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CONSENSUS STATEMENT
Extraskeletal benefits and risks of calcium, vitamin D
and anti-osteoporosis medications
J.-J. Body &P. Bergmann &S. Boonen &J.-P. Devogelaer &
E. Gielen &S. Goemaere &J.-M. Kaufman &
S. Rozenberg &J.-Y. Reginster
Received: 9 November 2011 / Accepted: 19 December 2011
#The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract
Summary Drugs used for the prevention and the treatment
of osteoporosis exert various favourable and unfavourable
extra-skeletal effects whose importance is increasingly
recognized notably for treatment selection.
Introduction The therapeutic armamentarium for the pre-
vention and the treatment of osteoporosis is increasingly
large, and possible extra-skeletal effects of available drugs
could influence the choice of a particular compound.
Methods The present document is the result of a national
consensus, based on a systematic and critical review of the
literature.
Results Observational research has suggested an inverse
relationship between calcium intake and cardiovascular dis-
eases, notably through an effect on blood pressure, but
recent data suggest a possible deleterious effect of calcium
supplements on cardiovascular risk. Many diverse studies
have implicated vitamin D in the pathogenesis of clinically
important non-skeletal functions or diseases, especially
muscle function, cardiovascular disease, autoimmune dis-
eases and common cancers. The possible effects of oral or
intravenous bisphosphonates are well-known. They have
been associated with an increased risk of oesophageal can-
cer or atrial fibrillation, but large-scale studies have not
J.-J. Body
Department of Medicine, CHU Brugmann,
Université Libre de Bruxelles,
Brussels, Belgium
P. Bergmann
Department of Radioisotopes, CHU Brugmann,
Université Libre de Bruxelles,
Brussels, Belgium
S. Boonen
Center for Metabolic Bone Diseases,
Katholieke University Leuven,
Leuven, Belgium
J.-P. Devogelaer
Department of Rheumatology, Saint Luc University Hospital,
Université Catholique de Louvain,
Brussels, Belgium
E. Gielen
Gerontology and Geriatrics Section,
Department of Experimental Medicine, K.U.Leuven,
Leuven, Belgium
S. Goemaere
Department of Rheumatology and Endocrinology,
State University of Gent,
Gent, Belgium
J.-M. Kaufman
Department of Endocrinology, State University of Gent,
Gent, Belgium
S. Rozenberg
Department of Gynaecology–Obstetrics,
Université Libre de Bruxelles,
Brussels, Belgium
J.-Y. Reginster
Department of Public Health, Epidemiology and Health
Economics, University of Liège,
Liège, Belgium
J.-Y. Reginster (*)
Bone and Cartilage Metabolism Research Unit,
CHU Centre-Ville, Policliniques L. BRULL,
Quai Godefroid Kurth 45 (9ème étage),
4020 Liege, Belgium
e-mail: jyreginster@ulg.ac.be
Osteoporos Int (2012) 23 (Suppl 1):S1–S23
DOI 10.1007/s00198-011-1891-8
found any association with bisphosphonate use. Selective
oestrogen receptor modulators have demonstrated favour-
able or unfavourable extra-skeletal effects that vary between
compounds. Strontium ranelate has a limited number of
non-skeletal effects. A reported increase in the risk of ve-
nous thromboembolism is not found in observational stud-
ies, and very rare cases of cutaneous hypersensitivity
reactions have been reported. Denosumab has been intro-
duced recently, and its extra-skeletal effects still have to be
assessed.
Conclusion Several non-skeletal effects of bone drugs are
well demonstrated and influence treatment choices.
Keywords Bisphosphonate .Calcium .Denosumab .
Osteoporosis .SERM .Strontium ranelate .Vitamin D
Introduction
The pharmacological armamentarium for the management of
osteoporosis has considerably expanded. Indeed, ability to
substantially reduce fracture risk with a generally favourable
risk–benefit ratio is now documented in well-conducted large
clinical trials for a series of different molecules encompassing
different pharmacological classes and different modes of ac-
tion [1]. Osteoporosis is a highly prevalent problem in the
ageing population, and the absolute number of affected sub-
jects increases as a consequence of demographic evolutions.
Albeit at present only a fraction of these patients at risk are
treated, progress is being made and awareness increases of the
consequences of osteoporotic fractures in terms of personal
suffering and burden for the public health. Therefore, a large
and steadily increasing number of patients are likely to be
exposed for prolonged periods of treatment to osteoporosis
medication. Availability of several treatment alternatives con-
fronts the clinician with the difficulty to make the best choice
for the individual patient, whereas the large-scale and pro-
longed prescription of osteoporosis medication puts much
emphasis on safety issues.
To compare treatments, there is little evidence available
from direct comparative trials, and no direct comparisons
are available with fracture incidence as primary evaluation
criterion. To select the ‘best choice treatment’for their
individual patient, clinicians thus depend on indirect com-
parisons, with little possibility of reliable differentiation in
terms of efficacy, taking into account a variety of drug
characteristics in relation to the patient’s clinical profile
and preferences. In this context, consideration of the non-
skeletal actions of the osteoporosis medications will not
seldom intervene in the final choice, be it positively in terms
of perceived potential ‘added value’or negatively because
of perceived potential risk for the patient. Aside from con-
troversies related to potential long-term osseous adverse
effects of osteoporosis treatments, a number of alleged
extra-skeletal safety issues have been raised in the recent
literature concerning as widely prescribed treatments as
calcium and bisphosphonates (BPs).
The present document is the result of a national consensus
based on a systematic review and a critical appraisal of the
literature. It aims at providing the clinicians with an overview
of what is the state of our knowledge on potentially deleterious
or beneficial non-skeletal actions of the main pharmacological
treatments of osteoporosis.
Methods
We included randomised controlled trials(RCTs), meta-
analyses as well as epidemiologic retrospective or prospective
studies and well documented case reports considering non-
skeletal actions of osteoporosis treatments. Relevant articles
related to treatment with calcium, vitamin D, bisphospho-
nates, selective oestrogen receptor modulators (SERMs),
strontium ranelate, teriparatide, parathyroid hormone (PTH)
and denosumab were identified through a systematic search,
from 1966 to 2011, in MEDLINE and databases such as
Cochrane Controlled Register. Following this extensive
search of the literature, a critical appraisal was obtained
through a consensus expert meeting.
Calcium
In the elderly, low calcium intake and vitamin D deficiency
result in a negative calcium balance. This stimulates the
secretion of PTH and induces age-associated secondary
hyperparathyroidism, which enhances bone turnover and
accelerates bone loss [2]. Adequate intake of calcium and
vitamin D, through diet and/or supplements, reverses this
secondary hyperparathyroidism and is recommended in the
prevention of osteoporotic fractures [1,3]. More specifically,
the National Institutes of Health (NIH) in the USA proposes a
recommended dietary allowance for calcium of 1,000 mg in
menaged50
–70 years and 1,200 mg in men older than
70 years and women older than 50 years.
In combination with vitamin D substitution, calcium
supplements have proven anti-fracture efficacy when tar-
geted to persons at risk of calcium and/or vitamin D insuf-
ficiency, including elderly or institutionalized individuals,
osteoporosis patients on antiresorptive or anabolic medica-
tion and persons receiving glucocorticoids [4–8]. Benefits
are most apparent when a daily dose of 1,000–1,200 mg
calcium is complemented with 800 IU vitamin D [6,8]. This
section reviews the evidence for the positive and negative
non-skeletal effects of calcium [9].
S2 Osteoporos Int (2012) 23 (Suppl 1):S1–S23
Calcium as potentially protective against cardiovascular
events
Observational research has suggested an inverse relationship
between calcium intake and vascular diseases. In the Iowa
Women’s Health Study in 34,486 postmenopausal women
aged 55 to 69 years, Bostick and colleagues found that the
highest quartile of total calcium intake (>1,425 mg/day),
when compared to the lowest quartile (<696 calcium/day),
was associated with a 33% reduction in ischaemic heart
disease mortality (risk ratio (RR) 0.67, 95% confidence
interval (CI) 0.47 to 0.94). According to the analysis, this
risk reduction was dependent of the high total intake of
calcium and could be attained by diet, supplements or both
[10]. Similarly, Knox found a strong negative correlation
between dietary calcium intake and mortality ratios for
ischemic heart disease [11]. In the Nurses’Health Study
cohort of 85,764 women aged 39 to 59 years followed for
14 years, women in the highest quintile of total calcium
intake (median calcium 1,145 mg/day) had a lower risk of
stroke (RR 0.69, 95% CI 0.50–0.95) than those in the lowest
quintile (median calcium 395 mg/day) [12].
To explain this observed protection against vascular dis-
eases, potential beneficial effects of calcium on a number of
vascular risk factors have been postulated. In particular,
reductions in blood pressure, serum lipid concentration
and body weight might be involved, although the data, to
some extent, remain inconsistent [9].
An inverse relationship between calcium and blood pres-
sure has been observed in several studies. In a meta-analysis
of randomised controlled trials, both dietary calcium intake
and calcium supplements were associated with reduced blood
pressure, with a trend towards larger effects with dietary
intake. However, the effect size was relatively small, with a
mean reduction in systolic and diastolic blood pressure
of −1.44 mmHg (95% CI −2.20 to −0.68) and −0.84 mmHg
(95% CI −1.44 to −0.24), respectively [13]. In line with these
findings, a recent trial showed significantly lower rates of
hypertension amongst women aged over 45 years with a
dietary calcium intake of at least 679 mg/day. In women in
the highest quintile of dietary calcium intake (1,000 to
2,560 mg calcium/day), the relative risk reduction was 13%
(RR 0.87, 95% CI 0.81 to 0.93). However, in women taking
calcium supplements, even in the highest dosed quintile
(1,000–2,100 mg), the risk of hypertension was unchanged
(RR 1.07, 95% CI 0.97 to 1.18) [14]. A recent Cochrane
review concluded that any association between calcium sup-
plements and reduction in blood pressure is uncertain and that
poor quality of individual trials and heterogeneity between
trials do not allow any firm conclusions [15]. Any antihyper-
tensive effect, if real, is at best small and transient [16].
Another potential cardioprotective mechanism might be a
reduction in serum lipid concentration, due to the binding of
calcium to fatty acids and bile acids in the gut, resulting in
malabsorption of fat, and a direct effect on adipocytes with
increased lipolysis [17–19]. In a randomised controlled trial
in men, a diet fortified with calcium significantly reduced
total cholesterol, LDL cholesterol and apolipoprotein B
[18]. Similarly, in a randomised placebo-controlled trial in
postmenopausal women, a supplement of 1,000 mg calcium
during 12 months increased high-density lipoprotein (HDL)
cholesterol levels and HDL to low-density lipoprotein
(LDL) cholesterol ratio [20]. In another randomised study
in men and women, however, no significant effect of calcium
supplements (1,000–2,000 mg) was seen on total cholesterol
or HDL cholesterol [21]. It is unclear, therefore, if and to what
extent calcium determines lipid profile.
Reduced body weight has been implicated as well. Several
large epidemiological studies have suggested that dietary cal-
cium intake and calcium supplements may be associated with
weight loss [22,23], an effect that might be mediated by the
same mechanisms affecting lipid profile [23]. However, sev-
eral systematic reviews of randomised controlled trials argued
against an inverse relationship between calcium (both dietary
intake and supplements) and body weight [24–26], suggesting
that any conclusions are preliminary and that the implications
of calcium intake for body weight remain to be clarified.
Calcium supplements potentially associated with an increase
in cardiovascular risk
Whereas spontaneous calcium intake, up to 800 mg/day,
was not related to any cardiovascular deleterious effects,
the cardiovascular safety of calcium supplements has been
questioned. Rather than having a neutral or even beneficial
effect, increased exposure to calcium might actually increase
cardiovascular risk. In a meta-analysis published in 2010 by
Bolland and colleagues in the British Medical Journal, more
than 12,000 individuals from 15 double-blind placebo-
controlled randomised trials were enrolled, and an increase
in the incidence of myocardial infarction of about 30% was
seen in individuals on calcium supplements (≥500 mg daily)
compared to those on placebo [27]. More specifically, the
analysis of patient level data showed that the relative risk of
incident myocardial infarction in individuals allocated to cal-
cium increased by 31% (HR 1.31, 95% CI 1.02 to 1.67) and
trial level analysis showed a similar increase in risk by 27%
(HR 1.27, 95% CI 1.01 to 1.59). However, no significant
increase was observed in the incidence of a number of related
vascular endpoints, including the incidence of stroke (HR
1.20, 95% CI 0.96 to 1.50), death (HR 1.09, 95% CI 0.96 to
1.23) and the composite end point of myocardial infarction,
stroke and sudden death (HR 1.18, 95% CI 1.00 to 1.39).
The findings of this meta-analysis were partly driven by a
previous randomised placebo-controlled trial from the same
group that contributed 17% to the overall weight [28]. In
Osteoporos Int (2012) 23 (Suppl 1):S1–S23 S3
this trial, calcium supplements were associated with a sig-
nificant increase in HDL cholesterol levels but, neverthe-
less, also an increase in the risk of myocardial infarction [20,
28]. The authors postulated that calcium supplements may
acutely elevate serum calcium levels [29] and, as a result,
may enhance vascular calcification [28]. In fact, in a number
of observational studies, high serum calcium levels have
been associated with vascular calcification and an increased
risk of vascular events, including myocardial infarction,
stroke and death [30,31]. Further support for a potentially
deleterious effect of an acute increase in serum calcium
comes from the observation that, in the meta-analysis, die-
tary intake was not associated with myocardial infarction, in
line with observations that calcium from dairy products
hardly affects serum calcium levels [27].
Whilst the meta-analysis of Bolland and colleagues
should be interpreted as a strong signal that calcium supple-
ments (without vitamin D) may potentially increase the risk
of myocardial infarction, several limitations and even incon-
sistencies should be taken into account as well. First, the
statistical outcome was only borderline significant (HR
1.31, 95% CI 1.02 to 1.67; p00.035), with a broad 95%
confidence interval that approached 1 in the lower limit,
suggesting that the findings have to be interpreted with
caution. Also, the studies included in the analysis had been
designed to assess the effects of calcium on bone density
and fracture risk. None of the included trials had cardiovas-
cular outcomes as primary or even secondary endpoint. As a
result, cardiovascular events had not been adjudicated in a
standardized manner, which may have resulted in over- or
underreporting. Third, whilst the meta-analysis provided
evidence for an increased risk of myocardial infarction, no
increase was observed in the incidence of stroke, death or
the composite end point of myocardial infarction, stroke and
sudden death. In addition, trials that combined calcium and
vitamin D supplements, the recommend strategy to prevent
fractures in most elderly individuals, were excluded. In this
context, it should be noted that a number of large-scale
studies of calcium combined with vitamin D did not docu-
ment an increase in cardiovascular risk [32,33]. It is possi-
ble but not known if correction of vitamin D deficiency
might counteract any potential detrimental vascular effect
of calcium supplements [34,35]. Finally, with the exception
of the relatively small-sized trial from the same group [28],
individual trials with calcium supplements did not show a
significant increase in cardiovascular risk. In fact, a recent
randomised placebo-controlled trial by Lewis et al., not in-
cluded in the meta-analysis, did not find a higher risk of death
or first-time hospitalization from atherosclerotic vascular dis-
ease in patients on calcium supplements [36]. A subset anal-
ysis even suggested a cardioprotective effect of calcium
supplements in patients with pre-existing cardiovascular dis-
eases. Nevertheless, the meta-analysis by Bolland et al. should
be taken seriously, not as conclusive evidence but as a signif-
icant safety signal. Future studies with calcium should be
designed to include careful assessment of cardiovascular end-
points, preferably by independent and blinded adjudication.
Calcium and cancer risk
There is also much controversy about the effect of calcium
on the risk of cancer, with observational studies showing no
effect, a protective effect or even an increased cancer risk
[37]. Because the topic is diverse and the findings inconsis-
tent, this section will only briefly discuss the association
between calcium exposure and colorectal cancer, breast
cancer and prostate cancer, since these have received most
attention in recent years [9].
Whilst several observational studies concluded that cal-
cium intake does not affect the risk of colorectal cancer
[38], a number of cohort studies did find evidence for a
protective effect of high total calcium intake (dietary intake
plus supplements) [37,39,40]. In one of the main studies, a
NIH-funded 7-year prospective trial in 293,907 men and
198,903 women aged 50 to 71 years, the risk reduction for
colorectal cancer in the highest compared to the lowest
quintile of total calcium intake was 0.79 (95% CI 0.70 to
0.89) in men and 0.72 (95% CI 0.61 to 0.86) in women [37].
Moreover, in a meta-analysis of randomised controlled trials
in patients with previously removed colorectal adenomas
and randomly assigned to calcium (1,200, 1,600 or
2,000 mg) or placebo, calcium supplements were signifi-
cantly associated with a reduction in the risk of recurrent
adenomas, considered as the precursors of colorectal cancer
[41]. In line with these findings, the American College of
Gastroenterology recommends daily dietary supplementa-
tion with 3 g calcium carbonate (1,200 mg calcium) in the
prevention of recurrent colorectal adenomas [42].
Despite these data from observational studies and adenoma
prevention trials, it is still uncertain if calcium supplements
prevent colorectal cancer because large-scale long-term rand-
omised controlled trials are not available. The only major
randomised placebo-controlled study, the Women’s Health
Initiative (WHI) trial in 36,282 postmenopausal women,
found no effect of daily supplementation with 1,000 mg cal-
cium and 400 IU of vitamin D for 7 years on colorectal cancer
risk [43]. A Cochrane review concluded that there is not
sufficient evidence to currently recommend the general use
of calcium supplements in the prevention of colorectal cancer
andthatmoreresearchisneeded[44].
The relationship between calcium exposure and breast
cancer is not clear either. Some observational studies in
premenopausal women found an inverse relationship be-
tween calcium intake and breast cancer [45–47], but some
did not [37,48]. Similarly, in trials in postmenopausal
women, a protective effect has been reported [47], but most
S4 Osteoporos Int (2012) 23 (Suppl 1):S1–S23
studies were negative [37,45,46,48]. If and to what extent
the source of calcium intake (dietary intake versus supple-
ments) plays any role is not known [48]. Overall, an inde-
pendent effect of calcium on the incidence of breast cancer
remains uncertain.
In men, epidemiological studies have suggested that a
higher total intake of calcium might be associated with an
increased risk of developing prostate cancer. In these stud-
ies, total intake of calcium varied from more than 1,500 mg
to more than 2,000 mg/day [49–51]. Calcium could poten-
tially suppress the active form of vitamin D (1,25-OH
2
-D
3
),
known to have an antiproliferative effect on prostate cancer
cells [50,52]. However, other studies could not confirm this
association and found no or only a weak relationship be-
tween calcium intake and prostate risk [37,53–55], even at
very high intakes of calcium [37,54]. As with colon cancer
and breast cancer, conclusive evidence is lacking and more
studies are required.
Calcium and the risk of kidney stones
Since most kidney stones are composed of calcium oxalate,
an association with calcium intake is a theoretical concern.
In the prospective Nurses’Health Study, women who took
supplemental calcium (1 to ≥500 mg/day) had a small but
significant increase in the risk of incident symptomatic
kidney stones (RR 1.20, 95% CI 1.02–1.41) compared to
those who did not take supplements [56]. Women in the
highest quintile of dietary calcium intake (median calcium
1,303 mg/day had, however, a lower risk (RR 0.65, 95% CI
0.50–0.83) compared to those in the lowest quintile (median
calcium 391 mg/day). Other trials also showed a slightly
increased risk of kidney stones in individuals on supplemental
calcium (1,000 mg/day) [32] and a lower risk in individuals on
a diet rich in calcium [57,58].
The lower incidence of kidney stones in individuals on
high dietary calcium intake is likely due to binding of
dietary calcium with dietary oxalate in the gut, with reduced
intestinal absorption and urinary excretion of oxalate. Cal-
cium supplements, on the other hand, do not bind dietary
oxalate when taken without meals. A combination of main-
tained oxalate excretion and increased calcium absorption
and excretion from supplements increases the risk of stone
formation [59].
In addition to beneficial musculoskeletal effects, espe-
cially when combined with vitamin D, calcium supple-
ments have been suggested to protect against colorectal
and breast cancer and to reduce some vascular risk
factors. At the same time, safety questions have been
raised about the role of calcium supplements in poten-
tially increasing cardiovascular events, prostate cancer
and kidney stones. Whilst these safety concerns have to
be taken seriously, currently available evidence is not
conclusive. In future research, priority should be given
to well-designed long-term studies to assess cardiovascular
and other safety endpoints.
Vitamin D
Rickets and osteomalacia are the diseases traditionally as-
sociated with severe vitamin D deficiency, defined as 25
(OH) vitamin D levels below 10 ng/ml (25 nmol/l). A
growing body of evidence has emerged indicating that less
severe degrees of vitamin D deficiency between 10 and
20 ng/ml (25 and 50 nmol/l) and even vitamin D insuffi-
ciency, defined as 25(OH) vitamin D levels between 20 and
30 ng/ml (50 and 75 nmol/l), impair gastrointestinal absorp-
tion of calcium and bone mineralization, contributing to the
pathogenesis of osteoporosis in older people [60]. Vitamin
D has an impact on bone density and bone quality. In
addition, by increasing muscle strength, adequate vitamin
D status reduces the risk of falling in older individuals (see
below). Therefore, vitamin D has a dual benefit for preven-
tion of fractures in the elderly, a benefit on bone density and
on muscle strength [61]. The importance of vitamin D for
the prevention and treatment of osteoporosis has notably
been reviewed in a previous Consensus of the Belgian Bone
Club [1].
Furthermore, many studies have implicated vitamin D
and its metabolites in the pathogenesis of a wide variety of
clinically important non-skeletal functions or diseases, es-
pecially muscle function, cardiovascular disease, autoim-
mune diseases and several common cancers. The principal
non-classical targets will be reviewed in this section. Whilst
the evidence on bone and muscle health is based on rando-
mised clinical trials, the evidence on other disease areas is
nevertheless of a lower level. Most trials are small to mod-
erate sized, and the outcomes of interest are only secondary
outcomes. Interestingly, a meta-analysis of 18 randomised
clinical trials including 57,311 individuals nevertheless con-
cluded that vitamin D supplementation was associated with
a decrease in total mortality (RR 0.93; 95% CI 0.77–0.96
compared to the control group) that could be due to effects
of vitamin D on the musculoskeletal system or, as summa-
rized below, on various non-skeletal diseases [35].
Vitamin D and muscular function
Vitamin D receptors have been shown to be present in
muscle tissue [62], and a direct effect of vitamin D on
muscle physiology is probable [63]. In muscle, vitamin D
activates protein kinase C, which promotes calcium release,
increasing the calcium pool that is essential for muscle
contraction [64]. The potential cell signalling pathways
affected by vitamin D in muscle have been recently
Osteoporos Int (2012) 23 (Suppl 1):S1–S23 S5
reviewed [65]. Vitamin D deficiency has long been clinical-
ly associated with impaired muscle strength [66] and is also
associated with loss of muscle mass [67]. With ageing, the
number of vitamin D receptors in muscle decreases and the
number of type II fibres, the first to be recruited to avoid
falls, also decreases [68]. Treatment of elderly stroke survi-
vors with 1,000 IU of vitamin D
2
daily increases mean type
II muscle fibre diameter by 2.5-fold over a 2-year period
[69]. Because muscle weakness is a major risk factor for
falls, it is not surprising that low vitamin D status is associ-
ated with an increased falls risk, as notably shown in a
longitudinal study [70]. A meta-analysis including seven
randomised, double-blind trials evaluating a daily dose of
700–1,000 IU/day of vitamin D demonstrated that falling was
significantly reduced by 19% (RR 0.81; 95% CI 0.71–0.92) in
vitamin D supplemented individuals compared with those
receiving calcium or placebo [71]. This benefit may not de-
pend on additional calcium supplementation, was significant
within 2–5 months of treatment and extended beyond
12 months of treatment.
Vitamin D insufficiency and deficiency are associated
with an increase in muscle fat as demonstrated by a signif-
icant negative relationship between circulating 25(OH) vi-
tamin D levels and computed tomography measures of
percent muscle fat (p<0.001) [72]. Most studies have not
found a significant relationship between baseline 25(OH)
vitamin D levels and muscle strength [73]. However, cor-
rection of vitamin D deficiency has most often been associ-
ated with an improvement in muscle strength. Vitamin D
supplementation in vitamin D-deficient Asian Indians dur-
ing 6 months has thus shown an enhancement in skeletal
muscle strength and physical performance [74]. A recent
randomised, placebo-controlled, double-blind trial of
1,000 IU/day of vitamin D for 1 year showed a significant
increase in muscle strength and mobility in subjects in the
lowest tertile of baseline 25(OH) vitamin D values [75]. A
longer duration trial showed that vitamin D and calcium
supplementation during 20 months were superior to calcium
alone in reducing fall frequency and improving muscle
function in community-dwelling elderly subjects with 25
(OH) vitamin D levels below 31 ng/ml [76]. These studies
are in agreement with a recent systematic review and meta-
analysis where the authors confirmed a beneficial effect of
vitamin D supplementation on proximal muscle strength in
adults with vitamin D deficiency but no significant effect on
muscle strength in vitamin D replete adults [77].
Vitamin D and cardiovascular risk
A low level of 25(OH) vitamin D could be an independent
risk factor for cardiovascular events, although a causal rela-
tionship has yet to be supported by large interventional
trials. The evidence supporting a link between vitamin D
deficiency and myocardial diseases has recently been
reviewed [78]. In addition to possible direct effects due to
the presence of the vitamin D receptor and of the 1-alpha
hydroxylase enzyme in cardiac myocytes and other cells of
the cardiovascular system [79], vitamin D has significant
effects on several cardiovascular risk factors. Studies, rang-
ing from animal studies to clinical trials, have shown that
pharmacological doses of vitamin D notably reduce inflam-
mation [80], improve endothelial function [81], control the
secretion of insulin and improve insulin sensitivity [82].
Furthermore, as recently reviewed, vitamin D status has
been linked to arterial hypertension [83].
Several observational studies suggest that 25(OH) vita-
min D levels less than 15 ng/ml are associated with an
excess risk of cardiovascular events when compared to
levels >30–40 ng/ml. A nested case–control study in
18,225 men in the Health Professionals Follow-up Study
(men aged 40–75 years, free of cardiovascular disease at
baseline) showed that men with a 25(OH) vitamin D
level ≤15 ng/ml had an increased risk for myocardial
infarction relative to men with a level ≥30 ng/ml (RR
2.42; 95% CI 1.35–3.84) [84].Evenmenwitha25(OH)
vitamin D level 22.6–29.9 ng/ml had an increased risk
(RR 1.60; 95% CI 1.10–2.32) compared with those with
alevel≥30 ng/ml. In the Framingham offspring cohort
study, 25(OH) vitamin D was measured in 1,739 participants
without prior heart disease. At a mean follow-up of 5.4 years,
amongst those with hypertension, there was a 2-fold increase
in the risk of cardiovascular events for the participants with a
25(OH) vitamin D level <15 ng/ml compared to those with a
level ≥15 ng/ml [34]. The Ludwigshafen Risk and Cardiovas-
cular Health Study, a prospective cohort comprising 3,300
patients referred to coronary angiography and followed for
7.7 years, demonstrated a strong association between vitamin
D status and several cardiovascular outcomes, such as cardio-
vascular mortality [85], stroke [86], heart failure and sudden
cardiac death with the lowest risk amongst those with the
highest 25(OH) vitamin D levels [87]. However, such associ-
ations have not been found in other studies. In the Osteopo-
rotic Fractures in Men Study, vitamin D intake was evaluated
in 3,094 men and 25(OH) vitamin D was measured in 813
men. The authors found no association between vitamin D
intake or 25(OH) vitamin D levels and incidence of cardio-
vascular disease during a median follow-up of 4.4 years [88].
Similarly, serum levels of 25(OH) vitamin D levels were not
independently associated with cardiovascular mortality
in the prospective Rancho Bernardo study including
1,073 community-dwelling older adults followed up to
10.4 years [89]. On the other hand, in a cross-sectional
study of 2,722 subjects, the prevalence of hypertension
was found to be increased in subjects with 25(OH) vitamin D
levels <40 ng/ml; odds ratios were 2.7 (1.4–5.2), 2.0 (1.4–5.2)
and 1.3 (1.2–1.6) for 25(OH) vitamin D levels <15, 15–29 and
S6 Osteoporos Int (2012) 23 (Suppl 1):S1–S23
30–39 ng/ml, respectively, compared with the >40-ng/ml
group [90]. This inverse relationship between 25(OH) vitamin
D levels and hypertension has been recently confirmed in a
meta-analysis of 18 studies [91]. These various sets of data
raise the question of whether vitamin D supplementation can
prevent hypertension and cardiovascular events.
The evidence of benefit of vitamin D supplementation
from randomised trials is, however, scarce. In a small trial,
8 weeks of supplementation with vitamin D3 (800 UI/day)
and calcium was reportedly more effective in reducing sys-
tolic blood pressure than calcium alone [92]. In the Wom-
en’s Health Initiative trial, including 36,282 postmenopausal
women, vitamin D3 plus calcium supplementation did not
reduce blood pressure, nor the risk of developing hyperten-
sion over 7 years of follow-up; however, in this trial, sup-
plementation consisted only of 400 IU/day and adherence to
supplementation was only around 60% [93]. A recent meta-
analysis of eight randomised clinical trials in patients with a
mean baseline blood pressure above 140/90 mmHg con-
cluded that vitamin D reduces blood pressure modestly but
significantly [94]. In summary, results from different studies
are conflicting and trials specifically assessing effects of
vitamin D on cardiovascular diseases as a primary endpoint
are lacking. It is therefore premature to recommend supple-
mental vitamin D intake for the prevention of cardiovascular
diseases or hypertension [95].
Vitamin D and the immune system
Vitamin D receptors are present in almost all immune cells,
including activated T and B lymphocytes and antigen-
presenting cells. Immune cells also express vitamin D-
activating enzymes, allowing local conversion of inactive
vitamin D into calcitriol within the immune system [96].
Several autoimmune diseases such as type 1 diabetes melli-
tus or multiple sclerosis are more frequent in countries with
less sunshine, and vitamin D deficiency in early life
increases the risk of autoimmune diseases and infections
later on [96,97]. There are several epidemiological studies
that have reported an association between vitamin D defi-
ciency and susceptibility to respiratory infections, especially
tuberculosis and Gram-negative infections [98]. Studies using
animal models of autoimmune diseases have identified vita-
min D as a potential modulator of differentiation, proliferation
and secretion processes in autoimmune reaction [96]. Supple-
mentation in humans might thus be preventive in a number of
autoimmune disorders.
A Finnish birth-cohort study, including >10,000 children
born in 1966, showed that vitamin D supplementation dur-
ing the first year of life (2,000 IU/day) was associated with a
risk reduction of 78% for developing type 1 diabetes (fol-
lowed up until end 1997) compared to no supplementation
or use of lower doses [99]. A meta-analysis of data from
four case–control studies and one cohort study support the
beneficial effects of vitamin D in prevention of type 1
diabetes [100]. A more recent supplementation study, how-
ever, was negative [101]. Data indicate that treatment with
vitamin D could be beneficial in reducing the risk of devel-
oping multiple sclerosis and diminishing its exacerbations
[102]. Although contradictory data exist concerning supple-
mentation benefits in rheumatoid arthritis (RA) and system-
ic lupus erythematosus, an association between low levels of
25(OH) vitamin D levels and activity of both diseases has
been reported [103,104]. Furthermore, an inverse associa-
tion between higher intake of vitamin D and risk of rheu-
matoid arthritis was demonstrated in the Iowa Women’s
Health Study [105]. However, we still lack non-biased large
cohort studies that can sustain the proposed benefits of
vitamin D supplementation for optimal immune function.
Large-scale intervention trials in humans that support the
findings in preclinical or observational studies are lacking
[96].
Vitamin D and cancer treatment and prevention
Many experimental data show that calcitriol stimulates ap-
optosis and differentiation and inhibits angiogenesis and
proliferation in tumour cells [106]. Numerous association
studies suggest that serum 25(OH) vitamin D levels are
inversely associated with the risk of many types of cancer.
Further, in some studies of patients with cancer, an associ-
ation between low 25(OH) vitamin D levels and poor prog-
nosis has been observed [107,108]. A meta-analysis of
available studies indicated that there is a trend for lower
incidence of colorectal carcinoma and adenoma with 25(OH)
vitamin D levels >20 ng/ml in a dose–response association
[109]. For breast cancer, a pooled analysis of two studies with
880 cases and 880 controls demonstrated that individuals with
sufficient serum 25(OH) vitamin D levels had 50% lower risk
of breast cancer than those with levels <13 ng/ml [110]. In
addition, a large case–control study on 1,394 post-menopausal
breast cancer patients and 1,365 controls also showed that the
25(OH) vitamin D level was significantly associated with
lower breast cancer risk, particularly at levels above 20 ng/ml
[111]. Most evidence concerning the link between vitamin D
and cancer is derived from laboratory studies andobservational
investigations of 25(OH) vitamin D levels in association with
cancer incidence and outcome. There are, however, sev-
eral possible confounding factors and association cannot
prove causation. Moreover, results from prospective stud-
ies only are more heterogeneous and do not support a
significant association between vitamin D status and
breast cancer [112].
There have been no clinical trials with cancer incidence
or mortality as a primary outcome to support causality
between vitamin D status and cancer. One population-
Osteoporos Int (2012) 23 (Suppl 1):S1–S23 S7
based randomised clinical trial found that calcium plus
vitamin D supplementation decreased cancer incidence as
a secondary outcome. In that study including 1,179 healthy
postmenopausal women aged >55 years, the mean level of
25(OH) vitamin D at baseline was 29 ng/ml. Supplementa-
tion with 1,100 IU vitamin D/day increased serum 25(OH)
vitamin D to 38 ng/ml. After 4 years of treatment, the
supplemented group had a 60% lower risk of developing
cancer than the placebo group [113]. However, a recent re-
analysis has indicated that this inverse association between
vitamin D levels and cancer incidence disappeared after
adjustment for BMI and physical activity [9,112]. In anoth-
er randomised trial, the Women’s Health Initiative, no effect
of calcium and 400 IU vitamin D/day was found on the
incidence of colorectal or breast cancer, which were second-
ary outcomes [114]. However, the dose of 400 IU used in
that trial may have been inadequate to raise 25(OH) vitamin
D blood levels significantly, particularly after factoring in
adherence levels. A recent review of randomised vitamin D
supplementation trials with cancer incidence as a secondary
endpoint concluded that the results were null [112]. More-
over, the recent large-scale “Cohort Consortium Vitamin D
Pooling Project of Rarer Cancers”showed no evidence link-
ing higher serum 25(OH) vitamin D levels to reduced risks
of less common cancers, including endometrial, gastric,
kidney, pancreatic and ovarian cancers [115]. In summary,
the available evidence that vitamin D reduces cancer inci-
dence is inconsistent and inconclusive. Randomised con-
trolled trials assessing vitamin D supplementation for
cancer prevention are in progress. Their results are to be
awaited before promoting vitamin D supplementation to
reduce cancer risk.
As a general conclusion, the importance of vitamin D for
bone health and the prevention of osteomalacia and osteo-
porosis are well recognized. More recently, vitamin D defi-
ciency has been associated with other chronic conditions,
including cardiovascular disease, autoimmune diseases and
cancer. However, most evidence for the importance of vita-
min D in these conditions comes from laboratory studies
and observational investigations. Randomised controlled
trials are needed to determine whether long-term supple-
mentation with vitamin D has a favourable impact on the
development or clinical course of non-skeletal diseases
[116].
Bisphosphonates
BPs are the mainstay in the treatment of osteoporosis and
other metabolic bone diseases such as Paget’s disease, as
well as in tumoural conditions such as multiple myeloma,
bone metastases and cancer-induced hypercalcaemia. Their
efficacy and safety have been thoroughly established on the
basis of multiple large pivotal trials dealing with their main
indications. Their daily use in clinical medicine since 1969
has confirmed the general conclusions of the trials. Their
strong affinity for the skeleton partially explains their excel-
lent safety profile for other systems of the body. Even at
high pharmacologic doses, their bone affinity grossly pre-
cludes tissue uptake outside the skeleton. First of all, intes-
tinal absorption after oral administration is weak, on the
order of less than 1%, even under ideal conditions (after a
prolonged fast, with a full glass of water, and remaining
fasting for at least 30 min in an upright position before any
other food or beverage intake), leading to very low peak
values in the plasma. After intravenous administration, how-
ever, if the plasma peak levels are higher, these levels are
transient and short-lived. Similarly to what is observed after
oral administration, serum levels rapidly decrease due to
their rapid adsorption on the surface of bone (±50%). The
rest is cleared by both glomerular filtration and proximal
tubular secretion (± the remaining 50%) [117]. The retention
time in the skeleton is extremely long and depends on the
individual bone affinity of the various BPs. Part of the
released BPs from the skeleton can be re-uptaken, and part
is eliminated in the urine. Even if their terminal half-life is
long, plasma levels remain very low. However, small
amounts have been detected in body fluids up to 8 years
after stopping the drug [118,119]. This justified some
warning regarding the use of BPs in premenopausal women
of child bearing age. Even if there has been no demonstrated
adverse foetal events in humans, large controlled studies are
lacking to confirm their widespread safe use [120]. Some
caution to restrict the use BPs to severe condition is still
justified.
Bisphosphonate and acute phase reaction
After the first intravenous administration of a nitrogen-
containing bisphosphonate (n-BP) (e.g. disodium pamidro-
nate, zoledronic acid, ibandronate), about 25% of patients
experienced flu-like symptoms, consisting of transient and
self-limited fever, myalgias and/or arthralgias for 2 to 3 days.
Acute phase reaction (APR) has been associated with the
release of serum inflammatory cytokines such as tumour
necrosis factor (TNFα) and IL-6, but not IL-1 [121]. The
origin of these pro-inflammatory agents was homed on
monocytes and/or macrophages [122] but also in human
peripheral blood γδ T cells, which could constitute the
trigger for activation of the former cells [123]. The APRs
were absent or at least strongly attenuated with subsequent
infusions with n-BPs. The APR has also been observed after
high-dose oral monthly ibandronate [124]. The post-
infusion syndrome can be reduced by acetaminophen
[125]. It has been suggested that the co-administration of
statins could prevent this reaction [123,126], but this
S8 Osteoporos Int (2012) 23 (Suppl 1):S1–S23
preventative effect does not seem to be systematic [127]. On
the contrary, concomitant glucocorticoid (GC) therapy did
not alleviate it [128]. Depletion in 25(OH)D could constitute
a factor favouring the occurrence of APR after n-BPs infu-
sion in n-BP-naive patients, but this remains to be confirmed
[129].
Bisphosphonate and musculoskeletal pain
Some cases of prolonged musculoskeletal pain have been
reported [130] in up to 20% to 25% of patients on alendr-
onate and risedronate, as well as zoledronic acid [128,131].
The majority of patients experienced gradual relief of pain
after discontinuation of the drug. A few patients redevel-
oped pain following re-challenge of the drug. No plausible
explanation has been proposed for their occurrence, and the
association between BPs and musculoskeletal pain has
therefore been questioned [132].
Bisphosphonate and the risk of renal failure
In line with the renal elimination of BPs, it is not recom-
mended to prescribe BPs to patients with a creatinine clear-
ance less than 30 ml/min, and this is specified in the
Summary of Products Characteristics of BP who were
granted an European Marketing Authorisation. In all pivotal
studies of BPs, chronic kidney diseases (CKD) constituted
an exclusion criterion, based on the calculated estimated
glomerular filtration rate using the formula of Miller et al.
[133]. In these large studies, however, several patients with
CKD, but without other calcium metabolism abnormalities,
notably in serum calcium, phosphate, alkaline phosphatase,
vitamin D and PTH were included. Some exceptions to this
30-ml/min rule could therefore be theoretically possible
[133–135]. Even if clinical trials and clear recommendations
in the population with CKD are lacking, many clinicians
suggested to halve the dose or reduce the frequency of
administration of BPs in CKD [135]. Potential indications
of BPs in CKD are the prevention of bone loss in kidney
after transplantation. However, in these cases, no antifrac-
ture efficacy has so far been demonstrated with BP use
[136–138]. Moreover, some patients treated with IV pamidr-
onate developed low-bone turnover adynamic bone [137].
Calciphylaxis is a rare complication of CKD. Case reports
have suggested the potential usefulness of BPs in its treat-
ment [139,140]. Proteinuria and proximal tubular necrosis
has been described in mice and rats after parenteral doses of
pamidronate sodium and clodronate five to 20 times higher
than clinical doses used in humans [141]. However, acute
renal toxicity was also reported in humans after rapid infu-
sion of high doses of non-n-BPs [142]. Renal function
deterioration, defined by elevations in the serum creatinine
level, was observed in up to 15% of the patients receiving
4 mg of zoledronic acid over 15 min in trials of treatment for
bone metastases (compared with 6.7% to 11.5% in patients
on placebo) [143]. In the doses registered for the treatment
of postmenopausal osteoporosis, oral BPs did not adversely
affect the renal function. With intravenous zoledronic acid
infusions, with infusion times of 15 min, short-term
increases in serum creatinine have been observed for 9 to
11 days in a small subset of patients [144]. It seems there-
fore justified that patients be well hydrated and avoid simul-
taneous therapeutic agents at risk of impairing renal
function. Patients with a glomerular filtration rate less than
30 ml/min should ideally be excluded, the precise diagnosis
of bone loss in such patients being uncertain. Other kinds of
bone disease than osteoporosis could be present [144]. As
there exists no head-to-head comparative trial, it is not
possible to determine whether intravenous n-BPs such as
pamidronate disodium or ibandronate would have a different
renal safety profile than zoledronic acid [144].
Bisphosphonate and ocular risk
Cases of iritis, episcleritis and scleritis, but also conjuncti-
vitis, have been reported after therapy with n-BPs (mainly
alendronate, pamidronate disodium and zoledronic acid) in
up to 1% [145–147]. This does not seem to constitute an
exclusive complication for n-BPs, but they were rarely
reported with first-generation BPs [148]. Eye inflammation
can resolve after local GC administration, but some patients
can recur after BP rechallenge. In severe cases of uveitis and
scleritis, it could be better to discontinue IV BP [149].
Bisphosphonate and the gastrointestinal tract
Digestive problems are at the origin of most drug with-
drawals with oral n-BPs, mainly due to oesophageal irrita-
tion and upper gastrointestinal side effects [150]. They are
poorly absorbed by the gastrointestinal tract, of the order of
about 1%. Moreover, their absorption is further reduced if
they are taken with food and beverage such as coffee, milk,
orange juice etc. Hence, the recommendation is to take them
in a fasting condition with a glass of water and to remain
fasting in an upright position for at least 30 min after
swallowing the drug until the first meal of the day. These
precautions help to prevent most upper gastrointestinal side
effects [151]. Moreover, the availability of weekly and
monthly BPs has further decreased the frequency of the
upper gastrointestinal tract symptoms [152–157]. It has been
suggested that a lot of adverse events in upper gastrointes-
tinal tract might be already present prior to start BPs therapy
[158] and that clinicians and patients may sometimes inap-
propriately attribute gastrointestinal complaints to therapy
[159]. Irrespective of whether gastrointestinal symptoms in
individual patients are linked with oral BPs or not, it should
Osteoporos Int (2012) 23 (Suppl 1):S1–S23 S9
be remembered that such a link has not been reported with
intravenous therapy.
A study based on the General Practice Research Database
containing anonymised patient records of about six million
people in UK suggested a doubling of the incidence of
oesophageal cancer with 5 years’use of oral BPs [160],
but this was not confirmed in another analysis of the same
database [161]. No excess of gastric and colorectal cancer
was found. Moreover, in patients with Barrett’s oesophagus
on oral BPs, no increased risk of oesophageal adenocarci-
noma was observed [162]. Even if no definitive conclusion
can be drawn from these studies, upper gastrointestinal
investigation is recommended if a patient on BPs develops
dysphagia and pain.
Bisphosphonates and cardiovascular risk
In the pivotal study of zoledronic acid versus placebo in
postmenopausal osteoporotic women, atrial fibrillation
reported as serious adverse events (SAEs) was more fre-
quent in the actively treated patients (1.3% versus 0.5%;
p<0.001). This was not observed in the HORIZON recurrent
fracture trial, in which a similar frequency of ‘serious’atrial
fibrillation was observed both in actively treated and placebo-
treated patients (1.1% versus 1.3%) [163]. Post hoc analyses
of previous main trials on alendronate, risedronate and ibandr-
onate having involved about 30,000 patients did not show any
clear-cut association with atrial fibrillation [164–166]. It is
possible that a lot of BP-treated patients have increased risks
of cardiovascular events already before the start of therapy
[167,168]. Also, any potential cardiovascular risk should be
weighted against the benefits of BP therapy. These include the
well-documented antifracture efficacy, of course, but may also
include additional benefits like the mortality benefit after hip
fracture with zoledronic acid therapy, a 30% mortality reduc-
tion not simply attributable to anti-fracture efficacy [163,
169].
Bisphosphonate and hypocalcaemia
BPs and in particular n-BPs are potent inhibitors of osteo-
clastic bone resorption. They can therefore provoke hypo-
calcaemia, hypocalciuria and PTH reaction in some cases.
Etidronate, however, did not induce any fall in serum and
urine calcium because it acutely impaired the accretion of
calcium into bone, offsetting a hypocalcaemic response
[170]. Even with intravenous potent n-BPs, symptomatic
hypocalcaemia rarely occurs in the treatment of osteoporosis
under usual conditions, i.e. with supplemental calcium and
vitamin D, lack of pre-existing hypoparathyroidism and/or
renal failure.
Miscellaneous
–Skin reactions like rash, pruritus and urticaria have been
rarely reported with BP use. Re-challenge was positive
in some cases [171]. Change of BP was not always
accompanied by resurgence of symptoms, suggesting
that BP-induced cutaneous reactions are probably not
attributable to a class effect [171].
–Extremely rare case reports of damage to the oral
mucosa, apparently not related to osteonecrosis of the
jaw, have been reported with the incorrect administra-
tion of n-BPs. Discontinuation of the inappropriate use
allowed healing of the mucosa ulcers, even with main-
tained oral intake, but taken according to the prescription
instructions [172].
–A few reports of transient hepatitis after months to years
of alendronate and/or risedronate, with liver biopsies
compatible with a drug-induced toxicity, have been
described [173,174]. Healing occurred soon or later
after stopping the drug.
Bisphosphonates and cancer
BPs constitute an efficacious therapy in order to prevent
skeletal complications in patients with bone metastases.
They might help to maintain functional independence and
quality of life [175]. Several BPs have shown some efficacy
in this regard, but owing to its easy mode of administration
and its potency, zoledronic acid became the most used drug.
Improved quality of life and prolonged disease-free survival
have been observed with adjuvant therapy with zoledronic
acid. In addition, zoledronic acid has shown a direct inhibi-
tion of tumorigenesis and cellular growth in preclinical
models. So far, clinical results remain controversial [160,
176–183].
SAPHO syndrome
Synovitis, acne, pustulosis, hyperostosis and osteitis syn-
drome is a rare condition consisting of sterile inflammatory
osteoarticular disorders, frequently associated with skin
lesions resistant to conventional anti-inflammatory therapy
[184]. Several case reports have shown successful therapy
with infusions of pamidronate disodium and zoledronic acid
[185,186].
Multicentric reticulohistiocytosis
Multicentric reticulohistiocytosis is a rare systemic condi-
tion characterized by erosive polyarthritis frequently pro-
gressing to arthritis mutilans and papulonodular lesions on
the skin. Alleviation of the arthritis and concurrent reduction
S10 Osteoporos Int (2012) 23 (Suppl 1):S1–S23
of the size and number of cutaneous nodules have been
observed in single case reports with therapy with alendronate,
pamidronate and zoledronic acid [187].
Hypertrophic osteoarthropathy
Hypertrophic osteoarthropathy can be disabling and resis-
tant to analgesic and anti-inflammatory drugs. Clubbing,
arthralgias, cutaneous and osseous (periosteal) proliferation
in the upper and lower extremities are frequently associated
with bronchogenic carcinoma and right-to-left cardiac
shunts. A few case reports have shown an effective
alleviation of symptoms after pamidronate disodium and
zoledronic acid in both benign and malignant conditions
[188].
There are potentially other indications for BPs such as
periodontitis leading to local bone loss. However, there is
not yet enough evidence to recommend a wide use of BPs in
the treatment of this condition. Moreover, the theoretical
albeit questioned risk of osteonecrosis of the jaw could deter
clinicians to use them thoughtlessly [189].
Selective oestrogen receptor modulators (SERMs)
SERMs and the risk of stroke
Several meta-analyses have reported an increased risk of
stroke with tamoxifen use. Braithwaite et al. [190] observed
a 49% increased stroke risk (RR 1.49; 95% CI 1.16 to 1.90).
Similarly, Bushnell and Goldstein [191] found an OR of
1.82 (95% CI 1.41 to 2.36) for ischemic stroke and 1.40
(1.14 to 1.72) for any stroke. During a mean follow-up
period of 4.9 years, the frequency of ischemic stroke was
0.71% with tamoxifen versus 0.39% for controls (absolute
increased risk, 0.32%; number needed to harm, 313).
In the Ruth study, the incidence of all strokes did not
differ between raloxifene (incidence rate per 100 woman-
years 00.95) and placebo (incidence rate 00.86) treatment
groups (p00.30). There was, however, in the group of
women assigned to raloxifene a higher incidence of fatal
strokes than amongst placebo users (incidence rates 00.22
and 0.15, respectively, p00.0499). No significant subgroup
interactions were found except that there was a higher
incidence of stroke associated with raloxifene use amongst
current smokers [192]. Lasofoxifene, contrary to other
SERMs, at a dose of 0.5 mg/day, as compared with placebo,
was associated with reduced stroke risk (2.5 versus 3.9 cases
per 1,000 person-years; hazard ratio 0.64; 95% CI 0.41 to
0.99) in a randomised osteoporosis trial (8,556 women)
[193].
SERMs and cardiovascular risk
In the meta-analysis conducted by Braithwaite et al. [190],
tamoxifen was associated with significantly decreased myo-
cardial infarction deaths (RR 0.62; 95% CI 0.41 to 0.93) but
not myocardial infarction incidence (RR 0.90; 95% CI 0.66
to 1.23). Five years of treatment with tamoxifen was asso-
ciated with reduced mortality from coronary heart disease
compared with that in the 2-year group (hazard ratio 00.67,
95% confidence interval 00.47 to 0.94. Ten years after
surgery, 2.1% of the patients in the 5-year group and 3.5%
of those in the 2-year group had died from coronary heart
disease.
Initial results from the breast prevention studies reported
that tamoxifen was associated with a doubling of the risk of
deep-vein thrombosis and pulmonary embolism. This was
reported for instance during the active treatment of the IBIS-
I trial (52 versus 23 cases, RR02.26, 95% CI 01.36 to 3.87),
but not after tamoxifen was stopped (16 versus 14 cases,
RR01.14, 95% CI00.52 to 2.53) [194]. Similarly,
Braithwaite et al., observed a 88% increased pulmonary
emboli risk (RR 1.88; 95% CI 1.77 to 3.01).
The Raloxifene Use for The Heart (RUTH) trial showed
that raloxifene had no overall effect on the incidence of
coronary events in women with established coronary heart
disease or coronary heart disease risk factors. In addition,
raloxifene had no effect on the incidence of coronary events
in any subgroup except in the case of a post hoc age subgroup
analysis using age categories defined in the Women’sHealth
Initiative randomised trials. The effect of raloxifene on the
incidence of coronary events differed significantly by age
(interaction p00.0118). The incidence of coronary events in
women <60 years of age was significantly lower in those
assigned raloxifene (50 events) compared with placebo (84
events; hazard ratio 0.59; 95% confidence interval, 0.41 to
0.83; p00.003; absolute risk reduction, 36 per 1,000 women
treated for 1 year). No difference was found between
treatment groups in the incidence of coronary events in
women > or 060 and <70 or > or 070 years of age [195].
Adomaityte et al. [196] assessed the risk of raloxifene on
venous thromboembolism using a meta-analysis (nine trials,
24,523 postmenopausal women) and found a 62% increase
in odds of either DVT or PE (odds ratio 1.62; 95% CI 1.25
to 2.09). Similarly, raloxifene therapy was associated with
54% increase in odds of DVT (odds ratio 1.54; 95% CI 1.13
to 2.11) and 91% increase in odds of PE alone (odds ratio
1.91; 95% CI 1.05 to 3.47). The excess event rate, in the
More trial, was 1.8 per 1,000 woman-years (95% CI −0.5–4.1),
and the number needed to treat to cause one event was 170
(95% CI 100–582) over 3.3 years [197]. Similarly to what is
observed with tamoxifen and with menopause hormone ther-
apy, the excess of risk is more pronounced during the first
2 years of use. Similar results were seen in the RUTH trial.
Osteoporos Int (2012) 23 (Suppl 1):S1–S23 S11
Overall, raloxifene use was associated with an increased VTE
risk (HR 1.44, 95% CI 1.06–1.95) versus placebo. Concomi-
tant use of aspirin or non-aspirin antiplatelet agents along with
raloxifene did not change VTE risk [198]. Still the risk with
raloxifene seems lower than with tamoxifen, since in the
updated report of the STAR trial (TAM versus RALOX),
Toxicity RRs (raloxifene/tamoxifen) were 0.75 (95% CI
0.60–0.93) for thromboembolic events.
Lasofoxifene was associated with reduced risks of coro-
nary heart disease events (5.1 versus 7.5 cases per 1,000
person-years; hazard ratio 0.68; 95% CI 0.50 to 0.93) [193].
There was a reduced risk of coronary revascularization
(hazard ratio 0.56; 95% CI 0.32 to 0.98), hospitalization
for unstable angina (hazard ratio 0.55; 95% CI 0.29 to
1.04) but no reduction of coronary death or nonfatal myo-
cardial infarction [199].
SERMs and global mortality and morbidity
In a post hoc analysis of the MORE osteoporosis treat-
ment trial (7,705 postmenopausal women), the global
index outcome (defined as described for the WHI trial;
i.e. occurrence of coronary heart disease, stroke, pulmo-
nary embolism, invasive breast cancer, endometrial can-
cer, colorectal cancer, hip fracture or death because of
other causes) resulted in annual rates of 1.39% and
1.83% in the raloxifene and placebo groups, respectively
(HR 0.75; 95% CI 0.62–0.92), which were compatible
with a favourable risk–benefit profile for raloxifene
[200]. A pooled analysis of mortality data was performed
from large clinical trials of raloxifene (60 mg/day) versus
placebo, including the MORE/CORE trials (7,705 post-
menopausal osteoporotic women followed for 4 years
and a subset of 4,011 participants followed for an additional
4 years; 110 deaths) and the RUTH trial (10,101 postmeno-
pausal women with coronary disease or multiple risk factors
for coronary disease followed for 5.6 years; 1,149 deaths).
All-cause mortality was 10% lower amongst women assigned
to raloxifene 60 mg/day versus placebo (relative hazard 0.90;
95% CI 0.80–1.00; p00.05). Lower overall mortality was
primarily due to lower rates of non-cardiovascular deaths,
especially a lower rate of non-cardiovascular, non-cancer
deaths [201]. The mechanism whereby raloxifene might
reduce the risk of non-cardiovascular death remains
unclear.
SERMs and cancer risk
It is well-known that tamoxifen is associated with signifi-
cantly increased risks of endometrial cancer (RR 2.70; 95%
CI 1.94 to 3.75) [190]. SERMS like tamoxifen and ralox-
ifene are approved in the USA, but not in Europe, for
reducing breast cancer risk in patients at risk of breast
cancer. It has been repeatedly shown that tamoxifen reduces
the risk of invasive ER-positive tumours [194].
On the hand, raloxifene did not increase risk for endo-
metrial hyperplasia (RR 1.3; 95% CI 0.4–5.1), or endome-
trial cancer (RR 0.9; 95% CI 0.3–2.7) [197]. In the updated
report of the STAR trial (TAM versus RALOX), Toxicity
RRs (raloxifene/ tamoxifen) were 0.55 (95% CI 0.36–0.83;
p00.003) for endometrial cancer (this difference was not
significant in the initial results) [202].
The MORE trial found that 4 years of raloxifene therapy
also decreased the incidence of invasive breast cancer
amongst postmenopausal women with osteoporosis by
72% compared with placebo. The CORE (an extension trial)
examined the effect of four additional years of raloxifene
therapy. Incidences of invasive breast cancer and ER-
positive invasive breast cancer were reduced by 59%
(HR00.41; 95% CI00.24 to 0.71) and 66% (HR 00.34;
95% CI00.18 to 0.66), respectively, in the raloxifene group
compared with the placebo group. There was no difference
between the two groups in incidence of ER-negative inva-
sive breast cancer. Over the 8 years of both trials, the
incidences of invasive breast cancer and ER-positive inva-
sive breast cancer were reduced by 66% (HR00.34; 95%
CI00.22 to 0.50) and 76% (HR00.24; 95% CI 00.15 to
0.40), respectively, in the raloxifene group compared with
the placebo group [203]. It has further been suggested that
breast cancer risk reduction persists for some time in
patients who discontinue raloxifene although this conclu-
sion is limited by the post hoc analyses in unrandomised
patients and the small sample sizes [204]. Raloxifene re-
duced also the incidence of invasive breast cancer by 44%
(HR00.56; 95% CI00.38 to 0.83; absolute risk reduction 0
1.2 invasive breast cancers per 1,000 women treated for
1 year) in the RUTH trial [205]. The lower incidence of
invasive breast cancer reflected a 55% lower incidence of
invasive ER-positive tumours (HR 00.45; 95% CI 00.28 to
0.72). However, raloxifene treatment did not reduce the
incidence of non-invasive breast cancer or of invasive ER-
negative breast cancer. The reduced incidence of invasive
breast cancer was similar across subgroups, including those
defined by age, body mass index, family history of breast
cancer, prior use of postmenopausal hormones and 5-year
estimated risk of invasive breast cancer. An updated analysis
with an 81-month median follow-up of the STAR trial
(tamoxifen (20 mg/day) or raloxifene (60 mg/day) for
5 years in women at high-risk breast cancer) was published
in 2010 [202]. The RR (raloxifene/ tamoxifen) for invasive
breast cancer was 1.24 (95% CI 1.05–1.47) and for non-
invasive disease, 1.22 (95% CI 0.95–1.59). Compared with
initial results, the RRs widened for invasive and narrowed
for non-invasive breast cancer [202]. There were no signif-
icant mortality differences. Long-term raloxifene retained
76% of the effectiveness of tamoxifen in preventing invasive
S12 Osteoporos Int (2012) 23 (Suppl 1):S1–S23
disease and grew closer over time to tamoxifen in preventing
non-invasive disease.
In the PEARL trial (n08,556), lasofoxifene 0.5 mg re-
duced the risk of total breast cancer by 79% (hazard ratio
0.21; 95% CI 0.08 to 0.55) and ER+ invasive breast cancer
by 83% (hazard ratio 0.17; 95% CI 0.05 to 0.57) compared
with placebo. This effect was similar regardless of Gail
score, whereas the effects were markedly stronger for women
with higher baseline estradiol levels [206].
SERMs and menopausal symptoms
In breast cancer patients, it has been well documented that
tamoxifen increases both severity and frequency of hot
flushes.
The situation is likely less severe when using raloxifene.
Some RCTs did not report an increased frequency or sever-
ity of vasomotor symptoms in women discontinuing oestro-
gen–progestin as compared with placebo [207,208].
Nevertheless, other studies reported an increase in hot
flushes when using raloxifene [209], which led to the sug-
gestion of a gradual conversion to raloxifene from low-dose
oestrogen, with a progression from 60 mg every alternate
day to 60 mg/day.
It has been showed in short duration studies that it is
possible to avoid SERMs associated hot flushes and meno-
pausal symptoms, using a combination of a SEM (bazedox-
ifene) and estrogens (conjugated estrogens) [210].
Some non-skeletal side effects are favourable (breast
cancer protection); others on the other hand are unfavourable
(stroke risk, thromboembolism and endometrial cancer). The
presence and the magnitude of these side effects vary between
SERMs concluding that women with breast cancer treated
with tamoxifen have an 82% increased risk of ischemic stroke
and a 29% increased risk of any stroke, although the absolute
risk remains small.
Strontium ranelate
Strontium ranelate is a first-line treatment for the man-
agement of postmenopausal osteoporosis. Its dual mode
of action simultaneously reduces bone resorption and
increases bone formation [211]. Strontium ranelate has
a limited number of non-skeletal effects, for which most
of the evidence comes from post hoc analyses of these
two trials.
Strontium and cartilage
Osteoarthritis involves the degeneration of joint cartilage
and the adjacent bone, which leads to joint pain and
stiffness.
There is some preclinical evidence for an effect of stron-
tium ranelate on cartilage degradation. Strontium ranelate
has been demonstrated to stimulate the production of pro-
teoglycans in isolated human chondrocytes, leading to car-
tilage formation without affecting cartilage resorption [212].
There is also evidence for an impact on biomarkers of
cartilage degradation. Treatment with strontium ranelate
was associated with significantly lower levels of urinary
excretion of a marker of cartilage degradation (CTX-II)
(p<0.0001) [213,214].
The potential for a clinical effect of strontium ranelate in
osteoarthritis indicated that 3 years’treatment with stron-
tium ranelate was associated with a 42% lower overall
osteoarthritis score (p00.0005 versus placebo) and a 33%
reduction in disc space narrowing score (p00.03 versus
placebo). These changes were concomitant to a 34% in-
crease in the number of patients free of back pain (p00.03
versus placebo) [215].
Strontium ranelate and cardiovascular risk
The possibility of a vascular effect was raised following
a pooled analysis of results in the SOTI and TROPOS
populations, which found a higher annual incidence of
venous thromboembolism over 5 years with strontium
ranelate than with placebo (0.9% versus 0.6%; relative
risk 1.4; 95% CI 1.0–2.0) [216]. Although these rates of
venous thromboembolism were similar to those in the
age-matched general population [217–219], they merited
further investigation. The possibility of an impact was
therefore explored in a retrospective study in the Gen-
eral Practice Research Database (GPRD) [220]. The
GPRD was used to identify 11,546 women with osteo-
porosis but no treatment, 20,084 women with osteopo-
rosis treated with alendronate and 2,408 women with
osteoporosis treated with strontium ranelate; 115,009
women without osteoporosis were used as a comparator
group [220]. Women with osteoporosis but no treatment
were at greater risk for venous thromboembolism than
women without osteoporosis (hazard ratio 1.43; 95% CI
1.10–1.86; p00.007; age-adjusted model), possibly due
to the reduced mobility associated with bone disease.
On the other hand, there was no difference in the rates
of venous thromboembolism in the samples of women
with osteoporosis (no treatment, strontium ranelate or
alendronate). Similar findings have been reported from
other observational studies [221,222],whichallaystoa
great extent the concerns.
Strontium ranelate and cutaneous adverse reactions
The other non-skeletal effect of concern with strontium rane-
late is the occurrence of rare cases of cutaneous
Osteoporos Int (2012) 23 (Suppl 1):S1–S23 S13
hypersensitivity reactions, which are manifested as drug reac-
tion with eosinophilia and systemic symptoms (DRESS) or
toxic epidermal necrolysis [223–226] (19-22). The pathogen-
esis of these hypersensitivity reactions remains unclear. Early
recognition and appropriate management, including drug
withdrawal, can improve the prognosis. The incidence of
these adverse reactions is extremely low, estimated at 1/
54,000 patient-years of treatment. This is most likely why
no cases were detected in the phase 3 clinical trials. Similarly,
no cases were reported in the observational study following
over 13,000 patients receiving strontium ranelate over 2 years
[222].
In conclusion, strontium ranelate has few non-skeletal
effects. A possible beneficial effect on cartilage degradation
and formation may translate into a new therapy for osteoarthri-
tis. Observational studies suggest no cause for concern over
possible vascular effects, whilst the rate of hypersensitivity
reactions with cutaneous effects remains very low.
Denosumab
Denosumab is a fully human monoclonal antibody that
inhibits the activity of the ligand for receptor activating
NFκB (RANKL), the main stimulator of osteoclastogenesis
and of osteoclast activity [227].
The potential extra skeletal effects of denosumab concern
its interaction with RANK function in non-skeletal tissues,
as RANK is largely expressed in several cell types, mainly
of the immunological and vascular systems [228].
Denosumab and the immune and inflammatory response
Besides its major role to regulate bone resorption, the
RANK/RANKL/OPG system is also an important regulator
of the immune system where it is produced by T cells and
enhances dendritic cells survival and antigen presentation
[229]. A theoretical concern is the possible effect of deno-
sumab on the susceptibility to infectious diseases and on the
risk of cancer. A deregulation of the immune system could
also lead to the appearance of atopic disease or autoimmune
diseases. Conversely, there could be a benefit in inflamma-
tory diseases. However, though RANK and RANK-L are
essential in mice for ontogeny of the lymphoid tissues [227],
patients with a mutation of the RANKL gene did not present
immunological defects [230]. Suppression of RANKL does
not interfere with inflammatory or immune response in
mature individuals, and RANKL inhibition did not prevent
inflammatory disease in several rat and mice models, except
in the IL-2-deficient mice whose lymphocytes over express
RANKL [229,231].
The only human model of inflammatory disease in which
denosumab has been used is RA. The authors followed at
MRI for 12 months 143 patients receiving 60 or 180 mg
injections of denosumab every 6 months. All patients were
treated with methotrexate. At 12 months, the MRI erosion
score was less increased from baseline in both denosumab
groups than in the patients receiving a placebo (p<0.012
and 0.007, respectively), but there was no evidence of an
effect of denosumab on joint space narrowing or on meas-
ures of RA disease activity [232]. Thus, denosumab cannot
substitute for DMARDs or anti-TNF in RA but could be an
interesting adjuvant in patients with progression of bone
erosions; beside, it could prevent osteoporosis associated
with RA, particularly in patients requiring glucocorticoid
treatment [233].
Concerning the problem of atopic disease and suscepti-
bility to infections, Stolina et al. have shown that mice
treated with OPG, the natural inhibitor of RANKL signal-
ling, did not differ from controls with regard to contact
hypersensitivity or infectious load induced by mycobacterial
infection [234]. There was no decrease of humoral or cellu-
lar immunity. Another study in mice showed that inhibition
of RANK signalling by a single dose of RANK-Fc 100 or
500 μg, which inhibits hypercalcaemia induced by 1,
25-dihydroxyvitamin D, did not decrease the immune
response to influenza infection [235].
In the first clinical study in postmenopausal women with
low bone density [236], the 1.9% of neoplasms in the
denosumab group versus none in the placebo or alendronate
groups was intriguing though not significant. However, in
the FREEDOM study, including nearly 4,000 patients trea-
ted for 3 years with denosumab, the incidence of neoplasia
did not differ significantly from the placebo group (3.7%
versus 3.2%) [237]. In this study, the authors found a sig-
nificant increase of eczema (3.0% versus 1.7%) and of
cellulitis (0.3% versus <0.1%) reported as SAEs in the
denosumab group but no difference in the overall proportion
of patients with skin infection. Other clinical trials did not
provide evidence for an increased risk of infectious compli-
cations either [238–240]. Because denosumab is a relatively
recent treatment option, continued follow-up of any poten-
tial safety signals will be required, as with other agents in
osteoporosis.
Denosumab and cardiovascular risks
RANKL and OPG could also play a role in the regulation of
vascular calcification. Mice knocked out for OPG developed
extensive vascular calcifications [241]. OPG produced lo-
cally by endothelial cells could promote endothelial survival
and decrease atherotic plate mineralisation [228]. Several
clinical studies have shown that circulating OPG was higher
in patients with cardiovascular diseases, particularly in ter-
minal renal failure [242,243], an increase considered as a
reaction to the inflammatory signal [244]. One human study
S14 Osteoporos Int (2012) 23 (Suppl 1):S1–S23
has shown conversely an inverse relationship between OPG
and echogenicity of carotid plaques, thus that individuals
with more fibrous and calcified plates had a lower serum
OPG concentration [245]. Inhibiting RANKL decreased
vascular calcifications in human RANKL knocked-in mice
with glucocorticoid induced osteoporosis [246]. Thus, one
could expect that besides protecting bone, denosumab could
decrease the risk of atherosclerosis. The clinical trials on
bone efficacy in osteoporosis and osteopenia did not show
differences in cardiovascular accidents in the denosumab-
treated patients. However, these studies were not designed
to study this end point, and the cardiovascular risk in the
patients included was not high (6.8% of the patients in the
placebo group of the FREEDOM study had a cardiovascular
event, stroke, coronary heart disease or peripheral vascular
disease). It would be interesting to look at high-risk subgroups
and to include cardiovascular events as an end point in osteo-
penia or osteoporosis studies conducted in patients at in-
creased risk of atheromatosis, like those with glucocorticoid
induced osteoporosis.
Teriparatide and parathyroid hormone(1–84)
The biological activity of the intact human PTH, i.e. PTH
(1–84), resides in its N-terminal sequence. Within the PTH
peptide family, teriparatide, the recombinant human PTH
(1–34) fragment has been most extensively developed
for clinical use in osteoporosis.
Miscellaneous effects
In clinical trials, commonly reported mild side effects have
been headaches (8%), nausea (8%), dizziness (9%) and leg
cramps (3%), with only for the latter two a significantly
higher incidence compared to placebo. These side effects tend
to occur within the first few hours following subcutaneous
injection [247,248].
Subcutaneous injection of 20 μg of teriparatide results in
a limited increase (around 0.8 mg/dl) of serum calcium,
peaking after 4 to 6 h, followed by a progressive return to
baseline before the next injection. These changes occur
usually within the physiologic range, with occasional, mild
hypercalcaemia having been observed in 11% of patients in
the pivotal clinical trial. Repeated or persistent hypercalcae-
mia necessitating reduction or cessation of concomitant
calcium supplementation and/or teriparatide dose reduction
occurred in about 3% of patients. In this trial, the 24-h urinary
calcium excretion showed a modest increase with a median of
30 mg/24 h. There were no clinical consequences, but patients
with history of hypercalciuria or of urinary calculi in the past
5 years were excluded from the trial. Significant increases of
serum uric acid have been observed in about 3% of patients.
Although these biochemical changes are generally mild, it has
been suggested that treatment with teriparatide should be
avoided in subjects with a history of nephrolithiasis or gout,
unless close monitoring is undertaken of serum and urinary
calcium excretion or serum uric acid [247,248].
The more limited data available on treatment with PTH
(1–84) suggests that at a proposed dose of 100 μg/day,
transient hypercalcaemia might be more frequent and mild
hypercalciuria observed in up to 10% of patients [249,250].
Mild local irritation with erythema at the injection site can
occur with teriparatide and PTH(1–84) [226,247].
Recently, teriparatide and PTH(1–84) have been proposed
as a possible therapeutic option for hypoparathyroidism [251,
252].
Conclusions
There is no doubt about the skeletal efficacy of bone drugs
as used in their registered indications: treatment of osteopo-
rosis in males and females, Paget’s disease of bone, multiple
myeloma, bone metastases, cancer-induced hypercalcaemia,
prevention and treatment of glucocorticoid induced osteo-
porosis or bone loss after hormonal deprivation in hormone
sensitive cancers as, e.g. prostate or breast. Fractures can be
prevented and bone pain and progressive bone disease lim-
ited. In this manuscript, an extensive review of non-skeletal
effects of these drugs is presented. These can be either
beneficial or deleterious.
Beneficial non-skeletal effects are proven for vitamin D
and SERMs. Fall reduction, improved muscular function
and physical performance are observed for substitution with
adequate doses of vitamin D (800 IU/day) in deficient
populations. As the health impact of falls is broader than
for fractures only, fall reduction is a separate, valuable
clinical outcome. For SERMs, long-term (up to 8 years)
primary chemoprevention of oestrogen receptor positive
breast cancers in postmenopausal women is documented.
Viewing the lower level of evidence of non-vertebral fracture
reduction by SERMs compared to other anti-resorptive bone
drugs, breast cancer prevention contributes to the preferred
use of SERMs in a specific therapeutic niche determined by
younger age, axial osteoporosis and increased breast cancer
risk.
More recently, some studies illustrated a reduction in mor-
tality (with vitamin D, SERMs, IV bisphosphonate), which
was probably not related to the fracture reduction. This inter-
esting observation requires confirmation by additional large
scaled and long-term studies including specific endpoints on
cardiovascular risk factors and events and cancer.
Other promising beneficial effects are described for
strontium on cartilage and spinal osteoarthritis and for deno-
sumab on the prevention of bone erosions in rheumatoid
Osteoporos Int (2012) 23 (Suppl 1):S1–S23 S15
arthritis. More clinical trials are needed to validate a poten-
tial use in these therapeutic areas. Furthermore animal or
observational data support some speculation on potential
benefits of calcium on ischemic cardiac mortality and
stroke; of vitamin D on cardiovascular outcomes, autoim-
mune diseases and cancer prevention and of SERMs on
coronary events and of denosumab on the prevention of
vascular calcification.
The most frequent non-skeletal side effects of bone drugs
are the gastrointestinal intolerance of calcium supplements
and oral bisphosphonates, contributing in part to the
reported low adherence of these drugs, and the acute phase
reactions following intravenous amino-bisphosphonates
applications. More important side effects in terms of sever-
ity, but fortunately infrequent, are stroke and venous throm-
boembolic events for SERMs and endometrium cancer for
tamoxifen. A severe cutaneous hypersensitivity reaction,
described as DRESS syndrome, has been reported in ex-
tremely rare case (only 16 reported) in clinical practice with
strontium ranelate, although etiologic linkage remains
doubtful. Hypocalcaemia has rarely been observed in
bisphosphonate and denosumab trials (including calcium
and vitamin D repleted patients); moreover, it was mild,
transient and asymptomatic. Some studies, but not all, report
kidney stones and myocardial infarction as side effects of
calcium supplements and renal toxicity for iv pamidronate
and zoledronate. Speculative side effects are discussed: mus-
culoskeletal pain, uveitis, scleritis and oesophageal cancer for
oral bisphosphonates and atrial fibrillation for iv zoledronate,
coronary disease for SERMs, venous thromboembolism of
strontium ranelate and skin infections for denosumab.
In conclusion, some of the non-skeletal effects of bone
drugs, either beneficial or deleterious, may influence treatment
choices, whereas others still require more studies to reveal
additional insights into remaining questions concerning the
clinical management of patients with bone diseases.
Conflicts of interest Jean-Jacques Body has received speaker and
consultant fees from Amgen and Novartis and research support from
Amgen, Daiichi Sankyo, GlaxoSmithKline, Merck Sharp & Dohme,
Novartis, Nycomed, Servier and SMB.
Pierre Bergmann has received speaker fees from Servier and Roche.
Steven Boonen has received consulting fees and/or research support
from Amgen, Merck, Novartis and Servier
Jean-Pierre Devogelaer has no conflict of interest.
Evelien Gielen has no conflict of interest.
Stephan Goemaere has received speakers fees and/or research sup-
port from Amgen, Daiichi Sankyo, Eli Lilly, Glaxo Smith Kline, Merck
Sharp & Dohme, Novartis, Nycomed, Warner Chillcott, Sanofi-
Aventis, Servier and Roche.
Jean-Marc Kaufman has received consulting fees, paid advisory
boards, lecture fees and/or grant support from Amgen, Eli Lilly, Glaxo
Smith Kline, Merck, Novartis, Procter & Gamble, Roche, Sanofi
Aventis, Servier and Warner Chilcott.
Serge Rozenberg has received speakers or/and consultant fees from
Amgen, Merck Sharp & Dohme and Pfizer.
Jean-Yves Reginster on behalf of the Department of Public Health,
Epidemiology and Health Economics of the University of Liège,
Liège, Belgium has received consulting fees or paid advisory boards
from Servier, Novartis, Negma, Lilly, Wyeth, Amgen, GlaxoSmithKline,
Roche, Merckle, Nycomed, NPS, Theramex and UCB; lecture fees when
speaking at the invitation of a commercial sponsor from Merck Sharp and
Dohme, Lilly, Rottapharm, IBSA, Genevrier, Novartis, Servier, Roche,
GlaxoSmithKline, Teijin, Teva, Ebewee Pharma, Zodiac, Analis,
Theramex, Nycomed and Novo-Nordisk and grant support from indus-
tries Bristol Myers Squibb, Merck Sharp & Dohme, Rottapharm, Teva,
Lilly, Novartis, Roche, GlaxoSmithKline and Amgen, Servier.
Funding This supplement was not sponsored by any outside com-
mercial interests. It was funded entirely by the Belgian Bone Club, a
non-profit scientific organisation.
Open Access This article is distributed under the terms of the Crea-
tive Commons Attribution Noncommercial License which permits any
noncommercial use, distribution, and reproduction in any medium,
provided the original author(s) and source are credited.
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