Louise Winstanley, BSc (Hons Pharm) MRPharmS,
Pharmacist Independent Prescriber,
Wylde Consortium Pharmacist Team Lead, Blackpool Teaching Hospitals NHS Foundation Trust, UK
Osteoporosis is a condition of skeletal bone and is associated with falls and fractures. According to the National Institute for Health and Clinical Excellence (NICE), it is defined as a “progressive, systemic, skeletal disorder characterised by low bone mass and micro-architectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture”.
Osteoporosis is diagnosed by Bone Mineral Density (BMD) measurements of more than 2.5 standard deviations below the adult mean (written as a T-score of -2.5). T-score measurements vary depending on the site and method of investigation. The use of hip and/or spine dual energy X-ray absorptiometry (DEXA) scanning is the recommended approach:
– osteopenia has a T-score of between −1 and −2.5
– osteoporosis has a T-score of −2.5 or below
– established (severe) osteoporosis has a T-score of 2.5 or below, with one or more associated fractures
Eighty per cent of human skeleton is made up of the outer layer of cortical bone and the remaining 20% consists of the inner mesh of trabecular bone—the element more affected by bone loss. Bone is continually being remodelled throughout our lives, and therefore the skeleton of an average older person will be completely different from the one that they were born with. Remodelling is the complex process whereby old bone is absorbed back into the body and then new bone is laid down. There is a wide range of factors involved in this process, including cells, proteins, bone minerals and hormones. Many conditions can affect bone metabolism, such as disorders of the thyroid and parathyroid glands, responsible for producing calcitonin.
Bone health in later life is determined by bone deposition as children and young adults. There is concern that due to changes in childhood activity and lack of awareness regarding the causes, the incidence of osteoporosis may increase. Bone loss of 0.5-1.0% per year begins at age 35-40 in both sexes. This rate accelerates to 10% during the menopause and then continues at 1–3%. During the menopause this is due to increased osteoclast activity, but in older age it is due to a decreasing number of osteoblasts.
In the UK, one in two women, and one in five men over the age of 50, will break a bone, with over 300,000 fragility fractures occurring annually.
Fragility fractures, defined as a fall from standing height, can have a huge impact on the quality of life of older adults. Up to 50% of older adults are unable to live independently after hip fracture and up to 14,000 people die annually as a result of such fractures. Almost half of all women will experience an osteoporotic fracture by the age of 70,1 and lifetime risk of osteoporotic fracture is 40% in women and 13% in men, with breakages of the wrist, hip or vertebrae the most common. Hip fracture is one of the most depressing possibilities of older age. Outcomes post-fracture are poor and people tend to deteriorate very quickly, live with immobility for many years or even die soon after hip fracture.
The most visible sign of osteoporosis is the significant loss of height, or kyphosis: the characteristic stooping position that occurs in older people due to vertebral fractures. Other warning symptoms are, however, unlikely and osteoporosis only causes pain when a bone is broken as a result of the condition. Vertebral fractures are the most common cause of chronic pain associated with the condition, although they are not always painful.
Measurement of BMD is by DEXA scanning. Diagnosis can only be confirmed by DEXA scan, although vertebral fractures can be seen on X-ray, and fragility fractures can suggest osteoporosis. A DEXA scan is not needed to confirm osteoporosis after the age of 75, as long as non-osteoporotic causes of fracture have been ruled out (for example, malignancy, osteomalacia and hyperparathyroidism).
The aim of treatment is to prevent or reduce the incidence of fractures by increasing bone strength. Guidance mainly relates to the postmenopausal treatment of women, or those using steroids. There is little guidance relating to men, as up to 50% of osteoporosis in men is due to secondary causes.
The National Institute for Health and Clinical Excellence (NICE) has published three technology appraisals relating to osteoporosis, which contain a large amount of information: TA160, 161 and 204:
2. TA161 – Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women
3. TA204 – Denosumab for the prevention of osteoporotic fractures in postmenopausal women
A short clinical guideline on risk assessment is to be produced by NICE, although there is no set date on when it will be available.
The National Osteoporosis Guideline Group (NOGG) was established to provide a clinical guideline for the management of men and women with high fracture risk. They have developed the FRAX® algorithms to calculate an individual’s 10-year probability of fracture. These guidelines are useful for people who fall outside NICE guidance.
Clinical questions based on research
Who should we treat to reduce the incidence of fracture?
The main body of evidence states treating postmenopausal women for both primary and secondary prevention of osteoporosis will reduce the incidence of fracture. As the lifetime risk of a vertebral fracture is one in three and with one in five for a hip fracture, this provides enough evidence to screen women by DXA scan if they are over 50 with risk factors. However, this is not current practice, mainly due to lack of access to DXA scanning.
The evidence suggests that all men with osteoporosis should be referred for treatment. However, it does not address the problem of how men with osteoporosis should be identified, as they often go undiagnosed or untreated until fragility fracture occurs. The literature about this topic is unfortunately scant.
The guidelines in Clinical Knowledge Summaries could be used to determine which people taking steroids should be offered prophylactic treatment.
Reduction in fracture following treatment, especially hip fracture for all older women, is the patient-oriented evidence that matters most. However, there is no information to support whether treatment should be for people who are mobile or immobile; the pragmatic decision is to treat people who are mobile with the intention of reducing their risk of further fracture. The incidence of vertebral fracture in people who are immobile and the effectiveness of treatment for this group are more difficult to assess. Currently, people who are immobile are not treated unless they are suffering painful symptoms from vertebral fracture.
Bisphosphonates work by the inhibition of bone resorption and also by changing osteoclast activity and function. The choice of which bisphosphonate to prescribe is based on the evidence between alendronate and risedronate, as the evidence for etidronate is poor. Once the evidence for safety, efficacy and tolerability of the three bisphosphonates has been taken into consideration, the decision for prescribing then rests on the lowest acquisition cost, although the Clinical Knowledge Summary gives advice about specific conditions. In this respect, alendronate is the drug of choice,1,13 although there are other bisphosphonates available.
Raloxifene is a selective oestrogen receptor modulator, which works by acting on bone, mimicking oestrogen, which has an important role in the production of new bone. Raloxifene is an option for women who are unable to take a bisphosphonate due to side effects. It is associated with an increased risk of thromboembolic events, similar to the reported risk for hormone replacement therapy (HRT). Liver function should be monitored during raloxifene treatment.
Teriparatide is a parathyroid hormone fragment that is recommended for women over 65 years who cannot take a bisphosphonate, or for whom a bisphosphonate has previously failed to prevent a fracture. This should only be initiated by a specialist experienced in the treatment of osteoporosis.1 Monitoring of urea and electrolytes is recommended during teriparatide treatment.
Strontium is thought to work by increasing bone formation and reducing bone resorption. It has recently been added to the NICE guidance as a second-line choice, with teriparatide. Monitoring of urea and electrolytes is recommended during strontium treatment.
Hormone replacement therapy is an option where other therapies are contraindicated or are not tolerated, and is more often used in women who have had a surgical or early menopause (NICE 2005). The Committee for the Safety of Medicines has recommended that HRT should not be used first-line for the long-term prevention of osteoporosis.
Calcitonin is produced naturally in the body and is involved in the metabolism of bone with parathyroid hormone. Its main licensed uses are for Paget’s disease, the prevention of acute bone loss due to sudden immobility, and hypercalcaemia of malignancy.
Calcium and vitamin D: Vitamin D is a hormone precursor, which is converted in the body into several biologically active metabolites. Its main action is in the maintenance of plasma calcium by increasing calcium absorption from the intestine and reducing renal excretion. Cholecalciferol (D3) is generated in the skin by ultraviolet light (such as sunlight), which in turn is acted on by liver and kidney enzymes to produce calcifediol and calcitriol. Calcifediol is the main vitamin D metabolite in the circulation.
Adequate levels of calcium and vitamin D are needed to ensure optimum effects of the treatment of osteoporosis, and therefore supplements should be provided unless intake of calcium and vitamin D is already sufficient.
A Cochrane Systematic Review of Calcium and Vitamin D Studies15 looked at females over one year and compared placebo with calcium & vitamin D. Vitamin D plus calcium: seven trials, 10,376 participants. The results included:
- Vitamin D alone: no significant results
- Vitamin D with calcium: hip fractures RRR 19%; non-vertebral fracture RRR 13%
- Effect restricted to those in institutional care
- NNT: Not calculated 15
- There was an increased risk of hypercalcaemia, RR 2.4% (14 trials 8035 people)
Calcitriol: Vitamin D requires hydroxylation by the kidneys before becoming active in the body; therefore this derivative is suitable for the treatment of secondary osteoporosis for people with severe renal impairment.
Side effects and contraindications
The main concerns relate to oesophageal irritation and ulceration, hypercalcaemia and osteonecrosis of the jaw.
Bisphosphonates: oesophagitis, oesophageal ulceration, osteonecrosis of the jaw, headache, constipation, nausea and abdominal pain.
Raloxifene: hot flushes, leg cramps
and flu syndrome.
Teriparatide: nausea, pain in limbs, headache and dizziness.
Strontium: headache, nausea, diarrhoea and dermatitis.
Hypercalcaemia (increased serum calcium): This can be caused by excess intake of calcium and vitamin D, so regular calcium monitoring is advisable. Calcium can be measured before prescribing, but it is often more useful to monitor about three months after starting treatment. If calcium levels are raised, levels return to normal on stopping treatment. There are also other causes of raised calcium, so if blood levels do not revert to normal one month after discontinuing calcium, further investigation of the cause is needed. Several serious conditions present with raised calcium (for example, malignancy). Serum calcium should be monitored at least annually.
Osteonecrosis of the jaw (ONJ): known risk factors for ONJ include a diagnosis of cancer with bone lesions, concomitant therapies (for example, chemotherapy, corticosteroids, radiotherapy to head and neck), poor oral hygiene, dental extractions, and co-morbid disorders (for example, pre-existing dental disease, anaemia, infection) and previous treatment with bisphosphonates. Good oral hygiene practices should be maintained during treatment. For patients who develop ONJ while on therapy, dental surgery may exacerbate the condition. If ONJ occurs during treatment, further advice on osteoporosis treatment is necessary.
Oral bisphosphonates: oesophageal cancer risk
“There is insufficient evidence to confirm a link between oral bisphosphonate use and an increased risk of oesophageal cancer. Patients should be advised to carefully follow the instructions in the patient information leaflet on how to take the medicine and report any symptoms of oesophageal irritation to their doctor.”16
New licensed drugs
Denosumab works by blocking a protein that controls production of osteoclasts. It is given every six months and, as long-term safety data is currently unavailable, use will be limited to consultant initiation.
Caution is advised when prescribing denosumab where patients:
- have severe renal impairment (creatinine clearance <30ml/min)or are receiving dialysis (and are at a greater risk of developing hypocalcaemia)
- have risk factors for developing osteonecrosis of the jaw
Role of the pharmacist
Medicines can contribute to falls and fractures, so it is crucial to ensure that all medicines for older people are appropriate and carefully managed.
Pharmacists are in an ideal situation to make a wide range of interventions. If the possibility of osteoporosis is considered for every person over the age of 55, then DEXA results can aid selection of the appropriate treatment. An easy algorithm for post-menopausal women during medication review is shown below.
There is often confusion between primary and secondary prevention of osteoporosis and their appropriate management. Pharmacists are in a good position to be able to educate both patients and other healthcare professionals with regard to guidance interpretation, treatment decisions and discussion about safe and correct medicine administration.