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
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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/m2
- 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 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 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 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). 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/cm2 (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
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
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 Androgen-Deprivation 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, parallel-group, 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).
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.
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Available throughNICE Evidence Search at