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NIHR Signal Bisphosphonates help prevent fractures in men with low bone density

Published on 16 September 2015

doi: 10.3310/signal-000124

This systematic review found that bisphosphonate drugs, taken for at least six months, improved bone density and lowered fracture risk in men with low bone density, compared with a placebo or supplements (calcium alone or with vitamin D). Bisphosphonates have been extensively researched for treating women with low bone density after the menopause, but this was the first review to look at their use in men. Significantly, the review looked not only at bone density measurements, but also at fracture rates - an important outcome for older at-risk men. Cost-effectiveness was not considered, but hip fractures alone cost the NHS about £2 billion a year, so prevention is likely to lead to cost savings.

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Why was this study needed?

Osteoporosis is a common condition that affects around 3 million people in the UK, The bones of those affected gradually lose density and become more fragile and brittle, raising the risk of fractures. A frequent cause of osteoporosis is age-related hormonal changes, such as after the menopause, and so research on bisphosphonate drugs – drugs that slow down or prevent bone damage  - for osteoporosis has tended to focus on older women.

However, about a quarter of hip fractures occur in men, and mortality after hip fracture is higher in men than women; about 20% after one year. Just a few trials have measured how well bisphosphonate drugs improve bone density in men, but very little research has recorded fractures rates.

This was the first systematic review to look at bisphosphonate drugs to treat osteoporosis and prevent fractures in men.

What did this study do?

This was a systematic review of nine randomised controlled trials including 2,464 men with low bone density. The trials looked at 6 to 36 month long treatments using one of the four bisphosphonate drugs available – alendronate, risedronate, zoledronate or ibandronate. The control treatment was either a placebo (two trials) or Vitamin D alone or alongside calcium supplements (seven trials). Zolendronate was given by annual injection, the other drugs were taken as tablets.

Of the nine trials seven were rated as high quality and two as moderate quality. The studies used different definitions of low bone density, and different approaches to adding calcium and vitamin D supplements, but nonetheless, the results appear reliable.

What did it find?

Compared with taking placebo or supplements (calcium alone or with vitamin D):

  • bisphosphonate treatment reduced the risk of spinal fracture by nearly two thirds (six trials; relative risk (RR) 0.36, 95% confidence interval (CI) 0.24 to 0.56), and non-spinal fracture by a half (five trials, RR 0.52, 95% CI 0.32 to 0.84). The time period this was measured over, or baseline risk of fracture, was not reported.
  • bisphosphonate treatment increased bone mineral density in all three parts of the skeleton assessed, the lower spine, the hip and top of the thigh bone, and at all times points: 6, 12 and 24 months (seven trials).
  • the rate of new bone formation increased in men taking bisphosphonates.

What does current guidance say on this issue?

UK national guidance from the National Osteoporosis Guideline Group (updated 2014) recommends weight-bearing exercise, stopping smoking, alcohol moderation and a diet containing sufficient calcium and vitamin D for all people with osteoporosis, including men. As well as lifestyle changes, taking a bisphosphonate drug is recommended as the first choice of medical treatments for those at high risk of fracture.

NICE guidance from 2008 on the effectiveness of drugs to prevent and treat osteoporosis focuses on post-menopausal women. The scope of future NICE guidance will include treating men, and updated NICE recommendations on using bisphosphonates to prevent osteoporosis are due to be published in November 2015.

What are the implications?

This systematic review consolidates existing evidence from nine trials showing that the same drugs used to treat low bone density and prevent fractures in women also work in men. The findings are in line with 2014 UK National Osteoporosis Guideline Group guidance.

Osteoporosis is an important health issue in older men, but many don’t get treatment. There is a lack of UK-based guidance on the effectiveness of bisphosphonate drugs for treating men with osteoporosis, so new guidance from NICE, due in November 2015, will be of particular interest to those affected, as well as practitioners and commissioners.

Citation

Chen L, Wang G, Zheng F, et al. Efficacy of bisphosphonates against osteoporosis in adult men: a meta-analysis of randomized controlled trials. Osteoporos Int. 26(9):2355-63.

Bibliography

Compston J, Cooper A, Cooper C, et al. Guidelines for the diagnosis and management of osteoporosis in postmenopausal women and men from the age of 50 years in the UK. Sheffield: National Osteoporosis Guideline Group; updated 2014.

Cosman F, De Beur S, LeBoff M, et al. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014;25(10):2359-81.

International Osteoporosis Foundation. Facts and statistics: osteoporosis in men [internet]. Nyon, Switzerland: International Osteoporosis Foundation; undated.

National Osteoporosis Society. Osteoporosis in men. Bath: National Osteoporosis Society; 2015.

NHS Choices. Hip fracture [internet] Leeds: NHS Choices; 2014.

NHS Choices. Osteoporosis [internet] Leeds: NHS Choices; 2014.

NICE. Osteoporosis: assessing the risk of fragility fracture. CG146  London: National Institute for Health and Care Excellence; 2012.

NICE. Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women (amended). TA160. London: National Institute for Health and Care Excellence; 2008.

Why was this study needed?

Osteoporosis is a common condition that affects around 3 million people in the UK, The bones of those affected gradually lose density and become more fragile and brittle, raising the risk of fractures. A frequent cause of osteoporosis is age-related hormonal changes, such as after the menopause, and so research on bisphosphonate drugs – drugs that slow down or prevent bone damage  - for osteoporosis has tended to focus on older women.

However, about a quarter of hip fractures occur in men, and mortality after hip fracture is higher in men than women; about 20% after one year. Just a few trials have measured how well bisphosphonate drugs improve bone density in men, but very little research has recorded fractures rates.

This was the first systematic review to look at bisphosphonate drugs to treat osteoporosis and prevent fractures in men.

What did this study do?

This was a systematic review of nine randomised controlled trials including 2,464 men with low bone density. The trials looked at 6 to 36 month long treatments using one of the four bisphosphonate drugs available – alendronate, risedronate, zoledronate or ibandronate. The control treatment was either a placebo (two trials) or Vitamin D alone or alongside calcium supplements (seven trials). Zolendronate was given by annual injection, the other drugs were taken as tablets.

Of the nine trials seven were rated as high quality and two as moderate quality. The studies used different definitions of low bone density, and different approaches to adding calcium and vitamin D supplements, but nonetheless, the results appear reliable.

What did it find?

Compared with taking placebo or supplements (calcium alone or with vitamin D):

  • bisphosphonate treatment reduced the risk of spinal fracture by nearly two thirds (six trials; relative risk (RR) 0.36, 95% confidence interval (CI) 0.24 to 0.56), and non-spinal fracture by a half (five trials, RR 0.52, 95% CI 0.32 to 0.84). The time period this was measured over, or baseline risk of fracture, was not reported.
  • bisphosphonate treatment increased bone mineral density in all three parts of the skeleton assessed, the lower spine, the hip and top of the thigh bone, and at all times points: 6, 12 and 24 months (seven trials).
  • the rate of new bone formation increased in men taking bisphosphonates.

What does current guidance say on this issue?

UK national guidance from the National Osteoporosis Guideline Group (updated 2014) recommends weight-bearing exercise, stopping smoking, alcohol moderation and a diet containing sufficient calcium and vitamin D for all people with osteoporosis, including men. As well as lifestyle changes, taking a bisphosphonate drug is recommended as the first choice of medical treatments for those at high risk of fracture.

NICE guidance from 2008 on the effectiveness of drugs to prevent and treat osteoporosis focuses on post-menopausal women. The scope of future NICE guidance will include treating men, and updated NICE recommendations on using bisphosphonates to prevent osteoporosis are due to be published in November 2015.

What are the implications?

This systematic review consolidates existing evidence from nine trials showing that the same drugs used to treat low bone density and prevent fractures in women also work in men. The findings are in line with 2014 UK National Osteoporosis Guideline Group guidance.

Osteoporosis is an important health issue in older men, but many don’t get treatment. There is a lack of UK-based guidance on the effectiveness of bisphosphonate drugs for treating men with osteoporosis, so new guidance from NICE, due in November 2015, will be of particular interest to those affected, as well as practitioners and commissioners.

Citation

Chen L, Wang G, Zheng F, et al. Efficacy of bisphosphonates against osteoporosis in adult men: a meta-analysis of randomized controlled trials. Osteoporos Int. 26(9):2355-63.

Bibliography

Compston J, Cooper A, Cooper C, et al. Guidelines for the diagnosis and management of osteoporosis in postmenopausal women and men from the age of 50 years in the UK. Sheffield: National Osteoporosis Guideline Group; updated 2014.

Cosman F, De Beur S, LeBoff M, et al. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014;25(10):2359-81.

International Osteoporosis Foundation. Facts and statistics: osteoporosis in men [internet]. Nyon, Switzerland: International Osteoporosis Foundation; undated.

National Osteoporosis Society. Osteoporosis in men. Bath: National Osteoporosis Society; 2015.

NHS Choices. Hip fracture [internet] Leeds: NHS Choices; 2014.

NHS Choices. Osteoporosis [internet] Leeds: NHS Choices; 2014.

NICE. Osteoporosis: assessing the risk of fragility fracture. CG146  London: National Institute for Health and Care Excellence; 2012.

NICE. Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women (amended). TA160. London: National Institute for Health and Care Excellence; 2008.

Efficacy of bisphosphonates against osteoporosis in adult men: a meta-analysis of randomized controlled trials

Published on 7 May 2015

Chen, L.,Wang, G.,Zheng, F.,Zhao, H.,Li, H.

Osteoporos Int , 2015

This meta-analysis of published randomized controlled trials (RCTs) aimed to analyze the efficacy of administration of bisphosphonates in men with osteoporosis. Compared with placebo, bisphosphonates could reduce the risk of vertebral and non-vertebral fractures, reduce bone-specific alkaline phosphatase (BSAP) and C-terminal telopeptide of type I collagen (CTX), and increase bone mineral density (BMD). INTRODUCTION: Bisphosphonates are well-investigated antiresorptive medications, approved as first-line drugs for osteoporosis in postmenopausal women. However, there is a paucity of high-quality evidence regarding the efficacy of bisphosphonates administered for osteoporosis in adult men. The aim of this meta-analysis was to analyse the efficacy of administration of bisphosphonates in men based on published RCTs. METHODS: PubMed, Embase, MEDLINE, and the Cochrane library were searched, and mean differences were calculated to evaluate the efficacy of bisphosphonates on reducing the risk of vertebral and non-vertebral fracture, reducing bone-turnover biomarkers, and increasing BMD. RESULTS: Nine RCTs were included and the total number of participants was 2464. Compared with placebo, the efficacy of bisphosphonates on vertebral and non-vertebral fracture risk reduction was confirmed [for vertebral fracture, RR (95 % CI) 0.36 (0.24, 0.56), P < 0.01; for non-vertebral fracture, RR (95 % CI) 0.52 (0.32, 0.84), P < 0.01)] and heterogeneity was insignificant. The efficacy of bisphosphonates on reducing BSAP [MD (95 % CI) -24.41 (-26.19, -22.62), P < 0.01) and CTX [MD (95 % CI) -34.51 (-41.03, -27.98), P < 0.01)] was significant. A sensitivity analysis was applied to explain the origination of heterogeneity in analysis of decreasing of BSAP. BMD was increased in the bisphosphonates group compared with the control group at lumbar spine, femoral neck, and total hip (P < 0.01), and the heterogeneity of all comparisons was significant. CONCLUSION: Compared with placebo, bisphosphonates could decrease the risk of vertebral and non-vertebral fractures, reduce BSAP and CTX, and increase BMD in men with osteoporosis.

Bone mineral density is measured using a special type of X-ray scan called a dual energy absorptiometry (DEXA) scan. The density reading is combined with risk factors such as age, gender and other aspects, such as existing treatment with corticosteroid drugs, to give an overall risk factor for fractures.

Expert commentary

Osteoporotic fractures are an important, but neglected, public health problem in older men. Several bisphosphonates are approved for treatment in men at high risk but treatment rates are low. Previous studies in men have mainly focused on bone mineral density changes. This meta-analysis of randomized controlled trials provides evidence that in addition to their beneficial effects on bone mineral density, bisphosphonates reduce vertebral and non-vertebral fractures in men. These results add significantly to previous knowledge and strengthen further the rationale for the use of bisphosphonate therapy in older men at high risk of fracture.

Professor Juliet E Compston, Professor of Bone Medicine, University of Cambridge