Download What is the evidence for use of weekly alendronic acid in men?

Medicines Q&As
Q&A 358.3
What is the evidence for use of weekly alendronic acid in
men?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at
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Date prepared: 29th July 2014
Background
Osteoporosis is a growing problem in men, though it does not have as clear a biological
aetiology as in the female disease. Factors in male osteoporosis may include corticosteroid
use, androgen deprivation therapy, and hypogonadism, and the incidence is thought to be
increasing due to the “greying” population. Up to 30% of all hip fractures may occur in men.
There is no specific guidance on the diagnosis of male osteoporosis, but the WHO suggest
that the bone mineral density cut-offs used in women are also suitable for use in men (1-4).
NICE recommends assessing fracture risk in all men aged over 75, and in men under 75 who
have risk factors such as: (5)
 previous fragility fractures
 history of oral or systemic glucocorticoid use
 history of falls
 family history of hip fracture
 other causes of secondary osteoporosis
 body mass index less than 18.5 kg/m 2
 smoking
 alcohol intake > 21 units per week
The bisphosphonates, including alendronic acid, are a group of drugs used to reduce bone
turnover in conditions including osteoporosis and Paget’s disease. In the UK, alendronic acid
is licensed for the prevention of osteoporotic fracture and bone loss in women at doses of
10mg daily or 70mg weekly (6, 7). However, only the daily formulation is licensed for use in
men, and it is not indicated for prophylaxis against male bone loss at any dose.
In contrast, weekly alendronate is already licensed for use in preventing osteoporotic
fractures in post-menopausal women, and is also licensed in the USA to increase bone mass
in men with osteoporosis (8). It has the advantage of being less expensive than the daily
regimen (£1.01 vs. £2.17 for 28 days treatment with a generic preparation), and may also
improve compliance (9). A large study examined the records of over 268,000 people from a
German medical insurance database, and found that 4% of patients receiving weekly
alendronate were still on treatment after 12 months compared to 17% of those taking daily
alendronate (10). Alendronic acid has very strict administration requirements, so the weekly
schedule also has the benefit of being more convenient for patients.
Answer
Alendronic acid, like all bisphosphonates, reduces bone turnover by inhibiting bone resorption
(4). Studies have shown that daily dosing is effective in men, although possibly not to the
same extent as in post-menopausal women (11). Several studies have investigated the
usefulness of weekly doses of 70mg alendronic acid for the prevention of bone loss and
osteoporotic fractures in men.
Several randomised controlled trials (RCTs) and 2 case-control studies have examined the
efficacy of weekly alendronic acid in men. In each case the primary endpoint was bone
mineral density (BMD) at various points of the skeleton, including lumbar spine, hip and
forearm. This has two drawbacks; firstly it assumes that BMD is a useful indicator of fracture
risk, and secondly BMD is not a patient-orientated outcome. In some cases fractures were
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collected as adverse events, but none of the trials were powered to detect a change in the
number of incident fractures. All studies provided some form of supplementation with calcium
and vitamin D. The evidence is all derived from studies of men with osteoporosis, or receiving
androgen deprivation therapy for prostate cancer.
Osteoporosis
Orwoll et al recruited men with primary osteoporosis or osteoporosis secondary to
hypogonadism for a randomised, double-blind, double-dummy, non-inferiority trial. (12)
Participants (n=302) were randomly assigned to receive alendronate 70mg weekly or
intravenous zoledronic acid 5mg once-yearly, and treatment was continued for two years.
Weekly alendronic acid was found to be non-inferior to zoledronic acid, with increased lumbar
spine BMD of 6.1% and 6.2% respectively in the two treatment groups. There was no
significant difference in the incidence of new vertebral fractures, change in height, or markers
of bone turnover between groups. In contrast a small study (n=92) by Ringe et al, published
in abstract only, found that annual zoledronic acid resulted in larger increases in BMD than
weekly alendronate.(13)
Miller et al conducted an RCT to examine the effect of alendronic acid 70mg once weekly in
167 men with osteoporosis diagnosed either by BMD at the lumbar spine and femoral neck,
or the presence of an osteoporotic fracture (14). The study showed that 12 months of
treatment significantly increased BMD at all of the sites measured, relative to both baseline
and placebo. The greatest effect was seen at the lumbar spine (4.28% increase) and the
least in the total body BMD (1.40% increase). Markers of bone turnover were also measured
and found to decrease.
Another RCT investigated the effect of changing the dose of alendronate from daily to weekly.
A group of osteoporotic men (n=22) with androgen-repleted hypogonadism were randomised
to receive either placebo or 10mg daily alendronate for 12 months. At the end of the blinded
phase all men received 70mg of alendronic acid weekly, open-label. Men in the alendronatealendronate group did not see any significant change in their lumbar spine BMD during the
open-label phase of the trial, although their femoral neck BMD continued to increase slowly.
Men in the placebo-alendronate group saw significant gains, and at 36 months the increase in
BMD at the lumbar spine reached 6.2% compared to the end of the placebo phase (p<0.05).
Femoral neck BMD increased by 1.9% (P<0.05) in the same period (15).
Hwang et al conducted a small (n=46) randomised, open-label study of weekly alendronate
therapy in Taiwanese men who had osteoporosis but were otherwise healthy.(16) The control
group received only calcium and vitamin D supplements. BMD at the lumbar spine and
femoral neck increased significantly in the alendronate group compared to baseline, and
compared to the control group (p<0.05).
Androgen deprivation therapy
Greenspan et al conducted a double-blind RCT in two phases, during which all subjects
(n=112) were receiving androgen deprivation therapy (ADT) as treatment for non-metastatic
prostate cancer. The first phase of the study had a similar design and results to those
described above, and also showed a comparable rate of adverse effects in both placebo and
treatment groups (17).
In the second phase of the study, men who had previously taken placebo were switched to
receive alendronic acid, and men in the treatment group were randomised to either continue
with the drug, or change to placebo. At the end of the second year it was found that men who
had received alendronic acid for the full two years had continued to see gains in their BMD,
and that men in the placebo-alendronate group had smaller gains in BMD than the
alendronate-placebo group. In other words, continuation of therapy for the full two years gave
more benefit than stopping after one year, and delaying treatment was detrimental to skeletal
health (18).
Klotz et al published a double-blind placebo-controlled RCT which randomised 186 men with
prostate cancer, all of whom required at least one year of androgen deprivation therapy (19).
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All patients received leuprolide acetate 30 mg every four months, plus either alendronate 70
mg or placebo once weekly for one year. All patients also took calcium 500 mg and vitamin D
400 IU daily. After one year, the primary outcome of spine BMD was significantly higher in the
alendronate group than with placebo (least squares mean difference 3.66, 95% CI 2.67 to
4.95, p<0.0001). Total hip BMD was a secondary outcome measure, and although
improvements were greater with alendronate the difference was lost when adjusting for
baseline BMD. Femoral BMD was increased in the alendronate group compared to placebo
(+ 0.85% vs. – 0.56%, p=0.032)
An accompanying editorial highlights that these results should be interpreted with caution,
since the effect in men with bone metastases may be different due to increase bone turnover.
Two case-control studies have also assessed weekly alendronate in men receiving ADT. The
first prospectively examined 31 men receiving ADT for prostate cancer, with 30 historical
controls. As in the other trials described treatment with weekly alendronic acid caused a
significant increase in BMD at all sites measured. In this case an attempt was also made to
estimate risk of hip fracture as a result of this change, which found that alendronic acid
increased femoral neck BMD by 0.75g/cm 2 (p=0.03). This translated to a 0.54% decrease in
risk of hip fracture (p=0.04) (20).
The final study examined the efficacy of weekly alendronate in preventing bone loss in men
(n=47) treated with ADT for prostate cancer. Men receiving alendronic acid experienced an
increase in their BMD at the lumbar spine and hip, whereas men receiving ADT alone lost
bone. All subjects lost bone at the forearm, and although men treated with alendronic acid
had smaller decreases in BMD the difference was not statistically significant (21).
Summary



Osteoporosis and fracture are a growing problem in the male population. Weekly doses
of alendronic acid are not licensed in this group for either treatment or prophylaxis of
bone loss.
Several randomised controlled trials have indicated that alendronic acid is effective in
increasing bone mineral density in men when administered in weekly doses of 70mg, and
can help prevent bone loss associated with androgen deprivation therapy.
Due to the very strict and inconvenient administration requirements for alendronic acid,
reducing administration frequency may improve compliance.
Limitations
 All of the studies discussed are small in size, and the majority of participants were
Caucasian men.
 All of the RCTs received funding or other support from Merck, who manufacture and hold
licenses for branded forms of alendronic acid. Merck do not recommend the use of 70mg
alendronate in men, as this is outside the terms of the marketing authorisation (22).
 All of the studies assume that BMD is a suitable surrogate endpoint for predicting fracture
risk, and although this is recommended by the WHO those guidelines are now aging.(4)
More complex tools have been developed in recent years to take into account the
multifactorial nature of osteoporosis (23).
 The adverse effects of alendronate and necessary precautions against them are well
known, and not dealt with here.
Quality Assurance
Prepared by
Nancy Kane, Regional Drug & Therapeutics Centre
Date Prepared
July 2014
Checked by
Hayley Johnson, Regional Drug & Therapeutics Centre
Available through NICE Evidence Search at www.evidence.nhs.uk
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Date of check
29th July 2014
Search strategy
EMBASE: ALENDRONIC ACID/ AND (70mg OR (70 AND mg) OR weekly) [Limit to: Male]
References
1. Ringe JD. Hip Fractures in Men. Osteoporosis International. 1996;Suppl. 3:S48-S51.
2. Gullberg B, Johnell O, Kanis JA. World-wide Projections for Hip Fracture. Osteoporosis
International. 1997;7(5):407-13.
3. WHO. Assessment of Fracture Risk and its Application to Screening for Postmenopausal
Osteoporosis: WHO; 1994.
4. WHO. Prevention and Management of Osteoporosis. Geneva: World Health Organization;
2000.
5. NICE. CG146: Osteoporosis: assessing the risk of fragility fracture August 2012. .
6. Merck Sharp & Dohme Limited. Summary of Product Characteristics Fosamax 10mg. Last
updated 26/12/11. 2010.
7. Merck Sharp & Dohme Limited. Summary of Product Characteristics Fosamax Once
Weekly 70mg Tablets. Last updated 22/02/2012. 2010.
8. Merck Sharp & Dohme Limited. FOSAMAX® (ALENDRONATE SODIUM) TABLETS AND
ORAL SOLUTION. 2010.
9. NHS Business Services Authority. Electronic Drug Tariff, August 2014
http://www.ppa.org.uk/edt/August_2014/mindex.htm.
10. Ziller V, Kostev K, Kyvernitakis I, et al. Persistence and compliance of medications used
in the treatment of osteoporosis--analysis using a large scale, representative, longitudinal
German database. International journal of clinical pharmacology and therapeutics. 2012
May;50(5):315-22.
11. Iwamoto J, Takeda T, Sato Y, et al. Comparison of the effect of alendronate on lumbar
bone mineral density and bone turnover in men and postmenopausal women with
osteoporosis. Clinical Rheumatology. 2007;26:161-7.
12. Orwoll ES, Miller PD, Adachi JD, et al. Efficacy and safety of a once-yearly i.v. Infusion of
zoledronic acid 5 mg versus a once-weekly 70-mg oral alendronate in the treatment of male
osteoporosis: a randomized, multicenter, double-blind, active-controlled study. J Bone Miner
Res. 2010 Oct;25(10):2239-50.
13. Ringe JD, Dorst A, Farahmand P. Comparing once yearly zoledronic acid with once
weekly generic alendronate in the treatment of established male osteoporosis Osteoporosis
International 21:S357.
14. Miller PD, Schnitzer T, Emkey R, et al. Weekly Oral Alendronic Acid in Male
Osteoporosis. Clinical Drug Investigaion. 2004;24(6):333-41.
15. Shimon I, Eshed V, Doolman R, et al. Alendronate for osteoporosis in men with
androgen-repleted hypogonadism. Osteoporosis International. 2005;16:1591-6.
16. Hwang JS, Liou MJ, Ho C, et al. The effects of weekly alendronate therapy in Taiwanese
males with osteoporosis. Journal of bone and mineral metabolism. 2010 May;28(3):328-33.
17. Greenspan SL, Nelson JB, Trump DL, et al. Effect of Once-Weekly Alendronate on Bone
Loss in Men Receiving Androgen Deprivation Therapy for Prostate Cancer. Annals of Internal
Medicine. 2007;146:416-24.
18. Greenspan SL, Nelson JB, Trump DL, et al. Skeletal Health After Continuation,
Withdrawal, or Delay of Alendronate in Men With Prostate Cancer Undergoing AndrogenDeprivation Therapy. Journal of Clinical Oncology. 2008;26(27):4426-34.
19. Klotz LH, McNeill IY, Kebabdjian M, et al. A phase 3, double-blind, randomised, parallelgroup, placebo-controlled study of oral weekly alendronate for the prevention of androgen
deprivation bone loss in nonmetastatic prostate cancer: the Cancer and Osteoporosis
Research with Alendronate and Leuprolide (CORAL) study. European urology. 2013
May;63(5):927-35.
20. Planas J, Trilla E, Raventós C, et al. Alendronate decreases the fracture risk in patients
with prostate cancer on androgen-deprivation therapy and with severe osteopenia or
osteoporosis. BJU International. 2009;104(1637-1640).
Available through NICE Evidence Search at www.evidence.nhs.uk
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21. Bruder JM, Ma JZ, Wing N, et al. Effects of Alendronate on Bone Mineral Density in Men
with Prostate Cancer Treated with Androgen Deprivation Therapy. Journal of Clinical
Densitometry. 2006;9(4):431-7.
22. Mapp E. RE: Fosamax® Once Weekly 70mg tablets (alendronate sodium). In: Kane N,
ed. Personal communication ed 2010:1.
23. Kanis JA, Johnell O, Oden A, et al. FRAX and the assessment of fracture probability in
men and women from the UK. Osteoporosis International. 2008;19:385-97.
Available through NICE Evidence Search at www.evidence.nhs.uk
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