Need to know - osteoporosis
Endocrinologist Dr Alastair McLellan answers Dr Linden Ruckert’s questions on managing side-effects and differences between bisphosphonates. If you have a question for Dr McLellan, post it in the comment box at the end.
Endocrinologist Dr Alastair McLellan answers Dr Linden Ruckert's questions on managing side-effects and differences between bisphosphonates. If you have a question for Dr McLellan, post it in the comment box at the end.
1. What do we know about the relationship between osteopaenia and osteoporosis? Can we predict the progression and can a case be made for starting treatment other than calcium earlier?
When osteopaenia is shown to be present in younger patients who are at low fracture risk, the response should be to optimise lifestyle factors including dietary calcium intake, and to correct any adverse risk factors such as smoking or inactivity.
But osteopaenia can be more important than just a stepping stone in the evolution of osteoporosis. Bone mineral density (BMD) is inversely proportional to fracture risk. For each standard deviation that BMD is reduced, fracture risk increases by 2.5 times. While those with osteoporosis are individually at greatest fracture risk, overall most fractures actually occur in the osteopaenic population.
The need for treatment is determined by fracture risk – primarily derived from age, BMD and past fracture history – although other risk factors also contribute. Depending on the risk factor profile, many patients with osteopaenia may have a higher fracture risk than patients who have osteoporosis but fewer risk factors. The recently published fracture risk calculator FRAX allows you to calculate fracture risk – expressed as 10-year risk of hip and ‘major osteoporotic fractures' – using key factors including BMD.
It remains to be seen at what level of fracture risk the NHS will agree to fund treatment. Treatment at 20% 10-year fracture risk is not controversial but some advocate treating when 10-year fracture risk is less than 10%.
There is also currently a debate as to whether there is a threshold of BMD above which treatment is unlikely to achieve fracture risk reduction.
Studies that suggest non-vertebral fracture risk can be reduced irrespective of BMD have been of elderly subjects, whereas the traditional view that osteoporosis is a prerequisite for treatment to reduce fracture risk has arisen from studies in younger women.
Our own practice is to treat women of 65 or older who have sustained a non-vertebral fracture if their T-score is -2 or less. For younger women with non-vertebral fracture, we require the T-score to be less than -2.5.
2. How long should someone stay on bisphosphonates? We have quite a few patients who have been on them for more than eight years and have read reports of concerns over the long-term effect on bone.
Placebo-controlled trials of oral bisphosphonates of up to four years' duration and continuous treatment for up to 10 years in extensions of these trials – without continuation of placebo groups for ethical reasons – have shown there are no adverse skeletal effects from prolonged treatment.
They also suggest fracture risk reduction is probably sustained for as long as treatment continues. BMD continues to accumulate in those treated for up to 10 years.
But there is no consensus on how long bisphosphonates should be given. Our own practice is to give everybody a minimum of five years' treatment and then to re-evaluate fracture risk. The options then include a drug ‘holiday' – either stopping treatment altogether or intermittently such as resuming it in alternate years, or continuing treatment indefinitely. Most patients, in my experience, prefer to continue therapy indefinitely.
3. How powerful are lifestyle interventions in preventing osteoporosis?
Adverse lifestyle can contribute to osteoporosis and indeed to fracture risk. Alcohol misuse and smoking are the most detrimental and should be avoided. For younger patients who are concerned to minimise the risk of osteoporosis, the genetic potential for bone mineralisation will be optimised by adoption of healthy lifestyle including
• a dietary calcium intake of between 750mg and 1000mg per day
• avoidance of smoking
• moderation of alcohol intake.
Most of the BMD that is amenable to exercise accumulates in response to normal ambulation and weight bearing – while additional exercise can add a further 1-2% of bone mineral to loadbearing bones over two to three years.
4. What do you do for someone with osteoporosis progressing despite bisphosphonate/calcium, when you know the patient is taking the treatment and has had other metabolic causes excluded? I had one patient who had multiple foot fractures (with normal foot use) and another who has developed vertebral fractures. Both are in their 60s.
Further fractures in patients on treatment should prompt re-assessment – to ensure the bisphosphonate is being taken:
• appropriately – that is, fasting, with avoidance of other treatments or food for 30 minutes and washed down only with water and
• regularly, as prescribed.
It is said that as many as 50% of patients who are prescribed oral bisphosphonates discontinue treatment within the first year. Evaluation should also include assessment for other diseases that might further compromise bone mineral density and fracture risk, such as myeloma, thyrotoxicosis or primary hyperparathyroidism or diseases that might compromise absorption of medication – such as coeliac disease.
If none of these is relevant, the options would be to consider either a different route of administration or a different drug.
While there have been no head-to-head comparisons of osteoporosis treatments, recent trials of annual administration of intravenous (IV) zoledronic acid suggest that this may have the greatest potential to reduce fracture risk and may now be the preferred second choice, if it is acceptable to the patient.
Strontium ranelate could be considered but GI intolerance is common. Teriparatide or PTH could be considered where recurrent vertebral fractures are the prime concern, but these options lack zoledronic acid's capacity to reduce the incidence of hip fractures.
5. Are there simpler or even better screening tests than DXA being evaluated? Are repeat DXA scans worthwhile once the patient is on treatment? How often?
DXA scanning is uniquely able to define the presence of osteoporosis. BMD is also the key component of fracture risk that is amenable to intervention with the various treatments. But fracture risk, which in significant part is determined by BMD, is the key determinant of the need for treatment.
Fracture risk can usefully be calculated using tools such as FRAX. There is currently no evidence that targeting treatment using FRAX without knowledge of BMD can reduce fracture risk.
Knowledge of fracture history, however, can be sufficient to merit treatment without prior DXA. This is true for patients with two or more vertebral fractures – in the absence of other diseases such as myeloma – and the recently published Horizon Recurrent Fracture Trial1 suggests that treating patients after hip fracture with annual infusions of zoledronic acid – without prior DXA screening – can decrease the incidence of secondary fractures too.
Our own practice is to DXA scan all patients aged 50 or over with low trauma fractures or other key risk factors, and to calculate the FRAX fracture risk score using the BMD result, to determine the need for treatment.
Most osteoporosis service providers give the option of DXA monitoring if their scanning capacity permits. If it is provided, monitoring BMD at lumbar spine is the preferred option.
Practice largely reflects scanning capacity and should be done no sooner than 18 months after starting treatment but some services, including our own, prefer to scan five years after starting treatment. Obviously, whether monitoring by DXA is available or not, opportunities should be taken to encourage compliance with medication.
6. What's the current view of osteoporosis risk prevention in steroid users? I'm particularly thinking of patients with COPD and asthma who use regular higher-dose inhaled steroids, aside from oral steroids.
Guidance on prevention and treatment of steroid-induced osteoporosis was published by the Royal College of Physicians in 20022. Where patients have been on, or are starting with the expectation of needing, oral steroids for three months or longer at doses of prednisolone 5mg per day or more, then risk of osteoporosis and fracture should be addressed.
For women and men over 65, or for those who are younger but have already sustained a fragility fracture, treatment with one of the licensed bisphosphonates – alendronate or risedronate or etidronate – should be started concurrently with the steroid. Treatment can start at any point in people who are already on steroid therapy without prior BMD.
BMD can subsequently be helpful, however, in determining how long the bisphosphonates should be continued if, as usually happens, the steroid dosage can eventually be reduced.
For younger patients and those without previous fragility fracture, DXA scanning should be performed to inform the need for treatment. Treatment with a licensed bisphosphonate can be started if the T-score is less than 1.5.
There is no robust evidence that high-dose inhaled steroids can increase fracture risk or significantly adversely affect BMD. That there is potential for harm with long-term use is suggested by the association between high-dose inhaled steroid use and suppression of markers of bone turnover which could, if sustained, predispose to lower BMD.
Often, of course, patients on high-dose inhaled steroids require frequent courses of oral steroids too.
Our own approach to patients treated with high-dose steroids is to recommend that they undergo DXA scanning. The result informs the need for treatment with bisphosphonates. We would tend not to automatically give bone protection in this scenario without prior DXA scanning.
7. What is the current position on giving calcium and vitamin D to all elderly housebound?
Housebound elderly patients are likely to be deficient in vitamin D because of their lack of exposure to sunshine. This contributes substantially to fracture risk through accelerated loss of bone mineral as a consequence of secondary hyperparathyroidism, and secondly through promotion of falls risk because of proximal myopathy.
Treatment of such individuals with 1g of calcium carbonate and 800 units of vitamin D has been shown to reduce the incidence of hip fractures by around 30%. Treatment of all elderly housebound patients with calcium and vitamin D supplementation is justifiable and there is a range of formulations that should allow patients to find a preparation that suits them.
Known hypercalcaemia or history of renal calculi are contraindications. If patients are using a thiazide diuretic, a check of serum calcium six weeks later is recommended as there is a small risk they might develop hypercalcaemia.
8. Is there much difference between the efficacy of different bisphosphonates? What are the differences in side-effects? How should problems like dyspepsia and reflux best be managed?
There has been no head-to-head comparison of the efficacy of different bisphosphonates. The main differentiation among these drugs arises from their reported ability to reduce the incidence of non-vertebral fractures including hip fractures.
Hip fracture reduction – in addition to reduction in risk of vertebral and other non-vertebral fractures – has been reported in clinical trial data of alendronate, risedronate and IV zoledronic acid.
Zoledronic acid is arguably the most potent and the most effective bisphosphonate on the basis of published evidence – perhaps because it is given as an intravenous infusion (annually) and it may be that intravenous administration circumvents difficulties with adherence and with absorption. But the logistics of annual IV infusion pose their own challenges.
If a patient develops dyspepsia with oral bisphosphonates, our practice is to interrupt bisphosphonate treatment for around a month and recommend use of a PPI preferably in the short-term. We would then re-try the bisphosphonate.
It has been reported that at least some of the benefit of oral bisphosphonates may be lost with concurrent use of PPI. More studies in this area are required to confirm if that is true.
If dyspepsia does recur with resumption of the oral bisphosphonate, we would then try another oral bisphosphonate. If that provoked recurrence of dyspepsia, IV zoledronic acid would be considered.
9. How effective is raloxifene in relation to other treatments?
The skeletal benefit of raloxifene is exclusively in relation to a reduction in the risk of vertebral fractures. The total absence of efficacy in reducing the incidence of non-vertebral fractures places it among the least useful of osteoporosis treatments.
Although raloxifene is not without other risks – such as increased incidence of DVT and cerebrovascular disease – it has the advantage of proven efficacy in reducing the incidence of oestrogen receptor-positive breast cancers. For most patients with osteoporosis, however, raloxifene's very limited efficacy places it far down the list of appropriate options.
10. Calcitriol, teriparatide, strontium, PTH – where do these fit in? And what should a GP be expected to know about their use?
The first choice treatment, in general, in patients with significant risk of vertebral and non-vertebral fractures (including hip), is oral, generic alendronate – plus calcium and vitamin D – based on efficacy and the low cost of generic medication.
Second choice is from among IV zoledronic acid and oral risedronate on the basis of their efficacy and tolerability. The choice ultimately will be influenced by patient preference and the availability of facilities for intravenous administration.
About 30% of patients treated with IV zoledronic acid experience a shortlived ‘flu-like' reaction, usually within the first 24 to 48 hours. This does not do any harm and can follow use of other IV and even oral bisphosphonates.
Strontium ranelate can also be considered but is associated with significant incidence of GI intolerance – especially diarrhoea – and very rarely has been reported to be associated with a potentially life-threatening immune reaction (DRESS).
Teriparatide and PTH are perceived to be particularly useful in patients who have multiple vertebral fractures, particularly those who continue to fracture despite conventional treatment with oral bisphosphonates. But both are very expensive and require self-administration by daily subcutaneous injection.
Calcitriol, like raloxifene, could be considered if these other agents proved to be unsuitable or unacceptable but like raloxifene, efficacy appears to be exclusively in reduction of vertebral fracture risk.
11. How powerful is genetic tendency in causing osteoporosis? With cardiovascular risk, we often find that relative(s) smoked heavily and the patient doesn't. Similarly with osteoporosis, we sometimes find the affected relative was very thin, had a poor diet or smoked heavily. How much would this affect the risk in a relative without these risk factors?
The life-time peak bone mass (PBM) is achieved between the ages of 25 and 35, and 70% of the variability is under genetic control. Other factors such as weight, hormonal environment, diet and exercise – whether independently or through interaction with genes – account for the remainder.
Compromise to PBM will predispose to earlier development of osteoporosis. There is little evidence to suggest that passive smoking or exposure to smoking by others in a household has an important influence on BMD.
12. What is the latest age one can make a difference to PBM?
As I said above-, PBM is achieved between the ages of 25 and 35 and is primarily determined by genetic factors. Some 70% of the variability of PBM is under genetic control.
The remainder of the determinants relate to diet, exercise, hormonal environment (among many factors) and it is unclear whether these are independent of, or work in conjunction with, genetic determinants.
The advice to patients irrespective of whether they think they have inherited the genetic predisposition to osteoporosis is to optimise well-being and lifestyle to maximise genetic potential for bone mineralisation throughout childhood, adolescence and young adulthood.
Dr Alastair McLellan is consultant endocrinologist and physician in the division of cardiovascular sciences and medicine at the Gardiner Institute, Western Infirmary, Glasgow. He is also chair of the National Osteoporosis Society's secondary care forum.
The National Osteoporosis Society is the only UK charity dedicated to improving the diagnosis, prevention and treatment of osteoporosis. Helpline 0845 450 0230
Competing interests None declaredWhat I will do now What I will do now
Dr Ruckert reflects
• I will put even more effort into managing risk factors now I have been reminded that most fractures occur in the osteopaenic patient
• I will try out the WHO fracture risk calculator but, as the author says, NHS funding of prescribing decisions may remain an issue
• It is helpful to discuss the dilemma of how long we should continue bisphosphonates by describing how consultants do not have a consensus – and the lay media focuses on risk
• I will refer for advice on the few patients I have with fractures on bisphosphonates
• I will refer those on frequent high-dose inhaled steroids for a DXA scan
Dr Linden Ruckert is a GP in north London