Clinical Topic A-Z Clinical Speciality

Osteoporosis - prevention of fragility fractures

Osteoporosis - prevention of fragility fractures
D010024Osteoporosis
D015663Fractures, Bone
D050723
Osteoporosis, Postmenopausal
MusculoskeletalPreventative medicine
2013-09-01Last revised in September 2013

Osteoporosis - prevention of fragility fractures - Summary

Osteoporosis is a disease characterized by low bone mass and structural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporosis itself is asymptomatic and often remains undiagnosed until a fragility fracture occurs.

An osteoporotic fracture is a fragility fracture occurring as a consequence of increased bone fragility caused by osteoporosis. Characteristically fractures occur in the wrist, spine and hip. A fragility fracture is defined as a fracture following a fall from standing height or less, although vertebral fractures may occur spontaneously, or as a result of routine activities.

In England and Wales, around 180,000 fractures present each year as a result of osteoporosis.

Risk factors for osteoporosis include:

Female gender.

Age.

Oral corticosteroids.

Smoking.

Alcohol.

Previous fragility fractures.

Rheumatological conditions.

Parental history of hip fracture.

Body mass index of less than 19 kg/m2.

Osteoporotic fracture risk is calculated using an assessment tool that calculates risk based on a person's risk factors. Recommended tools include FRAX® and QFracture®.

People at high risk are offered treatment without further assessment.

People at intermediate risk are offered a DEXA scan and their fracture risk recalculated incorporating their bone mineral density to more accurately determine their fracture risk using FRAX®. People found to be above the treatment threshold are offered treatment.

People at low risk are not offered treatment nor a DEXA scan.

Women who have experienced a premature menopause should be offered treatment with hormone replacement therapy to reduce their risk of osteoporotic fracture, and for the relief of menopausal symptoms.

Premenopausal women and men under 50 years of age who have had an osteoporotic fracture should be referred for specialist management.

Postmenopausal women and men over 50 years of age who are at high risk of an osteoporotic fracture should be offered treatment with a bisphosphonate. People who cannot take a bisphosphonate should be referred to secondary care for consideration of an alternative treatment such as strontium ranelate, raloxifene, denosumab, and teriparatide.

Risk factors for osteoporosis, such as smoking, alcohol consumption, calcium deficiency and vitamin D deficiency, should be managed if present.

Risk factors for falls should be managed if present.

Follow up should be arranged to assess and manage the:

Adverse effects of treatment.

Adherence to treatment.

Need for continuing treatment with bisphosphonates.

Have I got the right topic?

216months3060monthsBoth

This CKS topic is based on the National Institute for Health and Care Excellence (NICE) guideline Osteoporosis: assessing the risk of fragility fracture [National Clinical Guideline Centre, 2012] which makes recommendations on when and how to assess men and women of all ages, including people taking oral corticosteroids, for their fragility fracture risk. This topic also takes into account the National Osteoporosis Guideline Group's Guideline for the diagnosis and management of osteoporosis [NOGG, 2013].

This CKS topic covers the prevention of osteoporotic fragility fractures in postmenopausal women, men over 50 years of age and people of any age who are taking oral corticosteroids.

This CKS topic does not cover the prevention of osteoporosis, or the prevention and management of secondary osteoporosis, other than corticosteroid induced osteoporosis. There are separate CKS topics on, Coeliac disease, Crohn's disease, and Ulcerative colitis, which cover the prevention and management of secondary osteoporosis in these situations.

There is also a separate CKS topic on Falls - risk assessment.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary health care.

How up-to-date is this topic?

How up-to-date is this topic?

Changes

Last revised in September 2013

February 2014 — minor update. Update to the text to reflect the European Medicines Agency's (EMA) recommendations regarding strontium ranelate use, which is restricted to people who cannot be treated with other medicines approved for osteoporosis [EMA, 2014].

June to September 2013 — reviewed. A literature search was conducted in April 2013 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of this topic. The guideline has been extensively re-written to take into account the new method of assessment recommended by the National Institute of Health and Clinical Excellence (NICE) [National Clinical Guideline Centre, 2012] as well as new guidance issued by the National Osteoporotic Guideline Group [NOGG, 2013]. The guideline also takes into account new recommendations for prescribing vitamin D issued by the Department of Health [DH, 2012]. Recommendations for Didronel PMO® (a two component drug containing 400 mg of etidronate disodium and 1250 mg of calcium carbonate) have been removed from the topic, following the discontinuation of the product.

Previous changes

January 2013 — minor update. Change to the text to reflect updated prescribing advice for strontium ranelate, issued by the Medicines and Healthcare products Regulatory Agency (MHRA) regarding venous thromboembolism and adverse skin reactions [MHRA, 2012a].

October 2012 — minor update. The 2012 QIPP options for local implementation have been added to this topic [NPC, 2012].

March 2012 — minor update. The 2012/2013 QOF indicators have been added to this topic [BMA and NHS Employers, 2012]. Issued in April 2012.

January 2012 — minor update. Minor text change clarifying the definition of a T-score reference standard. Issued in January 2012.

September 2011 — minor update. A tool to assess if postmenopausal women meet NICE eligibility criteria for DXA scanning and drug treatment to prevent osteoporotic fragility fractures has been removed from the text. In addition a minor typographical error has been corrected. Issued in October 2011.

June 2011 — minor update. Prescribing information on atypical stress fractures and oral bisphosphonate treatment replaced. Issued in June 2011.

May 2011 — minor update. The 2010/2011 QIPP options for local implementation have been added to this topic [NPC, 2011]. Issued in June 2011.

November 2010 to December 2010 — this is a new CKS topic. The evidence-base has been reviewed in detail, and recommendations are clearly justified and transparently linked to the supporting evidence.

Update

New evidence

Evidence-based guidelines

Evidence-based guidelines published since the last revision of this topic:

Moyer, V.A. (2013) Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Service Task Force recommendation statement. Annals of Internal Medicine 158(9), 691-696. [Abstract] [Free Full-text]

HTAs (Health Technology Assessments)

No new HTAs since 1 April 2013.

Economic appraisals

No new economic appraisals relevant to England since 1 April 2013.

Systematic reviews and meta-analyses

Systematic reviews published since the last revision of this topic:

Eriksen, E.F., Diez-Peres, A. and Boonen, S. (2014) Update on long-term treatment with bisphosphonates for postmenopausal osteoporosis: a systematic review. Bone 58, 126-135. [Abstract]

Serrano, A.J., Begona, L., Anitua, E., et al. (2013) Systematic review and meta-analysis of the efficacy and safety of alendronate and zoledronate for the treatment of postmenopausal osteoporosis. Gynecological Endocrinology 29(12), 1005-1014. [Abstract]

Sharma, A., Chatterjee, S., Arbab-Zadeh, A., et al. (2013) Risk of serious atrial fibrillation and stroke with use of bisphosphonates: evidence from a meta-analysis. Chest 144(4), 1311-1322. [Abstract]

Varenna, M., Bertolda, F., Di Monaco, M., et al. (2013) Safety profile of drugs used in the treatment of osteoporosis: a systematical review of the literature. Reumatismo 65(4), 143-166. [Abstract] [Free Full-text]

Primary evidence

Randomized controlled trials published since the last revision of this topic:

Tsai, J.N., Uihlein, A.V., Lee, H., et al. (2013) Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial. Lancet 382(9886), 50-56. [Abstract]

New policies

No new national policies or guidelines since 1 April 2013.

New safety alerts

No new safety alerts since 1 April 2013.

Changes in product availability

No changes in product availability since 1 April 2013.

Goals and outcome measures

Goals

To support primary health care professionals:

To detect people at risk of osteoporotic fragility fractures

To minimize their risk of new or repeat osteoporotic fragility fractures

QOF indicators

Table 1 . Indicators related to osteoporosis: prevention of fragility fractures in the Quality and Outcomes Framework (QOF) of the General Medical Services (GMS) contract.
Indicator Points Payment stages
OST001 The contractor establishes and maintains a register of patients: 1. Aged 50 or over who have not attained the age of 75 with a record of a fragility fracture on or after 1 April 2012 and a diagnosis of osteoporosis confirmed on DXA scan, and 2. Aged 75 or over with a record of a fragility fracture on or after 1 April 2012 3 -
OST002 The percentage of patients aged 50 or over who have not attained the age of 75, with a fragility fracture on or after 1 April 2012, in whom osteoporosis is confirmed on DXA scan, who are currently treated with an appropriate bone-sparing agent 3 30–60%
OST003 The percentage of patients aged 75 or over with a fragility fracture on or after 1 April 2012, who are currently treated with an appropriate bone-sparing agent 3 30–60%
RA004 The percentage of patients aged 50 or over, and who have not attained the age of 91, with rheumatoid arthritis who have had an assessment of fracture risk using a risk assessment tool adjusted for rheumatoid arthritis in the preceding 24 months 5 40–90%
Data from: [BMA and NHS Employers, 2013]

Background information

Definition

What are osteoporosis and osteoporotic fractures?

Osteoporosis is a disease characterized by low bone mass and structural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporosis itself is asymptomatic, and it often remains undiagnosed until a fragility fracture occurs.

Osteoporosis is defined by the World Health Organization as a bone mineral density (BMD) of 2.5 standard deviations below the mean peak mass (average of young healthy adults) as measured by dual-energy X–ray absorptiometry (DEXA) applied to the femoral neck and reported as a T-score. However, BMD measurement does not assess the structural deterioration in bone and consequently, most osteoporotic fractures occur in women who do not have osteoporosis as defined by a T-score equal to or less than –2.5.

An osteoporotic fracture is a fragility fracture occurring as a consequence of osteoporosis. Characteristically, fractures occur in the wrist, spine, and hip, but they can also occur in the arm, pelvis, ribs, and other bones.

A fragility fracture is defined as a fracture following a fall from standing height or less, although vertebral fractures may occur spontaneously or as a result of routine activities such as bending or lifting. Fragility fractures may be the consequence of osteoporosis or other more serious conditions affecting bone such as metastatic bone cancer or myeloma.

A major osteoporotic fracture is defined as an osteoporotic fracture of the spine, hip, forearm, or proximal humerus.

[Compston, 2010; NOGG, 2013]

Causes

What causes osteoporosis and osteoporotic fractures?

Osteoporosis is the end result of an imbalance in the normal process of bone remodelling by osteoclasts and osteoblasts.

During normal ageing, bone breakdown by osteoclasts increases and is not balanced by new bone formation by osteoblasts, resulting in a combination of:

Reduced bone mineral density (BMD) which can be measured by dual energy X-ray absorptiometry (DEXA) scanning.

Changes in bone composition, architecture, size, and geometry — none of which can be easily measured.

The age when osteoporosis becomes apparent depends on:

Peak bone mass which depends predominantly on genetic factors, but also on other factors such as nutrition (particularly calcium and vitamin D), hormonal status, and physical activity. It is reached in the third decade and starts to decline in the fifth decade for men and women. In women, this decline accelerates after the menopause for a period of between 5 and 10 years.

The rate of bone loss depends on a number of factors including oestrogen deficiency in women and decreased testosterone in older men, vitamin D insufficiency, hyperparathyroidism, and reduced physical activity.

Osteoporotic fractures

Vertebral fractures may occur spontaneously or as a result of routine activities such as bending or lifting.

They often go unrecognized but may be diagnosed later by their characteristic X-ray appearance (morphometric vertebral fractures).

A minority of vertebral fractures (possibly around one–third) present with acute and severe pain at the site of the fracture (clinical vertebral fractures).

Multiple vertebral fractures result in spinal deformity (kyphosis) and height loss.

Hip and wrist fractures almost always follow a fall.

[Compston, 2010]

Prevalence

How common is it?

Osteoporosis

In England and Wales, more than 2 million women have osteoporosis [NICE, 2011b].

After the menopause, the prevalence of osteoporosis increases markedly with age, from approximately 2% at 50 years of age to almost 50% at 80 years of age [NICE, 2011b].

Osteoporotic fragility fractures

In England and Wales, around 180,000 of the fractures presenting each year are the result of osteoporosis [NICE, 2011b].

More than one in three women and one in five men will sustain one or more osteoporotic fractures in their lifetime [NOGG, 2013].

A large proportion of vertebral fractures do not come to medical attention and are therefore not included in routinely collected statistics. Most of these are osteoporotic fractures [Johansen et al, 2000].

Risk factors

Risk factors for osteoporotic fragility fractures

The risk of getting an osteoporotic fracture depends on an individual's risk of falls and their bone strength, determined by bone mineral density (BMD) and other factors independent of BMD including bone composition, architecture, size, and geometry. Fracture risk increases progressively with decreasing BMD, but BMD is poorly sensitive at predicting fracture risk when used without consideration of other risk factors.

Risk factors affecting bone strength by reducing BMD include:

Endocrine disease including diabetes, hyperthyroidism, and hyperparathyroidism.

Chronic gastrointestinal diseases that cause malabsorption such as Crohn's disease, ulcerative colitis, and coeliac disease.

Chronic renal disease.

Chronic liver disease.

Chronic obstructive pulmonary disease.

Immobility.

Body mass index of less than 19 kg/m2

Risk factors affecting bone strength by mechanisms that do not reduce BMD include:

Age — risk increases with age and is at least partly independent of bone mineral density.

Oral corticosteroids (dose dependent).

Smoking (depends on the number of cigarettes smoked).

Alcohol (depends on the number of units consumed).

Previous fragility fractures (risk increases with increasing number of fractures). Risk is highest for previous hip fractures and lowest for previous vertebral fractures.

Rheumatological conditions such as rheumatoid arthritis, and other inflammatory arthropathies.

Parental history of hip fracture.

Risk factors affecting bone strength by mechanisms which have not been established include the use of:

Selective serotonin reuptake inhibitors.

Proton-pump inhibitors.

Anticonvulsant drugs.

Risk factors for falls include:

Impaired vision.

Neuromuscular weakness and incoordination.

Cognitive impairment.

The use of alcohol and sedative drugs.

[Compston, 2010; NOGG, 2013]

Complications

What are the complications?

Complications of osteoporosis are fragility fractures and their consequences:

Hip fracture

About 50% of people with an osteoporotic fragility fracture of the hip can no longer live independently [Kanis et al, 2003].

Around 25% of the deaths following hip fractures are causally related to the fracture, and around 75% to comorbidities [Kanis et al, 2003].

Vertebral fracture

Osteoporotic fragility fractures of vertebrae do not necessarily cause symptoms: around 50–70% are clinically silent and do not come to clinical attention [NICE, 2011b].

Vertebral fractures can cause back pain, loss of height, and kyphosis (abnormal curvature of the spine). Severe kyphosis can lead to breathing difficulties; gastrointestinal problems; and difficulties in bending, reaching, and other activities of daily living [NICE, 2011b].

Around 30% of the deaths following vertebral fractures are causally related to the fracture, and around 70% to comorbidities [Kanis et al, 2004b].

Management

Management

Scenario: Assessment : covers guidelines developed by the National Osteoporosis Guideline Development Group and separate guidelines developed by the National Institute for Health and Care Excellence (NICE) on when and how to assess an individual's fragility fracture risk.

Scenario: Management : covers the guidelines developed by the National Osteoporosis Guideline Development Group (NOGG). It includes self-care advice (such as general lifestyle measures), when to offer vitamin D and calcium supplements, when to offer drug treatment to prevent osteoporotic fragility fractures.

Scenario: Assessment

Scenario: Assessment of osteoporotic fragility fracture risk

216months3060monthsBoth

Choosing NOGG or NICE guidelines

Should I use NOGG or NICE guidelines to assess fragility fracture risk?

The National Osteoporosis Guideline Group (NOGG) and the National Institute for Health and Care Excellence (NICE) provide separate and different guidance on when and how to assess osteoporotic fracture risk. Consider the following points when deciding which to use:

NOGG recommends:

Treatment without risk assessment for:

Postmenopausal women who have had a previous fragility fracture.

People on oral corticosteroids who are over 70 years of age, post menopausal women, and men over 50 years of age who are on high dose corticosteroids, or who have a bone mineral density of –1.5 or less.

Risk assessment before considering treatment for:

Postmenopausal women and men over 50 years of age with a significant risk factor for osteoporosis.

Premenopausal women and men under 50 years of age with a previous osteoporotic fracture or are receiving high dose corticosteroids.

The use of the FRAX® assessment tool to calculate the fracture risk. This:

Calculates the fragility fracture risk based on the principal risk factors but, does not incorporate all known risk factors in its calculation.

Can calculate fracture risk with or without bone mineral density (BMD) measurement.

Is based on international data rather than data from a UK population.

Allows the user to calculate osteoporotic fracture risk and determine the recommended management by linking to NOGG recommended treatment thresholds.

NICE recommends:

Risk assessment before considering treatment for:

All women over 65 years of age and all men over 75 years of age.

Women less than 65 years of age and men less than 75 years of age with a risk factor for fragility fracture (including the use of oral corticosteroids).

People less than 50 years of age with a major risk factor for a fragility fracture.

The use of the FRAX® or QFracture® assessment tools to calculate the osteoporotic fracture risk. The QFracture® assessment tool:

Is based on UK primary care data and incorporates more known risk factors in its calculation of fragility fracture risk than the FRAX® assessment tool.

Does not include BMD in its risk calculation; therefore, when measurements of BMD are available, the FRAX assessment tool must be used to calculate the fragility fracture risk.

Allows the user to calculate the osteoporotic fracture risk and provides treatment thresholds to determine if treatment is recommended.

If you decide to use NOGG guidelines, see:

NOGG - who to assess .

NOGG - how to assess .

If you decide to use NICE guidelines, see:

NICE - who to assess .

NICE - how to assess people over 40 years .

NICE - how to assess people under 40 years .

Basis for recommendation

Basis for recommendation

This information is based on Osteoporosis: Clinical guideline for prevention and treatment produced by the National Osteoporosis Guideline Group [NOGG, 2013] and Osteoporosis: fragility fracture risk produced by the National Institute for Health and Care Excellence [NICE, 2012].

NOGG - who to assess

When does NOGG recommend assessment of osteoporotic fracture risk?

The National Osteoporosis Guideline group recommends:

Treatment without risk assessment for:

Postmenopausal women who have had a previous fragility fracture.

People over 70 years of age on oral corticosteroids.

Postmenopausal women and men over 50 years of age who are on high dose corticosteroids.

Postmenopausal women and men over 50 years of age with a bone mineral density of –1.5 or less.

Risk assessment of premenopausal women and men under 50 years of age with a previous osteoporotic fracture or receiving high dose glucocorticoids.

Risk assessment of postmenopausal women and men over 50 years of age with a significant clinical risk factor for an osteoporotic fracture including:

A previous osteoporotic fracture (defined as a fracture caused by a fall from standing height or less).

Low body mass index (less than 19 kg/m2).

Parental history of hip fracture.

Current use of any dose of oral corticosteroid treatment for 3 months or more.

Current smoker.

Alcohol intake of 3 or more units daily.

A secondary cause for osteoporosis including:

Rheumatoid arthritis.

Untreated hypogonadism in men or premature menopause in women (menopause before 45 years of age).

Prolonged immobility.

Organ transplantation.

Type I diabetes.

Hyperthyroidism.

Chronic gastrointestinal diseases that cause malabsorption such as Crohn's disease, ulcerative colitis, and coeliac disease.

Chronic liver disease.

Chronic obstructive pulmonary disease.

Basis for recommendation

Basis for recommendation

These recommendations are based on Osteoporosis: Clinical guideline for prevention and treatment produced by the National Osteoporosis Guideline Group (NOGG) [NOGG, 2013].

The population of people that are recommended for treatment without formal risk assessment have risk factors that, in the opinion of NOGG, can safely be assumed to place them at high risk of a fragility fracture.

The population of people recommended for formal assessment have risk factors that are known to be associated with an increased fragility fracture risk. The risk factors used to identify people at risk of an osteoporotic fragility fracture have come from 12 prospectively studied population-based cohorts undertaken in many geographical territories [Kanis and World Health Organization Scientific Group, 2008].

The cohort participants had a baseline assessment documenting clinical risk factors for fracture. Approximately 75% also had bone mineral density measured at the hip. The follow up was approximately 250,000 patient–years in 60,000 men and women during which more than 5000 fractures were recorded.

NOGG - how to assess

How do I assess osteoporotic fracture risk, using NOGG recommendations?

For people with a fragility fracture, exclude:

Non-osteoporotic causes for fragility fractures (such as metastatic bone cancer and myeloma).

Undiagnosed secondary causes for osteoporosis (such as hyperthyroidism) especially in people who are at low risk for the condition (including men of any age, pre-menopausal women, and women in early menopause).

For people with an indication to assess osteoporotic fracture risk:

Calculate their 10 year fragility fracture risk using the online FRAX® calculator by entering the individual's risk factor data, ignore the 'Select DXA' box, and click 'Calculate'.

Determine if NOGG guidance recommends treatment, no treatment, or measurement of their bone mineral density (BMD), by clicking on the 'View NOGG Guidance' button and viewing the chart that plots an individual's calculated risk against their age. This graphically represents an individual as being at low (green zone), high (red zone), or intermediate risk (orange zone) for an osteoporotic fracture, depending on how close their calculated risk is to NOGG-recommended treatment thresholds.

For people at low risk — do not treat or measure their BMD. Offer self-care and lifestyle advice and follow up within 5 years (depending on their risk).

For people at high risk — treat but do not routinely measure their BMD. For further advice, see Scenario: Management.

For people at intermediate risk — measure their BMD to more accurately assess their risk before deciding on their need for treatment.

For people at intermediate risk of a fragility fracture who have had their BMD measured:

Re-calculate their 10 year fragility fracture risk by entering their BMD and other risk factor data into the online FRAX® calculator.

Click 'View NOGG Guidance' button and view the charts that plot the individual's calculated risk and age against NOGG-recommended treatment thresholds.

For people above the treatment threshold, offer treatment. For further advice, see Scenario: Management.

For people below the treatment threshold, offer self-care and lifestyle advice and follow up within 5 years (depending on their risk).

For people below but close to the treatment threshold, consider offering treatment if they have risk factors that are under-estimated by the FRAX® calculator (including regular use of corticosteroids equivalent to or less than 5 mg prednisolone daily; use of corticosteroids more than or equivalent to 7.5 mg prednisolone daily for more than 3 months; a history of multiple fragility fractures; high alcohol intake; and heavy smoking) or not included in the FRAX® calculator (including living in a care home; history of falls; and the use of drugs associated with impaired bone metabolism such as anti-convulsants, proton pump inhibitors, selective serotonin reuptake inhibitors, and anti-retroviral drugs).

Additional information

Additional information

For people with a fragility fracture, exclude non-osteoporotic causes and arrange investigations as appropriate if there are features of:

Metastatic bone cancer — bone pain in people known to have cancer (especially lung, thyroid, prostate, kidney, or breast cancer) or symptoms of undiagnosed cancer (unexplained general malaise or weight loss).

Multiple myeloma — bone pain, symptoms of bone marrow infiltration (anaemia, recurrent infections, bleeding), symptoms of hypercalcaemia, or renal impairment.

Osteomalacia — bone pain, muscle pains, or proximal muscle weakness.

Paget's disease — bone pain or deformity.

For people with an osteoporotic fracture, consider undiagnosed secondary causes for osteoporosis and arrange investigations as appropriate, especially in people with a fragility fracture who are at low risk for the condition (including men of any age, pre-menopausal women, and women in early menopause). Consider:

Endocrine conditions such as untreated premature menopause in women, hypogonadism in men, diabetes, and hyperthyroidism.

Rheumatological conditions such as rheumatoid arthritis, and other inflammatory arthropathies.

Chronic gastrointestinal diseases that cause malabsorption such as Crohn's disease, ulcerative colitis, and coeliac disease.

Chronic liver disease.

Chronic obstructive pulmonary disease.

Recommended routine investigations to exclude non-osteoporotic causes of fragility fractures and undiagnosed secondary causes of osteoporosis include:

X-ray of the fracture. Arrange lateral X-rays of the lumbar and thoracic spine when there is spinal pain, loss of height, or kyphosis.

Full blood count, ESR or C-reactive protein, liver function tests, renal function tests, bone profile, and thyroid function tests.

Basis for recommendation

Basis for recommendation

The clinical approach

The recommendations on excluding non-osteoporotic causes for fragility fractures and identifying secondary causes of osteoporosis are based on established good clinical practice and are recommended by the National Osteoporosis Guideline Group (NOGG) [NOGG, 2013].

Routine investigations to exclude non-osteoporotic fragility fractures and undiagnosed secondary causes of osteoporosis

These recommendations are based on the expert opinion of the National Osteoporosis Guideline Group [NOGG, 2013].

Estimating fragility fracture risk based on the FRAX®assessment tool

The FRAX® assessment tool uses risk factors associated with osteoporotic fragility fractures identified in 12 prospectively studied population-based cohorts in many geographical territories [Kanis and World Health Organization Scientific Group, 2008].

The cohort participants had a baseline assessment documenting clinical risk factors for fracture. Approximately 75% also had bone mineral density measured at the hip. The follow up was approximately 250,000 patient–years in 60,000 men and women during which more than 5000 fractures were recorded.

NICE - who to assess

When does NICE recommend assessment of osteoporotic fracture risk?

The National Institute for Health and Care Excellence recommends proactively identifying high risk groups through audit and opportunistically identifying individuals to assess osteoporotic fracture risk. These groups include:

All women aged over 65 years and all men aged over 75 years.

All women aged 50 to 65 years and all men aged between 50 to 75 years who have any of the following risk factors:

A previous osteoporotic fragility fracture (defined as a fracture caused by a fall from standing height or less).

Current use or frequent recent use of oral corticosteroids.

History of falls.

Low body mass index (less than 18.5 kg/m2).

Smoking.

Alcohol intake of more than 14 units per week for women and 21 units per week for men.

A secondary causes of osteoporosis including:

Hypogonadism in either sex including untreated premature menopause (menopause before 40 years of age) and men treated with aromatase inhibitors or androgen deprivation therapy.

Endocrine problems including diabetes, Cushing's disease, hyperthyroidism, hyperparathyroidism, and hyperprolactinaemia.

Conditions associated with malabsorption including inflammatory bowel disease, coeliac disease, and chronic pancreatitis.

Rheumatoid arthritis and other inflammatory arthropathies.

Haematological conditions such as multiple myeloma and haemaglobinopathies.

Chronic obstructive pulmonary disease.

Chronic liver failure.

Chronic renal disease.

Immobility.

Anybody aged less than 50 years with any of the following risk factors for a fragility fracture:

Current or frequent use of oral corticosteroids.

Untreated premature menopause.

A previous osteoporotic fracture.

Anybody aged less than 40 years of age with any of the following risk factors for a fragility fracture:

Current or recent use of high-dose oral corticosteroids equivalent to, or more than, 7.5 mg prednisolone daily for 3 months or more.

Previous fragility fracture of the spine, hip, forearm, or proximal humerus.

Multiple fragility fractures.

Basis for recommendation

Basis for recommendation

These recommendations are based on the expert opinion of the guideline development group (GDG) of the National Institute for Health and Care Excellence in their guideline Osteoporosis: fragility fracture risk [NICE, 2012].

The GDG of NICE wished to target opportunistic risk assessment at those individuals who are likely to be at increased risk of an osteoporotic fragility fracture using the risk factors identified from the data used in the development of the QFracture® and FRAX® assessment tools.

The FRAX® assessment tool uses risk factors associated with osteoporotic fragility fractures identified in 12 prospectively studied population-based cohorts in many geographical territories [Kanis and World Health Organization Scientific Group, 2008]. The cohort participants had a baseline assessment documenting clinical risk factors for fracture. Approximately 75% also had bone mineral density measured at the hip. The follow up was approximately 250,000 patient-years in 60,000 men and women during which more than 5000 fractures were recorded.

The QFracture® assessment tool uses risk factors associated with osteoporotic fragility fractures identified in a large cohort (3.6 million) from the Qresearch database. This is a database comprising of 12 million anonymized health records from 602 general practices in the UK.

NICE - how to assess people over 40 years

How do I assess osteoporotic fracture risk in people over 40 years of age using NICE recommendations?

For people with a fragility fracture, exclude:

Non-osteoporotic causes for fragility fractures (such as metastatic bone cancer and myeloma).

Undiagnosed secondary causes for osteoporosis (such as hyperthyroidism) especially in people with an osteoporotic fracture who are at low risk for the condition (including men of any age, pre-menopausal women, and women in early menopause).

For people over 40 years of age with an indication to assess osteoporotic fragility fracture risk, calculate their 10 year fragility fracture risk using either the online FRAX® calculator or the online QFracture® calculator (or, if available, using QFracture® integrated into the GP computer system).

Compare the calculated fragility fracture risk with the recommended treatment thresholds .

When using the FRAX® calculator, NOGG-recommended treatment thresholds can be accessed by clicking on the 'View NOGG Guidance' button and viewing the chart that plots an individual's calculated risk against their age. This graphically represents an individual as being at low (green zone), high (red zone), or intermediate risk (orange zone) for an osteoporotic fracture, depending on how close their calculated risk is to NOGG-recommended treatment thresholds.

When using the QFracture® calculator, women are considered to be at high risk if their 10 year risk is more than 11.1%, and men are considered to be at high risk if their 10 year risk is more than 2.6%.

For people at high risk whose fracture risk is clearly above the recommended treatment threshold, offer treatment without measurement of their bone mineral density (BMD). For further advice, see Scenario: Management.

For people at low risk whose fracture risk is clearly below the recommended treatment threshold:

Do not offer treatment or measure their BMD.

Offer self-care and lifestyle advice.

For people at intermediate risk whose fracture risk is close to the recommended treatment threshold — arrange a DEXA scan to measure their BMD and recalculate their fragility fracture risk using the online FRAX® calculator. Click the 'View NOGG Guidance' button and view the charts that plot the individual's calculated risk and age against NOGG-recommended treatment thresholds.

For people above the treatment threshold, offer treatment. For further advice see Scenario: Management.

For people below the treatment threshold, offer self-care and lifestyle advice, and follow up within 5 years (depending on their risk).

For people below but close to the treatment threshold, consider offering treatment if they have risk factors that are under estimated by the FRAX® calculator (including regular use of corticosteroids equivalent to or less than 5 mg prednisolone daily; use of corticosteroids more than or equivalent to 7.5 mg prednisolone daily for more than 3 months; a history of multiple fragility fractures; high alcohol intake; and heavy smoking) or not included in the FRAX® calculator (including living in a care home; history of falls; and the use of drugs associated with impaired bone metabolism such as anti-convulsants, proton pump inhibitors, selective serotonin reuptake inhibitors, and anti-retroviral drugs).

Additional information

Additional information

For people with a fragility fracture, exclude non-osteoporotic causes and arrange investigations as appropriate if there are features of:

Metastatic bone cancer — bone pain, people known to have cancer (especially lung, thyroid, prostate, kidney, or breast cancer) or symptoms of undiagnosed cancer (unexplained general malaise or weight loss).

Multiple myeloma — bone pain, symptoms of bone marrow infiltration (anaemia, recurrent infections, bleeding), symptoms of hypercalcaemia, or renal impairment.

Osteomalacia — bone pain, muscle pains, or proximal muscle weakness.

Paget's disease — bone pain or deformity.

For people with an osteoporotic fracture, consider undiagnosed secondary causes for osteoporosis and arrange investigations as appropriate especially in people with a fragility fracture who are at low risk for the condition (including men of any age, pre-menopausal women and women in early menopause). Consider:

Endocrine conditions such as untreated premature menopause in women, hypogonadism in men, diabetes, and hyperthyroidism.

Rheumatological conditions such as rheumatoid arthritis, and other inflammatory arthropathies.

Chronic gastrointestinal diseases that cause malabsorption such as Crohn's disease, ulcerative colitis, and coeliac disease.

Chronic liver disease.

Chronic obstructive pulmonary disease.

Recommended routine investigations to exclude non-osteoporotic causes of fragility fractures and undiagnosed secondary causes of osteoporosis include:

X-ray of the fracture. Arrange lateral X-rays of the lumbar and thoracic spine when there is spinal pain, loss of height, or kyphosis.

Full blood count, ESR or C-reactive protein, liver function tests, renal function tests, bone profile, and thyroid function tests.

Basis for recommendation

Basis for recommendation

Excluding other causes of fragility fracture

The National Institute for Health and Care Excellence (NICE) restricts recommendations to the assessment of people at risk of an osteoporotic fragility fracture. CKS has added recommendations to exclude other causes of fragility fractures before undertaking this assessment because all these other causes for fragility fractures are serious and should not be mistaken for osteoporosis.

Excluding undiagnosed secondary causes for osteoporosis

This recommendation is based on the expert opinion of the Guideline Development Group (GDG) of NICE [National Clinical Guideline Centre, 2012].

Recommended routine investigations to exclude non-osteoporotic fragility fractures and undiagnosed secondary causes of osteoporosis

NICE do not provide advice on recommended routine investigations to exclude non-osteoporotic fragility fractures and undiagnosed secondary causes of osteoporosis. These recommendations are therefore based on the expert opinion of the National Osteoporosis Guideline Group [NOGG, 2013].

Estimating fragility fracture risk

Recommendations to estimate the fragility fracture risk using either the FRAX® or QFracture® are based on the expert opinion of the GDG of NICE [National Clinical Guideline Centre, 2012]. The GDG considered it out of the scope of their guideline to recommend treatment thresholds.

The FRAX® assessment tool uses risk factors associated with osteoporotic fragility fractures identified in 12 prospectively studied population-based cohorts in many geographical territories [Kanis and World Health Organization Scientific Group, 2008].

The cohort participants had a baseline assessment documenting clinical risk factors for fracture. Approximately 75% also had bone mineral density measured at the hip. The follow up was approximately 250,000 patient-years in 60,000 men and women during which more than 5000 fractures were recorded.

The QFracture® assessment tool uses risk factors associated with osteoporotic fragility fractures identified in a large cohort (3.6 million) from the Qresearch database. This is a database comprising of 12 million anonymized health records from 602 general practices in the UK.

NICE - how to assess people under 40 years

How do I assess fragility fracture risk in people under 40 years of age using NICE recommendations?

For people with a fragility fracture, exclude:

Non-osteoporotic fragility fracture (such as metastatic bone cancer and myeloma).

Undiagnosed secondary causes for osteoporosis (such as hyperthyroidism) especially in people with an osteoporotic fracture who are at low risk for the condition (including men of any age, pre-menopausal women, and women in early menopause).

For people less than 40 years of age with a major risk factor for a fragility fracture including multiple fragility fractures, previous major osteoporotic fracture, and current or recent use of high-dose oral corticosteroids of more than or equivalent to 7.5 mg prednisolone daily for more than 3 months:

Arrange a DEXA scan to measure their bone mineral density.

Seek expert advice as to further management when the results are available.

Additional information

Additional information

For people with a fragility fracture exclude non-osteoporotic causes and arrange investigations as appropriate if there are features of:

Metastatic bone cancer — bone pain, people known to have cancer (especially lung, thyroid, prostate, kidney, or breast cancer) or symptoms of undiagnosed cancer (unexplained general malaise or weight loss).

Multiple myeloma — bone pain, symptoms of bone marrow infiltration (anaemia, recurrent infections, bleeding), symptoms of hypercalcaemia, or renal impairment.

Osteomalacia — bone pain, muscle pains, or proximal muscle weakness.

Paget's disease — bone pain or deformity.

For people with an osteoporotic fracture, consider undiagnosed secondary causes for osteoporosis and arrange investigations as appropriate especially in people with a fragility fracture who are at low risk for the condition (including men of any age, pre-menopausal women and women in early menopause). Consider:

Endocrine conditions such as untreated premature menopause in women, hypogonadism in men, diabetes, and hyperthyroidism.

Rheumatological conditions such as rheumatoid arthritis, and other inflammatory arthropathies.

Chronic gastrointestinal diseases that cause malabsorption such as Crohn's disease, ulcerative colitis, and coeliac disease.

Chronic liver disease.

Chronic obstructive pulmonary disease.

Recommended routine investigations to exclude non-osteoporotic causes of fragility fractures and undiagnosed secondary causes of osteoporosis include:

X-ray of the fracture. Arrange lateral X-rays of the lumbar and thoracic spine when there is spinal pain, loss of height, or kyphosis.

Full blood count, ESR or C-reactive protein, liver function tests, renal function tests, bone profile, and thyroid function tests.

Basis for recommendation

Basis for recommendation

Excluding other causes of fragility fracture

The National Institute for Health and Care Excellence (NICE) restricts recommendations to the assessment of people at risk of an osteoporotic fragility fracture. CKS has added recommendations to exclude other causes of fragility fractures before undertaking this assessment because all these other causes for fragility fractures are serious and should not be mistaken for osteoporosis.

Excluding undiagnosed secondary causes for osteoporosis

This recommendation is based on the expert opinion of the Guideline Development Group (GDG) of NICE [National Clinical Guideline Centre, 2012].

Recommended routine investigations to exclude non-osteoporotic fragility fractures and undiagnosed secondary causes of osteoporosis

NICE do not provide advice on recommended routine investigations to exclude non-osteoporotic fragility fractures and undiagnosed secondary causes of osteoporosis. These recommendations are therefore based on the expert opinion of the National Osteoporosis Guideline Group [NOGG, 2013].

Arranging a DEXA scan for people with a major risk factor

This recommendation is based on the expert opinion of the GDG of NICE [National Clinical Guideline Centre, 2012].

Seeking specialist advice

CKS recommend seeking specialist advice on how to manage people less than 40 years of age following a DEXA scan because there is no evidence or expert opinion from the GDG of NICE to inform management decisions.

Scenario: Management

Scenario: Management of osteoporosis

216months3060monthsBoth

Drug treatment

What drug treatments are recommended for people at high risk of an osteoporotic fracture?

For women who have experienced a premature menopause (menopause before 45 years of age), offer hormone replacement therapy (HRT) to reduce the risk of fragility fractures and for the relief of menopausal symptoms.

HRT should be continued up until 50 years of age and then stopped, and the need for continuing treatment with an alternative drug considered. For further information on prescribing HRT, see Scenario: Premature menopause in the CKS topic on Menopause.

For premenopausal women and men under 50 years of age who have had an osteoporotic fracture, refer for specialist management.

For people assessed to be at high risk of an osteoporotic fracture who are postmenopausal women, men over 50 years of age, and people of any age who are taking oral corticosteroids, offer a bisphosphonate. Explain that treatment is usually given for 3–5 years and that it reduces, but does not eliminate, the risk of osteoporotic fracture.

The choice of treatment for an individual should take into account:

Cost effectiveness:

Prescribe alendronate first-line for most people.

Consider risedronate second-line for people who can not tolerate alendronate.

Consider specialist referral for people who cannot take or tolerate alendronate or risedronate. Secondary care treatment options include strontium ranelate, raloxifene, denosumab, and teriparatide. Hormone replacement therapy is recommended for post-menopausal women under the age of 60 years who are at significant risk of osteoporotic fracture, for whom non-oestrogen treatments are unsuitable.

Licensed indications and spectrum of anti-fracture effects — for further information, see Table 1 in prescribing information.

Contraindications and interactions — for further information, see Bisphosphonate contraindications and drug interactions.

Table 1 . Licensed indications and spectrum of anti-fracture effects of drugs used to reduce fragility fracture risk in general practice.
Drug Licensed for the treatment of: Protective against:
Post-menopausal women Men Steroid induced osteoporosis Vertebral fracture Non-vertebral fracture Hip fracture
Alendronate Yes Yes Yes Yes Yes Yes
Risedronate Yes Yes Yes (only in women) Yes Yes Yes
Adapted from [Compston et al, 2009; NOGG, 2013].

Basis for recommendation

Basis for recommendation

Who to treat

Hormone replacement therapy (HRT) is recommended for the management of women with premature menopause based on evidence for their effectiveness at reducing the risk of fragility fractures. In addition, the Medicines and Healthcare products Regulatory Agency (MHRA) support the use of HRT based on considerations of their safety and effectiveness in women who have had a premature menopause [MHRA, 2003].

Treatment recommendations with anti-osteoporotic drugs are restricted to post-menopausal women, men over 50 years of age, and people of any age taking oral corticosteroids. This reflects recommendations in the Guideline for diagnosis and management of osteoporosis published by the National Osteoporosis Guidelines Group [NOGG, 2013]. These recommendations are based on evidence for the effectiveness of these treatments in these groups of people.

Most participants in trials examining the effectiveness of osteoporotic treatments have been post menopausal women, reflecting the prevalence of this condition in this group. A limited number of studies have examined the effectiveness of treatment for osteoporosis in older men and in people taking oral corticosteroids.

There is a lack of studies examining the effectiveness of treatment in other groups of people where the prevalence of the condition is very low.

CKS considers it good practice for people who have developed osteoporosis at an unusually young age to be under the care of a specialist.

Choice of treatment

Recommended drug treatments are based on evidence for their effectiveness in post menopausal women, men over 50 years of age, and people taking corticosteroids.

There are no good quality head-to-head trials comparing the effectiveness of different treatments. When a number of different drugs have been shown to be effective in a given group of people, the choice of treatment has been based on consideration, by the National Institute for Health and Care Excellence, of their relative costs and their relative risk of adverse effects [NICE, 2011b; NICE, 2011a]

CKS has recommended referring people for specialist management when treatment with raloxifene, denosumab, or teriparatide is to be considered, based on their costs and risks of adverse effects compared with bisphosphonates. This recommendation is supported by local protocols for the transfer of prescribing responsibilities between Primary and Secondary care [NHS South of Tyne and Wear, 2012].

The European Medicines Agency (EMA) has published a review that restricts the use of strontium ranelate to people who cannot be treated with other medicines approved for osteoporosis. In addition, people with a history of cardiovascular problems such as stroke or myocardial infarction should not receive strontium ranelate. The EMA noted that, compared with placebo, for every 1,000 patient-years there were four more cases of serious heart problems (including myocardial infarction) and four more cases of blood clots or blockages of blood vessels with strontium ranelate use. This was in addition to other risks, such as serious skin reactions, disturbances in consciousness, seizures, liver inflammation, and haematological changes. With regard to its benefits, the EMA stated that strontium ranelate has a modest effect in osteoporosis, preventing about five non-spinal fractures, 15 new spinal fractures, and 0.4 hip fractures for every 1,000 patient-years [EMA, 2014].

HRT is recommended by the National Osteoporosis Society for women under the age of 60 years when the benefits of treatments outweigh the risks [National Osteoporosis Society, 2010]. CKS considers this to be the case when non-oestrogen treatments are unsuitable and there is a significant risk of a fragility fracture.

Managing osteoporotic risk factors

How should I manage risk factors for osteoporosis?

Assess for vitamin D deficiency and inadequate calcium intake.

People are at risk of vitamin D deficiency if they are aged over 65 years or are not exposed to much sunlight (because they are confined indoors for long periods or because they wear clothes that cover the whole body).

A calcium intake of at least 1000 mg/day is recommended for people at increased risk of a fragility fracture. To calculate their dietary calcium intake, see Calculate your Calcium.

Correct vitamin D deficiency and ensure an adequate calcium intake.

For elderly people who are housebound or living in a nursing home, prescribe 20 micrograms (800 units) of vitamin D combined with at least 1 g of calcium daily. For a list of products, see Table 1 in Prescribing information.

For people over 65 years of age and people of any age not exposed to much sun, who have an adequate dietary calcium intake of more than 1000 mg/day, prescribe 10 micrograms (400 units) of vitamin D without a full replacement dose of calcium.

There are no plain UK licensed vitamin D tablets available for treating simple deficiency; however, there are multivitamin preparations that contain the recommended dose of vitamin D. Choices include Abidec® multivitamins (ergocalciferol 10 micrograms per 0.6mL), calcium and ergocalciferol tablets (calcium 97 mg, ergocalciferol 10 micrograms), and Dalivit® drops (ergocalciferol 10 micrograms per 0.6mL).

Multivitamin tablets containing 10 micrograms of vitamin D are also available to buy from pharmacies and health food stores.

For people who have a dietary calcium intake of less than 1000 mg/day, prescribe 10 micrograms (400 units) of vitamin D with at least 1000 mg of calcium daily, available as Calcichew D3® chewable tablets (calcium 500 mg, colecalciferol 5 micrograms).

Identify and where possible modify risk factors for falls. For more information, see the CKS topic on Falls - risk assessment.

Risk factors for falls include poor eye sight, cardiovascular disease, neurological disorders, medication that impairs alertness and balance, and home environmental hazards (slippery floors, obstacles, insufficient lighting, and loose or absent handrails).

Consider referring people at high risk of falls to a specialist falls service, especially people meeting any of the following criteria:

Two or more falls in the previous 12 months.

One fall plus a disorder of gait and balance or syncopal features.

A fall causing an injury.

Consider referring people with impaired muscular strength or co-ordination to a physiotherapist.

Advise the person to:

Take regular exercise (tailored to the individual) to improve muscle strength and reduce pain and stiffness:

Encourage walking, especially outdoors, as this will increase exposure to sunlight, increasing vitamin D production.

Encourage strength training of different muscle groups (for example hip, wrist, and spine).

Quit smoking, if appropriate (see the CKS topic on Smoking cessation).

Consume alcohol prudently because the risk of osteoporosis increases proportionally with the amount of alcohol consumed (see the CKS topic on Alcohol - problem drinking).

Basis for recommendation

Basis for recommendation

These recommendations are in line with guidelines developed by the National Institute for Health and Care Excellence (NICE) [National Clinical Guideline Centre, 2012] and the National Osteoporosis Guidelines Group (NOGG) [NOGG, 2013].

Calcium and vitamin D

Fracture risk:

Evidence suggests that calcium plus vitamin D is more effective than placebo, no treatment, or vitamin D alone for reducing the risk of hip fractures in older people. For elderly people living in a nursing home or residential care home, treatment can reduce the risk of both hip and non-vertebral fractures.

Safety:

There is evidence of increased myocardial infarct risk in people taking calcium supplements that were not combined with supplementary oral vitamin D. No increase in myocardial infarction risk was observed in people with a high dietary calcium intake.

There is evidence of an overall reduction in all cause mortality for people taking vitamin D with calcium compared to people taking vitamin D alone.

Having considered this evidence, the National Osteoporosis Guideline Group recommends [NOGG, 2013]:

Avoiding oral calcium supplements when an adequate dietary intake of calcium can be achieved.

Always using a combination of calcium and vitamin D rather than calcium supplements alone when an adequate dietary intake of calcium cannot be achieved, even when the person is not at risk of vitamin D deficiency.

Vitamin D

The Department of Health recommends supplementation with vitamin D based on evidence from the National Diet and Nutrition Survey for a high prevalence of vitamin D deficiency in people over 65 years of age. In addition, there is evidence that vitamin D supplementation can reduce the risk of falls in people over 60 years of age.

Assessing and managing the risk of falls

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline: The assessment and prevention of falls in older people [NICE, 2013], and the National Osteoporosis Guideline Group (NOGG) clinical guideline for prevention and treatment of osteoporosis [NOGG, 2013].

The supporting evidence and basis for the recommendations are discussed in detail in the CKS topic on Falls - risk assessment.

Exercise

A systematic review provides evidence that exercise reduces the rate of falls, risk of falling, and risk of fracture.

Stopping smoking

Indirect evidence from cohort studies suggests that stopping smoking may reduce the risk of osteoporotic fragility fracture in women. CKS found no evidence specific to men.

Prudent consumption of alcohol

Advice to consume alcohol prudently is based on evidence for an association between alcohol consumption and osteoporotic fragility fracture risk identified in 12 prospectively studied population-based cohorts [Kanis and World Health Organization Scientific Group, 2008].

Follow up

What follow up is recommended for people on treatment for osteoporosis?

After starting treatment, and at routine medication reviews:

Ensure that the person understands the recommended method of taking bisphosphonates.

Ask about adverse effects of treatment. In particular ask about:

Upper gastrointestinal adverse effects such as dyspepsia or reflux. These are common in the first month of treatment and often improve with continuing use. They are less likely if the recommended method of taking biphosphonates is followed.

Upper oesophageal pathology such as stricture or achalasia. If this occurs, stop treatment and refer to secondary care to consider starting an alternative to treatment with a biphosphonate.

Symptoms of atypical fracture including new onset hip, groin, or thigh pain. If this occurs, stop treatment, arrange an X-ray, and review with the result.

Ask about adherence to treatment with calcium and/or vitamin D supplements and anti-osteoporotic drugs.

See Drug treatment for recommended alternative treatments if adverse effects are unacceptable.

Consider prescribing an intermittent dosing regime for people who have difficulty adhering to daily treatment. For further information, see Prescribing information.

For people taking oral corticosteroids, continue treatment with bisphosphonates at least until they stop treatment with corticosteroids. After stopping corticosteroid treatment, reassess the osteoporotic fracture risk to determine the need for continuing treatment with bisphosphonates.

For people not taking oral corticosteroids, review the need for continuing treatment with bisphosphonates after 5 years.

For people who remain at high risk of an osteoporotic fracture, continue treatment without further assessment. This includes people with any of the following risk factors:

Age over 75 years.

A previous hip or vertebral fracture.

Continuous use of prednisolone 7.5 mg or more (or equivalent).

In other people, arrange a DEXA scan and consider:

Continuing treatment if they have a T-score of less than –2.5. Reassess their bone mineral density (BMD) and osteoporotic fracture risk using the online FRAX® calculator every 2–5 years to determine their need for continuing treatment.

Stopping treatment if they have a T-score of more than –2.5. Reassess their BMD and calculate their osteoporotic fracture risk using the online FRAX® calculator after a drug holiday of 2–3 years to determine their need for further treatment.

For people who sustain an osteoporotic fracture while on treatment, exclude poor adherence to treatment and secondary causes for osteoporosis. If excluded, consider referral to a specialist for an alternative treatment. Drug treatment is recommended for at least 5 years to reduce the risk of further fractures.

Basis for recommendation

Basis for recommendation

Assessment of adverse effects and tolerability of drug treatments at routine medication reviews

These recommendations are based on good medical practice.

Duration of treatment

Recommendations to continue treatment with a bisphosphonate at least until oral corticosteroids are stopped are based on the expert opinion of the National Osteoporosis Guideline Group (NOGG) [NOGG, 2013].

Recommendations to stop bisphosphonate treatment after 5 years are based on:

Evidence that a drug holiday after 5 years of treatment with alendronate is associated with only a small increase in clinically apparent vertebral fractures with no increase in other types of osteoporotic fractures.

Evidence of rare but serious adverse effects of bisphosphonates, with an increasing incidence of these adverse effects with continuing treatment.

Recommendations to continue treatment with a bisphosphonate after 5 years for people at continued high risk of a fragility fracture are based on the expert opinion of NOGG [NOGG, 2013] and on evidence that:

Women with a T-score of less than –2.5 after 5 years of treatment have less non-vertebral fractures if they continue treatment for up to 10 years.

Continuing treatment with alendronate after 5 years of treatment, for a further 5 years, is associated with a small reduction in clinically apparent vertebral fractures.

Management of people who sustain a fracture while on treatment

These recommendations are based on the expert opinion of NOGG [NOGG, 2013].

Patient information and support

What resources for information and support are there for people with osteoporosis?

The National Osteoporosis Society (www.nos.org.uk) provides support and information to people affected by osteoporosis, influences health and social care provision, and works to improve public understanding of osteoporosis.

Healthtalkonline (www.healthtalkonline.org) has a large collection of videos and transcripts of people's experiences of health and illness, including osteoporosis. There are also short articles for people with osteoporosis and the general public.

NHS Choices has a health encyclopaedia which has a printable article on Osteoporosis.

Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://medicines.org.uk/emc), or the British National Formulary (BNF) (www.bnf.org).

Calcium and colecalciferol (vitamin D3) preparations

Calcium and colecalciferol (vitamin D3) preparations

Preparations

Which calcium and colecalciferol (vitamin D3) preparations should I prescribe?

Licensed calcium and vitamin D preparations that provide a daily intake of at least 1 g of calcium are listed in Table 1.

To aid adherence, a variety of formulations are available. For example, soluble powder or effervescent granules/tablets can be considered for people for whom chewable tablets are not suitable.

For people who are allergic to peanuts or soya, preparations which do not contain soya (or soya bean) oil are available (see Table 1).

Table 1 . Licensed calcium and vitamin D preparations.
Preparation Calcium content per tablet/sachet Colecalciferol content per tablet/sachet Licensed dosage
Tablets/chewable tablets
Accrete D3® Calcium carbonate 1.5 g (calcium 600 mg) 10 micrograms (400 units) One tablet twice a day.
Adcal D3® chewable tablets* (Lemon or tutti-frutti flavour) Calcium carbonate 1.5 g (calcium 600 mg) 10 micrograms (400 units) One tablet twice a day.
Calceos® chewable tablets* (Lemon flavour) Calcium carbonate 1.25 g (500 mg calcium) 10 micrograms (400 units) One tablet twice a day.
Calcichew D3 forte® chewable tablets* (Lemon flavour) Calcium carbonate 1.25 g (500 mg calcium) 10 micrograms (400 units) Two tablets daily, preferably one tablet each morning and evening.
Calcichew D3 500 mg/400 unit Caplets®* (Lemon flavour) Calcium carbonate 1.25 g (500 mg calcium) 10 micrograms (400 units) (in the form of concentrate colecalciferol) One tablet twice a day (swallowed or chewed).
Natecal D3® chewable tablets* (Aniseed, peppermint, and molasses flavour) Calcium carbonate 1.5 g (calcium 600 mg) 10 micrograms (400 units) One tablet twice a day (for example, morning and evening).
Powder or effervescent granules/tablets
Adcal D3 Dissolve® effervescent tablets* (Lemon flavour) Calcium carbonate 1.5 g (calcium 600 mg) 10 micrograms (400 units) Two effervescent tablets daily, preferably one tablet each morning and evening. Dissolve the tablet in a glass of water (approx. 200 mL) and drink immediately
Cacit D3® effervescent granules (Lemon flavour, 4 g sachets) Calcium carbonate 1.25 g (500 mg calcium) Colecalciferol 11 micrograms (440 units) One or two sachets daily. Dissolve the granules in a large quantity of water and drink immediately.
Calfovit D3® powder (Lemon flavour) Calcium phosphate 3.1 g (1200 mg calcium) Colecalciferol 20 micrograms (800 units) One sachet daily. Dissolve the powder into a glass of water and drink immediately — preferably during the evening meal.
* Contains a small quantity of soya (or soya bean) oil (hydrogenated or partially hydrogenated). Manufacturers advise that these product are contraindicated in people who are allergic to peanuts or soya.
Data from: [ABPI Medicines Compendium, 2009a; ABPI Medicines Compendium, 2009b; ABPI Medicines Compendium, 2010b; ABPI Medicines Compendium, 2010a; ABPI Medicines Compendium, 2012c; ABPI Medicines Compendium, 2012d; ABPI Medicines Compendium, 2012e]
Basis for recommendation

This information is based on the respective manufacturer's Summary of Product Characteristics.

Contraindications

What are the contraindications for calcium and vitamin D preparations?

Do not prescribe calcium and vitamin D preparations if there is:

Any disease or condition which results in hypercalcaemia and/or hypercalciuria (for example some forms of malignant disease).

Nephrolithiasis.

Hypervitaminosis D.

Severe renal failure.

An allergy to peanuts or soya.

For these people, soya oil free products are available (see Table 1 in Preparations).

Calcium and ergocalciferol tablets are contraindicated in people with an overactive thyroid gland.

Basis for recommendation

These recommendations are based on the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2009a; ABPI Medicines Compendium, 2009b; ABPI Medicines Compendium, 2010a; ABPI Medicines Compendium, 2010b; ABPI Medicines Compendium, 2012c; ABPI Medicines Compendium, 2012d].

Precautions

What are the precautions for calcium and vitamin D preparations?

Prescribe calcium and vitamin D preparations with caution if the person has:

Mild to moderate renal failure or mild hypercalciuria.

Manufacturers recommend periodic checks of plasma calcium levels and urinary calcium excretion.

An increased risk of hypercalcaemia (for example sarcoidosis or cancer).

A history of renal stone disease.

Check urinary calcium excretion to exclude hypercalciuria.

Basis for recommendation

These recommendations are based on the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2009a; ABPI Medicines Compendium, 2009b; ABPI Medicines Compendium, 2010a; ABPI Medicines Compendium, 2010b; ABPI Medicines Compendium, 2012c; ABPI Medicines Compendium, 2012d].

Adverse effects

What are the adverse effects of calcium and vitamin D preparations?

Adverse effects are uncommon and are generally related to the calcium content of the preparation.

Adverse effects are mainly gastrointestinal disturbance such as constipation, flatulence, nausea, gastric pain, and diarrhoea.

Hypercalciuria (and rarely hypercalcaemia) may occur with long term use of high doses of calcium and vitamin D preparations.

Colecalciferol supplements have been reported to cause occasional skin rashes.

Basis for recommendation

This information is based on the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2009a; ABPI Medicines Compendium, 2010a; ABPI Medicines Compendium, 2010b].

Drug interactions

What are the key drug interactions with calcium and vitamin D preparations?

Oral bisphosphonates.

Calcium and colecalciferol preparations can interfere with the absorption of these drugs and should not be taken at the same time.

For further information, see Food and drug interactions of bisphosphonates.

Quinolones and tetracyclines

The absorption of these antibiotics can be reduced by calcium supplements; therefore, they should not be taken together:

Quinolones should be taken at least 2 hours before taking a calcium supplement.

Tetracyclines should be taken at least 2–3 hours before taking a calcium supplement.

Levothyroxine, sodium fluoride, and iron

The absorption of these drugs can be reduced by calcium supplements; therefore, they should be taken at least 2 hours before taking a calcium supplement.

Digoxin

The effects of digoxin may be increased by increases in blood calcium levels.

Some manufacturers recommend monitoring renal function during long-term calcium supplementation.

Thiazide diuretics

Thiazide diuretics reduce urinary calcium excretion. Due to the increased risk of hypercalcaemia:

Monitor serum calcium regularly during concomitant use of thiazide diuretics with calcium and vitamin D preparations.

Some manufacturers recommend monitoring renal function during long-term calcium supplementation.

Systemic corticosteroids

Systemic corticosteroids reduce calcium absorption.

During concomitant use, it may be necessary to increase the dose of the calcium and vitamin D preparation.

Phenytoin or barbiturates (long-term use)

These enzyme-inducing drugs can decrease the effects of vitamin D (by increasing its metabolism). However, there have only been a few reports of this effect.

Consider monitoring for vitamin D deficiency as a higher dose of vitamin D may be required.

Basis for recommendation

These recommendations are based on the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2009a; ABPI Medicines Compendium, 2010a; ABPI Medicines Compendium, 2010b] and a reference textbook on drug interactions [Baxter and Preston, 2013].

Quinolones and tetracyclines

The recommendations regarding when to take these antibiotics are based on expert opinion in a reference textbook on drug interactions [Baxter and Preston, 2013].

Recommendations from the manufacturers of calcium and colecalciferol preparations differ regarding when these antibiotics should be taken before the calcium supplement.

Bisphosphonates

Bisphosphonates

This section focuses primarily on oral bisphosphonates. For further information, seek specialist advice or consult the Summaries of Product Characteristics for these drugs (see www.medicines.org.uk).

Mechanism of action

Mechanism of action

Bisphosphonates are inhibitors of bone resorption.

They increase bone mineral density by altering osteoclast activation and function.

Basis for recommendation

This information is from a technology appraisal published by the 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) [NICE, 2011b] and on a narrative review article on bisphosphonates [Favus, 2010].

Indications and dosage

What dose should I prescribe?

Two oral bisphosphonates are recommended for the treatment of osteoporosis (see Table 1 for preparations and licensed indications). Their recommended dosages are:

Alendronate — 10 mg once daily or 70 mg once weekly.

Risedronate — 5 mg once daily or 35 mg once weekly.

Alendronate and risedronate are also available with vitamin D as combination products (see Table 1).

The weekly formulations are commonly prescribed (despite the differences in licensed indications compared with the once-daily preparations).

All the bisphosphonates are licensed for use in postmenopausal women. However, only alendronate (once-daily tablets) and risedronate (once-weekly tablets) are licensed for use in men (see Table 1).

Although off-label, the weekly formulation of alendronate is widely prescribed for men to aid adherence.

Table 1 . Oral bisphosphonate for the treatment of osteoporosis.
Preparations Licensed indications
Alendronate
Once daily, 10 mg tablets Treatment of osteoporosis in postmenopausal women to prevent fractures. Treatment of osteoporosis in men to prevent fractures. Treatment of glucocorticoid-induced osteoporosis and prevention of bone loss in postmenopausal women considered at risk of developing the disease.
Once weekly, 70 mg tablets Treatment of postmenopausal osteoporosis. Reduces the risk of vertebral and hip fractures.
Once weekly, 70 mg tablets with 70 micrograms (2800 IU) colecalciferol (vitamin D3) (Fosavance®) Treatment of postmenopausal osteoporosis in people at risk of vitamin D insufficiency.
Reduces the risk of vertebral and hip fractures.
Risedronate
Once daily, 5 mg tablets Treatment of postmenopausal osteoporosis to reduce the risk of vertebral fractures. Treatment of established postmenopausal osteoporosis to reduce the risk of hip fractures. Prevention of osteoporosis in postmenopausal women with increased risk of osteoporosis. To maintain or increase bone mass in postmenopausal women undergoing long-term (more than 3 months), systemic corticosteroid treatment at prednisolone doses 7.5 mg daily or greater or equivalent.
Once weekly, 35 mg tablets Treatment of postmenopausal osteoporosis to reduce the risk of vertebral fractures. Treatment of established postmenopausal osteoporosis to reduce the risk of hip fractures. Treatment of osteoporosis in men at high risk of fractures.
Actonel Combi® A combination product with a weekly regimen consisting of a once-weekly risedronate 35 mg tablet (taken on day 1) and six sachets containing 1000 mg calcium and 22 micrograms vitamin D3 (for the next 6 days). Treatment of postmenopausal osteoporosis to reduce the risk of vertebral fractures. Treatment of established postmenopausal osteoporosis to reduce the risk of hip fractures.
Data from: [ABPI Medicines Compendium, 2012a; ABPI Medicines Compendium, 2012b; ABPI Medicines Compendium, 2013b; ABPI Medicines Compendium, 2013a; ABPI Medicines Compendium, 2013c;]
Basis for recommendation

This information is based on the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2012a; ABPI Medicines Compendium, 2012b; ABPI Medicines Compendium, 2013a; ABPI Medicines Compendium, 2013b; ABPI Medicines Compendium, 2013c].

Daily and weekly formulations

The once weekly formulations of alendronate and risedronate are commonly prescribed. In trials lasting 2 years, they had the same effect on bone mineral density as the once-daily preparations and were equally well tolerated [Schnitzer et al, 2000; Brown et al, 2002; Rizzoli et al, 2002; Emkey, 2004; Harris et al, 2004].

The expert reviewers of this CKS topic support the use of the once-weekly formulation of alendronate in men (off-label) to aid adherence.

Administration

How should oral bisphosphonates be taken?

Oral bisphosphonates must only be taken on an empty stomach as their absorption is affected by food, drink, and other drugs (see Food and drug interactions).

Risedronate should be taken before breakfast; however, if this is not practical, it can be taken between meals or in the evening at the same time each day, with strict adherence to the following instructions, to ensure that it is taken on an empty stomach:

Before breakfast — must be taken at least 30 minutes before the first food, other medicinal product, or drink (other than plain water) of the day.

Between meals — should be taken at least 2 hours before or at least 2 hours after any food, other medicinal product, or drink (other than plain water).

In the evening — should be taken at least 2 hours after any food, other medicinal product, or drink (other than plain water).

Alendronate must be taken at least 30 minutes before the first food, other medicinal product, or drink (other than plain water) of the day.

Also advise that:

The tablet must be swallowed whole and taken with a glass of plain water (at least 200 mL); it must not be sucked or chewed because of a potential for oropharyngeal ulceration.

It should taken while in an upright position.

The person must not lie down for at least 30 minutes after taking the tablet.

The tablet must not be taken at bedtime or before getting up in the morning.

Once weekly preparations should be taken on the same day each week.

Basis for recommendation

These recommendations are based on the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2012a; ABPI Medicines Compendium, 2012b; ABPI Medicines Compendium, 2013b; ABPI Medicines Compendium, 2013a] and on guidance issued by the Medicines and Healthcare products Regulatory Agency (MHRA) [MHRA, 2012b].

Oral administration

The recommendations to drink at least 200 mL of water is based on advice from the MHRA to reduce the risk of oesophageal adverse reactions (such as oesophagitis, oesophageal ulcers, oesophageal strictures, and oesophageal erosions) [MHRA, 2012b]. For further information, see Oesophageal reactions.

These recommendations are different from those issued by the manufacturers of oral bisphosphonates, who recommend drinking at least 120 mL water when taking risedronate [ABPI Medicines Compendium, 2013b] and 200 mL for alendronate [ABPI Medicines Compendium, 2012a].

Missed doses

What advice should be given regarding missed doses of oral bisphosphonates?

For once-daily preparations of alendronate or risedronate, advise the person:

To skip the missed dose for that day.

To continue on the next day as usual.

Not to take a double dose to make up for the missed dose.

For once-weekly preparations of alendronate or risedronate, advise the person:

To take the missed tablet on the day that it is remembered.

To continue taking one tablet once a week, on the day the tablet is normally taken.

That two tablets should not be taken on the same day.

Basis for recommendation

These recommendations are based on the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2012b; ABPI Medicines Compendium, 2012a; ABPI Medicines Compendium, 2013b; ABPI Medicines Compendium, 2013a].

Contraindications

What are the contraindications for oral bisphosphonates?

Hypocalcaemia

Hypocalcaemia and other disturbances of bone and mineral metabolism (such as parathyroid dysfunction and hypovitaminosis D) should be treated before starting alendronate or risedronate.

Pregnancy or breastfeeding

Data on pregnancy and breastfeeding are scarce. Oral bisphosphonates are only licensed for use in postmenopausal women.

Severe renal impairment

The threshold varies between the different drugs:

Alendronate is not recommended if the estimated glomerular filtration rate (eGFR) is less than 35 mL/minute/1.73 m2.

Risedronate is not recommended if eGFR is less than 30 mL/minute/1.73 m2.

To reduce the risk of oesophageal reactions, do not prescribe alendronate or risedronate:

If the person is unable to stand or sit upright for at least 30 minutes.

If there are any abnormalities of the oesophagus or other conditions which could delay oesophageal emptying (such as stricture or achalasia).

For further information, see Oesophageal reactions.

Basis for recommendation

These recommendations are based on the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2012b; ABPI Medicines Compendium, 2013b].

Hypocalcaemia

Due to their effect of increasing bone mineral content, alendronate and risedronate can decrease serum calcium and phosphate levels. Although the effect is generally small and asymptomatic, there have been rare reports of severe symptomatic hypocalcaemia. This is more likely to occur in people with certain predisposing conditions (such as hypoparathyroidism, vitamin D deficiency, and calcium malabsorption).

Pregnancy and breastfeeding

The manufacturers warn that data are insufficient for the use of bisphosphonates in women who are pregnant or breastfeeding. Bisphosphonates are only licensed for use in postmenopausal women.

Renal impairment

Bisphosphonates undergo renal excretion. The manufacturers warn that data are insufficient for their use in people with severe renal impairment.

Precautions

What are the precautions for oral bisphosphonates?

Due to the risk of oesophageal reactions, bisphosphonates should be prescribed with caution to people with upper gastrointestinal (GI) problems such as:

Dysphagia, oesophageal disease, gastritis, duodenitis, and peptic ulceration.

A recent history (within the past year) of major GI disease (such as peptic ulcer, active GI bleeding, or surgery of the upper GI tract [other than pyloroplasty]).

Barrett's oesophagus — consider the benefit and risk of treatment on an individual basis.

Some manufacturers of bisphosphonates advise caution if nonsteroidal anti-inflammatory drugs are used in conjunction with bisphosphonates (due to the increased risk of GI irritation).

Basis for recommendation

These recommendations are based on the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2012a; ABPI Medicines Compendium, 2012b; ABPI Medicines Compendium, 2013a; ABPI Medicines Compendium, 2013b; ABPI Medicines Compendium, 2013c] and on guidance issued by the Medicines and Healthcare products Regulatory Agency (MHRA) [MHRA, 2012b].

Adverse effects

What are the adverse effects of oral bisphosphonates?

Adverse effects of oral bisphosphonates include:

Gastrointestinal adverse effects — most common.

Bone, joint, and/or muscle pain — common.

Oesophageal reactions — uncommon.

Osteonecrosis of the jaw — rare.

Atypical stress fractures have been reported (mainly with alendronate). An increased risk cannot be excluded for other bisphosphonates.

No strong evidence currently supports a definite causal association between oral bisphosphonates and oesophageal cancer. For further information, see Oesophageal cancer.

Although an increased risk of atrial fibrillation has been suggested for alendronate, the current evidence does not require atrial fibrillation to be added to the list of possible adverse effects for this bisphosphonate. For further information, see Atrial fibrillation.

Gastrointestinal adverse effects

What are the gastrointestinal adverse effects of oral bisphosphonates?

Gastrointestinal (GI) adverse effects are commonly reported with bisphosphonate treatment and include nausea, dyspepsia, mild oesophagitis/gastritis, and abdominal pain.

They are more likely to occur during the first month of treatment.

For information on oesophageal reactions, see Oesophageal reactions.

Basis for recommendation

This information is based on evidence reviewed by the National Institute for Health and Care Excellence (NICE) [NICE, 2011a; NICE, 2011b]. The evidence is summarized below. All the trials compared bisphosphonates with placebo or no treatment.

Alendronate

Of the 15 randomized controlled trials (RCTs) comparing alendronate with placebo or with no treatment in postmenopausal women, GI adverse events (including nausea, dyspepsia, mild oesophagitis/gastritis, and abdominal pain) were reported in at least one third of the participants. However, only one study found this to be statistically significant when compared with placebo. NICE found this to be consistent with post-marketing studies, indicating that approximately one third of people taking alendronate experience GI adverse events.

A high incidence of dyspepsia (particularly in the first month of treatment) was reported in prescription-event monitoring studies in people prescribed alendronate in primary care in England (11,916 people). Consultations for dyspepsia ranged from 32.2 per 1000 patient-months in the first month of treatment, compared with 10.9 per 1000 patient-months in months 2 to 6. However, these figures should be interpreted with caution as these studies lacked a comparator and it is not possible to assess the baseline levels for those not taking bisphosphonates.

Risedronate

In seven studies reviewed, rates of GI adverse events were similar between the risedronate and placebo groups.

However, in prescription-event monitoring studies involving 13,643 people prescribed risedronate in primary care in England, the data suggested a high incidence of dyspepsia, particularly in the first month of treatment. Consultations for dyspepsia were 26.9 per 1000 patients-months in the first month of treatment and 8.1 per 1000 patient-months in months 2 to 6.

Oesophageal reactions

What are the issues relating to oesophageal reactions and oral bisphosphonates?

Oesophageal adverse reactions have been reported with alendronate and risedronate.

Adverse effects include oesophagitis, oesophageal ulcers, oesophageal strictures, and oesophageal erosions.

Advise the person to stop taking the bisphosphonate if they develop oesophageal symptoms (such as difficulties or pain on swallowing, chest pain, or heartburn).

To minimize the risk of oesophageal reactions:

Ensure the person understands, and complies with, the instructions for taking bisphosphonates. For further information, see Administration.

Review the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin. For further information, see the CKS topics on Antiplatelet treatment and NSAIDs - prescribing issues.

Basis for recommendation

These recommendations are based on guidance issued by the Medicines and Healthcare products Regulatory Agency (MHRA) [MHRA, 1996; MHRA, 1998; MHRA, 2012b] and information in the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2012b; ABPI Medicines Compendium, 2013a].

Oesophageal reactions

The risk of oesophageal reactions with alendronate and risedronate has been been highlighted by the MHRA [MHRA, 1996; MHRA, 1998; MHRA, 2012b].

Oesophageal reactions can occur if the bisphosphonate tablet becomes lodged in the oesophagus, because the drug irritates the oesophageal mucosa [MHRA, 1998].

Around 1–2% of people taking alendronate may experience oesophageal reactions, even when the dosage instructions are followed [MHRA, 1998].

The manufacturers of oral bisphosphonates highlight that the risk of severe oesophageal adverse effects appears to be greater in people who do not comply with the dosing instructions and/or who continue to take the oral bisphosphonates after developing symptoms suggestive of oesophageal irritation [ABPI Medicines Compendium, 2012b].

NSAIDs and aspirin

The frequency of upper gastrointestinal adverse reactions appears to be greater when alendronate is used in conjunction with NSAIDs or aspirin [MHRA, 1996]. Subsequently, caution has been advised if the person is taking NSAIDs [MHRA, 1998].

For this reason, CKS advises reviewing the use of NSAIDs and aspirin in people taking bisphosphonates, to reduce the risk of oesophageal adverse reactions.

Bone, joint, and/or muscle pain

What are the issues regarding bone, joint, and/or muscle pain and oral bisphosphonate treatment?

Bone, joint, or muscle pain are common adverse effects with bisphosphonate treatment.

Symptoms are rarely severe or incapacitating. They can appear within 1 day to several months after starting treatment.

Symptoms can be relieved by stopping the bisphosphonate. Some people may experience a recurrence of symptoms if they subsequently take the same or a different bisphosphonate.

Basis for recommendation

This information is from a manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2012b].

Osteonecrosis of the jaw

What are the issues regarding osteonecrosis of the jaw and oral bisphosphonate treatment?

Osteonecrosis of the jaw (ONJ) related to bisphosphonate treatment is defined as:

An area of exposed or dead bone in the jaw that has lasted for more than 8 weeks in a person who has been, or is currently being, exposed to a bisphosphonate and has not received radiation therapy to the jaw.

Reassure the person that the risk of developing ONJ with oral bisphosphonate treatment is low.

The risk is greater for people receiving intravenous bisphosphonates for cancer than for people receiving oral bisphosphonates for osteoporosis.

Advise the person to:

Have a dental examination before starting oral bisphosphonate treatment if they have poor dental status.

Maintain good oral hygiene and attend routine dental check-ups.

Report any oral symptoms such as dental mobility, pain, or swelling.

Basis for recommendation

These recommendations are based on guidance issued by the Medicines and Healthcare products Regulatory Agency (MHRA) [MHRA, 2009b; MHRA, 2012b] and the European Medicines Agency’s (EMEA) Committee for Medicinal Products for Human Use (CHMP). The CHMP reviewed the currently available evidence on definition and diagnosis of ONJ related to bisphosphonates, including the possible underlying pathophysiological mechanism(s), risk stratification, and risk minimization [EMEA, 2009a; EMEA, 2009b].

Risk of osteonecrosis of the jaw

A European-wide review was undertaken, including published data, data from the manufacturers of bisphosphonates, and advice from experts [EMEA, 2009a; EMEA, 2009b]. The review concluded that the risk of ONJ in association with the use of bisphosphonates is greater for people receiving intravenous bisphosphonates for cancer than for people receiving oral bisphosphonates for osteoporosis or Paget’s disease of bone.

This is based on a position paper from the American Association of Oral and Maxillofacial Surgeons [American Association of Oral and Maxillofacial Surgeons, 2009]. The majority of published studies on the incidence of ONJ in people taking oral bisphosphonates for osteoporosis or Paget's disease reported an incidence of 0.0004% to 0.06%. Although one study reported a higher incidence in a dental school study (4% in people on alendronate after invasive dental procedures), this was regarded as an isolated study with important selection bias (such as all the people were at high risk of ONJ) and should be interpreted with caution.

The MHRA reported that of the UK Yellow Card reports of ONJ (up to October 2009) [MHRA, 2009b]:

The majority were in people treated with zoledronate (172 reports); there were 47 reports for alendronate and 11 reports for risedronate.

However, the number of reports for a particular bisphosphonate cannot be used to determine the incidence of ONJ for each individual drug because neither the total number of reactions occurring nor the number of people using the drug is known.

A European-wide review concluded that the 'risk of ONJ with intravenous bisphosphonates used for osteoporosis is not yet known but appears to be lower than in cancer indications' [EMEA, 2009b]. No data are available beyond 3 years of treatment.

Atypical stress fractures

What are the issues regarding atypical stress fractures and oral bisphosphonate treatment?

Atypical stress fractures of the shaft of femur occur rarely in people taking long-term bisphosphonates.

Complete fractures are clinically obvious, with immediate hospital admission required.

However, ‘incomplete’ fractures can occur, with some people experiencing pain weeks to months before presenting with a completed fracture.

Advise people taking bisphosphonates to report any pain in the thigh, hip, or groin. If following medical assessment an incomplete atypical fracture is suspected, arrange radiography of the femur.

If an incomplete fracture is identified, seek specialist advice on further investigation and management.

It would be usual to investigate the contralateral femur because fractures are frequently bilateral.

The bisphosphonate would usually be stopped. However, a specialist may advise continued treatment after considering the benefits versus the risks.

If the X-ray is normal but the symptoms are still concerning, seek specialist advice because further imaging such as CT or MRI scan may be indicated.

Basis for recommendation

These recommendations are based on a guideline issued by the European Medicines Agency (EMA) [EMA, 2010], with additional advice on the investigation of suspected atypical fracture based on a guideline issued by the American Society for Bone and Mineral Research [Shane et al, 2010].

In 2008, a review by the Pharmacovigilance Working Party of the EMA’s Committee for Medicinal Products for Human Use (CHMP) identified a very small risk of atypical stress fracture of the femur in people taking long-term alendronate (most case reports were in people taking alendronate for 18 months to 10 years) [MHRA, 2009a]. The CHMP reviewed the data on all bisphosphonates and concluded that the risk of atypical fracture of the femur is a class effect (but that the benefits of bisphosphonates continue to outweigh their risks) [EMA, 2010].

The EMA does not specify what investigations should be carried out if a person has symptoms suggestive of an atypical femoral fracture. American guidelines recommend that plain radiography of the femur is the first-line investigation for suspected atypical fracture of the femur, and is usually diagnostic [Shane et al, 2010]. However, plain radiographs can be negative in the very early stages of an evolving fracture, and if the person’s symptoms are very suggestive of an atypical fracture, further investigations may be required.

The EMA does not specifically state that specialist advice should be sought on the management of people found to have an incomplete atypical fracture. However, CKS recommends that specialist advice should be obtained as these are rare fractures which often heal poorly and specialist follow up with repeat X-rays may be required.

Atrial fibrillation

What are the issues regarding atrial fibrillation and oral bisphosphonate treatment?

An increased risk of atrial fibrillation has been suggested for intravenous bisphosphonates (zoledronic acid and pamidronic acid), and possibly for alendronate.

However, the current evidence does not require atrial fibrillation to be added to the list of possible adverse effects for alendronate.

Basis for recommendation

These recommendations are in line with those issued by the Medicines and Healthcare products Regulatory Agency (MHRA) [MHRA, 2008; MHRA, 2012b], and are based on two European-wide reviews.

The initial European review assessed the risk of atrial fibrillation and bisphosphonate use, including clinical trial data, spontaneous reports of suspected adverse drug reactions, and published data [MHRA, 2008]. The review concluded that although the risk seemed to be low, clinical trial results did suggest an increased risk of atrial fibrillation with zoledronic acid, pamidronate, and possibly alendronate [MHRA, 2012b].

The second European review on alendronate and atrial fibrillation was undertaken in April 2010 and evaluated four new studies [Abrahamsen et al, 2009b; Bunch et al, 2009; Grosso et al, 2009; Huang et al, 2010] and two meta-analyses [Loke et al, 2009; Mak et al, 2009]. The review concluded that atrial fibrillation currently did not need to be added to the list of possible side effects of alendronate. The risk of atrial fibrillation for all bisphosphonates is under continued review.

Oesophageal cancer

What are the issues regarding oesophageal cancer and oral bisphosphonates?

There is currently insufficient evidence to confirm a link between oral bisphosphonate use and oesophageal cancer.

Basis for recommendation

Evidence on oesophageal cancer

Based on post-marketing reports of oesophageal cancer linked to the use of oral bisphosphonates, a UK study was undertaken by the Medicines and Healthcare products Regulatory Agency (MHRA) and the Cancer Epidemiology Unit at the University of Oxford [MHRA, 2010a].

This study was a nested case-control analysis, within a primary-care cohort of about 6 million people in the UK, with prospectively-recorded information on the prescribing of bisphosphonates [Green et al, 2010].

The study suggested a small increase in the risk of oesophageal cancer in people who had taken oral bisphosphonates for more than 5 years, compared with a group who had not taken oral bisphosphonates [Green et al, 2010].

In the general population, the incidence of oesophageal cancer over 5 years in people aged 60–79 years was 0.5 women per 1000 and 1.5 men per 1000.

The study found that 5 years of bisphosphonate use increased the incidence to 1 woman per 1000 and 3 men per 1000.

This study was subsequently reviewed by the Commission on Human Medicines (CHM) (formerly the Committee on Safety of Medicines), who highlighted a number of limitations, including that [MHRA, 2010a]:

There was little available information on risk factors for oesophageal cancer (such as smoking, alcohol consumption, social deprivation, and previous oesophageal reactions).

People on oral bisphosphonates were more likely to be monitored for oesophageal reactions than those not receiving bisphosphonates. This may result in an increased detection of oesophageal cancer in people receiving bisphosphonates.

The findings of the study were not supported by other published studies [Abrahamsen et al, 2009a; Solomon et al, 2009; Cardwell et al, 2010].

The CHM concluded that there was insufficient evidence to confirm a link between oral bisphosphonates and oesophageal cancer [MHRA, 2010a; MHRA, 2010b]. Further information can be found in the Drug Safety Update (pdf) and a Questions and Answers document issued by the MHRA.

Food and drug interactions

What are the food and drug interactions for oral bisphosphonates?

Food, milk and dairy products, and medicinal products containing polyvalent cations (such as calcium, magnesium, iron, and aluminium — for example antacids):

Avoid co-administration as they interfere with the absorption of oral bisphosphonates.

Bisphosphonates should be taken at least 30 minutes before the first food, other medicinal product, or drink (other than water) of the day (for further information, see Administration).

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Due to the increased risk of of gastrointestinal irritation, some manufacturers of bisphosphonates advise caution if NSAIDs are used in conjunction with bisphosphonates.

Basis for recommendation

These recommendations are based on the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2012a; ABPI Medicines Compendium, 2012b; ABPI Medicines Compendium, 2013a; ABPI Medicines Compendium, 2013b; ABPI Medicines Compendium, 2013c].

In general, there are few clinically significant drug interactions with bisphosphonates because they:

Are not systemically metabolized.

Do not induce cytochrome P450 isoenzymes.

Have low protein-binding.

Advice

What advice should I give to a person taking oral bisphosphonates?

Encourage the person to keep taking the bisphosphonate.

Adherence declines significantly after the first year of treatment.

Remind the person that bisphosphonate treatment is long term for the prevention of fragility fracture.

Explain that they will also be prescribed calcium and vitamin D supplementation if their dietary calcium intake and vitamin D status have been assessed and are inadequate.

Provide information on:

How to take the bisphosphonate (see Administration). Explain that absorption of bisphosphonates is affected by food, drink, and certain medicines (see Food and drug interactions).

How to manage missed doses.

Advise the person to stop taking the bisphosphonate and seek medical advice if they experience any signs or symptoms of possible oesophageal reaction, for example dysphagia, pain on swallowing, retrosternal pain, or new/worsened heartburn (see Adverse effects).

Advise the person to have regular dental check ups and to tell their dentist that they are taking a bisphosphonate, particularly if they are going to undertake invasive dental procedures (due to a very rare risk of osteonecrosis of the jaw — see Adverse effects).

Basis for recommendation

These recommendations are based on the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2012a; ABPI Medicines Compendium, 2012b; ABPI Medicines Compendium, 2013a; ABPI Medicines Compendium, 2013b; ABPI Medicines Compendium, 2013c].

Adherence

Long-term adherence to osteoporosis treatment is poor [Kanis et al, 2013].

Adherence and persistence (how long the medication is taken) with bisphosphonate treatment were examined by the National Institute for Health and Care Excellence (NICE) [NICE, 2011b], who found a significant decline after the first year of treatment.

Based on data from 14 randomized controlled trials (RCTs), between 81% and 100% of people persisted with treatment after the first year. However, this declined to 51–89% in the third year of treatment (eight RCTs).

A prescription-event monitoring study involving 11,916 people prescribed alendronate in England found that 24% of people discontinued treatment within 1 year.

In a similar study of risedronate (11,742 people in primary care in England), 30% of people appeared to discontinue treatment within 6 months.

Persistence at 1 year ranged from 16% to 90% in the other 12 studies reviewed.

Evidence

Evidence

Supporting evidence

This section summarizes the evidence on effectiveness, from randomized controlled trials, that supports the recommendations about the primary care management of people at risk of osteoporotic fragility fracture. Studies were excluded if they could not provide useful information because of methodological limitations (such as having too few participants or too short duration).

Evidence summaries generally exclude:

Evidence on treatments which most healthcare professionals in primary care would not prescribe (these being prescribed in secondary care).

Thus, there are no evidence summaries for zoledronate, teriparatide, and parathyroid hormone.

Evidence on hazards and adverse effects

For each drug, full details of adverse effects and contraindications are in the SPC (Summary of Product Characteristics). See www.medicines.org.uk/emc.

However, the risks of long-term treatment with alendronate are summarized, as this information is necessary to make informed decisions on drug holidays.

Evidence on cost-effectiveness

The National Institute for Health and Care Excellence (NICE) explains and justifies its approach in the published technical appraisals of drugs used to reduce the risk of osteoporotic fragility fractures [NICE, 2010; NICE, 2011a; NICE, 2011b] and on its website (www.nice.org.uk).

The UK National Osteoporosis Guideline Group (NOGG) has produced its own guidelines [NOGG, 2013] 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, the Royal College of Physicians, and the Society for Endocrinology. The economic analyses used by NOGG and the International Osteoporosis Foundation are described in (or referenced by) various publications [Kanis et al, 2001; Kanis et al, 2002; Kanis et al, 2004a; Kanis et al, 2005b; Borgström and Kanis, 2008; Kanis et al, 2013; Kanis et al, 2008; Kanis et al, 2010].

Evidence on subgroups — such as with or without osteoporotic fragility fractures, at higher or lower risk for fractures, or older versus younger people — except where this is informative.

Evidence on drug treatments with outcomes that are not directly clinically important. Thus evidence on fracture risk is summarized, but evidence on bone mineral density, bone turnover, and other physiological markers is not covered.

Lifestyle advice for preventing osteoporotic fragility fractures

Evidence on lifestyle advice for preventing osteoporotic fragility fractures

The criteria for including and excluding studies are summarized in Supporting evidence.

Evidence on exercise

A systematic review of randomized controlled trials found that exercise reduced the risk of falling, and risk of fracture.

A Cochrane systematic review assessed the evidence from randomized controlled trials on interventions for preventing falls in older people living in the community [Gillespie et al, 2012].

Electronic databases were searched for trials published up to March 2012.

Meta-analysis found that compared to no intervention, exercise reduced the rate of falls, and risk of fracture.

Multiple-component group exercise programmes were found to significantly reduce the rate of falls in 16 trials (n = 3622): rate ratio (RaR) 0.71 (95%CI 0.63 to 0.82).

Multiple component home-based exercise programmes were found to significantly reduce the rate of falls in 7 trials (n = 951): RaR 0.68 (95%CI 0.58 to o.80).

Exercise interventions were found to significantly reduce the risk of sustaining a fall related fracture in 6 trials (n = 810): relative risk 0.34 (95%CI 018 to 0.63).

Evidence on stopping smoking

Indirect evidence from cohort studies suggests that stopping smoking may reduce the risk of osteoporotic fragility fracture in women. CKS found no such evidence in men.

CKS found no randomized controlled trials of smoking cessation for the prevent osteoporotic fragility fractures.

A meta-analysis of 10 prospective cohort studies (59,232 men and women) investigated the effect of current or past smoking on fracture risk [Kanis et al, 2005a].

The risk of a fracture in women who were former smokers was intermediate between never smokers and current smokers (statistic not reported). A similar analysis could not be made for men because their numbers were too small.

The proportion of fractures estimated to be due to smoking rose from 5% in people 50–64 years of age to 16% at 85 years of age or older.

Evidence on dietary calcium

Evidence on dietary calcium

For the prevention of osteoporotic fractures, the evidence on dietary calcium is uncertain. The Scottish Intercollegiate Guidelines Network (SIGN) recommends that postmenopausal women should aim for a dietary intake of 1000 mg calcium per day. This is based on a meta-analysis of case-control and cohort studies which reported that such an intake reduces the risk of hip fractures in postmenopausal women. However a subsequent meta-analysis of cohort studies did not support this finding. Calcium supplements, but not high dietary calcium intake, may be associated with an increased risk of myocardial infarction in people not taking therapeutic doses of oral vitamin D.

In a systematic review assessing the use of calcium supplements and/or dietary calcium for preventing osteoporotic fractures in postmenopausal women (search date: 1966 to 1997) identified by SIGN, no randomized controlled trials (RCTs) were found [Cumming and Nevitt, 1997]. Of the 23 observational studies identified, 18 reported hip fracture outcomes.

Meta-analysis of 16 case-control and cohort studies found that the risk of hip fractures was reduced with calcium intake but there was significant heterogeneity between the studies.

Odds ratio (OR) for hip fracture per 300 mg/daily increase in calcium intake (equivalent to one more glass of milk daily): 0.96 (95% CI 0.93 to 0.99).

For calcium intake of 1000 mg daily, the pooled OR was 0.88 (95% CI 0.88 to 0.97).

However, if only the five cohort studies were considered (mean calcium intake 391–713 mg daily), the result was not significant (OR 0.96, 95% CI 0.91 to 1.02).

The authors of the review concluded that the true relation between calcium intake and hip fracture risk is likely to be stronger than found in the above meta-analyses because dietary calcium intake is measured imperfectly in epidemiological studies.

However, this conclusion is not supported by a recent meta-analysis (search date: up to June 2010) of seven prospective cohort studies (mean follow up 3–26 years) in middle-aged or older men and women (no RCTs were identified) [Bischoff-Ferrai et al, 2011]. This meta-analysis examined the relative risk (RR) of hip fracture per daily glass of milk intake (approximately 300 mg calcium per glass). No overall association between milk intake and hip fracture was found in women. For men, more data are needed.

In women

No overall association was found between total milk intake and hip fracture risk (pooled RR per glass of milk per day 0.99, 95% CI 0.96 to 1.02) (six studies, 195,102 women, 3574 hip fractures).

The results were found to be strongly influenced by a large Swedish study (questionnaires filled in by 60,689 women) which found no dose-response association between dietary calcium intake and fracture risk. When this study was excluded, the result becomes marginally significant — with a 5% lower hip fracture risk per glass of milk daily (pooled RR 0.95, 95% CI 0.90 to 1.00; p = 0.049).

The authors found no apparent association between higher milk intake and hip fracture risk, even with intakes as high as three or four glasses per day (by pooling RRs for different categories of milk intake).

In men

The pooled RR per daily glass of milk was 0.91 (95% CI 0.81 to 1.01), based on three studies of 75149 men with 195 hip fractures.

Because of the limited data available, a possible benefit of a higher milk intake could not be excluded.

A prospective observational study (n = 23,980) assessed the risk of myocardial infarction in people with no previous history of heart disease who were taking calcium supplements alone (i.e. not combined with therapeutic doses of vitamin D) [Li et al, 2012].

Compared with people not taking calcium supplements, people taking calcium supplements alone had an increased risk of myocardial infarction (hazard ratio 1.86; 95% CI 1.17 to 2.96).

No increase in myocardial infarct risk was seen in people with a high intake of calcium from their diet alone.

Evidence on calcium and vitamin D

Evidence on calcium and vitamin D

Evidence suggests that calcium plus vitamin D is more effective than placebo, no treatment, or vitamin D alone for reducing the risk of hip fractures in older people. For elderly people living in a nursing home or residential care home, treatment can reduce the risk of both hip and non-vertebral fractures.

Although found to be as effective as combined supplements in terms of fracture outcomes, there are concerns that calcium supplements (without co-administered vitamin D) are associated with a modest increased risk of myocardial infarction.

Calcium plus vitamin D compared with placebo or no treatment

One systematic review (search date: up to March 2006) reported that, compared with placebo, the risk of hip fractures was reduced by combined vitamin D and calcium supplementation (pooled relative risk [RR] 0.82 [95% CI 0.71 to 0.94, p = 0.0005, six trials, 45,509 women and men]) [Boonen et al, 2007]. The authors calculated that, when compared with placebo, 276 elderly people need to be treated to prevent one hip fracture over 24–84 months (NNT 276, 95% CI 165 to 843).

If one trial using calcium and 400 units of vitamin D daily was excluded, a slightly greater reduction in hip fracture risk was found when trials using calcium and 700–800 units vitamin D daily were considered (RR 0.79, 95% CI 0.64 to 0.97, p = 0.025, five trials).

This is consistent with the finding of a Cochrane systematic review which assessed vitamin D and vitamin D analogues, with or without calcium supplementation, for preventing osteoporotic fragility fractures in older people (search date: up to October 2007) [Avenell et al, 2009].

For men over 65 years of age and postmenopausal women, vitamin D plus calcium reduced the risk of hip fractures, but not vertebral fractures, when compared with placebo or no treatment:

Hip fracture: RR 0.84 (95% CI 0.73 to 0.96, eight trials, 46,658 participants); the absolute risk reduction was 0.2%.

New non-vertebral fracture: RR 0.95 (95% CI 0.90 to 1.00, nine trials, 46,781 participants).

Vertebral fracture: RR 0.91 (95% CI 0.75 to 1.11, two trials, 38,990 participants).

The review concluded that, based on the pooled data, administration of 400–800 units vitamin D3 with 1000 mg calcium reduces the incidence of hip fractures, but not non-vertebral fractures, in the populations studied. Given a trend for hip fracture reduction was found in a large study which used a lower vitamin D3 dose of 400 units and 1000 mg calcium, the review suggested that a higher dose of vitamin D3 than 400 units would appear to be more effective.

For institutionalized residents (those living in a nursing home or residential care home), subgroup analysis found that vitamin D plus calcium reduced the incidences of hip fractures and new non-vertebral fracture. No differences were observed for the community-dwelling group.

Hip fractures: RR 0.75 (95% CI 0.62 to 0.92, two trials, 3853 participants).

New non-vertebral fracture: RR 0.75 (95% CI 0.62 to 0.92, two trials, 3853 participants).

Both studies used a daily dose of 1200 mg calcium and 800 units vitamin D3.

These findings for institutionalized residents support the recommendations issued by the Scottish Intercollegiate Guidelines Network (SIGN) and the National Osteoporosis Guideline Group [SIGN, 2003; NOGG, 2013]. They recommended 1000 mg to 1200 mg calcium and 20 micrograms (800 units) of colecalciferol daily to reduce the risk of hip fracture in elderly people who are housebound or living in a nursing home.

This was based on the results of an 18-month placebo-controlled trial (3270 elderly people living in nursing homes) which found that treatment with 1200 mg calcium and 20 microgram vitamin D3 reduced the number of hip fractures by 27% (p = 0.004) and non-vertebral fractures by 26% (p < 0.001) (based on intention-to-treat analysis) [Chapuy et al, 1992]. This was one of two trials used in the above Cochrane systematic review.

Calcium plus vitamin D compared with vitamin D alone

In a systematic review [Boonen et al, 2007], indirect comparison of the pooled estimates for hip fractures from two calculated meta-analyses (vitamin D plus calcium compared with placebo; and vitamin D compared with placebo) found the combination to be more effective than vitamin D alone in reducing the risk of hip fracture (adjusted RR 0.75, 95% CI 0.58 to 0.96, p = 0.021).

In a separate meta-analysis of randomized controlled trials with 70,528 participants with a median age of 70 years, an overall reduction in all cause mortality was found for people taking vitamin D with calcium compared to people taking vitamin D alone with a hazard ratio of 0.91 (95% C.I. 0.84-0.99) [Rejnmark et al, 2012].

Calcium plus vitamin D compared with calcium alone

When compared with calcium and vitamin D, the benefits and risks of calcium-only supplements are less certain.

A Cochrane systematic review (search date: up to October 2007) found vitamin D plus calcium to be no more effective than calcium alone for hip fractures, any non-vertebral fracture, vertebral fracture, or any fracture [Avenell et al, 2009].

For hip fracture, the RR was 0.83 (95% CI 0.61 to 1.12, four trials, 6988 participants).

Any non-vertebral fracture: RR 0.96 (95% CI 0.79 to 1.16, four trials, 3061 participants).

Vertebral fracture: RR 0.14 (95% CI 0.01 to 2.77, two trials, 2681 participants).

Any fracture: RR 0.76 (95% CI 0.48 to 1.21, two trials, 927 participants).

However, the use of a calcium supplement without vitamin D has been questioned in a recent meta-analysis which reported that calcium supplements alone (without co-administered vitamin D) are associated with a modestly increased risk of myocardial infarction [Bolland et al, 2010].

Using individual data (five trials, 8151 participants, median follow up 3.6 years), the incidence of myocardial infarction was higher in the calcium group than in the placebo group (hazard ratio 1.31, 95% CI 1.02 to 1.67, p = 0.035). A similar result was found using trial-level data (pooled RR 1.27, 95% CI 1.01 to 1.59, p = 0.038) (11 trials, 11 921 participants, mean duration 4.0 years).

However, limitations of this study highlighted by the authors include:

Studies comparing combined calcium and vitamin D preparations with placebo were excluded. Consequently, the results may not be applied to these preparations.

None of the trials had cardiovascular outcomes as the primary end points, and data on cardiovascular events were not gathered in a standardised manner.

Seven of the trials (representing 15% of the total number of participants) had incomplete or no data on cardiovascular outcomes. However, the authors concluded that the missing data were unlikely to change the results substantially as they were small in size, and the findings from the other eight larger trials were consistent.

Evidence on vitamin D-only supplements

Evidence on vitamin D-only supplements

Although evidence suggests that supplementation with vitamin D alone is not effective in reducing fractures in older people (when compared with placebo), it can reduce the risk of falls in people 60 years of age and older living in institutionalized care or in the community. Vitamin D alone is also less effective than calcium alone in preventing vertebral fracture or deformity.

Annual high-dose vitamin D supplementation has not been found to reduce fracture rates, and has been associated with an increased risk of falls and fractures in elderly women.

Vitamin D (daily dosing) compared with placebo

Fracture outcomes

A Cochrane systematic review (search date: up to October 2007) found vitamin D alone did not reduce the risk of fractures in older people when compared with placebo [Avenell et al, 2009]:

For hip fracture, the relative risk (RR) was 1.15 (95% CI 0.99 to 1.33; nine trials, 24,749 participants).

Vertebral fracture: RR 0.90 (95% CI 0.42 to 1.92; five trials, 9138 participants).

Any new fracture: RR 1.01 (95% CI 0.93 to 1.09; 10 trials, 25,016 participants).

These findings are consistent with an earlier systematic review (search date: up to March 2006) which also reported no reduction in hip fractures when vitamin D alone was compared with placebo (pooled RR 1.10, 95% CI 0.89 to 1.36; p = 0.38; four RCTs, 9083 women and men]) [Boonen et al, 2007].

An analysis of individual data from seven major vitamin D fracture trials in the US and Europe (involving 68,500 participants, mean age 69.9 years [range 47–107 years], 14.7% men) also found no significant effect of vitamin D alone (10–20 micrograms) on fracture outcomes, including any fracture (hazard ratio [HR] 1.01, 95% CI 0.92 to 1.12; p = 0.08), hip fracture (HR 1.09, 95% CI 0.92 to 1.29, p = 0.34), and clinical vertebral fracture (HR 1.12, 95% CI 0.70 to 1.79; p = 0.63) [DIPART, 2010].

Fall outcomes

Vitamin D insufficiency is implicated in declining muscular strength, a potential factor in falls in the elderly (see the CKS topic on Falls - risk assessment). A meta-analysis (search date February 2004) of five RCTs investigated vitamin D for the prevention of falls in 1237 people 60 years of age and older living in institutionalized care or in the community [Bischoff-Ferrari et al, 2004]:

Vitamin D reduced the corrected odds ratio (OR) of falling by 22% (corrected OR 0.78, 95% CI 0.64 to 0.92) compared with people receiving calcium or placebo. The number needed to treat (NNT) was 15 (95% CI 8 to 53).

The inclusion of five additional studies (10,001 participants) in a sensitivity analysis resulted in a smaller but still significant effect size (RR 0.87, 95% CI 0.80 to 0.96). Subgroup analyses suggested that the effect size was independent of calcium supplementation, type of vitamin D, duration of therapy, and sex; but reduced sample sizes made the results statistically non-significant, suggesting further studies are needed to clarify these findings.

Vitamin D (high-dose annual supplementation) compared with placebo

The rationale for the use of high-dose vitamin D supplementation is to prevent decreases in vitamin D level over the winter period and to address low adherence. However, evidence from a Cochrane systematic review and a recent Australian trial do not support the use of such treatment. In addition, two studies highlighted an increased risk of falls and fractures.

Vitamin D injection compared with placebo

Two trials using high-dose vitamin D injections were identified by the Cochrane systematic review (search date: up to October 2007) [Avenell et al, 2009] — one trial gave a single injection of vitamin D2 (300,000 units over 1 year) [Harwood et al, 2004] while the other gave an ergocalciferol injection (300,000 units every autumn over 3 years [Smith et al, 2007]). There was no protective effect against hip or other osteoporotic fractures from an annual injection of vitamin D2 in older people.

In the ergocalciferol injection trial [Smith et al, 2007], when the data for the two sexes were separated, there was an increased risk of hip, femur, or wrist fractures (hazard ratio 1.59, 95% CI 1.17 to 2.16, p = 0.003) in women when compared with placebo. The treatment had no effect in men.

High-dose oral vitamin D compared with placebo

One Australian double-blind randomized placebo-controlled trial (involving 2256 women aged 70 years or older, living in the community) compared oral colecalciferol (500,000 units given each autumn-winter for 3–5 years) with placebo [Sanders et al, 2010]. The study unexpectedly reported an increased risk of falls (incidence rate ratio [RR] 1.15, 95% CI 1.02 to 1.30; p = 0.03) and fractures (incidence RR 1.26, 95% CI 1.00 to 1.59; p = 0.047). A temporal pattern was observed in a post hoc analysis of falls (higher incidence in the first 3 months following dosing than for the remaining 9 months of the year).

Vitamin D compared with calcium

One Cochrane systematic review (search date: up to October 2007) found no statistical difference between vitamin D alone and calcium in the prevention of hip fracture or non-vertebral fractures [Avenell et al, 2009]. However, evidence suggests that vitamin D alone is less effective than calcium in preventing vertebral fracture or deformity.

Hip fracture: RR 0.90 (95% CI 0.61 to 1.32, two trials, 2718 participants).

Non-vertebral fracture: RR 1.08 (95% CI 0.90 to 1.31, three trials, 2976 participants).

Vertebral fracture or deformity: RR 2.21 (95% CI 1.08 to 4.53, three trials, 2976 participants).

Vitamin D compared with vitamin D plus calcium

See Evidence on calcium and vitamin D.

Drugs for reducing women's risk of osteoporotic fragility fractures

Evidence on drugs for reducing the risk of osteoporotic fragility fractures in women

The criteria for including and excluding studies are summarized in Supporting evidence.

Hormone replacement therapy

Evidence on the decreased risk of osteoporosis with long-term HRT

Hormone replacement therapy (HRT) (both oestrogen-only and combined HRT) is considered effective for the prevention of postmenopausal osteoporosis; however, it is generally recommended as an option only for women who have experienced a premature menopause, or in women up to the age of 60 years who are at significant risk of a fragility fracture, for whom non-oestrogen treatments are unsuitable.

A large Cochrane systematic review (search date: February 2012; n = 42,830) assessed the effects of long-term HRT on mortality, cardiovascular outcomes, cancer, gallbladder disease, fractures, cognition, and quality of life in perimenopausal and postmenopausal women, both during HRT use and after stopping HRT [Marjoribanks et al, 2012].

Seventy percent of the data were derived from the Women's Health Initiative (WHI) trial and the Heart and Estrogen/progestin Replacement Study (HERS), which were both reviewed by the Medicines and Healthcare Products Regulatory Agency (MHRA) in 2007 (see Hormone replacement therapy: safety update - UK public Assessment Report).

The results of this study are summarized below. For a full discussion of this study, see Long term hormone therapy for perimenopausal and postmenopausal women (Review), published in the Cochrane Library (www.thecochranelibrary.com).

Hip fractures

The WHI trial found a statistically significant reduction in the risk of hip fracture for women taking combined continuous HRT and oestrogen-only HRT.

In women taking oestrogen-only HRT, there was a statistically significant reduction at 7.1 years’ mean follow-up (RR 0.64, 95% CI 0.45 to 0.93). The absolute risk (AR) of a hip fracture decreased from 14 per 1000 in the control group to 9 per 1000 (95% CI 6 to 13) in the HRT group. However, the benefit from HRT was not maintained during extended follow-up (to 10.7 years).

In women taking combined continuous HRT, there was no statistically significant difference in the incidence of hip fractures during the first four years of follow-up, but at 5.6 years’ mean follow-up there was a statistically significant reduction in the risk of hip fracture (RR 0.68, 95% CI 0.48 to 0.97). The AR of a hip fracture decreased from 9 per 1000 in the control group to 6 per 1000 (95% CI 4 to 9) in the HRT group. The risk remained significantly lower in the HRT group at a mean follow-up of 7.9 years (RR 0.77, 95% CI 0.60 to 0.99).

The HERS trial found no statistically significant difference between combined continuous HRT and placebo for this outcome, and the unblinded extension of this study found a statistically significant increased risk in the group taking HRT from years 4.1 to 6.8 (post-randomisation) (RR 2.10, 95% CI 1.06 to 4.16).

Other studies found no statistically significant difference between the groups for this outcome.

Clinical vertebral fractures

The WHI trial reported:

Significantly fewer fractures in the oestrogen-only HRT group than in the placebo group (RR 0.64, 95% CI 0.44 to 0.93) at a mean of 7.1 years’ follow-up. The AR of a clinical vertebral fracture decreased from 13 per 1000 in the control group to 8 per 1000 (95% CI 6 to 12) in the HRT group.

Significantly fewer fractures in the combined continuous HRT group than in placebo (RR 0.68, 95% CI 0.48 to 0.97) at a mean of 5.6 years’ follow-up. The AR of a clinical vertebral fracture decreased from 10 per 1000 in the control group to 7 per 1000 (95% CI 5 to 10) in the HRT group. At a mean of 7.9 years’ follow up in there was no longer any significant difference between the groups.

The HERS trial found no statistically significant difference between the groups during follow-up for this outcome.

Any fractures

The WHI trial reported:

Statistically significant reduction in the risk of any fracture for women taking combined continuous HRT at mean follow-up of 5.6 years (RR 0.78, 95% CI 0.71 to 0.86) and at 7.9 years (RR 0.82, 95% CI 0.76 to 0.89). At 5.6 years the AR of any fracture decreased from 111 per 1000 in the control group to 86 per 1000 (95% CI 79 to 94) in the HRT group.

Statistically significant reduction in the risk of any fracture for women taking oestrogen-only HRT at mean follow-up of 7.1 years (RR 0.73, 95% CI 0.65 to 0.80). At 7.1 years the AR of any fracture decreased from 140 per 1000 in the control group to 102 per 1000 (95% CI 91 to 112) in the HT group.

None of the other studies found any statistically significant difference between HRT and placebo for this outcome.

Alendronate in women

Evidence on alendronate for osteoporotic fracture risk reduction in women

A systematic review of randomized controlled trials (RCTs) found that, compared with placebo, treatment with alendronate reduced the risk of vertebral fractures, non-vertebral fractures, and hip fractures in postmenopausal women with low bone mineral density (BMD). No head-to-head trials have compared alendronate with other drugs for reduction of fracture risk, but one observational study found no clinically important difference in effectiveness between alendronate and risedronate.

The National Institute for Health and Care Excellence (NICE) commissioned a systematic review of clinical trials of treatments to reduce the risk of osteoporotic fragility fracture in women [NICE, 2011a; NICE, 2011b]. In the review's meta-analysis, reductions in relative risk associated with a treatment were pooled regardless of baseline BMD, fracture status, and age of study participants.

Alendronate compared with placebo or no treatment

The systematic review included: two trials in postmenopausal women with low or normal BMD; one in women with osteopenia; eight in women with osteopenia or osteoporosis; four in women with osteoporosis; and one in women with established osteoporosis. Overall, 15 trials compared alendronate with placebo or with no treatment.

All the studies were conducted in women who had adequate levels of calcium, either from dietary intake or from calcium supplementation.

Fracture risk reduction

The meta-analysis conducted by NICE found the following relative risks (RRs) for alendronate compared with placebo or no treatment:

Vertebral fracture: RR 0.56 (95% CI 0.46 to 0.68; four RCTs, 7039 participants).

Hip fracture: RR 0.62 (95% CI 0.40 to 0.98; three RCTs, 7455 participants).

Wrist fracture: RR 0.67 (95% CI 0.34 to 1.31; four RCTs, 7931 participants).

Other non-vertebral fractures: RR 0.81(95% CI 0.68 to 0.97; six RCTs, 9973 participants).

Health-related quality of life and pain

The review found one study which reported health-related quality of life outcomes.

At 12 months there were statistically significant improvements, in the alendronate group compared with the control group, in scores for pain, social isolation, energy level, and physical ability.

Daily alendronate compared with weekly alendronate

One study found that daily and weekly doses of alendronate for 2 years were similar in terms of clinical fracture incidence and gastrointestinal adverse events.

Alendronate compared with other drugs

CKS found no trials that directly compared alendronate with other drugs used in primary care for reduction of fracture risk.

A large observational study based on insurance claims found no clinically important difference between alendronate and risedronate in hip fracture risk [Curtis et al, 2009].

Effect of baseline bone density on effectiveness of alendronate

A post-hoc analysis of data from the largest study on alendronate, the Fracture Intervention Trial investigating women with non-vertebral fractures, suggested that alendronate may be less effective at reducing fractures in women with T-scores greater than –2.5 than in women with osteoporosis. These results were not statistically significant.

When to discontinue drug treatment

See Benefits of long-term treatment.

Risedronate in women

Evidence on risedronate for osteoporotic fracture risk reduction in women

A systematic review of randomized controlled trials (RCTs) found that, compared with placebo, treatment with risedronate reduced the risk of vertebral fractures, non-vertebral fractures, and hip fractures in postmenopausal women with low bone mineral density (BMD). No head-to-head trials have compared risedronate with other drugs for reduction of fracture risk, but one observational study found no clinically important difference in effectiveness between alendronate and risedronate.

The National Institute for Health and Care Excellence (NICE) commissioned a systematic review of clinical trials of treatments to reduce the risk of osteoporotic fragility fracture in women [NICE, 2011a; NICE, 2011b]. In the review's meta-analysis, reductions in relative risk associated with a treatment were pooled regardless of baseline BMD, fracture status, and age of study participants.

Risedronate compared with placebo

The NICE systematic review included seven RCTs of risedronate in postmenopausal women: one study in women with normal BMD; one in women with osteopenia; one in women with osteopenia or osteoporosis; one in women with osteoporosis or specific risk factors for hip fracture, such as a recent fall; and three in women with established osteoporosis.

All studies compared risedronate with placebo. With the exception of those in the normal BMD study, all women also received calcium. No trials reported on health-related quality of life outcomes.

Fracture risk reduction

The meta-analysis conducted by NICE found the following relative risks (RRs) for risedronate compared with placebo or no treatment:

Vertebral fracture: RR 0.61 (95% CI 0.50 to 0.75; three RCTs, 2301 participants).

Hip fracture: RR 0.74 (95% CI 0.59 to 0.93; three RCTs, 11,770 participants).

Wrist fracture: RR 0.68 (95% CI 0.43 to 1.08; two RCTs, 2439 participants).

Other non-vertebral fractures: RR 0.76 (95% CI 0.64 to 0.91; five RCTs, 12,399 participants).

Health-related quality of life and pain

The NICE review found no study which reported health-related quality of life outcomes.

Risedronate compared with other drugs

CKS found no trials that directly compared risedronate with other drugs used in primary care for reduction of fracture risk.

A large observational study based on insurance claims found no clinically important difference between alendronate and risedronate in hip fracture risk [Curtis et al, 2009].

Discontinuation of risedronate and BMD

If risedronate is discontinued after 2 years in young postmenopausal women, a significant bone loss at both spine and hip has been shown during the first year after stopping treatment [Mortensen et al, 1998]. The effects of stopping treatment in older women or after longer treatment intervals are not known.

Duration of treatment

Evidence on duration of treatment

Benefits of long-term treatment

Evidence on benefits of long-term treatment

Data from the FLEX randomized controlled trial suggests that a drug holiday after 5 years of treatment with alendronate is associated with a small increase in clinically apparent vertebral fractures, but no increase in other types of osteoporotic fractures. Post-hoc subgroup analysis suggests that in women with a T-score of less than –2.5 after 5 years of treatment have less non-vertebral fractures if they continue treatment for up to 10 years but there was no benefit in continuing to treat women with a T-score of more than -2.0 for longer than 5 years.

Alendronate continued for 5 more years (after 5 years' treatment) compared with no treatment

An extension of a randomized controlled trial reported on the outcomes of women who had been treated with alendronate for 5 years and then randomized to receive either placebo or alendronate for a further 5 years. However, with only 247 participants, the study could not assess differences in fracture rates [Bone et al, 2004].

The FIT trial randomized postmenopausal women with low bone mineral density (BMD) to treatment with either alendronate or placebo for 5 years [Black et al, 1996]. The FLEX trial extended the FIT trial and randomized 1999 women who had been treated with alendronate for 5 years, to be treated with either alendronate 5 mg/day (30% of participants), or alendronate 10 mg/day (30%), or placebo for 5 years (50%) [Black et al, 2006; Black et al, 2007; Schwartz et al, 2010].

Incidence of fracture was an exploratory outcome measure. The primary outcome measure was total hip BMD.

Compared with continuing alendronate, a drug holiday for 5 years was associated with a moderate decline in BMD, increase in bone turnover markers, no statistically significant increase in non-vertebral or morphometric vertebral fractures, and a statistically significant increased risk of clinically recognized vertebral fractures [Black et al, 2006].

Non-vertebral fractures. There was no significant difference between those continuing (19%) and those discontinuing (18.9%) alendronate: relative risk (RR) 1.00 (95% CI 0.76 to 1.32).

Morphometric vertebral fractures. There was no significant difference between those continuing (9.8%) and those discontinuing (11.3%) alendronate: RR 0.86 (95% CI 0.60 to 1.22).

Clinically recognized vertebral fractures. There was a significant difference between those continuing (2.4%) and those discontinuing (5.3%) alendronate: RR 0.45 (95% CI 0.24 to 0.85).

Post-hoc analysis of data from the FLEX trial investigated the relationship between fracture risk and T-score at entry to the FLEX trial for the 720 women with no vertebral fracture when enrolled [Schwartz et al, 2010].

Continuing alendronate for 10 years in women with no vertebral fracture was associated with a reduced risk of non-vertebral fracture in women whose T-scores after 5 years of alendronate were –2.5 or less, but not in women whose T-scores were greater than –2.0.

Non-vertebral fractures (baseline T-score less than or equal to –2.5): RR 0.50 (95% CI 0.26 to 0.96).

Non-vertebral fractures (baseline T-score greater than –2.5 and less than or equal to –2.0): RR 0.79 (95% CI 0.37 to 1.66).

Non-vertebral fractures (baseline T-score greater than –2.0): RR 1.41 (95% CI 0.75 to 2.66).

Bisphosphonate treatment duration and treatment adherence

An observational study used administrative databases from a large US healthcare organization to determine the rates of hip fracture in women who discontinued bisphosphonate and in those who remained on treatment [Curtis et al, 2008].

The study identified 9063 women who were adherent bisphosphonate treatment, defined as a Medication Possession Ratio (MPR) greater than 65%.

Comparing discontinuation of bisphosphonates with continued treatment. Women who discontinued bisphosphonate treatment were at increased risk of hip fracture, but the risk was lower for women who were more adherent (MPR at least 80%) or had been on bisphosphonate treatment for at least 3 years.

Hip fractures. The rate of hip fractures in women who discontinued bisphosphonates was 8.43 per 1000 person-years, and 4.67 per 1000 person-years in those who continued treatment (p = 0.016).

Hip fractures and compliance. For women whose MPR was at least 80% and for those who had been adherent for 3 years, there were no significant differences in hip fracture risk associated with discontinuation. For women whose MPR was more than 65% but less than 80% and who had been adherent for 2 years, there was a significant difference in hip fracture risk associated with discontinuation.

The data were analysed with multiple binary comparisons (where multivariate regression would have been more appropriate to assess the contributions of MPR and time to fracture risk), or the p-values were adjusted for multiple comparisons.

Risks of long-term treatment

Evidence on risks of long-term treatment

Published information on adverse effects of long-term treatment with bisphosphonates is available from clinical trials designed to assess the effect of treatment on fracture risk, bone mineral density, and bone turnover markers. Because these trial were not statistically powered to detect rare events, uncertainty remains about the possible hazards of long-term treatment. A number of trials have found that long-term treatment with alendronate is associated with a two- to three-fold increased relative risk of atypical subtrochanteric or femoral shaft fractures, but the absolute risk is small (around 0.13% per year). Osteonecrosis of the jaw has been associated with bisphosphonates; the risk is greater in people with cancer receiving intravenous bisphosphonates than in people being treated for osteoporosis, and the risk is low for people taking oral bisphosphonates. Concerns have been expressed about a risk of oesophageal cancer, but the risk (if present) is small and is outweighed by the benefits of treatment.

Atypical subtrochanteric or femoral shaft fractures

Treatment with a bisphosphonate for more than 5 years is associated with an increased risk of atypical subtrochanteric or femoral shaft fractures. The absolute risk of these fractures is low, around 0.13%.

A nested case-control study assessed the association between bisphosphonate use and fractures in women 68 years of age or older [Park-Wyllie et al, 2011].

Women hospitalized with an atypical subtrochanteric fracture or femoral shaft fracture were matched to up to five controls with a typical osteoporotic fracture of the intertrochanteric region or femoral neck. There were 716 cases and 9723 controls.

Compared with transient bisphosphonate use, treatment for 5 years or longer was associated with an increased risk of atypical subtrochanteric fracture and a decreased risk of typical hip fracture.

Atypical subtrochanteric fracture: adjusted odds ratio (OR) 2.74 (95% CI 1.25 to 6.02). The absolute risk for fracture was 0.13% during the fifth year of treatment and 0.22% during the sixth and seventh year.

Typical hip fracture: OR 0.76 (95% CI 0.6 to 0.93).

A cohort study using Danish national healthcare data assessed the risk of atypical subtrochanteric or diaphyseal fractures of the femur in people taking long-term alendronate [Abrahamsen et al, 2010]

The cohort included 39,567 people taking alendronate without previous hip fracture and 158,268 untreated controls.

Compared with transient bisphosphonate use, treatment for 5 years or longer was associated with an increased risk of atypical subtrochanteric fracture and a decreased risk of typical fracture.

Atypical subtrochanteric fracture

In women, the rates of subtrochanteric and diaphyseal fractures were 13 per 10,000 patient-years in untreated women and 31 per 10,000 patient-years in women receiving alendronate; adjusted hazard ratio (HR) 1.88 (95% CI 1.62 to 2.17).

In men, the rates of subtrochanteric and diaphyseal fractures were 6 per 10,000 patient-years in untreated men and 31 per 10,000 patient-years in men receiving alendronate; HR 3.98 (95% CI 2.62 to 6.05).

Duration of treatment: the risks of atypical subtrochanteric fracture were similar in people who had received 9 years of treatment and in people who had stopped treatment after 3 months.

Typical hip fracture

In women, the HR for typical hip fracture was 1.37 (95% CI 1.30 to 1.46).

In men, the HR for typical hip fracture was 2.47 (95% CI 2.07 to 2.95) .

Osteonecrosis of the jaw

The European Medicines Agency reviewed the published literature and unpublished data provided by manufacturers of bisphosphonates [EMEA, 2009a]. The review concluded that:

The risk of osteonecrosis of the jaw was greater in people with cancer who were receiving intravenous bisphosphonates than in people being treated for osteoporosis.

The risk appears to be low for people taking oral bisphosphonates.

Oesophageal cancer

The Medicines and Healthcare products Regulatory Agency reviewed the evidence from epidemiological studies assessing the risk of developing oesophageal cancer while using oral bisphosphonates [MHRA, 2010b], and concluded:

'Given the study limitations and a lack of supporting evidence from other studies there is insufficient evidence to suggest a definite association between oral bisphosphonate use and oesophageal cancer. The benefits of bisphosphonate treatment are still considered to outweigh the risks.'

Drugs for reducing men's risk of osteoporotic fragility fractures

Evidence on drugs for reducing the risk of osteoporotic fragility fractures in men

The criteria for including and excluding studies are summarized in Supporting evidence.

Alendronate in men

Evidence on alendronate for osteoporotic fragility fracture risk reduction in men

A small randomized controlled trial found that men treated with alendronate for two years were less likely to have a morphometric vertebral fracture than men treated with placebo.

Alendronate plus vitamin D and calcium, compared with vitamin D and calcium alone, over 2 years

A double-blind controlled trial randomized 241 men with osteoporosis to treatment for two years with either alendronate or placebo (in a ratio of 3 to 2) [Orwoll et al, 2000]. All participants were also treated with vitamin D and calcium.

The primary outcome measure was change in bone mineral density.

Men who received alendronate had a lower rate of morphometric vertebral fractures than men who received placebo lower: 0.8% compared with 7.1%, p = 0.02.

There were too few events for meaningful statistical analysis of differences in rates of clinical vertebral fractures or fractures at non-vertebral sites.

Risedronate in men

Evidence on risedronate for osteoporotic fragility fracture risk reduction in men

One small unblinded randomized controlled trial (RCT) found that adding risedronate to vitamin D and calcium was associated with a significant reduction in the incidence of vertebral and non-vertebral fractures in men with primary or secondary osteoporosis.

Risedronate plus vitamin D and calcium, compared with vitamin D and calcium alone, over 2 years

One RCT assessed the benefit of adding risedronate to vitamin D and calcium [Ringe et al, 2009].

Men with primary or secondary osteoporosis were randomized in an open-label trial to be treated with either risedronate 5 mg daily plus vitamin D and calcium, or vitamin D and calcium alone (158 men in each group).

Vertebral fractures

Over 2 years, the incidence of vertebral fractures was significantly lower in the risedronate group (9% [14/152]) compared with control (24% [35/148], p = 0.003).

Non-vertebral fractures

Over 2 years, the incidence of non-vertebral fractures was significantly lower in the risedronate group (12% [18/152]) compared with control (22% [33/148], p = 0.03).

Drugs for reducing the risk of corticosteroid-induced osteoporosis

Evidence on drugs for reducing the risk of corticosteroid-induced osteoporosis

Fracture was not a primary endpoint in any of the studies of corticosteroid-induced osteoporosis, although in some of the larger studies vertebral fracture was a secondary or safety endpoint; the level of evidence for anti-fracture efficacy is thus less robust than for interventions used in postmenopausal women with osteoporosis. Many of the studies are small and the populations varied widely with respect to the underlying disease. In addition, the dose of corticosteroids, duration of use, cumulative dose before intervention, and criteria for inclusion, differ considerably between studies.

Bisphosphonates

Post-hoc analyses of studies of risedronate and etidronate, and analysis of secondary endpoints in a study of alendronate, found that these drugs all reduced the risk of vertebral fractures in people taking corticosteroids [RCP, 2002].

A more recent, open-label, randomized controlled trial (n = 349) compared 5 years' treatment with etidronate alone, calcium alone, etidronate plus calcium, and no treatment in people with asthma who were taking oral and/or inhaled corticosteroids. Baseline bone mineral density (BMD) was measured in 167 people (48%). Intention-to-treat analyses were conducted. Sample size calculations estimated that 750 people would be needed to achieve 80% power to detect a statistically significant difference in the primary outcome of new fracture. However, due to recruitment difficulties, this target was not reached. In addition, 23% of people were lost to follow up [Campbell et al, 2004].

Over the course of the trial, BMD levels at the lumbar spine were 4.1% higher in people treated with etidronate compared with the other groups (95% CI 2 to 6.2).

No significant differences in BMD at the hip were found.

No significant difference in fracture rates were found, possibly because the trial was underpowered.

Similar findings were found when only the people who were taking continuous oral corticosteroids were analysed.

Active vitamin D3 analogues (calcitriol, alfacalcidol)

A meta-analysis (search date: 2003) of 54 trials investigated the effectiveness of active vitamin D3 analogues in the treatment or prevention of corticosteroid-induced osteoporosis, in comparison with placebo and other anti-osteoporosis therapies. For the effect on BMD, results were expressed as a standardized mean difference (SMD), where an SMD greater than 0 implied benefit. For the effect on vertebral fracture rate, the results were expressed as a relative risk (RR), where an RR of less than one implied benefit for fracture reduction. Overall, vitamin D3 analogues not only preserved bone during corticosteroid therapy more effectively than no treatment, placebo, plain vitamin D3, and/or calcium, but were also more effective in decreasing the risk of vertebral fractures. Bisphosphonates, however, were more effective than active vitamin D3 analogues at preserving bone and decreasing the risk of vertebral fractures [de Nijs et al, 2004].

Pooled results of 11 trials (n = 577) found that BMD was greater in people taking active vitamin D3 analogues, compared with those taking no treatment, placebo, plain vitamin D3, and/or calcium alone (SMD 0.35, 95% CI 0.18 to 0.52).

Pooled results of seven trials (n = 428) found that BMD was less in people taking active vitamin D3 analogues, compared with those taking bisphosphonates (SMD –1.03, 95% CI –1.71 to –0.36).

Pooled results of seven trials (n = 446) found that the vertebral fracture rate was lower in people taking active vitamin D3 analogues, compared with those taking no treatment, placebo, plain vitamin D3, and/or calcium alone (RR 0.56, 95% CI 0.34 to 0.92).

Pooled results of five trials (n = 343) found that the vertebral fracture rate was greater in people taking active vitamin D3 analogues than in people taking bisphosphonates (RR 1.20, 95% CI 0.32 to 4.55).

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on the primary care management of Osteoporosis.

Search dates

November 2010 - April 2013

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

exp osteoporosis/, exp osteoporosis, postmenopausal/, osteoporosis.tw., exp fractures, bone/, exp osteoporotic fractures/, exp hip fractures/, fragility fractures.tw.

Table 1 . Key to search terms.
Search commands Explanation
/ indicates a MeSh subject heading with all subheadings selected
.tw indicates a search for a term in the title or abstract
exp indicates that the MeSH subject heading was exploded to include the narrower, more specific terms beneath it in the MeSH tree
$ indicates that the search term was truncated (e.g. wart$ searches for wart and warts)
Topic specific literature search sources

National Osteoporosis Guideline Group

Sources of guidelines

National Institute for Health and Care Excellence (NICE)

Scottish Intercollegiate Guidelines Network (SIGN)

Royal College of Physicians

Royal College of General Practitioners

Royal College of Nursing

NICE Evidence

Health Protection Agency

National Guidelines Clearinghouse

Guidelines International Network

TRIP database

GAIN

Institute for Clinical Systems Improvement

National Health and Medical Research Council (Australia)

Royal Australian College of General Practitioners

British Columbia Medical Association

Canadian Medical Association

Towards Optimal Practice

University of Michigan Medical School

Michigan Quality Improvement Consortium

Patient UK Guideline links

Driver and Vehicle Licensing Agency

Medline (with guideline filter)

Sources of systematic reviews and meta-analyses

The Cochrane Library :

Systematic reviews

Protocols

Database of Abstracts of Reviews of Effects

Medline (with systematic review filter)

EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

The Cochrane Library :

NHS Economic Evaluations

Health Technology Assessments

Canadian Agency for Drugs and Technologies in Health

International Network of Agencies for Health Technology Assessment

NIHR Health Technology Assessment programme

Sources of randomized controlled trials

The Cochrane Library :

Central Register of Controlled Trials

Medline (with randomized controlled trial filter)

EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Drug & Therapeutics Bulletin

Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

Department of Health

Health Management Information Consortium (HMIC)

Patient experiences

Healthtalkonline

BMJ - Patient Journeys

Patient.co.uk - Patient Support Groups

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

British National Formulary (BNF)

electronic Medicines Compendium (eMC)

European Medicines Agency (EMEA)

LactMed

Medicines and Healthcare products Regulatory Agency (MHRA)

REPROTOX

Scottish Medicines Consortium

Stockley's Drug Interactions

TERIS

TOXBASE

Micromedex

UK Medicines Information

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