Blog entry by Arif Khwaja
Bone disease post-transplantation remains a difficult clinical problem with an evidence base that can be difficult to interpret. In the landmark osteoporosis studies demonstrating benefit of bisphosphonates in the general population the sample size was huge (many RCTs with around 5000 subjects) in order to show a positive effect on patient fracture. Clearly such studies are not possible in the transplant population but several studies have shown significant loss of bone mineral density (BMD) particularly in the first 12-18 months after transplantation (1, 2). Furthermore bisphosphonates have been shown to significantly attenuate the decline in BMD in the early post-transplantation period (1, 2). Whilst BMD is accepted as a reasonable surrogate marker in the general population it cannot capture the qualitative changes in bone histomorphometry that characterise CKD-MBD and so may not be a particularly useful surrogate post transplantation. Crucially the 'standard care' aspect of management post-transplantation may impact on BMD loss and a few recent studies have highlighted this.
In a study from Norway, Smerud and colleagues allocated 129 patients to receive either ibandronate or standard treatment (calcium and calcitriol supplementation) (3). Lumbar spine BMD was increased at 12 months in both groups and the change in BMD did not significantly differ between the patients who received ibandronate therapy and those who received placebo. Ibandronate did improve femoral BMD but interestingly there was no statistically significant loss in BMD at the femur in the placebo group. Coco and colleagues randomised 42 live related transplant recipients to either risedronate or placebo and found no significant impact on BMD (4) - nor did they find any evidence of adynamic bone disease, which remains an important theoretical concern when giving bisphosphonates to patients with CKD. Thus the more recent studies of bisphosphonates tend to show lesser loss in BMD in the control arm than the earlier studies. This probably relates to the fact the cumulative steroid exposure is less in the current era and that treatment with calcitriol and calcium in itself has a beneficial effect on BMD.
So where does this leave us in practical terms? Well it seems reasonable to ensure that all transplant patients should be kept vitamin D replete and levels should be monitored in the first year post-transplantation. Whether BMD should be measured in all patients is difficult to know but it would certainly be sensible to do in all those who are maintained on steroids. Given the fact that there will never be an adequately powered RCT looking at fracture rates in the post-transplant period I suspect the best that centres can do is develop local protocols based on risk factors such as vitamin D and steroid exposure with active audit to determine the utility of such protocols. A very practical approach was proposed by Mainra and Elder in Sydney, Australia who have developed an individualised approach to bone loss that incorporated BMD, prevalent vertebral fracture, biomarkers of bone turnover, and risk factor assessment (5). In the absence of definitive evidence this kind of approach seems very pragmatic.