ARTICLE IN PRESS
Clinical Nutrition (2007) 26, 193–207
Available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/clnu
REVIEW
Picking a bone with contemporary osteoporosis
management: Nutrient strategies to enhance skeletal
integrity
Stephen J. Genuis, Gerry K. Schwalfenberg
Faculty of Medicine, University of Alberta, 2935-66 Street, Edmonton, Alberta, Canada T6K 4C1
Received 24 May 2006; accepted 27 August 2006
KEYWORDS
Bone resorption;
Essential fatty acids;
Medical education;
Nutrition;
Omega-3 fatty acids;
Omega-6 fatty acids;
Osteoporosis;
Preventive medicine;
Public health;
Strontium;
Vitamin D;
Vitamin K
Summary
Epidemic rates of osteoporosis in the western world have yielded intense efforts to
develop management approaches to combat this potentially devastating disorder; recent
research has unveiled innovative strategies which hold considerable promise for
prevention of skeletal compromise and amelioration of suboptimal bone health. According
to many algorithms and practice directives, the contemporary assessment and management of osteoporosis focuses heavily on determination of fracture risk and pharmaceutical
intervention for those patients deemed to be at high risk. While routine recommendations
for calcium and vitamin D have been incorporated into most regimens, disproportionately
little attention has been given to recent research elucidating improved bone health and
diminution in fracture rates experienced by patients receiving specific nutrients. In
mainstream medical practice, clinical analysis and management of nutritional or dietary
issues is sometimes perceived as unconventional, primitive or unsophisticated health care.
Recent evidence-based research, however, supports intervention with adequate amounts
of specific nutrients including vitamin D, strontium, vitamin K, and essential fatty acids in
the prevention and primary management of osteoporosis.
& 2006 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights
reserved.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Overview of osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Measurement of bone health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Causality of osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Corresponding author. Tel.: +1 780 450 3504; fax: +1 780 490 1803.
E-mail address: [email protected] (S.J. Genuis).
0261-5614/$ - see front matter & 2006 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
doi:10.1016/j.clnu.2006.08.004
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S.J. Genuis, G.K. Schwalfenberg
Causality of fractures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Personal and social implications of osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Contemporary management of osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Nutrient strategies in the prevention and management of osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . .
VTD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Strontium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
VTK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Essential fatty acids (EFAs). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction
Over the last decade, there has been a plethora of consumer
publications, medical papers, journal supplements, clinical
practice guidelines, and symposia relating to the assessment
and management of osteoporosis; most educational efforts,
however, focus on the clinical indications for bone mineral
density (BMD) assessment and the merits and indications for
various pharmaceutical agents. In undergraduate and continuing medical education programs, limited time and
attention have been allocated to dissemination of recent
evidence demonstrating the ineluctable benefits of nutritional assessment and management of various medical
conditions,1,2 including osteoporosis. In this paper, an
overview of osteoporosis will be presented, followed by a
discussion of innovative approaches to maximize skeletal
health through the use of specific nutrients including
vitamin D; strontium; Vitamin K (VTK), and essential fatty
acids.
Overview of osteoporosis
Osteoporosis is a skeletal disorder characterized by compromised bone strength, a disorder that predisposes to
fractures resulting from no identifiable injury or from
minimal trauma insufficient to fracture normal bone. Bone
strength is the result of two major determinants: bone
mineral content and bone quality.
Individual bone mineral content is determined by the
interaction of two key factors: the uppermost amount of
bone achieved during youth (called the peak bone
mass, PBM) in combination with the rate of subsequent
bone loss. Growth in bone size and strength occurs
during childhood, through adolescence and is usually
completed in the 20s. After age 35, bone loss may occur
at a slow rate; when menopause occurs, there is accelerated loss in women resulting from increased resorption of
existing bone associated with declining levels of estrogen.
The quality of bone refers to the composition and structure
of skeletal tissue and considers micro-architecture as
well as existing damage (e.g., micro-fractures).3 Dense
bone is not necessarily strong bone as it is possible to
have more quantity of poorer structural quality and less
quantity of better structural integrity; geometric and
structural differences in bone configuration can influence
fracture potential.
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200
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203
Measurement of bone health
Currently, there is no easily available and accurate measure
of overall bone strength incorporating both bone mass and
bone quality. Furthermore, technology to assess bone
resistance to fracture under external pressure is also
lacking. At present, the most widespread screening measure
for compromised bone health prior to the development of
fracture is BMD testing.4 Although BMD analysis does not
measure integrity, quality or overall strength of skeletal
tissue, meta-analytic studies have confirmed that, in
general, low BMD is a risk factor for subsequent fractures.5
Accordingly, the current definition of osteoporosis reflects
consensus perspectives on diminished BMD measurements;
classification of fracture risk is based on the amalgamation
of BMD data and individual risk factors such as age and
fracture history.
There is much current debate, however, about the
validity of contemporary BMD assessment.6,7 In a recent
editorial published in Osteoporosis International entitled
BMD: The Problem’,7 Heaney draws attention to various
drawbacks of BMD testing while in the Journal of Clinical
Endocrinology & Metabolism, Seeman discusses common
misconceptions resulting from bone densitometry.6 For
example, true volumetric density need incorporate depth
of bone, not only length and breadth (as visualized on areal
BMD testing); with bone densitometry—a smaller, weaker
bone may appear much denser than a stronger, larger bone.7
While some authors have suggested that measures of bone
mineral content should replace BMD,6–8 most research work
to date and most therapeutic recommendations utilize BMD
terminology.
With the shortcomings of BMD assessment, however,
various other indices for bone health have been
explored. In the Journal of Bone and Mineral Research, for
example, Eastell et al. 9 noted that changes in biochemical indicators of bone resorption have generally been
associated with subsequent risk for vertebral and nonvertebral fractures. In practicality, however, serum markers
of bone turnover, although useful for research assessment of the impact of various determinants on bone
metabolism, do not consistently predict fracture risk and
have limited clinical value. More recently, there has
been the introduction of testing for the architecture
of bones such as hip structure analysis which is used to
assess changes in the structure and strength at the
narrowest section of the femoral neck.8 In essence,
however, there is no simple test at present to adequately
ARTICLE IN PRESS
Nutrient strategies and bone health
195
quantify overall bone health, bone strength, or resistance to
fracture.
Causality of osteoporosis
In the assessment and management of osteoporosis, it is
important to consider and address the etiology of
this widespread disorder.10 Osteoporosis is usually the
result of one or both of the following situations: (a)
impaired PBM11; and/or (b) rapid rate of bone loss. In
contemporary western culture, osteoporosis may increasingly be the result of inadequate bone development in youth; osteoporosis is not exclusively the result of
bone loss associated with aging or menopause, as many have
assumed.
Bone mass attained early in life is a critical determinant
of life-long skeletal health and many factors including
lifestyle, nutrition, physical activity, environmental influences, genetics, and medication use may affect PBM. The
indoor sedentary lifestyle associated with western culture
has been a major factor contributing to weak bone
development: lack of direct sunlight leads to insufficient
levels of required vitamin D (VTD) and lack of physical
activity precludes the weight bearing and impact necessary
for development of healthy skeletal tissue. Poor dietary
Table 1
habits, use of steroids, malabsorption syndromes, and eating
disorders such as anorexia nervosa often contribute to the
development of suboptimal PBM. Obese and overweight
children also appear to have impaired bone development12—a particularly significant determinant considering
the escalating pandemic of obesity.13 Oral contraceptive
use, a risk factor which encompasses most women in
western culture, may also ‘‘prevent attainment of maximal
PBM in young women and thus increase the risk of
osteoporosis later in life.’’14 With increasing evidence of
various health issues related to environmental toxicants,15 it
is also noteworthy that exposure to certain adverse
chemicals appears to alter nutrient physiology required for
bone development—lead, cadmium and aluminum, for
example, may block normal VTD metabolism.16 In addition,
increasing research is investigating gestational habits and
conditions such as maternal nutrition, toxicant exposure,
smoking, soda-pop consumption and hypovitaminosis D as
potential determinants of fetal propensity to subsequent
osteoporosis.17,18
Rapid bone loss, resulting from accelerated bone resorption or from insufficient new production is the second major
source of osteoporosis. Although bone loss is facilitated by
the hypo-estrogenemia associated with menopause, various
lifestyle choices and medical factors are also significant
determinants of accelerated rates of bone loss. Several
Selected determinants of bone health in adults.
Determinant
Age
Family history of osteoporosis
Exercise
Protein
Calcium
Phosphate
Vitamin D
Alcohol
Smoking
Alkaline-producing dietary nutrients
Fruits and vegetables
Coffee
Green or black tea
Testosterone
Vitamin B12
Zinc
Viral cirrhosis
Hyperthyroidism
Hyperparathyroidism
Glucocorticoid use
Anticonvulsants or heparin
Omega-3 fatty acids (o3)
Omega-6 fatty acids (o6)
Phytoestrogen isoflavones
Vitamin C
Lycopene
Correlation with positive impact on
bone health
Regular exercise146
Adequate intake
Adequate intake80
Sufficient production or intake80
Low to moderate intake32,33
Correlation with adverse impact on
bone health
Advancing age144
Positive family history145
Excessive exercise147,148
Excessive protein intake27
Low calcium intake
Excessive phosphate intake27,144
Deficiency of vitamin D
Excessive alcohol intake32
Regular smoking30,31
Sufficient daily consumption149
Sufficient daily consumption150
More than 2 cups daily34,35
Regular intake of tea containing
flavonoids36,37
Regular intake25
Low testosterone28,29
Vitamin B12 deficiency26
Zinc deficiency
Viral cirrhosis with decreased BMD39
Primary or secondary
Primary or secondary
47.5 mg prednisone/day for43
months
Chronic consumption
Balanced o3:o6 intake23,137
Excessive o6 intake136
Adequate intake151
Adequate intake80
Adequate intake152,153
ARTICLE IN PRESS
196
medications including steroids, anticonvulsant therapy,
chronic heparin, Depot Provera and Lupron may contribute
to diminished bone health.19–21 Other risk factors that have
been correlated with hastened bone loss include residential
care, inactivity, low vitamin D, hypogonadism, and poor
nutrition.19
Through the different stages of life, skeletal remodeling
is subject to various systemic and local factors22–24 including
various nutrients, toxins, hormone levels and disease
conditions. For example, dietary minerals such as calcium
and zinc as well as vitamins such as B12 are required for
proper bone development.25,26 While adequate protein is
necessary for bone deposition, excess protein is a risk factor
for osteoporosis.27 Insufficient levels of hormones such as
estrogen in women and testosterone in males also predisposes to osteoporosis.28,29 Smoking and heavy alcohol intake
are risk factors for bone weakness,30–32 but statistics
indicate that alcohol in moderation offers some measure
of protection.32,33 And while consumption of more than two
cups of caffeine appears to decrease bone density,34,35 tea
drinking appears to offer slight benefit.36,37 Various clinical
conditions such as peripheral vascular disease and viral
cirrhosis have also been correlated with osteoporosis.38,39 In
review, numerous factors may act independently or in
concert to influence the health and deterioration of skeletal
tissue. (Table 1).
Causality of fractures
Although understanding the etiology of osteoporosis is
important in comprehensive management of bone health
concerns, the main endpoint of osteoporosis care is to
reduce fractures, a major contributor to compromised overall health and well-being. 40 From a clinical
perspective, the two foremost factors contributing to
fragility fractures are (a) the severity of osteoporosis
and (b) the risk for falling. While much attention is given
to the issue of osteoporosis, further emphasis on prevention
of accidental falls needs to be incorporated into
public health strategies for seniors.40 Many falls result from
impaired cognition and perception secondary to various
medications including sedatives, antidepressants, and some
blood pressure therapies.41,42 Musculoskeletal afflictions
and foot disorders such as deformities, bunions, and
calluses as well as environmental hazards such as throw
rugs, steps, and ice are also frequent culprits in accidental
stumbles. Furthermore, impaired vision and hearing may
contribute to the risk of falling. In clinical medicine, care for
patients at high risk for fractures should include proactive
evaluation and management of factors predisposing to
falling.
Osteoporosis and premature fracturing are largely preventable conditions which are potentially amenable to
lifestyle intervention. Within the western world, however,
current lifestyle patterns of sedentary indoor living,
dubious nutritional intake,43 and escalating multi-drug
consumption,44 portend that the incidence of osteoporosis
and fragility fractures may continue to escalate in years to
come.
S.J. Genuis, G.K. Schwalfenberg
Personal and social implications of osteoporosis
The cumulative burden of compromised bone health and
osteoporotic fractures on individuals, families and society is
enormous.45,46 Common sequelae of fragility fractures
include cosmetic deformity, pain, restricted mobility, as
well as increased morbidity and mortality arising from
complications. Although fractures may occur at various sites
including the pelvis, proximal femur, and proximal humerus,
three types of fractures are particularly common with
osteoporosis: distal forearm, vertebral, and hip fractures.
Distal forearm and wrist fractures frequently occur when a
person stumbles and brakes the fall by landing on their
outstretched hand, potentially resulting in impaired function and deformity. The most common and most problematic
fractures, however, are vertebral and hip fractures, respectively.
Vertebral fractures frequently result when vertebrae in
the osteoporotic spine are so weak that spontaneous
crushing occurs with minimal stress. Epidemiologically,
vertebral fractures often serve as a prelude to, but
generally occur 15 years before hip fractures. Most crushing
occurs on the anterior aspect of vertebrae which accounts
for the hunched over appearance known as Dowager’s
Hump. Vertebral fractures frequently result in significant
morbidity and reduction in quality of life47: as well as the
cosmetic deformity, repeated crush fractures are often
associated with serious discomfort, height loss, abdominal
protrusion, and shuffling gait.
Hip fractures are the most serious of the three common
skeletal incidents and often transform an active woman into
a chronically disabled woman.48 The overall incidence is
quite high as a 50 year old North American woman has, on
average, a 1 in 6 risk of a hip fracture during the rest of her
life. Seventy percent of hip fractures are related to
osteoporosis and 80% of osteoporosis expenditures are
consumed by the management of patients with hip
fractures. The prognosis for patients with osteoporotic hip
fractures can be troubling indeed49: only one-half of
patients regain pre-fracture level of function,40 about onethird of patients end up in nursing homes within a year, and
many survivors are wheelchair bound or bedridden. Furthermore, up to 20% of women who fracture a hip die within a
year from related complications such as thromboembolic
disease, pneumonia, and decubitus ulceration leading to
septicemia.
Osteoporotic fractures often have a profound effect on
individual well-being as well as on public health care.50
Individually, patients with fragility fractures frequently
experience impaired quality of life with higher rates of
anxiety, depression and loss of independence51,52; from a
social perspective, the direct cost of osteoporosis is
about $17 billion/year in America51 and 13 billion euros in
Europe,53 not including the expense related to lost
productivity. Furthermore, the loss of available acute care
beds due to extended occupation by patients with hip
fractures places a serious burden on public health
care provision. As bone compromise is a largely preventable
and potentially treatable condition, it is important to
evaluate management strategies and to implement all
means possible to prevent and address this troubling
disorder.
ARTICLE IN PRESS
Nutrient strategies and bone health
Contemporary management of osteoporosis
In the contemporary management of osteoporosis some
attention has been given to addressing concerns of diet
and lifestyle. As well as stressing the importance of
exercise, most intervention protocols encourage the inclusion of routine calcium and VTD as part of the
primary strategy to optimize bone strength. The use of
therapeutic pharmaceutical agents, however, remains the
mainstay of most management protocols for patients with
osteoporosis.54
The most commonly used drugs to manage patients with
compromised BMD are bisphosphonates which inhibit bone
resorption and which are effective, according to
recent studies, in reducing vertebral, non-vertebral and
hip fractures.55 These agents appear to be well tolerated in
the short term but long-term safety remains uncertain.
Recent reports of avascular necrosis of the jaw in
dental patients taking intravenous bisphosphonates56 as
well as delayed or absent fracture healing in some
patients using oral bisphosphonate therapy57 have
led to the introduction of the term bisphosphonateassociated osteonecrosis56 and have raised concern about
long-term use of these agents in any patient that may
require bone to heal.58 Less commonly used pharmaceutical
options include selective estrogen receptor modulators
(SERMs), hormone replacement therapy (HRT), and teriparatide.
SERMs serve as estrogen agonists with skeletal tissue but
act as estrogen antagonists with certain other tissues.
The estrogenic activity of these drugs on bone qappears to
provide some protection against vertebral fractures
but consistent efficacy against non-vertebralq fractures is not yet established. With the selective estrogen
antagonistic action, potential non-skeletal benefits and risks
of SERMs are also being explored.59 The use of preventive
HRT has been a source of much controversy in the last few
years.60 Clinical studies suggest some protective benefit
against fractures with the use of preventive HRT, but the
potential for adverse sequelae on overall health61,62 has
precluded recommendation of routine HRT as a
primary agent to prevent osteoporosis. The recently
introduced parathyroid hormone analog, teriparatide, stimulates bone formation and displays a reduction in
vertebral and some non-vertebral fractures (excluding hip)
in women with severe osteoporosis.54,63 The efficacy against
hip fractures and the effectiveness of teriparatide in less
severe forms of bone compromise is currently the subject of
ongoing study.
While the use of pharmaceutical agents to manage
osteoporosis has become the standard-of-care in much of
the world, preventing bone compromise by addressing
etiology and stimulating bone health with micronutrients is drawing attention in the research literature. In
mainstream medicine, therapeutic nutritional interventions are sometimes perceived as unsophisticated, primitive or alternative health care. With recent
scientific research probing into the molecular etiology of
bone compromise, however, the potential role for preventive and therapeutic biochemical nutrients in the mainstream management of osteoporosis is becoming more
evident.
197
Nutrient strategies in the prevention and
management of osteoporosis
The objective of osteoporosis care is to maximize bone
strength, to decrease fractures, and to minimize deformity
and discomfort. These objectives can best be achieved
conceptually by four approaches: (a) maximizing PBM (b)
achieving good bone quality (c) diminishing bone loss, and
(d) building new bone, if deficient. Comprehensive proactive programs should incorporate all of these approaches
including judicious prenatal care, pediatric health promotion and prudent care for adults and seniors. As guardians
responsible for public health, the medical community should
also be involved in public health initiatives to create
awareness of strategies to maintain and restore bone
health.
Contemporary medical education has not, however,
focused to any great degree on proactive programs to
prevent osteoporosis; most of the focus in undergraduate,
postgraduate and continuing medical education rests on
establishing diagnoses and providing pharmaceutical drugs
and devices to mitigate signs and symptoms of disease.10 In a
paper entitled ‘‘Battling Quackery’’ published in the
Archives of Internal Medicine, Goodwin et al. highlight the
scornful and dismissive approach that contemporary mainstream medicine takes with micronutrient therapy, regardless of evidence confirming benefit.64 The authors contend
that throughout medical history, novel treatments that do
not fit within the usual paradigm are rejected ‘‘in favor of
less effective or more toxic therapies that better fit’’64 the
prevailing mindset. Although the judicious use of pharmacological agents to deal with the manifestations of illness is
apposite, the neglect of underlying source causation and the
sometimes frosty attitude towards nutritional interventions
needs to be reconsidered.65 Recent research clearly
demonstrates that nutrient therapy deserves a central place
in the assessment and management of a variety of medical
afflictions including osteoporosis.66,67 There are various
nutrients that have been shown to play a role in bone
health including magnesium, selenium, vitamin C, and
others; recent data involving four specific nutrients–vitamin
D, strontium, VTK and essential fatty acids–will be discussed
here.
VTD
Recent literature has associated low levels of VTD with
myriad chronic debilitating conditions ranging from cancer68
to diabetes,69 and from cardiovascular disease70 to polycystic ovarian syndrome.71 As a requisite nutrient in the
proper absorption and deposition of calcium in bones, VTD is
required at all phases of human development for the normal
formation of skeletal tissue, the proper achievement of
PBM, and the maintenance of BMD. Inadequate serum VTD is
associated with secondary hyperparathyroidism, increased
bone turnover, accelerated bone loss, and increased
fracture risk. Hypovitaminosis D is very prevalent in both
adults and children72–75 and is responsible, in part, for the
high incidence of osteoporotic fractures.
Sun exposure is a main source for VTD as the rays from
direct sunlight act on 7–dehydrocholesterol in the skin to
ARTICLE IN PRESS
198
eventually form VTD. As many people receive limited solar
exposure and few foods naturally contain this vitamin,
supplementation has become a common means to fulfill
requirements. Recognizing the fundamental need for calcium and VTD in proper bone formation, many individuals
believe that dairy consumption can fulfill these requirements and others rely on the recommended intake for
calcium and VTD found in many osteoporosis protocols. The
benefits of milk consumption and supplementation with low
dose VTD in relation to bone health are not consistent in the
literature.
Although calcium and VTD are required nutrients for bone
development, some observational studies have failed to
demonstrate that routine consumption of dairy products
provides ample nutrition to maintain bone health. While some
interventional studies have found that milk supplementation
increases bone mass or prevents decline in bone density,76–78
recent data reveal that neither milk consumption nor highcalcium diets alone appear to consistently reduce the risk of
hip fracture.79 Furthermore, the standard recommendation
that postmenopausal women consume 600–800 I.U. of VTD
daily as the vitamin contribution to addressing osteoporosis
needs revision as the dose may be insufficient for many
individuals in this category.80,81 The RECORD trial, for
example, using 800 I.U. of VTD alone or in combination with
calcium, showed no benefit in preventing secondary fractures
in the elderly.82 This VTD recommendation also fails to
encompass concerns relating to widespread hypovitaminosis
D in relation to suboptimal PBM in young people.
A simple way to monitor and manage the status of VTD
throughout the life cycle is to measure 25–hydroxyvitamin-D
(25[OH]D) in blood and supplement to achieve healthy
levels.80 Recognizing that rises in bone resorption markers
can be detected in postmenopausal women when the serum
25[OH]D level falls below 60 nmol/l83 and that PTH levels
begin to rise when 25[OH]D values fall below 78 nmol/l,84
some have suggested that a healthy threshold level is in the
range of 80 nmol/l.73,84 Excessive doses of VTD may be harmful
but toxicity is not seen below serum 25[OH]D levels of
250 nmol/l.85 The enormous potential for adequate VTD levels
to prevent osteoporotic fractures has been demonstrated by
recent research.79,86,87 A long-term analysis conducted by
researchers from the Harvard School of Public Health revealed
that postmenopausal women consuming adequate VTD had a
37% lower risk of hip fracture.79 Another recent research paper
published in the British Medical Journal concluded that
patients receiving substantial VTD supplementation had a
decrease in hip, forearm and vertebral fractures.86
In review, hypovitaminosis D is an important, underestimated problem that has been correlated with myriad
medical problems including osteoporosis.72,88–90 Greater
awareness of the importance of VTD for skeletal health,
routine testing for levels of 25[OH]D,89 sensible sun
exposure,91 and more aggressive supplementation efforts
are needed to address this important public health
problem.72,89,90,92
Strontium
Strontium has received considerable global attention after a
major study reported in the New England Journal of
S.J. Genuis, G.K. Schwalfenberg
Medicine demonstrated that treatment of postmenopausal
osteoporosis with orally active strontium led to early and
sustained reduction in the risk of vertebral fractures.93 For
purposes of clarification, it is important to recognize
that strontium can occur in two forms: (a) stable strontium
(simply referred to as strontium) is a naturally
occurring mineral that is found in most foods as well as in
rocks and soil, and may be an essential nutrient
necessary for normal development and sustained health of
the skeletal system; (b) radioactive strontium is
typically formed in nuclear reactors or during the explosion
of nuclear weapons. While stable strontium may be used to
improve or maintain bone health, radioactive strontium is
therapeutically used to treat metastatic cancer but can
damage bone marrow and act as a potential carcinogen at
high doses.
Various studies have documented that low dose stable
strontium is well tolerated in adults, it increases bone
formation and decreases bone resorption,94,95 it is clinically
effective in preventing bone loss, it increases BMD and it
prevents fractures. Recent research has confirmed the
effectiveness of strontium in both vertebral as well as hip
fractures. In a randomized double-blind, placebo-controlled, trial of strontium involving 5091 postmenopausal
women with osteoporosis, hip fracture was reduced by 36%
among women at high risk for hip incidents, and vertebral
fracture was reduced by 39% in patients assessed by spinal Xrays. 96 Furthermore, BMD changes were evident: at 3 years,
patients receiving strontium had BMD advances of
8.2% at the femoral neck with a 9.8% total hip increase.
The authors conclude from the trial that strontium ‘‘offers a
safe and effective means of reducing the risk of fracture
associated with osteoporosis.’’96 In another clinical trial
involving postmenopausal women, strontium recipients also
demonstrated significantly increased lumbar, femoral neck
and total hip BMD at the 2 year mark compared with
placebo.97 Furthermore, strontium administration appears
to be effective in relieving bone pain and impaired
mobility.98,99
It is unclear as to why strontium supplementation has a
positive impact on bone health but it has been recently
reported that commercial foods grown on fields using
synthetic fertilizers, pesticides and herbicides have appreciably lower levels of strontium than organic food counterparts.100 There is speculation that young consumers of
predominantly commercial foods are often deficient in
strontium with development of suboptimal PBM and are
thus potentially more likely to have disordered bone
health–a circumstance which may subsequently respond in
some measure to therapeutic doses of strontium supplementation.
Recent studies using strontium have focused on strontium
ranelic acid salt (strontium ranelate), but previous work has
used many different forms of stable strontium, including
strontium gluconate,101,102 carbonate,98,102 lactate,99,103
and chloride,94 which all seem to be effective. The ranelic
acid salt is a purely synthetic molecular compound, while
lactate, gluconate, citrate and carbonate are naturally
occurring. It appears to be the strontium portion of the
molecules which exerts most or all of the positive effect on
bone. When consuming the strontium ranelate, for example,
the compound splits into two strontium ions and one
ARTICLE IN PRESS
Nutrient strategies and bone health
Table 2
199
Comparison of strontium to drug interventions in study outcomes.168,169
Intervention
BMD vertebral
BMD Hip
Vertebral fractures
Hip fractures
Peripheral fractures
Etidronate
Risedronate
Alendronate
HRT
Calcitonin
Raloxifene
PTH
Fluoride
Strontium
m
m
m
m
m
m
mm
mm
mm
m
m
m
m
m
m
k(cortical bone)154
NS
m
k
k
k
k
k
k
k
k
k
k or NS
k
k
k
NS
k or NS
NS
NS
k
NS
k
k
NS
NS
NS
k
m155
k
NS, no statistically significant change in studies.
molecule of ranelic acid, with each absorbed separately.
There is little evidence that the ranelic acid portion of the
strontium ranelate compound contributes to the effect of
strontium on skeletal tissue, and of the small amount of
ranelic acid that is absorbed into the body, almost all is
excreted within a week without ever being metabolized.104
All forms of strontium have bioavailabilities in the 25–30%
range,94 but gastric tolerance appears to be better with the
ranelate and citrate forms. An increased risk of thrombosis
has been noted with strontium ranelate,105 an effect not
reported (to our knowledge) with other forms of stable
strontium.
An abundance of work confirms that strontium supplementation is well-tolerated and an effective means to
prevent bone loss as well as to build bone and prevent
fractures in the postmenopausal period.96 A comparison of
outcomes related to strontium therapy and various drug
treatments is provided. (Table 2) The effects on bone health
of combining strontium and assorted pharmaceutical preparations such as bisphosphonates, however, are not fully
known. In review, the findings from the medical literature
suggest that judicious use of low dose stable strontium may
be an effective and safe way of assisting patients to
maintain and restore bone health.
VTK
VTK is a fat-soluble molecule that naturally occurs in two
forms: (a) VTK-1 (phylloquinone) is synthesized by plants
and is abundantly found in green leafy vegetables and some
vegetable oils (soybean, canola, and olive); (b) VTK-2
(menaquinones) refers collectively to a group of compounds
that are commonly synthesized from bacteria that normally
colonize the colon as well as from enteric metabolism of
VTK-1. The ‘‘K’’ component of VTK is derived from the
German word ‘‘Koagulation’’ as this essential molecule is a
required coenzyme involved in blood coagulation, but
recent work has also recognized VTK as a cofactor in many
biochemical pathways associated with cell growth, brain
development106 and bone health.107
Increasing epidemiological research has demonstrated
that healthy bone mineralization and adequate bone
integrity is dependent on adequate levels of VTK. Various
VTK-dependent proteins have been isolated in bone, the
deficiencies of which may be associated with diminished
BMD and other adverse sequelae.108,109 The Nurses Health
Study, for example, confirmed that women with low VTK
consumption had dramatically higher rates of hip fracture110
and the Framingham Heart study found that both men and
women with higher VTK intakes sustained about a 35%
relative risk of hip fracture compared to those with low
intake.111 Furthermore, a 3-year, double-blind, controlled
study recently concluded that 1 mg of VTK-1 daily may
substantially contribute to reducing postmenopausal bone
loss at the site of the femoral neck.112
More recently, there has been increased focus on the
VTK-2 form of this micro-nutrient. VTK-2 is involved in
the induction of bone mineralization in human osteoblasts113,114 and in vitro studies suggest that this molecule
also inhibits osteoclast formation115 as well as diminishing
bone resorption by inhibiting prostaglandin E2 synthesis.116
A form of VTK-2, menatetrenone (MK-4), is well tolerated
with oral intake and is under extensive study in Japan for
the management of osteoporosis and the prevention of
fractures.117–120 A number of human clinical trials have
been undertaken and prove VTK-2 to be an effective
agent in maintaining BMD and diminishing the risk of
fracture. In a recent randomized control trial, for example,
osteoporotic women receiving VTK-2 and calcium were
significantly less likely to sustain clinical fractures and
lose BMD than controls who received calcium alone.118
Furthermore, another recent trial on patients with
Alzheimer’s disease confirmed that supplemental VTK-2
preserved BMD and significantly decreased the risk of
non-vertebral fractures including hip fractures in these high
risk patients.121 Various authors report that no adverse
effects are usually associated with this intervention,122 but
caution has been expressed that VTK-2 may counteract the
effects of anticoagulant therapy and may be contraindicated in individuals who have sustained thrombotic illness
previously.
In a recent review paper on the effects of VTK on
osteoporosis, the authors conclude that deficiency may
contribute to osteoporotic fractures and that use of VTK-2
may stimulate bone formation and suppress bone resorption,
thus contributing to the prevention of osteoporotic fractures.107 Deficiency of this nutrient typically occurs with
ARTICLE IN PRESS
200
S.J. Genuis, G.K. Schwalfenberg
insufficient intake, or with depletion of bacterial flora in the
intestine potentially from antibiotic usage.123 Accordingly, it
appears prudent to ensure that dietary requirements for
VTK are being met,124 to incorporate laboratory testing for
functional measures of VTK status if indicated,125 and to
consider VTK-2 supplementation for patients with compromised bone health.126 It is uncertain whether probiotic
usage to enhance bacterial flora is associated with improved
VTK-2 production.
Essential fatty acids (EFAs)
Recent research confirms that adequate and balanced levels
of EFAs in the diet positively impact bone health and that
EFA deficiency may be a major contributor to osteoporosis.
Although the complex mechanisms of bone physiology
are not fully understood, many molecular factors which
are inextricably linked to bone formation and resorption
are controlled or influenced by the availability and
action of EFAs.127–130 The finding that animals deficient in
EFAs develop severe osteoporosis131 has prompted
further study of the role of these essential nutrients in
bone health.
There are two categories of EFAs: omega-3 fatty acids
(o3FAs) and omega-6 fatty acids (o6FAs); both groups
originate from lipids ingested in the diet as the body is
unable to synthesize them.132 While o6FAs are plentiful in
foods such as cereal grains, processed foods, meat, milk,
eggs and some vegetable oils, o3FAs are found in
significant quantity in only a few seeds and nuts, as well
as in fish oil. Both families of fatty acids provide required
substrate for the production of eicosanoids, which
include important bioactive compounds such as prostaglandins, leukotrienes and thromboxanes. (Fig. 1) Eicosanoids
originating from o6FAs act biochemically to promote
cell proliferation, inflammation and blood clotting
while eicosanoids originating from o3FAs oppose these
effects and facilitate anti-inflammatory action, inhibitory
effects on cell growth, and blood thinning.133 Both groups of
EFAs compete for the same limited supply of enzymes
in the biochemical assembly of eicosanoids and diets with
high o6FAs:o3FAs (o6/3) ratios will diminish the effectiveness of o3FAs-dependent processes, leading to an overabundance of omega-6 derived eicosanoids. The relative
concentration of o6FAs and o3FAs consumed in the diet is a
matter of major import to the biochemical and clinical
functioning of the individual,134 including skeletal tissue
function.130
The o6/3 dietary ratio affects calcium metabolism130
as bone formation and bone resorption are influenced
locally by prostaglandins and cytokines,22,24,135 which in
turn are regulated by EFAs. High intake of o6FAs results in
elevated prostaglandin E2 and other cytokines, which are
E s s e n t ia l F a t t y A c id
C o n s u m p tio n
Linoleic acid
(LA)
Alpha Linolenic
acid (ALA)
Compete for same desaturase
enzyme (delta 6)
Eicosapentaenoic acid
(EPA)
Gamma Linolenic acid
(GLA)
Compete for same desaturase
enzyme (delta 5 & 4)
Docosahexaenoic acid
(DHA)
Arachidonic acid
(AA)
Cyclo-oxygenase (competitive)
Lipoxygenase enzymes (competitive)
Anti-inflammatory
Omega 3 Eicosanoids
Reduces Bone Resorption
Figure 1
Pro-inflammatory
Omega 6 Eicosanoids
Increases Bone Resorption
Essential fatty acid metabolism.
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Nutrient strategies and bone health
Table 3
201
Examples of documented benefits of omega-3 fatty acids (o3FAs) in various disorders.
Trial/author
Cancer
Maillard et al. (2002)156
Terry P et al. (2001)157
Obstetrics and Gynecology
Olsen et al. (2002)158
Description of study
Outcome
Case–control study assessing EFA composition in
adipose tissue in women with breast cancer compared
to controls
Much less risk of breast
cancer in patients with
balanced o6/o3 ratio. Higher
levels of o3FAs associated
with less risk of disease.
2–3 fold lower frequency of
prostate cancer in men who
ate moderate or high amounts
of fish compared to no-fish
eaters.
30 year prospective study of large group of Swedish
men
Prospective cohort study examining relation between
maternal dietary intake of o3FAs via fish consumption
and preterm labor
Williams et al. (1995)159
Case–control study to examine the exposure-effect
relation between maternal intake of o3FAs and risk of
preeclampsia
Harel et al. ( 1996)160
RCT with intervention group given o3FAs via fish oil to
study the effect on dysmenorrhea in adolescents
Cardiovascular disease
Bucher et al. (2002)161
Indo-Mediterranean Diet
Heart Study (2002)162
Hypertension
Geleijnse et al. (2002)163
Appel et al. (1993)164
Osteoporosis
Weiss et al. (2005)127
Meta-analysis of RCTs studying the effect of o3FAs on
coronary artery disease
RCT with intervention group given diet high in o3FAs
Meta-analysis of RCTs studying the antihypertensive
effect of o3FAs
Meta-analysis of RCTs studying the antihypertensive
effect of o3FAs
Cohort study assessing bone mineral density in
relation to the ratio of dietary intake in o6FAs/ o3FAs
Once weekly fish consumers
had a 1.9% chance of preterm
birth vs. 7.1% for nonconsumers.
A 15% increase in the ratio of
o3FAs to omega-6 fatty acids
was associated with a 46%
reduction in risk of
preeclampsia.
Dietary supplementation with
o3FAs resulted in a marked
reduction of symptoms of
dysmenorrhea in adolescents.
Dietary and supplemental
intake of o3FAs reduces (a)
overall mortality, (b)
mortality due to myocardial
infarction, and (c) sudden
death in patients with
coronary heart disease.
Total cardiac end points,
sudden cardiac deaths, and
non-fatal myocardial
infarctions were significantly
fewer in the intervention
group.
High intake of fish oil may
lower BP, especially in older
and hypertensive subjects.
Diet supplementation with
o3FAs, can lead to clinically
relevant BP reductions in
individuals with untreated
hypertension.
A higher intake of o3FAs
relative to o6FAs is associated
with a higher BMD at the hip
in both sexes.
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S.J. Genuis, G.K. Schwalfenberg
Table 3 (continued )
Trial/author
Rheumatoid Arthritis
Kremer et al. (1990)165
Bipolar illness
Stoll et al. (1999)166
Alzheimer’s disease
Morris et al. (2003)167
Description of study
Outcome
RCT of dietary supplementation with fish oil in
patients with active rheumatoid arthritis
Significant clinical benefit
with high dose fish oil—the
number of tender joints
improved significantly over
controls.
Double-blind, placebo-controlled trial comparing
supplementation with o3FAs vs. placebo in addition to
usual treatment in patients with bipolar disorder
Patients supplemented with
o3FAs experienced significant
improvement in symptoms
and remission rates.
Prospective cohort study of a stratified random
sample from a defined population. Dietary intake of
o3FAs was correlated with development of Alzheimer
disease
60% less likely to develop
Alzheimer’s with consumption
of fish at least once a week.
pro-inflammatory136 and which activate osteoclasts and
bone resorption. As a result, excess o6FAs in the diet has
been associated with increased periodontal disease and
bone resorption23 as well as lower bone density at the hip in
both men and women.127
On the other hand, o3FAs downregulate inflammatory
cytokines137; bone resorption is reduced when o3FAs
levels are high.23 Adequate dietary o3FAs facilitate
absorption of calcium in the gut, reduce excretion of
calcium in the urine, increase calcium deposition in
bone and enhance bone collagen synthesis. Significant
reductions in cytokine production can be achieved by
dietary supplementation with foods containing abundant
o3FAs such as fish oil,138 flaxseeds, and flaxseed oil139
resulting in increased calcium absorption, bone calcium and
BMD.
Abundant volumes of recent literature confirm that a low
o6/3 ratio ‘‘may be necessary for optimal health, normal
development, and prevention of chronic disease.’’127
(Table 3) The relatively high o6/3 ratio in the typical North
American diet may have a significant impact on osteoporosis
and other degenerative diseases; while the o6/3 ratio was
about 1–2:1 as recent as 200 years ago, it is now estimated
at 16:1.134 By way of contrast, osteoporotic hip fractures are
much less prevalent in Japan,140 a country where the dietary
ratio of o6/3 is 4:1.141
In review, a low nutritional ratio of o6/3 appears to
enhance calcium absorption, reduce excretion, and increase
calcium deposition in bone, which in turn decreases the risk
of osteoporosis and resultant fragility fractures. Furthermore, by improving bone quality and BMD,130 in addition to
reducing inflammatory cytokines, o3FA supplementation has
been shown to slow the rapid rate of postmenopausal bone
loss.142 Accordingly, it may be prudent in clinical medicine
to discuss EFA intake with patients and to supplement o3FAs
as a routine aspect of care for individuals with compromised
bone health.
Conclusion
The medical community is facing an escalating pandemic of
bone disease with an estimated 1 in 3 women and 1 in 10
men now aged 55 or older destined to have osteoporosis in
their lifetime.143 Juxtaposed with this public health challenge, however, is the perplexing reality that the spectrum
of existing research on bone health has not been translated
into clinical recommendations—nutrient interventions have
not yet been mobilized to address the swelling concerns of
impaired PBM in youth and osteoporosis in later life.
Innovative strategies to meet the challenge of skeletal
compromise throughout the life cycle are urgently required.
The physiology of bone formation and loss involves a
complex interplay of nutritional, lifestyle, genetic, metabolic, and environmental factors. Although existing treatment
regimens usually include mention of diet, lifestyle, and
nutrient supplementation, the principal spotlight of contemporary osteoporosis care rests on indications for BMD testing
and the pharmaceutical intervention. The importance of
education relating to preventive and therapeutic nutrition in
the management of osteoporosis is evident; copious scientific
work confirms that routine utilization of specific nutrients
including vitamin D, stable strontium, vitamin K, and essential
fatty acids are able to significantly improve bone health and
diminish rates of serious compromise resulting in osteoporotic
fracture (Fig. 2). Although evidence-based data confirms that
each of these agents individually may provide benefit for bone
health, further study is required to determine synergistic
potential and the therapeutic impact of an ‘‘osteoporosis
cocktail’’ containing a mixture of these nutrients.
Nobel Prize winner and pioneer in nutritional medicine,
Dr. Linus Pauling, once commented that innovations which
promote scientific knowledge 10 years prior to general
consensus are rewarded with Nobel Prize recognition while
innovators who present the same information 20 years prior
to consensus are discarded as heretics. From the vantage
ARTICLE IN PRESS
Nutrient strategies and bone health
203
Diet & Lifestyle
- Maximize factors which enhance bone health
- Avoid determinants which detract from bone health
Vitamin D
- Achieve optimal levels of 25[OH]D
- Common sources: skin conversion from sun exposure; fortified foods;
fatty fish; supplementation
Essential Fatty Acids
- Balanced ω6/3 intake ratio appears to be optimal
- Consistent ω3 intake to ensure adequate consumption
- Common sources of ω3: seafood; some plant sources such as flaxseed
and walnuts; supplementation
consider Strontium
- Recent studies use daily strontium to achieve improved bone health
- Common sources:food sources include some spices, seafood, whole grains,
root and leafy vegetables, and legumes; supplementation
consider Vitamin K2
- Recent reports use 100ug - 45 mg/day to achieve improved bone health
- Common sources: produced by intestinal bacteria; some fermented soy
products (natto); supplementation
Figure 2
Potential approach to ameliorate osteoporosis.
point of mainstream medical consensus it is difficult to say
where the nutritional management of osteoporosis currently
rests on the continuum from heresy to medical hypothesis to
clinical use; the amalgamation of scientific research on
nutrient supplementation as presented in this review paper,
however, suggests that ongoing re-evaluation of osteoporosis
management is in order.
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