477714

2013
TAB531759720X13477714Therapeutic Advances in Musculoskeletal DiseaseDL Diab and NB Watts

Therapeutic Advances in Musculoskeletal Disease Editorial

Bisphosphonate drug holiday: Ther Adv Musculoskel Dis

(2013) 5(3) 107­–111

who, when and how long DOI: 10.1177/

1759720X13477714

© The Author(s), 2013.

Reprints and permissions:
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Abstract:  Bisphosphonates have been widely used in the treatment of osteoporosis with
robust data from numerous placebo-controlled trials demonstrating efficacy in fracture risk
reduction over 3–5 years of treatment. Although bisphosphonates are generally safe and
well tolerated, concerns have emerged about adverse effects related to long-term use. For
most patients with osteoporosis, the benefits of treatment outweigh the risks. Because these
agents accumulate in bone with some persistent antifracture efficacy after therapy is stopped,
it is reasonable to consider a ‘drug holiday.’ There is considerable controversy regarding the
optimal duration of therapy and the length of the holiday, both of which should be based on
individual assessments of risk and benefit.

Keywords:  bisphosphonates, drug holidays, fractures, osteoporosis

Introduction Therefore, each bisphosphonate has a unique Correspondence to:

Bisphosphonates are widely prescribed for the
treatment of osteoporosis. These popular and effec­
tive agents have a high affinity for bone and reduce
bone resorption by causing loss of osteoclastic
resorptive function as well as accelerating osteo­
clast apoptosis by inhibiting farnesyl pyrophos­
phate synthase, an enzyme in the HMG-CoA
reductase pathway. The four nitrogen-containing
bisphosphonates currently in clinical use for the
treatment of osteoporosis differ in the strength for
binding to bone. The rank order for binding affin­
ity is zoledronate > alendronate > ibandronate >
risedronate [Russell et  al. 2008]. Higher-affinity
bisphosphonates will bind avidly to the bone sur­
face but will spread through bone more slowly,
while lower-affinity agents will be distributed more
widely through the bone but have a shorter resi­
dence time in bone if treatment is stopped. These
agents also differ in the potency for inhibiting
farnesyl pyrophosphate synthase. The rank order
of potency for inhibiting this enzyme is zoledro­
nate > risedronate >> ibandronate > alendronate
[Russell et al. 2008]. Bisphosphonate use results in
a rapid and substantial decrease in bone turnover
markers that is dose and compound dependent,
with a maximum effect in 3–6 months. This effect
is maintained in a new steady state for at least 10
years with continued treatment [Bone et al. 2004].
Dima L. Diab, MD
profile of binding affinity and antiresorptive Cincinnati VA Medical
potency that likely result in clinically meaningful Center, University of
Cincinnati Bone Health
differences in the degree of reduction of bone and Osteoporosis Center,
turnover and the speed of onset and offset of Division of Endocrinology/
Metabolism, Department
effect. of Internal Medicine, 260
Stetson Street, Suite 4200,
Cincinnati, OH 45219, USA
The skeletal binding sites for bisphosphonates diabd@ucmail.uc.edu
are virtually unsaturable, so a substantial amount Nelson B. Watts, MD
Director, Mercy Health
could be accumulated over time, leading to a res­ Osteoporosis and
ervoir that continues to be released for months or Bone Health Services,
Cincinnati, OH, USA
years after treatment is stopped [Papapoulos and
Cremers, 2007]. Since release depends in part on
the level of bone turnover, which is reduced by
the presence of bisphosphonates, the actual
amount released may be fairly small. For exam­
ple, the amount of alendronate released from
bone over the next several months or years after
a 10-year treatment period with alendronate
would be equivalent to taking one quarter of the
usual dose [Rodan et al. 2004]. When treatment
is stopped, if there is continued presence of bis­
phosphonate in bone and continued release (and
possible re-attachment to bone), there might be
some lingering antifracture effect after treatment
is stopped. This is why it is reasonable to con­
sider a ‘drug holiday’ from bisphosphonate ther­
apy, a period of time when treatment is stopped
after continuous treatment. However, the term

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Therapeutic Advances in Musculoskeletal Disease 5 (3)
‘holiday’ implies that treatment will be restarted
after some time off.
Studies of long-term use of bisphosphonates
Approval of bisphosphonates in the US was
based on studies of 3–4 years duration, although
some of these studies have been extended, with
alendronate, risedronate and zoledronic acid
suggesting efficacy for up to 10 years [Black et al.
2006; Schwartz et al. 2010], 7 years [Mellstrom
et  al. 2004], and 6 years [Black et  al. 2012b],
respectively.
The extension of the alendronate Fracture
Intervention Trial (FLEX) enrolled subjects who
had approximately 5 years of alendronate treat­
ment in the FLEX study into a second 5-year
study where subjects were randomized to either
continue alendronate or start placebo. At the end
of the FLEX study, spine bone mineral density
(BMD) increased more (+3.8%) in the long-term
treated groups as opposed to the placebo group.
Discontinuation of alendronate was associated
with gradual increases of bone turnover markers,
although at the end of 5 years after stopping
alendronate, levels remained somewhat below
pretreatment levels 10 years earlier. There were
fewer clinical vertebral fractures in the long-term
treated group (55% reduction) that met statistical
difference from the placebo group (~2% versus
5%, relative risk (RR) 0.45, p = 0.013) [Black
et al. 2006]. A post hoc analysis of the FLEX data
indicated that nonvertebral fracture risk reduc­
tion was also observed in the subset of patients
without prior vertebral compression fractures but
only in those with T-scores entering FLEX of
–2.5 or lower at the femoral neck hip [Schwartz
et al. 2010].
The extension of the risedronate VERT-NA study
was a 1-year follow up of subjects who completed
3 years of blinded therapy with risedronate or
placebo, then stopped their study medications. In
the year off treatment, BMD decreased in the for­
mer risedronate users, but remained higher than
baseline and higher than in the former placebo
subjects. Furthermore, bone turnover markers
increased and were no different from the former
placebo subjects. Despite the apparent resolution
of treatment effect on these markers, the risk of
new vertebral fractures was reduced by 46% in
the former risedronate users compared with the
former placebo subjects [Watts et  al. 2008].
Similarly, a recent study looking at the effect of
108 http://tab.sagepub.com
discontinuing risedronate for 1 year after 2 or 7
years of treatment also showed decreasing BMD
in the total hip and trochanter regions as well as
increasing bone turnover markers [Eastell et  al.
2011].
In the 3-year extension of the zoledronate
HORIZON pivotal fracture trial, subjects who
received three doses of zoledronate in the pla­
cebo-controlled were assigned at random to one
of two arms: a continuation group that received
6 years of zoledronic acid administration and a
discontinuation group that received the initial
3 years of zoledronic acid then went to placebo
[Black et al. 2012b]. There were small differences
in bone density and bone turnover markers in
those who continued versus those who stopped
treatment, suggesting residual effects. However,
there were significantly fewer morphometric
vertebral fractures in the group that continued
treatment compared with the placebo group (14
versus 30, odds ratio [OR] 0.51, 95% confidence
interval [CI] 0.26–0.95, p = 0.035), suggesting
that patients at high fracture risk may benefit
from continued treatment. Since the majority of
subjects in the HORIZON registration trial had
prevalent vertebral fractures, the continuation
efficacy is most likely confined to those higher-
risk patients with vertebral compression fractures
[Black et al. 2012b].
In terms of long-term safety of bisphosphonate
use, concerns about two uncommon but possi­
ble time-related adverse events have emerged:
osteonecrosis of the jaw (ONJ) and atypical
femur fractures (AFFs). Although no specific
issues were identified in the above-mentioned
studies, recent evidence supports an association
between prolonged bisphosphonate exposure
and these two serious conditions. In a retrospec­
tive review of the HORIZON trial with intrave­
nous (IV) zoledronate for osteoporosis [Grbic
et al. 2010], one case of ONJ was reported in the
treatment group and another in the placebo
group. A total of 12 fractures in 10 women were
classified as subtrochanteric in secondary analy­
ses of the FIT, FLEX and HORIZON Pivotal
Fracture Trials, indicating that the risk of such
fractures with use of bisphosphonates was very
low, even in women who received bisphospho­
nates for up to 10 years [Black et  al. 2010].
Furthermore, iliac crest biopsies after up to 10
years of treatment have not shown oversuppres­
sion of bone turnover. Importantly, no causal
relationship has been established between

prolonged bisphosphonate exposure and either
of these outcomes. Even though the risks of ONJ
and AFF may increase after 5 years of bisphos­
phonate therapy, the likelihood remains low.
Nevertheless, these safety concerns have led to
considerable debate about how long to treat with
bisphosphonates.
Drug holidays
On 9 September 2011, the US Food and Drug
Administration (FDA) held a hearing to review
the long-term safety and efficacy of bisphos­
phonates including alendronate, risedronate,
ibandronate and zoledronate. The majority of
the advisory committee (17 to 6) voted that
labeling for these drugs should further clarify
the duration of use for bisphosphonates but
there was a lack of panel consensus on label
changes. The FDA wrote their opinion on this
perspective, suggesting reevaluation of the need
for continuing bisphosphonate therapy beyond
3–5 years in individual patients [Whitaker et al.
2012]. The FDA suggested that a drug holiday
may not be advisable in high-risk patients, but
for patients discontinuing treatment, there were
no concrete recommendations on what should
be done.
Subsequently, there has been considerable dis­
cussion about who benefits from a drug holiday,
when to initiate it, and the ideal duration of the
holiday. It is important to note that data from the
clinical trials discussed above suggest that the
risk of vertebral fractures is reduced beyond
5 years of therapy. In FLEX, the number needed
to treat (NNT) for 5 years to prevent one clinical
vertebral fracture was 17 in women with a preva­
lent vertebral fracture and a femoral neck T-score
of –2.0 or below at the start of the extension trial,
and 24 for women without vertebral fracture and
a femoral neck T-score of –2.5 or below [Black
et al. 2012a]. Hence, there is evidence for benefit
with continued therapy through 10 years in
this subset of patients. The 10-year fracture risk
assessments with the fracture risk assessment
system (FRAX) are increasingly used to guide
treatment decisions. A recent study by Leslie and
colleagues suggested that the FRAX tool can be
used to predict fracture probability in women
currently or previously treated for osteoporosis,
which may help in guiding the need for contin­
ued treatment or treatment withdrawal [Leslie
et al. 2012].
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DL Diab and NB Watts
Therefore, although there is some residual bene­
fit in terms of fracture reduction for some time
after a 3- to 5-year course of bisphosphonate
therapy, continuing treatment for 10 years seems
to be a better choice for high-risk patients. Even
though the risks of bisphosphonate therapy for
osteoporosis are small, the risk/benefit ratio may
be harmful for low-risk patients. For patients
who were candidates for treatment, treatment
may be stopped for a drug holiday after a course
of some years.
At present, it is difficult to find evidence to sup­
port the need for a drug holiday or to establish the
effectiveness of treatment after restarting therapy.
Similarly, there is no strong evidence to provide
guidance in terms of how long to treat, how long
the holiday should be, and when the holiday
should be stopped. Nevertheless, we believe there
is logic to support the following clinical scenarios
[Diab and Watts, 2012; Watts and Diab, 2010].
1. Low risk of fracture: treatment is not
needed. If a bisphosphonate has been pre­
scribed, it should be discontinued and not
restarted unless/until the patient meets
treatment guidelines. Example: 54-year-
old woman, menopause at age 51, lowest
T-score –1.5, no risk factors, bisphospho­
nate therapy for 3 years. Treatment was not
indicated in the first place and can be
discontinued.
2. Mild risk of fracture: treat with bisphos­
phonate for 3–5 years, then stop. The ‘drug
holiday’ can be continued until there is
significant loss of BMD (i.e. more than the
least significant change as determined by
the testing center) or the patient has a
fracture, whichever comes first. Example:
68-year-old woman, menopause at age 50,
initial lowest T-score –2.3, parent with a
hip fracture, bisphosphonate treatment for
5 years, BMD stable over that time.
Treatment was indicated, but a drug holi­
day might be considered after 5 years of
treatment.
3. Moderate risk of fracture: treat with bis­
phosphonate for 5–10 years, offer a ‘drug
holiday’ of 3–5 years or until there is signifi­
cant loss of BMD or the patient has a
fracture, whichever comes first. Example:
72-year-old woman, menopause at age 48,
lowest initial T-score –2.8, no risk factors,
bisphosphonate therapy for 7 years, BMD
Therapeutic Advances in Musculoskeletal Disease 5 (3)
increased over that time so lowest T-score
now is –2.3. Treatment was indicated but
after 7 years of treatment, a drug holiday
might be considered.
4. High risk of fracture (fractures, corticos­
teroid therapy, very low BMD): treat with
bisphosphonate for 10 years, offer a ‘drug
holiday’ of 1–2 years, until there is signifi­
cant loss of BMD or the patient has a
fracture, whichever comes first. A nonbis­
phosphonate treatment (e.g. raloxifene or
teriparatide) may be offered during the
‘holiday’ from the bisphosphonate. Example:
75-year-old woman, menopause at age 45,
lowest initial T-score –3.6, rheumatoid
arthritis requiring ongoing corticosteroid
therapy for 12 years, two vertebral fractures
by vertebral fracture assessment (VFA),
treatment with bisphosphonate therapy for
10 years. Treatment was indicated and she
remains at high risk of fracture after 10
years. If a holiday from the bisphosphonate
is considered, interval treatment with teri­
paratide or raloxifene would be prudent.
If a drug holiday is advised, reassessment of risk
should occur sooner for drugs with lower skeletal
affinity, with a suggestion to reassess after 1 year
for risedronate, 1–2 years for alendronate, and
2–3 years for zoledronic acid [Compston and
Bilezikian, 2012]. Although it has been proposed
that a decrease in BMD or an increase in bone
turnover marker (BTM) might be used to decide
when to end a drug holiday, there is lack of data
on risk for fracture when these surrogate markers
begin to change off bisphosphonates. The risedro­
nate study showed that fracture risk remained
reduced despite what appeared to be unfavorable
changes in these parameters. Conversely, there is
no evidence that fracture risk is reduced if BMD
is stable or BTM is low off treatment. That being
said, in clinical practice, monitoring BMD and
BTM are the only means of gaining some sense
of the loss of the effect of the bisphosphonate
on bone remodeling, but ultimately the duration
of the holiday should be based on clinical
judgment.
Conclusion
In conclusion, bisphosphonates that have been
approved for the treatment of postmenopausal
osteoporosis are effective and generally safe agents
that have robust evidence for fracture risk
reduction. Their systemic safety is related to their
110 http://tab.sagepub.com
binding to bone and lack of uptake by other tis­
sues other than the kidney. A reservoir of bispho­
sphonates accumulates after years of treatment
that is gradually released over months or years
and appears to result in a lingering antifracture
benefit for some time after therapy is stopped.
This makes it possible to consider ‘drug holidays’,
time off bisphosphonate therapy (but possibly
on another agent), and then resuming therapy.
Although there is no strong evidence to guide us,
we believe that some time off treatment should be
offered to most patients on long-term bisphos­
phonate therapy. The duration of treatment and
the length of the ‘holiday’ should be tailored to
individual patient circumstances and based on
individual assessments of risk and benefit. In the
higher-risk population treated for the right dura­
tion, bisphosphonates have an exceptionally high
benefit/risk ratio. While lower-risk patients may be
offered a ‘drug holiday’ after 3–5 years of use,
higher-risk patients should be counseled on the
greater risk for fracture if discontinuation is initi­
ated. The strength of the evidence for fracture
reduction in high-risk individuals and the rarity of
long-term adverse effects indicate that the bene­
fits of continued treatment outweigh the risks in
individuals at high risk of fracture.
Funding
This research received no specific grant from any
funding agency in the public, commercial, or
not-for-profit sectors.
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