Interventions considered in the scope of this report
Five interventions will be considered within this assessment: oral alendronic acid, oral ibandronic acid, intravenous (i.v.) ibandronic acid, oral risedronic acid and i.v. zoledronic acid. These are all nitrogen- containing bisphosphonates.
Mode of action
Bisphosphonates are adsorbed onto hydroxyapatite crystals in bone. Aminobisphosphonate inhibits prenylation of proteins and leads to osteoclast apoptosis, reducing the rate of bone turnover.29 Marketing licence and administration method
The dosages and administration routes for each treatment are summarised below (seeTable 1).
Alendronic acid
Alendronic acid has a UK marketing authorisation for treating postmenopausal osteoporosis, orally once daily or weekly. The 10-mg daily dose has also has a UK marketing authorisation for treating osteoporosis in men and for preventing and treating glucocorticoid-induced osteoporosis in postmenopausal women not receiving hormone replacement therapy (HRT), orally once daily.23
Non-proprietary alendronic acid (AAH, Accord, Actavis, Alliance Healthcare, Almus, APOTEX UK, Fannin UK, Focus, Generics (UK), Kent, Mylan UK, Phoenix Healthcare Distribution, PLIVA, Ranbaxy Laboratories,
Rosemont, Somex, Sun Pharmaceuticals Industries Ltd, Teva UK, Waymade, Wockhardt UK and Zentiva N.V.) also has a UK marketing authorisation for the same indications.23
People presenting in any health-care setting
Fragility fracture risk assessment Primary prevention of osteoporotic fragility fractures in postmenopausal women Secondary prevention of osteoporotic fragility fractures in postmenopausal women Treatment of vertebral compression fractures
NICE pathway on patient experience in adult NHS services 1 4 3 5 2 6
FIGURE 1 Osteoporosis overview pathway. Reproduced from NICE.Osteoporosis Overview–NICE Pathway. London:
NICE; 2014.27
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People presenting in any
health-care setting
People starting treatments that af
fect bone density
People aged <
50 years
People <
40 years with
major risk factors
People 40–49 years with
major risk factors
Consider risk assessment using FRAX or QFracture Factors that may af
fect
accuracy
When to consider measuring BMD
When to recalculate
fracture risk
Osteoporosis overview
W
omen aged 50–64 years
and men aged 50–74 years
with risk factors
W
omen aged >
65 years
and men aged >
75 years 12 67 3 45 8 9 10 11 12 FIGURE 2 Fragility fracture risk assessment pathway. Reproduced from NICE. Fragility Fracture Risk Assessment – NICE Pathway ; London: NICE; 2014. 28
Alendronic acid in the treatment of postmenopausal osteoporosis is administered orally: 10 mg daily or 70 mg once weekly. Treatment of osteoporosis in men is administered as 10 mg daily. Prevention and treatment of glucocorticoid-induced osteoporosis in postmenopausal women not receiving HRT is
administered as 10 mg daily. Treatment is administered while sitting or standing and patients should remain seated or have stood for at least 30 minutes.30
Ibandronic acid
Ibandronic acid has a UK marketing authorisation for treating postmenopausal osteoporosis, orally once monthly or every 3 months by i.v. injection. Non-proprietary ibandronic acid (produced by Actavis UK, Consilient Health, Mylan UK, Sun Pharmaceuticals Industries Ltd and Teva UK) also has a UK marketing authorisation for the same indications.23
Ibandronic acid in the treatment of postmenopausal osteoporosis is administered either by mouth, 150 mg once a month, or by i.v. injection over 15–30 seconds, 3 mg every 3 months. Oral treatment is administered while sitting or standing and patients should remain seated or stand for at least 1 hour.30 Oral and i.v. ibandronic acid are treated as separate interventions within our analysis.
Risedronic acid
Risedronic acid has a UK marketing authorisation for treating postmenopausal osteoporosis to reduce the risk of vertebral or hip fractures, orally once daily or weekly. It has a marketing authorisation for preventing osteoporosis (including glucocorticoid-induced osteoporosis) in postmenopausal women, orally once daily, and for treating osteoporosis in men at high risk of fractures, orally once weekly. Non-proprietary
risedronic acid (produced by AAH, Actavis, Alliance Healthcare, Aspire, Aurobindo Pharma, Bluefish Pharmaceuticals AB, Dr Reddy’s Laboratories, Mylan UK, Phoenix Healthcare Distribution, Ranbaxy
Laboratories, Sandoz, Sovereign Medical, Teva UK and Zentiva N.V.) also has a UK marketing authorisation for the same indications.23
Risedronic acid in the treatment of postmenopausal osteoporosis to reduce the risk of vertebral or hip fractures is administered as 5 mg daily or 35 mg once weekly. For the prevention of osteoporosis (including glucocorticoid-induced osteoporosis) in postmenopausal women, treatment is administered as 5 mg daily. Treatment of osteoporosis in men at high risk of fractures is administered as 35 mg once weekly. Patients should remain seated or stand for at least 1 hour after administration.30
Zoledronic acid
Zoledronic acid (Aclasta®, Novartis Pharmaceuticals) has a UK marketing authorisation for treating postmenopausal osteoporosis and osteoporosis in men (including glucocorticoid-induced osteoporosis in postmenopausal women and men) by i.v. infusion once a year.
Zoledronic acid in the treatment of postmenopausal osteoporosis and osteoporosis in men (including glucocorticoid-induced osteoporosis in men and postmenopausal women) is administered by i.v. infusion, 5 mg over at least 15 minutes once a year. In patients with a recent low-trauma hip fracture, the dose should be given≥2 weeks following hip fracture repair.30Non-proprietary zoledronic acid (produced by Sun Pharmaceuticals Industries Ltd, Dr Reddy’s Laboratories and Teva UK) also has a UK marketing authorisation for the same indications.31
Contraindications, special warnings and precautions
The summary of product characteristics (SmPC) for each intervention describes the contraindications and special warnings for bisphosphonates.31–37
Alendronic acid
The alendronic acid 10-mg daily tablet and 70-mg weekly tablet are contraindicated in patients with abnormalities of the oesophagus or other factors that delay oesophageal emptying, such as stricture or
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achalasia, inability to stand or sit upright for at least 30 minutes, hypersensitivity to alendronic acid or to any of the excipients, or hypocalcaemia. Additional contraindications for the 70-mg oral solution are patients who have difficulty swallowing liquids and patients at risk of aspiration.32,33
Special warnings and precautions for use include patients with active upper gastrointestinal (GI) problems and patients with known Barrett’s oesophagus. Patients with signs or symptoms signalling a possible oesophageal reaction should be instructed to discontinue treatment. While on treatment, patients with concomitant risk factors for osteonecrosis of the jaw (e.g. cancer, chemotherapy, radiotherapy, glucocorticoids, poor oral hygiene, periodontal disease) should avoid invasive dental procedures if possible.32,33
Ibandronic acid
The ibandronic acid 150-mg tablet is contraindicated in patients with hypersensitivity to ibandronic acid or to any of the excipients, hypocalcaemia, abnormalities of the oesophagus that delay oesophageal
emptying, such as stricture or achalasia, or inability to stand or sit upright for at least 60 minutes. The 3 mg/3 ml solution for injection every 3 months is contraindicated in patients with hypersensitivity to ibandronic acid or to any of the excipients and in patients with hypocalcaemia.34,35
Special warnings and precautions for use include patients with existing hypocalcaemia and patients with active upper GI problems (e.g. known Barrett’s oesophagus, dysphagia, other oesophageal diseases, gastritis, duodenitis or ulcers) (oral administration). Intravenous administration may cause a transient decrease in serum calcium values. Adequate intake of calcium and vitamin D is important in all patients. Patients should be instructed to discontinue ibandronic acid and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn. While on treatment, patients with concomitant risk factors for osteonecrosis of the jaw (e.g. cancer, chemotherapy, radiotherapy, glucocorticoids, poor oral hygiene, periodontal disease) should avoid invasive dental procedures if possible.34,35
Risedronic acid
The risedronic acid 5-mg daily tablet and 35-mg weekly tablet are contraindicated in patients with hypersensitivity to the active substance or to any of the excipients, hypocalcaemia, or severe renal impairment (a creatinine clearance of<30 ml/minute) and during pregnancy and lactation.36,37
Special warnings and precautions for use include patients who have a history of oesophageal disorders that delay oesophageal transit or emptying (e.g. stricture or achalasia, patients who are unable to stay in the upright position for at least 30 minutes after taking the tablet and patients with active or recent oesophageal or upper GI problems, including known Barrett’s oesophagus). Patients should be instructed to seek timely medical attention if they develop symptoms of oesophageal irritation such as dysphagia, pain on swallowing, retrosternal pain or new or worsened heartburn. While on treatment, patients with concomitant risk factors for osteonecrosis of the jaw (e.g. cancer, chemotherapy, radiotherapy, glucocorticoids, poor oral hygiene, periodontal disease) should avoid invasive dental procedures if possible.36,37
Zoledronic acid
A 5-mg annual infusion of zoledronic acid is contraindicated in patients with hypersensitivity to the active substance, to any bisphosphonates or to any of the excipients, patients with hypocalcaemia, patients with severe renal impairment with a creatinine clearance of<35 ml/minute, and during pregnancy and breastfeeding.31
Special warnings and precautions for use are required in patients with severe renal impairment (creatinine clearance<35 ml/minute) and in those with pre-existing renal dysfunction or other risk factors, including advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy or dehydration occurring after administration, or with pre-existing hypocalcaemia. Adequate calcium and vitamin D intake are recommended. The incidence of post-dose symptoms occurring within the first 3 days after administration can be reduced with the administration of paracetamol (Panadol®, GlaxoSmithKline Consumer Healthcare) or ibuprofen [Nurofen, Reckitt Benckiser Healthcare (UK) Ltd].31
The SmPCs for each intervention also state that atypical subtrochanteric and diaphyseal femoral have been reported with bisphosphonate therapy; during bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.31–37
Place in treatment pathway
Alendronic acid is recommended as first-line treatment for the primary prevention of fragility fractures in postmenopausal women with osteoporosis who have an increased fracture risk. Risedronic acid, raloxifene, strontium ranelate and teriparatide are recommended for women at specific risk of fracture who cannot take alendronic acid.
In addition to first-line treatment for the primary prevention of fragility fractures in postmenopausal women, alendronic acid is also recommended as a treatment option for the secondary prevention of osteoporotic fragility fractures in postmenopausal women who are confirmed to have osteoporosis. Risedronic acid, raloxifene, strontium ranelate and teriparatide are recommended for women at specific risk of fracture who cannot take alendronic acid.24
Ibandronic acid and zoledronic acid do not have recommendations from NICE for the prevention of fragility fractures.
Denosumab is recommended as a treatment option for the primary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fracture who are unable to comply with the special instructions for administering alendronic acid and either risedronic acid or etidronic acid, or who have an intolerance of, or a contraindication to, those treatments.22
Identification of important subgroups
The final NICE scope specified subgroups based on patient characteristics that increase the risk of fracture (those specified in NICE CG146)16or that affect the impact of fracture on lifetime costs and outcomes.23 Current usage in the NHS
Data from thePrescription Cost Analysis: England 201338were analysed to determine the level of bisphosphonate usage within primary care across England in 2013. It can be seen from the data
summarised inTable 1that generic weekly alendronic acid was the most commonly prescribed preparation in primary care. Furthermore, generic prescriptions were more common than branded prescriptions across all treatments, where generic prescriptions were reported. Unlike primary care, there is no central NHS collation of information on medicines issued and used in NHS hospitals. However, a report on hospital prescribing in 201242provides data on treatments recommended by NICE. From table 4 of the report42it can be seen that the vast majority of prescribing for alendronic acid and risedronic acid occurred in primary care, with only 5% of the costs attributable to alendronic acid and risedronic acid prescribing occurring within secondary care. As data fromPrescription Cost Analysis: England 201338cover those medicines dispensed only in the community, and i.v. bisphosphonates are usually prescribed in secondary care, it should be noted that the figures inTable 1will underestimate the prescribing of i.v. ibandronic acid and zoledronic acid. Data on i.v. bisphosphonates are not included in hospital prescribing data, as data were provided for individual drugs only if they had already been recommended by NICE.
Anticipated costs associated with interventions
Table 1summarises the 2014 net costs associated with the interventions based on their list prices.23 A list price was not available for generic zoledronic acid so the price reported in the manufacturer’s product catalogue has been included inTable 1.
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TABLE 1 Summary of dosages, preparations, list prices and primary care prescribing for bisphosphonates treatments
Interventions
Dosing schedule
Generic or
branded Description of preparations List price per unit
Prescriptions in thousandsa
Alendronic acid (oral)
Daily, 10 mg Branded Fosamax tablets, alendronic acid (as sodium alendronate), 10 mg
28-tablet pack=£23.12b
0.749 Generic Tablets, alendronic acid
(as sodium alendronate), 10 mg
28-tablet pack=£2.17b
46.605 Weekly,
70 mg
Branded Fosamax tablets, alendronic acid (as sodium alendronate), 70 mg
Four-tablet pack=£22.80b
25.655 Generic Tablets, alendronic acid
(as sodium alendronate), 70 mg
Four-tablet pack=£1.01b
7273.660 Oral solution, sugar-free,
alendronic acid (as sodium alendronate), 70 mg/100 ml
Four × 100 ml=
£22.80b 10.442
Risedronic acid (oral)
Daily, 5 mg Branded Actonel tablets, risedronate sodium, 5 mg (yellow)
28-tablet pack=£17.99b
1.023 Generic Tablets, risedronate sodium,
5 mg 28-tablet pack=£13.24b 25.777 Weekly, 35 mg
Branded Actonel Once a Week tablets, orange, risedronate sodium, 35 mg
Four-tablet pack=£19.12b
19.961
Generic Tablets, risedronate sodium, 35 mg Four-tablet pack=£1.18b 679.026 Ibandronic acid (oral) Monthly, 150 mg
Branded Bonviva tablet, 150 mg One-tablet pack=£18.40b
22.670 Three-tablet
pack=£55.21b Generic Ibandronic acid tablet, 150 mg 150-mg tablet,
one-tablet pack=£1.61c
204.006
Ibandronic acid tablet, 50 mg 50-mg tablet, 28-tablet pack=£10.78b Ibandronic acid (i.v.) Quarterly, 3 mg
Branded Bonviva injection, 3 mg/3 ml 3-ml prefilled syringe=£68.64b
0.181 Generic Ibandronic acid injection,
3-mg/3-ml prefilled syringe 3-ml prefilled syringe=£65.20c 0.324 Zoledronic acid (i.v.) Annually, 5 mg
Branded Aclasta i.v. infusion, 5-mg/100-ml bottle
100-ml
bottle=£253.38b
0.070 Generic i.v. infusion, zoledronic acid,
5 mg/100 ml
100-ml
bottle=£217.68d
Not reported
MIMS,Monthly Index of Medical Specialities. a Prices based onBritish National Formulary.39
b Prescription items dispensed in the community in 201338
(prescriptions for i.v. bisphosphonates dispensed in secondary care are not captured in these figures).
c Prices based on MIMS.40