Use of bisphosphonates in chronic kidney disease
Bisphosphonates are synthetic drugs that are chemically similar to organic pyrophosphates. The bioavailability of intravenous preparations is 100 (%) percent, whereas oral therapy is only 1 to 5 percent (%). Between 50 and 80 percent (%) of free bisphosphonates are incorporated into bone. Bisphosphonates must be administered with caution in chronic kidney disease (CKD) patients due to their urinary elimination. Despite this, bisphosphonates can be used safely in all stages of CKD, including dialysis and kidney transplant.
Treatment strategies using bisphosphonates:
The renal toxicity of these compounds appears to differ, owing primarily to their protein binding and the average lifespan in renal tissues. In practice, renal toxicity has been linked to infusion velocity and overdosage. The administration of bisphosphonates is recommended during the hemodialysis session in hemodialysis patients.
Bisphosphonates are bone antiresorptive agents that are widely used to treat postmenopausal or glucocorticoid-induced osteoporosis, as well as other conditions characterized by excessive osteoclastic bone resorption, such as Paget’s disease, multiple myeloma, osteolytic bone metastases, and malignancy-related humoral hypercalcemia.
Figure 1: Pictorial representation of the treatments associated with Bisphosphonates.
Bisphosphonates bind to hydroxyapatite in bone in a manner similar to pyrophosphate compounds. Bisphosphonate release causes osteoclast death and, as a result, a reduction in bone resorption without a corresponding decrease in bone formation during osteoclastic bone resorption. This results in a shift toward an initial net increase in bone mass, followed by a decrease in bone formation. Because bone remodeling and vascular calcification appear to be closely related in CKD patients, there has been interest in developing therapeutic strategies that influence this interaction. Bisphosphonate has been studied in both experimental and clinical settings.
Bisphosphonates are used to treat hypercalcemia episodes, prevent bone loss after renal transplantation, and treat low bone mineral density in all stages of CKD, including transplantation. They are a promising therapy for calciphylaxis and vascular calcification prevention.
Bisphosphonates, which are excreted through the kidneys, may accumulate in patients with impaired renal function and cause toxicity. Bisphosphonates have the potential to cause nephrotoxicity.
The primary goal of postmenopausal osteoporosis (PMO) treatment is to reduce fracture risk. As a result, bisphosphonates (BF) are the most commonly used drugs to treat such osteoporosis. Bisphosphonates must be administered with caution in chronic kidney disease (CKD) patients due to their urinary elimination. Renal toxicity appears to differ among these compounds, owing to their protein binding and the average lifespan of renal tissues. In practice, renal toxicity has been linked to infusion speed and overdosage. Treatment decisions are more difficult in patients with stage 4 and, particularly, stage 5 CKD who have fragility fractures. Despite this, bisphosphonates can be used safely at stages 1 – 3 of CKD, during hemodialysis, and after a kidney transplant.
Side effects of bisphosphonates:
Because bisphosphonates are cleared by the kidneys, they may impair kidney function and exacerbate other side effects common in adults with CKD on renal replacement therapy, such as hypocalcemia, hypophosphatemia, and gastrointestinal events.
Figure 2: Pictorial representation of common side effects of Bisphosphonates.
Bisphosphonates, in general, are not metabolized and are excreted in urine.
In patients with creatinine clearance as low as 30-35mL/min, oral bisphosphonates are approved for the primary and secondary prevention of osteoporotic fractures.
While there is data confirming the safety and efficacy of bisphosphonates in patients with impaired renal function, there is little data to support the use of bisphosphonates in patients with chronic kidney disease (CKD) stages 4 and 5, so more research is needed.
Bisphosphonates may cause nephrotoxicity; however, previous studies of patients with CKD have not found a greater deterioration in kidney function in patients taking bisphosphonates compared to control groups.
Adynamic bone disease has been linked to the use of bisphosphonates in people.
Pharmacokinetics: Bisphosphonates are not metabolized; instead, they are retained and re-cycled into the circulation in the same molecular structure as the parent formulation. Oral bisphosphonate absorption is poor (only 1% of the formulated dose is absorbed). Because of their strong affinity for the bone (calcium–phosphorus surface), between 27 and 62 percent of the drug in the blood binds to bone mineral very quickly. Any remaining bisphosphonate is excreted primarily through the kidneys within the first few hours after administration. Renal excretion is accomplished through both passive glomerular filtration and active transport in renal proximal tubular cells. Many drugs share these excretion pathways. A number of these medications have been linked to changes in kidney function and structure, which can lead to reversible or permanent renal dysfunction. Permanent renal damage has been reported in case reports involving first-generation IV bisphosphonates, but this information has not been validated by randomized, controlled clinical trials.
Figure 3: Pictorial representation of pharmacokinetics profile of bisphosphonates.
Following intravenous administration of bisphosphonates, approximately half of the dose is absorbed by the bone. Aside from a small amount of drug that is transiently exposed to other tissues, the majority of the remainder is excreted unchanged in urine via the same filtration and proximal tubular secretion pathways as oral bisphosphonates. Bisphosphonates are long-lasting in bone, slowly released during bone remodeling cycles, and can re enter the systemic circulation, as well as the kidney, with no change in molecular structure or metabolic activity. Bisphosphonates, in general, do not undergo detectable metabolism, do not induce or inhibit cytochrome P450 activity, and do not use the anionic or cationic renal transport systems that are involved in the excretion of many other drugs.
Bisphosphonates bind to hydroxyapatite and significantly reduce resorptive activity, resulting in a decrease in bone turnover rate. This action is responsible for the consistent improvement in bone density observed in the non-CKD population following the start of bisphosphonate therapy. However, it is this action that, in some cases, may jeopardize bone quality. Micro fracturing has been observed in bisphosphonate-treated dogs.
Conclusion: Bisphosphonates are currently used to prevent fractures in osteoporosis and high-risk osteopenia patients; however, the clinical utility of bisphosphonate therapy in CKD is yet to be established. Furthermore, bisphosphonates accumulate in bone, inhibit osteoclasts, and may cause or worsen low-turnover (adynamic) bone disease, particularly in patients with low PTH levels or receiving treatment for secondary hyperparathyroidism.