Although no interaction between bisphosphonates and PPIs is documented, the increased risk of fractures when given together should be reviewed and managed

Increased risk of fractures

The National Institute for Health and Clinical Excellence (NICE) technology appraisal (TA) on secondary prevention of osteoporotic fragility fractures highlights an increased risk of fractures when PPIs and bisphosphonates are taken together.

The TA states that evidence from cohort and case-control studies suggests that fracture risk at some fracture sites may be increased in women taking acid-suppressive medication, which includes PPIs and histamine H2 receptor antagonists (H2RAs).


The UK Summary of Product Characteristics (SPC) for bisphosphonates state that atypical fractures of the femur have been reported with bisphosphonate therapy, primarily in individuals receiving long-term treatment for osteoporosis.


The UK SPCs for PPIs state that ‘proton pump inhibitors, especially if used in high doses and over long durations (>1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in presence of other recognised risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fracture by 10-40%. Some of this increase may be due to other risk factors.

Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of vitamin D and calcium’.

Review bisphosphonate therapy

Individuals taking bisphosphonates should be reviewed after 5 years of treatment with alendronic acid, risedronate sodium or ibandronic acid, and after 3 years of treatment with zoledronic acid.

Based on fracture-risk assessment, continuation beyond 5 years can generally be recommended for the following individuals:

  • over 75 years of age
  • history of previous hip or vertebral fracture
  • one or more fragility fractures during treatment
  • on long-term glucocorticoid treatment

The NICE guidelines for osteoporosis states that QFracture and FRAX can both be used to assess risk fracture for individuals taking bisphosphonates.

Evidence for duration

There is no evidence for treatment with bisphosphonates beyond 10 years. Management of these individuals should be on a case-by-case basis with specialist input as appropriate.

Some individuals may benefit from a bisphosphonate-free period as their therapeutic effects last for some time after stopping treatment, although there is limited evidence to support this.

Evidence recommendations on duration are based on limited extension studies in postmenopausal women.

Review PPI therapy

If starting a bisphosphonate in individuals established on PPIs, the PPI should be reviewed to see if this is still required. Some individuals may have been started a PPI for gastro-protection against a medicine that has been stopped.

Consider a dose reduction or an alternative agent for individuals still requiring gastro-protection.

Management options for dyspepsia

Dyspepsia is a common side effect of bisphosphonates. Evidence shows this is the most frequently reported adverse effect in the first month of treatment with risedronate or alendronate.


If a PPI is required, this should be prescribed at the lowest dose needed to control symptoms and for shortest duration of time. The individual may use treatment on as ‘as-needed’ basis which could reduce the increased risk of fractures.


An annual review should be performed for individuals with dyspepsia to assess their symptoms and treatment. A ‘step down’ approach, or stopping treatment should be encouraged if possible and clinically appropriate.


Consider whether an H2RA would be more appropriate to prescribe than a PPI. The UK SPCs for H2RAs do not mention fracture risk. However, there is conflicting information as studies have shown that H2RAs have been associated with both small increases and decreases in fracture risk.


There are no guidelines on monitoring the use of famotidine for dyspepsia however best practice would suggest a similar approach with PPIs would be acceptable. An annual review to assess symptoms and a ‘step down’ approach, or stopping treatment should be encouraged if possible and clinically appropriate.

Counselling points

Ensure individuals are aware of the fracture risk associated with concomitant use.

Individuals should be advised to report any thigh, hip or groin pain as this may be a sign of an atypical femur fracture.


Full referencing is available on request.

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