Oral bisphosphonates are a cornerstone of osteoporosis treatment and have well-documented efficacy in reducing the risk of fractures in osteoporotic patients. These agents are not without safety concerns and have been associated with adverse effects such as osteonecrosis of the jaw and esophagitis <3,4>. Two of the most common oral bisphosphonates commonly used in Ontario (alendronate and risedronate) carry a warning to avoid use in patients with creatinine clearance (Clcr) values less than 30-35 mL/min <3,4>. This is concerning given the prevalence of chronic kidney disease (CKD) and osteoporosis <5>; many patients with osteoporosis may have Clcr values that fall below 30-35 mL/min. Despite warnings, some evidence has suggested that oral bisphosphonates are safe to use when Clcr falls below 30 mL/min in some patients <6,7>. While the RANKL inhibitor denosumab is safe in Clcr<30 mL/min, in Ontario its use is limited to patients who have failed bisphosphonate therapy or cannot tolerate them due to hypersensitivity or esophagitis <8>. Thus, decisions regarding bisphosphonate use in renally impaired patients must be made. This article will discuss evidence surrounding the issue of oral bisophosphonate safety in patients with chronic kidney disease, specifically in patients whose Clcr is less than 30-35 mL/min.
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Note: For the purposes of this article, Clcr refers to glomerular filtration estimated by the Cockgroft-Gault (C-G) equation whereas eGFR refers to glomerular filtration calculated using Modification of Diet in Renal Disease (MDRD) equation. Clcr was used by many of the studies discussed in the article, as well as in product monographs to guide dosing; eGFR is recommended to stage CKD <9>.
Where do these safety concerns come from?
Recommendations to avoid use of oral bisphophonates with Clcr<30-35 mL/min are derived from several studies. Firstly, large clinical trials conducted to investigate efficacy and safety of bisphosphonates excluded very elderly patients and those with CKD; thus, their safety was unclear in such patients <6,7>. Warnings were also prompted from animal studies, which observed kidney damage after rapid IV administration of high doses of bisphosphonates <10>. Other studies have demonstrated acute kidney injury and renal failure associated with IV bisphosphonates, which appears to depend on the rate of infusion and dose <11>. It is clear that the risk of kidney injury has been largely associated with use of IV bisphosphonates; thus, prudent use of these agents is certainly warranted (only in patients with Clcr>30 mL/min and infusion times >15 minutes) <12>. However, the issue is not as clear in patients who are candidates for oral bisphosphonates <12>.
Assessing reduced bone strength and CKD
CKD is typically staged from 1-5 based on eGFR (see Table 1), while osteoporosis is typically diagnosed based on bone mineral density and bone mass <12-14>. From stages 1-3 and in some stage 4 patients, reduced bone strength has been shown to be associated mainly with osteoporosis <14>. Yet in many stage 4 and 5 CKD patients, reduced bone strength can be a result of CKD- mineral and bone disorder (CKD-MBD) rather than osteoporosis alone <13>. CKD-MBD is a complex disorder characterized by dysregulation in bone metabolism (including abnormalities in parathyroid hormone, phosphate, vitamin D and calcium metabolism) that may cause reduced bone strength <13>.
Because the pathogenesis of bone fragility and subsequent treatment modalities can differ in CKD patients, careful assessment is imperative to guide treatment. Bone biopsy and biochemical testing can be helpful to differentiate osteoporosis from CKD-MBD and bone biopsy is recommended by the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines prior to initiating bisphosphonate therapy in CKD patients with stage 3-5 disease <15>. While bisphosphonate therapy may be useful for both CKD-MBD and osteoporosis patients, CKD-MBD usually requires more complex treatment modality and the evidence for bisphosphonate use is not clear in these patients, as discussed below.
What does the evidence tell us?
In patients identified as osteoporotic with stage 4 age-related CKD, some evidence suggests that bisphosphonates may be safe and effective to reduce the risk of fractures. As mentioned above, clinical trials with oral bisphosphonates excluded CKD patients. However, post-hoc analysis of alendronate and risedronate trials found that several patients actually had age-related CKD (because trials used a serum creatinine cutoff rather than a Clcr cutoff) <6,7>. This prompted further analysis of risedronate and alendronate in patients with age-related decline in renal function (Clcr<60-80 mL/min) <6,7>. It is important to point out that in these studies, patients were staged based on Clcr rather than eGFR.
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These studies showed that in stage 2-4 CKD patients without CKD-MBD, bisphosphonates were not associated with any increased risk of kidney damage (kidney failure, hematuria, nephritis, rate of decline in SCr) versus placebo. Further, efficacy in the CKD group was similar to patients with normal kidney function. While post-hoc analyses contained relatively few patients whose Clcr fell below 30 mL/min, investigators found that even in this group renal adverse events (including decline in Clcr) did not differ between oral bisphosphonates or placebo. These findings support the safety of oral risedronate and alendronate in patients with CKD, even when Clcr falls below 30 mL/min. It is important to bear in mind; however, that these trials did not involve patients whose Clcr was <15mL/min (stage 5 CKD); thus, safety and efficacy has not been established in these patients. Further, trials involved only elderly females; thus, their application to men and younger patients is unclear.
What are the limitations of current evidence?
Despite evidence that supports use of oral bisphosphonates when Clcr is less than 30 mL/min, some important considerations remain. As discussed above, in patients with Clcr between 30-90 mL/min (patients in post-hoc analyses), impaired bone strength is mainly caused by osteoporosis; thus, they can be treated as osteoporotic patients and receive bisphosphonates (after ruling out biochemical abnormalities) <12,15>.
In stage 4 CKD, the situation is not as straightforward as many patients have CKD-MBD <12>. Importantly, the trials discussed above excluded patients with metabolic abnormalities and patients with CKD-MBD <6,7>. Thus, evidence supporting bisphosphonate use in Clcr < 30 mL/min in patients with age-related CKD cannot be applied to patients with reduced bone strength caused by CKD-MBD. Indeed, there is a lack of safety and efficacy data for bisphosphonates in CKD-MBD and little evidence to guide recommendations <11>.
Another important issue to consider is that of staging. In the post-hoc analysis of a trial involving risedronate <6>, stage 4 patients were included; however, they were staged using C-G rather than MDRD. This differs from the KDIGO recommendations for staging CKD, where the Modification of Diet in Renal Disease (MDRD) equation is preferred given its improved accuracy in older patients <15>. Interestingly, if the MDRD equation is used to estimate renal function in post-hoc analysis of a the risedronate trial, patients classified as stage 4 CKD have eGFR values of on average 42 mL/min/1.73m2<15>. Therefore, most patients would not actually meet the stage 4 criteria <15>. While controversy exists regarding appropriate estimations of Clcr in the elderly, even if C-G is used, the average Clcr of stage 4 patients in the risedronate trial was 27 mL/min, which barely falls below the Clcr contraindication for alendronate and risedronate.
Looking closer at post-hoc analysis of the alendronate trial in CKD patients reveals that only 20 patients had stage 4 CKD, which is a small sample size to draw conclusions from <7,15>. It is also important to note that CKD patients typically have more bone loss in cortical bone (at the femur) compared to vertebral bone and there was no improvement in bone loss of the femur in stage 4 patients <7,15>.
Clearly, there is lack of strong evidence supporting bisphosphonate use in CKD patients when ClCr falls below 30 mL/min. Recommendations suggest thorough investigation of stage 4 CKD patients to rule out CKD-MBD before a bisphosphonate is considered <12,15>. Careful assessment of a patient with respect to fracture risk, etiology of reduced bone strength and renal function may reveal that a patient without CKD-MBD and with Clcr < 30 mL/min would benefit from bisphosphonate therapy <12>. However, in patients with stage 4 CKD-MBD there is a lack of high-quality safety and efficacy data to guide treatment and no data in stage 5 patients. Thus, bisphosphonate use in this population is still controversial and further research is needed to identify effective and safe treatments to reduce fracture risk.