Osteoporosis

What is osteoporosis?

Osteoporosis is a progressive systemic skeletal disease characterised by reduced bone density and micro-architectural deterioration of bone tissue. As a result, bone is increasingly fragile and more susceptible to fracture.

Osteoporotic (fragility) fractures are fractures that result from mechanical forces that would not ordinarily result in fracture. Osteoporotic fractures are defined as fractures associated with low bone mineral density (BMD) and include spine, forearm, hip, and shoulder fractures.

For clinicians, managing osteoporosis is a challenge due to conflicting guidelines and as yet incomplete evidence (and therefore guidance) in important areas.

Bone density

Bone density values in individuals can be expressed in relation to a reference population in standard deviation (SD); when SDs are used in relation to the young healthy population. This measurement is referred to as the T score. A Z score compares bone density to the normal at that age, and a score of -2 indicates bone density below normal for a person of that age.

BMD categories established by the World Health Organization (WHO):

• Normal: hip BMD greater than the lower limit of normal which is taken as 1 SD below the young adult reference mean (T score ≥-1).

• Low bone mass (osteopenia): hip BMD between 1 and 2.5 SD below the young adult reference mean (T score less than -1 but above -2.5).¹

• Osteoporosis: hip BMD 2.5 SD or more below the young adult reference mean (T score ≤-2.5).²

• Severe osteoporosis: hip BMD 2.5 SD or more below the young adult reference mean in the presence of one or more fragility fractures (T score ≤-2.5 PLUS fracture).³

Bone density can be measured by a number of investigative tests but the one most commonly used is dual-energy X-ray absorptiometry (now abbreviated to DXA). See the 'Investigations' section below for further details.

Who gets osteoporosis? (Epidemiology) ⁴

• In England and Wales more than 2 million women have osteoporosis.

• In England and Wales there are around 180,000 fractures per year due to osteoporosis.

• 1 in 3 women and 1 in 5 men will have an osteoporotic fracture in their lifetime.

• Osteoporosis is in general an age-related disease. Bone formation initially exceeds bone resorption but by the third decade this has reversed resulting in a net loss of bone mass. Therefore, bone mass declines with age and this is accelerated for a time in women after menopause. Prevalence of osteoporosis increases markedly with age, from 2% at 50 years to more than 25% at 80 years in women.

Risk factors for fragility fractures⁵

Reduced BMD is a major risk factor for fragility fracture.

As well as reduced BMD, a number of other risk factors increase fracture risk. Some do this by increasing the risk of osteoporosis, some are independent risk factors and some work in more than one way. Identification of these risk factors is important as it guides case-finding and treatment.

• Increasing age (risk increased partly independent of reducing BMD).

• Female sex.

• Low body mass (<19 kg/m²) and anorexia nervosa.

• Parental history of hip fracture.

• Past history of fragility fracture (especially hip, wrist, and spine fracture).

• Corticosteroid therapy (current treatment at any dose orally for three months or more).

• Cushing's syndrome.

• Alcohol intake of three or more units per day.

• Smoking.

• Falls and conditions increasing the risk of falls, such as:

  • Visual impairment.

  • Lack of neuromuscular co-ordination or strength.

  • Cognitive impairment.

  • Sedative medication and alcohol.

• Secondary osteoporosis causes, such as:

  • Rheumatoid arthritis and other inflammatory arthropathies.

  • Prolonged immobilisation or a very sedentary lifestyle.

  • Primary hypogonadism (men and women).

  • Primary hyperparathyroidism.

  • Hyperthyroidism.

  • Post-transplantation.

  • Chronic kidney disease.

  • Gastrointestinal disease such as Crohn's disease, ulcerative colitis and coeliac disease.

  • Untreated premature menopause (<45 years) or prolonged secondary amenorrhoea.

  • Type 1 diabetes mellitus.

  • Chronic liver disease.

  • Chronic obstructive pulmonary disease.

Osteoporosis symptoms⁶

Unfortunately, the process that leads to established osteoporosis is asymptomatic and the condition usually presents only after bone fracture. It is important that clinicians be alert to recognise low-trauma 'fragility fractures' (fracture caused by a low-impact injury which would not usually cause a fracture, such as a fall from standing height).

Fragility fractures occur most commonly in the spine (vertebrae), hip (proximal femur) and wrist (distal radius). They may also occur in the arm (humerus), pelvis, ribs and other bones. Signs differ according to the fracture site.

Investigations⁶⁷

See also the separate Osteoporosis risk assessment and primary prevention article.

Osteoporosis diagnosis

Diagnosis of osteoporosis centres on the assessment of BMD. DXA, or DEXA, stands for dual-energy X-ray absorptiometry and is regarded as the gold standard technique for diagnosis. The accuracy at the hip exceeds 90%. Residual errors arise for various reasons. Incorrect diagnosis of osteoporosis can be caused by osteomalacia, osteoarthritis, or soft-tissue calcification.

The WHO, the International Osteoporosis Foundation (IOF) and the National Osteoporosis Guideline Group (NOGG) recommend the use of DXA at the hip for the diagnosis of osteoporosis. Other radiological investigations sometimes used for screening purposes are: ²

• Single-energy X-ray absorptiometry (SXA).

• Digital X-ray radiogrammetry (DXR). DXR is simpler and less time-consuming than DXA. It can be carried out anywhere where there is the facility to perform a standard radiograph of the hand. It may be used as a screening tool for osteoporosis (for example, following Colles'/other forearm fractures), without the need for additional radiographs.

• Ultrasonic measurement of bone, usually measured at the heel. This can be used for the assessment of fracture risk or for selection of those in need of DXA. It is unreliable for diagnosis of osteoporosis and is associated with underdiagnosis.

Consider the following screening blood tests, in patients suffering from osteoporosis, to identify treatable underlying causes of osteoporosis and to rule out differential diagnoses (osteomalacia, myeloma):

• FBC and ESR or CRP.

• U&E, LFTs, TFTs, bone profile, vitamin D.

• Testosterone/gonadotrophins in men, FSH and LH in women.

• Serum immunoglobulins and paraproteins, urinary Bence-Jones' proteins.

Assessment of fracture risk⁶⁷

Although osteoporosis indicates a high likelihood of fracture, many fragility fractures occur in people with bone density values above the defined level. Measurements of BMD by DXA at the lumbar spine, femoral neck, total hip, and wrist have been shown to predict future fracture occurrence. Peripheral DXA has some predictive value but less so than measurements at the hip and spine. The use of BMD alone to assess risk, however, has a high specificity but low sensitivity and most osteoporotic fractures will occur in people who do not have osteoporosis as defined by a T score of ≤2.5. Fractures can be better predicted by adding clinical risk factors that contribute to fracture risk independently of BMD. BMD should not therefore normally be routinely measured without the prior use of a risk assessment tool as follows.

The WHO risk calculator available (FRAX®) calculates the ten-year probability of a major osteoporotic fracture in people aged 40-90 (with or without BMD result). The result then leads to a position on a chart of low, intermediate and high risk and subsequent NOGG advice as to the need for treatment.

For UK populations, the QFracture® score may be more appropriate for fracture risk assessment as it was based on UK data.⁵ It may be used for ages 30-99 and does not include BMD.

NOGG guidelines advocate the use of FRAX®, whilst National Institute for Health and Care Excellence (NICE) guidelines allow for use of either FRAX® or QFracture®. Scottish Intercollegiate Guidelines Network (SIGN) guidelines encourage the use of QFracture prior to BMD measurement as a risk calculation tool.

Case finding

There is no national screening protocol for osteoporosis. Guidelines from NOGG, NICE, SIGN, and IOF differ, making it difficult for the clinician to choose whom to carry out risk assessments or BMD measurement upon. Broadly, consider a risk assessment in:

• Those with a history of fragility fracture. Some guidelines suggest this should trigger BMD measurement; others suggest these should be considered for treatment without the need for further assessment.

• Postmenopausal women with risk factors.

• Women or men with significant risk factors.

• Women or men on oral corticosteroid treatment. (Any dose taken continuously over three months or frequent courses. 7.5 mg prednisolone or equivalent per day over three months continuously is considered high dose by NICE and confers higher risk.)

• All women over 65 and all men over 75 (NICE only).

Osteoporosis treatment and management²⁴⁶

General

As osteoporosis is an asymptomatic condition, management is centred on preventing fragility fractures, which are associated with enormous morbidity and mortality. Treatment for osteoporosis should include not only drug treatment but also advice on lifestyle, nutrition, exercise, and measures to reduce falls. Advise on smoking cessation and moderation of alcohol intake should also be given where indicated. Advise regular weight-bearing exercise. Evidence suggests this has a modest but significant effect in improving bone.⁸⁹

Assess for risk of falls and consider referral to a falls prevention service. Consider hip protectors. Reduce polypharmacy, especially sedatives.

Calcium and vitamin D

Ensure adequate calcium intake and vitamin D status; local medicines management rules will guide you towards prescribing or advising over the counter purchase. Dietary calcium may be assessed by one of a number of online tools.¹⁰ Elderly people who are housebound or living in a nursing home may be assumed to require vitamin D supplementation. If there is adequate dietary calcium intake of more than 1000 mg/day but a lack of vitamin D, consider prescribing 10 micrograms (400 units) of vitamin D without a full replacement dose of calcium. 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 (eg, as two Calcichew D3® tablets - calcium 500 mg, colecalciferol 5 micrograms). There is ongoing research into the safety of calcium supplementation but no risk has been found where calcium is combined with vitamin D and, thus far, evidence suggests combined calcium and vitamin D are more effective than vitamin D alone in preventing fractures.¹¹ Additionally it has been shown that vitamin D supplementation does not prevent fractures or falls or have clinically meaningful effects on bone mineral density.^{12 13}

The detail in the following two sections reflects NICE guidance. NOGG thresholds do not differentiate between primary and secondary prevention, other than where previous fragility fractures affect the FRAX® score upon which management advice is based. To follow NOGG guidelines on whether to treat or not, simply follow the algorithm following risk calculation in the FRAX® link above. Once the FRAX® risk has been calculated, your patient will be placed in a category on an intervention chart which will advise on subsequent management (low risk: lifestyle advice; intermediate risk: measure BMD and recalculate risk; high risk: consider treatment).

Bisphosphonates

• Bisphosphonates are the mainstay of treatment and the only treatment regularly started in primary care. They inhibit the actions of osteoclasts.

• They are poorly absorbed and need to be taken separately from food; they must be taken sitting up, with plenty of water, to avoid oesophageal irritation.

• Side-effects include osteonecrosis of the jaw; this is much more common in patients having intravenous bisphosphonates as part of cancer treatment than those taking them orally for osteoporosis. Risk factors include the potency of the bisphosphonate, the route of administration, the duration, the cumulative dose, and the existence of comorbid conditions and smoking. All patients with cancer, and any with poor dental status, should have a dental check-up and any necessary work done before starting a bisphosphonate.

• They are taken weekly or monthly; less frequent dosing may improve adherence.

• A single NICE guidance covers the oral bisphosphonates (alendronic acid, ibandronic acid, and risedronate sodium) and the intravenous bisphosphonates (ibandronic acid and zoledronic acid).

• NICE:¹⁴

  • The population eligible for such a risk assessment is women aged over 65, men aged over 75, and people under those age who have at least one risk factor for osteoporosis.

  • Fracture risk should generally not be assessed under the age of 50 unless there are major risk factors such as long-term use of oral corticosteroids, untreated premature menopause, or a previous fragility fracture.

  • The decision on choice of treatment should be individualised and be the least expensive formulation where generics are available. Patients may find the NICE decision aid useful.

  • Ask about adherence and adverse effects at each medication review.¹⁵

Denosumab

• Denosumab is a monoclonal antibody that reduces osteoclast activity (and hence bone breakdown) which is given by six-monthly subcutaneous injections.

• It is generally given in secondary care, unless there is a suitable resourced and supported shared care agreement for use in primary care.

• There is an increased risk of multiple vertebral fractures in the 18 months after stopping or delaying treatment with 60mg denosumab; an MHRA warning says that patients should not stop without specialist review and that the balance of risks and benefits should be re-evaluated 'periodically' and at least after five or more years of use.¹⁶

• NICE:¹⁷

  • Recommended for primary prevention of osteoporotic fragility fractures in postmenopausal women at increased risk of fractures:

    • Who cannot comply with the instructions for administering alendronate and either risedronate or etidronate, or for whom these are contraindicated or not tolerated and

    • Who have a combination of T-score, age, and clinical risk factors as indicated in the following table. Clinical risk factors are parental history of hip fracture, alcohol intake of four or more units per day and rheumatoid arthritis.

Strontium ranelate

This is of historical interest only - strontium has been withdrawn worldwide.

Raloxifene

• Raloxifene is a selective oestrogen receptor modulator (SERM), which reduces postmenopausal bone loss and reduces vertebral fractures but, like oral HRT, may increase the risk of venous thromboembolism.

• Unlike HRT, however, it decreases the risk of breast cancer (oestrogen-positive tumours) but may exacerbate hot flushes.

• NICE:

  • Not recommended for primary prevention of osteoporotic fragility fractures.

  • Recommended for primary prevention of osteoporotic fragility fractures in postmenopausal women at increased risk of fractures:

    • Who cannot comply with the instructions for administering alendronate and either risedronate or etidronate, or for whom these are contraindicated or not tolerated and

    • Who have a combination of T-score, age and clinical risk factors (the same as for denosumab) as indicated in the following table. Clinical risk factors are parental history of hip fracture, alcohol intake of four or more units per day, and rheumatoid arthritis. ¹⁸

Teriperatide

• Teriparatide is a recombinant fragment of parathyroid hormone prescribed in secondary care.

• NICE:¹⁸

  • Recommended as an alternative treatment option for the secondary prevention of osteoporotic fragility fractures in postmenopausal women:

    • Who are unable to take or have a contra-indication to or intolerance of alendronate and risedronate and

    • Who are 65 or older with:

      • A T score of -4 SD or below; or

      • A T score of -3.5 SD or below plus a history of more than two fractures.

      • 55-65 with a T score of -4 SD or below plus a history of more than two fractures.

Romosozumab

• Romosozumab is a monoclonal antibody that increases bone formation, and decreases bone resorption.

• This anabolic or bone-forming therapy has a novel mechanism of action that differs from that of teriparatide.

• Romosozumab is given in a monthly dose of 210 mg subcutaneously for 12 months followed by a transition to antiresorptive therapy with the aim of maintaining the increase in BMD.

• NICE:¹⁹

  • Recommended as an option for treating severe osteoporosis in postmenopausal women at high risk of fracture, only if:

    • They have had an osteoporotic fracture of the spine, hip, forearm or humerus in the last 24 months and

    • It is provided as per the agreed commercial arrangement.

Abaloparatide

• Abaloparatide is a synthetic analogue of human parathyroid hormone-related protein which stimulates bone formation by acting as an agonist at the parathyroid hormone 1 receptor.

• NICE:²⁰

  • Recommended as an option for postmenopausal women only if:

    • They have a very high risk of fracture (exceeding the FRAX intervention threshold by 60%) and

    • It is provided as per the agreed commercial arrangement.

Osteoporosis in men and premenopausal women^{7 2}

Treatment for men is less well evaluated and researched and not as extensively covered by guidelines; a lower threshold for referral to secondary care would be appropriate, although the NICE guidance for bisphosphonates covers men aged over 75. Osteoporosis is more likely to be related to a secondary cause in men, so investigation for an underlying cause is important.

Hormone replacement therapy may be used as part of the management of osteoporosis in premenopausal women.

Treatment of fractures^{21 22}

Where fractures have occurred, these are managed in accordance with relevant guidance. Treatment of fractures is discussed in the related separate articles Femoral fractures, Wrist fractures, etc.

Compression fractures cause:

• Pain and morbidity associated with high doses of analgesia.

• Loss of height.

• Difficulty breathing.

• Loss of mobility.

• Gastrointestinal symptoms.

• Difficulty sleeping.

• Symptoms of depression.

Management aims to reduce these problems and options include:

• Analgesia.

• Back braces.

• Physiotherapy.

• Percutaneous vertebroplasty - injection of bone cement into the vertebral body.

• Balloon kyphoplasty - inflation of a balloon-like device into the vertebral body to restore its height, followed by injection of bone cement.

NICE advises the latter surgical options only in those with severe pain despite conservative measures, and where it has been confirmed that the pain is due to the fracture. A 2018 Cochrane review advises however that patients should be informed about both the high- to moderate-quality evidence that shows no important benefit of vertebroplasty and its potential for harm.²³

Length of osteoporosis treatment

One of the difficult areas for primary care clinicians currently managing people with osteoporosis is to know how to monitor treatment and when to stop it. There is no consensus on how often BMD should be measured for individuals on treatment; guidelines generally suggest between three and five years.

Bisphosphonates bind to bone mineral and inhibit osteoclastic bone resorption. Continual bone remodelling is important in maintaining a healthy skeleton by repairing microdamage, and there has been a theoretical concern that prolonged treatment could potentially have a weakening effect on bone. Furthermore, the bisphosphonates are retained in bone for some time after treatment is stopped, and the effects can continue for months or years after treatment has been stopped.

It is clear that there should be a review of the need for treatment vs the risks at some point, and this is mostly agreed to be after around five years. Where risk factors have changed (steroid treatment discontinued, for example, or T score above -2.5), this becomes a simple decision; however, in the majority of cases it is not so straightforward.

At this time, NOGG has the most clear algorithm to help determine whether to continue treatment at this point. It advises:

Review after five years of bisphosphonate treatment (three years for zoledronic acid).

• If there have been recurrent fractures:

  • Check adherence.

  • Exclude secondary causes.

  • Reconsider treatment choice.

  • Continue treatment.

• If no fractures, re-measure BMD and FRAX®:

  • If T score at femoral neck ≤-2.5 or above NOGG intervention threshold:

    • Check adherence.

    • Exclude secondary causes.

    • Reconsider treatment choice.

    • Continue treatment.

  • If T score at femoral neck >-2.5 or results are below NOGG intervention threshold, consider a drug holiday. Repeat BMD and FRAX® in two years.

Generally the following are likely to need to continue treatment at five years:

• Those aged 75 years or more.

• Those who have previously sustained a hip or vertebral fracture.

• Those on continuous oral glucocorticoids in a dose of 7.5 mg/day prednisolone or equivalent.

• Those who have had one or more low-trauma fractures during treatment, after exclusion of poor adherence to treatment (for example, less than 80% of treatment has been taken) and after causes of secondary osteoporosis have been excluded. In such cases the treatment option should be re-evaluated.

• Those in whom the total hip or femoral neck BMD T score is ≤-2.5 SD.

When treatment is discontinued, reassess fracture risk after two years, or earlier if a fragility fracture is sustained.

Prognosis ²⁶

Osteoporotic fragility fractures can cause substantial pain and severe disability, often leading to a reduced quality of life, and hip and vertebral fractures are associated with decreased life expectancy.

Hip fracture nearly always requires hospitalisation, is fatal in 20% of cases and permanently disables 50% of those affected; only 30% of patients fully recover. Surgery carries risks of complications. Fixation failure is more likely to be a problem in osteoporotic bone.

Vertebral fractures are often undiagnosed. They are associated with long-term pain and disability. One study found a year after the event, four out of five people with vertebral fracture still had significant pain and loss of quality of life.²⁴ One vertebral fracture increases a patient's risk of sustaining another vertebral fracture five-fold - 20% of these within a year.