Dr Pam Brown shares some key points for the assessment, management, and review of people at risk of fragility fracture

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Read this article to learn more about:

  • how to identify those at high risk of fragility fractures and reduce their risk
  • how long to continue therapy to optimise benefit and minimise risk
  • special groups at high risk of fractures who are often poorly treated.

 

1 Treat people at high risk of fragility fractures

Fragility fractures (i.e. fall from standing height or less, spontaneous vertebral fracture, or with normal activities) occur in 1 in 5 men and 1 in 3 women aged over 50 years,1 and cause significant pain, morbidity, mortality, and loss of independence. Most people who experience hip fracture do not regain their previous mobility and independence. One half of people with hip fracture have had a previous fragility fracture, but few are on bone-sparing treatment. Treatments reduce risk of future vertebral fractures by 40–70% and hip fractures by 20–50% over 3–4 years, depending on the drug and individual fracture risk.1

2 Quantify risk and help identify who needs treatment

Measure bone mineral density (BMD) with dual-energy X-ray absorptiometry (DXA) to assess fracture risk in:2,3

  • people starting aromatase inhibitors or androgen deprivation therapy
  • people aged under 40 years with a history of:
    • multiple fragility fractures, or a hip, spine, humerus, or forearm fracture
    • current or recent use of high-dose oral steroids (>7.5 mg prednisolone daily for ≥3 months)
  • people aged over 50 years with a history of fragility fracture.

Refer those aged under 40 years who have a major risk for fragility fracture for specialist management.2,3

FRAX® and QFracture®
The World Health Organization Fracture Risk Assessment Tool (FRAX®)4,5 or QFracture®6 are used to assess fracture risk and determine whether DXA is required for:3

  • all women aged ≥65 years and men aged ≥75 years
  • others over 50 years of age with risk factors such as:
    • body mass index <18.5 kg/m2
    • falls
    • family history of hip fracture
    • oral steroid use
    • secondary causes of osteoporosis
    • smoking
    • >14 units alcohol/week (women) or >21 units alcohol/week (men)
  • people younger than 50 years on oral steroids or untreated menopause.

Consider assessing fracture risk for those taking SSRIs, antiepileptic medication, proton pump inhibitors, and thiazolidinediones especially if other risk factors are present.2

Measure BMD with DXA if fracture risk is high or close to treatment threshold with risk factors underestimated by calculators.2

FRAX® and QFracture® calculate 10-year absolute fracture risk:

  • FRAX® can be used with or without femoral neck BMD DXA T-score, and to reassess fracture risk on treatment.5 After submitting answers in the FRAX® calculation tool to calculate risk, the National Osteoporosis Guideline Group (NOGG) guidance is viewed (by clicking on the 'view NOGG guidance' button); a graph is displayed showing the 10-year probability of major osteoporotic fracture against age, and recommends whether lifestyle advice and reassurance, measuring BMD with DXA (if not done previously), or treatment, is the appropriate next step4
  • QFracture® incorporates additional risk factors including falls and ethnicity, but not DXA measurements. Women with a 10-year fracture risk of more than 11.1% are at high risk; for men this threshold is 2.6%.2 The NICE osteoporosis clinical knowledge summary (CKS)2 provides guidance on when risk scores may be less accurate and how to interpret them.

These are tools only, so practitioners should continue to use clinical judgment.

3 Code fractures and fracture risk assessments

The Quality and Outcomes Framework (QOF)7 encourages developing a register of patients who have suffered fragility fractures from hospital letters. Fractures of the fingers, toes, or skull do not increase future fracture risk. As well as coding fracture type, consider adding the fragility fracture code to simplify future searches to identify whether people are appropriately treated.

4 Optimise management of the current fracture

Pain relief helps people maintain mobility and independence post-fracture. Ideally pain relief should be achieved without inducing sedation, dizziness, or increasing the risk of falls.

Identify and treat secondary causes of osteoporosis or non-osteoporotic causes of fracture (e.g. myeloma, bony metastases). Investigations may include: full blood count, C-reactive protein/erythrocyte sedimentation rate, thyroid function tests, coeliac screen, myeloma screen, testosterone level—see NICE osteoporosis CKS for more detail.2

At least one half of vertebral fractures are asymptomatic or undiagnosed,2 yet these increase future fracture risk as much as diagnosed fractures.1 If people with vertebral fractures may benefit from vertebroplasty/kyphoplasty, refer promptly to a spinal surgeon.

5 Reduce future fracture risk

Provide lifestyle advice. Treat those with osteoporosis confirmed on DXA (T-score ≤–2.5) and those on high-dose oral steroids. First-line treatment for those at high fracture risk, with or without previous fragility fracture, is once-weekly alendronate or risedronate unless there are contraindications.8,9 Once-monthly ibandronic acid may be used for treatment of osteoporosis if the patient is intolerant to alendronate and risedronate. Assess calcium intake (aim for 700 mg daily) and check that the patient is vitamin D replete; prescribe supplements if needed—be aware of possible drug interactions (see Table 1, below). Identifying and managing risk factors for falls will further reduce future fracture risk.2

DrugInteractions with calcium and vitamin D preparationsCourse of action
Table 1: Key drug interactions with calcium and vitamin D preparations2
Oral bisphosphonates Reduced absorption of bisphosphonates Take at least 30 minutes before supplement
Quinolones Reduced absorption of quinolones Take at least 2 hours before calcium supplement
Strontium ranelate Reduced absorption of strontium ranelate Take 2 hours before or after calcium supplement
Levothyroxine, iron, and zinc Reduced absorption of levothyroxine, iron, and zinc Take at least 2 hours before calcium supplement
Tetracyclines Reduced absorption of tetracyclines Take at least 2–3 hours before calcium supplement
Digoxin Increased effects of digoxin Consider monitoring an ECG and renal function during long-term calcium supplementation to check for cardiac arrhythmias
Thiazide diuretics Reduced urinary calcium excretion Monitor serum calcium levels regularly during concomitant use of thiazide diuretics with calcium and vitamin D preparations
Consider monitoring renal function during long-term calcium supplementation in people also taking a thiazide diuretic
Oral corticosteroids Reduced calcium absorption Consider increasing the dose of calcium and vitamin D supplements
Phenytoin or barbiturates (long-term use) Decreased effects of vitamin D (due to an increase in its metabolism) Consider monitoring for vitamin D deficiency and increase dose if required

Refer people who are intolerant of oral therapy for consideration for subcutaneous denosumab (specialist initiated then shared-care agreement; GP initiation in some areas) or intravenous zoledronic acid (specialist administered).

Consider hormone replacement therapy (HRT) for menopausal women age ≤40 years to reduce fracture risk and treat symptoms.

Consult NICE Technology Appraisals 1608 and 1619, and the NICE osteoporosis CKS2 for guidance on other therapies.

6 Optimise therapy adherence

Bone mineral density increases are greater with good adherence to therapy; >75% adherence further reduces fracture risk.10 Less than one half of people starting oral bisphosphonates choose to continue for >1 year, and 30% of those initiating zoledronic acid do not receive a second dose.11

Discuss how to take therapy to optimise absorption and minimise side-effects:2

  • bisphosphonate tablets must be swallowed whole first thing in the morning on an empty stomach, while upright, with >200 ml of tap water
  • delay eating, drinking, or other medication for at least 30 minutes (alendronate, risedronate) or 60 minutes (ibandronic acid). Ensure calcium and vitamin D supplements are not taken at the same time.

Discuss side-effects and adherence 3 to 4 months after initiating treatment, and annually at medication review.

Calcium and vitamin D preparations can reduce absorption of quinolones, tetracyclines, levothyroxine, and iron so these should not be taken at the same time as taking supplements (see Table 1, above).2 Thiazide diuretics may increase the risk of hypercalcaemia so calcium levels should be monitored. Calcium and vitamin D preparations may also increase the effects of digoxin (see Table 1, above).2

7 Discuss risks of therapies

Bisphosphonates can cause oesophageal symptoms that can be minimised by taking therapy exactly as directed. Non-steroidal anti-inflammatory drugs should be used with caution in patients taking bisphosphonates due to the increased risk of gastrointestinal (GI) irritation.2

If upper-GI symptoms occur, stop therapy and consider restarting the same or different therapy once symptoms resolve. Do not treat the GI side-effects with a proton pump inhibitor and continue bisphosphonate therapy.

Zoledronic acid may induce a flulike acute phase response lasting a few days, particularly after the first infusion.5 Treat with paracetamol.

Check estimated glomerular filtration rate (eGFR) regularly to ensure it is safe to continue bisphosphonate therapy (i.e. alendronate, zoledronic acid eGFR ≥35 ml/min/1.73 m2; risedronate, ibandronic acid eGFR ≥30 ml/min/1.73 m2.)12

Atypical femoral fractures may be associated with duration of osteoporosis treatment. Risk of these fractures is low (50 per 100,000/year) with <5 years bisphosphonate therapy but risk increases (113 per 100,000/ year) after 8–9 years, making the risk/benefit balance more uncertain.1 The fractures may present with hip, thigh, or groin pain prior to the completed fracture; those at risk should be X-rayed if symptoms develop.1,5

Osteonecrosis of the jaw (ONJ) occurs in 1 in 10,000 to 1 in 100,000 of those on oral bisphosphonates (only slightly higher than the population risk). Risk is higher in people receiving higher cumulative bisphosphonate doses for breast cancer.1 Those with poor oral hygiene should have dental treatment prior to bisphosphonate therapy; all should be encouraged to maintain good oral hygiene and avoid invasive dental treatment. It is not appropriate to stop therapy for necessary dental treatment since bisphosphonate remains in bone for years.1

Strontium ranelate may increase cardiovascular disease risk and should only be used in those at high risk of fracture, in whom other treatments are contraindicated or not tolerated. Regular assessment of cardiovascular risk is required.12,13

8 Is a 'drug holiday' appropriate?

There is limited evidence from two long-term extension studies that 10 years of alendronate and 6 years of zoledronic acid may further reduce vertebral fracture risk in people at high risk, compared with 5 and 3 years, respectively.1

Review patients after 5 years if on an oral bisphosphonate (or after 3 years if on zoledronic acid). Carrying out a DXA scan is helpful. Recalculate FRAX® using femoral neck T-score. Consider an X-ray of lumbar and thoracic spine in those perceived to be at lower risk, as undiagnosed vertebral fractures may influence longer treatment (50–70% of vertebral fractures may be asymptomatic or not diagnosed).2

People at lower risk of fracture should consider stopping therapy (a 'drug holiday'); review the patient with a DXA scan 2–3 years after stopping therapy (1–2 years if they were taking risedronate/ibandronate as the benefits are less persistent).1

People at high risk of fracture should be considered for longer therapy (see Box 1, below). Counsel about possible small increased risk of atypical fractures and ONJ. A drug holiday is usually appropriate after a maximum of 10 years treatment (6 years on zoledronic acid), although this is an 'evidence-free zone'. Careful risk–benefit analysis, shared decisionmaking, and reassessment after 2–3 years, or if a new fracture occurs at any time, are recommended.1

Box 1: People at high risk of fracture who should consider longer-term treatment2,5

People who are at high risk of fracture who should consider longer-term treatment include those:

  • who are on drugs that cause bone loss (e.g. aromatase inhibitors, androgen deprivation therapy, steroids)
  • who have had a major osteoporotic fracture (e.g. hip, spine)
  • who have had fractures while on treatment
  • whose bone mineral density T-score at total hip or femoral neck is ≤-2.5
  • who are aged over 75 years.

Those who fracture after >1 year of therapy are at high risk—check adherence, consider referral for change of bone-sparing therapy (including teriparatide, denosumab).

Rapid bone loss occurs after stopping denosumab in some studies, with BMD improvements lost within 12–24 months, therefore drug holidays from denosumab are not recommended.14

9 Men get osteoporosis and fractures too

One in 5 men over the age of 50 years experiences a fragility fracture. Around 50% of men with osteoporosis and fractures have secondary osteoporosis, commonly due to low testosterone, high alcohol intake, or steroid therapy, so identifying and treating underlying causes is important. Evidence for treatment efficacy in men is more restricted. Daily alendronate, weekly risedronate,2 teriparatide, and strontium ranelate are licensed for men. Most guidelines recommend similar management to that of post-menopausal women (apart from treatment with HRT or raloxifene).

10 Manage steroid-induced osteoporosis in an evidence-based way

Fractures occur at higher BMD in those individuals who are on steroids. FRAX® and QFracture® calculators include steroids when calculating fracture risk. When FRAX® is used to calculate fracture risk in patients taking steroids, and NOGG guidance is viewed, fracture risks for low- and high-dose steroids are plotted on the graphs and accounted for in DXA and treatment recommendations.

Bisphosphonates are the mainstay of therapy for prevention and treatment of steroid-induced osteoporosis. Men and women should be treated similarly. Although licensing studies were short, if ≥7.5 mg/day prednisolone is continued for 3 months or longer, then bisphosphonate treatment should be continued.2 Fracture risk decreases after discontinuing steroid therapy so reassess risk and stop bisphosphonates if risk is low.2

References

  1. Adler R, Fuleihan G, Bauer D et al. Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2016; 31 (1): 16–35.
  2. NICE. Clinical knowledge summaries. Osteoporosis—prevention of fragility fractures. NICE, 2016. Available at: cks.nice.org.uk/osteoporosis-prevention-of-fragilityfractures#!topicsummary
  3. NICE. Osteoporosis: assessing the risk of fragility fracture. Clinical Guideline 146. NICE, 2012. Available at: www.nice.org.uk/cg146
  4. FRAX website. WHO fracture risk assessment tool. Available at: www.shef.ac.uk/FRAX/tool.jsp
  5. National Osteoporosis Guideline Group.Osteoporosis clinical guideline for prevention and treatment. London: NOGG, updated 2016. Available at: www.shef.ac.uk/NOGG/NOGG_ Executive_Summary.pdf
  6. Scottish Intercollegiate Guidelines Network.Management of osteoporosis and the prevention of fragility fractures. SIGN 142, Edinburgh: SIGN, 2015. Available at: www.sign.ac.uk/ guidelines/fulltext/142/index.html
  7. British Medical Association. NHS Employers. 2016/17 General Medical Services (GMS) contract Quality and Outcomes Framework (QOF) guidance for GMS contract 2016/17. Available at: www.nhsemployers.org/~/media/Employers/Documents/Primary%20care%20contracts/QOF/2016-17/2016-17%20QOF%20guidance%20documents.pdf
  8. NICE. Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women. Technology Appraisal 160. NICE, 2008 (updated 2011). Available at: www.nice.org.uk/guidance/TA160
  9. NICE.Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. Technology Appraisal 161. NICE, 2008 (updated 2011). Available at: www.nice.org. uk/guidance/TA161
  10. Siris E, Harris S, Rosen C et al. Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases.Mayo Clin Proc 2006; 81 (8): 1013–1022.
  11. Curtis J, Yun H, Matthews R et al. Adherence with intravenous zoledronate and intravenous ibandronate in the United States Medicare population. Arthritis Care Res 2012; 64 (7): 1054–1060.
  12. British Medical Association and Royal Pharmaceutical Society.British National Formulary: Vol. 70. London: BMJ Group and Pharmaceutical Press, 2015.
  13. Protelos—summary of product characteristics. June 2014. Available at: www.medicines. org.uk/emc/medicine/15410 (accessed 14 July 2016).
  14. McClung M. Cancel the denosumab holiday. Editorial. Osteoporos Int 2016; 27 (5): 1677–1682.