Bone densitometry, most commonly performed by dual-energy X-ray absorptiometry (DXA), is a readily available, noninvasive, rapid, cost-effective, and relatively precise method of screening BMD with low radiation exposure. However, the usefulness of DXA scans in patients with CKD and post-transplantation is limited because they do not reflect bone quality, turnover, or architecture [66]. The scans do not distinguish the underlying cause of bone loss. Low BMD measurements in post-kidney transplant recipients may be a consequence of osteoporosis and/or osteodystrophic bone disease [67]. The World Health Organization (WHO) [68] criteria defining fracture risk for osteopenia and osteoporosis are based on studies performed in normal postmenopausal Caucasian populations, thus limiting their applicability to kidney transplant recipients. Furthermore, there is no proven predictive relationship between BMD and fracture risk in kidney transplant recipients; in fact at least one study demonstrated that BMD did not distinguish those who went on to experience a fracture from those who did not [55]. BMD measurements in kidney transplant patients should not be looked at in isolation but should be analyzed and considered in the setting of a clinical assessment with biochemical data and possibly bone histology. However despite all of these limitations, BMDs may have a role in the transplant population. Sequential measurements of BMD may be helpful to guide antiresorptive therapy. KDIGO guidelines recommend measuring BMD at the time of transplantation or within the first 3 months after transplantation [23, 56, 69] when estimated GFR is >30 mL/min/m², particularly in patients with risk factors for rapid bone loss. However, KDIGO does not recommend DXA scans in patients with eGFR < 30 mL/min/1.73 m² as they are of no proven benefit in predicting fracture risk or the type of post-transplant bone disease [56]. DXA scans can be repeated at 12-month intervals if BMD decreases by greater than 5 % or half of a standard deviation; otherwise, DXA scan can be obtained every 2 years [70] to monitor response to therapy or to help decide whether therapy should be continued.

Bisphosphonates are synthetic analogues of pyrophosphates that bind to hydroxyapatite in the bone and directly inhibit osteoclastic bone resorption [92–94]. Bisphosphonates also reduce osteoclastic activity by decreasing osteoclast progenitor development and recruitment and by promoting osteoclast apoptosis [92–94]. As well bisphosphonates prevent osteocyte and osteoblast apoptosis [95]. Data from clinical trials show that both oral and intravenous bisphosphonates prevent bone loss in the lumbar spine and femoral neck in the first post-transplant year [33–43] and beyond [55]. There is a lack of evidence, however, that bisphosphonate use has any beneficial effect on bone strength or fracture prevention in the kidney transplant population. This lack of supporting data may be because of the underpowered nature of studies undertaken to examine this issue. When dosed appropriately in properly selected patients and used for limited periods of time, bisphosphonate therapy is well tolerated, safe, and effective for the prevention and management of post-transplant bone loss. Intravenous zoledronic acid or ibandronate can be an alternative to oral bisphosphonates in patients who cannot tolerate the oral formulation or have difficulty with the dosing requirements. Bisphosphonates should be used with caution in patients with reduced kidney function and their use should be avoided in patients with eGFR of less than 30–35 mL/min, given the prolonged duration of action and accumulation in bone resulting in the possibility of inducing or perpetuating adynamic bone disease [40, 96]. To reiterate, though bisphosphonates have been demonstrated to attenuate bone loss following transplantation, they have not been shown to reduce fractures. In fact, one study demonstrated increased fractures in patients receiving bisphosphonate therapy [55]. Bisphosphonate therapy is generally contraindicated in patients with evidence of low bone turnover [40], and obtaining a bone biopsy before institution of bisphosphonate therapy is the most accurate means of characterizing bone turnover and avoiding its use in adynamic bone states.

A Cochrane review of 24 trials, including 1,209 kidney transplant recipients, evaluating the risks and benefits of bisphosphonates, vitamin D analogues, and calcitonin versus no treatment found that all of the interventions provided clinically significant prevention of bone loss in both the femoral neck and lumbar spine, with the exception of calcitonin [38] which did not improve femoral neck BMD [33]. Bisphosphonates were superior to calcitriol in preserving BMD. No single therapy was found to prevent fractures; however, lack of demonstration does not necessarily mean they do not reduce fractures, because as noted earlier, none of these trials were powered to detect a reduction in fracture risk. However, combining the effect of all therapies versus no intervention, there was a 49 % reduction in the relative fracture risk (confidence interval 0.27–0.99). In another meta-analysis by Stein et al., 11 trials evaluated fracture incidence in 780 solid organ transplant recipients (4 of the 11 trials and 42 % of the patients had kidney transplants) that received either bisphosphonates or vitamin D receptor agonists (VDRAs) within the first-year post-transplant [97]. There were 134 reported fractures in these studies. The use of bisphosphonates or VDRAs was associated with a reduced number of subjects with any fracture and vertebral fractures specifically. The discordance in findings between the Cochrane review and the meta-analysis by Stein et al. may be attributable to discrepancies in the methodology of the analyses, differences between the study populations, the timing of initiation of therapy and most importantly that not all studies included reported on fractures. Specifically in the Palmer et al. review, only 11/24 studies (34/514 patients) had reported fracture data [33], while in the Stein et al. review, 134 incident fractures were reported in the 659 subjects who had follow-up information [97]. These data suggest that preventive therapy including bisphosphonates or VDRAs is likely better than no therapy or calcium alone in preventing post-transplant bone loss and perhaps even fractures. In summary, bisphosphonates may have a role in select patient populations: specifically those at risk for fracture but without evidence for low turnover bone disease. The appropriate duration of therapy is not known; however, a maximum of 12–18 months of therapy immediately post-transplantation may be sufficient. Prospective appropriately controlled studies are required to determine the optimal role of bisphosphonate therapy.

VDRAs can preserve and improve BMD by several mechanisms. VDRAs promote differentiation of osteoblast precursors into mature cells, significantly suppress osteoclastic bone activity, and maintain trabecular bone volume and wall thickness [98, 99]. In addition VDRAs can reverse glucocorticoid-induced decreases in intestinal calcium absorption and mitigate against secondary hyperparathyroidism [99].

Some studies demonstrate that oral calcitriol lowers PTH in patients with persistent post-transplant hyperparathyroidism [100, 101]. Several placebo controlled clinical trials demonstrate that active vitamin D preserves and improves BMD at both the lumbar spine and femoral neck in renal allograft recipients [45–49]. None of these studies show that VDRAs have any deleterious effects on renal allograft function. Clinically important outcomes such as mortality, hospitalizations, or fractures were not evaluated in these studies. Although, bisphosphonates have been shown to be superior to VDRAs in preserving and improving BMD in clinical trials [33, 102, 103], there is emerging evidence that suggests the use of either bisphosphonates or VDRAs in solid organ transplant recipients prevents fractures in the first post-transplant year [97]. Table 24.2 summarizes the indications, risks, and contraindications of VDRA therapy.