Guidance on which patients to treat
Management of osteoporosis to reduce fracture risk has been addressed by a variety of bodies in the past decade, giving different approaches. Links to summaries of national guidance are given below and some areas may have locally agreed protocols in place that describe which patients can access which treatments.
In England and Wales, NICE Technology Appraisals provide guidance on postmenopausal women with osteoporosis. Whether or not a postmenopausal woman with osteoporosis is offered one of the drugs to prevent bone fractures will depend on her age, her bone density and how many risk factors for fracture and indicators of fragile bones she has. In the Quality and Outcomes Framework indicators, it is assumed that the NICE treatment thresholds should also be applied to men over 50, and this is the practice in many locations.
NICE TA160: Alendronate, Etidronate, Risedronate, Raloxifene and Strontium Ranelate for the Primary Prevention of Osteoporotic Fragility Fractures in Postmenopausal Women.
NICE TA161: Alendronate, Etidronate, Risedronate, Raloxifene, Strontium Ranelate and Teriparatide for the Secondary Prevention of Osteoporotic Fragility Fractures in Postmenopausal Women.
NICE TA204: Denosumab for the Prevention of Osteoporotic Fractures in Postmenopausal Women. NICE recommends denosumab as a possible treatment for preventing bone fractures in postmenopausal women with osteoporosis who can't take alendronate and either risedronate or etidronate. It is appropriate to use for both primary and secondary fracture prevention.
In Northern Ireland, guidance produced by NICE is generally applied. However, Guidance on the Prevention and Treatment of Osteoporosis was published by CREST (now superseded by GAIN) in March 2001. A short update statement was published in July 2004.
In Scotland, the Scottish Intercollegiate Guidelines Group published SIGN 71: Management of Osteoporosis in 2003. A quick reference guide is also available. The guidance makes recommendations on the management of osteoporosis in men and women over the age of 60. This guideline is currently being updated.
The Royal College of Physicians published Glucocorticoid-Induced Osteoporosis: Guidelines for Prevention and Treatment in 2002, which makes recommendations specific to this high risk group. The administration of oral glucocorticoids is associated with a significant increase in fracture risk at the hip and spine. Although the greatest increase in risk is observed with higher dose therapy, increased risk is seen even at daily doses of prednisolone less than 7.5 mg. Fracture risk increases rapidly after the onset of treatment and declines rapidly after stopping therapy.
The National Osteoporosis Guideline Group (NOGG) has published Guideline for the Diagnosis and Management of Osteoporosis in Postmenopausal Women and Men from the Age of 50 Years in the UK. It makes recommendations on the UK interpretation of the fracture risk assessment tool, FRAX(r), providing intervention thresholds and recommendations. The guidance was updated in 2013 to include sections on treatment of glucocorticoid-induced osteoporosis, rare side effects, and duration and monitoring of treatment.
Which drug to use
All the available drugs are effective in reducing fracture risk in those with osteoporosis, although some, due to their higher cost, are usually reserved for severe disease or people who are intolerant of first-line therapies. An overview of osteoporosis drug treatments can be found on the National Osteoporosis Society website as well as an information leaflet for patients. Further information on the individual treatment options is available from the links below:
NICE and NOGG both agree that generic alendronate should be first-line therapy unless contraindicated, since this is the most cost-effective. Giving the choice of a liquid preparation for alendronate may improve adherence.
Risedronate is now also generic, may be better tolerated and is also recommended for first-line use in some areas, although this was not its positioning in the NICE appraisals. This was simply due to the fact that at the time of the economic modeling for the NICE guidelines risedronate was more expensive: the TAG 161 has not yet been updated to take this change of lower cost risedronate into account. Although cyclical etidronate is recommended in NICE guidance, it is a weaker bisphosphonate and has no randomised controlled trial evidence of hip fracture reduction and is therefore very rarely prescribed now. This treatment was previously available as Didronel PMO. However, as it is used infrequently in clinical practice, it has been withdrawn.
Intravenous zoledronate is given by an infusion, and is generally well-tolerated but may cause flu-like symptoms due to an acute phase reaction, especially after the first dose. NICE has not provided guidance on thresholds for use and as a result it is used at the discretion of the clinician. Intravenous zoledronate is approved for the use of glucocorticoid-induced osteoporosis (whereas, for example, denosumab does not have that license). It is also used in Paget's disease. It can be used in those who qualify for but are intolerant of oral bisphosphonates, and who do not meet the criteria for other therapies. But it is up to the whim of individual CCGs policy across England (check local guidelines).
Bisphosphonates are poorly absorbed and it is important that they are taken correctly to optimise absorption and minimise side effects. Guidance on how to take these drugs should be provided when treatment is initiated and at every review (and be reiterated by pharmacists). Upper gastrointestinal side effects should prompt change of therapy rather than attempts to treat these with proton pump inhibitors.
There may be an increased risk of osteonecrosis of the jaw (ONJ) and atypical subtrochanteric fractures with prolonged therapy (i.e. more than 5-10 years of use.) Although these side effects are uncommon, some patients may be very concerned about them. Discussion about the benefit of treatment versus the occurrence of these side effects may help alleviate their anxiety. The incidence of ONJ in oral bisphosphonate therapy for osteoporosis is low - between 1 in 10,000 and 1 in 100,000. For each case of atypical fracture occurring during long-term bisphosphonate therapy, it is estimated that 50 hip fractures are prevented.
Calcium and vitamin D
•Fultium (vitamin D only)
NICE guidance assumes that women receiving osteoporosis treatment have an adequate calcium intake and are vitamin D replete, and NOGG advocates correction of nutritional deficiencies, particularly of calcium and vitamin D. Those with osteoporosis and who are taking drug treatments may benefit from increasing their intake of calcium to around 1000 mg and vitamin D to around 800 IU daily as patients did in the clinical trials that proved osteoporosis treatments were effective.
Calcium and vitamin D3 supplementation is routine practice in those on treatment with bone-sparing agents who are unlikely to be replete. It is worth highlighting that large-scale meta-analyses have suggested that calcium supplements with or without vitamin D, in those with an adequate dietary intake, may be associated with a small increase in cardiovascular events. However, there has been much controversy around this data and experts suggest that there is insufficient data to change practice. Food remains the best source of calcium but supplements should be considered if dietary calcium intake is insufficient.
Denosumab is a monoclonal human antibody to RANK ligand, which has antiresorptive effects. It is given twice-yearly by subcutaneous injection. Currently some CCGs recommended that treatment be initiated in secondary care but transferred to primary care after one or two doses. But in other CCGs (e.g. Oxfordshire) denosunab can be initiated by a GP in primary care for secondary prevention, provided the guidelines are adhered to. NICE has recommended treatment thresholds for primary and secondary prevention.
Hormone Replacement Therapy
HRT is an effective treatment for menopausal symptoms that also offers protection against fractures at both hip and spine. For the large proportion of women affected by osteoporosis who are over the age of 60, HRT is not considered a suitable treatment for osteoporosis. However, in the under-60 age group HRT still has a role to play in the management of osteoporosis.
The National Osteoporosis Society's position statement, HRT in the Treatment and Prevention of Osteoporosis outlines in full its recommendations about the role of HRT in bone health.
Parathyroid hormone (teriparatide and recombinant human PTH 1-84) use is restricted to patients with a low T-score (NICE) or high risk of fracture (NOGG).
Raloxifene reduces vertebral fractures but not hip fractures and is therefore less cost-effective and is restricted in NICE secondary prevention guidance (found at the top of this page) to use in those with previous fractures and a specified combination of risk factors and DXA T-scores. It reduces the risk of developing an oestrogen receptor positive breast cancer.
Strontium ranelate has a different mode of action to bisphosphonates that is not clearly understood. It reduces hip, vertebral and non-vertebral fractures. NICE guidance recommends its use only in those who meet specific combinations of risk factors and T-scores. It is contraindicated in those with a previous history of DVT. Rarely it can cause severe allergic skin reactions including DRESS. Patients should be warned to discontinue treatment and seek medical care immediately if a rash develops. Patients on Strontium with known cardiovascular risks have been shown to double their future cardiovascular events, leading to an MHRA warning in March 2014.
Strontium ranelate is now restricted to the treatment of severe osteoporosis in postmenopausal women and adult men at high risk of fracture who cannot use other osteoporosis treatments due to, for example, contraindications or intolerance. Treatment should only be started by a physician with experience in the treatment of osteoporosis.
The risk of developing cardiovascular disease should be assessed before starting treatment. Treatment should not be started in people who have or have had:
•ischaemic heart disease
•peripheral arterial disease
Cardiovascular risk should be monitored every 6-12 months
Treatment should be stopped if the individual develops ischaemic heart disease, peripheral arterial disease, or cerebrovascular disease, or if hypertension is uncontrolled.
Alternatives to oral therapies
People with osteoporosis who cannot tolerate oral therapies should be referred to secondary care (or if allowed in your local CCG guidelines, initiated in primary care) for consideration of subcutaneous denosumab, or intravenous zoledronate.