Medicines Q&As
Q&A 358.2
What is the evidence for use of weekly alendronic acid in
men?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Date prepared: July 2012
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,
and although there is no specific guidance on the diagnosis of male osteoporosis, WHO
suggest that the female criteria are suitable for use in men (1-4).
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 (5, 6). However, only the daily formulation is licensed for use in
men, and the drug is not indicated for prophylaxis against male bone loss at any dose. NICE
and WHO guidance for the use of alendronic acid covers only the female population (4, 7, 8).
The weekly treatment is already licensed for use in preventing osteoporotic fractures in postmenopausal women, and is also licensed in the USA to increase bone mass in men with
osteoporosis (9). It has the advantages of being slightly less expensive than the daily
regimen (£0.98 vs. £1.39 for four weeks treatment with a generic preparation), and also
potentially improving compliance by decreasing oesophageal side effects (10, 11).
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 it is effective in men, although possibly not to the same extent
as in post-menopausal women (12). Several studies have investigated the usefulness of
weekly doses of 70mg alendronic acid for the prevention of bone loss and osteoporotic
fractures in men.
Five 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
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.
Randomised Controlled Trials
Orwoll et al recruited men with primary osteoporosis or osteoporosis secondary to
hypogonadism for a randomised, double-blind, double-dummy, noninferiority trial. (13)
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
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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.(14)
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 (15). 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.
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 (16).
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 (17).
The final 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
alendronate-alendronate 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 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 (18).
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.(19) 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).
Case Control Studies
The first case study 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 lost bone. All
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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
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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 studies 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 intervals to weekly 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.
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.
Disclaimer
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 Each Q&A relates only to the clinical scenario described.
 Q&As are believed to accurately reflect the medical literature at the time of writing.
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used for commercial or marketing purposes.
 See NeLM for full disclaimer.
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) Merck Sharp & Dohme Limited. Summary of Product Characteristics Fosamax 10mg.
Last updated 26/12/11. 2010.
(6) Merck Sharp & Dohme Limited. Summary of Product Characteristics Fosamax Once
Weekly 70mg Tablets. Last updated 22/02/2012. 2010.
(7) NICE. TA160: Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for
the primary prevention of osteoporotic fragility fractures in postmenopausal women (updated
Jan 2011); 2008.
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Medicines Q&As
(8) NICE. TA161: Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and
teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal
women (updated Jan 2011); 2008.
(9) Merck Sharp & Dohme Limited. FOSAMAX® (ALENDRONATE SODIUM) TABLETS AND
ORAL SOLUTION. 2010.
(10) NHS Business Services Authority. Drug Tariff, July 2012
http://www.ppa.org.uk/ppa/edt_intro.htm
(11) ADIS. Alendronic Acid. R&D Insight.
(12) Iwamoto J, Takeda T, Sato Y, Uzawa M. 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.
(13) 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.
(14) 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.
(15) Miller PD, Schnitzer T, Emkey R, et al. Weekly Oral Alendronic Acid in Male
Osteoporosis. Clinical Drug Investigaion. 2004;24(6):333-41.
(16) Greenspan SL, Nelson JB, Trump DL, Resnick NM. 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.
(17) 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.
(18) Shimon I, Eshed V, Doolman R, Sela B-A, Karasik A, Vered I. Alendronate for
osteoporosis in men with androgen-repleted hypogonadism. Osteoporosis International.
2005;16:1591-6.
(19) 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.
(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).
(21) Bruder JM, Ma JZ, Wing N, Basler J, Katselnik D. 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, Johansson H, McCloskey E. FRAX and the assessment of
fracture probability in men and women from the UK. Osteoporosis International. 2008;19:38597.
Quality Assurance
Prepared by
Nancy Kane, Regional Drug and Therapeutics Centre, Newcastle upon Tyne
Date Prepared
July 2010, updated July 2012
Checked by
Hayley Johnson, Regional Drug and Therapeutics Centre
Date of check
23rd July 2012
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Medicines Q&As
Search strategy
Embase
ALENDRONIC ACID/ AND 70mg.af OR weekly.af [Limit to: Male]
Medline
ALENDRONATE/ AND 70mg.af OR weekly.af [Limit to: Male]
eMC
ADIS R&D Insight
Internet Search (alendronic acid 70mg)
www.nice.org.uk
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