Interventions for preventing bone disease in kidney transplant recipients

What is the issue?
People who have a kidney transplant can have more fragile bones because of changes to the ways bones are formed in kidney disease and because anti-rejection medicines including prednisone can make their bones thinner. Bone fractures can cause difficulty with walking and carrying out the activities of everyday living such as work and family life. There are several treatment options for preventing fracture for people with thinner bones but whether these are helpful for kidney transplant patients is not clear. An earlier version of this Cochrane review in 2004 (and updated in 2007) did not find that any of these treatments prevented fractures.

What did we do?

We looked for new studies available since our last review published in 2007 to learn whether there is new information about available treatments for bone disease in people who have had a kidney transplant.

What did we find?
In 2019, there are 65 research studies (involving 3598 people) that looked at whether medicines can prevent bone fractures after kidney transplant. The most common medicine in the studies was a bisphosphonate which slows bone breakdown. Bisphosphonates were given at around the time of kidney transplantation (generally just before or within a few weeks) and continued for about one year on average. Other treatment options in the studies were vitamin D, calcitonin, denosumab, teriparatide, or cinacalcet. Bisphosphonate treatment given after a transplant possibly prevents fractures and bone pain, however the range where the actual effect of treatment might be (the "margin of error") indicates that treatment might make little or no difference. Bisphosphonates possibly lower the chances of a rejection of the transplant kidney but because of problems with the research studies, we can't be very certain that this is true. Bisphosphonates caused low blood calcium levels for some people. There was low or very low confidence in the information about all the other possible treatments for bone fractures after a kidney transplant, as the studies were often too small. There was only one study for medicines in children so we don't know whether these drugs are useful and safe for younger people.

Conclusions
It is still unclear whether bisphosphonate therapy makes any difference to bone fractures or are safe for both adults and children with a kidney transplant.

Authors' conclusions: 

Bisphosphonate therapy may reduce fracture and bone pain after kidney transplantation, however low certainty in the evidence indicates it is possible that treatment may make little or no difference. It is uncertain whether bisphosphonate therapy or other bone treatments prevent other skeletal complications after kidney transplantation, including spinal deformity or avascular bone necrosis. The effects of bone treatment for children and adolescents after kidney transplantation are very uncertain.

Read the full abstract...
Background: 

People who have chronic kidney disease (CKD) have important changes to bone structure, strength, and metabolism. Children experience bone deformity, pain, and delayed or impaired growth. Adults experience limb and vertebral fractures, avascular necrosis, and pain. The fracture risk after kidney transplantation is four times that of the general population and is related to Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) occurring with end-stage kidney failure, steroid-induced bone loss, and persistent hyperparathyroidism after transplantation. Fractures may reduce quality of life and lead to being unable to work or contribute to community roles and responsibilities. Earlier versions of this review have found low certainty evidence for effects of treatment. This is an update of a review first published in 2005 and updated in 2007.

Objectives: 

This review update evaluates the benefits and harms of interventions for preventing bone disease following kidney transplantation.

Search strategy: 

We searched the Cochrane Kidney and Transplant Register of Studies up to 16 May 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Selection criteria: 

RCTs and quasi-RCTs evaluating treatments for bone disease among kidney transplant recipients of any age were eligible.

Data collection and analysis: 

Two authors independently assessed trial risks of bias and extracted data. Statistical analyses were performed using random effects meta-analysis. The risk estimates were expressed as a risk ratio (RR) for dichotomous variables and mean difference (MD) for continuous outcomes together with the corresponding 95% confidence interval (CI). The primary efficacy outcome was bone fracture. The primary safety outcome was acute graft rejection. Secondary outcomes included death (all cause and cardiovascular), myocardial infarction, stroke, musculoskeletal disorders (e.g. skeletal deformity, bone pain), graft loss, nausea, hyper- or hypocalcaemia, kidney function, serum parathyroid hormone (PTH), and bone mineral density (BMD).

Main results: 

In this 2019 update, 65 studies (involving 3598 participants) were eligible; 45 studies contributed data to our meta-analyses (2698 participants). Treatments included bisphosphonates, vitamin D compounds, teriparatide, denosumab, cinacalcet, parathyroidectomy, and calcitonin. Median duration of follow-up was 12 months. Forty-three studies evaluated bone density or bone-related biomarkers, with more recent studies evaluating proteinuria and hyperparathyroidism. Bisphosphonate therapy was usually commenced in the perioperative transplantation period (within 3 weeks) and regardless of BMD. Risks of bias were generally high or unclear leading to lower certainty in the results. A single study reported outcomes among 60 children and adolescents. Studies were not designed to measure treatment effects on fracture, death or cardiovascular outcomes, or graft loss.

Compared to placebo, bisphosphonate therapy administered over 12 months in transplant recipients may prevent fracture (RR 0.62, 95% CI 0.38 to 1.01; low certainty evidence) although the 95% CI included the possibility that bisphosphonate therapy might make little or no difference. Fracture events were principally vertebral fractures identified during routine radiographic surveillance. It was uncertain whether any other drug class decreased fracture (low or very low certainty evidence). It was uncertain whether interventions for bone disease in kidney transplantation reduce all-cause or cardiovascular death, myocardial infarction or stroke, or graft loss in very low certainty evidence. Bisphosphonate therapy may decrease acute graft rejection (RR 0.70, 95% CI 0.55 to 0.89; low certainty evidence), while it is uncertain whether any other treatment impacts graft rejection (very low certainty evidence). Bisphosphonate therapy may reduce bone pain (RR 0.20, 95% CI 0.04 to 0.93; very low certainty evidence), while it was very uncertain whether bisphosphonates prevent spinal deformity or avascular bone necrosis (very low certainty evidence). Bisphosphonates may increase to risk of hypocalcaemia (RR 5.59, 95% CI 1.00 to 31.06; low certainty evidence). It was uncertain whether vitamin D compounds had any effect on skeletal, cardiovascular, death, or transplant function outcomes (very low certainty or absence of evidence). Evidence for the benefits and harms of all other treatments was of very low certainty. Evidence for children and young adolescents was sparse.

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