- Email: [email protected]
Prevention and management of osteoporosis
BONE DISORDERS
Prevention and management of osteoporosis
Key points
Richard Eastell
C
It is worthwhile measuring bone mineral density (BMD) in patients with strong risk factors (e.g. those taking long-term corticosteroids, older patients with low-trauma fractures)
C
There is good evidence that treatment prevents fractures in women with vertebral fractures or with BMD T-scores of 2.5 or less
C
It is usual to give a 5-year course of oral bisphosphonates (or a 3-year course of intravenous bisphosphonates) and then a drug holiday; in more severe cases, it is usual to give a 10-year course of oral bisphosphonates (or a 6-year course of intravenous bisphosphonate)
C
Denosumab should be given every 6 months, punctually, and treatment should not be stopped without considering alternative therapy
C
Hip fracture can be prevented in frail, elderly patients by calcium and vitamin D supplements
Abstract Fractures resulting from osteoporosis are a major public health problem. Physicians should be aware of the chief risk factors for osteoporosis and refer appropriately for bone densitometry. Risk factors include previous fracture, family history of fracture, slender habitus, early menopause, treatment with drugs known to affect bone (glucocorticoids) and diseases known to affect bone (rheumatoid arthritis). The diagnosis of osteoporosis can be made if the bone density Tscore is 2.5 or below. This information can be used with other risk factors to estimate the 10-year risk of fractures. Patients at the highest risk for fracture benefit from many licensed treatments. These can be given orally (alendronic acid, disodium etidronate, risedronate sodium, ibandronic acid, calcitriol, raloxifene, hormone replacement therapy), subcutaneously (parathyroid hormone, denosumab) or intravenously (ibandronic acid, zoledronic acid) and usually result in an increase in bone mineral density and a reduction in fracture risk. Osteoporosis can be prevented by careful attention to exercise and diet.
developed countries as a result of the increase in the proportion of elderly people in the population, and an increase in the incidence of fracture within the elderly population resulting, perhaps, from a more sedentary lifestyle. It is now possible to determine an individual’s risk of osteoporosis and fracture accurately, and to monitor their response to treatment by bone densitometry. The prediction algorithm FRAXÔ allows estimation of 10-year risk,2 and treatment guidance can be based on this. Many cases of osteoporosis are preventable, and treatment is effective in reducing the number of further fractures in patients with established osteoporosis.
Keywords Bone mineral density; kyphoplasty; MRCP; osteoporosis; treatment; vertebroplasty
Introduction Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration, with a consequent increase in bone fragility and susceptibility to fracture, particularly of the vertebral body, distal forearm and proximal femur in postmenopausal women.1 A more practical definition of osteoporosis is based on bone mineral density (BMD). The BMD of the older person is compared with the average BMD of a person of the same gender at age 30 years, and the results expressed in standard deviation units, the so-called ‘T-score’. If the T-score is equal to or less than 2.5, osteoporosis may be diagnosed. Fractures that result from osteoporosis cause considerable morbidity and mortality. Their incidence is increasing in
Diagnostic testing Investigations Patients with an osteoporosis-related low-trauma fracture should undergo systematic investigation to identify underlying causes (or secondary osteoporosis) (Tables 1 and 2).1 Identification of a low-trauma fracture (a fall from standing height or less) of the hip or distal forearm is straightforward. However, identification of vertebral fracture can be difficult because it may not be painful. Radiology The most reliable finding on a spine radiograph to support the diagnosis of osteoporosis is the presence of a deformed vertebra. Vertebral fracture is characterized by depression of the endplate and can appear as: a wedge deformity (loss of anterior height) an endplate deformity (loss of middle height) a compression deformity (loss of anterior, posterior and middle height). Subtle changes of osteoporosis may be identified on spine radiographs (e.g. low density compared with soft tissue, prominence of vertical trabeculae), but these changes are unreliable,
Richard Eastell FRCP (London, Edinburgh, Ireland) FRCPath FMedSci is Professor of Bone Metabolism at the University of Sheffield and Honorary Consultant Physician at the Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. Competing interests: Professor Eastell receives consulting fees from Amgen, AstraZeneca, Chronos, GSK, Immunodiagnostic Systems, Fonterra Brands, Ono Pharma, Lilly, Bayer, Janssen Research, Alere, CL Biosystems, Teijin Pharma, D-Star, Roche Diagnostics and Inverness Medical, and grant support from Amgen, Alexion, Immunodiagnostic Systems, Roche and AstraZeneca.
MEDICINE --:-
1
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Eastell R, Prevention and management of osteoporosis, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.06.004
BONE DISORDERS
Dual-energy X-ray absorptiometry (DXA) is precise and accurate, involves exposure to only low doses of X-rays and allows the measurement of bones of clinical interest (lumbar spine, proximal femur). In DXA, two energy peaks of X-rays are absorbed to different extents by bone and soft tissue, and the density of bone is calculated, in g/cm2, using simultaneous equations. The measurement is compared with two reference ranges: one for young adults (aged 30 years; giving a T-score) and one for age-matched adults (giving a Z-score). These BMD measurements have several uses (Table 3).
Factors affecting rate of bone loss Nutrition Increase Sodium bone loss Caffeine
Body weight Lifestyle
Genetic
Thinness
Family history Female sex
Decrease Calcium Obesity bone loss Unknown Phosphate effect on bone loss Sex hormones Increase bone loss
Alcohol abuse Cigarette smoking Bed rest High activity
Race (black)
Normal activity
Diseases
Early Cushing’s syndrome menopause Oophorectomy Hyperthyroidism Postmenopause Hyperparathyroidism Amenorrhoea
Decrease bone loss
Bone turnover Bone biopsy can be useful in unusual forms of osteoporosis (e.g. idiopathic osteoporosis in young adults). It provides information about the rate of bone turnover and the presence of secondary forms of osteoporosis (e.g. systemic mastocytosis). Patients with high bone turnover usually respond better to antiresorptive drugs (e.g. oestrogen, bisphosphonates, calcium).
Drug therapy Glucocorticoids Thyroxine Heparin Diuretics (furosemide) Aromatase inhibitors Hormone replacement therapy
Biochemical markers of bone turnover (Table 4) reflect the processes of bone resorption and bone formation (see Bone structure and metabolism on pages xxx of this issue). Markers that are specific to bone (e.g. osteocalcin, N-terminal telopeptides) are useful in predicting individuals at risk of osteoporosis (‘fast bone-losers’) or in monitoring the effect of drugs used in treatment. Markers of bone resorption can be particularly useful, as changes in their concentration reflect the reduction in risk of fracture following treatment with bisphosphonates more closely than do changes in measured BMD. The changes in bone resorption markers are usually maximal after 6 months of treatment. This makes them more suitable for treatment monitoring than bone density as changes in density are often not apparent for 2 years. Also, access to bone density facilities can be limited.
Table 1
Diagnostic evaluation of osteoporosis Establish presence of low-trauma fracture C Spine radiography Evaluate degree of osteopenia C Bone densitometry Exclude secondary osteoporosis C Primary hyperparathyroidism (serum calcium) C Thyrotoxicosis (plasma thyroid-stimulating hormone) C Multiple myeloma (erythrocyte sedimentation rate, protein electrophoresis, urinary Bence Jones protein) C Osteomalacia (serum 25-hydroxyvitamin D, plasma parathyroid hormone, serum calcium, phosphate, alkaline phosphatase, 24hour urinary calcium and creatinine) C Malabsorption syndrome (full blood count) C Hypogonadism in men (testosterone) Evaluate bone turnover C Biochemical markers C Bone histomorphometry
Management and prevention Treating established osteoporosis The aims of treatment of established osteoporosis are alleviation of symptoms and reduction of the risk of further fractures. Currently available drugs can prevent further bone loss and reduce the risk of further fractures by up to 50%. Drug treatments should be monitored by BMD or bone turnover marker measurements as some patients fail to respond to certain drugs. The rate of bone loss can be accelerated once treatment is stopped; it therefore remains important to measure BMD or bone turnover markers after stopping treatment. Pain relief: this is provided by analgesic drugs or physical measures (e.g. lumbar support for a limited period of time, transcutaneous nerve stimulator). Fracture pain usually resolves within 3 months, but patients with vertebral fractures can require long-term analgesia because of secondary degenerative disease. During the early phase (6 weeks), some patients can benefit from percutaneous vertebroplasty (injection of bone cement into a collapsed or fractured vertebra) or balloon kyphoplasty (inflation of a balloon within the collapsed vertebral body before stabilization with bone cement). During the later phase (after 6
Table 2
and the apparent low bone density seen on a radiograph may be a technical artefact introduced by overexposure. Osteoporosis must therefore be confirmed by BMD measurement. Bone mineral density measurement BMD measurement has become more reliable and more widely available.
MEDICINE --:-
2
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Eastell R, Prevention and management of osteoporosis, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.06.004
BONE DISORDERS
of BMD testing and preventive drugs according to clinical variables including the patient’s age.5
Uses of bone density measurements To establish current fracture risk by comparison with young adult reference range C A decrease in spine density of one standard deviation (or 12%) is associated with a doubling of fracture risk To establish future fracture risk by comparison with age-matched adults C This is particularly useful in perimenopausal women; assuming that bone loss proceeds at the average rate, those who will be at high risk of fracture by 70 years of age can be detected To monitor the effect of treatment C Measurements are made every 2 years C A difference of >3% can be detected by DXA of the lumbar spine (the average rate of bone loss in untreated osteoporosis is about 2% per year; the average rate of bone gain in osteoporosis treated with antiresorptive agents is 3% per year)
Antiresorptive drugs: in the UK, seven agents are currently approved for use in osteoporosis: disodium etidronate, alendronic acid, risedronate sodium, ibandronic acid, zoledronic acid (all bisphosphonates), denosumab (a human monoclonal antibody that inhibits osteoclast formation, function and survival) and raloxifene (a selective oestrogen receptor modulator). Bisphosphonates are considered to be the treatment of choice.1e5 Calcium 1000 mg/day and vitamin D 800 IU/day given together have been shown to prevent hip fracture in housebound, elderly patients. This treatment is safe and inexpensive, and does not require monitoring. It is commonly given with other treatments for osteoporosis. There has been some concern about an increased risk of cardiovascular disease with calcium supplementation, so it is wise to encourage obtaining adequate calcium from the diet, if possible.1 Disodium etidronate is less potent than other oral bisphosphonates and is now rarely used. It is given in a cyclical regimen at a dose of 400 mg/day for 2 weeks, followed by elemental calcium, 500 mg daily for 11 weeks. The effects on spine BMD are similar to those of HRT. Adverse effects are uncommon. Alendronic acid is given in a dose of 10 mg/day continuously or 70 mg once weekly. It must be taken at least 30 minutes before breakfast (to help absorption) with a full glass of water, and the patient must not lie down for at least 30 minutes after taking the tablet (to avoid oesophagitis). Alendronic acid is equally effective for the hip, forearm and spine, and has been shown to prevent fracture at all these sites. Risedronate sodium is given in a dose of 5 mg/day continuously or 35 mg once weekly. Risedronate can be taken at least 30 minutes before breakfast or 2 hours after a meal. It has been shown to prevent spine, hip and other fractures. Ibandronic acid is given in a dose of 150 mg once monthly. It reduces the risk of vertebral fracture (and other fractures, if the BMD T-score is less than 3). It can also be given by intravenous injection (3 mg) every 3 months. Zoledronic acid is given by intravenous infusion (5 mg over 15 minutes) every 12 months. It reduces fractures of the spine and hip and all other fracture sites; it has also been shown to reduce further fractures in patients presenting with hip fractures. Denosumab is given at a dose of 60 mg every 6 months by subcutaneous injection. It has been shown to reduce the risk of spine, hip and non-spine fractures. After stopping treatment, there is a rebound increase in bone turnover markers; therefore it should be given at intervals of no less than 6 months, and another drug should be started as soon as it is withdrawn to prevent this increase in bone turnover and a likely increase in the risk of vertebral fractures. Raloxifene is given in a dose of 60 mg/day continuously. Raloxifene has been shown to reduce the risk of spine (but not other) fracture, and can reduce the risk of breast cancer. However, it can increase the risk of deep vein thrombosis and does not prevent hot flushes. HRT is an effective treatment for osteoporosis even in elderly women. However, compliance and acceptability are often low in older patients, and the observation that HRT is associated with increased risk of stroke and ischaemic heart disease means that it
Table 3
Biochemical markers of bone turnover Bone resorption C
C
C
Pyridinium cross-links of collagen Pyridinoline Deoxypyridinoline Cross-linking telopeptides of type I collagen N-terminal (NTX) C-terminal (CTX) Tartrate-resistant acid phosphatase
Bone formation C C
C
Osteocalcin Bone-specific alkaline phosphatase Procollagen type I C-terminal (PICP) and N-terminal (PINP) propeptides
The International Osteoporosis Foundation has recommended the use of CTX as a marker of bone resorption and PINP as the reference for bone turnover markers (see Further reading).
Table 4
months), some patients benefit from injection of local anaesthetic into the facet joints of the spine. Drugs to increase or maintain bone mass: drugs either inhibit bone resorption or stimulate bone formation. Most drugs approved for use in osteoporosis inhibit bone resorption, but some of these (e.g. hormone replacement therapy (HRT), bisphosphonates) increase BMD by 5e10% over the first 2 years of treatment. We can try to prevent osteoporosis in people who have osteoporosis but not yet a fracture (primary prevention) and people who have already had a fracture (secondary prevention). These treatments are usually given for secondary prevention and treatment according to the National Institute of Health and Care Excellence guidance.3,4 It is usual to consider treating patients who have low-trauma fractures of the hip and spine. It is usual to treat people who have a BMD T-score at the lumbar spine or total hip of e2.5 or less (osteoporosis). The National Osteoporosis Guideline Group recommends the FRAXTM tool to guide the use
MEDICINE --:-
3
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Eastell R, Prevention and management of osteoporosis, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.06.004
BONE DISORDERS
is no longer routinely used for the treatment of osteoporosis. It is still used up to the age of 50 years in women with early or premature menopause. Testosterone therapy is effective in men with hypogonadism. Three other agents can be useful in special circumstances, for example intolerance of other agents: Strontium ranelate works by mechanisms that are not yet fully elucidated. It reduces the risk of spine and non-spine fracture and is given in a dose of 2 g/day in water. However, it increases the risk of cardiovascular disease so should not be given to patients at risk of this. Following these cardiovascular concerns, strontium ranelate will no longer be available in the UK after August 2017. Calcitonin intranasally has recently been withdrawn by the Medicines and Healthcare products Regulatory Agency for use in osteoporosis. Its use has been associated with an increased risk of cancer. Calcitriol stimulates calcium absorption and may stimulate osteoblasts directly. It appears to be effective in corticosteroid-induced osteoporosis, in which it can be considered an alternative to HRT or bisphosphonates, particularly in younger patients. Regular monitoring of serum calcium is required because hypercalcaemia is a common adverse effect.
Prevention of osteoporosis Optimize peak bone mass C Exercise must be regular and weight-bearing (e.g. walking, aerobics); exercise that results in amenorrhoea can lead to bone loss C Dietary calcium can be important, particularly during growth Reduce rate of bone loss C Regular exercise C Maintain calcium intake C Moderate alcohol intake C Stop smoking Table 5
Preventing osteoporosis Preventive treatments aim to increase peak bone mass and reduce the subsequent rate of bone loss (Table 5). Prophylactic treatment against bone loss can be considered in postmenopausal women whose BMD at the lumbar spine or hip is more than one standard deviation below the mean for their age. However, this approach has not gained general acceptance because it is not cost-effective. Women with BMD above the mean for young adults probably do not require treatment for prevention of osteoporosis. Women with intermediate BMD may benefit from these treatments if they lose bone at a faster than average rate; this can be determined from a repeat measurement of BMD after 2 years. In future, it may be possible to predict who will lose bone quickly using biochemical markers of bone turnover.
Formation-stimulating drugs: have recently been licensed for osteoporosis.3 Use of a recombinant fragment of parathyroid hormone (teriparatide) may be advised for patients with severe osteoporosis (very low T-score, vertebral fractures) who have failed to respond to or are intolerant of antiresorptive therapy. Teriparatide treatment increases the thickness of cortical bone and the connectivity of trabecular bone. These improvements in bone quality and quantity are particularly associated with reductions in fractures of the spine. It is given by daily subcutaneous injection (20 micrograms/day), with calcium supplementation for a 2-year course; it no longer works if given for longer, and there has been concern (from studies on rats) that long-term therapy might result in osteosarcoma.
Case report A 62-year-old woman developed acute-onset, low-back pain after lifting. Radiography showed superior end-plate deformity of vertebra L1. She developed abdominal distension. The major risk factor present was bilateral oophorectomy at the age of 38 years. Biochemical tests to exclude secondary osteoporosis were normal. The results of bone densitometry of her lumbar spine are shown below. The BMD of the proximal femur was also measured.
Long-term treatment with bisphosphonates: the bisphosphonates have an excellent safety record. However, there have been case reports of osteonecrosis of the jaw (particularly after tooth extraction) and atypical femur fractures (subtrochanteric or femoral shaft stress fractures) that might be caused by long-term use. Experts1,5 have proposed that oral bisphosphonate therapy be continued for up to 5 years and intravenous therapy up to 3 years; if bone density of the femoral neck is then above 2.5, treatment is stopped and bone density (or bone turnover markers) measured every 2 years until bone loss resumes. If the bone density is 2.5 or lower, the bisphosphonate should be continued up to 10 years and then stopped. Bisphosphonates such as alendronic acid and zoledronic acid suppress bone turnover and prevent bone loss for several years after they have been stopped.
Bone mineral density (g/cm2) Young normal (standard deviation units) Age-matched (%)
Femoral neck
0.65 4.2 65
0.72 2.4 91
SD, standard deviation.
This patient is at high risk of future fracture of the spine (about 16-fold) and proximal femur (about eightfold). She was treated with alendronic acid, vitamin D (800 IU/day) and calcium supplements, 1000 mg/day, and BMD increased at both the lumbar spine and the femoral neck. The increase at the lumbar spine showed the pattern typical for antiresorptive drugs such as oestrogen and bisphosphonates (an increase in BMD over 3 years followed by a plateau), although the increase was greater than that usually seen. She sustained a further fracture after 2 years’ treatment; therapy reduces the incidence of fractures by 50%, but does not prevent them completely. A
Treating secondary osteoporosis often leads to partial recovery of bone mass. Preventing falls (see Falls in Medicine 2017; 45(1): 28e33).
MEDICINE --:-
Spine
4
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Eastell R, Prevention and management of osteoporosis, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.06.004
BONE DISORDERS
2 University of Sheffield. FRAX: fracture risk assessment tool. https:// www.shef.ac.uk/FRAX/. 3 National Institute for Health and Care Excellence. Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. https://www.nice.org.uk/ guidance/TA161. 4 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. https://www.nice.org.uk/guidance/ TA160. 5 Compston J, Bowring C, Cooper A, et al. National Osteoporosis Guideline Group. Diagnosis and management of osteoporosis in postmenopausal women and older men in the UK: National Osteoporosis Guideline Group (NOGG) update 2013. Maturitas 2013; 75: 392e6.
20
Bone mineral density (% change)
Spine 15
10
Hip
5
0 0
12
24
36
48
60
Time (months)
FURTHER READING Vasikaran S, Eastell R, Bruyere O, et al. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int 2011; 22: 391e420.
Figure 1
KEY REFERENCES 1 Eastell R, O’Neill TW, Hofbauer LC, et al. Postmenopausal osteoporosis. Nat Rev Dis Primers 2016; 2: 1e16.
TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here. had osteoporosis (T-score e2.6 at the spine and hip), treated with denosumab for 5 years.
Question 1 A 71-year-old woman presented with a 3-week history of sudden onset of lower back pain. On clinical examination, she was tender over vertebra L1.
What is the most appropriate advice to give? A. After 5 years, it is now safe for her to stop B. Discuss changing to bisphosphonate treatment C. Advise that denosumab therapy is entirely safe and she should never stop it D. Switch to teriparatide E. Switch to strontium ranelate
Investigations No evidence of secondary osteoporosis X-ray of the spine showed collapse of L1 but preservation of the disc spaces Bone densitometry of L2eL4 gave a T-score of e3.5
Question 3
What is the most appropriate treatment to prevent further fractures? A. Teriparatide, as she has severe osteoporosis. B. Alendronate with supplemental calcium and vitamin D C. Calcitonin, as it will help relieve the pain and reduce fracture risk D. Strontium ranelate E. No treatment other than pain relief
A 46-year-old woman had had an early menopause aged 45 years. She also had a family history of osteoporosis. She was taking hormone replacement therapy (HRT) although she had no perimenopausal symptoms. She wants to know whether to continue HRT to prevent fractures. What is the most appropriate next step in her management? A. Measure bone density B. Assess bone turnover markers C. Continue with HRT but do not undertake investigations D. Stop HRT and add calcium and vitamin D E. Stop HRT and advise diet and exercise
Question 2 A 65-year-old woman wanted to stop her treatment as she was fed up with injections and concerned about adverse effects. She
MEDICINE --:-
5
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Eastell R, Prevention and management of osteoporosis, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.06.004
Prevention and management of osteoporosis
Key points
Richard Eastell
C
It is worthwhile measuring bone mineral density (BMD) in patients with strong risk factors (e.g. those taking long-term corticosteroids, older patients with low-trauma fractures)
C
There is good evidence that treatment prevents fractures in women with vertebral fractures or with BMD T-scores of 2.5 or less
C
It is usual to give a 5-year course of oral bisphosphonates (or a 3-year course of intravenous bisphosphonates) and then a drug holiday; in more severe cases, it is usual to give a 10-year course of oral bisphosphonates (or a 6-year course of intravenous bisphosphonate)
C
Denosumab should be given every 6 months, punctually, and treatment should not be stopped without considering alternative therapy
C
Hip fracture can be prevented in frail, elderly patients by calcium and vitamin D supplements
Abstract Fractures resulting from osteoporosis are a major public health problem. Physicians should be aware of the chief risk factors for osteoporosis and refer appropriately for bone densitometry. Risk factors include previous fracture, family history of fracture, slender habitus, early menopause, treatment with drugs known to affect bone (glucocorticoids) and diseases known to affect bone (rheumatoid arthritis). The diagnosis of osteoporosis can be made if the bone density Tscore is 2.5 or below. This information can be used with other risk factors to estimate the 10-year risk of fractures. Patients at the highest risk for fracture benefit from many licensed treatments. These can be given orally (alendronic acid, disodium etidronate, risedronate sodium, ibandronic acid, calcitriol, raloxifene, hormone replacement therapy), subcutaneously (parathyroid hormone, denosumab) or intravenously (ibandronic acid, zoledronic acid) and usually result in an increase in bone mineral density and a reduction in fracture risk. Osteoporosis can be prevented by careful attention to exercise and diet.
developed countries as a result of the increase in the proportion of elderly people in the population, and an increase in the incidence of fracture within the elderly population resulting, perhaps, from a more sedentary lifestyle. It is now possible to determine an individual’s risk of osteoporosis and fracture accurately, and to monitor their response to treatment by bone densitometry. The prediction algorithm FRAXÔ allows estimation of 10-year risk,2 and treatment guidance can be based on this. Many cases of osteoporosis are preventable, and treatment is effective in reducing the number of further fractures in patients with established osteoporosis.
Keywords Bone mineral density; kyphoplasty; MRCP; osteoporosis; treatment; vertebroplasty
Introduction Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration, with a consequent increase in bone fragility and susceptibility to fracture, particularly of the vertebral body, distal forearm and proximal femur in postmenopausal women.1 A more practical definition of osteoporosis is based on bone mineral density (BMD). The BMD of the older person is compared with the average BMD of a person of the same gender at age 30 years, and the results expressed in standard deviation units, the so-called ‘T-score’. If the T-score is equal to or less than 2.5, osteoporosis may be diagnosed. Fractures that result from osteoporosis cause considerable morbidity and mortality. Their incidence is increasing in
Diagnostic testing Investigations Patients with an osteoporosis-related low-trauma fracture should undergo systematic investigation to identify underlying causes (or secondary osteoporosis) (Tables 1 and 2).1 Identification of a low-trauma fracture (a fall from standing height or less) of the hip or distal forearm is straightforward. However, identification of vertebral fracture can be difficult because it may not be painful. Radiology The most reliable finding on a spine radiograph to support the diagnosis of osteoporosis is the presence of a deformed vertebra. Vertebral fracture is characterized by depression of the endplate and can appear as: a wedge deformity (loss of anterior height) an endplate deformity (loss of middle height) a compression deformity (loss of anterior, posterior and middle height). Subtle changes of osteoporosis may be identified on spine radiographs (e.g. low density compared with soft tissue, prominence of vertical trabeculae), but these changes are unreliable,
Richard Eastell FRCP (London, Edinburgh, Ireland) FRCPath FMedSci is Professor of Bone Metabolism at the University of Sheffield and Honorary Consultant Physician at the Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. Competing interests: Professor Eastell receives consulting fees from Amgen, AstraZeneca, Chronos, GSK, Immunodiagnostic Systems, Fonterra Brands, Ono Pharma, Lilly, Bayer, Janssen Research, Alere, CL Biosystems, Teijin Pharma, D-Star, Roche Diagnostics and Inverness Medical, and grant support from Amgen, Alexion, Immunodiagnostic Systems, Roche and AstraZeneca.
MEDICINE --:-
1
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Eastell R, Prevention and management of osteoporosis, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.06.004
BONE DISORDERS
Dual-energy X-ray absorptiometry (DXA) is precise and accurate, involves exposure to only low doses of X-rays and allows the measurement of bones of clinical interest (lumbar spine, proximal femur). In DXA, two energy peaks of X-rays are absorbed to different extents by bone and soft tissue, and the density of bone is calculated, in g/cm2, using simultaneous equations. The measurement is compared with two reference ranges: one for young adults (aged 30 years; giving a T-score) and one for age-matched adults (giving a Z-score). These BMD measurements have several uses (Table 3).
Factors affecting rate of bone loss Nutrition Increase Sodium bone loss Caffeine
Body weight Lifestyle
Genetic
Thinness
Family history Female sex
Decrease Calcium Obesity bone loss Unknown Phosphate effect on bone loss Sex hormones Increase bone loss
Alcohol abuse Cigarette smoking Bed rest High activity
Race (black)
Normal activity
Diseases
Early Cushing’s syndrome menopause Oophorectomy Hyperthyroidism Postmenopause Hyperparathyroidism Amenorrhoea
Decrease bone loss
Bone turnover Bone biopsy can be useful in unusual forms of osteoporosis (e.g. idiopathic osteoporosis in young adults). It provides information about the rate of bone turnover and the presence of secondary forms of osteoporosis (e.g. systemic mastocytosis). Patients with high bone turnover usually respond better to antiresorptive drugs (e.g. oestrogen, bisphosphonates, calcium).
Drug therapy Glucocorticoids Thyroxine Heparin Diuretics (furosemide) Aromatase inhibitors Hormone replacement therapy
Biochemical markers of bone turnover (Table 4) reflect the processes of bone resorption and bone formation (see Bone structure and metabolism on pages xxx of this issue). Markers that are specific to bone (e.g. osteocalcin, N-terminal telopeptides) are useful in predicting individuals at risk of osteoporosis (‘fast bone-losers’) or in monitoring the effect of drugs used in treatment. Markers of bone resorption can be particularly useful, as changes in their concentration reflect the reduction in risk of fracture following treatment with bisphosphonates more closely than do changes in measured BMD. The changes in bone resorption markers are usually maximal after 6 months of treatment. This makes them more suitable for treatment monitoring than bone density as changes in density are often not apparent for 2 years. Also, access to bone density facilities can be limited.
Table 1
Diagnostic evaluation of osteoporosis Establish presence of low-trauma fracture C Spine radiography Evaluate degree of osteopenia C Bone densitometry Exclude secondary osteoporosis C Primary hyperparathyroidism (serum calcium) C Thyrotoxicosis (plasma thyroid-stimulating hormone) C Multiple myeloma (erythrocyte sedimentation rate, protein electrophoresis, urinary Bence Jones protein) C Osteomalacia (serum 25-hydroxyvitamin D, plasma parathyroid hormone, serum calcium, phosphate, alkaline phosphatase, 24hour urinary calcium and creatinine) C Malabsorption syndrome (full blood count) C Hypogonadism in men (testosterone) Evaluate bone turnover C Biochemical markers C Bone histomorphometry
Management and prevention Treating established osteoporosis The aims of treatment of established osteoporosis are alleviation of symptoms and reduction of the risk of further fractures. Currently available drugs can prevent further bone loss and reduce the risk of further fractures by up to 50%. Drug treatments should be monitored by BMD or bone turnover marker measurements as some patients fail to respond to certain drugs. The rate of bone loss can be accelerated once treatment is stopped; it therefore remains important to measure BMD or bone turnover markers after stopping treatment. Pain relief: this is provided by analgesic drugs or physical measures (e.g. lumbar support for a limited period of time, transcutaneous nerve stimulator). Fracture pain usually resolves within 3 months, but patients with vertebral fractures can require long-term analgesia because of secondary degenerative disease. During the early phase (6 weeks), some patients can benefit from percutaneous vertebroplasty (injection of bone cement into a collapsed or fractured vertebra) or balloon kyphoplasty (inflation of a balloon within the collapsed vertebral body before stabilization with bone cement). During the later phase (after 6
Table 2
and the apparent low bone density seen on a radiograph may be a technical artefact introduced by overexposure. Osteoporosis must therefore be confirmed by BMD measurement. Bone mineral density measurement BMD measurement has become more reliable and more widely available.
MEDICINE --:-
2
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Eastell R, Prevention and management of osteoporosis, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.06.004
BONE DISORDERS
of BMD testing and preventive drugs according to clinical variables including the patient’s age.5
Uses of bone density measurements To establish current fracture risk by comparison with young adult reference range C A decrease in spine density of one standard deviation (or 12%) is associated with a doubling of fracture risk To establish future fracture risk by comparison with age-matched adults C This is particularly useful in perimenopausal women; assuming that bone loss proceeds at the average rate, those who will be at high risk of fracture by 70 years of age can be detected To monitor the effect of treatment C Measurements are made every 2 years C A difference of >3% can be detected by DXA of the lumbar spine (the average rate of bone loss in untreated osteoporosis is about 2% per year; the average rate of bone gain in osteoporosis treated with antiresorptive agents is 3% per year)
Antiresorptive drugs: in the UK, seven agents are currently approved for use in osteoporosis: disodium etidronate, alendronic acid, risedronate sodium, ibandronic acid, zoledronic acid (all bisphosphonates), denosumab (a human monoclonal antibody that inhibits osteoclast formation, function and survival) and raloxifene (a selective oestrogen receptor modulator). Bisphosphonates are considered to be the treatment of choice.1e5 Calcium 1000 mg/day and vitamin D 800 IU/day given together have been shown to prevent hip fracture in housebound, elderly patients. This treatment is safe and inexpensive, and does not require monitoring. It is commonly given with other treatments for osteoporosis. There has been some concern about an increased risk of cardiovascular disease with calcium supplementation, so it is wise to encourage obtaining adequate calcium from the diet, if possible.1 Disodium etidronate is less potent than other oral bisphosphonates and is now rarely used. It is given in a cyclical regimen at a dose of 400 mg/day for 2 weeks, followed by elemental calcium, 500 mg daily for 11 weeks. The effects on spine BMD are similar to those of HRT. Adverse effects are uncommon. Alendronic acid is given in a dose of 10 mg/day continuously or 70 mg once weekly. It must be taken at least 30 minutes before breakfast (to help absorption) with a full glass of water, and the patient must not lie down for at least 30 minutes after taking the tablet (to avoid oesophagitis). Alendronic acid is equally effective for the hip, forearm and spine, and has been shown to prevent fracture at all these sites. Risedronate sodium is given in a dose of 5 mg/day continuously or 35 mg once weekly. Risedronate can be taken at least 30 minutes before breakfast or 2 hours after a meal. It has been shown to prevent spine, hip and other fractures. Ibandronic acid is given in a dose of 150 mg once monthly. It reduces the risk of vertebral fracture (and other fractures, if the BMD T-score is less than 3). It can also be given by intravenous injection (3 mg) every 3 months. Zoledronic acid is given by intravenous infusion (5 mg over 15 minutes) every 12 months. It reduces fractures of the spine and hip and all other fracture sites; it has also been shown to reduce further fractures in patients presenting with hip fractures. Denosumab is given at a dose of 60 mg every 6 months by subcutaneous injection. It has been shown to reduce the risk of spine, hip and non-spine fractures. After stopping treatment, there is a rebound increase in bone turnover markers; therefore it should be given at intervals of no less than 6 months, and another drug should be started as soon as it is withdrawn to prevent this increase in bone turnover and a likely increase in the risk of vertebral fractures. Raloxifene is given in a dose of 60 mg/day continuously. Raloxifene has been shown to reduce the risk of spine (but not other) fracture, and can reduce the risk of breast cancer. However, it can increase the risk of deep vein thrombosis and does not prevent hot flushes. HRT is an effective treatment for osteoporosis even in elderly women. However, compliance and acceptability are often low in older patients, and the observation that HRT is associated with increased risk of stroke and ischaemic heart disease means that it
Table 3
Biochemical markers of bone turnover Bone resorption C
C
C
Pyridinium cross-links of collagen Pyridinoline Deoxypyridinoline Cross-linking telopeptides of type I collagen N-terminal (NTX) C-terminal (CTX) Tartrate-resistant acid phosphatase
Bone formation C C
C
Osteocalcin Bone-specific alkaline phosphatase Procollagen type I C-terminal (PICP) and N-terminal (PINP) propeptides
The International Osteoporosis Foundation has recommended the use of CTX as a marker of bone resorption and PINP as the reference for bone turnover markers (see Further reading).
Table 4
months), some patients benefit from injection of local anaesthetic into the facet joints of the spine. Drugs to increase or maintain bone mass: drugs either inhibit bone resorption or stimulate bone formation. Most drugs approved for use in osteoporosis inhibit bone resorption, but some of these (e.g. hormone replacement therapy (HRT), bisphosphonates) increase BMD by 5e10% over the first 2 years of treatment. We can try to prevent osteoporosis in people who have osteoporosis but not yet a fracture (primary prevention) and people who have already had a fracture (secondary prevention). These treatments are usually given for secondary prevention and treatment according to the National Institute of Health and Care Excellence guidance.3,4 It is usual to consider treating patients who have low-trauma fractures of the hip and spine. It is usual to treat people who have a BMD T-score at the lumbar spine or total hip of e2.5 or less (osteoporosis). The National Osteoporosis Guideline Group recommends the FRAXTM tool to guide the use
MEDICINE --:-
3
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Eastell R, Prevention and management of osteoporosis, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.06.004
BONE DISORDERS
is no longer routinely used for the treatment of osteoporosis. It is still used up to the age of 50 years in women with early or premature menopause. Testosterone therapy is effective in men with hypogonadism. Three other agents can be useful in special circumstances, for example intolerance of other agents: Strontium ranelate works by mechanisms that are not yet fully elucidated. It reduces the risk of spine and non-spine fracture and is given in a dose of 2 g/day in water. However, it increases the risk of cardiovascular disease so should not be given to patients at risk of this. Following these cardiovascular concerns, strontium ranelate will no longer be available in the UK after August 2017. Calcitonin intranasally has recently been withdrawn by the Medicines and Healthcare products Regulatory Agency for use in osteoporosis. Its use has been associated with an increased risk of cancer. Calcitriol stimulates calcium absorption and may stimulate osteoblasts directly. It appears to be effective in corticosteroid-induced osteoporosis, in which it can be considered an alternative to HRT or bisphosphonates, particularly in younger patients. Regular monitoring of serum calcium is required because hypercalcaemia is a common adverse effect.
Prevention of osteoporosis Optimize peak bone mass C Exercise must be regular and weight-bearing (e.g. walking, aerobics); exercise that results in amenorrhoea can lead to bone loss C Dietary calcium can be important, particularly during growth Reduce rate of bone loss C Regular exercise C Maintain calcium intake C Moderate alcohol intake C Stop smoking Table 5
Preventing osteoporosis Preventive treatments aim to increase peak bone mass and reduce the subsequent rate of bone loss (Table 5). Prophylactic treatment against bone loss can be considered in postmenopausal women whose BMD at the lumbar spine or hip is more than one standard deviation below the mean for their age. However, this approach has not gained general acceptance because it is not cost-effective. Women with BMD above the mean for young adults probably do not require treatment for prevention of osteoporosis. Women with intermediate BMD may benefit from these treatments if they lose bone at a faster than average rate; this can be determined from a repeat measurement of BMD after 2 years. In future, it may be possible to predict who will lose bone quickly using biochemical markers of bone turnover.
Formation-stimulating drugs: have recently been licensed for osteoporosis.3 Use of a recombinant fragment of parathyroid hormone (teriparatide) may be advised for patients with severe osteoporosis (very low T-score, vertebral fractures) who have failed to respond to or are intolerant of antiresorptive therapy. Teriparatide treatment increases the thickness of cortical bone and the connectivity of trabecular bone. These improvements in bone quality and quantity are particularly associated with reductions in fractures of the spine. It is given by daily subcutaneous injection (20 micrograms/day), with calcium supplementation for a 2-year course; it no longer works if given for longer, and there has been concern (from studies on rats) that long-term therapy might result in osteosarcoma.
Case report A 62-year-old woman developed acute-onset, low-back pain after lifting. Radiography showed superior end-plate deformity of vertebra L1. She developed abdominal distension. The major risk factor present was bilateral oophorectomy at the age of 38 years. Biochemical tests to exclude secondary osteoporosis were normal. The results of bone densitometry of her lumbar spine are shown below. The BMD of the proximal femur was also measured.
Long-term treatment with bisphosphonates: the bisphosphonates have an excellent safety record. However, there have been case reports of osteonecrosis of the jaw (particularly after tooth extraction) and atypical femur fractures (subtrochanteric or femoral shaft stress fractures) that might be caused by long-term use. Experts1,5 have proposed that oral bisphosphonate therapy be continued for up to 5 years and intravenous therapy up to 3 years; if bone density of the femoral neck is then above 2.5, treatment is stopped and bone density (or bone turnover markers) measured every 2 years until bone loss resumes. If the bone density is 2.5 or lower, the bisphosphonate should be continued up to 10 years and then stopped. Bisphosphonates such as alendronic acid and zoledronic acid suppress bone turnover and prevent bone loss for several years after they have been stopped.
Bone mineral density (g/cm2) Young normal (standard deviation units) Age-matched (%)
Femoral neck
0.65 4.2 65
0.72 2.4 91
SD, standard deviation.
This patient is at high risk of future fracture of the spine (about 16-fold) and proximal femur (about eightfold). She was treated with alendronic acid, vitamin D (800 IU/day) and calcium supplements, 1000 mg/day, and BMD increased at both the lumbar spine and the femoral neck. The increase at the lumbar spine showed the pattern typical for antiresorptive drugs such as oestrogen and bisphosphonates (an increase in BMD over 3 years followed by a plateau), although the increase was greater than that usually seen. She sustained a further fracture after 2 years’ treatment; therapy reduces the incidence of fractures by 50%, but does not prevent them completely. A
Treating secondary osteoporosis often leads to partial recovery of bone mass. Preventing falls (see Falls in Medicine 2017; 45(1): 28e33).
MEDICINE --:-
Spine
4
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Eastell R, Prevention and management of osteoporosis, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.06.004
BONE DISORDERS
2 University of Sheffield. FRAX: fracture risk assessment tool. https:// www.shef.ac.uk/FRAX/. 3 National Institute for Health and Care Excellence. Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. https://www.nice.org.uk/ guidance/TA161. 4 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. https://www.nice.org.uk/guidance/ TA160. 5 Compston J, Bowring C, Cooper A, et al. National Osteoporosis Guideline Group. Diagnosis and management of osteoporosis in postmenopausal women and older men in the UK: National Osteoporosis Guideline Group (NOGG) update 2013. Maturitas 2013; 75: 392e6.
20
Bone mineral density (% change)
Spine 15
10
Hip
5
0 0
12
24
36
48
60
Time (months)
FURTHER READING Vasikaran S, Eastell R, Bruyere O, et al. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int 2011; 22: 391e420.
Figure 1
KEY REFERENCES 1 Eastell R, O’Neill TW, Hofbauer LC, et al. Postmenopausal osteoporosis. Nat Rev Dis Primers 2016; 2: 1e16.
TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here. had osteoporosis (T-score e2.6 at the spine and hip), treated with denosumab for 5 years.
Question 1 A 71-year-old woman presented with a 3-week history of sudden onset of lower back pain. On clinical examination, she was tender over vertebra L1.
What is the most appropriate advice to give? A. After 5 years, it is now safe for her to stop B. Discuss changing to bisphosphonate treatment C. Advise that denosumab therapy is entirely safe and she should never stop it D. Switch to teriparatide E. Switch to strontium ranelate
Investigations No evidence of secondary osteoporosis X-ray of the spine showed collapse of L1 but preservation of the disc spaces Bone densitometry of L2eL4 gave a T-score of e3.5
Question 3
What is the most appropriate treatment to prevent further fractures? A. Teriparatide, as she has severe osteoporosis. B. Alendronate with supplemental calcium and vitamin D C. Calcitonin, as it will help relieve the pain and reduce fracture risk D. Strontium ranelate E. No treatment other than pain relief
A 46-year-old woman had had an early menopause aged 45 years. She also had a family history of osteoporosis. She was taking hormone replacement therapy (HRT) although she had no perimenopausal symptoms. She wants to know whether to continue HRT to prevent fractures. What is the most appropriate next step in her management? A. Measure bone density B. Assess bone turnover markers C. Continue with HRT but do not undertake investigations D. Stop HRT and add calcium and vitamin D E. Stop HRT and advise diet and exercise
Question 2 A 65-year-old woman wanted to stop her treatment as she was fed up with injections and concerned about adverse effects. She
MEDICINE --:-
5
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Eastell R, Prevention and management of osteoporosis, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.06.004