There are many treatment options for osteoporosis, here we outline the evidence for the commonly prescribed treatments in primary care.
For the primary prevention of fracture in the general population, RCTs and meta-analyses of supplementation with calcium or vitamin D do not show significant benefit, except in vitamin D-depleted patients in residential care.
| Treatment and setting | Meta-analysis finding |
| Vitamin D alone, community dwelling pateints | No benefit (n/s ARR 0.5%) |
| Calcium supplements alone, community-dwelling patients | No benefit (n/s ARR 2.5%) |
| Calcium and vitamin D, community-dwelling patients | No benefit (n/s ARR 1% ) |
| Calcium and vitamin D, residential care setting, low vitamin D levels | see graphics below |
n/s, not statistically significant; ARR, Absolute Risk Reduction.
Figures for vitamin D and calcium+vitamin D combined were derived from a 2019 systematic review1:
Figures for calcium alone were derived from a 2017 systematic review2:
References
1)Yao P, Bennett D, Mafham M et al. Vitamin D and Calcium for the Prevention of Fracture: A Systematic Review and Meta-analysis. JAMA Netw Open 2019; 2(12): e1917789
2)Zhao J, Zeng X, Wang J, Liu L. Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis. JAMA 2017; 318(24): 2466-2482
| This research provides some indication of the treatment effect.
There is a high possibility that the true effect is smaller or greater. |
The systematic review authors rated the evidence for vitamin D and calcium+vitamin D as LOW quality1
However,
The systematic review authors rated the evidence for calcium supplements alone as MODERATE quality2
However,
References
1)Yao P, Bennett D, Mafham M et al. Vitamin D and Calcium for the Prevention of Fracture: A Systematic Review and Meta-analysis. JAMA Netw Open 2019; 2(12): e1917789
2)Zhao J, Zeng X, Wang J, Liu L. Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis. JAMA 2017; 318(24): 2466-2482
The participant characteristics in the two trials1,2 involving people in residential care settings testing calcium+vitamin D were:
The participant characteristics in the systematic reviews3,4 were varied:
References
1)Chapuy MC, Arlot ME, Duboeuf F et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 1992; 327(23): 1637-1642
2)Chapuy MC, Pamphile R, Paris E et al. Combined calcium and vitamin D3 supplementation in elderly women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II study. Osteoporos Int 2002; 13(3): 257-64
3)Yao P, Bennett D, Mafham M et al. Vitamin D and Calcium for the Prevention of Fracture: A Systematic Review and Meta-analysis. JAMA Netw Open 2019; 2(12): e1917789
4)Zhao J, Zeng X, Wang J, Liu L. Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis. JAMA 2017; 318(24): 2466-2482
If dietary calcium intake is adequate and a patient has adequate vitamin D levels, then supplements are not compulsory alongside bisphosphonates.
However, deficiency of these may impair the effect of bisphosphonates. The National Osteoporosis Guideline Group (NOGG), says1:
An adequate intake of dietary calcium is defined as 700mg per day.
An adequate vitamin D level for adults is >50nmol/L.
References
1)National Osteoporosis Guideline Group. NOGG 2021. Accessed online Jan 2023
2)Burchell K, Webb A, Rhodes L. Sunlight exposure and vitamin D: Getting the balance right: sunlight exposure advice that ensures adequate vitamin D while minimising the risk of sunburn and cancer. Sunlight and vitamin D policy briefing. University of Manchester, 2019
Harms of calcium supplements
Constipation
1 in 71 people will experience constipation due to calcium supplements1:
Bloating
1 in 111 will experience bloating due to calcium supplements1:
Renal stones
1 in 250 will develop renal stones over 7 years due to calcium supplements1:
Risk of myocardial infarction
If prescribed with vitamin D, there is only borderline evidence of an increase in the risk of MI with calcium supplements.
more
A 2010 meta-analysis of RCTs of calcium supplements alone, suggested a relative increase in the risk of MI (HR 1.31 [95% CI 1.02–1.67]; p=0.035)2.
Further analysis including new data on calcium and vitamin D combined showed a lower level of risk (relative risk 1.16 [95% CI 1.02–1.32], p=0.02).
The MHRA and Commission on Human Medicines reviewed the data and state that, due to methodological limitations, there was not ‘convincing evidence that calcium and vitamin D supplements were associated with an increased risk of cardiovascular events‘3
Vitamin D, harms at high doses
Fracture risk is increased with long term high doses (>4000iu/day) of vitamin D4:
Data note
The RCT evidence providing the data for Calcium harms compared calcium+vitamin D to placebo in an all female population1. These harms/side effects are assumed to be attributable to calcium.
References
1)Jackson R, LaCroix A, Gass M et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006; 354: 669-683
2) Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis.
3)MHRA Drug Safety Update. Oct 2011, vol 5 issue 3: H1
4)Reid I. Calcium and vitamin D: To supplement or not?
The benefits of bisphosphonates on fracture prevention for an individual depend on their baseline risk of fracture.
An individual’s 10-year risk of fracture can be calculated using either the FRAX or QFracture scores:
Bone mineral density increases by approximately 3% over 2 years with bisphosphonate treatment1.
Figures derived from a network meta-analysis from a 2015 NICE evidence review1:
The risk reductions shown here were used by NICE to create their 2019 Patient Decision Aid for bisphosphonates2.
References
1) ScHARR, University of Sheffield. Technology Assessment Report commissioned by the NIHR HTA Programme on behalf of the National Institute for Health and Care Excellence. Bisphosphonates for preventing osteoporotic fragility fractures (including a partial update of NICE technology appraisal guidance 160 and 161). Accessed online Feb 2023
2)National Institute for Health and Care Excellence. Bisphosphonates for treating osteoporosis. Patient decision aid. 2019 [Internet]. [London]: NICE; 2019. Accessed online Feb 2023
| The overall quality of the clinical trials in the evidence base is MODERATE.
However, extrapolating the trial data into practical figures to be used here or in a decision aid creates significant imprecision. The figures presented above are good enough to regard as “ballpark” estimates to support decision making, but there is a high possibility that the true effect is smaller or greater. |
For clinical trials comparing alendronate to placebo, a 2008 Cochrane review rated the evidence as MODERATE quality1:
However,
Assumptions and extrapolations from trial data
more
Data detail
The Cochrane review for alendronate is referenced here as it provides a straightforward judgement of evidence quality on the most commonly prescribed bisphosphonate.
References
1)Wells GA, Cranney A, Peterson J. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD001155
2)ScHARR, The University of Sheffield. Technology Assessment Report commissioned by the NIHR HTA Programme on behalf of the National Institute for Health and Care Excellence. Bisphosphonates for preventing osteoporotic fragility fractures (including a partial update of NICE technology appraisal guidance 160 and 161). Accessed online Feb 2023
The population characteristics in the trials of alendronate in the Cochrane review were, roughly:
Data detail
This population profile is broadly representative of the populations studied in other bisphosphonate trials.
Reference
1)Wells GA, Cranney A, Peterson J. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD001155
The terms “all osteoporotic fractures” and “major osteoporotic fractures” occur a lot in the literature, but what do they mean?
The Cochrane and NICE reviews found that overall, these definitions are poorly reported.
However, these data from one major trial can serve as a guide:
| Type of Fracture | Approx % of total fractures in trial population
(placebo group) |
| Sub-clinical vertebral* | 41% |
| Clinical vertebral | 14% |
| Wrist | 12% |
| Ankle and foot | 10% |
| Other arm and shoulder | 7% |
| Hip | 6% |
| Hand and fingers | 3.5% |
| Ribs | 3% |
| Other leg | 3% |
| Pelvis | 2.5% |
* Sub-clinical vertebral fractures are those detected by X-ray alone, i.e., asymptomatic. Though as single events they are unnoticed, over time multiple fractures may accrue into symptomatic postural deformity. They are also strong predictors of future fracture.
The profile of participants in this study were:
References
1)Wells GA, Cranney A, Peterson J. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD001155
2)ScHARR, The University of Sheffield. Technology Assessment Report commissioned by the NIHR HTA Programme on behalf of the National Institute for Health and Care Excellence. Bisphosphonates for preventing osteoporotic fragility fractures (including a partial update of NICE technology appraisal guidance 160 and 161). Accessed online Feb 2023
3)Black D, Cummings S, Karpf D et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348(9041):1535-1541
How long to continue taking a bisphosphonate, and if or how long someone should take a “bisphosphonate holiday” have been controversial questions. Current guidance varies:
The National Osteoporosis Guideline Group (NOGG) advise to:
NICE’s multimorbidity guideline advises that:
What evidence is there to guide us?
There is a lack of robust randomised controlled trial data to settle this question, hence the confusion.
Arguments for continuing treatment are based on lower level evidence1,2,3:
Why have a bisphosphonate holiday?
One reason is simply to reduce treatment burden temporarily.
The other is to reduce the chance of atypical femoral fractures:
References
1)National Osteoporosis Guideline Group. NOGG 2021. Accessed online Jan 2023
2)National Institute for Health and Care Excellence. Multimorbidity: Clinical assessment and management [Internet]. [London]: NICE; 2016 (NICE Guideline 56 [NG56])
3)Reid IR. Bisphosphonate holidays. Drug and Therapeutics Bulletin 2021;59:35-36
Systemic glucocorticoids reduce bone density with long term use.
NOGG1 and SIGN2 both recommend prescribing bisphosphonates to patients who are being prescribed glucocorticoids at doses of ≥7.5 mg for 3 months or more.
A 2016 Cochrane review3 found benefits for vertebral fracture prevention and bone density:
| Placebo | Bisphosphonate | Absolute Risk Reduction | Number Needed to Treat | Evidence Quality | |
| Vertebral fracture | 7.7% | 4.4% | 2.3% | 43 | HIGH |
| Non-vertebral fracture | 5.5% | 4.2% | 1.3% | 77 | Not statistically significant |
| Change in lumbar spine bone density from baseline | -3.9% | +3.5% | – | – | MODERATE |
| Change in femoral neck bone density from baseline | -1.6% | +2.1% | – | – | MODERATE |
References
1)National Osteoporosis Guideline Group. NOGG 2021. Accessed online Jan 2023
2)Management of osteoporosis and fragility fracture. 2015, rev 2021. Accessed online Jan 2023
3)Allen C, Yeung J, Vandermeer B, Homik J. Bisphosphonates for steroid‐induced osteoporosis. Cochrane Database of Systematic Reviews 2016, Issue 10. Art. No.: CD001347
Gastrointestinal side effects
No increase was seen compared to placebo in the RCTs reviewed by NICE which included over 40,000 patients1.
more
However, the NICE review mentions that ‘prescription monitoring data has a high level of reporting within the first month of treatment’.
It may be that gastrointestinal side effects seen in clinical practice are related to initial reactions, a population of patients who may have more background oesophageal problems and/or failure to follow treatment instructions (take on empty stomach, wash down with glass of water and stay upright for 30 minutes).
Oesophageal cancer
~1 in 1000 people may develop oesophageal cancer after 5 years due to bisphosphonate treatment, though this is uncertain.
more
An 2010 observational study suggested a small increase in the risk of oesophageal cancer in patients who had taken oral bisphosphonates for over 5 years:
| Oesophageal cancer risk in general population | Oesophageal cancer risk in those with
>5 years bisphosphonate treatment |
|
| Women age 60-79 | 0.5 per 1000 | 1 per 1000 |
| Men age 60-79 | 1.5 per 1000 | 3 per 1000 |
However, the evidence was not judged to be strong enough to suggest a definite causal link, and the MHRA advised that patients did not need to stop taking bisphosphonates2.
Atypical femoral fractures (AFFs)
1 – 10 per 10,000 depending on treatment duration
more
AFFs are uncomminuted transverse fractures of the femoral shaft occurring after no or minimal trauma.
Exact rates are uncertain and only seen in large observational studies.
A study in California involving 200,000 women3 reported the following rates:
| Duration of bisphosphonate treatment | Rate of AFF per 10,000 women | Rate of AFF as a percentage |
| No bisphosphonate | 0.1 | 0.001% |
| 3 years | 0.6 | 0.006% |
| 5 years | 2.5 | 0.025% |
| 8 years | 6 | 0.06% |
| >8 years | 13 | 0.13% |
Osteonecrosis of the jaw
1 in 10,000 – 100,000 for patients taking oral bisphosphonates for osteoporosis4
References
1) ScHARR, The University of Sheffield. Technology Assessment Report commissioned by the NIHR HTA Programme on behalf of the National Institute for Health and Care Excellence. Bisphosphonates for preventing osteoporotic fragility fractures (including a
partial update of NICE technology appraisal guidance 160 and 161). Accessed online Feb 2023
2) MHRA. Bisphosphonates: use and safety. Guidance 18 December 2014. Accessed online Jan 2023
3) Black D, Geiger E, Eastell R et al Atypical femur fracture risk versus fragility fracture prevention with bisphosphonates. N Engl J Med 2020;383:743–53
4) Khan A, Morrison A, Hanley D et al Diagnosis and Management of Osteonecrosis of the Jaw: A Systematic Review and International Consensus. J Bone Miner Res. 2015 30: 3-23
People who have an adverse event
People whose adverse event is prevented by treatment
People who were never going to have an adverse event anyway
Graphics and NNTs are rounded to the nearest integer
These three statistical terms offer three different ways of looking at the results of trial data.
Absolute Risk Reduction
This tells you how many people out of 100 who take a treatment have an adverse event prevented.
MoreThe value of the ARR changes with the baseline risk of the person (or population) taking the treatment. The higher the starting risk, the greater the absolute chance of benefit.
You need to think about over what time the trial data show this benefit, as it is usually assumed that more absolute risk reduction is gained over time.
Your patient might be taking the treatment for much longer than the length of a clinical trial (or, if life expectancy is limited, perhaps for less time).
Number Needed to Treat
This tells you how many people need to take the treatment in order for one person to avoid an adverse event.
The lower the number, the more effective the treatment.
MoreThe value of the NNT changes with the baseline risk of the person (or population) taking the treatment. The higher the starting risk, the smaller the NNT.
You need to think about over what time the trial data show benefit, as it is usually assumed that more benefit is gained over time and therefore the NNT will drop over time.
Your patient might be taking the treatment for much longer than the length of a clinical trial (or, if life expectancy is limited, perhaps for less time).
Relative Risk Reduction
This tells you the proportion of adverse events that are avoided if the entire population at risk is treated.
MoreThe value of the RRR is usually constant in people (or populations) at varying degrees of risk.
It is also usually assumed to stay constant over time.
This can be helpful, especially when thinking about population outcomes, but can be misleading for an individual person:
For example, a RRR of 25% in someone with a baseline risk of 40% would give them an ARR of 10% and an NNT of 10.
A RRR of 25% in someone with a baseline risk of 4% would give them an ARR or 1% and an NNT of 100.
This website is designed for use by General Practitioners and other healthcare professionals. The content is not exhaustive and assumes a standard level of GP professional knowledge. The information here is intended to support clinical judgement and shared decision making alongside clinical guidelines and standard practice.
If you are a patient/member of the public, do feel free to look around, but please don’t make any changes to your treatments based on information here. If you find something which seems relevant to you, you could show this website to your healthcare professional to help a discussion.