Treatment of osteoporosis with annual iv zoledronic acid: effects on hip fracture
Background: Several treatments for postmenopausal osteoporosis have been available in the
past decade, but adherence to these treatments has been judged inadequate. The prevention of
hip fracture by these medications is still modest. Methods: A literature search was performed for treatment with zoledronic acid for the preven-
tion of hip fracture. Results: In the The Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial, involving 7765 postmenopausal women with low bone min-
eral density or with prevalent vertebral fracture, women taking zoledronic acid had a 41% relative
risk reduction for hip fracture, at 3 years, compared to placebo. In the HORIZON Recurrent
Fracture Trial, 2127 patients (76% were women) were randomized to receive either zoledronic
acid or placebo after sustaining a ﬁ rst hip fracture. A reduction of 30% in the second hip fracture
risk was observed, but it did not reach statistical signiﬁ cance. Zoledronic acid was generally safe
in these trials, although a slightly increased rate of severe atrial ﬁ brillations was observed in the
HORIZON Prevention Fracture Trial, but not in the HORIZON Recurrent Fracture Trial. Conclusion: Yearly zoledronic acid reduces the risk of hip fracture, both in postmenopausal osteoporotic women with and without prevalent vertebral fracture and in men and women with
a recent ﬁ rst hip fracture. Keywords: osteoporosis, bisphosphonates, hip fracture, zoledronic acid Introduction Hip fracture is the most devastating complication due to bone fragility. Mortality is
increased in women with hip fracture, 10% to 20% higher than expected for their age
within the ﬁ rst year1,2 and this excess mortality persists for several years after hip fracture.3,4
Loss of independence and entry in nursing homes are also common consequences of hip
fractures.5 Prevention of hip fracture, however, is challenging because one needs to target
both the bone – with anti-osteoporosis agents – and the triggering event that is generally a
fall from standing height. In addition, hip fracture occurs mostly in individual over 75 years
of age,6 and the mean age at hip fracture is currently increasing.7,8 The second hip fracture
is not a rare event, with an estimated incidence of around 2% per year.9,10 Elderly patients
with hip fracture often present with several comorbidities hampering pharmacologic treat-
ment because of drug interaction, and a negative inﬂ uence on drug persistence. Cognitive
impairment may also have a negative impact on drug persistence.
Preventing falls has proven to be difﬁ cult, although some studies suggest that
vitamin D supplements,11 certain types of exercise, including tai chi,12 and cataract
surgery13 might reduce the risk of fall. Limiting the consequences of the fall may
Professor of Rheumatology, INSERM U831, Université de Lyon, Division
be possible with hip protectors, but their effectiveness has never been convincingly
established, mainly due to poor compliance.14
Hospices Civils de Lyon, 69437, Lyon cedex 03, France
A reduction in the incidence of hip fracture has been observed in some trials test-
ing the efﬁ cacy of oral alendronate and risedronate,15–17 but the magnitude of fracture
Therapeutics and Clinical Risk Management 2009:5 169–175
2009 Chapurlat, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.
risk reduction was about half of that observed for vertebral
androgen-def iciency-induced bone loss in prostate cancer
fracture efﬁ cacy. For the other drugs the evidence is less
patients, prostate cancer bone metastases, and osteolytic
compelling. In the BONE trial, examining the effect of iban-
bone metastases. This BP has also been marketed more
dronate on fracture risk, no efﬁ cacy on hip fracture events
recently for the treatment of postmenopausal osteoporosis,
could be obtained in the primary intent to treat analysis.18
and should be available soon for the treatment of male
With teriparatide, a 50% reduction in non-vertebral fracture
osteoporosis and of glucocorticoid-induced bone loss.
risk was shown, but the hip fracture risk reduction was not
In rat models, zoledronic acid – administered with sub-
signiﬁ cant. This latter result may stem from the study design,
cutaneous injections for 10 days – produces dose-dependent
as women were too young to have a sizeable hip fracture
increases in cancellous bone volume and connectivity,
incidence.19 With intact parathyroid hormone, no efﬁ cacy
100-times more effectively than pamidronate, and decreases
on non-vertebral fracture, and hip fracture speciﬁ cally,
was observed either.20 Although treatment with strontium
In another animal model of postmenopausal bone loss – the
ranelate has been able to diminish the rate of non-vertebral
ovariectomized adult rhesus monkey – animals were randomly
fracture by 16%, it is only in a post-hoc analysis that a 33%
assigned to one control group and four ovariectomy groups.
reduction of hip fracture risk could be found in a sub-group
The control and one ovariectomized group received saline,
of women at higher risk of hip fracture.21 No reduction in
and the three other ovariectomized groups were given 0.5, 2.5
hip fracture risk and all non-vertebral fracture risk has been
or 12.5 μg/kg by a single weekly subcutaneous injection, for
shown with the ﬁ rst selective estrogen receptor modulator
69 weeks.25 Spine, total body and radius bone mineral den-
(SERM) to be marketed for the treatment of postmenopausal
sity (BMD) were either preserved or increased by zoledronic
osteoporosis, raloxifene.22 With a new, more potent com-
acid, dose-dependently, up to week 39, and stabilized there-
pound, lazofoxifene, it has been shown that a reduction of
after. Simultaneously, biochemical markers of bone turnover
24% in the incidence of non-vertebral fracture risk could be
decreased signiﬁ cantly in monkeys receiving zoledronic acid,
obtained, but the 23% reduced risk in hip fracture risk did
proportionally to the dosage, and remained reduced until the
end of the study, compared with animals on placebo.
So, there is a clear need for new drugs to improve reduc-
In a phase II, randomized, double-blind, placebo-controlled
tion in hip fracture risk. These drugs should be adequately
trial, zoledronic acid or placebo were given intravenously to
tolerated in the elderly and their regime should be acceptable
351 postmenopausal women with low BMD (T score Յ 2),
in those patients who often have many co-prescriptions. In this
for 1 year. These patients received placebo or intravenous
context, we will review the effectiveness of the treatment with
zoledronic acid at doses of 0.25, 0.5 or 1.0 mg every 3 months,
annual intravenous zoledronic acid to prevent hip fracture.
or 2.0 mg every 6 months, or a single annual 4.0 mg dose.26
All women received a 1 g per day calcium supplement. All
zoledronic acid regimens produced similar increases in lum-
Our literature search in PubMed used the following terms:
bar spine and femoral neck BMD, spanning 4.3% to 5.1% at
zoledronic acid and hip fracture (50 articles), bisphosphonates
the spine, compared with stable BMD in the placebo group.
and hip fracture (693 articles). Titles and/or abstracts were
Biochemical markers of bone resorption (urinary N-terminal
reviewed to determine the relevance for this review. We have
telopeptide of type I collagen [NTX], serum C-terminal telo-
selected articles relevant to the prevention of hip fracture with
peptide of type I collagen [CTX]) were suppressed during the
zoledronic acid, including all clinical trials and some relevant
trial, while markers of bone formation were also diminished,
papers on the pharmacology of the compound and some stud-
albeit later after beginning treatment. Post-infusion myalgia
ies related to the clinical use of bisphosphonates. We have
and transient fever were the most common adverse events.
also used studies on zoledronic acid we were aware of, which
Two consecutive, open-label extensions of this phase II
had been released only in the form of abstracts at the time of
study have been conducted over 5 years.27 In the ﬁ rst exten-
sion, most patients received 4 mg once a year. They entered
the second extension thereafter and received either zoledronic
Pharmacology of zoledronic acid
acid 4 mg per year or calcium alone. Patients were analyzed
Zoledronic acid is a potent nitrogen-containing BP,
according to the duration of their treatment with zoledronic
which has been widely used in the treatment of Paget’s
acid (2, 3 or 5 years). Substantial increases in BMD were
disease of bone, hypercalcemia, multiple myeloma,
observed in all groups, along with signiﬁ cant reduction in
Therapeutics and Clinical Risk Management 2009:5
biochemical markers of bone turnover. A third of patients,
osteoporosis therapies. Patients with no bone medication at
however, did not benefit from an optimal reduction in
baseline were in stratum 1, whereas those in stratum 2 were
bone-speciﬁ c alkaline phosphatase, even after several zole-
on an antiosteoporosis drug when they started the trial.
dronic acid infusions. This frequent suboptimal response
Two primary endpoints were adopted in this trial: the
was not observed when examining results of serum CTX-1
incidence of new vertebral fracture in stratum 1 and the
measurements. Taken together, these results may suggest
incidence of hip fracture in both strata 1 and 2. Secondary
that a 4 mg yearly infusion may not have been adequate for
efﬁ cacy endpoints included any non-vertebral fracture, any
clinical fracture, and clinical vertebral fracture. Other second-
The one-year phase II trial26 has paved the way for
ary endpoints were changes in BMD at the total hip, femoral
conducting a large phase III trial program (the HORIZON
neck, and lumbar spine, and changes in markers of bone
trials) designed to demonstrate the ability of zoledronic acid
resorption (serum C-telopeptide of type I collagen, CTX)
5 mg once a year given intravenously to reduce osteoporotic
and formation (bone-speciﬁ c alkaline phosphatase, BSAP,
and N-terminal propeptide of type I collagen, PINP).
A total of 7765 women were randomized to receive
Clinical results with zoledronic acid
either zoledronic acid (n = 3889) or placebo (n = 3876).
in the prevention of hip fracture
Their mean age was 73 years, 63% had prevalent vertebral
Results of two large phase III multicenter randomized
fracture and 79% had no other osteoporosis medication at
placebo-controlled trials have been published so far. The
baseline (stratum 1). Eighty-four percent of patients were
HORIZON Pivotal Fracture Trial has been conducted among
postmenopausal osteoporotic women with and without preva-
The relative risk reduction for hip fracture in women
lent fracture.27 The HORIZON Recurrent Fracture Trial has
taking zoledronic acid was 41% with zoledronic acid and the
tested the ability of the compound to reduce fracture risk
vertebral fracture relative risk reduction at 3 years was 70%.
among men and women with a recent hip fracture.28
Fracture risk reduction after 1 and 2 years of treatment was
comparable to that observed after 3 years. Non-vertebral frac-
tures were reduced by 25%, all clinical fractures by 33% and
The Health Outcomes and Reduced Incidence with Zole-
clinical vertebral by 77%, in women on zoledronic acid.
dronic Acid Once Yearly (HORIZON) Pivotal Fracture
BMD at the hip increased by 6% and at the spine by 6.7%
Trial was an international, multicenter, randomized, double-
after 3 years of follow-up, compared with the placebo. All
blind, placebo-controlled trial in postmenopausal women
three markers of bone turnover (serum CTX, BSAP and
with osteoporosis, who were randomly assigned to receive
PINP) decreased signiﬁ cantly compared with the placebo
either a 15-minute intravenous injection of zoledronic acid
group, when they were measured 12 months after starting
(5 mg) or placebo, at baseline (day 0), at 12 months, and at
therapy. At 6 and 12 months after each infusion, there was
24 months. All women received oral daily calcium (1000 to
no further decline in their concentrations.
1500 mg) and vitamin D (400 to 1200 IU) and were moni-
The numbers of patients who died, had a serious adverse
tored for 3 years, to estimate the incidence of new vertebral
event, or discontinued follow-up because of an adverse
event did not signiﬁ cantly differ between the study groups.
Postmenopausal women between the ages of 65 and
Among patients on zoledronic acid, 31.6% had a brief ﬂ u-like
89 years could be enrolled if they had a BMD T-score
syndrome after the ﬁ rst infusion, compared with 6.2% in the
of −2.5 or less at the femoral neck, with or without preva-
placebo group. A transient increase of more than 0.5 mg/dL
lent vertebral fracture, or a T-score of −1.5 or less, with
in serum creatinine levels was observed 9 to 11 days after
radiological evidence of at least two mild vertebral frac-
the infusion, among 1.3% of patients with zoledronic acid
tures or one moderate vertebral fracture. Previous use of
and 0.5% of patients in the placebo group. The number of
oral bisphosphonates was permitted, the duration of the
patients who had arrhythmia in the zoledronic acid group
washout period depending on the duration of previous use.
(266 patients, or 6.9%) was signiﬁ cantly higher than that in
Concomitant use of several other antiosteoporosis drugs was
the placebo group (203 patients, or 5.3%; p = 0.003), as well
allowed, such as raloxifene, calcitonin, tibolone, tamoxifen,
as serious atrial ﬁ brillation. In the zoledronic acid group,
dehydroepiandrosterone, ipriﬂ avone, and medroxyproges-
50 patients had serious atrial ﬁ brillation (1.3%), compared
terone. Patients were stratiﬁ ed according to these baseline
with 20 patients (0.5%) in the placebo group. Among these
Therapeutics and Clinical Risk Management 2009:5
50 serious atrial ﬁ brillation events, 47 occurred more than
comparable in the groups. Similarly, there was no difference
30 days after the infusion. The occurrence of stroke, or death
for the occurrence of serious renal adverse events, arrhythmia
from stroke, did not differ between the two groups. Two cases
and atrial ﬁ brillation. No case of osteonecrosis of the jaw
of potential osteonecrosis of the jaw were identiﬁ ed (one in
the placebo group and one in the zoledronic acid group).
In a substudy of the HORIZON fracture trial, 152 patients
underwent a bone biopsy. Zoledronic acid reduced bone
Among postmenopausal women with osteoporosis, zole-
turnover by a median 63% and preserved bone structure and
dronic acid administered once a year at 5 mg was associated
volume, with evidence of ongoing bone remodeling in 99% of
with a 40% reduction in hip fracture risk. In men and women
the biopsies.30 Bone formation was normal, with no evidence
receiving the same regimen starting shortly after a ﬁ rst hip
of mineralization defect. The concomitant administration of
fracture, a trend toward a one third reduction in second hip
other antiosteoporosis drugs did not affect the tissue-level
fracture incidence has been observed.
Although no direct comparison in head-to-head trials
examining fracture efﬁ cacy has been made in comparison
with other antiresorptive drugs, prescribed orally, the mag-
The Health Outcomes and Reduced Incidence with Zole-
nitude of the effect looks somewhat larger with zoledronic
dronic Acid Once Yearly (HORIZON) Recurrent Fracture
acid. It is also possible to make an indirect comparison
Trial was an international, multicenter, randomized, placebo-
between placebo-controlled trials, as outlined by Bucher
controlled trial involving men and women with recent hip
and al.31 In indirect comparisons examining risedronate vs
fracture.29 Patients were randomized to receive a yearly
zoledronic acid and alendronate vs zoledronic acid, there
infusion of either 5 mg of zoledronic acid or an infusion of
was no signiﬁ cant difference between these drugs for hip
placebo. The treatment was administered within 90 days of
fracture efﬁ cacy.32 Several assumptions, however, need to be
the surgical repair of the hip fracture, and once a year thereaf-
made when those calculations are made. First, the samples
ter. All patients were supplemented with calcium and a load-
of patients in the different trials must be drawn from the
ing dose of vitamin D was administered soon after the ﬁ rst hip
same kind of population. This is not necessarily the case in
fracture. All these patients were unable or unwilling to take
these studies, as inclusion/exclusion criteria differed mark-
an oral bisphosphonate. A parallel therapy with calcitonin, a
edly between these trials. Second, the relative risks have
SERM, tibolone and hip protectors was authorized.
to be derived from the intent-to-treat analyses, which was
The primary endpoint was a new clinical fracture. Sec-
the case. Third, the dropouts must be accounted for in the
ondary endpoints included a second hip fracture and death, as
trials, which was possible. Rates of compliance, deﬁ nition
well as the change in BMD at the non-fractured hip, and new
of outcomes and methodologic quality of the trials can also
vertebral and non-vertebral fracture. Among 2127 patients,
affect the inferences from these indirect comparisons. So, at
1065 received zoledronic acid and 1062 were on placebo,
this stage, there is no absolute answer as to whether the hip
fracture risk reduction observed with zoledronic acid is more
After a median follow-up of 1.9 years, the observed
important than with other bisphosphonates.
fracture rate of clinical fracture was 8.6% in the zoledronic
The Pivotal Fracture Trial involved both women with
acid group and 13.9% in the placebo group, representing an
and without prevalent fracture. This the ﬁ rst time that a
absolute risk reduction of 5.3% and a relative risk reduction
reduction in hip fracture risk has been demonstrated in a
of 35%. There was also a non-signiﬁ cant 30% second hip
population treated with bisphosphonates including women
fracture relative risk reduction associated with the use of
with no prevalent vertebral fracture. So, this compound
zoledronic acid. Death from all causes was reduced by 28%
appears to be efﬁ cacious at various stages of the severity of
in the zoledronic acid group. BMD at the total hip increased
in the zoledronic acid group by 2.6% at 12 months, 4.7%
The Recurrent Fracture Trial is the ﬁ rst trial with an anti-
at 24 months, and 5.5% at 36 months and declined in the
osteoporosis drug that showed a decrease in mortality. This
placebo group by 1.0%, 0.7%, and 0.9%, respectively.
reduction was observed after about 16 months of follow-up.
The incidence of pyrexia, myalgia and bone pain was
Given the number of fractures that were avoided by the reduc-
increased among patients who received zoledronic acid,
tion of bone fragility, the reduction in fracture risk explained
whereas the incidence of serious adverse events was
2% of the mortality reduction.33 In a post-hoc sub-group
Therapeutics and Clinical Risk Management 2009:5
analysis, men experienced a greater mortality benefit,
after 3 years in the FIT I trial testing alendronate,15 complete
with fewer cardiac-related events. Death from pneumonia,
follow-up data at 3 years were available for only 64% of the
neoplasms, and cardiovascular disease in patients treated with
women in the HIP trial examining risedronate,16 or 64% to
zoledronic acid were reduced, whereas the incidence of these
68% (according to different treatment groups) completed
diseases was similar to that in the placebo group, suggesting
the study in the 3-year BONE trial testing the efﬁ cacy of
that the drug might inﬂ uence physiologic reserves.
oral ibandronate.18 In the HORIZON Recurrent Fracture
One of the limitations of the ﬁ rst oral bisphosphonates
Trial.29 which was an event-driven trial, 71% of the patients
was their daily dosage. Weekly regimens have been devel-
completed the trial, but only 3% were lost to follow-up.
oped later to diminish the treatment annoyance. In a recent
Results from the HORIZON program apply to a large range
analysis, 46% of women on a weekly formulation were still
of severity of postmenopausal osteoporosis, because women
taking their drug at 1 year, whereas only 33% of those on
could have osteoporosis with or without prevalent vertebral
a daily dosage were still on medication.34 Another limita-
fracture, the ages ranging from 65 to 89. They could have
tion of oral bisphosphonates is the possibility of digestive
already received certain osteoporosis medications, and there
adverse events such as abdominal pain, dyspepsia and,
were few exclusion criteria. Patients in the HORIZON Recur-
rarely, oesophagitis. Persistence on antiosteoporosis drugs
rent Fracture Trial had a recent hip fracture.
is poor, like with most chronic diseases.34 Thus, in a cohort
Patients at risk of hip fracture are generally elderly,
of older american women, drug persistence was only 45%
over 75. So, the tolerability of drugs is essential in this frail
1 year after starting a treatment for osteoporosis.35 In another
population. In the HORIZON Pivotal Fracture Trial, 2.3%
analysis performed in California, only 25% of women were
of women had hypocalcemia, deﬁ ned as serum calcium
still taking their medication at 1 year.36 In another study
below 2.075 mmol/L, 9 to 11 days after the infusion. These
conducted in North America, raloxifene and bisphosphonates
episodes were transient and asymptomatic in all cases. In
were frequently stopped and the main reason for treatment
the HORIZON Recurrent Fracture Trial, although patients
interruption was the occurrence of adverse events.37 Anti-
were older and more frail, fewer episodes of hypocalcemia
fracture beneﬁ t, however, improves as much as compliance
were observed (0.3%), possibly due to the loading dose of
increases.38 The efﬁ cacy of zoledronic acid on hip fracture
vitamin D patients received before their ﬁ rst infusion. So,
may be related, at least in part, to its iv administration,
hypocalcemia appears to be a rare and subclinical event in
allowing for a better delivery of the drug at the bone level,
women receiving zoledronic acid. In older patients, however,
it is probably wise to measure serum dihydroxy-vitamin D
This effect of yearly intravenous zoledronic acid on hip
and to give an adequate vitamin D supplement, including a
fracture may also be inﬂ uenced by the quick onset of the
loading dose if judged necessary, to avoid hypocalcemia as
antiresorptive action. In a randomized, double blind, double-
dummy trial comparing the onset of action of zoledronic acid
In the HORIZON Pivotal Fracture Trial, but not in the
5 mg and alendronate 70 mg in postmenopausal women with
HORIZON Recurrent Fracture Trial, serious atrial ﬁ brillation
low BMD,39 the reduction in markers of bone resorption was
occurred more frequently in the zoledronic acid group (1.3%)
signiﬁ cantly greater at week one in women on zoledronic
than in the placebo group (0.5%, p Ͻ 0.001). This ﬁ nding has
acid than in those on alendronate. The difference between the
prompted several groups to report data on atrial ﬁ brillation
two drugs waned over time, but a slight difference in favor
from other bisphosphonates trials. In the FIT trials, a trend was
of zoledronic acid remained after 12 weeks.
observed for the occurrence of serious atrial ﬁ brillation, with
The quality of trials, ie, their validity, is critical for
a relative hazard of 1.51 (0.97, 2.40).40 In the phase III trials
clinical practice and for health care systems who reimburse
of risedronate for osteoporosis, there was no difference in the
the drugs. The drop-out rate must be low so the intention to
incidence of atrial ﬁ brillation, stroke, or death related to car-
treat analysis remains reliable, along with sound randomiza-
diovascular disease between the placebo and treated groups.41
tion and statistical analysis. A wide spectrum of the disease
In a population-based case control study in Denmark based
must be enrolled to allow for good generalizability of trial
on medical databases, involving 13,694 patient with atrial
results. In the HORIZON Pivotal Fracture trial,28 84% of
ﬁ brillation/ﬂ utter and 68,470 controls, there was no associa-
patients remained in active follow-up and 81% received all
tion between use of oral bisphosphonate and the risk of atrial
three infusions. For comparison with other major phase III
ﬁ brillation/ﬂ utter.42 In this context of conﬂ icting data on the
osteoporosis trials, 88% of patients were still taking the drug
inﬂ uence of bisphosphonates on the risk of atrial ﬁ brillation,
Therapeutics and Clinical Risk Management 2009:5
it remains possible that the observation of increased risk in the
osteonecrosis of the jaw that might be observed in patients
HORIZON Pivotal Fracture Trial is a chance ﬁ nding induced
receiving zoledronic acid is comparable to that encountered
by multiple comparisons. The possibility that this arrhythmia
with previous oral bisphosphonates used for osteoporosis.
might be related to subclinical hypocalcemia and the result-
The occurrence of this adverse event is certainly related to the
ing secondary hyperparathyroidism,43 however, points to the
dose and not to the mode of administration. So, at this stage,
need for monitoring this potential cardiovascular event when
it has been recommended by the American Society for Bone
and Mineral Research Task Force45 that patients be informed
One of the concerns with new antiresorptive agents
about the risk of osteonecrosis of the jaw, maintain good oral
is their bone safety, regarding the risk of mineralization
hygiene and have regular dental visits. There is no contra-
defects and the risk of over-suppression of bone turnover.
indication to dental implant placement. Current evidence
In the ancillary bone biopsy study of the HORIZON trial,
supports the same recommendations for annual zoledronic
there was no mineralization defect.30 All 152 but 1 biopsies
acid as for older oral bisphosphonate therapies.
showed evidence of tetracycline label, indicating preserved
remodeling capacity. One year after treatment, before the next
infusion, an increase in serum markers of bone resorption was
Yearly intravenous zoledronic acid 5 mg is an effective
visible, consistent with this preservation of bone remodel-
treatment to reduce the incidence of hip fracture among
ing capacity. It is likely that zoledronic acid may be started
postmenopausal osteoporotic women. A trend toward a
among patients who have already received other bisphos-
second hip fracture risk reduction has also been observed
phonates. In a randomized double blind double dummy trial,
in patients with a ﬁ rst hip fracture. This treatment has been
conducted in postmenopausal women with low BMD who
had been previously treated with alendronate for an average
4 years, patients received either yearly zoledronic acid 5 mg
or oral weekly alendronate 70 mg over 1 year.44 BMD was
The author discloses no conﬂ icts of interest.
maintained in both groups, with no signiﬁ cant difference in
BMD change between the two groups. In addition, zoledronic
acid further diminished markers of bone resorption, which
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Therapeutics and Clinical Risk Management 2009:5
Pollenallergie: Fakten, Tipps und Links Über die ersten frühblühenden Sträucher freuen sich manche Menschen weniger als sie es gerne täten. Tränende Augen oder heftiges Niesen sind die unangenehmen Anzeichen für den «Heuschnupfen». Gut 15 Prozent der Schweizer Bevölkerung leiden darunter und die Tendenz ist steigend. Wer auf bestimmte Pollen allergisch reagiert, muss aber nicht a
The to facilitate your studying, the following list contains many of the terms and items found on the upcoming exam. Tetracycline, acne, papules, peeling lotion, topical antibiotic agent, comedones on her face. You tell her to apply retinoicacid, Retin A cream, dry skin, toenails, dermatitis, steroid creams, Psoriasis, Trichophyton rubrum infection, Atopic dermatitis,seborreheic dermatitis,