The results demonstrate a low incidence of fracture following liver transplantation in this centre over the past 10 years. In common with other groups, we had reported a high incidence of fractures in the early post-operative period; 27% of 37 adults undergoing liver transplantation between 1993 and 1995 developed new vertebral fractures within the first three post-operative months.14
In contrast, this audit of the years 1998–2008 demonstrated a fracture incidence post-transplant of only 3.7%.
The reasons for the lower fracture incidence in recent years cannot be defined precisely on the basis of this audit, but are likely to include reduction in the dose and duration of glucocorticoid therapy and the use of bone-protective therapy in individuals at high risk of fracture. In the early days of liver transplantation, very large doses of prednisolone were used for prolonged periods, whereas much lower doses are used now and for shorter periods. For example, in the early 1990s the starting dose of prednisolone used in most patients in the 1980s was 60
mg/day falling to 30
mg/day in the early 1990s and this was continued for 6 months with gradual reductions thereafter. In contrast, in current practice the initial dose is 20
mg/day with the aim of stopping glucocorticoids between 6 and 12 weeks for patients transplanted for conditions other than autoimmune liver disease. Further, some patient groups such as those transplanted with hepatitis C virus infection are not treated with glucocorticoids at all. Secondly, an established standard protocol for bone health assessment prior to transplantation identifies individuals at high risk of fracture for bone-protective therapy before and after transplant. Both these changes in clinical practice are likely to have contributed to the low-fracture incidence post-transplant.
In addition, it is possible that improved nutritional support prior to and after transplantation may have played a role. Evidence for better bone health prior to transplant can be obtained from a comparison of the prevalence of osteoporosis (BMD T
−2.5) in earlier and later studies from this centre. Thus, we reported osteoporosis in 36.6% of 243 consecutive patients undergoing liver transplantation in the early to mid-1990s,18
whereas osteoporosis was present in only 18% of patients pre-transplant in the present study. Furthermore, the prevalence of fracture prior to transplantation was low (5.6%) in this study.
In the general population, the use of clinical risk factors in addition to BMD is widely used to improve prediction of fracture risk, using tools such as FRAX®, the WHO-supported risk algorithm.19–22
While this approach is reasonably well validated at a population level, risk factors for fracture post-transplantation are less clearly documented. Older age,8,15,23
the presence of a prevalent vertebral fracture prior to transplantation8,15
and in some studies, chronic cholestatic liver disease,3,13
have been associated with increased fracture risk in patients undergoing liver transplantation, but a clear relationship with BMD has not emerged from most studies. The contribution of other clinical risk factors such as smoking, alcohol abuse and a parental history of a fractured hip to fracture risk in the transplant population has not been assessed and requires further study. However, at present it seems reasonable to recommend bone-protective therapy in all patients with a previous history of fragility fracture and/or those with low BMD, although the threshold for the latter is arbitrary and to some extent age dependent. The T
-score of ≤−1.5 chosen in this centre was based on the UK guidelines for glucocorticoid therapy;24
however, because of the strong independent effect of age on fracture risk, treatment might be advised at a higher BMD in elderly subjects and a lower BMD in younger subjects.
Although a standard management protocol was in place during the period of the audit, not all individuals who fulfilled the criteria for bone-protective therapy received treatment. Thus, ~30% of patients received treatment post-transplant, while 47.7% had a BMD T
≤−1.5 before the transplant. We were not able to identify the reasons for this apparent under-treatment in the audit; only oral bisphosphonates were approved for osteoporosis during almost the whole period of the audit and contraindication to or intolerance of oral bisphosphonate therapy is likely to have prevented treatment in some cases, particularly those with a history of haemorrhage from oesophageal varices. In the relatively small number of cases in whom BMD measurements were available before and 24–48 months after transplantation, there was a significant increase in BMD in the spine, but not the hip. Other studies have mostly demonstrated an increase in BMD after the first year or so after transplantation, although recovery in the hip may be slower than in the spine.16,25,26
A number of studies have investigated the effect of bone-protective therapy in patients undergoing liver transplantation.17,27–36
However, these have often been relatively small and not all have been randomized or controlled; while beneficial effects on BMD have been demonstrated in some, none has been adequately powered to demonstrate reduction in fracture. Most data exist for the bisphosphonates pamidronate, alendronate and zoledronate, all of which have been shown to reduce or prevent bone loss in the spine and in most cases, also the proximal femur. Of these, zoledronate may be the most appropriate treatment option in many of the liver transplant population in view of its intravenous mode of administration and infrequent dosing regimen. However, although untested in the transplant population, once yearly infusion of 5
mg is likely to be adequate37
rather than the more frequent dosing regimens used in the studies reported to date.34,35
Our study has several limitations. It was not possible to retrieve all the medical records of patients undergoing liver transplant during the audit period, particularly of those who had died. For those in whom records were available, there were some missing data, for example, only about two-thirds and one-half, respectively, of patients had BMD measurement before and after transplantation. Similarly, only 59 patients had a spine X-ray both before and after transplantation and since the majority of vertebral fractures are asymptomatic,38
it is possible that the incidence of vertebral fractures was underestimated. Finally, we relied on medical records and X-ray reports for fracture diagnosis and this provides another possible reason for underestimating fracture incidence.
In summary, our audit has demonstrated a low incidence of clinical fracture in patients undergoing liver transplantation in our unit over the period 1998–2008. This is likely to reflect reduction in the total dose of glucocorticoids used for immune suppression and the use of bone-protective therapy in individuals at high risk of fracture. Bisphosphonates provide a rational approach to the prevention of fracture in the transplant population; because of its low cost, alendronate is the front-line option, but intravenous zoledronate should be considered in patients who cannot take or are intolerant to alendronate and in those unlikely to be compliant with long-term oral bisphosphonate therapy. The optimal duration of therapy has not been defined but in view of the tendency for BMD to improve 1–2 years post-transplant and the prolonged action of zoledronate, one dose may be sufficient for many patients.