Article Text
Abstract
Fragility fracture is the clinically apparent and relevant outcome in osteoporosis.1–3 Osteoporotic fragility fractures occur most commonly in the vertebrae, hip and wrist, and are associated with substantial disability, pain and reduced quality of life. It is estimated that more than 2 million women have osteoporosis in England and Wales.2,3 In the UK, there are over 300,000 fractures each year,4 causing severe pain and disability to individuals at an estimated annual cost to the NHS of over £1.73 billion.4 As a result of increased bone loss after the menopause in women, and age-related bone loss in both women and men, the prevalence of osteoporosis increases markedly with age, from 2% at 50 years to more than 25% at 80 years in women.5 Despite the development of a number of guidelines for the diagnosis and treatment of osteoporosis, management of the condition is not straightforward. Here we provide a reminder of some specific dilemmas facing generalists in regards to the management of osteoporosis, including diagnosis and investigation for reversible secondary causes; the effectiveness and duration of pharmacological management with oral bisphosphonates; and the role of calcium and vitamin D.
Statistics from Altmetric.com
Diagnosis of osteoporosis
Prior to 1994, the definition of osteoporosis was uncertain and as a result a World Health Organization (WHO) working group produced recommendations on diagnosis, screening and treatment.1 The recommended diagnostic categories (see Box 1) are dependent upon a measure of bone mineral density (BMD).
WHO definition of osteoporosis in white postmenopausal women1
Normal: a BMD value not more than 1 SD below the young adult reference mean (T-score ≥–1)
Osteopenia: a BMD value more than 1 SD below the young adult mean but less than 2.5 SD below this value (T-score less than –1 but above –2.5)
Osteoporosis: a BMD value 2.5 SD or more below the young adult mean (T-score ≤–2.5)
Severe osteoporosis: a BMD value more than 2.5 SD below the young adult mean in the presence of one or more fragility fractures
BMD, bone mineral density; SD, standard deviation.
However, BMD measurement does not assess the structural deterioration in bone, and many osteoporotic fractures occur in women who do not have osteoporosis as defined by a T-score equal to or less than –2.5.6 In addition, there are many causes of low bone density, and the first dilemma for the clinician is to determine the underlying aetiology and ensure that any reversible causes of osteoporosis are addressed.
Dilemma 1: identifying secondary causes
A 2005 literature review found that secondary causes of osteoporosis occurred in more than half of premenopausal women and about one fifth of postmenopausal women diagnosed with osteoporosis, as well as almost two thirds of men presenting with the condition (see Box 2).7
Common secondary causes of osteoporosis6,7
Hypogonadism (particularly hypoestrogenaemia e.g. amenorrhea, anorexia nervosa)
Drugs (androgen deprivation therapy, immunosuppressants, corticosteroids, heparin, anticonvulsants)
Hyperthyroidism, hyperparathyroidism, hyperprolactinaemia
Vitamin D deficiency
Solid organ transplantation (heart, liver, lung)
Gastrointestinal disease (Crohn's, ulcerative colitis, coeliac sprue)
Haematological causes (myeloma, leukaemia, lymphoma)
Cushing's syndrome
Idiopathic hypercalciuria
Chronic renal disease
Chronic liver failure
Immobility
In a prospective study of 204 postmenopausal women with osteoporosis, 82% were found to have low 25-hydroxyvitamin D levels (defined as <30ng/mL), 35% had increased parathyroid hormone levels (defined as >65pg/mL) and 20% had hypercalciuria (defined as >250mg/24hours).8
Therefore, before considering first-line drug therapy for osteoporosis (e.g. bisphosphonates) it might be important to address any underlying reversible causes of osteoporosis.7
Dilemma 2: case finding for osteoporosis
It is important to distinguish assessment of fracture risk from the diagnosis of osteoporosis.1 Osteoporosis is a risk factor for fracture and is set by arbitrary thresholds much like thresholds for hypertension are set as a risk factor for cardiovascular disease. Other risk factors include diseases affecting bone strength, certain drug treatments and risk of falls. Two major tools for assessing fracture risk have been developed in an effort to help identify patients at high risk of fracture. The FRAX tool (www.shef.ac.uk/FRAX/) can be used for people aged between 40 and 90 years, QFracture (www.qfracture.org) for those aged between 30 and 84 years.5
The National Institute for Health and Care Excellence (NICE) advocates assessing fracture risk in all women aged 65 years and over and all men aged 75 years and over.5 Assessment of fracture risk is also recommended in younger people (women aged under 65 years and men aged under 75 years) if they have one or more independent risk factors for fracture (see Box 3):
Risk factors5
Previous fragility fracture
Current use or frequent recent use of oral or systemic glucocorticoids
History of falls
Family history of hip fracture
Body mass index (BMI) <18.5kg/m2
Smoking
Alcohol intake >14 units/week women, >21 units/week men
NICE guidance advises the use of either the FRAX or QFracture tool to assess fracture risk.5 However, it acknowledges that these tools are limited in that they may not include all risk factors.5 Furthermore, it is not clear whether they are equally accurate and whether choice of tool should depend on circumstances.5 The guideline also notes that there are “no definitive studies…evaluating whether the addition of BMD to FRAX improves the accuracy of the predicted fracture risk” and that “studies are also needed to evaluate the clinical usefulness (net benefit) of adding BMD to FRAX; that is, how many more patients are correctly classified as high risk (true positives) and low risk (true negatives)”. The scope of the guideline did not include the recommendation of intervention thresholds and advises that healthcare professionals should follow local protocols or other national guidelines for advice on intervention thresholds.
Bisphosphonate therapy
National guidance advises the use of an oral bisphosphonate (alendronate, risedronate) as first-line treatment for postmenopausal osteoporosis.2,3 Bisphosponates slow the rate of bone growth and dissolution, and therefore reduce the rate of bone turnover.9
A systematic review of 11 trials assessed incidence of fracture among 12,068 women with postmenopausal osteoporosis who received at least 1 year of alendronate daily, or placebo and/or concurrent calcium/vitamin D. Both primary and secondary prevention trials were included.10 For alendronate 10mg daily, there was a statistically significant reduction in vertebral fractures (relative risk [RR] 0.55, 95% CI 0.45 to 0.67). This was significant for both primary prevention (RR 0.55, 95% CI 0.38 to 0.80; absolute risk reduction [ARR] 2%; number-needed-to-treati [NNT] 50) and secondary prevention (RR 0.55, 95% CI 0.43 to 0.69; ARR 6%; NNT 17).
Non-vertebral fractures were also reduced (RR 0.84, 95% CI 0.74 to 0.94). This was statistically significant for secondary prevention (RR 0.77, 95% CI 0.64 to 0.92; ARR 2%; NNT 50), but not for primary prevention (RR 0.89, 95% CI 0.76 to 1.04). There was a significant reduction in hip fractures (RR 0.60, 95% CI 0.40 to 0.92), but only for secondary prevention (RR 0.47, 95% CI 0.26 to 0.85; ARR 1%; NNT 100). A statistically significant reduction in secondary prevention of wrist fractures was found (RR 0.50, 95% CI 0.34 to 0.73; ARR 2%; NNT 50).
In a systematic review of risedronate 5mg daily versus placebo (14,049 postmenopausal women) the reduction of fractures was not statistically significant for primary prevention.11 In terms of secondary prevention, there was a statistically significant reduction in vertebral fractures (RR 0.61, 95% CI 0.50 to 0.76; ARR 5%; NNT 20), non-vertebral fractures (RR 0.80, 95% CI 0.72 to 0.90; ARR 2%; NNT 50) and hip fractures (RR 0.74, 95% CI 0.59 to 0.94; ARR 1%; NNT 100).
Dilemma 3: is there an optimal duration of bisphosphonate treatment
It is known that bisphosphonates are retained in bone for over 10 years and powerfully inhibit bone turnover.12 Furthermore, a Europe-wide review of bisphosphonates and atypical stress fractures concluded that alendronic acid use was associated with an increased risk of atypical stress fractures of the proximal femoral shaft, mainly in patients receiving long-term treatment for osteoporosis.13 The Medicines and Healthcare products Regulatory Agency (MHRA) noted that atypical femoral fractures are considered a class effect of bisphosphonates. Some authors have raised the possibility that treatment may not need to be continued indefinitely and have discussed the concept of drug holidays.12
Two studies have examined the effect of treatment duration: the first involved oral alendronate with the results published in two separate papers14,15 and the second study used intravenous zoledronic acid.16 However, the primary outcome in both studies was change in BMD and not fracture rate.
In a randomised double-blinded extension study to a placebo-controlled trial of alendronate, a total of 1,009 women who had already received treatment for at least 3 years and then completed the open-label phase (average 1.9 years) were then randomised to either alendronate 5mg or 10mg daily or placebo for a further 5 years.14,15 Those with a hip BMD T-score equal or less than –3.5 at entry to the extension study were excluded. The primary outcome was change in total hip BMD. After 3 years, the average total hip BMD in the groups receiving alendronate had decreased by 0.34% compared with a 2.38% decrease in the placebo group (2.04% difference, p<0.001). After 5 years the loss of BMD was 1.0% with alendronate and 3.4% with placebo (difference 2.4%, p<0.001).15 At the lumbar spine, women receiving alendronate had an increase in BMD of 3.5% compared with an increase of 1.0% in the placebo group (2.5% difference, p<0.001). After 5 years BMD had increased by 5.3% with alendronate and 1.5% with placebo (difference 3.7%, p<0.001).15 However, despite discontinuation of alendronate for at least 5 years, total hip BMD in women receiving placebo during the study was greater than that at their baseline examination 10 years previously (p<0.001).15
Although fracture rate was not a primary or secondary outcome in the extension study, two post-hoc analyses have attempted to assess the risk and incidence of fracture.17,18 The first study set out to test methods of assessing fracture risk in women discontinuing alendronate after 5 years.17 Older age and lower hip BMD at the point of discontinuation were associated with subsequent fracture risk.
In a further post-hoc analysis of the extension trial data, there was no significant difference in fracture rate except for one subgroup; women with a non-vertebral fracture at the start of the extension trial with baseline femoral neck T-scores of –2.5 or less (RR 0.50, 95% CI 0.26 to 0.96).18 The authors suggested that continuing alendronate therapy for more than 5 years in women with T-scores of greater than –2 does not appear to provide benefit in the prevention of non-vertebral fractures.
In the second study that reviewed the duration of treatment with a bisphosphonate, a total of 1,233 postmenopausal women who had already received intravenous zoledronic acid 5mg once yearly for 3 years were randomised to receive either zoledronic acid or placebo annually for the next 3 years.16 The average age of women entering this extension trial was 75.5 years. The primary endpoint was percentage change in femoral neck BMD from years 3–6. In years 3–6, there was a difference of 1.04% in femoral neck BMD between the treatment and placebo group (0.24% vs. –0.8%; 95% CI 0.4% to 1.7%; p=0.0009). With regards to the secondary endpoint of fractures, new morphometric fractures were lower in the treatment group than placebo (3% vs. 6.2%; odds ratio [OR] 0.51, 95% CI 0.26 to 0.95; p=0.035), but there was no statistically significant difference in non-vertebral, clinical vertebral, hip or all clinical fractures. The authors suggested that those at high fracture risk may benefit from prolonged treatment.
A review article published by the authors of the two studies reviewing duration of treatment acknowledge study limitations (e.g. both trials were carried out solely in postmenopausal women, primary endpoints assessed BMD, fracture rates were only reported as an ‘exploratory endpoint’).19 An accompanying table based upon data from the alendronate extension study attempted to define a 5-year clinical risk of fracture based on subgroups according to BMD and prevalence of vertebral fracture at the beginning of the extension trial. The authors suggest that patients with low BMD of the femoral neck (T-score <–2.5) after 3–5 years of treatment with alendronate are at the highest risk of vertebral fractures and therefore appear to benefit most from continuation of bisphosphonates.
The MHRA advises that although “the optimum duration of bisphosphonate treatment for osteoporosis has not been established…the need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of bisphosphonate therapy for individual patients, particularly after 5 or more years of use”.13
Guidelines from the National Osteoporosis Guideline Group advise a review of treatment, including checking adherence to treatment and reassessment of those at high risk of fragility fracture, after 3 or 5 years of zoledronic acid and oral bisphosphonate therapy, respectively.4 They also suggest consideration of a ‘drug holiday’ in those patients who have received 3 or 5 years of treatment, who do not experience a fracture by that point and who are below intervention threshold on repeat FRAX and BMD testing at that time; however, these guidelines are based upon expert consensus.
Calcium and vitamin D
In clinical trials, bisphosphonates have usually been assessed in conjunction with calcium and/or vitamin D.20 Doses of calcium have varied from 500–1,000mg and vitamin D from 6.25–20µg (250–800 IU) per day.
Dilemma 4: ensuring adequate intake
Guidelines from NICE for both primary and secondary prevention of fragility fractures assume that women who receive treatment have an adequate calcium intake and are vitamin D replete, as most studies reviewed for the guidelines ensured that women in all trial arms had normal calcium levels, adequate supplementation, and some studies used additional supplementation with vitamin D.2,3 It has become common practice to co-prescribe calcium and vitamin D supplements when treating osteoporosis.
However, two recent meta–analyses suggested that there may be adverse cardiovascular outcomes associated with calcium-only and combination (calcium with vitamin D) therapy.21,22 A meta-analysis of 8,151 patients found that those taking calcium compared with placebo had an increased risk of non-fatal myocardial infarction (hazard ratio [HR] 1.31; 95% CI 1.02 to 1.67),21 while a second meta-analysis using re-analysed patient-level data from over 24,000 postmenopausal women in the Women's Health Initiative found that calcium, or calcium and vitamin D supplements, increased the risk of myocardial infarction compared with placebo (HR 1.26, 95% CI 1.07 to 1.47), although the authors acknowledged the limited information available in the dataset, with the MHRA also acknowledging these limitations.22,23 A large prospective cohort study of 23,980 adults aged 35–64 years old followed for 11 years for both fatal and non-fatal cardiovascular risk factors found users of calcium supplements had a statistically significantly increased myocardial infarction risk in comparison with non-users of any supplements (HR 1.86; 95% CI 1.17 to 2.96), and the association was more pronounced for calcium supplement only users (HR 2.39; 95% CI 1.12 to 5.12): the authors advised use of calcium supplements ‘with caution’.24
In a Swedish prospective population study of 61,433 women, born between 1914 and 1948, based on a mammography cohort between 1987 and 1990 and followed up for a median of 19 years, it was found that those with a higher calcium intake (>1,400mg daily) had higher death rates from all causes (HR 1.40, 95% CI 1.17 to 1.67), cardiovascular disease (HR 1.49, 95% CI 1.09 to 2.02), and ischaemic heart disease (HR 2.14, 95% CI 1.48 to 3.09) but not from stroke (HR 0.73, 95% CI 0.33 to 1.65).25
Currently, guidance from the MHRA recommends following NICE guidelines regarding calcium and vitamin D supplementation in both primary and secondary prevention of osteoporosis, with no change to prescribing practice currently recommended.23 The MHRA notes that National Osteoporosis Society guidance advises that increasing dietary intake in those with low intake of calcium and vitamin D is considered preferable to the use of supplements. Therefore, for some patients it may be clinically appropriate to review the use of calcium supplements in light of their dietary calcium intake. A calcium intake of at least 1,000mg/day is recommended for people at increased risk of a fragility fracture.6 A daily intake of 1,000mg calcium can be obtained from 400mL milk (480mg), 125g plain yoghurt (250mg), 30g of hard cheese (225mg) and two 30g slices of wholemeal bread (60mg).20
Conclusion
Osteoporosis predisposes to fragility fractures that are associated with substantial morbidity and considerable health and social care costs. Although testing confirms presence of low bone density, further assessment of secondary causes must be undertaken, and is essential in men who have a higher rate of secondary causes. There are tools available to help identify those at increased risk of fracture but how they should be used in clinical practice is still uncertain. Bisphosphonate therapy is well established as first-line therapy but there is debate over the optimal duration of treatment. The option of a drug holiday has been suggested for some patients but it is not clear how to identify those patients most likely to benefit. There is some evidence that indiscriminate use of calcium supplements may be inappropriate; calcium intake (preferably via the diet) and vitamin D status should be optimised in all patients with osteoporosis. Healthcare professionals face a difficult challenge in balancing targeted case finding, appropriate investigation and instigation of treatment with the limitations in evidence for long-term pharmacotherapy of osteoporosis.