Archives of Biochemistry and Biophysics 523 (2012) 115122

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Review

Vitamin D and osteoporosis-related fracture

Neil Binkley
University of Wisconsin Osteoporosis Clinical Research Program, University of WisconsinMadison, WI, USA

a r t i c l e

i n f o

Article history:
Available online 13 February 2012
Keywords:
Vitamin D
25-Hydroxyvitamin D
Osteoporosis
Fracture
Falls
Sarcopenia

a b s t r a c t
The age-related decline in mass and quality of bone (osteoporosis) and muscle (sarcopenia) leads to an
exponential increased risk for osteoporosis-related fracture with advancing age in older adults. As vitamin D inadequacy plausibly causally contributes to these declines, optimization of vitamin D status
might reduce the deterioration of bone and muscle function with age. Putative mechanisms by which
vitamin D inadequacy may increase fracture risk include both direct and indirect effects on bone and
muscle. However, controversy currently clouds the role(s) of vitamin D in osteoporosis-related fracture,
the amount of vitamin D required and the optimal 25-hydroxyvitamin D level. This review provides an
overview of current knowledge and suggests a clinical approach to vitamin D status in older adults with,
or at risk for, osteoporosis-related fracture. These recommendations are likely to evolve as additional data
becomes available.
2012 Published by Elsevier Inc.

Introduction
Vitamin D has long been recognized to play an important role in
bone health with vitamin D deciency causing rickets/osteomalacia
via impairment of GI calcium absorption [1,2]. Subsequently, low
vitamin D status has been associated with secondary hyperparathyroidism, thus contributing to age-related bone loss and resultant increased fracture risk. Importantly, vitamin D deciency is associated
with muscle weakness, thus potentially leading to an increased risk
for falls [3]. As many osteoporosis-related fractures result from falling [4], it is plausible that benecial effects of vitamin D on both
bone and muscle/falls risk might result in reduced risk for osteoporosis-related fractures. However, the required amount of vitamin D,
and circulating 25(OH)D concentration, necessary to achieve optimal musculoskeletal benet remains extremely controversial [5].
A Herculean evaluation of this topic was recently conducted by
the Institute of Medicine [6,7]; this review will provide an overview
of current knowledge surrounding the role of vitamin D in bone and
muscle, and provide an opinion regarding vitamin D use in patients
with, or at risk for, fragility fracture.

women and 25% of older men sustain such fractures in their lifetime [9,10]. These fractures reduce quality and quantity of life and
cause major healthcare costs [1113]. Given current population
demographics [14], the number of osteoporosis-related fractures
will increase for the foreseeable future. Determining optimal
approaches to reduce the impact of this devastating disease has
major personal, economic and societal importance [13]. Thus,
understanding potential roles of vitamin D in osteoporosis pathogenesis is an area of intense interest.
Ultimately, osteoporosis results from disordered bone remodeling in which osteoclastic bone resorption exceeds osteoblastic
bone formation [15]. Such imbalanced bone remodeling becomes
common in older adults such that a negative bone balance exists
at each remodeling site [16]. As such, factors leading to increased
remodeling rates will tend to produce greater bone loss thereby
reducing bone strength and increasing fracture risk [17]. Therefore,
vitamin D deciency, with associated calcium malabsorption and
resultant secondary hyperparathyroidism, could be expected to
enhance age-related bone loss thus increasing fracture risk.
Vitamin D and BMD

Osteoporosis
Osteoporosis is a common disease characterized by low bone
mass and deterioration of bone microarchitecture leading to an increased risk of fragility fracture [8]. Osteoporosis-related fractures
are extremely common; approximately 4050% of postmenopausal
Address: University of Wisconsin Osteoporosis Clinical Research Program, 2870
University Avenue, Suite 100, Madison, WI 53705, USA. Fax: +1 608 265 6409.
E-mail addresses: nbinkley@facstaff.wisc.edu, nbinkley@wisc.edu
0003-9861/$ - see front matter 2012 Published by Elsevier Inc.
doi:10.1016/j.abb.2012.02.004

Human physiology requires maintenance of a normal circulating

calcium concentration, if necessary at the expense of increased bone
remodeling. As such, it is intuitive that vitamin D deciency could,
over time, contribute to age-related bone loss. Multiple studies have
evaluated this relationship. To summarize a substantial and diverse
literature, some [1821], but clearly not all [2226], studies nd a
positive relationship between serum 25(OH)D and BMD. It is not
surprising that published studies report variable results as cohorts
of differing age, race, gender and health/nutritional status have been

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studied. For example, a recent study of men age 5079 found no effect of supplementation with 1000 mg calcium + 800 IU vitamin D3
daily on BMD as measured by DXA or QCT [27]. However, in this
study, the mean daily calcium intake was 1000 mg and the mean
serum 25(OH)D 34 ng/mL. It comes as no surprise that provision of
more calcium and vitamin D to a population replete in these factors
had no effect on BMD. An additional confounder is that many studies of the 25(OH)D/BMD relationship evaluated the co-administration of calcium with vitamin D. For such studies, denition of the
effect of vitamin D alone is not possible. An additional confounder
is that BMD is not a single simple endpoint; it varies by skeletal
site. Additionally, BMD as measured by DXA is often affected by
degenerative changes. Specically, the most consistent association
between 25(OH)D and BMD is observed at the hip. This is not surprising given the nearly universal presence but variable severity
of spinal degenerative changes in older adults, which increases
BMD as measured by DXA [28,29]. As these degenerative changes
often worsen with advancing age, they blunt or prevent detection
of age-related bone loss and thereby confound assessment of the
relationship of vitamin D with lumbar spine BMD. Finally, the
amount of vitamin D required and/or circulating 25(OH)D to
achieve optimal calcium absorption (and therefore logically BMD
effect) remains controversial [3033]. Synthesizing a complex, diverse and controversial literature, the 2011 IOM report endorsed
20 ng/mL (50 nmol/L) and specically found no increase in calcium
absorption above serum 25(OH)D values of 20 ng/mL [6].
Despite the above noted complexities, meta-analyses do nd a
positive relationship of 25(OH)D with BMD. For example, a 2007
report by AHRQ-Ottawa found fair evidence that 25(OH)D concentration is positively associated with BMD in associational and randomized trials [34]. Similarly, the 2011 IOM report found fair
evidence to support a positive association between serum
25(OH)D concentration and BMD or change in femoral neck BMD
[6]. In summary, low vitamin D status is associated with low
BMD and bone loss; the challenge is dening what constitutes
low vitamin D, appropriately identifying such individuals, and
providing proper supplementation.
Sarcopenia
Similar to bone, an age-related decline in muscle mass and
function occurs. This decline has been termed sarcopenia [35]
and is associated with increased risk for falls and fractures. Recent
consensus denitions of sarcopenia include both low appendicular
(leg and arm) muscle mass and impaired muscle function, for
example, slow gait speed [36,37]. The pathogenesis of sarcopenia
(similar to that of osteoporosis) is often multifactorial and includes
nutritional deciencies, chronic inammation, toxin exposure and
motor neuron loss [38]. Despite variable denitions of sarcopenia
in the past, it is clear that this condition becomes common with
advancing age. For example, NHANES III data estimate a 711%
prevalence of sarcopenia in older adults; moreover, these data
establish a relationship between sarcopenia and impairment/disability [39]. Specically, decreased muscle function is associated
with reduced ability to perform activities of daily living [40] and
leads to increased morbidity and all-cause mortality [41,42].
Healthcare costs related to sarcopenia are estimated at $18.5 billion annually in the United States [43]. Importantly, sarcopenia is
associated with increased falls risk, thereby increasing the likelihood of osteoporosis-related fractures.
Vitamin D and sarcopenia
In cross-sectional studies, low 25(OH)D is associated with lower
appendicular lean mass in older men [44] and women [45]. Indeed,

Fig. 1. Variability of 25(OH)D despite similar amounts of sun exposure. In

individuals with large amounts of sun exposure at 21 latitude, substantial
variation in 25(OH)D concentration is observed. Despite 2040 h of sun exposure
per day (rectangles) not all individuals achieve a 25(OH)D concentration above the
commonly recommended cutpoints of 20 or 30 ng/mL (depicted by red and green
dashed lines respectively). Raw data from Binkley et al. [144].

Fig. 2. Variability of 25(OH)D response to oral vitamin D3 supplementation. In this

1 year study, individual variation of 25(OH)D change in older adults receiving
1600 IU of daily vitamin D3 daily is apparent. Thus, while a rule of thumb is that
1000 IU of daily D3 will increase circulating 25(OH)D by 610 ng/mL, this response
cannot be assured in all patients. Raw data from Binkley et al. [162].

25(OH)D is signicantly lower in older adults with sarcopenia than

in those without [46]. Additionally, in observational studies, low
25(OH)D is associated with greater muscle loss in older adults. This
was demonstrated over 2.6 in the TASOAC (TASmanian Older Adult
Cohort study) [45] and over 3 years in the LASA (Longitudinal
Aging Study Amsterdam) study [47]. Prospective randomized studies of vitamin D relevant to sarcopenia are limited, however, two
small studies of vitamin D supplementation do report increases
in number and cross sectional area of type II muscle bers
[48,49]. The mechanism(s) by which vitamin D could be involved
in sarcopenia pathogenesis are complex and include muscular,
neurologic and inammatory effects [50].
Falls
Approximately one-third of individuals over age 65, and
roughly half of those over age 80, fall each year [51]. Falls are the
leading cause of injury related hospitalizations and injury-related
mortality for older adults, leading to almost 16,000 deaths annually [52]. In addition to the economic costs associated with falls
(estimated at over $19 billion annually) [53], the personal costs
are substantial in that fallers may develop fear of falling and thus
reduce their activities thereby further reducing mobility and also
leading to social isolation [54]. As the vast majority, approximately

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117

Fig. 3. Variability of physiologic response to 25(OH)D concentration. While much effort has focused upon determining the value at which the curve depicting the 25(OH)D to
PTH relationship plateaus, it is obvious that there is major between individual variability in this relationship. For example, in (a), this is highlighted by the rectangle
demonstrating that PTH can vary from 15 to 70 pg/mL despite a 25(OH)D value of 612 ng/mL. Raw data from Holick et al. [163]. Similarly, substantial variability between
individuals in the relationship of osteoid volume (a direct measure of bone mineralization) with 25(OH)D is observed (b). Moreover, it is worthy of emphasis that 6/29
individuals with 25(OH)D between 20 and 30 ng/mL had elevated osteoid using a conservative 2% denition (blue line). Applying the more rigorous 1.2% osteoid volume to
dene osteomalacia proposed by Delling [164] (orange line), osteomalacia was not observed when the 25(OH)D concentration was above 32 ng/mL. Data from Priemel et al.
[149] as adapted by R. Heaney and used with permission.

Fig. 4. Variability of serum 25(OH)D measurement between laboratories. Aliquots of serum from two patients were sent to eight clinical laboratories for 25(OH)D
measurement using a variety of methodologies. It is apparent that between-laboratory variability confounds use of a cutpoint diagnostic approach. For example, if one were
to use 20 ng/mL to dene adequacy, patient 1 would be considered adequate (green) in ve laboratories and insufcient (orange) in three. Similarly, if one were to apply
30 ng/mL for patient 2, three laboratories would classify this specimen as sufcient (green) and ve insufcient (orange). Raw data from Binkley et al. [165].

90%, of hip fractures are due to falls [4], interventions to reduce

falls risk will have a major impact to reduce osteoporosis-related
fractures.
Does vitamin D supplementation reduce falls? Many studies,
both associational and prospective in nature have explored the
possibility that vitamin D supplementation might decrease falls
risk in older adults [5564]. Some meta-analyses of these studies
nd a falls risk reduction of approximately 20% [65,66]. However,
it must be recognized that many of the existing studies used vitamin D plus calcium and also that the data quality of studies in
existing meta-analyses is not of high quality (low to moderate)
and furthermore these analyses could be complicated by publication bias and study heterogeneity [67]. In contrast to the positive
meta-analyses noted above, a meta-analysis performed by the
IOM committee concluded that there was no relationship of falls
with serum 25(OH)D [6]. Clearly, there is not consensus that vitamin D supplementation does reduce falls risk. Some potential

effects of vitamin D on factors related to falls risk are reviewed

below.
Vitamin D and falls
Severe vitamin D deciency has long been recognized to cause
myopathy with muscle pain, weakness, muscle wasting and a waddling gait that is improved with vitamin D treatment [3,48,6871].
Muscle biopsies of patients with osteomalacia demonstrate type II
(fast) ber atrophy. Certainly, muscle weakness and muscle loss
could be expected to increase falls risk. As type II muscle bers
are the rst to be recruited to avoid falling, this nding may, at least
in part, explain the increased falls risk reported in vitamin D decient individuals [60]. Indeed, low 25(OH)D is associated with
poorer performance in classic functional tests and predicts the
development of incident disability in older adults [72,73]. Moreover, some, but not all [27], randomized trials do nd vitamin D

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Fig. 5. Serum 25(OH)D in highly sun or ultraviolet light exposed adults. In these
170 adults who were highly sun exposed or habitual tanners (n = 170), the mean
25(OH)D was 36.3 ng/mL. The vast majority were between 20 and 50 ng/mL (yellow
bars). Specically, 9% were below 20 ng/mL (red bars) and 13% were above 50 ng/
mL (green bars). Thus the Paleolithic model supports 3050 ng/mL as a
reasonable clinical 25(OH)D range. Raw data adapted from Tangpricha et al.
[157], Barger-Lux and Heaney [158], Binkley et al. [144].

supplementation to increase muscle strength [74]. In fact, it has

been suggested that a vitamin D effect upon muscle performance
is not limited to older adults; a 2009 review concludes that vitamin
D may improve athletic performance [75].
Multiple mechanism(s) by which vitamin D might affect muscle
function have been proposed including both genomic and nongenomic effects [76,77]. Though it is often stated that the vitamin
D receptor is present in muscle [78,79], recent work fails to nd this
receptor in skeletal, smooth or cardiac muscle [80]. This strongly
suggests that muscle effects are not mediated via the known vitamin D receptor or alternatively indicate an indirect effect. In this regard, it could well be that muscle weakness occurs due to the
metabolic derangements resulting from vitamin D deciency; notably hypophosphatemia. Vitamin D stimulates phosphate absorption [81] and skeletal muscle weakness in vitamin D decient rats
is corrected by phosphate repletion [82]. Whether this is the case
in elderly humans is unknown. However, it is possible that the falls
risk reduction reported in institutionalized elders is due to correction of hypophosphatemia in severely vitamin D decient patients.
Despite the above, not all reports nd effects of vitamin D on
muscle mass and/or strength. For example, a recent study of over
600 men and women of mean age 57 found no association of
25(OH)D with skeletal muscle mass or strength [83]. Moreover,
meta-analyses of existing data are conicting. For example, two
meta-analyses published in 2011 reach divergent conclusions;
one including 13 studies nds supplemental vitamin D to consistently demonstrate benecial effects on strength and balance
[84], while a second including 17 randomized studies involving
over 5000 individuals found no effect of vitamin D supplementation on leg or grip strength in adults with 25(OH)D levels above
10 ng/mL [85]. In this second meta-analysis two studies involving
those with severe deciency did demonstrate improvement in
strength.
In summary, severe vitamin D deciency is associated with
muscle weakness, perhaps via hypophosphatemia. Existing, albeit
limited, evidence suggests that vitamin D supplementation may
lead to improved muscle strength and hypertrophy of type II muscle bers. However, it may well be that muscle weakness is produced only if vitamin D deciency is profound; whether vitamin
D has effects on individuals with less severe deciency remains
to be determined.
Vitamin D supplementation might reduce falls risk via nonmuscular effects, for example, nervous system performance [86].
In this regard, it is plausible that vitamin D deciency adversely

affects neural function as the vitamin D receptor is present in neuronal and glial cells [87,88], and thereby may alter neurotransmitter activity or neurotropic factor production [89,90]. Consistent
with this, low vitamin D status has been associated with impaired
cognitive function [91,92]. As over 40% of hip fracture patients
have cognitive impairment [93], if vitamin D has any effect on cognition there is potential to reduce this contributor to fracture risk.
Moreover, reaction time slows with advancing age [94] and fallers
have signicantly slower reaction times than do non-fallers
[95,96]. Slower reaction times in older women may be associated
with reduced ability to move their hands to reduce the impact
from a fall [97] thus potentially increasing hip fracture risk. A study
of 139 women found 600,000 IU of vitamin D2 improves reaction
time by 14% [59]. To summarize, it is plausible that vitamin D
deciency adversely affects neurologic function thus increasing
falls risk. This possibility has received extremely limited attention;
additional study is needed.
Moreover, it is plausible vitamin D deciency alters vestibular
function leading to poorer balance and attendant increased falls
risk. This possibility is suggested by impaired vestibular function
of VDR knockout mice [69,98]. Potentially consistent with vestibular system effects, in older adults, higher 25(OH)D is associated
with better balance and lower body sway [24,99]. Moreover, in a
prospective study, 8400 IU of vitamin D weekly reduced body sway
only in those older adults with elevated sway [100]. Whether such
individuals had vestibular function impairment improved by vitamin D is unknown, but worthy of investigation.
An additional plausible mechanism by which vitamin D might
affect falls risk is via alteration of sex steroid levels. This possibility
is suggested by the presence of vitamin D receptors in the testes and
the presence of hypogonadism in vitamin D receptor knockout mice
[101,102]. Consistent with a vitamin D effect on sex steroids, distinct seasonality of circulating testosterone concentration exists,
with highest values observed during summer, thus correlating with
the seasonal uctuation of 25(OH)D [103]. This seasonal uctuation
in total testosterone and free androgen index was recently correlated with 25(OH)D in 2299 men of mean age 62 years in whom
peaks of circulating 25(OH)D, testosterone and free androgen index
were observed in late summer with nadirs in spring [104]. Moreover, a recent small randomized trial found administration of
3332 IU of vitamin D daily to vitamin D decient men (mean
25(OH)D = 13 ng/mL) led to an increase in total testosterone by a
mean of 25% [105]. Though these results are biologically plausible,
the studies are small and in need of further validation. As testosterone has positive effects on bone and muscle, it is plausible that benecial effects of vitamin D supplementation variously reported for
bone, falls and fractures might result indirectly from elevations in
circulating testosterone. Additional studies are needed to evaluate
this possibility.
Given the above confusion surrounding potential effects of vitamin D on falls risk, it is not surprising that there is controversy
regarding the 25(OH)D concentration necessary to optimize function in older adults. In this regard, various 25(OH)D cutpoints have
been suggested [106,107]. Briey, one review nds 25(OH)D concentrations below 16 ng/mL to be associated with substantially
poorer leg function and additionally nds that values above
3640 ng/ml to be optimal [66]. In contrast, as the IOM did not
nd convincing evidence of benet above 20 ng/mL, this value
was endorsed [6].
It is intuitive that more severe vitamin D deciency would have
greater effects on falls risk. Similarly, common sense holds that too
much of anything, e.g., vitamin D, may have adverse consequences.
This was emphasized by a 2010 study in which 500,000 IU of oral
vitamin D3 increased the risk of falls and fractures, most notably in
the rst 3 months after dosing [63]. Congruent results, i.e., an
increase in fracture risk, were reported following high dose

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intramuscular vitamin D administration [108]. While the mechanism(s) underlying this increased risk remain to be determined,
it has been speculated that an increase in falls risk might reect
accelerated 1, 25 vitamin D catabolism resulting from the high
dose or, alternatively, non-classical vitamin D effects such as
reduction in pain or improvements in mood leading to increased
mobility and therefore to an increased chance to falls [109].
Regardless of the mechanism, these observations do raise concern
about the commonly recommended clinical approach of high dose
vitamin D administration to rapidly replete vitamin D decient patients [110].
To summarize, low vitamin D status has been associated with
muscle weakness, neurologic dysfunction, balance impairment
and hypogonadism. It is therefore not surprising that low vitamin
D status would be associated with higher falls rates and therefore
increased fracture risk. However, as noted above, recent metaanalyses of the effect of vitamin D on falls risk are contradictory.
It seems probable/likely that the variable effect of vitamin D on
falls risk reects, in part, the vitamin D status at time of study initiation and that falls risk reduction may be observed only in those
with severe vitamin D deciency. Consistent with this, the Murad
et al. meta-analysis [67], found the falls risk reduction to be more
prominent in those who were vitamin D decient.
25(OH)D and fracture risk
Many [24,111115], but not all [116,117], observational or
case-control studies nd lower 25(OH)D in patients with osteoporosis-related fracture than in controls. Additionally, multiple randomized controlled trials have evaluated the effect of vitamin D
supplementation on fracture risk in older adults [5557,63,118
127]; meta-analyses of these RCTs nd vitamin D supplementation
to reduce fracture risk [34,128,129]. Overall, this effect to reduce
fracture risk appears to be more pronounced in institutionalized elderly people [129]. As is the case for BMD noted above, many of
these studies were conducted using combinations of calcium and
vitamin at variable doses. Additionally, the majority of these studies used vitamin D doses of 800 IU daily or less. In summary, fracture reduction benet of vitamin D supplementation appears quite
well established for older adults in institutional settings; for community dwelling older adults these effects are less clear.
As noted above, is possible that vitamin D is uniquely important
in reducing fracture risk by both bone and non-bone, i.e., muscle/
falls-related mechanisms. In this regard, it has been speculated
that individuals with both osteoporosis and sarcopenia, so called
sarco-osteoporosis, [130] might be at greatest risk for fragility
fracture. Therapies to treat patients with sarco-osteoporosis should
ideally target both bone and muscle, thereby reducing falls and
fracture risk; vitamin D may be one such agent. Despite the conicting data noted above for BMD, muscle function and falls, the
clinical endpoint of importance, i.e., fragility fracture, is positively
impacted by vitamin D supplementation. As such, optimization of
vitamin D status in older adults is indicated.
Vitamin D plus pharmacologic osteoporosis treatment
Should vitamin D supplementation be considered routine when
osteoporosis medications are prescribed? Clearly, vitamin D supplementation was included in virtually all of the pivotal studies
documenting fracture risk reduction with pharmacologic therapies
and is often part of osteoporosis treatment recommendations
[131,132]. Despite such recommendations, it is not certain that
concomitant vitamin D supplementation does in fact improve
response to standard osteoporosis therapy. It is not surprising that
no large prospective studies of osteoporosis medications have been

119

done in populations selected to be vitamin D decient. As such,

data largely consist of small and/or clinic based reports. For example, Adami et al. reported in a cohort of 1515 women receiving
anti-resorptive therapy for slightly more than 1 year that low vitamin D status was associated with a less robust BMD response and a
greater risk of fragility fracture [133]. An additional small prospective study in postmenopausal women reported that a
25(OH)D > 25 ng/mL was required for optimal response to alendronate [134]. Similarly, preliminary data reported in abstract form
of 210 women followed clinically on oral or IV bisphosphonate
therapy reported that those with a 25(OH)D level > 32 ng/mL had
a 4.5-fold increased likelihood of positive BMD response to therapy
[135].
Randomized trials of vitamin D plus pharmacologic therapy
have largely consisted of active vitamin D plus alendronate. For
example, a study of 120 postmenopausal osteoporotic women
comparing alendronate alone with alendronate plus 0.5 lg of calcitriol found a greater lumbar spine BMD increase (6.8%) with the
combination compared with 3.7% with alendronate alone [136].
Similarly, combination of 1 lg alfacalcidol plus alendronate produced an approximate doubling of lumbar spine BMD increase
after 2 years of therapy (9.6%) compared to alendronate alone
(5.4%) [137]. These human ndings of greater BMD increase with
combination therapy mimic observations in rats [138,139]. The
mechanism(s) underpinning these observations have been speculated upon, and include the possibility of relative uncoupling of
bone resorption and formation with resorption being inhibited
by alendronate and formation stimulated by vitamin D analogues
[137]. Such speculation remains to be conrmed. As there is no
reason to believe that these greater BMD increases are due to
abnormal bone quality, it is clear that additional study of the combination of vitamin D analogues with antiresorptive therapy is
needed as higher BMD increases could be expected to translate
to greater reduction in fracture risk. In the meantime, when osteoporosis patients are treated with pharmacologic therapy, it seems
prudent to measure serum 25(OH)D and, if needed, supplemental
vitamin D recommended to achieve and maintain a 25(OH)D concentration of at least 30 ng/mL.

Vitamin D, osteoporosis and fracture: Whats a clinician to do?

It is apparent that the role of vitamin D in bone health, muscle
function, falls and fractures is controversial, and that existing data
are inadequate to reach denitive conclusions. Moreover, attempts
to resolve these controversies via performance of meta-analyses
yield contradictory results, which likely serves to confuse healthcare providers and patients. This has led Bolland et al., to make
the following very reasonable recommendation: We suggest that
no further meta-analyses are conducted on vitamin D and falls or fractures until more adequately powered RCTs are performed [140].
As the existing data are imperfect, a reasonable synthesis and
recommendation for clinical care is suggested. Specically, summarizing available data it is apparent that severe vitamin D deciency
leads to calcium malabsorption, secondary hyperparathyroidism,
osteomalacia and muscle weakness. This sequence could be
expected to translate to bone loss, increased falling and fractures.
It should be emphasized that these outcomes are associated with
deciency; a reasonable denition of which is 25(OH)D values
of < 12 ng/mL [7,141,142]. However, it is far less clear that the
aforementioned sequence occurs with 25(OH)D values in what
many consider the insufcient range of 2030 ng/mL [143].
The extensive report performed by the IOM endorsed 20 ng/mL as
the desirable 25(OH)D level, above which there is inadequate
evidence for benet [6,7]. It must be recognized that this is a public
health recommendation, not necessarily a recommendation for

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individual patient care. Other patient care guidelines have endorsed

30 ng/mL based on review of virtually the same data [110]. When
experts in the eld do not agree, it is to be expected that patients
and physicians will be confused; what is a clinician to do?
Initially it seems appropriate to recognize the obvious; public
health recommendations are not identical to patient care guidelines. Doctors generally care for one patient at a time (not populations) and none of these individuals are identical. This is clearly
true for vitamin D production and for response to oral supplementation. For example, in young individuals with high, and identical,
reported sun exposure and similar skin pigmentation, serum
25(OH)D can vary markedly (Fig. 1) [144]. Why such variability occurs remains to be dened, however it is reasonable that this variation reects differences in cutaneous vitamin D production and/or
rapidity of degradation. Clearly, any simple recommendation to
achieve a given amount of sun exposure will not assure achievement of whatever serum 25(OH)D one intends to achieve (e.g., 20
or 30 ng/mL). Similarly, substantial between-individual variability
in response to oral supplementation exists. While a reasonable
rule of thumb is that 1000 IU of daily vitamin D3 will increase circulating 25(OH)D concentration by 610 ng/mL [145148], this
may not be the case on an individual patient level (Fig. 2). Consistent with variable response between individuals, anecdotally, some
patients will have 25(OH)D levels of 30 ng/mL with a reported daily
intake of 400 IU and little UV exposure, while others will require
substantially more oral supplementation. This variability could
well reect not yet well understood differences in absorption, volume of distribution, i.e., body size or body fat mass, and/or rate of
degradation. Future research is needed to understand this variability and inform clinicians regarding vitamin D supplementation
requirements. In the interim, based upon this known variability in
25(OH)D response to supplementation, repeating 25(OH)D
measurement following 36 months of supplementation, as recommended by the International Osteoporosis Foundation [132], seems
appropriate.
Importantly, individual variability in physiologic response exists at any given level of 25(OH)D. This is particularly evident for
circulating PTH concentration where some individuals with low
25(OH)D will have normal PTH levels whereas others with normal 25(OH)D will have high PTH (example in Fig. 3a). Multiple potential explanations exist for this observation including dietary
calcium intake, differential calcium absorption efcacy, renal function differences, serum magnesium concentration and others. Similar variability has recently been reported between osteoid volume
(a direct assessment of bone mineralization) on bone biopsy and
circulating 25(OH)D (Fig. 3b) [149]. It must be appreciated that
25(OH)D is not a physiologically directly regulated parameter,
i.e., it is not equivalent to thyroid stimulating hormone (TSH)1,
the measurement of which can be used to adjust individual thyroid
hormone replacement dosing. It is obviously a clinically desirable
goal to identify a parameter analogous to TSH to dene how much
vitamin D is enough for a given individual; to date, such a tool does
not exist.
Finally, to again state the obvious, it must be appreciated that
no laboratory assay is perfect; all measurements have variability.
Measurement of 25(OH)D historically was problematic [150], however substantial improvements have been made facilitated by
organizations such as DEQAS and NIST [151153]. Currently standard reference materials are available from NIST to facilitate between laboratory standardization. Nonetheless, some variability
is present in all laboratory assays and 25(OH)D measurement is
no exception. Such variability confounds application of a single
cutpoint value to dene deciency, inadequacy or optimal

Abbreviation used: TSH, thyroid stimulating hormone.

25(OH)D status. For example, Fig. 4 demonstrates values obtained

from clinical laboratories measuring 25(OH)D in aliquots of the
same sera; depending on the laboratory, rigid application of a cutpoint diagnostic classication scheme would lead to different diagnoses and clinical recommendations.
Given the current status of imperfect data, known between-individual variability in response to oral supplementation and sun
exposure, lack of a TSH-equivalent for vitamin D to guide
individual patient therapy and modest variability in 25(OH)D measurement, can guidance be provided for clinical care? One reasonable approach is to consider the Paleolitic or ancestral human
model to help dene normal 25(OH)D status. This approach argues that humans have lived outdoors for the vast majority of their
existence on Earth and as such cutaneous synthesis of vitamin D
occurred frequently [154,155]. When one takes this approach and
reviews the relatively few available studies of highly sun exposed
humans, the vast majority of 25(OH)D levels are between 20 and
65 ng/mL (Fig. 5) [144,156158]. Thus, the Paleolithic model
supports current recommendations [110,159] which target
3050 ng/mL for care of patients with osteoporosis. Moreover, this
model implies use of daily vitamin D administration rather than
intermittent high-dose treatment. The studies noted earlier demonstrating increased falls and fracture risk with intermittent bolus
administration further argue against such an approach to vitamin
D supplementation. Finally, limited data nding increased mortality
[160] and increased risk of rare cancers at higher 25(OH)D levels
[161] argues against wanton vitamin D supplementation.
Conclusion
In conclusion, vitamin D deciency causes calcium malabsorption, osteomalacia and muscle weakness. It is not surprising that
meta-analyses nd vitamin D supplementation to reduce fracture
risk. However, there is immense controversy surrounding, and inadequate data to dene, what constitutes vitamin D insufciency.
Performance of additional randomized trials of vitamin D supplementation (some of which are currently ongoing) is necessary.
In the interim, a reasonable clinical recommendation is that
physicians target 25(OH)D of 3040 ng/mL in patients with osteoporosis. This is based upon substantial between individual variation of 25(OH)D in response to oral supplementation, major
individual variability of PTH and osteoid response to 25(OH)D,
and modest 25(OH)D assay variability in concert with the Paleolitic
model. Limited data support that this level of 25(OH)D leads to
greater BMD increases with current osteoporosis medications.
Achieving this 25(OH)D level may require 10002000 IU of vitamin
D3 daily, however this amount will vary in the individual patient. It
is to be expected that evidence-based recommendations may
change as additional data accrues.
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