The role of calcium and vitamin D in the management of osteoporosis

Abstract

The role of calcium and vitamin D supplementation in the treatment of osteoporosis has been extensively studied. The aim of this paper was to reach, where possible, consensus views on five key questions relating to calcium and vitamin D supplementation in the management of osteoporosis. Whereas global strategies that target supplementation to the general population could not be justified in terms of efficacy and health economics, there is a clearer rationale for supplementing patients who are at increased risk of osteoporosis and those who have developed osteoporosis, including those already taking other treatments for osteoporosis. The combination of vitamin D with calcium may be beneficial in terms of efficacy and, perhaps, for optimising adherence.

Full text

The role of calcium and vitamin D in the management of osteoporosis
R. Rizzoli
a,
⁎, S. Boonen
b
, M.L. Brandi
c
, N. Burlet
d
, P. Delmas
e
, J.Y. Reginster
f
a
Division of Bone Diseases, World Health Organization Collaborating Center for Osteoporosis Prevention, Department of Rehabilitation and Geriatrics,
University Hospitals and Faculty of Medicine, 1211 Geneva 14, Switzerland
b
Leuven University Centre for Metabolic Bone Diseases & Division of Geriatric Medicine, Katholieke Universiteit Leuven, Belgium
c
Department of Internal Medicine, University of Florence, Italy
d
International Osteoporosis Foundation, Switzerland
e
INSERM Research Unit 831 and Université Claude Bernard Lyon 1, Lyon, France
f
On behalf of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO), Belgium
Received 3 April 2007; revised 21 August 2007; accepted 10 October 2007
Available online 22 October 2007
Abstract
The role of calcium and vitamin D supplementation in the treatment of osteoporosis has been extensively studied. The aim of this paper was to
reach, where possible, consensus views on five key questions relating to calcium and vitamin D supplementation in the management of osteoporosis.
Whereas global strategies that target supplementation to the general population could not be justified in terms of efficacy and health economics, there
is a clearer rationale for supplementing patients who are at increased risk of osteoporosis and those who have developed osteoporosis, including those
already taking other treatments for osteoporosis. The combination of vitamin D with calcium may be beneficial in terms of efficacy and, perhaps, for
optimising adherence.
© 2007 Elsevier Inc. All rights reserved.
Keywords: Calcium; Osteoporosis; Vitamin D; Menopause; Fracture
Introduction
Osteoporosis is a chronic, progressive bone disease in which
bone resorption exceeds bone formation, leading to a reduction
in bone mineral density and disruption of bone micro-
architecture. Patients with osteoporosis have an increased risk
of fractures that occur with stresses which would not normally
cause fracture in a non-osteoporotic individual. The incidence of
osteoporosis increases with age and occurs most frequently in
postmenopausal women because the decrease in ovarian
oestrogen associated with the menopause accelerates bone loss
and increases bone remodelling [1]. Many studies have
investigated the effect of vitamin D and calcium supplements
on osteoporosis and fracture risk in postmenopausal women. A
round table discussion was held between experts in order to
reach a consensus on a number of issues regarding the use of
dietary supplements of vitamin D and calcium in the prevention
and treatment of osteoporosis. The panel considered five specific
questions that have arisen in the light of recent publications
casting doubt on the benefit of supplementation for postmen-
opausal women [2–5]. The conclusions reached were based on a
consideration of available evidence.
Is there a rationale to supplement postmenopausal women
with calcium and vitamin D?
In order to address this question it is necessary to consider
threshold intakes of vitamin D and calcium below which
skeletal health is compromised. Ideally, this should be based
on the establishment of the relationship between nutrient
intake and a measurable index of skeletal health. For vitamin
D it is possible to determine a plausible threshold in that
many studies have characterised a relationship between low
circulating levels of 25-hydroxyvitamin D (25[OH]D) and
increased secretion of parathyroid hormone (PTH) which in
turn, induces bone loss in the elderly through increased bone
resorption [6–8].
Bone 42 (2008) 246 –249
www.elsevier.com/locate/bone
⁎Corresponding author. Tel.: +41 22 372 99 50; fax: +41 22 382 99 73.
E-mail address: Rene.Rizzoli@medecine.unige.ch (R. Rizzoli).
8756-3282/$ - see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.bone.2007.10.005

Published estimates of the level of circulating 25(OH)D
required to maintain normal levels of PTH range between 30 and
100 nmol/l [9]. This in turn means that estimates of vitamin D
insufficiency within populations vary greatly depending on the
threshold used. In a study of 8532 postmenopausal, osteoporotic
European women, 79.6% were found to have vitamin D
insufficiency where the serum 25(OH)D threshold was consid-
ered to be 80 nmol/l, and 32.1% if the threshold was set at
50 nmol/l [10]. In one study, PTH fell by 35% in subjects with
baseline 25(OH)D levels between 27.5 and 39.9 nmol/l after
8 weeks of supplementation, by 26% in those with levels
between 40 and 49.9 nmol/l, but there was no significant change
in PTH in those with 25(OH)D levels superior to 50 nmol/l,
despite a 66% increase in the vitamin D metabolite [11]. After
discussion of current evidence it was agreed by the panel that
80 nmol/l may be an overestimate and that 50 nmol/l was a more
conservative and acceptable threshold.
The situation regarding an acceptable threshold for dietary
calcium intake is far less clear, and recommendations range from
400 to 1500 mg daily. There is little evidence to suggest that
countries with lower dietary calcium intakes are at higher risk of
osteoporotic fracture, and there are few long term studies to address
this issue within populations that take appropriate account of the
slow adaptation to changes in dietary intake. For these reasons, it
was agreed that there is insufficient evidence to support the
widespread supplementation of the dietary intakes of women in the
general population who are not at increased risk of osteoporosis.
In contrast, the majority of studies that have investigated the
effects of combined calcium and vitamin D supplementation in
postmenopausal women have shown a reduction in fracture risk,
providing that sufficient patient compliance (75–80%) was
reached [3,7,12–14].
The panel's consensus was that supplementation with
calcium and vitamin D should be recommended in women at
increased risk of osteoporosis and those who have developed
osteoporosis. In the case of vitamin D, the dose given should be
enough to ensure that circulating levels of 25(OH)D reach the
threshold of 50 nmol/l.
Is it appropriate to use various doses or regimens of calcium
and vitamin D depending upon age?
Since calcium and vitamin D supplementation should be
targeted to those individuals at increased risk of fracture and since
age is a very important determinant of fracture risk, a target for
intervention is the elderly, particularly those over 65 years. The
need for dietary supplementation with calcium and vitamin D may
be increased in the elderly for a number of reasons. Dietary intake
of calcium and vitamin D generally falls in the elderly. In addition,
endogenous production of vitamin D decreases due to a
combination of decreasing exposure to sunlight and age-related
changes in the dermis which diminish the capacity for cutaneous
synthesis of vitamin D [15,16]. Intestinal absorption and renal
tubular re-absorption of calcium both decrease with age, as does
the ability to adapt to a low calcium diet [1,17]. It was therefore
agreed that individuals over 65 years should be considered for
supplementation without the need to assess their status beforehand.
In addition, younger women with dietary insufficiency and/or an
increased risk of fractures should also receive appropriate
supplementation following assessment of their status. It was
agreed, therefore, that from a health economic perspective,
supplementation of vitamin D in addition to calcium can be
justified in women less than 65 years with proven calcium
insufficiency as a combination of vitamin D and calcium could
reduce bone turnover. In terms of dosage, it is plausible that those at
greatest risk may benefit from higher doses than those at lower risk.
Vitamin D supplementation must be sufficient to ensure that
serum 25(OH)D values reach the threshold level, otherwise it
will not confer the desired benefit. Studies investigating the
anti-fracture efficacy of different dosing regimens of vitamin D
have shown that 400 IU per day was not sufficient to have an
effect on fracture rate [18]. Oral doses of N700–800 IU taken
daily or 100,000 IU taken quarterly both showed a positive anti-
fracture effect, whereas an intramuscular dose of 300,000 IU
annually showed inconsistent efficacy [18,19]. This suggests
that supplementation is most effective in osteoporotic patients if
given orally either daily or quarterly, and if given daily, should
be in excess of 700–800 IU daily [20].
Is there any interest to adding calcium to vitamin D
supplementation or adding vitamin D to
calcium supplementation?
Many studies have shown that persistence and compliance
with supplementation regimens can be low, and that poor
compliance impairs efficacy [3,21]. It is necessary therefore,
from both an efficacy and a health economic perspective, to
ensure that any dosing regimen is designed with this in mind.
Where medically appropriate, combination treatments may
improve treatment compliance by reducing the number of
medications which patients need to take.
Current evidence suggests the role that calcium and vitamin
D play in fracture prevention is not attributable to calcium alone
[4,22] and a meta-analysis of data from 9 randomized clinical
trials, including a total of 53,260 patients, found that where the
effects of supplementation with vitamin D alone were explored
(in a total of 9038 patients), this was not sufficient to
significantly reduce the risk of hip fracture in postmenopausal
women [6]. However the same study found that combined
supplementation with vitamin D and calcium reduced the risk of
hip fracture by 25% (95% CI: 4–42) and the risk of non-
vertebral fracture by 23% (95% CI: 1–40) compared to sup-
plementation with vitamin D alone. The meta-analysis estimat-
ed the number needed to treat (NNT) to prevent one adverse
outcome to be 276 (95% CI: 165–843) for hip fractures and 72
(95% CI: 35–834) for non-vertebral fractures [6].
These results support a previous meta-analysis which has
shown a reduction of 19% (95% CI: 4–32) for hip fracture and of
13% (95% CI: 3–22) for any non-vertebral fracture [23].
Two recent studies, the RECORD study and the Women's
Health Initiative (WHI), both of which were included in the meta-
analysis by Boonen et al. [6], have reported results which appear
to show that combined vitamin D and calcium supplementation is
not effective in fracture prevention [3,21].However,theWHI
247R. Rizzoli et al. / Bone 42 (2008) 246–249

study did not target individuals at high fracture risk, and in both
studies the adherence was poor. The RECORD trial did not assess
vitamin D levels or PTH response so it is unknown whether
subjects had vitamin D insufficiency. In addition, the number of
fractures within this trial was low and together with the poor
adherence, suggests that the study was underpowered.
The WHI, whilst not showing a reduction in the risk of
fractures with supplementation (1000 mg calcium, 400 IU
vitamin D
3
daily), did find significantly greater preservation of
hip bone mineral density in women in the treatment group
compared to those taking a placebo. Importantly, the WHI trial
was carried out in healthy postmenopausal women with an
average calcium intake above 1000 mg per day, 80% of whom
were under 70 years old. It is also important to note that in this
study, personal supplementation of calcium (up to 1000 mg/day)
and vitamin D
3
(up to 600 IU/day raised up to 1000 IU/day) was
allowed. In addition, vitamin D status at baseline was unknown
in all but 1% of individuals, so it is not possible to judge the
level of vitamin D insufficiency with certainty in this study
population. The administered dosage of vitamin D in this study
was 400 IU, a dose shown in other studies to be insufficient to
have an effect on fracture rate [18,24,25]. Finally, treatment
compliance (defined as use of 80% or more of the assigned study
medication) was low, estimated as less than 60%. Importantly,
when analysis was carried out on only those subjects who were
compliant, a significant (29%) reduction in hip fracture risk
compared to the placebo group was found. Compliance in the
various trials could explain the difference in the number needed
to treat (NNT) reported in 2 recent meta-analyses, one including
mainly high quality randomized controlled trials [18] and the
other one including additional studies with lower compliance,
such as the RECORD and WHI trials [6]. In the former meta-
analysis, NNT was 45 (95% CI: 28–114) and 27 (95% CI: 19–
49), for hip and any non-vertebral fracture, respectively.
Given the low cost of vitamin D and calcium supplements,
compared to the high economic burden of osteoporotic fractures,
combined supplementation can be economically justified. This
case becomes even stronger if supplementation is targeted
primarily to those at increased risk in whom the NNT figures
given above would be lower still.
It was concluded that in order to reduce fracture risk,
combined supplementation should be administered to those at
increased risk of fracture at doses adjusted depending on
baseline levels, but potentially in the region of 800 IU of vitamin
D and 1000–1200 mg of calcium daily.
Should particular caution be taken when supplementing
postmenopausal women with calcium and/or vitamin D?
The risks of calcium and vitamin D supplementation and side
effects are not well reported from clinical trials. The current
recommendation for vitamin D intake in the United States is
400 IU for adults aged between 51 and 70 years and 600 IU for
adults of 70+ years old. The Commission of the European
Communities recommends 400 IU daily for people over 65 years
[26]. An acceptable upper limit for vitamin D intake has been set at
2000 IU/day. The “no observed adverse event level”is 10,000 IU
daily and the “lowest observed adverse event level”is 40,000 IU/
day [27]. The level at which vitamin D intoxication occurs is
unknown, but is likely to be considerably higher than the above
mentioned doses. High dose supplementation carries a risk of
hypercalcaemia with subsequent impairment of kidney function.
Predisposing factors for expression of vitamin D intoxication
include high calcium intake, hypercalcaemia, idiopathic hyper-
calciuria, sarcoidosis, overproduction of vitamin D metabolites,
reduced vitamin D binding and hyper responsivity to vitamin D
[28–30].
There are no specific warnings or precautions for use of
vitamin D and calcium specifically relating to postmenopausal
women. To the contrary, increased prevalence of albuminuria,
which is a risk factor for chronic kidney disease progression, has
been reported with decreasing levels of 25(OH)D [31]. Some
caution may be required in the treatment of patients with
cardiovascular disease as the effect of cardiac glycosides may be
accentuated by supplementation with vitamin D and calcium.
However, calcium and vitamin D supplementation does not
influence coronary or cerebrovascular risk in generally healthy
postmenopausal women [32]. The use of calcium supplements
may give rise to mild gastro-intestinal disturbances non
consistently detected such as constipation, flatulence, nausea,
gastric pain, and diarrhoea [3,4].
Should anti-osteoporotic treatments be used in
combination with calcium and vitamin D?
The vast majority of evidence for efficacy of anti-osteoporotic
treatments is based upon combining treatment with calcium and
vitamin D supplementation [33–39]. Vitamin D deficiency in
humans and animals has been shown to reduce the response to
some treatments for osteoporosis. In addition, animal studies have
shown that the efficacy of bisphosphonates was blunted when the
animals were exposed to a vitamin D deprived diet [40] It is
concluded therefore that anti-osteoporotic treatments should be
used in combination with calcium and vitamin D supplementa-
tion. Little evidence is available regarding the combination of anti-
osteoporotic treatments with calcium alone or vitamin D alone.
Conclusion
Supplementation with calcium and vitamin D can be justified
both in terms of efficacy and health economics in women at
increased risk of osteoporotic fracture, including those who have
not yet sustained a fracture. Women can be considered to be at
increased risk of fracture if they are over 65 years of age, or; if
osteopenic and/or with proven calcium and/or vitamin D
insufficiency when they are younger. Evidence suggests that
for the greatest reduction in fracture risk, women at increased
risk should be given both calcium and vitamin D supplements, in
the order of 1000–1200 mg calcium (depending on baseline
status) and 800 IU vitamin D daily. Patient adherence is essential
for efficacy. Combining vitamin D and calcium into one
supplement is recommended as this may increase patient
adherence, which in turn improves overall efficacy. In
conclusion, combined vitamin D and calcium supplementation
248 R. Rizzoli et al. / Bone 42 (2008) 246–249

is recommended for all women at increased risk of fracture,
including those also taking other anti-osteoporostic treatments.
Acknowledgments
The authors thank Antonia Pickup for the medical writing
assistance. S. Boonen is a senior clinical investigator of the Fund
for Scientific Research (F.W.O. —Vlaanderen) and holder of the
Leuven University Chair in Metabolic Bone Diseases.
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