Article

ChemInform Abstract: Adverse Reactions and Drug-Drug Interactions in the Management of Women with Postmenopausal Osteoporosis

Division of Bone Disease, Department of Rehabilitation and Geriatrics, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
Calcified Tissue International (Impact Factor: 3.27). 06/2011; 89(2):91-104. DOI: 10.1007/s00223-011-9499-8
Source: PubMed
ABSTRACT
The pharmacological management of disease should involve consideration of the balance between the beneficial effects of treatment on outcome and the probability of adverse effects. The aim of this review is to explore the risk of adverse drug reactions and drug-drug interactions with treatments for postmenopausal osteoporosis. We reviewed evidence for adverse reactions from regulatory documents, randomized controlled trials, pharmacovigilance surveys, and case series. Bisphosphonates are associated with gastrointestinal effects, musculoskeletal pain, and acute-phase reactions, as well as, very rarely, atrial fibrillation, atypical fracture, delayed fracture healing, osteonecrosis of the jaw, hypersensitivity reactions, and renal impairment. Cutaneous effects and osteonecrosis of the jaw are of concern for denosumab (both very rare), though there are no pharmacovigilance data for this agent yet. The selective estrogen receptor modulators are associated with hot flushes, leg cramps, and, very rarely, venous thromboembolism and stroke. Strontium ranelate has been linked to hypersensitivity reactions and venous thromboembolism (both very rare) and teriparatide with headache, nausea, dizziness, and limb pain. The solidity of the evidence base depends on the frequency of the reaction, and causality is not always easy to establish for the very rare adverse reactions. Drug-drug interactions are rare. Osteoporosis treatments are generally safe and well tolerated, though they are associated with a few very rare serious adverse reactions. While these are a cause for concern, the risk should be weighed against the benefits of treatment itself, i.e., the prevention of osteoporotic fracture.

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Available from: John A Kanis
REVIEW
Adverse Reactions and Drug–Drug Interactions
in the Management of Women with Postmenopausal Osteoporosis
Rene
´
Rizzoli
Jean-Yves Reginster
Steven Boonen
Ge
´
rard Bre
´
art
Adolfo Diez-Perez
Dieter Felsenberg
Jean-Marc Kaufman
John A. Kanis
Cyrus Cooper
Received: 28 November 2010 / Accepted: 31 March 2011 / Published online: 3 June 2011
Ó The Author(s) 2011. This article is published with open access at Springerlink.com
Abstract The pharmacological management of disease
should involve consideration of the balance between the
beneficial effects of treatment on outcome and the proba-
bility of adverse effects. The aim of this review is to
explore the risk of adverse drug reactions and drug–drug
interactions with treatments for postmenopausal osteopo-
rosis. We reviewed evidence for adverse reactions from
regulatory documents, randomized controlled trials, phar-
macovigilance surveys, and case series. Bisphosphonates
are associated with gastrointestinal effects, musculoskeletal
pain, and acute-phase reactions, as well as, very rarely,
atrial fibrillation, atypical fracture, delayed fracture heal-
ing, osteonecrosis of the jaw, hypersensitivity reactions,
and renal impairment. Cutaneous effects and osteonecrosis
of the jaw are of concern for denosumab (both very rare),
though there are no pharmacovigilance data for this agent
yet. The selective estrogen receptor modulators are asso-
ciated with hot flushes, leg cramps, and, very rarely,
venous thromboembolism and stroke. Strontium ranelate
has been linked to hypersensitivity reactions and venous
thromboembolism (both very rare) and teriparatide with
headache, nausea, dizziness, and limb pain. The solidity of
the evidence base depends on the frequency of the reaction,
and causality is not always easy to establish for the very
rare adverse reactions. Drug–drug interactions are rare.
Osteoporosis treatments are generally safe and well toler-
ated, though they are associated with a few very rare
serious adverse reactions. While these are a cause for
concern, the risk should be weighed against the benefits of
Rizzoli has received lecture fees and/or on advisory boards for Merck
Sharp and Dohme, Eli Lilly, Amgen, Wyeth, Novartis, Servier,
Nycomed, Nestle
´
and Danone.
Reginster has received consulting and lecture fees, on paid advisory
boards, and/or grant support from Servier, Novartis, Negma, Lilly,
Wyeth, Amgen, GlaxoSmithKline, Roche, Merckle, Nycomed, NPS,
Theramex, UCB, Merck Sharp and Dohme, Rottapharm, IBSA,
Genevrier, Teijin, Teva, Ebewee Pharma, Zodiac, Analis, Novo-
Nordisk, and Bristol Myers Squibb.
Boonen has received consulting and lecture fees, on paid advisory
boards, and/or grant support from Amgen, Eli Lilly,
GlaxoSmithKline, Merck, Novartis, Ono, Roche, Sanofi-Aventis,
Servier, and Warner Chilcott.
Bre
´
art has received consulting fees and on paid advisory boards from
Servier.
Diez-Perez has received consulting and lecture fees, on paid advisory
boards, and/or grant support from Servier, Lilly, Amgen,
GlaxoSmithKline, Merck Sharp and Dohme, and ViiV.
Felsenberg has received consulting and lecture fees, on paid advisory
boards, and/or grant support from Amgen, Chugai, GE, Glaxo, Lilly,
MSD, Novartis, Nycomed, Roche, Servier, Teva, Warner/Chilcott,
and Wyeth/Pfizer.
Kaufman has received speaker and/or consultant fees and/or research
support from Amgen, Daiichi-Sankyo, Glaxo SmithKline, Merck
Sharp & Dohme, Novartis, Nycomed, Servier, and Roche.
Kanis has received consulting and lecture fees, on paid advisory
boards, and/or grant support from Abiogen, Italy; Amgen, USA,
Switzerland and Belgium; Bayer, Germany; Besins-Iscovesco,
France; Biosintetica, Brazil; Boehringer Ingelheim, UK; Celtrix,
USA; D3A, France; European Federation of Pharmaceutical Industry
and Associations, (EFPIA) Brussels; Gador, Argentina; General
Electric, USA; GSK, UK, USA; Hologic, Belgium and USA; Kissei,
Japan; Leiras, Finland; Leo Pharma, Denmark; Lilly, USA, Canada,
Japan, Australia and UK; Merck Research Labs, USA; Merlin
Ventures, UK; MRL, China; Novartis, Switzerland and USA; Novo
Nordisk, Denmark; Nycomed, Norway; Ono, UK and Japan;
Organon, Holland; Parke-Davis, USA; Pfizer USA; Pharmexa,
Denmark; Procter and Gamble, UK, USA; ProStrakan, UK; Roche,
Germany, Australia, Switzerland, USA; Rotta Research, Italy; Sanofi-
Aventis, USA; Schering, Germany and Finland; Servier, France and
UK; Shire, UK; Solvay, France and Germany; Strathmann, Germany;
Tarsa Therapeutics, US; Tethys, USA; Teijin, Japan; Teva, Israel;
UBS, Belgium; Unigene, USA; Warburg-Pincus, UK; Warner-
Lambert, USA; Wyeth, USA.
Cooper has received consulting fees from Alliance for Better Bone
Health, Lilly, Merck Sharp and Dohme, GlaxoSmithKline, Roche,
Novartis, Amgen, and Servier.
123
Calcif Tissue Int (2011) 89:91–104
DOI 10.1007/s00223-011-9499-8
Page 1
treatment itself, i.e., the prevention of osteoporotic
fracture.
Keywords Osteoporosis Adverse drug reaction
Drug–drug interaction Bisphosphonate Denosumab
SERM Strontium ranelate Teriparatide
The management of osteoporosis is a major priority for
public health. The disease affects about one-third of women
over the age of 50 years, with a combined lifetime risk of
hip, forearm, or vertebral fracture of around 50%, on a par
with the risk associated with cardiovascular disease [1]. The
total direct costs in Europe were estimated at 31.7 billion
in 2000 and are expected to nearly double by 2050 due to
demographic changes in the population [2]. Effective and
safe treatments are clearly essential to reduce this burden.
Fortunately, there is currently a wide range of osteo-
porosis treatments, which reduce the risk for vertebral
fracture from 40 to 75% and, in some cases, nonvertebral
fractures by about 20% and hip fractures up to 40% [3].
Like any disease, the pharmacological management of
patients with osteoporosis should always involve consid-
eration of the balance between the risk of adverse drug
reactions and beneficial effects in terms of reduction in the
risk of outcome. For osteoporosis, the outcome is vertebral
and nonvertebral fracture, which is associated with sig-
nificant levels of morbidity and disability and, in the case
of vertebral and hip fracture, an increase in mortality.
Treatment decisions should be made to attain the maximum
reduction in risk of fracture with the minimum occurrence
of adverse reactions. On the whole, osteoporosis treatments
are remarkably well tolerated, though pharmacovigilance
and case studies have highlighted some rare serious
adverse drug reactions, which deserve further investigation.
The Working Group of the European Society for Clinical
and Economic Aspects of Osteoporosis and Osteoarthritis
(ESCEO) has focused on adverse reactions and drug–drug
interactions in the management of women with osteoporo-
sis. This review was prepared following these discussions.
An adverse drug reaction is defined as an unintended
harmful or unpleasant response to a medicinal product,
which predicts hazard for future administration and war-
rants prevention or specific treatment, alteration of dosage,
or discontinuation [4, 5]. In general medicine, adverse drug
reactions are far more common than many physicians sup-
pose [5]. In one prospective observational analysis of nearly
20,000 hospital admissions, 6.5% of patients had some form
of adverse drug reaction, mainly due to aspirin, diuretics,
warfarin, and nonsteroidal anti-inflammatory drugs [6]. The
overall fatality in that analysis was 0.15%. Despite this,
many of the reactions are preventable through proper sur-
veillance and education of physicians and patients.
In this review, we examine the evidence for adverse
drug reactions with the following osteoporosis treatments:
bisphosphonates (alendronate, risedronate, ibandronate,
and zoledronic acid), denosumab, selective estrogen
receptor modulators (SERMs, raloxifene and bazedoxif-
ene), strontium ranelate, teriparatide, and PTH(1–84). We
report the prevalence of side effects and adverse reactions
according to the definitions used by the European Medi-
cines Agency (EMA): common (C1/100, \1/10), uncom-
mon (C1/1,000, \1/100), rare (C1/10,000, \1/1,000), and
very rare (\1/10,000).
Accurate interpretation of the risk of adverse reactions
and drug–drug interactions is difficult due to the variety of
R. Rizzoli
Division of Bone Disease, Department of Rehabilitation
and Geriatrics, Geneva University Hospitals and
Faculty of Medicine, Geneva, Switzerland
J.-Y. Reginster (&)
Department of Public Health and Health Economics,
University of Lie
`
ge, Lie
`
ge, Belgium
e-mail: jyreginster@ulg.ac.be
S. Boonen
Leuven University Center for Metabolic Bone Disease
and Division of Geriatric Medicine, Katholieke
Universiteit Leuven, Leuven, Belgium
G. Bre
´
art
INSERM U953, Ho
ˆ
pital Tenon, Paris, France
A. Diez-Perez
Department of Internal Medicine, Autonomous
University of Barcelona, Hospital del Mar, Barcelona, Spain
D. Felsenberg
Center of Muscle and Bone Research, Charite
´
–University
Medicine, Campus Benjamin Franklin, Berlin, Germany
J.-M. Kaufman
Department of Endocrinology and Unit for Osteoporosis
and Metabolic Bone Diseases, Ghent University Hospital,
Ghent, Belgium
J. A. Kanis
WHO Collaborating Centre for Metabolic Bone Diseases,
University of Sheffield Medical School, Sheffield, UK
C. Cooper
MRC Epidemiology Resource Centre, University
of Southampton, Southampton, UK
C. Cooper
NIHR Musculoskeletal Biomedical Research Unit, Department
of Musculoskeletal Science, University of Oxford, Oxford, UK
92 R. Rizzoli et al.: Adverse Reactions to Osteoporosis Treatments
123
Page 2
sources of information that provide varying levels of evi-
dence. The detection of an adverse reaction depends on the
relative frequency of the event and the temporality, the
mechanism of drug-induced toxicity, the number of
patients exposed to the drug, and the methods used to
detect the effect. There are three main sources of infor-
mation in addition to regulatory documents: randomized
controlled trials (RCTs), pharmacovigilance, and case
reports [4]. Table 1 summarizes the source of evidence for
the various adverse reactions with the osteoporosis treat-
ments described herein and the duration of postapproval
surveillance for each agent. Evidence from RCTs is
restricted to the most common adverse reactions due to the
small population size limited, at most, to a few thousand
patients, as well as the relatively short observation times.
On the other hand, rare side effects may not be detectable
by RCTs and only become evident in pharmacovigilance
surveys, which can cover hundreds of thousands of patients
over many treatment years. Case reports also constitute an
important source of information for the very rare events,
though causality is not always easy to establish. It should
be noted that the osteoporosis treatments that have been in
clinical use for longer are more likely to have reported
cases of rare adverse reactions than more recent arrivals to
the therapeutic armamentarium.
Adverse Reactions to Bisphosphonates
Bisphosphonates are stable derivatives of inorganic pyro-
phosphate and potent antiresorptive agents. They are
widely prescribed and highly effective at limiting bone loss
in osteoporosis. There have been a number of recent
reviews on the safety and tolerability of bisphosphonates in
osteoporosis [714] as well as in oncology, where higher
doses are applied alongside anticancer agents to prevent
skeletal complications and relieve bone pain [12, 15].
All of the bisphosphonates discussed below have proven
fracture efficacy in phase III trials [3]. The phase III trials
for alendronate were carried out in the mid-1990s by the
Fracture Intervention Trial (FIT) investigators, who dem-
onstrated efficacy against vertebral and nonvertebral frac-
ture, including hip [16, 17]. Alendronate was the first oral
bisphosphonate and has 15 years of postapproval
Table 1 Source of evidence for adverse reactions to treatments in osteoporosis
Source of evidence Duration of postapproval experience in 2010
RCT Pharmacovigilance Case series
Bisphosphonates Alendronate, 15 years
Risedronate, 10 years
Ibandronate (oral), 5 years
Ibandronate (IV), 4 years
Zoledronic acid, 3 years
GI effects 44
Musculoskeletal pain 4
Acute-phase reactions 44
Atrial fibrillation 44
Atypical fracture/delayed fracture healing 44
Osteonecrosis of the jaw 44
Hypersensitivity reactions 44
Renal impairment 4
Denosumab New agent
Severe infection 4
Osteonecrosis of the jaw 44
Cancer 4
SERMs Raloxifene, 13 years
Bazedoxifene, new agent
Lasofoxifene, new agent
Hot flushes 44
Leg cramps 44
Venous thromboembolism 44
Stroke 4
Endometrial effects 4
Strontium ranelate 8 years
Venous thromboembolism 4
Hypersensitivity reactions 44
Teriparatide or PTH(1–84) 8 years
Headache, nausea, dizziness, and limb pain 44
Osteosarcoma 44
R. Rizzoli et al.: Adverse Reactions to Osteoporosis Treatments 93
123
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surveillance data [18]. Similar fracture efficacy was found
for oral risedronate, in the Vertebral Efficacy with
Risedronate Therapy (VERT) trials [19, 20] and the Hip
Intervention Program (HIP) [21]. Risedronate was laun-
ched at the end of the 1990s, and there are now 10 years of
postapproval surveillance for this agent [22]. Ibandronate
has proven efficacy against vertebral fracture, as shown by
the Oral Ibandronate Osteoporosis Vertebral Fracture Trial
(BONE) [23]; but pivotal trials have not shown nonverte-
bral or hip fracture risk reduction with this agent. Ibandr-
onate is prescribed both as a monthly oral formulation,
with 5 years of postapproval surveillance, and as a tri-
monthly intravenous (IV) formulation, with 4 years of
postapproval surveillance [24]. The most recently available
bisphosphonate is zoledronic acid, for which there is evi-
dence for the prevention of both vertebral and nonvertebral
fractures, including those of the hip, from the Health
Outcomes and Reduced Incidence with Zoledronic Acid
Once Yearly (HORIZON) trial [25]. Zoledronic acid has
been prescribed as a once-yearly IV formulation since 2007
[26], and there are 3 years of postapproval surveillance.
Gastrointestinal Effects
In their oral formulations, bisphosphonates may irritate the
upper gastrointestinal (GI) mucosa since it is exposed to
high concentrations at intake [27]. Proper adherence to
administration instructions can reduce frequency of GI
effects [27]. These include swallowing the drug with a
large glass of water and remaining in the upright position
for at least 30 min after intake (60 min for ibandronate).
Upper GI reactions are ‘common’ with alendronate
[18]. They are the most frequently reported adverse reac-
tions with risedronate in drug monitoring, though the reg-
ulatory authorities do not cite an increased frequency of
upper GI reactions with risedronate [22] and pooled anal-
ysis of RCTs found no evidence for an increase in risk
compared with placebo [28]. Regarding ibandronate, GI
tolerability was initially thought to be of concern with the
high dosages necessary for monthly oral administration
(150 mg), but the investigators of the Monthly Oral
Ibandronate in Ladies (MOBILE) trial found no apparent
difference in GI adverse reactions between monthly and
daily formulations [29], with rates comparable to alendr-
onate (about 22%). Upper GI effects are less frequent with
weekly or monthly dosing than daily dosing for the same
agent. Oral alendronate, risedronate, and ibandronate tab-
lets also contain lactose, which causes abdominal dis-
comfort in some patients but is rarely a severe problem.
The prevalence of esophageal reactions with alendronate
is ‘common to rare’ [18]. Two conflicting reports have
appeared on the association of the long-term use of oral
bisphosphonates (up to 5 years) and incidence of esophageal
cancer [30, 31], both performed in the UK General Practice
Research Database (GPRD). One of these reported a rate of
2/1,000 over 5 years (against a background rate of 1/1,000)
[30], while the other reported no association with esophageal
or gastric cancer in users vs. nonusers [31]. Another analysis
of over 15,000 patients identified in RCTs or postapproval
surveys found rates of esophageal cancer similar to the
background rates in the population [32], with an incidence of
\1/1,000,000 patient-years of exposure. The Food and Drug
Administration (FDA) currently recommends avoidance of
oral bisphosphonates in patients with Barrett’s esophagus, a
precursor of esophageal cancer, and has called for further
research on possible risk factors [33].
Musculoskeletal Pain
Chronic bone, joint, and muscle pain has been associated
with intake of both oral and IV bisphosphonates [34
] and
was the subject of a warning from the FDA in 2008 [35].
The pathological basis for the reaction remains unclear,
though there may be a link with elevated parathyroid
hormone (PTH) levels [12]. Musculoskeletal pain is
‘common to rare’ with alendronate [18] and ‘common’
with zoledronic acid [26]. The FDA reports occurrences
with alendronate, ibandronate, risedronate, and zoledronic
acid, for which there was a (nonsignificant) difference vs.
placebo [35]. Musculoskeletal pain can occur at any time
during the course of treatment, though there may be some
overlap with acute-phase reactions (see below). It can be
difficult to manage, especially if severe [7, 8, 10]. Stopping
treatment may give complete relief of symptoms, though
there are cases of slow or incomplete resolution [34].
Acute-Phase Reactions
Acute-phase reactions have been reported with alendro-
nate, ibandronate, and zoledronic acid [9, 10, 12] and are
characterized by low-grade fever, sometimes with rigors,
and influenza-type symptoms, such as fatigue, malaise,
headache, myalgia, arthralgia, and bone pain. They are
attributed to altered activation and proliferation of c-d T
cells [36]. Onset may occur within 3 days of drug admin-
istration. The reaction is transient and generally resolves
within 3 days [14].
These are rated as ‘rare’ to ‘uncommon’ by the EMA
[18, 24, 26]; they appear to be more frequent with the IV
bisphosphonates and are very rare following oral admin-
istration [37]. In the Dosing Intravenous Administration
(DIVA) study, flu-like illness (33 symptoms) was reported
to occur with an incidence of 4.9% with IV ibandronate vs.
1.1% for oral ibandronate [38]. They were also more
common after the first injection of ibandronate than after
subsequent administrations. Acute-phase symptoms have
94 R. Rizzoli et al.: Adverse Reactions to Osteoporosis Treatments
123
Page 4
also been recorded after infusion of zoledronic acid (31.6%
after first infusion vs. 6.2% in the placebo group, less so
after second infusion) [25, 26]. Acute-phase reactions are
generally mild to moderate in intensity and are rarely the
cause of withdrawal in RCTs. They can be treated symp-
tomatically with paracetamol or other analgesics or anti-
pyretics. The likelihood of experiencing this reaction can
be reduced by administration of analgesics for a few days
just after dosing [10].
Atrial Fibrillation
Concern over the possibility that bisphosphonates could
induce atrial fibrillation [39, 40] followed the observation
of a small but significant increase in this event with
zoledronic acid in HORIZON when reported as serious
adverse events (50 events [1.3%] with zoledronic acid vs.
20 events [0.5%] with placebo, P \0.001) [25]. The
treatment–placebo difference was no longer significant
when the events were analyzed separately as atrial fibril-
lation or atrial flutter events, sick sinus syndrome, or
arrhythmias, adjudicated or not. Similar findings were
reported for alendronate in a post hoc analysis of the FIT
trial [41], in which there was a trend toward significance
for atrial fibrillation (47 events [1.5%] with alendronate vs.
31 events [1.0%] with placebo, P = 0.07). Possible
mechanisms for the modification of atrial conduction by
bisphosphonates include intracellular electrolyte homeo-
stasis and proinflammatory, profibrotic, and antiangiogenic
effects [40].
Observational studies have failed to detect an increase in
atrial fibrillation with any of the bisphosphonates [42, 43].
There is no RCT evidence that risedronate is associated
with atrial fibrillation [44], and postapproval surveillance
indicates an incidence of \1/1,000,000 patient-years with
this agent. Similarly, there was no increase in atrial fibril-
lation in any of the ibandronate trials. Finally, a recent
systematic review and meta-analysis concluded that,
though there are data linking bisphosphonate use to atrial
fibrillation, the exact nature of the risk remains unclear
because of the heterogeneity of the evidence and the lack
of information on some of the agents [45]. In 2008, the
FDA concluded that no change in treatment should be
made with respect to atrial fibrillation [34].
Atypical Subtrochanteric Fracture and Delayed
Fracture Healing
The occurrence of atypical subtrochanteric fracture and
delayed fracture healing with bisphosphonates has been the
subject of a separate ESCEO Working Group meeting and
review [46] and a report from a Task Force of the Amer-
ican Society for Bone and Mineral Research [47] and will
be discussed only briefly here. Case reports draw attention
to an association between subtrochanteric fractures and
exposure to bisphosphonates, possibly related to long-term
suppression of bone turnover [48], as demonstrated by the
absence of tetracycline labeling [49]. Cortical bone appears
to be the most affected, and patients with thick cortices
may be more susceptible to an effect on fracture [48].
Further supporting results for the deterioration of bone
structural quality with long-term bisphosphonate use were
presented at the annual meeting of the American Academy
of Orthopedic Surgeons in March 2010 [50, 51].
There is no RCT evidence for an increase in the risk of
subtrochanteric fractures with any of the bisphosphonates
[52]. There have been case reports of atypical fracture or
delayed fracture healing with long-term alendronate
[18, 5355], even though there are no quantitative differ-
ences in bone microarchitecture with alendronate [56].
There is also evidence from case series with risedronate
[54, 55], for which postapproval surveys indicate \1/
100,000 patient-years [57]. There are three cases of atyp-
ical subtrochanteric fracture with ibandronate [55], which
occurred after 4 months to 1 year of ibandronate treatment
preceded by 3–10 years of alendronate. There was no
delayed fracture healing in the HORIZON trial (3.2% with
zoledronic acid vs. 2.7% with placebo, nonsignificant) [58].
The evidence for a link between increased atypical
subtrochanteric fracture or delayed fracture healing and
long-term bisphosphonate therapy [46] generally comes
from retrospective case series with small numbers of
patients involved. The low frequency of atypical subtro-
chanteric fractures and the difficulties surrounding the
definition of patients at risk considerably complicate the
attribution of causality [52]. Current hypotheses include a
possible association of reduced bone turnover induced by
the bisphosphonate and other risk factors, such as younger
age at initiation or concomitant therapy with corticoste-
roids, proton pump inhibitors, or other antiresorptive
treatments [47, 52]. Further studies, including prospective
controlled studies, meta-analyses, and nested case-control
studies, are necessary to determine the role of other con-
comitant risk factors [46].
Osteonecrosis of the Jaw
Osteonecrosis of the jaw is the appearance of exposed bone
in the mandible, maxilla, or both that persists for at least
8 weeks in the absence of radiotherapy or jaw metastases.
The condition is known to affect patients receiving IV
bisphosphonate for metastatic disease [59]. Patients in
oncology generally receive much larger doses than those
with osteoporosis. Assessment of causality is very difficult,
though there is a possible role of inflammation and infec-
tion [60, 61].
R. Rizzoli et al.: Adverse Reactions to Osteoporosis Treatments 95
123
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The association of osteonecrosis of the jaw and bis-
phosphonate treatment for osteoporosis has already been
the subject of a separate ESCEO Working Group paper
[61]. Osteonecrosis of the jaw is very rare with oral bis-
phosphonates in the management of osteoporosis, and
current estimates of incidence stand at around 1/38,000
patient-years of treatment [6164]. Data from the GPRD
and The Health Improvement Network (THIN) suggest that
the annual incidence of all osteonecrosis is 2 to 3/100,000,
independently of bisphosphonate use [65]. The lower doses
of bisphosphonates used in osteoporosis, in comparison
with oncology, appear to be safe [66].
There have been no cases of osteonecrosis of the jaw
reported with risedronate in RCTs, and the postapproval
reporting rate is\2/100,000 patient-years, with 434 reports
in which 30–35% of patients had taken the drug for
\1 year (S. Boonen, personal communication). There were
two cases of osteonecrosis of the jaw in the HORIZON
trial, one in the zoledronic acid group and one in the pla-
cebo group [67]. The rate in the zoledronic acid-treated
osteoporotic population is currently estimated at 0.9/
100,000 patient-years of treatment. For ibandronate, the
rate is 0.9/1,000,000 patients exposed in osteoporosis vs.
2.3/100,000 patients exposed in oncology (R. Schimmer,
personal communication).
Some strategies for prevention of osteonecrosis of the
jaw have been proposed in oncology, including good oral
hygiene, completion of dental work prior to initiation of
treatment, and discontinuation of treatment for 3 months in
the event that a dental procedure is necessary [61, 66]. Any
intervention at the jaw in patients using bisphosphonates
for osteoporosis should include antibiotic therapy for
3 weeks. Management of osteonecrosis of the jaw involves
treatment of secondary infections, analgesia, and surgical
removal of necrotic debris [63, 68].
Hypersensitivity Reactions
Cutaneous adverse reactions are the subject of a separate
ESCEO report [69]. Cases of Stevens-Johnson syndrome
and toxic epidermal necrolysis have been reported for all
the bisphosphonates [13, 69], though these remain very rare
(\1/10,000 patients). These reactions have a strong tem-
porality and appear within 5–10 days of initiation of
treatment. Unsurprisingly for a very rare reaction, there are
more case reports for the agents that have been in clinical
use for the longest. The prognosis is good if the reaction is
recognized early and managed appropriately [69].
Renal Safety
The use of IV bisphosphonates in oncology has been
associated with rare cases of deterioration of renal function
due to the high doses administered over a short period of
time [70]. Analysis of the HORIZON trial demonstrated
the renal safety of IV zoledronic acid in osteoporosis [70],
with no long-term change in renal function in terms of
creatinine clearance. There were transient rises in serum
creatinine in 1.8% of treated patients vs. 0.8% of the pla-
cebo group, but all cases were completely resolved. The
FDA reports 24 cases in postapproval (i.e., very rare),
while the EMA describes renal impairment as ‘uncom-
mon’ and advises precaution in at-risk patients [26]. Fur-
ther support for the good renal safety of IV
bisphosphonates in osteoporosis comes from a pooled
analysis of the renal tolerability of ibandronate in four
RCTs. No relevant differences in parameters of renal tox-
icity were found between the IV formulation and oral
formulations (incidence of increase in serum creatinine
from baseline of C 0.5 mg/dl of about 0.4%). Regardless
of dose, creatinine clearance remained at baseline levels
and was comparable to placebo [71].
Adverse Reactions to Denosumab
The efficacy of denosumab in the prevention of fracture in
postmenopausal osteoporosis was demonstrated vs. placebo
in the Fracture Reduction Evaluation of Denosumab in
Osteoporosis Every 6 Months (FREEDOM) trial [72].
Denosumab is a fully human monoclonal antibody against
the RANK ligand and a potent inhibitor of osteoclast-
mediated bone resorption. Denosumab was approved for
clinical use very recently, so the only evidence for safety
and adverse reactions in osteoporosis is based on phase III
studies [72, 73] and regulatory documents [74]. Case
reports with the agent are rare, and there are not yet any
pharmacovigilance data.
There were no significant differences between denosu-
mab and placebo in terms of the total incidence of adverse
events in FREEDOM or in the Denosumab Hormone
Ablation Bone Loss Trial (HALT) [72, 73]. In FREEDOM,
adverse events occurring with an incidence of 2% or
greater and a significant difference from placebo
(P B 0.05) were eczema and flatulence [72]. Serious
adverse events occurring with an incidence of 0.1% or
greater and a significant difference from placebo
(P B 0.01) included cellulitis and concussion.
Infections
Data from RCTs indicate a higher rate of serious infection
with denosumab than placebo (4.4% vs. 3.6%, respec-
tively) [7476], including infection of the skin, the ear, the
GI tract, and the urinary tract. These can be related to
bacteria or unspecified pathogens. This is biologically
96 R. Rizzoli et al.: Adverse Reactions to Osteoporosis Treatments
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plausible since RANKL is expressed on activated T and B
lymphocytes, which, in the lymph nodes, are responsible
for recognition of foreign antigens [77]. RANKL inhibition
with denosumab may therefore play some role in arresting
these processes, though further research is necessary.
Infection of the urinary tract is rated as ‘common’ by the
FDA [74].
The cutaneous effects observed in the denosumab RCTs
(eczema and cellulitis) were generally localized infections
in the lower extremities and often occurred in patients with
risk factors such as skin wounds or peripheral vascular and
venous stasis disorders. The clinical course generally
consisted of full recovery with no recurrence, though
cutaneous effects were linked to one death in FREEDOM
(one case of fatal cellulitis). These cutaneous effects do not
appear to be a local reaction to injection. It is too early to
determine causality, though an increase in cutaneous
effects with denosumab vs. placebo remained when data
from FREEDOM and HALT were combined (D. Felsenberg,
personal communication). The rate can be estimated as
‘very rare’ (\1/10,000 patients). The risk should be
monitored.
Osteonecrosis of the Jaw
Given the observations with the bisphosphonates, it might
be expected that a potent antiresorptive agent such as
denosumab could also pose a potential risk for osteone-
crosis of the jaw [78]. There were no cases of osteonecrosis
of the jaw in the phase III studies of denosumab in oste-
oporosis. There is one case report of osteonecrosis of the
jaw in a male patient receiving denosumab in a trial in
oncology [79]. Moreover, the reaction has been reported in
34 subjects receiving denosumab for the management of
metastatic disease [80]. The rate can be estimated at around
2/100, but the true risk is unknown and should be moni-
tored. It should be noted that in this comparative trial the
rate of occurrence of osteonecrosis of the jaw was 1.4% in
zoledronic acid-treated patients.
Cancer
Preregistration RCTs with denosumab indicate slightly
higher rates of malignancy in osteoporotic women (4.0%
with denosumab vs. 3.3% with placebo) [74], principally
cancer of the pancreas, the GI and reproductive tracts, and
the breast. Breast cancer was the most common adverse
event that led to discontinuation in clinical trials (0.5%
denosumab vs. 0.3% placebo). The mechanisms underlying
these processes remain unclear, particularly in the absence
of an appropriate animal model as denosumab is not active
in rodents. The rate can be estimated as ‘very rare,’
though further monitoring is necessary. A postmarketing
survey of more than 4,500 women has been launched in
postmenopausal women receiving the agent for up to
10 years.
Adverse Reactions to SERMs
SERMs partially mimic the effect of estrogens on bone and
the cardiovascular system and have estrogen antagonist
properties in the endometrium and breast. The efficacy of
the SERM raloxifene in the prevention of osteoporotic
fracture was extensively studied in the Multiple Outcomes
of Raloxifene Evaluation (MORE) [81] and Continuing
Outcomes Relevant to Evista (CORE) [82]. Its effects on
breast cancer and other outcomes were explored in the
Study of Tamoxifen and Raloxifene (STAR) [83] and the
Raloxifene Use for the Heart (RUTH) trial [84, 85].
Raloxifene was launched in the 1990s and has 13 years of
postapproval surveillance [86].
There are two newcomers to the class. The SERMs
bazedoxifene and lasofoxifene were registered by the EMA
in 2009, but only basedoxifene is currently available for
clinical use [8789]. The efficacy of bazedoxifene at pre-
venting osteoporotic fracture over 3 years has been inves-
tigated vs. placebo [90], and its endometrial, ovarian, and
breast safety profiles have been evaluated in an RCT in
postmenopausal osteoporotic women, also over 3 years
[91]. Lasofoxifene has been studied in the 5-year Post-
menopausal Evaluation and Risk Reduction with Laso-
foxifene (PEARL) trial, which reported efficacy at
increasing bone mineral density and reducing radiographic
vertebral fracture [92, 93].
Hot Flushes and Leg Cramps
The most common adverse reactions of the SERMs are
linked to their vasomotor effects. The incidence of hot
flushes and leg cramps was significantly increased in the
raloxifene trials [94, 95]. The mechanisms behind these
phenomena are believed to be related to the competing
effect of the SERM on the relevant estrogen receptor. In a
pooled analysis of nearly 900 women participating in phase
III trials, the relative risk of hot flushes has been estimated
as 1.32 vs. placebo [94], with no apparent impact on the
natural course of incident hot flushes. Regarding tempo-
rality, an 8-year analysis indicated that the increase in risk
was greatest within the first 6 months of initiation of
raloxifene [95]. While hot flushes and leg cramps were
more common in those receiving raloxifene over 8 years
than placebo, this was almost entirely explained by the
increased incidence of hot flushes with raloxifene in the
first 5 years. This observation may be due to the with-
drawal of those with severe hot flushes or leg cramps from
R. Rizzoli et al.: Adverse Reactions to Osteoporosis Treatments 97
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the trial or to an effect of aging of the population, which
effectively reduces the risk for hot flushes. These effects
are noted as ‘very common’ for hot flushes and ‘com-
mon’ for leg cramps for raloxifene by the EMA [86].
Similar rates of hot flushes and leg cramps are reported for
bazedoxifene and lasofoxifene [87, 88, 90, 92, 96].
Venous Thromboembolism
Like hormone replacement therapy, treatment with SERMs
is associated with an increased risk for venous thrombo-
embolism, including deep vein thrombosis and pulmonary
embolism [97]. The frequency of venous thromboembo-
lism was increased in phase III trials with raloxifene, with a
relative risk of about 1.7 vs. placebo in the combined
analysis of MORE and CORE [85, 95, 98]. A large pro-
portion of cases (69%) had some contraindication to
raloxifene (e.g., immobilization or hypercoagulability) [99].
The incidence was reduced in the long-term trial CORE [95],
though this may have been linked to discontinuation due to
these adverse reactions and because these events occurred at
the beginning of treatment. The EMA notes this adverse
reaction as ‘uncommon’ with raloxifene [86].
There are fewer data for bazedoxifene and lasofoxifene.
There was a higher incidence of deep vein thrombosis in
the RCTs with bazedoxifene (0.7% with bazedoxifene
20 mg/day vs. 0.3% with placebo) [90, 96]. Venous
thromboembolic events constituted an adjudicated end
point in the PEARL trial [92], in which lasofoxifene more
than doubled the relative risk, though the absolute risk was
very small (2.9 venous thromboembolic events per 1,000
patient-years with lasofoxifene 0.5 mg/day vs. 1.4 events
with placebo and 0.7 pulmonary embolism events per
1,000 patient-years vs. 0.2 events with placebo) [92]. The
EMA reports deep vein thrombosis as ‘uncommon’ for
both lasofoxifene and bazedoxifene [87, 88].
Cardiovascular Events and Stroke
An increase in fatal stroke with raloxifene was reported in
RUTH (hazard ratio = 1.49, 95% confidence interval [CI]
1.00–2.24, with an absolute increase in risk of 0.7 per 1,000
patient-years) [85], though secondary analysis of the trial
indicated that the risk of stroke varied according to
smoking status [100]. Analysis of the MORE and CORE
data set has demonstrated that raloxifene has no significant
beneficial or harmful impact on cardiovascular events (i.e.,
coronary or cerebrovascular) [101]. This observation is
also supported by the results of the RUTH study, in which
participants were at higher cardiovascular risk [85] and in
which there was no significant difference in total strokes or
death from any cause. Moreover, there is evidence from
animal experiments that high doses of raloxifene may be
associated with some neuroprotective effects [102]. In the
MORE study, higher doses of raloxifene (120 mg/day)
were associated with some improvement in the results of
cognitive tests [103]. Regarding the other SERMS, there
was a moderate, nonsignificant increase in fatal stroke with
lasofoxifene in the PEARL study [92
] and no difference
from placebo for bazedoxifene in the 3-year phase III trial
[90, 96]. The EMA rates the incidence of stroke (arterial
thromboembolic disorders) as ‘very rare’ [86].
Gynecological Safety
Raloxifene and bazedoxifene have no impact on endome-
trial thickness [96, 104]. There was no significant differ-
ence in the incidence of uterine cancer, endometrial
hyperplasia, ovarian cancer, or postmenopausal bleeding
between raloxifene and placebo in the analysis of MORE
and CORE [95]. There was a greater incidence of uterine
polyps, though all of these were benign and not associated
with endometrial cancer. Uterine polyps were also more
common with lasofoxifene than placebo in the PEARL
study [92]. The rate of these events can be estimated as
‘very rare’ (\1/10,000 patients).
Adverse Reactions to Strontium Ranelate
Strontium ranelate is an orally active agent which decrea-
ses bone resorption and increases bone formation markers,
with a net result of improved microarchitecture [105]. The
efficacy of strontium ranelate in the prevention of vertebral
and nonvertebral fractures, including hip fracture in a
subgroup at risk of hip fracture, has been demonstrated in
postmenopausal osteoporotic women over 3 years in the
Spinal Osteoporosis Therapeutic intervention (SOTI) [106]
and up to 5 years in the Treatment of Peripheral Osteo-
porosis (TROPOS) trial [107]. There were no significant
safety issues in either of these phase III trials. Strontium
ranelate has been in clinical use since 2004 and has 6 years
of postapproval surveillance.
Venous Thromboembolism
There was no increase in venous thromboembolism with
strontium ranelate in the SOTI and TROPOS populations.
However, when the two trial populations were pooled, the
annual incidence of venous thromboembolism over 5 years
was 0.9% with strontium ranelate vs. 0.6% with placebo
(relative risk = 1.4, 95% CI 1.0–2.0) [108]. While these
rates of venous thromboembolism are similar to those in
the age-matched general population [109111], they
required further investigation. A retrospective study in the
GPRD database identified 11,546 untreated osteoporotic
98 R. Rizzoli et al.: Adverse Reactions to Osteoporosis Treatments
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women, 20,084 osteoporotic women treated with
alendronate, 2,408 osteoporotic women treated with
strontium ranelate, and 115,009 nonosteoporotic women
[112]. The risk for venous thromboembolism in this
population-based sample was significantly increased in
the untreated osteoporotic patients compared with their
nonosteoporotic counterparts (hazard ratio = 1.43, 95%
CI 1.10-1.86; P = 0.007, age-adjusted model). The
authors attributed this increase in risk to the reduced
mobility associated with osteoporosis. There was no
difference between the rates of venous thromboembolism
in untreated and treated osteoporotic patients, whatever
their treatment (strontium ranelate or alendronate). Sim-
ilar findings have been reported from two other obser-
vational studies, so the postmarketing data are reassuring
[113, 114].
Hypersensitivity Reactions
Strontium ranelate has been associated with rare cases of
the hypersensitivity drug reaction with eosinophilia and
systemic symptoms (DRESS). The incidence of this
adverse reaction is extremely low, estimated at 1/54,000
patient-years of treatment. This has been discussed in a
recent ESCEO Working Group review [69]. Early recog-
nition and proper management by stopping the agent are
mandatory and improve prognosis.
Adverse Reactions to Teriparatide or PTH(1–84)
Teriparatide, the 1–34 N-terminal fragment of human PTH,
has bone-forming properties [115]. It has been demon-
strated to effectively reduce vertebral and nonvertebral
fractures over 21 months in postmenopausal osteoporotic
women [116]. Its use is limited to 24 months of treatment
[115, 117]. Teriparatide has been in clinical use since 2002
and has 8 years of postapproval surveillance. PTH(1–84)
was approved for vertebral fracture prevention in 2006 and
is available in some countries [118].
Nervous System Disorders
In the placebo-controlled trials of teriparatide and
PTH(1–84), there were a number of minor adverse reac-
tions, including headache, nausea, and dizziness, which are
rated as ‘common’ to ‘very common’ by the EMA.
Teriparatide also appears to be associated with an increase
in limb pain [117], which is noted as ‘very common’ by
the EMA. In a study exploring the efficacy of combination
teriparatide and raloxifene in osteoporosis, muscle spasm
was the only adverse reaction reported to be related to
treatment with teriparatide [119].
Osteosarcoma
There were no cases of osteosarcoma in the RCTs with
teriparatide or PTH(1–84), though teriparatide has been
reported to induce osteosarcoma in experimental animals
[120, 121]. There is one case report of osteosarcoma with
teriparatide in a 70-year-old postmenopausal woman with a
complex medical history [122]. This reaction is rated as
extremely rare (1/100,000 patients) and should be consid-
ered against the background incidence in the general pop-
ulation, which is around 0.4/100,000 per year in a
population aged over 60 years [8, 122]. However, this has
led to an FDA warning [123], including a statement that
patients who have skeletal metastases, Paget disease, or
open epiphyses should not be prescribed teriparatide.
Drug–Drug Interactions in Osteoporosis
Drug–drug interactions are rare in the management of
osteoporosis and discussed only briefly here. Coadminis-
tration of oral bisphosphonates and calcium or acid-sup-
pressant medication, or indeed any other oral medications
containing divalent cations, is known to interfere with
absorption of the bisphosphonate. Calcium supplementa-
tion should therefore be distanced from bisphosphonate
intake. An apparent increase in the risk of fracture has been
reported in individuals receiving acid-suppressant medi-
cation (proton pump inhibitors) but not with histamine H
2
-
receptor antagonists [124]. This increase in risk remained
in patients receiving acid-suppressant medication in com-
bination with bisphosphonates vs. bisphosphonate alone.
Given the nature of the risk, this issue requires further
exploration.
Caution is also recommended with oral bisphosphonates
and the concomitant use of agents that irritate the gastric
mucosa (e.g., nonsteroidal anti-inflammatory drugs) due to
the GI effects of the bisphosphonate. There does not appear
to be cause for concern over drug–drug interactions for
ibandronate [125]. Renal damage due to bisphosphonates
could be exacerbated by nonsteroidal anti-inflammatory
agents, aminoglycoside antibiotics, antiretroviral therapies,
or diuretics [126, 127]. Thus, care should be taken to
administer IV bisphosphonates to only fully hydrated
patients. Regarding zoledronic acid, renal function should
be monitored and drugs affecting cardiac arrhythmias
should be used with caution. One case of transient elevated
liver enzymes has been reported with zoledronic acid and
ibuprofen. There are not yet any reported drug–drug
interactions of concern for denosumab.
Cholestyramine and colestipol may also affect the
absorption and enterohepatic recycling of raloxifene.
Levothyroxine may decrease the absorption of the drug.
R. Rizzoli et al.: Adverse Reactions to Osteoporosis Treatments 99
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There are few drug–drug interactions with strontium
ranelate. There are possible interactions with quinolones,
tetracycline antibiotics, and aluminum and magnesium
hydroxides; and the administration of strontium ranelate
should be separated from intake of dietary calcium by 2 h.
There is a possible interaction between teriparatide and
other treatments that affect serum calcium, though no
interaction has been detected with digoxin or thiazides.
Discussion and Conclusion
This review indicates that the most serious adverse reac-
tions are very rare in the management of postmenopausal
osteoporosis and that the osteoporosis treatments are gen-
erally free of serious drug–drug interactions. We have
reviewed the most commonly used osteoporosis treatments
in Europe as well as new agents in the field.
Causality is notoriously difficult to attribute for rare
adverse drug reactions, e.g., osteonecrosis of the jaw and
atypical subtrochanteric fracture [4, 5, 128]. Such decisions
are also fraught with interrater differences in opinion since
studies repeatedly show low agreement between experts
regarding causality when they assess the same case reports
[129]. Causality can only be definitively established if a
certain number of criteria are met: (1) a plausible tempo-
rality in relation to administration; (2) a reasonable
mechanism in view of the agent concerned; (3) a frequency
that differs from the background rate of the event in the
population; and (4) evidence from dechallenge and
rechallenge (though this is clearly not an option in the case
of life-threatening events). One example of the difficulties
in establishing causality in osteoporosis is osteosarcoma
with teriparatide, which appears to occur at rates similar to
the background rate in the elderly population. While the
best evidence for causality should ideally come from RCT
Table 2 Adverse reactions to treatments in osteoporosis
Prevalence Strength of
association
Consistency
of association
Dose–
response
Temporality Biological
plausibility
Bisphosphonates
GI effects (oral formulations) Common (C1/100) ?? ?? ? ? ?
Musculoskeletal pain Common (C1/100) ?? -? -
Acute-phase reactions (IV formulations) Common (C1/100) ?? ?? ? ? ?
Atrial fibrillation Very rare (\1/10,000) -- -- -
Atypical fracture/delayed fracture healing Very rare (\1/10,000) ±- -? ?
Osteonecrosis of the jaw Very rare (\1/10,000) -- -- ?
Hypersensitivity reactions Very rare (\1/10,000) ?? -? -
Renal impairment Very rare (\1/10,000) ?? ?? ?
Denosumab
Severe infection Common (C1/100) ?? -? ?
Osteonecrosis of the jaw Very rare (\1/10,000) -- -- ?
Cancer Very rare (\1/10,000) -- -- -
SERMs
Hot flushes Very common ([1/10) ?? ?? ? ? ?
Leg cramps Common (C1/100) ?? ?? ?
Venous thromboembolism Uncommon (C1/1,000
to \1/100)
?? ?? ?
Stroke Very rare (\1/10,000) -- -- -
Endometrial effects Very rare (\1/10,000) ?? ?? ?
Strontium ranelate
Venous thromboembolism Very rare (\1/10,000) ?- -- -
Hypersensitivity reactions Very rare (\1/10,000) ?- -? -
Teriparatide or PTH(1–84)
Headache, nausea, dizziness,
and limb pain
Common (C1/100) ?? ?? ?
Osteosarcoma Very rare (\1/10,000) -- -- ±
??
strong evidence, ? evidence, ± mixed evidence, - no evidence
100 R. Rizzoli et al.: Adverse Reactions to Osteoporosis Treatments
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data, this is virtually impossible for the rare events. For
instance, there were only two reports of bisphosphonate-
related osteonecrosis of the jaw in RCTs, and one of those
was in the placebo group.
The monitoring of risk and pharmacovigilance are
therefore central features of any drug safety program.
Improvements in pharmacovigilance should increase the
knowledge of adverse reactions via intensive monitoring
and database studies (such as those performed on venous
thromboembolism and osteonecrosis of the jaw in the
GPRD) and the use of algorithms for assessing the proba-
bility of an adverse reaction [130, 131]. Indeed, postap-
proval studies are necessary to make objective decisions
regarding rare serious adverse reactions. As shown in
Table 1, the rare adverse reactions are generally only
reported in pharmacovigilance or as case series and often
only appear with widespread clinical use of the agent
concerned. Regarding case reports, the evidence base is
less solid, partly because they may be biased by opinions of
the reporter and partly because they do not necessarily give
an accurate assessment of the risk due to underreporting or
selective reporting [130].
Table 2 synthesizes and classifies the adverse drug
reactions to osteoporosis treatments in terms of their
prevalence, the strength and consistency of the association,
dose–response and temporality, and biological plausibility
as reported in this review. For the sake of simplicity, we
have assumed class effects for the bisphosphonates and
SERMs. The more common adverse reactions, e.g., GI
effects with oral bisphosphonates and hot flushes with
SERMs, are well documented and generally associated
with higher values for strength and consistency of the
association, dose–response, temporality, and biological
plausibility. On the other hand, the rarer adverse reactions
have no strong evidence on any of these points and yet are
serious enough to require further monitoring. For example,
osteonecrosis of the jaw and atypical subtrochanteric
fracture have been clearly documented as issues of concern
by regulatory authorities for the antiresorptive agents;
however, the low incidence of the reactions and the limited
capacity to explore it using conventional evidence criteria,
such as RCTs, make it difficult to be categorical about the
association.
A good management strategy should always weigh the
risk of adverse reactions against the benefits of treatment,
i.e., the prevention of osteoporotic fracture. We should
recall that all the osteoporosis treatments covered in this
review have proven efficacy at reducing vertebral fracture
in women with postmenopausal osteoporosis, and some
have evidence for nonvertebral and hip fractures. It should
be noted that perhaps the biggest risk associated with
adverse drug reactions might be that a patient’s fear of an
adverse reaction would prevent him or her from taking the
osteoporosis medication in the appropriate manner, thereby
increasing the risk of fracture. In this context, great care
should be applied in the provision of information on
adverse drug reactions to patients, particularly in light of
studies that show that patients significantly overestimate
the likelihood of an adverse reaction occurring [132, 133].
In conclusion, osteoporosis treatments are generally safe
and well tolerated. They are associated with a few very rare
serious adverse reactions, such as osteonecrosis of the jaw,
atypical fracture, and atrial fibrillation. While these are
clearly a cause for concern and should be the subject of
further investigations and monitoring, the risk of these rare
events, which occur at a prevalence of less than 1 in 10,000
patients, should be weighed against the benefits of treat-
ment itself, i.e., the prevention of osteoporotic fracture and
associated morbidity.
Acknowledgments We thank the following people for their valu-
able input to this review: P. Borenstein, D. Cahall, A. Chines,
S. Korte, B. Mitlak, R. Schimmer, and M. Spratka. S. Novack is
deeply acknowledged for editorial assistance.
Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
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    • "Experts on this field but also end users (patients) should be involved in such process. A recently updated review about the benefits and harms of pharmacologic osteoporosis treatments might also be helpful for that purpose although not all the drugs included in our fact sheet are included in the review [26]. Another potential weakness is that, although we recommend the patient to discuss non-pharmacological options (such as physical activity or nutrition) with doctors, our PET focused mainly on pharmacological options, and we therefore did not include an option grid for all possible nonpharmacological options. "
    [Show abstract] [Hide abstract] ABSTRACT: A personalized patient education tool for decision making (PET) for postmenopausal women with osteoporosis was developed by means of a systematic development approach. A prototype was constructed and refined by involving various professionals and patients. Professionals and patients expressed a positive attitude towards the use of the PET. Introduction: The purpose was to systematically develop a paper-based personalized PET to assist postmenopausal women with osteoporosis in selecting a treatment in line with their personal values and preferences. Methods: The development of the PET was based on a systematic process including scope, design, development of a prototype, and alpha testing among professionals and patients by semi-structured interviews. Results: The design and development resulted in a four-page PET prototype together with a one-page fact sheet of the different drug options. The prototype PET provided the personal risk factors, the estimated individualized risk for a future major osteoporotic fracture and potential reduction with drugs, and a summary of advantages and disadvantages whether or not to start drugs. The drug fact sheet presents five attributes of seven drugs in a tabular format. The alpha testing with professionals resulted in some adaptations, e.g., inclusion of the possibility to calculate fracture risk based on various individual risk scoring methods. Important results from the alpha testing with patients were differences in the fracture risk percentage which was seen as worthwhile to start drugs, the importance of an overview of side effects, and of the timing of the PET into the patient pathway. All women indicated that the PET could be helpful for their decision to select a treatment. Conclusion: Physicians and patients expressed a positive attitude towards the use of the proposed PET. Further research would be needed to test the effects of the PET on feasibility in clinical workflow and on patient outcomes.
    Preview · Article · Apr 2016 · Osteoporosis International
  • Source
    • "both effective and cost-effective in preventing vertebral , peripheral, and hip fractures also in older populations [1][2][3]. Bisphosphonates are considered relatively safe [4]. However, oral bisphosphonates may cause gastrointestinal problems, esophagitis, and, in rare cases, atypical fractures of the femur. "
    [Show abstract] [Hide abstract] ABSTRACT: We studied the incidence and duration of cumulative bisphosphonate use among older Finnish women and men with or without Alzheimer's disease (AD). The MEDALZ-2005 cohort is a nationwide sample of all persons with clinically diagnosed AD on 31 December 2005 and their age-, gender-, and region of residence-matched control persons without AD. Information on bisphosphonate use by persons with an AD diagnosis and their controls without AD during 2002-2009 was obtained from the prescription register database containing reimbursed medications. A total of 6,041 (11.8%) persons used bisphosphonates during the 8-year follow-up. Bisphosphonates were more commonly used among persons without AD (n = 3121, 12.3%) than among persons with AD (n = 2,920, 11.2%) (p = 0.001). The median duration of bisphosphonate use was 743 days (IQR). Among persons with AD, the median duration of use was 777 days (IQR) and among persons without AD, 701 days (IQR) (p = 0.011). People without AD more often used bisphosphonate combination preparations including vitamin D than did people with AD (p < 0.0001). Bisphosphonate use was more common among people without AD who had comorbidities, asthma/COPD, or rheumatoid arthritis compared with users with AD. Short-term users were more likely to be male, at least 80 years old, and not having AD. Although the incidence of bisphosphonate use was slightly higher among persons without AD, the cumulative duration of bisphosphonate use was longer in persons with AD. Short-term use was associated with male gender, older age, and not having AD.
    Preview · Article · Mar 2016 · Journal of Alzheimer's disease: JAD
  • Source
    • "With the aging of the world's population , osteoporosis has become a serious global health problem. Several drugs are used to reduce bone loss in osteoporosis, including oestrogen, bisphosphonates, and parathyroid hormone, and many studies show that longterm use of these drugs might cause many adverse reactions , such as increasing the risk of endometrial and ovarian cancer [2] [3], atypical femoral fractures [4], osteonecrosis of the jaw [5], venous thromboembolism [6], and nervous system disorders [7]. Consequently, it is necessary to develop an alternative with promising efficiency and fewer undesirable side effects to prevent or reverse postmenopausal osteoporosis. "
    [Show abstract] [Hide abstract] ABSTRACT: Alpinia officinarum Hance (AOH) is a traditional herbal medicine specific to south China and serves as a civil medication application of an antioxidant. Growing evidence demonstrates that antioxidants are beneficial for the treatment of osteoporosis. This study was designed to investigate the antiosteoporotic effects of total extracts from AOH in ovariectomised (OVX) rats and the different fractions in AOH on primary osteoblasts activities.
    Full-text · Article · Oct 2015
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