Applied Evidence

Bone disease in patients with kidney disease: A tricky interplay

J Fam Pract. 2016 September;65(9):606-608,610-612

From The Journal of Family Practice | 2016;65(9):606-608,610-612

References

1. United States Renal Data System. Chapter 1: CKD in the general population. Available at: https://www.usrds.org/2015/download/vol1_01_General_Pop_15.pdf. Accessed July 27, 2016.

2. Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United States. JAMA. 2007;298:2038-2047.

3. Uhlig K, Berns JS, Kestenbaum B, et al. KDOQI US commentary on the 2009 KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of CKD-Mineral and Bone Disorder (CKD-MBD). Am J Kidney Dis. 2010;55:773-799.

4. Martin KJ, Gonzalez EA. Metabolic bone disease in chronic kidney disease. J Am Soc Nephrol. 2007;18:875-885.

5. Roberts DM, Singer RF. Management of renal bone disease. Aust Prescr. 2010;33:34-37.

6. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl. 2009:S1-130.

7. Palmer SC, Hayen A, Macaskill P, et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis. JAMA. 2011;305:1119-1127.

8. Cannata-Andia JB, Martin KJ. The challenge of controlling phosphorus in chronic kidney disease. Nephrol Dial Transplant. 2016;31:541-547.

9. US Food and Drug Administration. Food Labeling Guide. Available at: http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/LabelingNutrition/ucm2006828.htm. Accessed July 25, 2016.

10. Kalantar-Zadeh K. Patient education for phosphorus management in chronic kidney disease. Patient Prefer Adherence. 2013;7:379-390.

11. Kalantar-Zadeh K, Gutekunst L, Mehrotra R, et al. Understanding sources of dietary phosphorus in the treatment of patients with chronic kidney disease. Clin J Am Soc Nephrol. 2010;5:519-530.

12. USDA National Nutrient Database for Standard Reference. 2015; Available at: https://ndb.nal.usda.gov. Accessed April 25, 2016.

13. Bellasi A. Pro: Should phosphate binders be used in chronic kidney disease stage 3-4? Nephrol Dial Transplant. 2016;31:184-188.

14. Kestenbaum B. Con: Phosphate binders in chronic kidney disease. Nephrol Dial Transplant. 2016;31:189-194.

15. Ketteler M, Elder GJ, Evenepoel P, et al. Revisiting KDIGO clinical practice guideline on chronic kidney disease-mineral and bone disorder: a commentary from a Kidney Disease: Improving Global Outcomes controversies conference. Kidney Int. 2015;87:502-528.

16. Wolters Kluwer. Lexicomp. Clinical Drug Information. Available at: http://www.wolterskluwercdi.com/lexicomp-online/. Accessed April 26, 2016.

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19. Patel L, Bernard LM, Elder GJ. Sevelamer versus calcium-based binders for treatment of hyperphosphatemia in CKD: a meta-analysis of randomized controlled trials. Clin J Am Soc Nephrol. 2016;11:232-244.

20. Jamal SA, Vandermeer B, Raggi P, et al. Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis. Lancet. 2013;382:1268-1277.

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24. Chonchol M, Locatelli F, Abboud HE, et al. A randomized, double-blind, placebo-controlled study to assess the efficacy and safety of cinacalcet HCl in participants with CKD not receiving dialysis. Am J Kidney Dis. 2009;53:197-207.

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Native vitamin D becomes less effective at reducing PTH levels as kidney disease advances. This is likely due to a decline in renal conversion of 25(OH)D to 1,25-(OH)₂vitamin D (1,25[OH]₂D), the most active form of vitamin D and the form of vitamin D that decreases PTH production. By stage 5 CKD, it is unlikely that native vitamin D will significantly decrease PTH levels; treatment with activated vitamin D products or cinacalcet is generally required.

Because the enzyme responsible for converting 25(OH)D into the most active form can be found in multiple tissues outside of the kidney, and the 1,25(OH)₂D converted for use by these organs may help prevent such conditions/events as hypertension, type 2 diabetes, myocardial infarction, and stroke (in patients with and without kidney disease), some specialists prescribe native vitamin D to patients with CKD for reasons unrelated to PTH suppression. There are no data, however, confirming that 25(OH)D supplementation mitigates these outcomes.²¹

Don’t forget calcium

All of the active vitamin D products can increase serum calcium and phosphate levels. Calcitriol, however, may cause more hypercalcemia than paricalcitol.²² If hypercalcemia develops, you may need to stop, or reduce the dose of, vitamin D analogues. Or you may need to switch patients from calcium-based to non-calcium-based phosphate binders. If hyperphosphatemia develops, intensify phosphate binder therapy or reduce the dose of, or stop, vitamin D analogues. If iPTH levels go below the target range, reduce the dose of the vitamin D analogue to avoid iatrogenic adynamic bone disease.

Avoid this agent in the non-dialyzed patient. Cinacalcet effectively treats SHPT in patients receiving dialysis, but is not recommended for use in undialyzed patients.²³ That’s because unacceptably high rates of hypocalcemia have been observed in non-dialyzed patients who were taking the drug.^23,24 In addition, while cinacalcet neutrally affects, or causes a slight decrease in, serum phosphate in patients receiving dialysis, it increases serum phosphate in patients who are not.^24,25

Drug therapy for osteoporosis

Therapy to prevent and treat fractures in patients with CKD is controversial because patients with CKD stage 3 to 5 with and without MBD were excluded from clinical trials of commercially available treatments. Furthermore, in adynamic bone disease, bones are capable of neither breaking down nor building (ie, reduced resorption). Bisphosphonates and other antiresorptive therapies are more effective at decreasing fractures in patients who are in a state of increased bone resorption, such as menopausal women, so the benefits of these medications in terms of their ability to reduce fractures in CKD patients are questionable, as is their safety.^26,27

In addition, while dual-energy x-ray absorptiometry (DXA) is typically used to identify patients who would benefit from these agents, studies have recently demonstrated that femoral neck bone density measured via DXA may underestimate fracture risk in patients with CKD-MBD (ie, bone density may actually be lower than measured).^26,28

Antiresorptive agents and teriparatide

Osteoporosis treatments include antiresorptive agents (ie, the bisphosphonates, raloxifene, denosumab), and the anabolic bone agent teriparatide.

Evidence supports treating patients with stage 1 to 3 CKD the same as patients without CKD.¹⁵ Bisphosphonates are labeled as contraindicated in patients with a glomerular filtration rate (GFR) <30 mL/min/1.73m², due to concerns arising from animal trials and subsequent human case reports (both with intravenous formulations only) regarding acute kidney injury.²⁷

While raloxifene lacks a warning regarding use in patients with stage 3 to 5 CKD, it has not been shown to prevent hip fractures in any population.²⁹

Denosumab is not contraindicated for use in patients with CKD stage 3 to 5 without MBD, but it can worsen hypocalcemia, particularly in patients receiving dialysis.³⁰

Teriparatide is contraindicated in patients with CKD and SHPT,³¹ and there are no studies of its use in patients with CKD-MBD.

What the guidelines say about antiresorptive treatment

For patients with stage 3 to 5 CKD with manifestations of MBD, 2009 KDIGO guidelines recommend a bone biopsy to evaluate for adynamic bone disease before initiating antiresorptive treatment.⁶ Because few physicians in most communities are trained to conduct and evaluate bone biopsies, this recommendation is infrequently followed. Without a bone biopsy to rule out adynamic bone disease, options to prevent or treat fractures in the setting of CKD-MBD are limited.

CORRESPONDENCE
Karly Pippitt, MD, Department of Family and Preventive Medicine, University of Utah School of Medicine, 375 Chipeta Way, Suite A, Salt Lake City, UT 84108; karly.pippitt@hsc.utah.edu.