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.