Professors Juliet Compston (left) and Eugene McCloskey explain how the updated NOGG guideline covers all approved drug interventions and possible treatment complications
Osteoporotic fractures are a major public health problem in the elderly population, causing significant morbidity and mortality and imposing huge economic costs on health and social services. One in three women and one in five men over the age of 50 years will have a fracture during their remaining lifetime,1 with estimated annual costs of over £2 billion.2 These fractures account for more hospital bed days than ischaemic heart disease, chronic obstructive pulmonary disease, diabetes, or heart failure.1 Despite the availability of a range of pharmacological interventions that reduce fracture risk, the majority of elderly men and women at increased risk of fracture do not receive appropriate investigation and treatment.3,4
NICE amended its technology appraisals on primary and secondary prevention of osteoporotic fractures in 2011; these appraisals provide recommendations on the use of alendronate, etidronate, risedronate, and strontium ranelate for primary prevention and these therapies plus raloxifene and teriparatide for secondary prevention of osteoporotic fractures. These technology appraisals remain cumbersome, limited in their scope, exclude men and people taking glucocorticoids, and do not cover some of the more newly approved interventions (see below).5–8 The National Osteoporosis Guideline Group (NOGG) has addressed these deficits in its guideline and bases its intervention thresholds on 10-year fracture probability estimated by the FRAX® tool.9,10
New indications: zoledronate and teriparatide
Over the past 2 years new indications have been added for certain osteoporotic interventions:
- In addition to its indication in post-menopausal women at increased risk of fracture, zoledronate is now also approved for treatment of men at increased risk of fracture and for the treatment of osteoporosis associated with long-term systemic glucocorticoid therapy in men and post-menopausal women11
- Similarly, the approval for teriparatide has been extended from post-menopausal women at increased risk of fracture to men and to glucocorticoid-treated individuals at increased risk of fracture.12
Denosumab is a fully humanised monoclonal antibody to receptor activator of NFkB ligand (RANKL), a major regulator of osteoclast development and activity.13 It is approved for the treatment of osteoporosis in post-menopausal women at increased risk of fractures and is given as a subcutaneous injection of 60 mg once every 6 months.14 Denosumab has been shown to reduce the incidence of fractures in post-menopausal women with osteoporosis. The FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) study was a randomised placebo-controlled double-blind trial in 7868 post-menopausal women with osteoporosis. The results from this trial demonstrated that 3 years’ treatment with denosumab was associated with a:13
- 68% reduction in vertebral fractures
- 20% reduction in non-vertebral fractures
- 40% reduction in hip fractures.
Denosumab is suitable for administration in primary care, although some PCTs request that the first injection is given in secondary care, with subsequent injections in primary care. When therapy is stopped, there is a rapid increase in bone turnover and decrease in bone mineral density (BMD), so it is important that individuals receiving this treatment are followed up, and if treatment with denosumab is stopped, alternative bone protective therapy is given.15
Denosumab, like most other anti-resorptive therapies in osteoporosis, is contraindicated in women with hypocalcaemia, and vitamin D status should be assessed and, if appropriate, corrected before administration.13 No dose adjustment is required in patients with renal impairment. Side-effects include skin infection, predominantly cellulitis, and hypocalcaemia.1
Osteonecrosis of the jaw and atypical femoral fractures
In the past few years osteonecrosis of the jaw (ONJ) and atypical femoral fractures have emerged as possible complications of bisphosphonate therapy. Both occur only very rarely; the incidence of ONJ in patients receiving bisphosphonate therapy for osteoporosis is estimated at <1/100,000 person years while atypical femoral fractures comprise only about 1% of all hip and femoral fractures.16,17 Osteonecrosis of the jaw, but not atypical femoral fractures, has also been reported in patients receiving denosumab therapy. There is some evidence that both conditions are related to the duration of therapy. In the case of ONJ, there also appears to be a relationship with dose: higher incidence rates being reported in oncology patients receiving higher doses of bisphosphonates or denosumab.18 The product information for bisphosphonates and denosumab has been updated to contain warnings about ONJ and warnings about atypical femoral fractures are now included in the product information for bisphosphonates (see individual summaries of product characteristics).19
Development of NICE guidance for osteoporosis was started in 2002, but following several appeals and judicial reviews, final appraisal determination documents were not issued until 2008 and were subsequently amended in 2010 and 2011.5,6 The guidance is now outdated since it does not include zoledronate or ibandronate and recommends etidronate—a drug for which the evidence base is weak—as a second-line treatment option. In addition, the guidance excludes men, individuals on glucocorticoids, and post-menopausal women aged ≤75 years who are not osteoporotic as defined by a BMD T-score of ≤-2.5 standard deviations, whether or not they have sustained one or more fragility fractures.
In October 2010, a single technology appraisal on denosumab was performed by NICE.7 This permits the use of denosumab as a second-line agent to alendronate in post-menopausal women with a fragility fracture, provided that they are also contraindicated to or intolerant of risedronate or etidronate.7 The use of denosumab for primary prevention is more restrictive, with the need for more stringent BMD and risk factor criteria than those required for alendronate.5,7
The clinical guideline that should have accompanied the NICE final appraisal determinations in 2008 was suspended by NICE before its completion. NICE has recently announced that it intends to develop a short clinical guideline that will address fracture risk assessment, but not treatment.20
- is web-based
- provides a simple and rapid approach to the management of osteoporosis
- is underpinned by cost-effectiveness analysis21
- covers the management of osteoporosis in women and men, including those receiving glucocorticoids
- takes account of all approved interventions
- emphasises that the recommendations are designed to aid management decisions, but should not replace clinical judgement.
Treatment thresholds in the NOGG guideline are based on the previous Royal College of Physicians guidelines of 2000 and 2002,22,23 but risk assessment is performed using the WHO-supported fracture risk algorithm FRAX (see Figure 1).24,25 The addition, in FRAX, of clinical factors that contribute independently to risk improves fracture prediction and reduces the need for bone densitometry in high- and low-risk individuals. Following estimation of 10-year fracture probability using FRAX, the values are automatically superimposed on charts containing the intervention thresholds.26 In cases where the FRAX estimation is made without a measurement of BMD and the 10-year probability lies in an intermediate zone, BMD measurement is recommended and its value included in reassessment using FRAX.
NOGG recommends a case-finding strategy in which individuals are identified on the basis of a fragility fracture or the presence of clinical risk factors. Treatment should be considered in post-menopausal women with a fragility fracture; measurement of BMD is not necessary in all cases, but may be useful in younger women or if there is uncertainty about the degree of trauma involved in the fracture.
Alendronate is recommended as the first-line treatment option because of its superior cost effectiveness. In the substantial minority of women unable to take or tolerate alendronate, second-line options include other bisphosphonates including zoledronic acid, denosumab, raloxifene, and strontium ranelate. Unlike NICE, NOGG does not require more stringent treatment criteria for second-line options than those for alendronate. Because of their significantly higher cost, parathyroid hormone peptides are reserved for very high-risk individuals and those unable to take any of the other approved interventions.1
In men with fracture and in post-menopausal women and men aged over 50 years without fracture in whom clinical risk factors are present, fracture risk assessment using FRAX is recommended, with BMD if indicated. Treatment recommendations for those achieving the intervention threshold are the same as for post-menopausal women with a fragility fracture.1
|Figure 1: The WHO fracture risk assessment tool (FRAX®)10|
Reproduced with kind permission from the WHO Collaborating Centre for Metabolic Bone Diseases www.shef.ac.uk/FRAX/
Role of primary care
Recent advances in risk assessment and treatment offer the opportunity for better detection of men and women at risk of fracture and implementation of cost-effective therapies, thus reducing the clinical and economic burden of osteoporosis. Primary care healthcare professionals have a key role in identifying individuals at risk of fracture and ensuring that those who have sustained a fragility fracture receive appropriate management.
General practitioners also have an important role in the management of patients receiving denosumab therapy. Although arrangements may vary between primary care trusts, the process most commonly followed is for the first injection to be given in the secondary care setting and subsequent injections delivered in primary care. General practitioners will therefore need to ensure that shared-care guidelines are followed and that appropriate follow-up arrangements are in place.
Over the past year, documents on the NOGG website have been updated to include the new indications for zoledronate and teriparatide in men and in individuals receiving glucocorticoid therapy. Information on denosumab has been added following regulatory approval of this intervention in 2010. Finally, a section has been added with updated information on ONJ and atypical femoral fractures.
FRAX is available for 30 countries in 13 languages (www.shef.ac.uk/FRAX) and is now incorporated increasingly into assessment guidelines including the US.27 Its major use is through the website, which currently receives around 8000–9000 visits per working day. The NOGG website can be accessed directly from the FRAX website and receives approximately 400–450 visits per working day. In addition to the website, FRAX has been incorporated into dual energy X-ray absorptiometry scanners to provide FRAX probabilities at the time of scanning. For those without internet access, handheld calculators and an application for the iPhone and iPad have been developed by the International Osteoporosis Foundation (itunes.apple.com/gb/app/frax/id370146412?mt=8). It is expected that FRAX/NOGG will shortly be incorporated into primary care software systems and standalone versions will be downloadable from the internet for offline use.
The National Osteoporosis Guideline Group gratefully acknowledges the collaboration of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the support of the Bone Research Society, British Geriatrics Society, British Orthopaedic Association, British Society of Rheumatology, International Osteoporosis Foundation, National Osteoporosis Society, Osteoporosis 2000, Osteoporosis Dorset, Primary Care Rheumatology Society, Royal College of Physicians and Society for Endocrinology.
- Morbidity from fragility fractures secondary to osteoporosis is a major burden on NHS resources especially for non-elective admission budgets
- Commissioners can help reduce this burden and improve health through effective targeted interventions in at-risk groups
- Effective secondary prevention in people who have already sustained a fragility fracture (as incentivised through the osteoporosis directed enhanced service) is probably the most cost-effective intervention
- In the absence of comprehensive NICE guidance, local osteoporosis specialists and GP commissioners should define local pathways and formularies, drawing on NICE and NOGG guidance, for the use of bone-protection agents for fragility fractures in at-risk groups
- GP commissioners will need to balance the immediate cost of bone protection agents and DXA scans against possible future reductions in their non-elective admission budgets
- Tariff prices:a,b
- Non-elective admission for fractured neck of femur best practice tariff (HA11A) = £9423
- DXA scan (RA15Z) non mandatory tariff = £68
- Alendronic acid 70 mg = £1.08 per month
- Calcium and vitamin D supplements (prices vary with preparation) costs approximately £3.88 per month
- Denosumab injection every 6 months = £183 for 60 mg/ml.
- National Osteoporosis Guideline Group on behalf of the Bone Research Society, British Geriatrics Society, British Orthopaedic Association, British Society of Rheumatology, National Osteoporosis Society, Osteoporosis 2000, Osteoporosis Dorset, Primary Care Rheumatology Society, and Society for Endocrinology. Osteoporosis—clinical guideline for prevention and treatment. Executive summary. London: NOGG, 2010. Available at: www.shef.ac.uk/NOGG/downloads.html
- Burge R, Worley D, Johansen A et al. The cost of osteoporotic fractures in the UK: projections for 2000–2020. J Med Economics 2001; 4 (1–4): 51–62.
- Hippisley-Cox J, Bayly J, Potter J et al. Evaluation of standards of care in osteoporosis and falls in primary care. London: QRESEARCH and The Information Centre for Health and Social Care, 2007. Available at: www.ic.nhs.uk/statistics-and-data-collections/primary-care/general-practice/evaluation-of-standards-of-care-for-osteoporosis-and-falls-in-primary-care
- Premaor M, Pilbrow L, Tonkin C et al. Low rates of treatment in postmenopausal women with a history of low trauma fractures: results of audit in a Fracture Liaison Service. QJM 2010; 103 (1): 33–40.
- National Institute for Health and Care Excellence. Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women (amended). Technology Appraisal 160. London: NICE, 2011. Available at: www.nice.org.uk/TA160
- National Institute for Health and Care Excellence. Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women (amended). Technology Appraisal 161. London: NICE, 2011. Available at: www.nice.org.uk/TA161
- National Institute for Health and Care Excellence. Denosumab for the prevention of osteoporotic fractures in postmenopausal women. Technology Appraisal 204. London: NICE, 2010. Available at: www.nice.org.uk/guidance/TA204
- Kanis J, McCloskey E, Jönsson B et al. An evaluation of the NICE guidance for the prevention of osteoporotic fragility fractures in postmenopausal women. Arch Osteoporosis 2010; 5 (1–2): 19–48.
- Compston J, Cooper A, Cooper C et al. National Osteoporosis Guideline Group (NOGG). Guidelines for the diagnosis and management of osteoporosis in postmenopausal women and men from the age of 50 years in the UK. Maturitas 2009; 62 (2): 105–108.
- National Osteoporosis Guideline Group website. www.shef.ac.uk/NOGG/
- Novartis Pharmaceuticals UK Ltd. Aclasta summary of product characteristics. May 2010. www.medicines.org.uk/EMC/medicine/18171/SPC/Aclasta+5+mg+solution+for+infusion/
- Eli Lilly and Company Limited. Forsteo summary of product characteristics. November 2010. www.medicines.org.uk/EMC/medicine/12561/SPC/Forsteo+20+micrograms+80+microlitres%2c+solution+for+injection%2c+in+pre-filled+pen/
- Cummings S, San Martin J, McClung M; FREEDOM Trial et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009; 361 (8): 756–765.
- Amgen Ltd. Prolia summary of product characteristics. December 2010. www.medicines.org.uk/EMC/medicine/23127/SPC/Prolia/
- Bone H, Bolognese M, Yuen C et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab 2011; 96 (4): 972–980.
- Khosla S, Burr D, Cauley J et al; American Society for Bone and Mineral Research. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007; 22 (10): 1479–1491.
- Giusti A, Hamdy N, Dekkers O et al. Atypical fractures and bisphosphonate therapy: a cohort study of patients with femoral fracture with radiographic adjudication of fracture site and features. Bone 2011; 48 (50): 966–971.
- Stopeck A, Lipton A, Body J et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 2010; 28 (35): 5132–5139.
- electronic Medicines Compendium website. www.medicines.org.uk/EMC/ (accessed 25 May 2011).
- National Institute for Health and Care Excellence website. Osteoporosis: risk assessment of people with osteoporosis. www.nice.org.uk/guidance/CG/Wave25/2 (accessed 23 May 2011).
- Kanis J, Adams J, Borgström F et al. The cost-effectiveness of alendronate in the management of osteoporosis. Bone 2008; 42 (1): 4–15.
- Royal College of Physicians, Bone and Tooth Society of Great Britain. Osteoporosis—clinical guidelines for prevention and treatment; update on pharmacological interventions and an algorithm for management. London: RCP, 2000.
- Bone and Tooth Society, National Osteoporosis Society, Royal College of Physicians. Glucocorticoid-induced osteoporosis: guidelines for prevention and treatment. London: RCP, 2002.
- Kanis J on behalf of the World Health Organization Scientific Group. Assessment of osteoporosis at the primary health-care level. Technical Report. WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, 2008.
- University of Sheffield website. FRAX®—WHO fracture risk assessment tool. www.shef.ac.uk/FRAX (accessed 23 May 2011).
- Kanis J, McCloskey E, Johansson H et al; National Osteoporosis Guideline Group. Case finding for the management of osteoporosis with FRAX®—assessment and intervention thresholds for the UK. Osteoporos Int 2008; 19 (10): 1395–1408.
- National Osteoporosis Foundation. Clinician's guide to prevention and treatment of osteoporosis. Washington DC, USA: National Osteoporosis Foundation, 2008.G