass with the menopause have
resulted in enormous interest over the last two decades as to the
effectiveness of calcium supplementation in reducing perimenopausal
bone loss. Debates have been intense and indeed continue42'43. Table 1
provides a summary of calcium supplementation trials in peri- and early
postmenopausal women44"49. The failure of many studies in the
postmenopausal stage to identify the special circumstances created by
oestrogen withdrawal in the years following hormonal loss may help to
explain why there was so much disagreement amongst studies as shown
in the table. In 1990, Dawson-Hughes's study was the first to divide
women into years postmenopause. Calcium supplementation (500
mg/day) failed to reduce bone loss in women who were less than 5 years
postmenopause, but, in women who have been postmenopausal for 6
years or more and with a daily calcium intake of less than 400 mg/day,
bone loss was significantly reduced46. This finding has received further
support from other supplementation studies which have divided women
according to their time since menopause. As shown in Table 2, all of
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British Medical Bulletin 1999, 55 (No 3)
Bone health: the role of micronutrients
Table 1 Calcium supplementation studies in peri- and early postmenopausal women
Authors
Study
duration (years)
Aloia eta/(1994)"
Elders etal (1991)"
Dawson-Hughes etal (1990)"
Ettinger eta/0987)47
Riis etal (1987)"
2.9
3
2
2
2
2
Nilas eta/(1984r
n
Age
(years)
TSM
(years)
Ca-C
(mg)
Ca-S
(mg)
Ca-effect
101
248
67
73
36
103
52
49
54
51
49
-
3-6
1.2
<5
<3
<3
<3
470
1150
513
994
-
1700
2500
1013
2950
2000
1410
+ve
+ve
No change
No change
+ve
No change
910
TSM, time since menopause in years; Ca-C, control group calcium intake (mg); Ca-S, supplemented group calcium intake
(mg); Ca-effect, effect of Ca supplementation.
Table 2 Calcium supplementation studies in late postmenopausal women
Authors
Study
duration (years)
Dawson-Hughes et al (1995)50
Prince etal (1995)sl
Reid etal (1995)"
Reid etal (1993)"
Nelson et al (1991)54
Dawson-Hughes et al (1990)"
2
2
4
2
2
2
n
Age
(years)
TSM
(years)
Ca-C
(mg)
Ca-S
(mg)
Ca-effect
169
168
78
122
36
67
60
63
58
58
60
>5
> 10
9
9
11
>5
283
787
710
730
761
274
783
1672
1570
1590
1462
774
+ve
+ve
+ve
+ve
+ve
+ve
-
TSM, time since menopause in years; Ca-C control group calcium intake (mg); Ca-S, supplemented group calcium intake (mg);
Ca-effect, effect of Ca supplementation.
these show a positive effect of calcium supplementation in reducing late
postmenopausal bone loss50"55. The study by Reid et al (1995) provides
evidence that calcium is still effective in reducing bone loss after 4 years
of supplementation 52 .
Vitamin D
Vitamin D is the generic term for two molecules, egocalciferol (vitamin
D2) and cholecalciferol (vitamin D 3 ). The former is derived by UV
irradiation of the ergosterol that is widely distributed in plants and other
fungi, whereas the latter is formed from the action of UV irradiation on
the skin. The action of sunlight on the skin converts 7-dehydrocholesterol
to previtamin D which is then metabolised to vitamin D by a temperaturedependent isomerization. The vitamin D is then transported via the
general circulation to the liver where the enzyme 25-hydroxylase converts
it to 25 hydroxy-vitamin D. Further conversion to 1,25 (OH) 2 D 3 occurs
British Medical Bulletin 1999, 55 (No. 3)
625
Micronutrients in health and disease
in the kidney. 25 OHD is the main circulating vitamin D metabolite and
is the best indicator of clinical status, whereas 1,25 OH2D3 is the active
form of the vitamin which is involved in calcium homeostasis. It is now
well established that there are two sources of this vitamin: (i) endogenous
(skin); and (ii) exogenous (diet). Although, the relative contributions of
these two sources are known to vary widely among individuals and
between different geographical areas, it is generally believed that the
major source of vitamin D is the exposure of skin to the UV B-rays
contained in sunlight55.
Influence of climate on vitamin D status
Much of the UV in sunlight is absorbed by clouds, ozone and other
forms of atmospheric pollution. Thus, due to the reduced zenith angle
of the sun and increased path length of sunlight through the atmosphere,
the effective level of UV energy decreases north-south distance from the
seasonally varying latitude at which the sun is directly overhead56. In a
recent paper investigating 117 published studies of vitamin D status
from a total of 27 regions, variation was shown, not only between
seasons, but also between geographical area such that levels were lower
during the winter and spring/autumn months in Europe than in either
North America or Scandinavian countries57. In the UK, there is no UV
radiation of the appropriate wavelength (280-310 nm) from the end of
October to the end of March and for the remaining months of the year,
60% of the effective UV radiation occurs between 11.00 am and 3.00
pm56. Studies in the UK have shown there to be a seasonal variation in
vitamin D levels being highest in the summer months and lowest in the
winter months in a variety of regions including London, Middlesex,
West Midlands, Sunderland and Manchester.
Influence of dietary intake on vitamin D status
Dietary intake of vitamin D, although of lesser significance to vitamin D
status than UV radiation, is still a crucial factor to be considered when
assessing vitamin D status, especially during winter time when there is
no skin production of the vitamin. In the paper cited earlier investigating
differences in vitamin D status between the different geographical -areas
world-wide, oral intake of vitamin D was found to be significantly lower
in Europe compared with both North America and Scandinavia57.
Furthermore, the study also showed that residents in North America and
Scandinavia, both young and old, were more apt to take vitamin D
supplements than their counterparts in Europe. For example, in the UK
and Ireland only 15% of the elderly take supplements compared with
30% in North America and 50% in Denmark.
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British Medical Built tin 1999; 55 (No. 3)
Bone health: the role of micronutrients
There are actually relatively few dietary sources of vitamin D, the
major providers being fat spreads, fish, eggs, fortified cereals and pastry
products58*59. Up until fairly recently, information on vitamin D intake
from meat was not available, but new analytical data for the
composition of meat now includes the contribution from the metabolite
25-hydroxycholecalciferol (25(OH)D3 ) rather than just cholecalciferol
itself60. Recently published work in this area has highlighted meat to be
much more significant contributor to vitamin D intake than was
previously considered61.
Vitamin D and bone health
Vitamin D status is known to be affected by the ageing process and there
is now some good evidence to show that: (i) vitamin D levels fall with
age62; (ii) vitamin D levels are inversely related to PTH63 (which is also
known to have seasonal variation64); (iii) menopausal bone loss is
partially regulated by dietary intake of vitamin D65; and (iv) the elderly
population66 are susceptible to vitamin D deficiency or vitamin D
'insufficiency'. The effect of vitamin D and its metabolites on bone is
very complex. It is known to stimulate matrix formation and bone
maturation, enhance osteoclastic activity and may influence
differentiation of bone cell precursors. Together with PTH and calcium,
it regulates calcium and phosphorus metabolism and promotes calcium
absorption from the gut and kidney tubules. A deficiency of vitamin D
has been shown to reduce calcium absorption, increase PTH excretion
thereby stimulating osteoclastic activity and thus increasing bone loss67.
Supplementation of 25(OH)D has been found to improve calcium
absorption, lower PTH levels64, and reduce winter time bone loss in
postmenopausal women68.
Other micronutrients
Zinc, copper and manganese may also have an important role to play in
bone health since they are known to be essential metallic cofactors for
enzymes involved in the synthesis of various bone matrix constituents.
Supplementation of these trace minerals have been shown to be effective
in older postmenopausal women69. Furthermore, together with vitamin
C they may also function in their antioxidant capacity and thus high
intakes may be important if the connective tissue of bone is a target for
free-radical damage. Two recent studies suggest that they may have an
important role to play in bone health but further research is required35-36.
British Medical Bulletin 1999, 55 (No. 3)
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Micronutrients in health and disease
Role of micronutrients to the risk of fracture
Calcium
Epidemiological studies investigating the relationship between calcium
and risk of fracture published in the last decade have shown conflicting
results. Holbrook etal\n& 14 year longitudinal US study showed that hip
fracture rates were lower in individuals ingesting high calcium diets70 and
these findings have been further supported by data published on populations from Hong Kong71. However, two UK studies did not find a
protective effect of calcium on risk of fracture in women72'73. This
discrepancy may be explained, in part, by the fact that there were differences in the distribution of calcium intake within each of the population
groups. In more recent studies, calcium supplementation has been shown
to reduce fracture rates in late postmenopausal women74 and the elderly75.
Vitamin D
Reduced vitamin D levels have been reported in patients with hip fracture
and hence attempts have been made to investigate the effect of vitamin D
supplementation on prevention of fracture. In a three-year study of 3270
institutionized elderly, supplementation with cholecalciferol and calcium
resulted in a significant reduction in fracture rate. Protection was apparent
after 6-12 months of treatment with a reduction of fractures of more than
30% by 18 months76. The only randomised placebo controlled clinical
trial of vitamin D supplementation alone and fracture incidence showed
that after 3 years of supplementation with 10 (i.g of vitamin D, there was
no difference in fracture rates between the supplemented and unsupplemented groups77.
Vitamin K
Vitamin K was first discovered as an anti-haemorrhagic factor, and is
now known to be required for the production of y-carboxylated
glutamyl residues in several blood coagulation factors and coagulation
inhibitors (prothrombin - Factors VII, IX and X - proteins S and C). It
may have a role in bone metabolism as bone y-carboxyglutamic acid
(bone Gla protein; the principal non-collagenous protein of bone) and
matrix Gla protein (found in most mineralized tissues and cartilaginous
tissues) are dependent upon vitamin K for their synthesis78.
Two forms of vitamin K exist - vitamin K, (phylloquinone) and
vitamin K2 (menaquinone), which is a family of compounds whose side
628
British Medical Bulletin 1999; 55 (No. 3)
Bone health: the role of micronutrients
chains consist of a number of isoprene units which vary from 1-14
(MK). There is now some evidence of significantly reduced circulating
levels of menaquinone-8 (MK-8) in healthy elderly women79, and
following osteoporotic fractures of the spine and hip80. Knapen et al
(1989) reported increased urinary calcium and hydroxyproline excretion
in patients with osteoporosis, with levels falling in response to physiological doses of vitamin K81. Although bone Gla protein has also been
shown to be under-carboxylated in osteoporotic women, with recovery
in response to physiological doses of vitamin K82 there are considerable
technical problems associated with its measurement, as indicated by the
number of conflicting reports in the literature83. Furthermore, osteocalcin is dependent on vitamin D for its synthesis and, hence, supplementation with vitamin D alone may have an ability to normalise the
carboxylation values.
It is important to note that poor nutritional status has been associated
with osteoporotic individuals84 and, thus, vitamin K levels (which are
generally good indicators of nutritional status) may merely be reflecting
this, rather than suggesting an independent effect per se. Further work is
required. Due to the lack of dietary vitamin K databases, few studies have
examined the direct relationship between dietary sources of vitamin K and
bone mass. With recently developed tables in both the US85 and UK86, the
importance of dietary vitamin K to bone health can now be established.
Conclusions
The changes which occur in bone mass with ageing highlight the
importance of maintaining adequate nutrition during peak bone mass
development and in reducing postmenopausal bone loss. Our knowledge
as to the essential ingredients for optimum bone health throughout life is
yet to be fully established due to a focus of attention on calcium with little
reference to other micronutrients, many of which have plausible mechanisms of action on bone metabolism. There is, however, a general consensus
of opinion that calcium is important to maximising peak bone mass, but
more work is required to see if the effect is greatest in calcium alone or in
a combination of milk and milk products. Consistent data have also been
reported as to the positive effect of increased calcium intake in reducing
bone loss in women who are greater than 5 years postmenopause, but
clearly more research is required to see if additional micronutrient
supplementation would assist women in the earlier stages of menopause,
when bone loss is at a greater intensity. For the elderly, more research is
required to identify whether malnutrition per se is a key risk factor for
fracture and within specific communities, how best this is treated.
British Medical Bulletin 1999; 55 (No. 3)
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Micronutrients in health and disease
On a final note, within a population based strategy, clearly a healthy
lifestyle should be encouraged at all ages, with the inclusion of a varied
and adequate dietary intake and appreciable level of physical activity
which has an emphasis on its weight bearing capacity. This strategy is one
of the main recommendations of the recently published COMA report on
nutrition and bone health87. Furthermore, whilst the genetic component
has a major role to play in the pathogenesis of osteoporosis, it may be
useful to target specific nutrition intervention on those individuals who
are genetically more susceptible to poor bone health.
References
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
630
Schapira D, Schapira C. Osteoporosis: the evolution of a scientific term. Osteoporos Int 1992;
2:164-7
World Health Organization. Assessment of fracture risk and its application to screening for
osteoporosis. Technical Series Report 843. Geneva: WHO, 1994
Consensus Development Conference. Prophylaxis and treatment of osteoporosis. Am J Med
1991; 90: 107-10
Cooper C. Epidemiology and public health impact of osteoporosis. Balhere's Clin Rheumatol
1993; 7: 459-77
Dolan P, Torgerson DJ, Kakarlapudi TK. The costs of treating osteopororic fractures in the
United Kingdom female population. Osteoporos Int 1999; In press
Pococok NA, Eisman JA, Hopper JL et al. Generic determinants of bone mass in adults. / Clin
Invest 1987; 80: 706-10
Lutz J, Tesar R. Mother and daughter pairs: spinal and femoral bone densities and dietary
intakes. Am J Clin Nutr 1992; 52: 872-7
Morrison NA, Qi JC, Tokita A et al. Predication of bone density from vitamin D receptor
alleles. Nature 1994; 367: 284-7
Kobayashi S, Inoue S, Hosoi R et al. Association of bone mineral density with polymorphism
of the estrogen receptor gene. / Bone Miner Res 1996; 11: 306-11
Grant SFA, Reid DM, Blake G et al. Reduced bone density and oesteoporotic fracture associated
with a polymorphic Sp binding in collagen type I a 1 gene. Nat Genet 1996; 14: 203-5
Martin TJ, Dempster DW. Bone structure and cellular activity. In: Stevenson JC, Lindsay R
(Eds) Osteoporosis. London: Chapman & Hall Medical, 1998; 1-10
Smith R. Bone mineral. In: Garrow JS, James WPT (Eds) Human Nutrition and Dietetics.
London: Churchill Livingstone. 1993; 162-73
Orr JB. Milk consumption and the growth of school children. Lancet 1928; i: 202-3
Leighton G, Clark ML. Milk consumption and growth of school children; second preliminary
report on tests to the Scottish Board of Health. Lancet 1929; ii: 40-3
Lee WTK, Leung SSF, Lui SSH et al. Relationship between long-term calcium intake and bone
mineral content of children aged from birth to 5 years. Br J Nutr 1993; 70: 235-48
Matkovic V, Fontano D, Tominac C et al. Factors that influence peak bone mass formation: a
study of calcium balance and the inheritance of bone mass in adolescent females. Am ] Clin
Nutr 1990; 52: 878-88
Fehily AM, Coles R, Evans RJ et al. Factors affecting bone density in young adults. Am ] Clin
Nutr 1992; 56: 579-86
Valimaki MJ, Karkkainen M, Lamberg-Allardt C et al. Exercise, smoking and calcium intake
during adolescence and early adulthood as determinants of peak bone mass. BMJ 1994; 309:
230-5
Ho SC, Leung PC, Swaminathan R et al. Determinants of bone mass in Chinese women aged
21—40 years. II Patterns of dietary calcium intake and association with bone mineral density.
Osteoporos Int 1994; 4: 167-75
British Medical Bulletin 1999; 55 (No. 3)
Bone health: the role of micronutrients
20 Recker RR, Davies MM, Hinders SM et al . Bone gain in young adult women. JAMA 1992;
268: 2403-8
21 Johnston CC, Millar JZ, Slemenda CJW et al. Calcium supplementation and increases in bone
mineral density in children. N Engl} Med 1992; 327: 82-7
22 Lloyd T, Andon M, Rollings N et al Calcium supplementation and bone mineral density in
adolescent girls. JAMA 1993; 270: 8 4 1 ^
23 Lee WTK, Leung SSF, Lui SSH et al. Double blind, controlled calcium supplementation and bone
mineral accretion in children accustomed to a low-calcium diet. Am J Clin Nutr 1994; 60; 744—50
24 Nowson CA, Green RM, Hopper JL et al. A co-twin study of the effect of calcium
supplementation on bone density during adolescence. Osteoporos Int 1997; 7: 219-25
25 Bonjour JP, Carrie AL, Ferrari B et al. Calcium-enriched foods and bone mass growth in
prepubertal girls: a randomized, double blind, placebo controlled trial. / Chn Invest 1997; 99:
1287-94
26 Chan GM, Hoffman K, McMurry M. Effects of dairy products on bone and body composition
in pubertal girls. / Pediatr 1995; 126: 551-6
27 Cadogan J, Eastell R, Jones N, Barker M. Milk intake and bone mineral acquisition in
adolescent girls: randomised controlled intervention trial. BMJ 1997; 315: 1255—60
28 New SA, Ferns G. Starkey B. Milk intake and bone mineral acquisition in adolescent girls increases in bone density may be result of micronutrients in additional cereal [letter]. BMJ
1998; 316:1747
29 Ross RJM, Buchanan CR. Growth hormone secretion: its regulation and the influence of
nutritional factors. Nutr Res Rev 1990; 3: 143-62
30 Reid DM, New SA. Nutritional influences on bone mass: a review. Proc Nutr Soc 1997; 56:
977-87
31 Robins SP, New SA. Markers of bone metabolism. Proc Nutr Soc 1997; 56: 903-14
32 Teegarden D, Lyle RM, McCabe J et al. Dietary calcium, protein and phosphorus are related to
bone mineral density and content in young women. Am J Clin Nutr 1998; 68: 749-54
33 Calvo MS, Kumar R, Heath H.. Elevated secretion and action of serum PTH in young adults
consuming high phosphorus, low calcium diets assembled from common foods. / Clin
Endocrmol Metab 1988; 66: 823-9
34 Heaney, RP, Recker RR. Effects of nitrogen, phosphorus and caffeine on calcium balance in
women. J Lab Clin Med 1982; 99: 46-55
35 New SA, Bolton-Smith C, Grubb DA, Reid DM. Nutritional influences on bone mineral
density: a cross-sectional study in pre-menopausal women. Am J Clin Nutr 1997; 65: 1831—9
36 New SA, Robins SP. Reid DM. Fruit and vegetable consumption and bone health: is there a
link? In: Dawson-Hughes B, Burckhardt P. Heaney RP (Eds) Challenges of Modern Medicine.
Nutritional Aspects of Osteoporosis '97 (3rd International Symposium on Nutritional Aspects
of Osteoporosis, Switzerland, 1997). Italy: Ares-Serono Symposia Publications, 1998; 199-207
37 Wachman A, Bernstein DS. Diet and osteoporosis. Lancet 1968; 1: 958-9
38 Sebastian A, Harris ST, Ottawat JH, Todd KM, Morris RC. Improved mineral balance and
skeletal metabolism in postmenopausal women treated with potassium bicarbonate. N Engl J
Med 1994; 330: 1776-81
39 Crawley H. The energy, nutrient and food intakes of British teenagers. BrJ Nutr 1993; 70: 15-26
40 Armstrong N et al. Patterns of physical activity among 11-16 year old British children. BMJ
1990; 301: 203-5
41 McMiller P, Plant M. Drinking, smoking and illicit drug use among 15 and 16 year olds in the
United Kingdom. BMJ 1996; 313: 394-7
42 Kanis JA, Passmore R. Calcium supplementation of the diet I and II. BMJ 1989; 298: 137-40,
205-8
43 Nordin BEC, Heaney RP. Calcium supplementation of the diet: justified by present evidence.
BMJ 1990; 300: 1056-60 "
44 AJoia JF, Vaswani A, Yeh JK et al. Calcium supplementation with and without hormone
replacement therapy to present postmenopausal bon loss. Ann Intern Med 1994; 120: 97-103
45 Elders PJ, Netelenbos JC, Lips P et al. Calcium supplementation reduces vertebral bone loss in
perimenopausal women: a controlled trial in 248 women between 46 and 55 years of age. / Clin
Endocrinol Metab 1991; 73: 533-40
British Medial Bulletin 1999; 55 (No. 3)
631
Micronutrients in health and disease
46 Dawson-Hughes B, Dallal GE, Krall EA et al. A controlled trial of the effect of calcium
supplementation on bone density in postmenopausal women. N EnglJ Med 1990; 323: 878-83
47 Ettinger B, Genant HK, Cann CE. Postmenopausal bone loss is prevented by treatment with
low-dosage oestrogen with calcium. Ann Intern Med 1987; 106: 870-3
48 Riis B, Thomsen K, Christiansen C. Does calcium supplementation prevent postmenopausal
bone loss? N EnglJ Med 1987; 316: 173-7
51 Prince RL, Smith M, Dick IM et al. Prevention of postmenopaual osteoporosis: a comparative
study of exercise, calcium supplementation and hormone-replacement therapy. N Engl J Med
1991; 325: 1189-95
52 Reid IR, Ames RW, Evans MC et al. Long term effects of calcium supplementation on bone loss and
fractures in postmenopausal women: a randomised controlled trial Am J Med 1995; 98: 331-5
53 Reid IR, Ames RW, Evans MC et al. Effect of calcium supplementation on bone loss in
postmenopausal women. N Engl] Med 1993; 328: 460-4
54 Nelson ME, Fisher EC, Avraham Dilmanian FA et al. A 1-yr walking program and increased
dietary calcium in postmenopausal women: effects on bone. Am] Clin Nutr 1991; 53: 1304—11
55 Fraser DR. Regulations of the metabolism of vitamin D. Physiol Rev 1980; 60: 551-613
56 Meteorological Offices. The climate of England. Some facts and figures. National Meteorological Library 1996
57 McKenna MJ. Differences in vitamin D status between countries in young adults and the
elderly. Am ] Med 1992; 93: 69-77
58 Gregory J, Foster K, Tyler H, Wiseman M. The Dietary and Nutritional Survey of British
Adults. London: HMSO, 1990
59 Gregory J, Foster K, Tyler H, Wiseman M. The Dietary and Nutritional Survey of British
Adults - Further Analysis. London: HMSO, 1990
60 Lee SM, Buss DH,HattonD. Vitamin D activity of meat [Abstract]. ProcN«frSoc 1995; 54:130A
61 Gibson SA, Ashwell M. New vitamin D values for meat and their implication for vitamin D
intake in British Adults [Abstract]. Proc Nutr Soc 1997; 56: 116A
62 McKenna MJ, Freaney R, Meade A, Muldowney FP. Hypovitaminosis D and elevated serum
alkaline phosphatase in elderly Irish people. Am } Clin Nutr 1985; 41: 101-9
63 Khaw KT, Sneyd MJ, Compston J. Bone density, parathyroid hormone and 25 hydroxyvitamin
D concentrations in middle aged women. BMJ 1992; 305: 273—7
64 Krall EA, Sahyoun N, Tannenbaum S, Dallal GE, Dawson-Hughes B. Effect of vitamin D intake
on seasonal variations in parathyroid hormone secretion in postmenopausal women. N Engl J
Med 1989; 321: 1777-83
65 Lukert BP, Higgins J, Stosopf M. Menopausal bone loss is partially regulated by dietary intake
of vitamin D. Calcif Tissue Int 1992; 51: 173-9
66 Chapuy MC, Preziosi P, Maamer M et al. Prevalence of vitamin D insufficiency in an adult
population. Osteoporos Int 1997; 7: 439^13
67 Henry HL, Norman AW. Vitamin D: metabolism and biological actions. Annu Rev Nutr 1984;
4: 493-520
68 Dawson-Hughes B, Dallas GE, Krall EA, Harris S, Sokoll LJ, Kakoner C. Effect of vitamin D
supplementation in wintertime and overall bone loss in healthy post-menopausal women. Ann
Intern Med 1991; 115: 505-12
69 Strause L, Salrman P, Smith KT, Bracker M, Adnon MB. Spinal bone loss in postmenopausal
women supplemented with calcium and trace minerals. / Nutr 1994; 124: 1060—4
70 Holbrook TL, Barrett-Connor E, Windgard DL. Dietary calcium and risk of hip fracture: 14
year prospective population study. Lancet 1988; ii: 1046—9
71 Lau E, Donnan S, Barker DJP, Cooper C. Physical activity and calcium intake in fracture neck
of femur in Hong Kong. BMJ 1988; 297: 1441-3
72 Cooper C, Barker DJP, Wickham C. Physical activity, muscle strength and calcium intake in
fracture of the proximal neck of femur in Britain. BMJ 1988; 297: 1443-6
73 Wickham CAC, Walsh K, Cooper C et al. Dietary calcium, physical activity and risk of hip
fracture: a prospective study. BMJ 1989; 299: 889-91
74 Reid IR, Ames RW, Evans MC, Gable GD, Sharpe SJ. Long-term effects of calcium supplementation on bone loss and fractures in postmenopausal women: a randomised controlled trial.
Am J Med 1995; 98: 331-5
632
British Medical Bulletin 1999; 55 (No. 3)
Bone health: the role of micronutrients
75 Chevalley T, Rizzoli R, Nydegger V et al. Effects of calcium supplements on femoral bone
mineral density and vertebral fracture rate in vitamin D-replete elderly patients. Osteoporos Int
1994; 4: 245-52
76 Chapuy MC, Arlot ME, Duboeuf F et al. Vitamin D and calcium to prevent hip fractures in
elderly women. N Engl J Med 1992; 327: 1637-42
77 Lips P, Graafmans WC, Ooms ME, Bezemer D, Bouter LM. Vitamin D supplementation and
fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial. Ann Intern
Med 1996; 124: 400-6
78 Price PA. Role of vitamin-K-dependent proteins in bone metabolism. Annu Rev Nutr 1988; 8:
565-83
79 Hodges SJ, Pilkingtn MJ, Shearer MJ, Bitensky L, Chayen J. Age-related changes in the
circulating levels of congeners of vitamin K2, menaquinone-7 and menaquinone-8. Chn Sci
1990; 78: 63-6
80 Hodges SJ, Akesson K, Vergaud P, Obrant K, Delmas PD. Circulating levels of vitamin K, and
vitamin K2 decreased in elderly women with hip fracture. / Bone Miner Res 1993; 8: 1241
81 Knapen MHJ, Hamulyak K, Vermeer C. The effect of vitamin K supplementation on circulating
osteocalcin (bone Gla protein) and urinary calcium excretion. Ann Intern Med 1989; 111:
1001-5
82 Douglas AS, Robins SP, Hutchison JD, Porter RW, Stewart A, Reid DM. Carboxylation of
osteocalcin m postmenopausal osteoporotic women following vitamin K and D supplementation.
Bone 1995; 17: 15-20
83 Delmas P, Christiansen C, Mann K, Price P. Bone Gla protein (osteocalcin): assay standardization
report. / Bone Miner Res 1990; 5: 5-11
84 Rico H, Revilla M, Villa LF, Hernandez ER, Fernandez JP. Crush fracture syndrome in senile
osteoporosis: a nutritional consequence. / Bone Miner Res 1992; 7: 317-9
85 Booth SI, Sokoll LJ, O'Brien ME, Tucker K, Dawson-Hughes B, Sadowski JA. Assessment of
dietary phylloquinone intake and vitamin K status in postmenopausal women. Eur J Clin Nutr
1995; 49: 832^1
86 Price R, Fenton S, Shearer M, Bolton-Smith C. Daily and seasonal variation in phylloquinone
(vitamin K,) intake in Scotland [Abstract]. Proc Nutr Soc 1996; 55: 244A
87 Department of Health. Nutrition and Bone Health. London. Report on Health and Social
Subjects No. 49. London: HMSO 1998
British Medical Bulletin 1999; 55 (No. 3)
633