Incidence

• 1 in 3 women over 50 will experience osteoporotic fractures, as will 1 in 5 men
• Peak bone mass is reached in women at about 30 years of age
• Osteoporosis causes approximately 70,000 hip fractures in England and Wales each year
• The strongest predictor of a fracture is the existence of a prior osteoporotic fracture

Common causes of osteoporosis

Risk factors for osteoporosis alone do not predict well who will benefit from drug treatment but can be an indicator for a bone mineral density (BMD) scan.

• Corticosteroids
• Hypogonadal states, e.g. premature menopause, anorexia nervosa, taking aromatase inhibitors, receiving anti-androgen therapy
• Malabsorption, e.g. coeliac disease, ileal Crohn's disease, pancreatic insufficiency
• Endocrine, e.g. thyrotoxicosis, hyperparathyroidism, Cushing's disease
• Impaired vitamin D hydroxylation, e.g. renal and liver impairment, taking anticonvulsants
• Malignancy, especially lymphoma, multiple myeloma
• Chronic inflammatory conditions, e.g. rheumatoid arthritis, bronchiectasis
• Lifestyle issues, e.g. low BMI, smoking, excess alcohol, immobility

• Diet - adequate intake of calcium and vitamin D during growth, pregnancy and particularly in the elderly. See vitamin D deficiency guidance for more information
• Weight bearing exercise
• Smoking cessation
• Moderation of alcohol - reduction to less than national limit for females (3 units/day or 14 units/week) and for males (4 units/day or 21 units/week)
• Reduction of fall risk - falls risk assessment

First line: Oral bisphosphonates

Alendronic acid

• 70mg once weekly

Risedronate

• 35mg once weekly

Consider trial of risedronate if patient is unable to tolerate alendronic acid. Due to the shorter half-life of risedronate it may be more suitable for younger patients or whose renal function is compromised.

See section 6.6 Drugs affecting bone metabolism

Criteria for treatment with alendronic acid or risedronate for primary prevention:

Postmenopausal women younger than 65 years

• 1 or more risk factor plus
• 1 or more indicator of low BMD plus
• T-score less than or equal to -2.5 SD

65-69 years

• 1 or more risk factor plus
• T-score less than or equal to -2.5 SD

70-74 years

• 1 or more risk factor or
• 1 or more indicator of low BMD plus
• T-score less than or equal to -2.5 SD

75 or older

• As for 70-74 years unless:
• 2 or more risk factors or indicators of low BMD in which case DXA may not be needed if clinically inappropriate or unfeasible or older

The FRAX tool has been developed by WHO to evaluate fracture risk of patients. It is based on individual patient models that integrate the risks associated with clinical risk factors as well as bone mineral density (BMD) at the femoral neck.

Risk factors for fracture:

• Parental history of hip fracture
• Alcohol intake of 4 or more units per day
• Rheumatoid arthritis

Indicators of low BMD

• Low BMI (less than 22kg/m²)
• Medical conditions such as ankylosing spondylitis, Crohn's disease, conditions resulting in prolonged immobility, untreated premature menopause

Notes

1. Oral bisphosphonates should be swallowed whole with a full glass of water and the patient should remain upright (seated or standing) for at least 30-45 minutes to minimise the chance of oesophageal ulceration. Only water should be consumed within this time period. Ensure patient can comply with administration regimen.
2. All bisphosphonates bind to dietary calcium. It is essential that alendronate and risedronate are taken at least 30-45 minutes before breakfast. In studies of taking bisphosphonates in the middle of daytime fasts it is found that they are much less effective.
3. Calcium and vitamin D should be prescribed for all patients, who should be instructed to take in the evening, or omit it on the day of taking the weekly bisphosphonate, to avoid binding of the calcium to the bisphosphonate in the GI tract.
4. There is no clear evidence of a change in fracture risk when PPIs are co-prescribed with bisphosphonates.
5. Avoid in patients with significant upper GI pathology and moderate to severe renal impairment. Bisphosphonates are contra-indicated in pregnancy and lactation.

Escalation of therapy

Consider Prolia (denosumab) or zoledronic acid for primary prevention in patients intolerant of oral bisphosphonates. (NICE TA 204, NICE CG146 or www.sheffield.ac.uk/NOGG/)

Denosumab initiation and prescription in accordance with NICE TA204 in postmenopausal women.

Patients should be Calcium and Vitamin D replete prior to initiation of osteoporotic treatments.

MHRA Drug Safety Update July 2015

Before prescribing denosumab or intravenous bisphosphonates:

• give patients the patient reminder card for their medicine (online Drug Safety Update)
• explain the risk of osteonecrosis of the jaw and advise patients on precautions to take—advise patients to:
  • tell their doctor if they have any problems with their mouth or teeth before starting treatment; if they wear dentures they should make sure their dentures fit properly before starting treatment
  • maintain good oral hygiene and get routine dental check-ups during treatment
  • tell their doctor and dentist that they are receiving denosumab or an intravenous bisphosphonate if they need dental treatment or dental surgery
  • tell their doctor and dentist immediately if they have any problems with their mouth or teeth during treatment (e.g. loose teeth, pain, swelling, non-healing sores or discharge

Prolia (denosumab)

• S/C 60mg every 6 months

Notes

1. Refer to individual shared care guidelines
2. See section 6.6.2 Bisphosphonates and other drugs affecting bone metabolism
3. To avoid unnecessary out of pocket expenses, practices or pharmacies should order Prolia direct from AAH
4. Consider Denosumab for the primary prevention of osteoporotic fragility fractures in patients at increased risk of fractures:
   1. who are unable to comply with the special instructions for administering alendronate and either risedronate or etidronate, or have an intolerance of, or a contraindication to, those treatments and
   2. who have a combination of T-score, age and number of independent clinical risk factors for fracture as described in NICE TA204

Zoledronic acid (Aclasta)

• 5mg by infusion every 12 months

Notes

1. Zoledronic acid is a treatment option for patients who are at high risk of fracture who are intolerant or have contraindications to oral bisphosphonates.
2. Rarely, osteonecrosis of the jaw has been associated with bisphosphonates usually when given in much higher doses by the intravenous route in oncology.
3. Patients may experience flu-like symptoms for 3 days after the infusion. This can be minimised by co-prescribing paracetamol and ibuprofen if appropriate.

Calcium and vitamin D

Supplements should be given to all patients at risk of osteoporosis unless diet is rich in calcium and vitamin D. Patients have received supplementation with calcium and vitamin D in all clinical trials of therapies showing a fracture reduction.

Attention should be made to the fact that routine Vitamin D testing may be unnecessary for patients with osteoporosis or fragility fracture who are co-prescribed vitamin D with an oral bisphosphonate.

See also: MHRA Drug Safety Update - Calcium and vitamin D (October 2011)

See section 9.6 Vitamins

First line: Oral bisphosphonates

Alendronic acid

• 70mg once weekly

If patient is unable to tolerate alendronic Acid due to gastrointestinal side effects then according to NICE TA204 a trial of risedronate is recommended. Due to the shorter half-life of risedronate it may be more suitable for younger patients or whose renal function is compromised, see section 6.6 Drugs affecting bone metabolism for further information.

Risedronate

• 35mg once weekly

See section 6.6 Drugs affecting bone metabolism

Treatment is recommended for all individuals with a T-score less than or equal -2.5 SD regardless of risk factor status. For those aged 75 years or older, a DXA scan may not be needed if clinically inappropriate or unfeasible.

Notes

1. Oral bisphosphonates should be swallowed whole with a full glass of water and the patient should remain upright (seated or standing) for at least 30-45 minutes to minimise the chance of oesophageal ulceration. Only water should be consumed within this time period. Ensure patient can comply with administration regimen.
2. All bisphosphonates bind to dietary calcium. It is essential that alendronate and risedronate are taken at least 30-45 minutes before breakfast. In studies of taking bisphosphonates in the middle of daytime fasts it is found that they are much less effective.
3. Calcium and vitamin D should be prescribed for all patients, who should be instructed to take it at lunchtime or in the evening to avoid binding of the calcium to the bisphosphonate in the GI tract.
4. There is no clear evidence of a change in fracture risk when PPIs are co-prescribed with bisphosphonates.
5. Avoid in patients with significant upper GI pathology and moderate to severe renal impairment. Bisphosphonates are contra-indicated in pregnancy and lactation.

Escalation of therapy

Patients intolerant to oral bisphosphonates for secondary prevention or who have further fractures whilst on oral bisphosphonates should be switched to parenteral therapy (Prolia [denosumab] or zoledronic acid). NICE TA204

Denosumab initiation and prescription in accordance with NICE TA204 in postmenopausal women with eGFR greater than 30mL/min.

Patients should be Calcium and Vitamin D replete prior to initiation of osteoporotic treatments.

MHRA Drug Safety Update July 2015

Before prescribing denosumab or intravenous bisphosphonates:

• give patients the patient reminder card for their medicine (online Drug Safety Update)
• explain the risk of osteonecrosis of the jaw and advise patients on precautions to take—advise patients to:
  • tell their doctor if they have any problems with their mouth or teeth before starting treatment; if they wear dentures they should make sure their dentures fit properly before starting treatment
  • maintain good oral hygiene and get routine dental check-ups during treatment
  • tell their doctor and dentist that they are receiving denosumab or an intravenous bisphosphonate if they need dental treatment or dental surgery
  • tell their doctor and dentist immediately if they have any problems with their mouth or teeth during treatment (e.g. loose teeth, pain, swelling, non-healing sores or discharge)

Prolia (denosumab)

• S/C 60mg every 6 months

Notes

1. Refer to individual shared care guidelines
2. See section 6.6.2 Bisphosphonates and other drugs affecting bone metabolism
3. To avoid unnecessary out of pocket expenses, practices or pharmacies should order Prolia direct from AAH
4. Denosumab is recommended as a treatment option for the secondary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fractures who are unable to comply with the special instructions for administering alendronate and either risedronate or etidronate, or have an intolerance of, or a contraindication to, those treatments

Zoledronic acid (Aclasta)

• 5mg by infusion every 12 months

Notes

1. Zoledronic acid is a treatment option for patients who are at high risk of fracture who are intolerant or have contraindications to oral bisphosphonates.
2. Rarely, osteonecrosis of the jaw has been associated with bisphosphonates usually when given in much higher doses by the intravenous route in oncology.
3. Patients may experience flu-like symptoms for 3 days after the infusion. This can be minimised by co-prescribing paracetamol and ibuprofen if appropriate.

Calcium and vitamin D

Supplements should be given to all patients at risk of osteoporosis unless diet is rich in calcium and vitamin D. Patients have received supplementation with calcium and vitamin D in all clinical trials of therapies showing a fracture reduction.

See also: MHRA Drug Safety Update - Calcium and vitamin D (October 2011)

See section 9.6 Vitamins

Guidance has also been issued by the National Osteoporosis Guideline Group (NOGG), Clinical guideline for prevention and treatment of osteoporosis. Fracture probability of glucocorticoids is dose dependent. When the FRAX UK model glucocorticoid box is filled, 2 points now appear on the NOGG graphs, one for medium dose and one for high dose

In patients who have been taking corticosteroids (at any dose) for 3 months or more, or who are likely to do so:

• Aged 65 years or over, or under 65 years of age with a previous fragility fracture
  • Start treatment to prevent osteoporosis. Measurement of BMD is not required before starting treatment.
• Age less than 65 years with no previous fragility fracture.
  • Prophylaxis should be based on DXA result:
  • If T score between 0 and -1.5 SD repeat BMD in 1-3 years if corticosteroids continued.
  • If T score less than or equal to -1.5 SD, consider treatment based on age and fracture probability.
  • Prophylaxis with calcium and vitamin D is recommended for those at lower risk, particularly younger patients

Bisphosphonates should be used with great caution in premenopausal women since they cross the placenta and teratogenic effects have been demonstrated in animals.

See resources for: contraception for drugs with teratogenic potential, and prescribing in pregnancy and lactation

The daily formulations of alendronic acid 10mg and risedronate 5mg are licensed for use in glucocorticoid-induced osteoporosis in postmenopausal women, although in clinical practice the weekly tablets may be used (unlicensed indication).

Current advice regarding long-term bisphosphonate treatment is limited to expert opinion.

Please refer to National Osteoporosis Guideline Group (NOGG), Clinical guideline for the prevention and treatment of osteoporosis for an algorithm in regard to duration of treatment.

Review treatment after 5 years of alendronate or risedronate therapy, or after 3 years of zoledronic acid.

Withdrawal of treatment is associated with decreases in BMD. Continuation of treatment without the need for further assessment is recommended for:

• High-risk individuals, e.g:
  • aged 75 years or more
  • who have previously sustained a hip or vertebral fracture
  • who are taking continuous oral glucocorticoids in a daily dose of 7.5mg (or over) prednisolone or equivalent
• Individuals sustaining one or more low trauma fractures during treatment. Re-evaluate treatment option and check adherence if this occurs.

After re-assessment at 3-5 years individuals with a T-score of less than or equal to -2.5 should not be considered for a drug holiday.

Consider a "treatment holiday" in appropriate patients as follows:

• 18 months for patients taking risedronate; re-assess fracture risk
• 3 years for patients taking alendronic acid or zoledronic acid; re-assess fracture risk

Calcium and vitamin D supplementation should continue throughout.

If treatment is discontinued, fracture risk should be reassessed after a new fracture regardless of when this occurs, using FRAX. and consider rescanning.

Atypical femoral fractures have been reported rarely in patients receiving bisphosphonate therapy or denosumab.

Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered while they are evaluated, and should be based on an assessment of the benefits and risks of treatment. The need to continue bisphosphonate treatment for osteoporosis should be re-evaluated periodically based on the benefits and potential risks of bisphosphonate therapy for individual patients, particularly after 5 or more years of use.

Discontinuation of denosumab therapy should be considered if an atypical femur fracture is suspected, while the patient is evaluated.

See

• MHRA Drug Safety Update: Bisphosphonates: atypical femoral fractures (June 2011)
• MHRA Drug Safety Update: Denosumab 60mg (Prolia): rare cases of atypical femoral fracture with long-term use (February 2013)

Hormone replacement therapy (HRT) maintains Bone Mineral Density (BMD) for as long as it is taken.

Should not be used for osteoporosis protection only unless all other therapies are contra-indicated or not tolerated - see 6.4 Sex hormones for further guidance.

• Avoid prolonged rest. The patient should be encouraged to mobilise within the first few days with adequate analgesia
• Strong opioids, e.g. morphine in adequate doses may be needed for a few weeks. Subsequently, consider simple analgesics and/or NSAIDs. If NSAIDs are prescribed, take into account the safety profile of NSAIDs and the age of the patient
• Calcitonin 100 IU im on alternate days for 3 weeks can reduce the duration of pain post vertebral fracture but this is probably equivalent in analgesic effect to strong opioids
• Consider vertebroplasty for severe disabling pain
• Commence therapy for osteoporosis to reduce risk of further fracture
• Advice from physiotherapy regarding lifting and upper body strengthening