NAMS Practice Pearl

Drug Holidays in Women Treated for Postmenopausal Osteoporosis

Released April 19, 2018

Michael R McClung, MD
(Oregon Osteoporosis Center, Portland, OR; Institute of Health and Ageing,
Australian Catholic University, Melbourne, VIC, Australia)

In this Practice Pearl, the experience with long-term treatment of osteoporosis with
bisphosphonates and denosumab will be reviewed as well as the effects of discontinuing
therapy, providing the platform for recommendations about “drug holidays” for these
medications.

Postmenopausal osteoporosis is a chronic condition requiring long-term management.

Bisphosphonates and denosumab, an inhibitor of the receptor activator of nuclear factor kappa β
(RANK) ligand, are the drugs considered for long-term therapy, but uncertainty exists about the
appropriate duration of these therapies.1,2

Efficacy of long-term therapy. Bisphosphonates increase bone mineral density (BMD) in the
proximal femur by 5% to 6% during the first 3 to 5 years of treatment. Values then plateau with
continued therapy out to 9 to 10 years. In contrast, total hip BMD increases progressively over
10 years of treatment with denosumab, with the average gain from baseline of 9.2%.3 In placebo-
controlled studies lasting 3 to 5 years in women with postmenopausal osteoporosis,
bisphosphonates and denosumab reduced the incidence of new vertebral and hip fractures by
30% to 70% and 20% to 50%, respectively.1 With both bisphosphonates and denosumab, the full
effect of vertebral fracture risk reduction is observed within the first year of therapy and persists
with ongoing treatment lasting 7 to 10 years. In the Fracture Reduction Evaluation of
Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial extension with denosumab, the
risk of nonvertebral fracture progressively decreased with long-term treatment.3 There has been
no evidence of resistance to either bisphosphonate or denosumab therapy.

Safety of long-term therapy. Long-term bisphosphonate therapy is associated with a risk of

subtrochanteric and shaft fractures of the femur having atypical radiographic features, increasing
to about 1 in 1,000 patients after 8 to 10 years of therapy.1 In a Swedish nationwide cohort study,
weak evidence is presented that, after drug withdrawal, the risk of atypical femoral fracture
decreased by 70% for each year off therapy.

In the FREEDOM Extension study, no progression in the incidence of adverse events was
observed with continued therapy out to 10 years or in the group that switched from placebo to
denosumab.2 Lesions consistent with osteonecrosis of the jaw were found in 13 patients (5.2 per
10,000 participant-years). In the 12 cases with follow-up, resolution of the oral lesions occurred
with conservative therapy, including in patients who continued denosumab therapy. Two femoral

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shaft fractures met criteria for having atypical radiographic features. Too few cases of either
adverse event occurred to determine whether there was a relationship with duration of
denosumab therapy.

Effects of discontinuing therapy. Because of the binding of bisphosphonates to bone mineral,

BMD decreases slowly, and biochemical markers of bone turnover gradually increase toward
baseline values when treatment is stopped. Protection from vertebral and probably nonvertebral
fracture is gradually but not completely lost over 3 to 5 years.1 In 3- and 5-year extensions of the
placebo-controlled studies with zoledronic acid and alendronate, risk of radiologic or clinical
vertebral fracture risk was 50% higher in patients who discontinued versus those who remained
on therapy. In a post hoc analysis of patients with femoral neck BMD T-score values of −2.5 or
lower, nonvertebral fracture risk was 50% lower in the group of patients that continued
alendronate therapy for 5 years compared to those who had stopped therapy.

In contrast, skeletal effects of denosumab abate quickly when treatment is stopped,4 even after
treatment for as long as 8 years. Bone mineral density falls quickly because of a transient
rebound in bone remodeling markers that return to baseline levels after 2 years. Case reports of
multiple or severe vertebral fractures occurring within 2 to 10 months of discontinuing
denosumab have been reported.5

An analysis of patients in FREEDOM and its extension compared the incidence of radiographic
vertebral fracture in patients who discontinued denosumab therapy to that in patients who had
discontinued placebo therapy.6 On stopping denosumab, the incidence of vertebral fracture
increased but to a level similar to that in patients who had discontinued placebo therapy.
Although a somewhat larger proportion of the patients experiencing fracture after stopping
denosumab had multiple fractures, the overall risk of vertebral fracture was not higher after
stopping denosumab than would have been seen if they had not been treated. These results
suggest that the risk of vertebral fracture returns to pretreatment levels within months of stopping
denosumab therapy. These changes in BMD, bone turnover, and the rapid loss of vertebral
fracture protection on stopping denosumab are very similar to what is observed when estrogen
therapy is discontinued.7

Drug “holiday.” As suggested by FDA in a 2012 editorial, “Patients at low risk for fracture may
prove to be good candidates for discontinuation of bisphosphonate therapy after 3 to 5 years.”8
This so-called “bisphosphonate holiday” is an opportunity to temporarily interrupt therapy that
can be considered (but is not mandated) in patients who are not at high risk after several years of
bisphosphonate therapy. Holidays in selected patients are justified by the gradual offset of
protection from fragility fracture, coupled with the possibility of a reduction in the risk of
fractures with atypical features on stopping treatment.

An American Society for Bone and Mineral Research Task Force provided clear guidance about
managing long-term bisphosphonate therapy.9 Continuing fracture-preventing treatment is
recommended after 3 to 5 years of bisphosphonate therapy in patients remaining at high fracture
risk, defined as those with a history of hip or spine fracture or of multiple other fragility fractures
before or during bisphosphonate therapy and with hip BMD values remaining in osteoporosis
range (T-score <−2.5) or who are at high risk of fracture because of other risk factors such as
advanced age or glucocorticoid therapy. This recommendation essentially suggests continuing
treatment in patients who still meet criteria for being on an osteoporosis drug. After 3 to 5 years
of therapy, continuing a bisphosphonate would not be expected to promote further increase in
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BMD, whereas switching to denosumab provides additional BMD gain and may possibly further
reduce fracture risk.10

It is clear that the concept of a drug holiday does not pertain to patients on denosumab or other
nonbisphosphonate osteoporosis drugs.7 There is no time limit on the duration of denosumab
therapy. If treatment is discontinued for any reason, switching to another antiremodeling agent
(eg, a bisphosphonate) should be considered. As observed when postmenopausal women on
estrogen were switched to alendronate, following denosumab therapy with alendronate prevents
the rapid bone loss that would otherwise occur.11

Summary
 Long-term therapy of postmenopausal osteoporosis is needed to provide persistent reduction
in fracture risk.
 The gradual attenuation of protection from fragility fracture coupled with the possibility of a
decrease in risk of fractures with atypical features on stopping bisphosphonate therapy
provides the possibility of temporary discontinuation of that therapy after 3 to 5 years in
patients who are no longer at high fracture risk.
 For patients remaining at high fracture risk after 3 to 5 years of bisphosphonate therapy,
switching to denosumab is an appealing option albeit with no evidence regarding the effect
of the switch on fracture risk.
 There is no time limit to the duration of denosumab therapy and no justification for
interruption of that therapy.
 If denosumab therapy is stopped, treatment with another antiresorptive agent should be
considered to prevent rapid loss of fracture protection.

References
1. McClung M, Harris ST, Miller PD, et al. Bisphosphonate therapy for osteoporosis: benefits,
risks, and drug holiday. Am J Med 2013;126:13-20.
2. Hanley DA, McClung MR, Davison KS, et al; Writing Group for the Western Osteoporosis
Alliance. Western Osteoporosis Alliance Clinical Practice Series: evaluating the balance of
benefits and risks of long-term osteoporosis therapies. Am J Med 2017;130:862.e1-862.e7.
3. Bone HG, Wagman RB, Brandi ML, et al. 10 years of denosumab treatment in
postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM
trial and open-label extension. Lancet Diabetes Endocrinol 2017;5:513-523.
4. Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab treatment and
discontinuation on bone mineral density and bone turnover markers in postmenopausal
women with low bone mass. J Clin Endocrinol Metab 2011;96:972-980.
5. Anastasilakis AD, Polyzos SA, Makras P, Aubrey-Rozier B, Kaouri S, Lamy O. Clinical
features of 24 patients with rebound-associated vertebral fractures after denosumab
discontinuation: systematic review and additional cases. J Bone Miner Res 2017;32:1291-
1296.
6. Brown JP, Ferrari S, Gilchrist N, et al. Discontinuation of denosumab and associated
fracture incidence: analysis from FREEDOM and its Extension [abstract]. J Bone Miner Res
2016:31:www.asbmr.org/education/AbstractDetail?aid=03c2777e-2cd5-4b06-8ffe-
0bef664a71ee. Accessed January 19, 2018. Abstract 1100.
7. McClung MR. Cancel the denosumab holiday. Osteoporos Int 2016;27:1677-1682.
8. Whitaker M, Guo J, Kehoe T, Benson G. Bisphosphonates for osteoporosis—where do we
go from here? N Engl J Med 2012;366:2048-2051.

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 9. Adler RA, El-Hajj Fuleihan G, Bauer DC, et al. Managing osteoporosis in patients on long-
term bisphosphonate treatment: report of a Task Force of the American Society for Bone
and Mineral Research. J Bone Miner Res 2016;31:16-35.
10. Miller PD, Pannacciulli N, Brown JP, et al. Denosumab or zoledronic acid in
postmenopausal women with osteoporosis previously treated with oral bisphosphonates.
J Clin Endocrinol Metab 2016;101:3163-3170.
11. Freemantle N, Satram-Hoang S, Tang ET, et al; DAPS Investigators. Final results of the
DAPS (Denosumab Adherence Preference Satisfaction) study: a 24-month, randomized,
crossover comparison with alendronate in postmenopausal women. Osteoporos Int
2012;23:317-326.

Disclosure
Dr. McClung reports speaker and consultant fees from Amgen and Radius Health.

This Practice Pearl, developed by the author, provides practical information on

current controversial topics of clinical interest. It is not an official position of The
North American Menopause Society (NAMS). Clinicians must always take into
consideration the individual patient along with any new data published since the
publication of this statement. The Practice Pearl series is coordinated by the
NAMS Practice Pearl Task Force, edited by Dr. Andrew Kaunitz, and approved by
the NAMS Board of Trustees.

Made possible by donations to the NAMS Education & Research Fund.

©2018 The North American Menopause Society

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