What is the relationship between Bisphosphonates (bone resorption inhibitors) and impaired renal (kidney) function?

From the Guidelines

Bisphosphonates should be used with caution in patients with kidney disease, and the most recent guidelines recommend monitoring serum creatinine before each dose of pamidronate or zoledronic acid, as well as considering dose adjustments based on creatinine clearance 1. For patients with mild to moderate kidney impairment (creatinine clearance 30-60 mL/min), oral bisphosphonates like alendronate and risedronate can generally be used at standard doses. However, these medications are contraindicated in severe kidney disease (creatinine clearance below 30-35 mL/min) due to risk of further kidney damage. Intravenous bisphosphonates like zoledronic acid require dose adjustments based on creatinine clearance and are not recommended when clearance falls below 35 mL/min, as supported by the 2007 American Society of Clinical Oncology guideline update on the role of bisphosphonates in multiple myeloma 1. Before starting bisphosphonate therapy, kidney function should be assessed with serum creatinine and estimated glomerular filtration rate (eGFR), and patients should maintain adequate hydration when taking these medications, especially with IV formulations. The caution with bisphosphonates in kidney disease stems from their renal excretion pathway - these drugs are eliminated primarily through the kidneys, so reduced kidney function leads to drug accumulation and potential toxicity. Additionally, bisphosphonates can cause acute kidney injury through direct tubular toxicity, particularly when administered intravenously at high doses or infusion rates, as noted in the 2011 American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer 1. It is also important to consider the risk of osteonecrosis of the jaw (ONJ) associated with the use of bone-modifying agents, including bisphosphonates, and to take preventive measures such as dental examination and maintenance of optimal oral hygiene, as recommended in the 2018 American Society of Clinical Oncology clinical practice guideline update on the role of bone-modifying agents in multiple myeloma 1. Overall, the use of bisphosphonates in patients with kidney disease requires careful consideration of the potential risks and benefits, and close monitoring of kidney function and other potential adverse effects.

From the FDA Drug Label

5.7 Renal Impairment Risedronate sodium delayed-release is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min) because of lack of clinical experience.

• Bisphosphonates and kidney: Risedronate sodium delayed-release is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min) due to lack of clinical experience 2.
• The use of bisphosphonates in patients with kidney problems should be approached with caution.
• Patients with renal impairment should be carefully evaluated before starting bisphosphonate therapy.

From the Research

Bisphosphonates and Kidney Disease

• Bisphosphonates are commonly used to treat osteoporosis, but their use in patients with chronic kidney disease (CKD) is a concern due to potential renal toxicity 3, 4, 5, 6, 7.
• Studies have shown that oral bisphosphonates are generally safe in patients with CKD, but may be associated with a modest increased risk of CKD progression 3.
• Intravenous bisphosphonates, such as zoledronic acid, may cause short-term increases in serum creatinine concentrations, but are generally safe when used at recommended doses and infusion rates 5, 6.
• The use of bisphosphonates in patients with severe renal impairment (creatinine clearance <30 or <35 mL/min) is contraindicated or should be used with caution 4, 5, 6, 7.

Renal Safety of Bisphosphonates

• Renal safety analyses of pivotal trials of oral alendronate, risedronate, and ibandronate for postmenopausal osteoporosis showed no short-term or long-term effects on renal function 5.
• Transient postinfusion increases in serum creatinine have been reported in patients receiving intravenous ibandronate and zoledronic acid, but studies showed that treatment with these agents did not result in long-term renal function deterioration in clinical trial patients with osteoporosis 5, 6.
• Bisphosphonates are eliminated from the human body by the kidney, and renal clearance is both by glomerular filtration and proximal tubular secretion 6, 7.

Use of Bisphosphonates in CKD Patients

• Bisphosphonates can be used in patients with CKD, but the dose may need to be reduced, especially in patients with stage 4 or 5 CKD 4, 7.
• The indications of bisphosphonates in CKD include hypercalcemia episodes, prevention of bone loss after renal transplantation, treatment of low bone mineral density in all CKD stages, including transplantation 4.
• In patients with CKD, it is essential to maintain the time of infusion and avoid excessive dosage to minimize the risk of renal toxicity 4, 6.