John A. Goldman, MD, FACR, FACP, CCD
At the ISCD 2006 Annual Meeting in San Diego, Dr. Paul Miller discussed the use of bisphosphonates in patients with possible impaired renal function (1). I have had the opportunity to discuss this with him recently. Dr. Miller pointed out that the glomerular filtration rate (GFR) may be below 30 ml/min in many seemingly healthy postmenopausal women over age 70. Reduction in kidney function may not be reflected by serum creatinine concentration. Serum creatinine is derived from the breakdown of the muscle precursor creatine. As muscle mass declines with aging, the source of serum creatinine declines as well and older patients may often have serum creatinine concentrations within the normal range of a reference laboratory and yet have GFRs below 30 ml/min (2-4).
One can obtain a 24 hour urine collection to measure GFR (creatinine clearance) but there are some relatively simple formulas that can be used to estimate the GFR using the serum creatinine level (2 -6).
1. Cockcroft-Gault (CG) Equations:
In men: GFR = (140-age) x weight in kg ÷ (72 x serum creatinine)
In women: GFR = [(140-age) x weight in kg ÷ (72 x serum creatinine)] x 0.85
2. Modification of Diet in Renal Disease (MDRD):
This formula is preferred by and available from the National Kidney Foundation (NKF) (http://www.kidney.org/professionals) .
GFR (ml/min/1.73 m2) =
186 x Scr (mg/dl)-1.154
x Age (years) -0.203
x (0.742 if female)
x (1.21 if African American)
Dr. Miller pointed out that inaccuracies in the estimated GFR (eGFR) can occur at the extremes of age and weight, and that this can impact serial GFR measurements. Depending on your preference, one can ask the reference labs to automatically printout the CG or MDRD eGFR (5, 6).
There are 5 stages of chronic renal disease* with Stage 5 requiring histomorphometry.
|1||Kidney damage with normal or increased GFR||greater than or equal to 90ml/min|
|2||Kidney damage with mild decreased GFR||60-89|
|3||Kidney damage with moderate decreased GFR||30-59|
|4||Kidney damage with severe decreased GFR||15-29|
|5||Kidney failure (on dialysis)||less than 15|
* National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kid Dis. 2003;42(4 suppl 3):S10-201. (2)
Dr. Miller points out that the Food and Drug Administration (FDA) labeling recommends avoiding bisphosphonates in patients with GFRs below 30-35 ml/min, but since some patients with GFRs in this range may have occult renal dysfunction (i.e., “normal” serum creatinine), many physicians are probably administering bisphosphonates to patients with GFRs below 30-35 ml/min without realizing it. He recommends that when one finds an eGFR less than 30 ml/min but above 15 ml/min (e.g., stage 4), one may consider reducing by half the FDA approved dose of oral bisphosphonates based on the known pharmacokinetics of bisphosphonate elimination from the body: 50% remains bound to bone and 50% is excreted by the kidney both by filtration and tubular secretion.
There have not been any studies that have examined either the safety or efficacy of approved doses of oral bisphosphonates in stage 5 chronic kidney disease (CKD) as there has been for stage 4 CKD (3).In this meta-analysis, safety and efficacy were demonstrated for treatment duration of no more than two years. Prospective studies are needed to confirm these results (2, 4). In addition, one should be aware that although bisphosphonates are cleared by the kidney, they may not be removed by all dialysis machines.
The FDA labeling for zoledronic acid (not FDA approved for treatment of osteoporosis) advises adjusting the dosage according to the pre-treatment GFR. Dr. Miller suggests that if intravenous bisphosphonates such as pamidronate or zoledronate need to be used, the rate of infusion should be slowed to double the infusion time in patients with stage 4 CKD. Injectable ibandronate is given over 15-30 seconds. It is not to be administered in patients with a GFR below 30 or a serum creatinine of 2.3 or greater. The package insert recommends measuring the serum creatinine concentration before each three month 3 mg injection.
Patients may well have CKD, even though their serum creatinine concentrations are normal. Since the serum creatinine concentration may not accurately reflect a patient’s real GFR, because of increased age and/or reduced muscle mass, clinicians should assess the GFR in all patients over age 70 who are being considered for treatment with a bisphosphonate. Also, in patients with baseline serum creatinine concentrations of 2.0 mg/dl, measuring the GFR or eGFR is important.
1. Miller P. Use of bisphosphonates with impaired renal function, ISCD Annual Meeting, February 4, 2006
2. Miller P. Osteoporosis and Chronic Kidney Disease, National Osteoporosis Foundation Clinical Updates, Summer 2005.
3. Miller PD, Roux C, Boonen S, Barton I, Dunlap L , and Burgio D. Safety and Efficacy of Risedronate in Patients with Age-Related Reduced Renal Function as Estimated by the Cockcroft and Gault Method: A Pooled Analysis of Nine Clinical Trials. J Bone Miner Res 2005 (Dec) 20 (12); 2105-2115
4. Miller PD. Treatment of osteoporosis in chronic kidney disease and end-stage renal disease. Current Osteoporosis Reports, 2005; 3:5-12. 5. National Kidney Foundation. http://www.kidney.org/ [last accessed March 11]
6. MDRD GFR Calculator (with SI Units) http://www.kidney.org/professionals/kdoqi/gfr_calculator.cfm [last accessed March 11, 2006].
Last modified: December 17, 2012