Osteoporosis Management 
Two experts on osteoporosis answer readers’ questions on managing this debilitating condition.
Dr Mark Edwards Clinical Lecturer in Rheumatology, University of Southampton, Southampton General Hospital

Cyrus Cooper Director and Professor of Rheumatology, University of Southampton; Professor of Musculoskeletal Science, University of Oxford

Q How is FRAX used, how is it calculated and how do you act on it? 

A
FRAX is a very useful tool in the assessment of fracture risk. It can be found online at http://www. shef.ac.uk/FRAX/. There is also a desktop application available at the same website. The user enters easily available data regarding the patient; specifcally, age, sex, weight, height, previous fracture, parental hip fracture, current smoking, glucocorticoid use, rheumatoid arthritis, disorders strongly associated with secondary osteoporosis, and alcohol consumption greater than three units per day. From this information an assessment is made of the risk of hip fracture and major osteoporotic fracture in the next 10 years. This represents the likelihood of fracture in this period taking into account the competing risk of death (Figure 1). 
Burning Questions 2-6 Osteoporosis Fig 1-2
These values can then be compared with the National Osteoporosis Guideline Group (NOGG) thresholds by the click of a mouse (Figure 2). At present, the overall threshold above which treatment is recommended corresponds to the risk of an individual of the same age with a previous fracture. If the risk is suffciently above this threshold, treatment is recommended without the need for a dual energy x-ray absorptiometry (DXA) scan. If the risk is suffciently lower, the patient can be reassured and given lifestyle advice alone. If the risk is intermediate, and therefore near to the threshold, a DXA scan is recommended to refne the estimated fracture risk. Following completion of a DXA, the data can be reentered into FRAX along with the femoral neck bone mineral density (BMD) result in order to determine whether or not to intervene. 
 
Clearly, FRAX provides guidance only and the final decision to assess BMD or to initiate therapeutic intervention lies with the individual clinician. It can, however, be exceptionally useful particularly to reassure both yourself and the patient when they are concerned about their risk of osteoporotic fracture, perhaps due to a single risk factor, and their true risk is, in fact, low.

Q When should we order a DXA scan?

A DXA scans give T scores, at the lumbar spine and hips, which represent the number of standard deviations the patient’s BMD lies away from the mean of a young adult population. In 1994, the World Health Organization defined osteoporosis as a T score of <-2.5 and osteopenia as a score of between -1.0 and -2.5.1 Consequently, a significant proportion of the general population, even young adults, fall into the osteopenic category. 
 
There are several times at which a DXA scan may be useful. The first is at the point of initial assessment, however, when FRAX is used, this is clearly not required in all patients. Another use of DXA is in the assessment of response to therapy. In general, scans are not repeated within two years as the level of precision of the technique often prevents a signifcant difference being identifed if insuffcient time is allowed. The interpretation of DXA results can also be challenging. Although a significant increase or stable BMD tends to suggest that treatment is working, some argue that a decline alone, in the absence of fracture, does not represent a treatment failure per se and would not therefore require a change in therapy. 
 
DXA scanning can also include a vertebral fracture assessment (VFA). This is a technique that allows production of an image of the lateral spine, usually between T4 and L4, which allows vertebral morphometry to be assessed. As two-thirds of vertebral fractures are occult but represent a substantial risk factor for future fracture, their identifcation can infuence the decision to treat. This assessment is particularly useful in those with features suggesting vertebral fractures, such as height loss or an excessive kyphosis.

Q What factors should infuence choice of bisphosphonate?

A Oral bisphosphonates tend to be used first line as bone-sparing agents; these include alendronate, risedronate and etidronate. The NICE guidance on the primary prevention of osteoporotic fragility fractures in postmenopausal women from 2008 recommends the latter two as alternatives in those unable to comply with the special instructions for the administration of alendronate, and those that have a contraindication to, or are intolerant of, alendronate, if they meet the required risk criteria.2 When taking alendronate, patients must do so when fasted (usually on waking), ideally with a glass of tap water, and then remain in an upright position (sitting or standing) for at least 30 minutes, during which time they do not eat or drink anything else. 
 
Intravenous (IV) bisphosphonates are most commonly used when the patient is unable to take oral bisphosphonates due to a contraindication or intolerance. This is generally related to problems in the upper GI tract, such as gastro-oesophageal refux disease (GORD). There is evidence that IV bisphosphonates may have greater efficacy than their oral counterparts and, consequently if, for example, a patient fails on alendronate you may wish to consider switching to IV zoledronate. 
 
The last benefit of using IV therapy is improved compliance and the ability to monitor this. Compliance and persistence with oral bisphosphonates is known to be poor, even as early as one year into treatment. Therefore, if this is likely to be a particular issue then it may be best to consider IV treatment at an early stage.

Q When should we use calcium and vitamin D? 

A The studies that have assessed the efficacy of treatments, such as bisphosphonates and denosumab, have invariably trialled the drug in combination with calcium and vitamin D supplementation. Consequently, these therapies have only been shown to be effective when used in such a manner. It is therefore normal practice to use the two together. However, an argument could be made for omitting supplementation if the physician felt strongly that the patient was receiving suffcient vitamin D in their diet alone although this would not be evidence based. 
 
The other common use of these supplements is in patients who do not reach the threshold for treatment with bisphosphonates but in whom the risk of fracture is not negligible. Although the evidence for calcium and vitamin D alone in the prevention of fracture is not strong, ensuring that patients are replete in these micronutrients may have a benefcial effect on their BMD, particularly if they are initially deplete, with a consequent benefcial effect on fracture risk.

Q Do you advise vitamin D alone or in combination with calcium, given the potential cardiovascular risk associated with calcium? 

A
Calcium and vitamin D are usually used as a combination preparation. However, it is certainly possible to give vitamin D alone. Recent studies have been conficting in terms of the effect of calcium supplementation on cardiovascular risk, in particular myocardial infarction.4,5 However, there is certainly some evidence that it may lead to a small increase in risk.6 As a result, we tend to take a pragmatic approach to deciding in which patients to treat with the combination of calcium and vitamin D, and which to treat with vitamin D alone. This is based on an assessment of potential risks and previous benefits. 
 
In those individuals with a low risk of cardiovascular disease, we would tend to treat with combination as it is felt that the potential benefits, as described in the above question, are likely to outweigh the risk. If a patient has known cardiovascular disease, or is at high risk, we would consider using vitamin D alone. Further studies are required to more conclusively determine the risks and benefts of these treatments.

Q If someone is being treated for primary prevention of osteoporosis, should they be given a ‘drug holiday’ and if so, how often?  

A
There has been recent concern about the link between long-term bisphosphonate use and atypical femoral diaphyseal fractures. Although these can occur in the absence of therapy, their rate appears to be higher in patients on bisphosphonates, particularly when prolonged.7 Therefore, there has been discussion regarding whether to limit the duration for which these drugs are taken continuously. The argument against this is the potential for fracture rates to increase when medication is ceased. 
 
A pragmatic approach has therefore been developed. As the benefcial effects of zoledronate are maintained for several years, the majority of patients can have a period of time off treatment after three years of therapy. This is unless they have had a previous vertebral fracture or a pre-treatment hip BMD T-score of ≤-2.5 as they may be at increased risk of vertebral fracture if the drug is not continued.8 In these cases, a switch to an alternative treatment, such as denosumab, would be considered. 
 
Patients on oral bisphosphonates are treated for fve years and then reassessed. If they are deemed to be at high risk, for example, over the age of 80 years, continuing to take oral glucocorticoids, or developed fractures whilst on therapy (with which they are compliant), treatment should be continued. The physician may, however, wish to consider an alternative therapy, such as denosumab or, if within the NICE guidelines, teriparatide. 
 
Alternatively, if these criteria are not present, the physician could consider a period off treatment prior to a further evaluation of risk. This could be two to three years for alendronate or ibandronate, and one year for risedronate. The variance in suggested duration is due to the different rates of offset of the treatments. Clearly, if the patient fractures during this period, then the assessment should be expedited.

Q What are the guidelines about starting bisphosphonates in people on long-term steroids? 

A
When considering bone-sparing agents, such as bisphosphonates, in patients on long-term glucocorticoids, the frst step is to assess whether such treatment is necessary. Initial guidelines, such as those from the Royal College of Physicians in 2002, used age and BMD cut offs as the main evaluation tools. However, risk assessment is now advised using the FRAX tool, in the same manner as any other patient, and the treatment thresholds again correspond to the NOGG guidelines (found on the FRAX website). 
 
FRAX only gives a yes or no option for whether an individual is currently exposed or has been exposed to more than three months of glucocorticoids at a dose equivalent to prednisolone 5mg daily. However, it has been shown that the dose of steroid is important in fracture risk and so the assessment can be modifed by the clinician. If the dose is less than 2.5mg daily, the risk of major osteoporotic fracture should be multiplied by 0.8 and if greater than 7.5mg daily, multiplied by 1.15. This information is not currently included on the FRAX website but may be added in the future. 
 
It is important to remember that the greatest loss of BMD due to oral glucocorticoids occurs in the frst few months of use and therefore prophylaxis should not be unnecessarily delayed. Interestingly, the increase in fracture risk with steroid use occurs above and beyond that which can be explained by the lowering of BMD. Thus, the physician should be aware that in patients on long-term glucocorticoid therapy, for a given BMD, the risk of fracture is greater than in individuals not on steroids.
Burning Questions 2-6 Osteoporosis Hips

References
 
1. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ. TechRepSer. 1994;843:1-129. 
2. [TA160] Nta. Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women (amended). 2008. 
3. Cramer JA, Gold DT, Silverman SL, Lewiecki EM. Osteoporos Int. 2007;18(8):1023-31. 
4. Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS, Gamble GD, et al. BMJ. 2010;341:c3691. 
5. Heaney RP, Kopecky S, Maki KC, Hathcock J, Mackay D, Wallace TC.. Advances in nutrition (Bethesda, Md). 2012;3(6):763-71. 
6. Reid IR, Bolland MJ, Avenell A, Grey A. Osteoporos Int. 2011;22(6):1649-58. 
7. Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD, Cheung AM, et al. Journal of bone and mineral research : the offcial journal of the American Society for Bone and Mineral Research. 2014;29(1):1-23. 
8. Black DM, Reid IR, Boonen S, Bucci-Rechtweg C, Cauley JA, Cosman F, et al. Journal of bone and mineral research : the offcial journal of the American Society for Bone and Mineral Research. 2012;27(2):243-54