Calcitriol, Etelcalcitide, and Paricalcitol Injections

Number: 0022

Policy

Aetna considers calcitriol (Calcijex) or paricalcitol (Zemplar) injection medically necessary for the management of hypocalcemia and/or secondary hyperparathyroidism in members with chronic renal failure undergoing hemodialysis.

Aetna considers calcitriol injection experimental and investigational for the treatment of the following diseases (not an all-inclusive list) because its safety and effectiveness for these indications has not been established:

  • Atopic dermatitis
  • Cystic fibrosis
  • Diabetic nephropathy
  • Glucocorticoid-induced osteoporosis
  • IgA nephropathy
  • Multiple sclerosis
  • Non-small-cell lung cancer
  • Prostate cancer, other solid tumors/cancers (e.g., breast, colon, endometrium, glioblastoma, kidney, ovary, and pancreas)
  • Sepsis.

Aetna considers paricalcitol injection experimental and investigational for the treatment of the following diseases (not an all-inclusive list) because its safety and effectiveness for these indications has not been established:

  • Atopic dermatitis
  • Cardiovascular diseases (e.g., heart failure, hypertension, peripheral vascular disease, vascular calcification, and ventricular hypertrophy)
  • Diabetic nephropathy
  • Myelodysplastic syndrome
  • Pancreatic cancer
  • Pentylenetetrazol-induced seizures
  • Post-transplantation nephropathy
  • Renal ischemia-reperfusion injury
  • Reduction of graft inflammation and fibrosis in kidney transplant recipients
  • Reduction of proteinuria in kidney transplant recipients

Aetna considers etelcalcetide (Parsabiv) medically necessary for the treatment of secondary hyperparathyroidism (PTH ≥400 pg/ml) in adults with chronic kidney disease (CKD) on hemodialysis when all of the following criteria are met:

  • Corrected calcium level is at or above the lower limit of normal prior to initiation (≥8.3mg/dL); and
  • Member has therapeutic failure/insufficient response, contraindication or intolerance to at least 2 phosphate binders (e.g., PhosLo, Fosrenol, Renvela, Renagel)Footnotes1*; and
  • Member has therapeutic failure/insufficient respone, contraindication or intolerance to at least 2 vitamin D analogs (e.g., calcitriol, Hectorol (doxercalciferol), Zemplar (paricalcitol))Footnotes1*; and
  • Member has therapeutic failure, contraindication or intolerance of cinacalcet (Sensipar)Footnotes2**.

Footnotes1*For purposes of this policy, treatment failure is defined as at least a 2 month trial of each 

Footnotes2**For purposes of this policy, treatment failure is defined as at least a 6 month trial of cinacalcet (Sensipar) at the maximum tolerated dose.

Aetna considers concurrent use of cinacalet and etecalcetide experimental and investigational because there is inadequate evidence of the effectiveness of the use of these drugs in combination. Initiation of etecalcetide within 7 days of discontinuing cinacalcet is considered experimental and investigational.

Aetna considers etelcalcetide experimental and investigational for all other indications, including the following (not an all-inclusive list), because its safety and effectiveness for these indications has not been established:

  • Adults with CKD who are not on hemodialysis
  • Parathyroid carcinoma
  • Primary hyperparathyroidism

See also CPB 0020 - Injectable Medications.

Background

Calcitriol is an anti-hypocalcemic agent or calcium regulator.  It is used to suppress the levels of parathyroid hormone (PTH).  Calcijex, the parenteral form of calcitriol, is used when patients have not responded to an oral form of calcitriol (Rocaltrol).  Calcijex is administered intravenously.  Paricalcitol (Zemplar), a vitamin D analog, is administered as an intravenous bolus injection and can be delivered at any time during dialysis.  Paricalcitol is the most widely used vitamin D analog in the United States.

Studies have reported that parenteral calcitriol is more effective than pulse oral calcitriol in suppressing PTH (Andress 2001).  Available evidence indicates that parenteral vitamin D therapy is associated with fewer episodes of hypercalcemia and hyperphosphatemia and that patients receiving pulse oral calcitriol require more phosphate binders.  Because of the documented high non-compliance rate with oral medications in the dialysis population, parenterally administered vitamin D or vitamin D analog is expected to more completely suppress PTH and result in fewer parathyroidectomies.

Calcitriol is also available in oral form.  Oral calcitriol (Rocaltrol) is indicated for hypoparathyroidism and pseudohypoparathyroidism.  Oral calcitriol is also indicated for secondary hyperparathyroidism and resultant metabolic bone diseases in persons with moderate to severe renal failure not yet on dialysis.

Topical calcitriol (e.g., Vectical) is used for treatment of mild to moderate plaque psoriasis in adults.

Investigators are studying the potential anti-tumor effects of calcitriol and paricalcitol.  In a review, Beer et al (2005) stated that calcitriol has been reported to exhibit significant anti-neoplastic activity in pre-clinical models of prostate cancer and many other tumor types.  Its mechanisms of activity may include inhibition of proliferation, cell cycle arrest, induction of apoptosis, as well as reduction of invasiveness and angiogenesis.  Differing mechanisms may be involved in different tumor types and under different experimental conditions.  Pre-clinical data suggest that calcitriol acts via a synergistic and/or additive manner when combined with anti-neoplastic agents that are relevant to prostate cancer such as dexamethasone and several classes of cytotoxic agents.  However, the anti-neoplastic effects of calcitriol occur at levels that markedly exceed the normal physiological range and cannot be safely attained with conventional daily dosing.  Intermittent administration of calcitriol has allowed significant dose escalation.  When used with weekly docetaxel (Taxotere), calcitriol produced encouraging results in a single-center phase II clinical trial.  These investigators noted that an international placebo-controlled randomized study is under way to ascertain the safety and effectiveness of this combinational therapy.

In a phase I and pharmacokinetics study, Muindi et al (2009) determined the maximum tolerated dose (MTD) of intravenously (i.v.) calcitriol administered in combination with a fixed oral dose of dexamethasone and gefitinib in patients with refractory solid tumors.  A fixed oral dose of dexamethasone of 4 mg/day was given every 12 hrs x 3 doses starting 12 hrs prior to i.v. calcitriol administration.  Calcitriol was administered i.v. over 1 hr on weeks 1, 3, and weekly thereafter.  The starting calcitriol dose level was 57 ug and escalation occurred in cohorts of 3 patients until the MTD was defined.  Gefitinib was given at a fixed oral daily dose of 250 mg starting at week 2 (day 8).  Serum calcitriol pharmacokinetics studies were performed on day 1 (calcitriol + dexamethasone) and on day 15 (calcitriol + dexamethasone + gefitinib).  A total of 20 patients were treated.  Dose-limiting hypercalcemia was observed in 2 out of the 4 patients receiving 163 mcg/week of calcitriol.  Mean (+/- SE) peak serum calcitriol concentration (C (max)) at the MTD (125 microg/week calcitriol) was 11.17 +/- 2.62 ng/ml and the systemic exposure (AUC (0 to 72 hr)) of 53.30 +/- 10.49 ng h/ml.  The relationship between calcitriol dose and either C (max) or AUC was linear over the 57-163 microg dose range.  The authors concluded that the addition of a low-dose of dexamethasone allowed the safe escalation of calcitriol to the MTD of 125 microg/week.  This dose level resulted in serum calcitriol concentrations that are associated with pre-clinical anti-tumor activity.  However, no anti-tumor activity was noted clinically in patients with solid tumors.

Vitamin D analogues are being investigated in pancreatic cancer and other cancers.  Chiang and Chen (2009) noted that pancreatic cancer is ranked 5th among cancer-related deaths worldwide with a 5-year survival rate of less than 5 %.  Currently, surgery is the only effective therapy.  However, most patients are diagnosed in the late stage and are not suitable for receiving curative surgery.  Moreover, pancreatic cancer doesn't respond well to traditional chemotherapy and radiotherapy, leaving little effective treatment for advanced pancreatic cancer cases.  1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], the biologically active form of vitamin D(3), was originally identified during studies of calcium and bone metabolism, though it is now recognized that it exerts biological effects in almost every tissue in the body.  Abundant evidence has shown that 1alpha,25(OH)(2)D(3) has anti-proliferative, apoptotic, pro-differentiation and anti-angiogensis effects in many types of cancer cells in vivo and in vitro, including breast, prostate, and colon.  Similarly, the anti-tumor growth effect of 1alpha,25(OH)(2)D(3) on pancreatic cells has been demonstrated.  The clinical use of 1alpha,25(OH)(2)D(3) is impeded by the lethal side effects of hypercalcemia and hypercalciuria.  Thus, 1alpha,25(OH)(2)D(3) analogs, which are either equipotent or more potent than 1alpha,25(OH)(2)D(3) in inhibiting tumor cell growth but with fewer hypercalcemic and hypercalciuric side effects, have been developed for the treatment of different cancers.  Recently, a pre-clinical study demonstrated that a less calcemic analog of 1alpha,25(OH)(2)D(3), 19-nor-1alpha,25(OH)(2)D(2) (paricalcitol), is effective in inhibiting tumor growth in vitro and in vivo, via up-regulation of p21 and p27 tumor suppressor genes.  The authors stated that studies on the anti-tumor effects of a more potent analog of paricalcitol are underway; 1alpha,25(OH)(2)D(3) and its analogs are potentially attractive novel therapies for pancreatic cancer.

In a phase II clinial trial, Chadha et al (2010) examined the effects of intravenous calcitriol at a dose of 74 ug weekly (based on a recent phase I trial) and dexamethasone in patients with castration-resistant prostate cancer (CRPC).  A 2-stage Kepner-Chang design was used.  Oral dexamethasone at a dose of 4 mg was given weekly on days 1 and 2, and i.v. calcitriol (74 ug over 1 hour) was administered weekly on day 2 from 4 to 8 hours after the dexamethasone dose in patients with CRPC.  Laboratory data were monitored weekly, and renal sonograms, computed tomography scans, and bone scans were obtained every 3 months.  Disease response was assessed by using the Response Evaluation Criteria in Solid Tumors (RECIST) and standard criteria for prostate-specific antigen (PSA) response.  The calcitriol dose was derived from the authors' recent phase I study.  Of 18 evaluable patients, 15 patients were Caucasian (83 %).  No patients had a complete or partial response by either RECIST or PSA response criteria.  Fourteen patients had progressive disease, 2 patients refused to continue treatment (after 64 days and 266 days), and 2 patients remain on the trial (for 306 days and 412 days).  The median time to disease progression was 106 days (95 % confidence interval [CI]: 80 to 182 days).  Fourteen episodes of grade 3 or 4 toxicity were noted in 7 patients (cardiac arrhythmia, chest pain, dyspnea, hyperglycemia, hypercalcemia, hypocalemia, hypophosphatemia, and pain).  Only 1 episode of grade 3/ 4 toxicity was related definitely to calcitriol (hypercalcemia).  No treatment-related deaths were noted.  The authors concluded that high-dose, i.v. calcitriol at a dose of 74 ug weekly in combination with dexamethasone was well-tolerated but failed to produce a clinical or PSA response in men with CRPC.

In a clinical trial (n = 12), Koeffler and colleagues (2005) examined the effect of oral paricalcitol in the treatment of patients with myelodysplastic syndrome (MDS) whose disease varied between an international prognostic scoring system of low to high.  Drug was well-tolerated in all patients.  No responses were observed according to international working group criteria.  However, the platelet count of 1 of the 12 subjects rose from 53,500 to 120,000/ul blood over 5 weeks; but the patient succumbed to a fatal fungal infection.  These investigators concluded that paricalcitol given as a single agent to MDS patients is therapeutically not very effective; further trials of the vitamin D analog should be considered in combination with other approaches.

In a randomized, placebo-controlled, double-blind study, de Zeeuw et al (2010) evaluated if paricalcitol could be used to reduce albuminuria in patients with diabetic nephropathy.  Patients with type 2 diabetes and albuminuria who were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were enrolled.  Patients were assigned (1:1:1) by computer-generated randomization sequence to receive 24 weeks’ treatment with placebo,1 μg/day paricalcitol, or 2 μg/day paricalcitol.  The primary end-point was the percentage change in geometric mean urinary albumin-to-creatinine ratio (UACR) from baseline to last measurement during treatment for the combined paricalcitol groups versus the placebo group.  Analysis was by intention-to-treat.  A total of 281 patients were enrolled and assigned to receive placebo(n = 93), 1 μg paricalcitol (n = 93), or 2 μg paricalcitol (n = 95); 88 patients on placebo, 92 on 1 μg paricalcitol, and 92 on2 μg paricalcitol received at least one dose of study drug, and had UACR data at baseline and at least one time-point during treatment, and so were included in the primary analysis.  Change in UACR was: -3 % (from 61 to 60 mg/mmol; 95 % CI: 16 to 13) in the placebo group; -16 % (from 62 to 51 mg/mmol; -24 to -9) in the combined paricalcitol groups, with a between-group difference versus placebo of -15 % (95 % CI: -28 to 1; p = 0.071); -14 % (from 63 to 54 mg/mmol; -24 to -1) in the 1 μg paricalcitol group, with a between-group difference versus placebo of -11 % (95 % CI: -27 to 8; p = 0.23); and -20 % (from 61 to 49 mg/mmol; -30 to -8) in the 2 μg paricalcitol group, with a between-group difference versus placebo of -18 % (95 % CI: -32 to 0; p = 0.053).  Patients on 2 μg paricalcitol showed a nearly, sustained reduction in UACR, ranging from -18 % to -28 % (p = 0.014 versus placebo).  Incidence of hypercalcaemia, adverse events, and serious adverse events was similar between groups receiving paricalcitol versus placebo.  The authors concluded that addition of 2 μg/day paricalcitol to renin-angiotensin-aldosterone system inhibition safely lowers residual albuminuria in patients with diabetic nephropathy, and could be a novel approach to lower residual renal risk in diabetes.  Moreover, they stated that the safety, effectiveness, and minimal need for monitoring of this drug should encourage future studies with hard renal outcomes to prove its renal and cardiovascular protective effects.  Soloway (2010) commented that this study suggests that paricalcitol might augment protection of renal function in patients with diabetes when added to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.  But this trial employed only surrogate endpoints; proof of efficacy will require longer studies with definitive renal and safety endpoints.

Vitamin D analogues are being examined as a treatment for multiple sclerosis.  Niino and colleagues (2008) stated that multiple sclerosis (MS) is a major inflammatory and demyelinating disease of the central nervous system and has an increasing prevalence in populations residing at higher latitudes.  This observation may indicate a protective effect of sunlight exposure, which is reduced at higher latitudes and may contribute to insufficient levels of vitamin D in the MS population.  The vitamin D hormone is important for bone metabolism and can regulate cell proliferation and differentiation as well as apoptosis and immune regulation in immune cells such as T-helper cells and dendritic cells.  Evidence from experimental autoimmune encephalomyelitis and prospective studies on MS suggests an important role of vitamin D as a modifiable environmental factor in MS.  These provide guidance for future studies with regard to the potential role of vitamin D in the prevention and/or treatment of MS.  In this regard, Smolders et al (2008) noted that there is a sound basis on which to initiate double-blind placebo-controlled studies that not only examine the effect of vitamin D on the clinical outcome of MS, but also on the regulatory T-cell compartment..

Reis (2010) stated that the management of cyclosporine A-induced nephrotoxicity remains one of the main challenges in kidney transplantation.  The animal study by Park et al proposes that paricalcitol, a vitamin D analog with reno-protective actions reported in other conditions, attenuates cyclosporine A-induced kidney injury via the suppression of inflammatory, fibrotic, and apoptotic factors.  However, before paricalcitol can be considered a feasible new therapeutic option for the management of patients with post-transplantation nephropathy, these interesting data require further studies evaluating other mechanisms of cyclosporine A-induced nephrotoxicity.

Henderson and Lester (1997) noted that serum levels of the important hormone 1,25-dihydroxyvitamin D (1,25-diOHD, calcitriol) have not been extensively evaluated in patients with cystic fibrosis (CF) during the critical period of skeletal growth and development.  This study was a cross-sectional, observational assessment of 25-hydroxyvitamin D (25-OHD, calcidiol) and 1,25-diOHD levels in 54 patients with CF.  The patients' ages ranged from 4.9 years to 19.5 years (mean of 11.0 years).  Levels were correlated with pulmonary function tests, chest x-ray scores, height and weight Z scores, skinfold percentiles, CF genotype, serum chemistries, and use of a vitamin supplement.  Levels were compared with those in more than 160 other pediatric patients living in the same region, and all assays were done in the same laboratory.  Despite low-normal levels of the 25-OHD precursor, there was a high prevalence of low (18 %) and marginal (18 %) levels of 1,25-diOHD.  None of the various parameters examined correlated with either 25-OHD or 1,25-diOHD levels.  The cause, clinical significance, and treatment of low levels of this important hormone in children with CF warrant further study.

Ferguson and Chang (2009) stated that CF is a genetic disorder with multi-organ effects.  In a subgroup with pancreatic insufficiency, malabsorption of the fat soluble vitamins (A, D, E, K) may occur.  Vitamin D is involved in calcium homeostasis and bone mineralization and may have extra-skeletal effects.  In a Cochrane review, these investigators evaluated the effects of vitamin D supplementation on the frequency of vitamin D deficiency, respiratory outcomes and vitamin D toxicity in the CF population.  They searched the Cochrane CF and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.  Most recent search was June 9, 2009.  Randomized and quasi-randomized controlled trials of vitamin D supplementation compared to placebo in the CF population regardless of exocrine pancreatic function.  Both authors independently assessed the "risk of bias" of each included trial and extracted outcome data (from published trial information) for assessment of bone mineralization, growth and nutritional status, frequency of vitamin D deficiency, respiratory status, quality of life and adverse events.  Three studies were included, although only data from 2 were available (41 adults and children with CF).  One of these studies compared supplemental 800 international units (IU) vitamin D and placebo for 12 months in 30 osteopenic pancreatic insufficient adults; both groups continued 900 IU vitamin D daily.  The other (abstract only) compared supplemental 1 g calcium alone, 1,600 IU vitamin D alone, 1,600 IU vitamin D and 1 g calcium and placebo in a double-blind randomized cross-over trial; only 11 children (vitamin D and placebo groups) after 6-months supplementation are included; inclusion criteria, pancreatic sufficiency or disease status of participants were not defined.  There were no significant differences in primary or secondary outcomes in either study.  The studies were not directly comparable due to differences in supplementation, outcome reporting and possibly participant characteristics (e.g., severity of lung disease, growth and nutrition, pancreatic sufficiency).  There were no adverse events in either study.  The 3rd study (abstract only) compared daily calcitriol (0.25 or 0.5 ug) with placebo in pancreatic insufficient children and young adults, only pre-intervention data were available.  The authors concluded that there is no evidence of benefit or harm in the limited number of small-sized published trials.

Tamez et al (2012) noted that left atrial enlargement, a sensitive integrator of left ventricular diastolic function, is associated with increased cardiovascular (CV) morbidity and mortality.  Vitamin D is linked to lower CV morbidity, possibly modifying cardiac structure and function; however, firm evidence is lacking.  These investigators examined the effect of an activated vitamin D analog on left atrial volume index (LAVi) in a post-hoc analysis of the PRIMO trial.  A total of 196 patients with chronic kidney disease (CKD; estimated glomerular filtration rate [GFR] 15 to 60 ml/min per 1.73m(2)), mild-to-moderate left ventricular hypertrophy, and preserved ejection fraction were randomly assigned to 2 μg of oral paricalcitol or matching placebo for 48 weeks.  Two-dimensional echocardiography was obtained at baseline and at 24 and 48 weeks after initiation of therapy.  Over the study period, there was a significant decrease in LAVi (-2.79 mL/m(2), 95 % CI: -4.00 to -1.59 ml/m(2)) in the paricalcitol group compared with the placebo group (-0.70 ml/m(2) [95 % CI: -1.93 to 0.53 mL/m(2)], p = 0.002).  Paricalcitol also attenuated the rise in levels of brain natriuretic peptide (10.8 % in paricalcitol versus 21.3 % in placebo, p = 0.02).  For the entire population, the change in brain natriuretic peptide correlated with change in LAVi (r = 0.17, p = 0.03).  The authors concluded that 48 weeks of therapy with an active vitamin D analog reduces LAVi and attenuates the rise of BNP.  They stated that in a population where only few therapies alter CV-related morbidity and mortality, these post-hoc results warrant further confirmation.

In a multi-national, double-blind, randomized, placebo-controlled trial, Thadhani et al (2012) examined the effects of paricalcitol on left ventricular mass over 48 weeks in patients with an estimated GFR of 15 to 60 ml/min/1.73 m(2).  A total of 227 patients (from 11 countries) with CKD, mild-to-moderate left ventricular hypertrophy, and preserved left ventricular ejection fraction, were included in this study.  Participants were randomly assigned to receive oral paricalcitol, 2 μg/day (n =115), or matching placebo (n = 112).  Main outcome measures were change in left ventricular mass index over 48 weeks by CV magnetic resonance imaging; secondary end points included echocardiographic changes in left ventricular diastolic function.  Treatment with paricalcitol reduced PTH levels within 4 weeks and maintained levels within the normal range throughout the study duration.  At 48 weeks, the change in left ventricular mass index did not differ between treatment groups (paricalcitol group, 0.34 g/m(2.7) [95 % CI: -0.14 to 0.83 g/m(2.7)] versus placebo group, -0.07 g/m(2.7) [95 % CI: -0.55 to 0.42 g/m(2.7)]).  Doppler measures of diastolic function including peak early diastolic lateral mitral annular tissue velocity (paricalcitol group, -0.01 cm/s [95 % CI: -0.63 to 0.60 cm/s] versus placebo group, -0.30 cm/s [95 % CI: -0.93 to 0.34 cm/s]) also did not differ.  Episodes of hypercalcemia were more frequent in the paricalcitol group compared with the placebo group.  The authors concluded that 48-week therapy with paricalcitol did not alter left ventricular mass index or improve certain measures of diastolic dysfunction in patients with CKD.

Gonzalez-Parra et al (2012) stated that vitamin D has been recently associated with several renal, cardiovascular and inflammatory diseases, beyond mineral metabolism and bone health.  This is due in part to widespread expression of vitamin D receptor (VDR) on tissues and cells such as heart, kidney, immune cells, brain and muscle.  In CKD and other chronic disorders, vitamin D deficiency [serum 25(OH)D less than 20 ng/ml] is very common and is associated with adverse outcomes.  Paricalcitol has demonstrated in several experimental and clinical studies of diabetic and non-diabetic CKD a favorable profile compared to other VDR activators, alone or as add-on to standard therapy.  These beneficial effects are mediated by different actions such as reduction of oxidative stress, inflammation, down-regulation of cardiac and renal renin expression, down-regulation of calcifying genes and direct vascular protective effects.  Furthermore, paricalcitol beneficial effects may be independent of baseline serum PTH, calcium and phosphate levels.  They stated that these benefits should be confirmed in large and well-designed ongoing clinical trials.

Cozzolino et al (2012) noted that in CKD patients, CV morbidity and mortality rate is higher than in the general population, because of frequently concomitant hypertension, peripheral vascular disease, heart failure, vascular calcification (VC), diabetes and mineral bone disease.  Recently, another important factor associated to CV risk in CKD has been deeply investigated: vitamin D deficiency.  Vitamin D receptors are present in several systems and tissues and VDR activation is associated with positive effects, resulting in better blood pressure control and prevention of diabetic nephropathy.  Unfortunately, the natural, non-selective vitamin D receptor activator (VDRA), calcitriol, is associated with higher serum calcium and phosphate levels, thus worsening CV risk in CKD.  Recent data showed that the selective VDRA paricalcitol might have ameliorative CV effects.  The authors concluded that the potential positive impact of the use of paricalcitol on diabetic nephropathy, cardiac disease, hypertension, and VC may open new paths in the fight against CV disease in CKD patients.

In a phase I/II pharmacokinetic and pharmacogenomic study, Ramnath et al (2013) determined the recommended phase II dose (RP2D) of 1,25-D3 (calcitriol) with cisplatin and docetaxel and its effectiveness in metastatic non-small-cell lung cancer.  Patients were greater than or equal to 18 years, PS 0-1 with normal organ function.  In the phase I portion, patients received escalating doses of calcitriol intravenously every 21 days prior to docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) using standard 3 + 3 design, targeting dose-limiting toxicity (DLT) rate less than33 %.  Dose levels of calcitriol were 30, 45, 60, and 80 mcg/m(2).  A 2-stage design was employed for phase II portion.  These investigators correlated CYP24A1 tagSNPs with clinical outcome and calcitriol pharmacokinetics (PK).  A total of 34 patients were enrolled.  At 80 mcg/m(2), 2/4 patients had DLTs of grade 4 neutropenia.  Hypercalcemia was not observed.  The RP2D of calcitriol was 60 mcg/m(2).  Among 20 evaluable phase II patients, there were 2 confirmed, 4 unconfirmed partial responses (PR), and 9 stable disease (SD).  Median time to progression was 5.8 months (95 % CI: 3.4 to 6.5), and median overall survival 8.7 months (95 % CI: 7.6 to 39.4).  CYP24A1 SNP rs3787554 (C > T) correlated with disease progression (p = 0.03) and CYP24A1 SNP rs2762939 (C > G) trended toward PR/SD (p = 0.08).  There was no association between calcitriol PK and CYP24A1 SNPs.  The authors concluded that the RP2D of calcitriol with docetaxel and cisplatin was 60 mcg/m(2) every 21 days.  Pre-specified end-point of 50 % confirmed RR was not met in the phase II study.

In a randomized, placebo-controlled, cross-over trial, Joergensen et al (2015) evaluated the effects of paricalcitol on markers of cardiovascular risk and kidney function in people with type 1 diabetes mellitus and diabetic nephropathy.  A total of 48 participants on stable renin angiotensin aldosterone system blockade and diuretics were assigned, in random order, to 12 weeks of paricalcitol and 12 weeks of placebo therapy, separated by a 4-week washout period.  Primary and secondary end-points were changes in plasma N-terminal probrain natriuretic peptide and urinary albumin excretion rate obtained before and after each intervention.  Glomerular filtration rates were estimated and measured (51 Cr-EDTA plasma clearance GFR) after each intervention.  The mean (SD) age of the participants was 57 (9) years, the baseline geometric mean (95 % CI) urinary albumin excretion rate was 148 (85 to 259) mg/24 hour, the mean (SD) HbA1c was 70 (9) mmol/mol [8.6 (3)%], the mean (SD) estimated GFR was 47 (15) ml/min/1.73 m2 and the mean 24-hour blood pressure was 135 (17)/74 (10) mmHg.  Compared with placebo therapy, vitamin D analog therapy had no significant effect on plasma N-terminal probrain natriuretic peptide concentration (p = 0.6), urinary albumin excretion rate was reduced by 18 % (p = 0.03 for comparison), estimated GFR was reduced by 5 ml/min/1.73 m2 (p < 0.001) and measured GFR was reduced by 1.5 ml/min/1.73 m2 (p = 0.2).  The authors concluded that paricalcitol therapy did not affect plasma N-terminal probrain natriuretic peptide concentration in people with type 1 diabetes and diabetic nephropathy; however, the urinary albumin excretion rate was significantly lowered.

Trillini et al (2015) noted that secondary hyperparathyroidism contributes to post-transplant CKD mineral and bone disorder.  Paricalcitol decreased serum PTH levels and proteinuria in patients with secondary hyperparathyroidism.  This single-center, prospective, randomized, cross-over, open-label study compared the effect of 6-month treatment with paricalcitol (1 μg/day for 3 months and then up-titrated to 2 µg/day if tolerated) or non-paricalcitol therapy on serum PTH levels (primary outcome), mineral metabolism, and proteinuria in 43 consenting recipients of renal transplants with secondary hyperparathyroidism.  Participants were randomized 1:1 according to a computer-generated sequence.  Compared with baseline, median (interquartile range) serum PTH levels significantly declined on paricalcitol from 115.6 (94.8 to 152.0) to 63.3 (52.0 to 79.7) pg/ml (p < 0.001) but not on non-paricalcitol therapy.  At 6 months, levels significantly differed between treatments (p< 0.001 by analysis of co-variance).  Serum bone-specific alkaline phosphatase and osteocalcin decreased on paricalcitol therapy only and significantly differed between treatments at 6 months (p < 0.001 for all comparisons).  At 6 months, urinary deoxypyridinoline-to-creatinine ratio and 24-hour proteinuria level decreased only on paricalcitol (p < 0.05).  Moreover, L3 and L4 vertebral mineral bone density, assessed by dual-energy x-ray absorption, significantly improved with paricalcitol at 6 months (p < 0.05 for both densities).  Paricalcitol was well-tolerated.  Overall, 6-month paricalcitol supplementation reduced PTH levels and proteinuria, attenuated bone remodeling and mineral loss, and reduced eGFR in renal transplant recipients with secondary hyperparathyroidism.  The authors concluded that long-term studies are needed to monitor directly measured GFR, ensure that the bone remodeling and mineral effects are sustained, and determine if the reduction in proteinuria improves renal and cardiovascular outcomes.

Note on documentation requirements:

Laboratory tests results (before initiation of therapy) should be documented in the member's medical record showing the medical necessity of the treatment.  The member's medical record should clearly document the need for the calcitriol or paricalcitol injection(s).  These records should be available upon request.

Glucocorticoid-Induced Osteoporosis

In open-label, randomized controlled study, Chen and colleagues (2015) evaluated the safety and effectiveness of calcitriol in the prevention and treatment of glucocorticoid-induced osteoporosis.  A total of 66 patients treated with glucocorticoids (GC) for primary nephrotic syndrome (NS) were randomly assigned to 3 groups.  Groups were designated as follows:
  1. calcitriol alone (n = 22),
  2. calcitriol plus calcium carbonate (n = 23), or
  3. calcium carbonate alone (n = 21). 

Serum markers of bone metabolism and bone mineral density (BMD) were tested at 3 different time-points: the initiation of GC treatment (baseline), 12 weeks, and 24 weeks after the initiation of treatment.  Levels of serum 25-hydroxy vitamin D, serum osteocalcin, and total serum collagen type N-terminal extension of the peptide were significantly decreased following GC therapy (p < 0.05).  β-collagen serum-specific sequences were significantly increased following GC therapy.  The above-mentioned changes were less dramatic in patients treated with calcitriol, although the differences were significant (p < 0.05).  Changes in serum levels of calcium, phosphorus, alkaline phosphatase, and PTH were not significant; 24 weeks after the initiation of treatment, BMD of the lumbar spine and femoral bone significantly decreased in all of 3 groups.  However, patients who received calcitriol had significantly higher BMD of the lumbar spine than patients who received calcium carbonate alone (calcitriol plus calcium carbonate versus calcium carbonate alone: 0.82 ± 0.19 g/cm2 versus 0.62 ± 0.23 g/cm2 p < 0.05; calcitriol versus calcium carbonate alone 0.805 ± 0.203 g/cm2 versus 0.615 ± 0.225 g/cm2 p < 0.05), respectively.  No serious adverse events were observed.  The authors concluded that calcitriol may be more effective than calcium carbonate in preventing and treating GC-induced osteoporosis in patients with NS.  These preliminary findings need to be validated by well-designed studies.

Sepsis

In a phase II clinical trial, Leaf et al (2014) examined if administration of 1calcitriol to critically ill patients with sepsis would have beneficial effects on markers of innate immunity, inflammation, and kidney injury.  These researchers performed a double-blind, randomized, placebo-controlled, physiologic study among 67 critically ill patients with severe sepsis or septic shock.  Patients were randomized to receive a single dose of calcitriol (2 μg intravenously) versus placebo.  The primary outcome was plasma cathelicidin protein levels assessed 24 hours after study drug administration.  Secondary outcomes included leukocyte cathelicidin mRNA expression, plasma cytokine levels (IL-10, IL-6, tumor necrosis factor-α, IL-1β, and IL-2), and urinary kidney injury markers.  Patients randomized to calcitriol (n = 36) versus placebo (n = 31) had similar plasma cathelicidin protein levels at 24 hours (p = 0.16).  Calcitriol-treated patients had higher cathelicidin (p = 0.04) and IL-10 (p = 0.03) mRNA expression than placebo-treated patients 24 hours after study drug administration.  Plasma cytokine levels (IL-10, IL-6, tumor necrosis factor-α, IL-1β, and IL-2) and urinary kidney injury markers were similar in calcitriol- versus placebo-treated patients (p > 0.05 for all comparisons).  Calcitriol had no effect on clinical outcomes nor were any adverse effects observed.  The authors concluded that calcitriol administration did not increase plasma cathelicidin protein levels in critically ill patients with sepsis and had mixed effects on other immunomodulatory markers.  They stated that additional phase II trials investigating the dose and timing of calcitriol as a therapeutic agent in specific sepsis phenotypes may be warranted.

Diabetic Nephropathy

Chokhandre and colleagues (2015) stated that nephropathy is one of the major complications of diabetes often leading to CKD.  Inflammation and oxidative stress are associated with pathogenesis of diabetic nephropathy (DN) and found to be regulated by nuclear receptors such as VDR.  Vitamin D and its analogs have been effectively used in patients with CKD.  These investigators summarized the available evidence on the role of vitamin D in DN.  Electronic databases (MEedline, Embase, and Cochrane Library) were searched for studies assessing the role of vitamin D or its analogs on kidney function in type 2 diabetic patients.  Studies evaluating kidney functions (urinary albumin/protein creatinine ratio, albuminuria and estimated GFR) were included and quality and risk of bias assessment performed.  Additionally effect on 25 (OH) vitamin D, calcium and HbA1c were evaluated.  The mean or its % change along with their standard deviation was used for reporting the results.  RevMan (V5.2) was used for data analysis.  A total of 6 studies included in this review evaluated the role of cholecalciferol, calcitriol and paricalcitol in patients with DN.  Study designs differed 3 randomized, 1 non-randomized and 2 uncontrolled trials) with varying degree of quality and risk of biases.  Vitamin D analogs showed significant improvement in kidney function in 2 randomized studies.  None of the studies reported significant incidences of hypercalcemia.  The authors concluded that vitamin D analogs showed significant improvement of kidney function in DN.  Moreover, they stated that randomized controlled trials (RCTs) with longer duration, comparing the effectiveness of vitamin D and its analogs are needed.

Pentylenetetrazol-Induced Seizures

Uyanıkgil and associates (2016) noted that vitamin D has various systemic effects on bone metabolism, modulation of the immune system, stabilization of the cell membrane, oxidative stress, inflammation, apoptosis, and various other hormones.  Differing from active vitamin D, paricalcitol is a relatively safe VDR agonist due to its relatively few side effects.  These researchers investigated the anti-convulsant effect of paricalcitol in convulsions induced by pentylenetetrazole (PTZ).  A total of 36 male Sprague-Dawley rats were divided randomly into 2 groups:
  1. 18 for EEG recording (PTZ 35 mg/kg), and
  2. 18 for behavioral studies (PTZ 70 mg/kg). 

Forty-five minutes before the PTZ injection, both groups of rats were given 5 and 10 μg/kg of paricalcitol i.p., respectively.  Racine convulsion scores, first myoclonic jerk time, spike percentages, and anti-oxidant status were evaluated in the groups.  The results showed that the Racine's Convulsion Scale (RCS) score significantly dropped in the paricalcitol-treated group, analysis of the first myoclonic jerk (FMJ) latencies demonstrated a significantly longer latency in the paricalcitol-applied group, and spike percentages at EEG recordings significantly decreased with paricalcitol.  Moreover, MDA levels were lower and SOD activity were higher in the 5 μg/kg paricalcitol group compared to the saline group; these results were more prominent in 10 μg/kg paricalcitol group.  The authors concluded that the findings of this study showed that paricalcitol has protective effects on PTZ-induced convulsions.  These preliminary findings of an animal study need to be validated in well-designed human studies.

Calcitriol for the Treatment of IgA Nephropathy

In a meta-analysis, Deng and colleagues (2017) evaluated the safety and effectiveness of calcitriol for treating patients with IgA nephropathy presenting as non-nephrotic range proteinuria using the related RCTs.  These investigators searched for RCTs of calcitriol for the treatment of IgA nephropathy in the CNKI, CBM, Cochrane Central Register of Controlled Trials, PubMed, and Embase databases.  The studies included in this meta-analysis were strictly determined according to the inclusion and exclusion criteria.  These researchers evaluated the quality of the included studies using the Jadad score sheet and performed the meta-analysis using RevMan software (version 5.30).  This meta-analysis, which included 7 RCTs totaling 310 Chinese participants, showed that calcitriol contributed to a decrease in proteinuria standard mean difference (SMD) -1.49, 95 % CI: -2.37 to -0.62; p = 0.0008).  No significant differences were observed in serum creatinine (SMD -0.13, 95 % CI: -0.53 to 0.27); p = 0.52), serum calcium (SMD 0.28, 95 % CI: -0.08 to 0.65); p = 0.13), or serum phosphorus (SMD 0.03, 95 % CI: -0.07 to 0.14; p = 0.57) levels.  All of the adverse reactions mentioned in these studies were mild.  The authors concluded that these findings indicated that calcitriol is a promising therapy to reduce proteinuria in patients with IgA nephropathy presenting as non-nephrotic range proteinuria, and it has only mild side effects.

Calcitriol for the Treatment of Atopic Dermatitis

Bothou and associates (2018) stated that atopic dermatitis (AD) is a chronic inflammatory disease affecting children and adolescence.  The traditional therapeutic options for AD, including emollients topically and immune modulatory agents systemically, focus on reducing skin inflammation and restoring the function of the epidermal barrier, are proven ineffective in many cases.  Several studies have linked vitamin D supplementation with either a decreased risk to develop AD or a clinical improvement of the symptoms of AD patients.  These investigators presented the case of a girl with severe AD who under adequate supplementation with cholecalciferol was treated with calcitriol and subsequently with paricalcitol.  She had significant improvement -- almost healing of her skin lesions within 2 months, a result sustained for more than 3 years now.  Because of hypercalciuria as a side effect from calcitriol therapy, treatment was continued with paricalcitol, a vitamin D analog used in SHPT in CKD.  Calcitriol therapy may be considered as a safe and effective therapeutic option for patients with severe AD, particularly for those with refractory AD, under monitoring for possible side effects.  The authors concluded that treatment with calcitriol/paricalcitol resolved hypercalciuria, was safe, and should be further investigated as an alternative treatment of AD and possibly other diseases of autoimmune origin.  They stated that RCTs in children are needed to prove the safety and  effectiveness of this therapeutic approach, especially to establish the optimal dosage and type of vitamin D administration.

Calcitriol for the Treatment of Solid tumors (e.g. Breast, Colon, Endometrium, Glioblastoma, Kidney, Ovary, and Pancreas)

Waheed and co-workers (2017) stated that they previously have demonstrated that progesterone and calcitriol synergistically inhibit growth of endometrial and ovarian cancer by enhancing apoptosis and causing cell cycle arrest.  Metastasis is the main reason of mortality in cancer patients.  Activation of ADP-ribosylation factor 6 (ARF6), neural precursor cell expressed developmentally downregulated 9 (NEDD9), and membrane-type-1 matrix metalloproteinase (MT1-MMP) have been implicated in promoting tumor growth and metastasis.  These researchers examined the effects of progesterone, calcitriol and progesterone-calcitriol combination on metastasis promoting proteins in endometrial cancer.  Expression of ARF6, NEDD9, and MT1-MMP was enhanced in advanced-stage endometrial tumors and in cancer cell lines compared to normal tissues and immortalized EM-E6/E7-TERT endometrial epithelial cells.  Knockdown of these proteins significantly inhibited the invasiveness of the cancer cells.  The expression levels of all 3 proteins was reduced with progesterone and progesterone-calcitriol combination treatment, whereas calcitriol alone showed no effect on their expression but moderately decreased MT1-MMP activity.  Fluorescence microscopy showed membrane expression of MT1-MMP in vehicle and calcitriol-treated endometrial cancer cells.  However, progesterone and calcitriol-progesterone combination treatment revealed MT1-MMP in the cytoplasm.  Furthermore, progesterone and calcitriol reduced the activity of MT1-MMP, MMP-9, and MMP-2.  In addition, invadopodia regulatory proteins were attenuated in both progesterone and progesterone-calcitriol combination treated cells as well as in MT1-MMP knockdown cells.  The authors concluded that targeting the aberrant MT1-MMP signaling with progesterone-calcitriol may be a novel approach to impede MT1-MMP mediated cancer dissemination and may have therapeutic benefits for endometrial cancer patients.

Shen and associates (2017) noted that calcitriol is a biologically active form of vitamin D and has a wide range of anti-cancer activity against various cancer cell lines.  However, the mechanism of calcitriol remains to be further studied.  These researchers examined the biological effect and epigenetic regulation of calcitriol on kidney cancer cells.  Calcitriol could significantly inhibit cell proliferation of kidney cancer cell lines 786-O (p < 0.05).  Calcitriol also induced cell apoptosis and senescence of 786-O and ACHN (p < 0.05).  Calcitriol can increase the expression of histone demethylase JMJD3 and cell senescence marker p16INK4A (p < 0.05).  Knockdown of JMJD3 decreased p16INK4A upregulation after calcitriol treatment (p < 0.05), and also reduced calcitriol-induced cell senescence (p < 0.05).  The authors concluded that the findings of this study revealed a new mechanism of anti-cancer activity of calcitriol by showing that histone demethylase JMJD3 induced by calcitriol increases p16INK4A expression and cell senescence; these results provided new strategy for treatment and prevention of kidney cancer.

Gilzad-Kohan and co-workers (2017) examined the effects of pre-treatment of capan-2 pancreatic cancer cells with calcitriol, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) or silibinin on the induction of 3 major efflux proteins and the main gemcitabine influx protein.  The influence of the pre-treatments on the net cellular uptake of gemcitabine, total ATPase activity, and cell death rate were also evaluated.  Capan-2 pancreatic cancer cells were pre-treated for 24 hours with calcitriol, BHT, BHA, or silibinin, followed by gemcitabine treatment.  The concentration of gemcitabine was quantified using ultra-performance liquid chromatography (UPLC).  Real-time polymerase chain reaction (RT-PCR) was utilized in order to examine the expression of the mRNAs.  The expression of the proteins was assessed using Western blotting.  Measurement of the ATPase activity was conducted utilizing a colorimetric method and viability of the cells was determined using a luminescent cell viability assay.  Protein expression studies showed that BHT, silibinin, and BHA increased expression of the efflux proteins and decreased the overall uptake of gemcitabine, whereas calcitriol significantly inhibited expression of the efflux proteins and increased gemcitabine uptake.  Expression of specific mRNAs correlated reasonably well with the levels of corresponding proteins.  Additionally, the expression of efflux proteins and ATPase activity were well-correlated, signifying that the induced efflux proteins were functionally active.  Moreover, pre-treatment with calcitriol resulted in a significant increase in cell death with gemcitabine treatment, whereas, BHA significantly reduced the cell death rate.  On the other hand, pre-treatment with BHT and silibinin had no significant effect on the cell death rate.  The authors concluded that re-treatment of the pancreatic cancer cells with calcitriol significantly increased gemcitabine cellular uptake and consequently decreased cell viability after treatment with gemcitabine, whereas BHA significantly reduced gemcitabine uptake and decreased cell death rate, which were at least partially attributed to the alteration of expression of efflux and influx proteins.

Nicolas and colleagues (2018) noted that clinical use of calcitriol as an anti-cancer agent is currently limited by the requirement of supra-physiological doses and associated hypercalcemia.  Nano-encapsulation of calcitriol is a strategy to overcome these drawbacks, allowing reduced administrated doses and/or frequency, while retaining the therapeutic activity towards cancer cells.  These investigators examined the impact of calcitriol encapsulation on its anti-proliferative activity and optimized formulation parameters with that respect.  Calcitriol-loaded polymeric nanoparticles with different polymer/oil ratios were prepared by the nano-precipitation method.  Nano-particles had similar mean size (200 nm) and EE (85 %) whereas their release profile strongly depended on formulation parameters.  Anti-proliferative and cytotoxic activities of formulated calcitriol were evaluated in-vitro using human breast adenocarcinoma cells (MCF-7) and showed that calcitriol-induced cell growth inhibition was closely related to its release kinetics.  For the most suitable formulation, a sustained cell growth inhibition was observed over 10 days compared to free form.  Advantages of calcitriol encapsulation and the role of formulation parameters on its biological activity in-vitro were demonstrated.  The authors concluded that selected nanoparticle formulation is a promising calcitriol delivery system ensuring a prolonged anti-cancer activity that could improve its therapeutic efficiency.

Schroll and co-workers (2018) stated that vitamin D deficiency is a common problem worldwide.  In particular, it is an issue in the Northern Hemisphere where ultra-violet B (UVB) radiation does not penetrate the atmosphere as readily.  There is a correlation between vitamin D deficiency and colorectal cancer incidence and mortality.  Furthermore, there is strong evidence that cancer of the ascending (right side) colon is different from cancer of the descending (left side) colon in terms of prognosis, tumor differentiation, and polyp type, as well as at the molecular level.  Right-side tumors have elevated Wnt signaling and are more likely to relapse, whereas left-side tumors have reduced expression of tumor suppressor genes.  These researchers sought to understand both the proteomic and metabolomic changes resulting from treatment of the active metabolite of vitamin D, calcitriol, in right-sided and left-sided colon cancer.  The results showed that left-sided colon cancer treated with calcitriol has a substantially greater number of changes in both the proteome and the metabolome than right-sided colon cancer.  These investigators found that calcitriol treatment in both right-sided and left-sided colon cancer caused a down-regulation of ribosomal protein L37 and protein S100A10.  Both of these proteins are heavily involved in tumorigenesis, suggesting a possible mechanism for the correlation between low vitamin D levels and colon cancer.

Ferronato and colleagues (2018) noted that glioblastoma multiforme (GBM) is the worst and most common brain tumor, characterized by high proliferation and invasion rates.  The current standard treatment is mainly based on chemo-radiotherapy and this approach has slightly improved patient survival.  Thus, novel strategies aimed at prolonging the survival and ensuring a better quality of life (QOL) are necessary.  In the present study, these investigators examined the anti-tumoral effect of the novel analog of calcitriol EM1 on GBM cells employing in-vitro, in-silico, and in-vivo assays.  In-vitro, these researchers demonstrated that EM1 treatment selectively decreased the viability of murine and human tumor cells without affecting that of normal human astrocytes.  The analysis of the mechanisms showed that EM1 produces cell cycle arrest in the T98G cell line, which is accompanied by an increase in p21, p27, p57 protein levels and a decrease in cyclin D1, p-Akt-S473, p-ERK1/2 and c-Jun expression.  Moreover, EM1 treatment also exerted in GBM cells anti-migratory effects and decreased their invasive capacity by a reduction in MMP-9 proteolytic activity.  In-silico, these investigators demonstrated that EM1 was able to bind to the vitamin D receptor with greater affinity than calcitriol.  Finally, the authors showed that EM1 treatment of nude mice administered at 50 ug/kg body weight during 21 days neither induced hypercalcemia nor toxicity effects.  The authors concluded that all the results indicated the potential of EM1 analog as a promising therapeutic alternative for GBM treatment.

Srivastava and associates (2018) stated that cancer stem cells (CSCs) represent the root of many solid tumors including ovarian cancer.  Eradication of CSCs represents a novel cancer therapeutic strategy.  Calcitriol is an active metabolite of vitamin D, functioning as a potent steroid hormone.  Calcitriol has shown anti-tumor effects in various cancers by regulating multiple signaling pathways.  It has been reported that calcitriol can regulate the properties of normal and CSCs.  However, the effect of calcitriol on the ovarian cancer growth and ovarian CSCs is still unclear.  By means of a mouse subcutaneous xenograft model generated with human ovarian cancer cells, these researchers have demonstrated that administration of calcitriol was able to strikingly delay the tumor growth.  Calcitriol treatment can also deplete the ovarian CSC population characterized by ALDH+ and CD44+CD117+; decrease their capacity to form sphere under the CSC culture condition, and reduce the frequency of tumor-initiating cells, as evaluated by in-vivo limiting dilution analysis.  Mechanistic investigation revealed that calcitriol depletes CSCs via the nuclear vitamin D receptor (VDR)-mediated inhibition of the Wnt pathway.  Furthermore, the activation of VDR pathway is more sensitive to calcitriol in ovarian CSCs than in non-CSCs, although the expression levels of VDR are comparable.  The authors concluded that these findings indicated that calcitriol was able to deplete the ovarian CSC population by inhibiting their Wnt signaling pathway, consequently, impeding the growth of xenograft tumors.

Paricalcitol for the Treatment of Renal Ischemia-Reperfusion Injury

Ersan and colleagues (2017) stated that ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI).  The inflammatory response that drives IRI involves up-regulation of matrix metalloproteinases (MMPs), which results in proteolytic degradation of renal microvascular matrix.  Evidence suggested a potential protective role of active vitamin D on ischemic injury by down-regulating MMPs.  In the present study, these researchers determined the expression and level of MMP-2 and MMP-9 in renal IRI model and the potential beneficial effect of paricalcitol on both level and expression of MMPs and tubular injury caused by IRI.  A total of 20 Wistar albino rats were divided into 3 groups:
  1. sham-operated,
  2. ischemia-reperfusion, and
  3. paricalcitol-pretreated. 

IRI model was induced by bilateral clamping of renal arteries for 45 minutes followed by 24 hours of reperfusion.  The analysis of serum creatinine and levels of MMPs were performed after 24 hours of IRI.  The effects of paricalcitol on the quantity and expression of MMP-2 and MMP-9 in renal tubular epithelial cells were investigated by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, respectively.  The pathological examinations were performed to score tubular damage by light microscopy.  Creatinine levels decreased in the paricalcitol group, although this was not proven to be significant.  Rats in the paricalcitol group showed significant decrease in both level and expression of MMPs and in tubular injury scores as compared to the IRI group.  The authors concluded that paricalcitol may attenuate renal tubular injury caused by IRI by decreasing both level and expression of MMPs.  Moreover, they stated that further studies are needed to examine the interplay between activated vitamin D and MMPs in AKI.

Paricalcitol for the Reduction of Graft Inflammation and Fibrosis in Kidney Transplant Recipients

Oblak and colleagues (2017) noted that paricalcitol decreases proteinuria and may reduce graft failure risk in kidney transplant recipients.  In a placebo-controlled, double-blind RCT, these researchers evaluated the effect of paricalcitol on renin-angiotensin system (RAS) activity as well as interleukin (IL)-6 and transforming growth factor (TGF)-β plasma concentrations as biomarkers of inflammation and fibrosis.  This trial enrolled a national cohort of kidney transplant recipients with urinary protein-to-creatinine ratio (UPCR) of greater than or equal to 20 mg/mM despite optimization of the RAS blockade.  Patients were randomly assigned to receive 24 weeks of treatment with 2 µg/day paricalcitol or placebo.  The primary end-point was the percent change in geometric mean UPCR.  In this secondary analysis, these investigators examined the effect of paricalcitol on plasma renin activity (PRA) and aldosterone levels as well as IL-6 and TGF-β plasma concentrations from baseline to last measurement during treatment.  Of the 168 patients with UPCR greater than or equal to  20 mg/mM who consented to undergoing randomization, 83 were allocated to paricalcitol and 85 to placebo.  Baseline patient demographics, clinical characteristics, PRA, and aldosterone levels were similar between groups.  Mean change in IL-6 was -29 % (from 2.53 to 2.02 pg/ml) in the paricalcitol group and 23 % (from 2.07 to 2.54 pg/ml) in the placebo group (p < 0.001).  Mean change in TGF-β was -12 % (from 8,011 to 6,935 pg/ml) in the paricalcitol group and 21 % (from 7,418 to 8,992 pg/ml) in the placebo group (p < 0.001).  The authors concluded that in kidney transplant recipients, the addition of 2 µg/day paricalcitol to RAS inhibition lowered IL-6 and TGF-β concentrations, which may be beneficial for reducing graft inflammation and fibrosis.

The authors stated that this study had several drawbacks:
  1. although this study included pre-specified secondary end-points, the paricalcitol trial was not primarily designed to evaluate changes in the levels of biomarkers as the result of paricalcitol treatment,
  2. several patients did not take maximum doses of RAS inhibitors, so the results might have varied in patients receiving different types or amounts of these drugs.  Also, when iPTH levels were suppressed less than 15 pg/ml or calcium levels were greater than 2.60 mM/L, the dose of paricalcitol was decreased.  While this is like usual clinical practice and reflects prudent care, it may have had an influence on the levels of biomarkers observed,
  3. surveillance graft biopsies were not performed, so the effect of paricalcitol on histologic markers of inflammation and fibrosis in the renal graft could not be assessed, and 
  4. although these researchers observed significant suppression of IL-6 and TGF-β, the duration of the study was not long enough to examine the clinical significance in terms of hard outcomes (e.g., incidence of rejection, doubling of serum creatinine, and graft failure).

In an exploratory study, Donate-Correa and associates (2017) evaluated the anti-inflammatory profile of paricalcitol in kidney-transplant recipients.  A total of 31 kidney transplant recipients with secondary hyperparathyroidism (SHPT) completed 3 months of treatment with oral paricalcitol (1 μg/day).  Serum concentrations and gene expression levels of inflammatory cytokines in peripheral blood mononuclear cells were analyzed at the beginning and end of the study.  Paricalcitol significantly decreased PTH levels with no changes in calcium and phosphorous.  It also reduced serum concentrations of IL-6 and tumor necrosis factor-alpha (TNF-α) by 29 % (p < 0.05) and 9.5 % (p < 0.05) compared to baseline, respectively.  Furthermore, gene expression levels of IL-6 and TNF-α in peripheral blood mononuclear cells decreased by 14.1 % (p < 0.001) and 34.1 % (p < 0.001), respectively.  The ratios between pro-inflammatory cytokines (TNF-α and IL-6) and anti-inflammatory cytokines (IL-10), both regarding serum concentrations and gene expression, also experienced a significant reduction.  The authors concluded that paricalcitol administration to kidney transplant recipients has been found to have beneficial effects on inflammation, which may be associated with potential clinical benefits.

Paricalcitol for Reduction of Proteinuria in Kidney Transplant Recipients

Oblak and colleagues (2018) noted that proteinuria after kidney transplantation is accompanied by an increased risk of graft failure.  In a single-center, placebo-controlled, double-blind clinical trial, these researchers examined if paricalcitol might reduce proteinuria.  Patients with urinary protein-to-creatinine ratio (UPCR) greater than or equal to 20 mg/mmol despite optimization of the renin-angiotensin-aldosterone system (RAAS) blockade were randomly assigned to receive 24 weeks' treatment with 2 μg/day paricalcitol or placebo.  Primary end-point was change in UPCR, and main secondary end-points were change in urinary albumin-to-creatinine ratio (UACR) and 24-hour proteinuria.  Analysis was by intention-to-treat.  A total of 168 patients undergo randomization, and 83 were allocated to paricalcitol, and 85 to placebo.  Compared with baseline, UPCR declined in the paricalcitol group (-39 %, 95 % CI: -45 to -31); but not in the placebo group (21 %, 95 % CI: 9 to 35), with a between group difference of -49 % (95 % CI: -57 to -41; p < 0.001).  UACR and 24-hour proteinuria decreased only on paricalcitol therapy and significantly differed between groups at end-of-treatment (p < 0.001).  Paricalcitol was well-tolerated but incidence of mild hypercalcemia was higher than in placebo.  The authors concluded that addition of 2 μg/day paricalcitol lowered residual proteinuria in kidney transplant recipients.  Moreover, they stated that long-term studies are needed to determine if the reduction in proteinuria improves transplant outcomes.

Etelcalcetide for the Treatment of Secondary Hyperparathyroidism

Block and colleagues (2017a) noted that SHPT contributes to extra-skeletal complications in chronic kidney disease (CKD).  These researchers evaluated the effect of the intravenous (IV) calcimimetic etelcalcetide on serum PTH concentrations in patients receiving hemodialysis.  Two parallel, phase-III, randomized, placebo-controlled trials were conducted in 1,023 patients receiving hemodialysis with moderate-to-severe SHPT.  Trial A was conducted in 508 patients at 111 sites in the US, Canada, Europe, Israel, Russia, and Australia from March 12, 2013 to June 12, 2014; trial B was conducted in 515 patients at 97 sites in the same countries from March 12, 2013 to May 12, 2014.  Interventions: were IV administration of etelcalcetide (n = 503) or placebo (n = 513) after each hemodialysis session for 26 weeks.  The primary effectiveness end-point was the proportion of patients achieving greater than 30 % reduction from baseline in mean PTH during weeks 20 to 27.  A secondary effectiveness end-point was the proportion of patients achieving mean PTH of 300 pg/ml or lower.  The mean age of the 1,023 patients was 58.2 (SD, 14.4) years and 60.4 % were men.  Mean PTH concentrations at baseline and during weeks 20 to 27 were 849 and 384 pg/ml versus 820 and 897 pg/ml in the etelcalcetide and placebo groups, respectively, in trial A; corresponding values were 845 and 363 pg/ml versus 852 and 960 pg/ml in trial B.  Patients randomized to etelcalcetide were significantly more likely to achieve the primary effectiveness end-point: in trial A, 188 of 254 (74.0 %) versus 21 of 254 (8.3 %; p < 0.001), for a difference in proportions of 65.7 % (95 % CI: 59.4 % to 72.1 %) and in trial B, 192 of 255 (75.3 %) versus 25 of 260 (9.6 %; p < 0.001), for a difference in proportions of 65.7 % (95 % CI: 59.3 % to 72.1 %).  Patients randomized to etelcalcetide were significantly more likely to achieve a PTH level of 300 pg/ml or lower: in trial A, 126 of 254 (49.6 %) versus 13 of 254 (5.1 %; p < 0.001), for a difference in proportions of 44.5 % (95 % CI: 37.8 % to 51.2 %) and in trial B, 136 of 255 (53.3 %) versus 12 of 260 (4.6 %; p < 0.001), for a difference in proportions of 48.7 % (95 % CI: 42.1 % to 55.4 %).  In trials A and B, respectively, patients receiving etelcalcetide had more muscle spasms (12.0 % and 11.1 % versus 7.1 % and 6.2 % with placebo), nausea (12.4 % and 9.1 % versus 5.1 % and 7.3 %), and vomiting (10.4 % and 7.5 % versus 7.1 % and 3.1 %).  The authors concluded that among patients receiving hemodialysis with moderate-to-severe SHPT, the use of etelcalcetide compared with placebo resulted in greater reduction in serum PTH over 26 weeks.  Moreover, they stated that further studies are needed to assess clinical outcomes as well as longer-term safety and effectiveness.

Block and associates (2017b) stated that SHPT contributes to extra-skeletal calcification and is associated with all-cause and cardiovascular mortality.  Control is suboptimal in the majority of patients receiving hemodialysis.  An intravenously administered calcimimetic could improve adherence and reduce adverse gastro-intestinal (GI) effects.  In a randomized, double-blind, double-dummy active clinical trial, these investigators evaluated the safety and effectiveness of the IV calcimimetic etelcalcetide and the oral calcimimetic cinacalcet.  A study was conducted comparing IV etelcalcetide versus oral placebo and oral cinacalcet versus IV placebo in 683 patients receiving hemodialysis with serum PTH concentrations higher than 500 pg/ml on active therapy at 164 sites in the US, Canada, Europe, Russia, and New Zealand.  Patients were enrolled from August 2013 to May 2014, with end of follow-up in January 2015.  Interventions were etelcalcetide intravenously and oral placebo (n = 340) or oral cinacalcet and IV placebo (n = 343) for 26 weeks.  The IV study drug was administered 3 times weekly with hemodialysis; the oral study drug was administered daily.  The primary effectiveness end-point was non-inferiority of etelcalcetide at achieving more than a 30 % reduction from baseline in mean pre-dialysis PTH concentrations during weeks 20 to 27 (non-inferiority margin, 12.0 %).  Secondary end-points included superiority in achieving biochemical end-points (greater than 50 % and greater than 30 % reduction in PTH) and self-reported nausea or vomiting.  The mean (SD) age of the trial participants was 54.7 (14.1) years and 56.2 % were men.  Etelcalcetide was non-inferior to cinacalcet on the primary end-point.  The estimated difference in proportions of patients achieving reduction in PTH concentrations of more than 30 % between the 198 of 343 patients (57.7 %) randomized to receive cinacalcet and the 232 of 340 patients (68.2 %) randomized to receive etelcalcetide was -10.5 % (95 % CI: -17.5 % to -3.5 %, p for non-inferiority, < 0.001; p for superiority, 0.004); 178 patients (52.4 %) randomized to etelcalcetide achieved more than 50 % reduction in PTH concentrations compared with 138 patients (40.2 %) randomized to cinacalcet (p = 0.001; difference in proportions, 12.2 %; 95 % CI: 4.7 % to 19.5 %).  The most common adverse effect was decreased blood calcium (68.9 % versus 59.8 %).  The authors concluded that among patients receiving hemodialysis with moderate-to-severe SHPT, the use of etelcalcetide was not inferior to cinacalcet in reducing serum PTH concentrations over 26 weeks; it also met superiority criteria.  They stated that further studies are needed to evaluate clinical outcomes as well as longer-term safety and effectiveness.

Shigematsu and co-workers (2017) noted that SHPT is a serious major complication in hemodialysis patients with CKD.  Long-term maintenance of serum phosphate, calcium, and PTH levels in appropriate ranges in these patients is a major challenge.  In a multi-center, open-label study, these investigators examined the safety and effectiveness of long-term treatment with etelcalcetide, a novel intravenous calcimimetic, in Japanese SHPT patients on long-term hemodialysis.  A total of 191 hemodialysis patients with serum intact PTH (iPTH) greater than 240 pg/ml were enrolled.  Etelcalcetide was administered thrice-weekly for 52 weeks, with an initial dose of 5 mg and flexibility to adjust the dose between 2.5 and 15 mg and to adjust the dosing of concomitant medications for SHPT.  The effectiveness end-point was the proportion of patients with serum iPTH decreased to the target range (60 to 240 pg/ml).  Serum iPTH levels decreased immediately after etelcalcetide was started.  At the end of the study, 87.5 % (95 % CI: 81.4 to 92.2; 140/160 patients) of patients achieved target serum iPTH levels, with control of serum calcium and phosphate levels.  Adverse events (AEs), mostly mild-to-moderate, were reported by 96.8 % of patients and led to study discontinuation in 7.4 % of patients.  Nausea, vomiting, and symptomatic hypocalcemia were found in 4.7, 9.5, and 1.1 %, with 0.5, 1.1, and 1.1 % considered treatment-related.  The authors concluded that etelcalcetide effectively maintained serum iPTH, calcium, and phosphate levels in appropriate ranges with concomitant medications for SHPT for 52 weeks in Japanese hemodialysis patients, and was safe and well-tolerated.

On February 7, 2017, the Food and Drug Administration (FDA) approved etelcalcetide (Parsabiv) for SHPT in adult patients with CKD on hemodialysis.

Etelcalcetide for Diabetic Patients Undergoing Hemodialysis

Ye and co-workers (2018) stated that etelcalcetide is the first IV calcimimetic agent authorized for the treatment of SHPT in patients undergoing hemodialysis in Europe, the US, and Japan.  The relationship between SHPT and diabetes resides on complex, bi-directional effects and largely unknown homeostatic mechanisms.  Although 30 % or more patients with end-stage renal disease (ESRD) are diabetics and about the same percentage of those patients suffer from SHPT associated with hemodialysis, no data on the specificities of the use of etelcalcetide in such patients are available yet.  Regarding pharmacokinetic interactions, etelcalcetide may compete with oral hypoglycemics recommended for use in patients undergoing hemodialysis and insulins detemir and degludec, causing unexpected hypocalcemia or hypoglycemia.  More importantly, hypocalcemia, a common side effect of etelcalcetide, may cause decompensation of pre-existing cardiac insufficiency in diabetic patients or worsen dialysis-related hypotension and lead to hypotension-related cardiac events, such as myocardial ischemia.  In diabetic patients, hypocalcemia may lead to dangerous ventricular arrhythmias, as both insulin-related hypoglycemia and hemodialysis prolong QT interval.  Patients with diabetes, therefore, should be strictly monitored for hypocalcemia and associated effects.  Due to an altered parahormone activity in this patient group, plasma calcium should be the preferred indicator of etelcalcetide effects.  The authors concluded that until clinical data refute the current theoretical concerns, the clinicians should be cautious when using this calcimimetic in patients with diabetes; and they should avoid the use of oral hypoglycemic agents in combination with etelcalcetide and strictly monitor plasma levels and histomorphometric parameters of diabetic patients, at the same time surveilling them for cardiovascular events.

Appendix

Dosage for Calcijex

The FDA recommended initial dose of Calcijex (calcitriol), depending on the severity of the hypocalcemia and/or secondary hyperparathyroidism, is 1 meg (0.02 meg/kg) to 2 meg administered intravenously 3 times weekly, approximately every other day.  Doses as small as 0.5 meg and as large as 4 meg 3 times weekly have been used as an initial dose.  If a satisfactory response is not observed, the dose may be increased by 0.5 to 1 meg at 2 to 4 week intervals.  During this titration period, serum calcium and phosphorus levels should be obtained at least twice-weekly.  If hypercalcemia or a serum calcium times phosphate product greater than 70 is noted, the drug should be immediately discontinued until these parameters are appropriate.  Then, the Calcijex dose should be re-initiated at a lower dose.  Doses may need to be reduced as the PTH levels decrease in response to the therapy.  Thus, incremental dosing must be individualized and commensurate with PTH, serum calcium and phosphorus levels. 

Dosage for Zemplar

Initial dose: 0.04 to 0.1 mcg/kg (2.8 to 7 mcg), injected as a bolus dose through a hemodialysis vascular access port at any time during dialysis.

Dosage for Parsabiv

Serum levels of phosphate should be maintained between 3.5 and 5.5 mg/dL (1.13 to 1.78 mmol/L)

Ensure corrected serum calcium is at or above the lower limit of normal (≥8.3mg/dL) prior to initiation, dose increase, or re-initiation.

The recommended starting dose is 5 mg administered by intravenous bolus injection 3 times/week at the end of hemodialysis treatment.

The maintenance dose is individualized and determined by titration based on parathyroid hormone (PTH) and corrected serum calcium response.  The dose range is 2.5 to 15 mg 3 times/week.

The dose may be increased in 2.5 mg or 5 mg increments no more frequently than every 4 weeks.

Measure serum calcium within 1 week after initiation or dose adjustment and every 4 weeks for maintenance.

Measure PTH after 4 weeks from initiation or dose adjustment.

Decrease or temporarily discontinue Parsabiv, in individuals with PTH levels below the target range of 150 - 300 pg/ml..|

Consider decreasing or temporarily discontinuing Parsabiv or use concomitant therapies to increase corrected serum calcium in patients with a corrected serum calcium below the lower limit of normal but at or above 7.5 mg/dL without symptoms of hypocalcemia.

Stop Parsabiv and treat hypocalcemia if the corrected serum calcium falls below 7.5 mg/dL or patients report symptoms of hypocalcemia. Parsabiv may be re-initiated when corrected calcium level is at or above the lower limit of normal prior to initiation (≥8.3mg/dL).


Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

Other CPT codes related to the CPB:

82310 - 82331 Calcium
83970 Parathormone (parathyroid hormone)
84100 Phosphorus inorganic (phosphate)
96372 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
96379 Unlisted therapeutic, prophylactic, or diagnostic intravenous or intra-arterial injection or infusion

Calcitriol:

HCPCS codes covered if selection criteria are met:

J0636 Injection, calcitriol, 0.1 mcg

Other HCPCS codes related to the CPB:

J1270 Injection, doxercalciferol, 1 mcg

ICD-10 codes covered if selection criteria are met:

E83.51 Hypocalcemia
N18.6 End stage renal disease
N25.81 Secondary hyperparathyroidism of renal origin
Z99.2 Dependence on renal dialysis

ICD-10 codes not covered for indications listed in the CPB:

A40.0 - A41.9 Sepsis
C00.0 - D09.9 Malignant neoplasm
E08.21, E09.21, E10.21, E11.21, E13.21 Diabetes mellitus with diabetic nephropathy
E84.0 - E84.9 Cystic fibrosis
G35 Multiple sclerosis
L20.0 - L20.9 Atopic dermatitis
M81.8 Other osteoporosis without current pathological fracture [glucocorticoid – induced]
N08 Glomerular disorders in diseases classified elsewhere
Z94.0 Kidney transplant status

Paricalcitol:

HCPCS codes covered if selection criteria are met:

J2501 Injection, paricalcitol, 1 mcg

Other HCPCS codes related to the CPB:

J1270 Injection, doxercalciferol, 1 mcg

ICD-10 codes covered if selection criteria are met:

E83.51 Hypocalcemia
N18.6 End stage renal disease

ICD-10 codes not covered for indications listed in the CPB:

C25.0 - C25.9 Malignant neoplasm of pancreas
D01.7 Carcinoma in situ of other specified digestive organs
D46.0 - D46.9 Myelodysplastic syndromes
D89.810 - D89.813 Graft-versus-host disease [graft inflammation in kidney transplant recipients]
E08.21, E09.21, E10.21, E11.21, E13.21 Diabetes mellitus with diabetic nephropathy
G40.501 Epileptic seizures related to external causes, not intractable, with status epilepticus [not covered for pentylenetetrazole-induced seizures]
G40.509 Epileptic seizures related to external causes, not intractable, without status epilepticus [not covered for pentylenetetrazole-induced seizures]
I10 - I16.2 Hypertensive heart disease
I42.1 - I42.2 Hypertrophic cardiomyopathy
I50.1 - I50.9 Heart failure
I73.0 - I73.9 Other peripheral vascular disease
L20.0 - L20.9 Atopic dermatitis
N08 Glomerular disorders in diseases classified elsewhere
N28.0 Ischemia and infarction of kidney
R80.0 - R80.9 Proteinuria
T50.7X5 Adverse effect of analeptics and opioid receptor antagonists [not covered for pentylenetetrazole-induced seizures]
T86.10 - T86.19 Complications of kidney transplant [post-transplantation nephropathy] [fibrosis in kidney transplant recipients]
Z94.0 Kidney transplant status

Etelcalcetide:

HCPCS codes covered if selection criteria are met:

J0604 Cinacalcet, oral, 1 mg, (ESRD on dialysis) [not covered for concurrent use with etelcalcetide]
J0606 Injection, etelcalcetide, 0.1 mg

ICD-10 codes covered if selection criteria are met:

N18.6 End stage renal disease
N25.81 Secondary hyperparathyroidism of renal origin
Z99.2 Dependence on renal dialysis

ICD-10 codes not covered for indications listed in the CPB:

C75.0 Malignant neoplasm of parathyroid gland
D35.1 Benign neoplasm of parathyroid gland
E21.0 Primary hyperparathyroidism
N02.1 Recurrent and persistent hematuria with focal and segmental glomerular lesions
N02.2 Recurrent and persistent hematuria with diffuse membranous glomerulonephritis
N02.3 Recurrent and persistent hematuria with diffuse mesangial proliferative glomerulonephritis
N02.5 Recurrent and persistent hematuria with diffuse mesangiocapillary glomerulonephritis
N02.8 Recurrent and persistent hematuria with other morphologic changes
N02.9 Recurrent and persistent hematuria with unspecified morphologic changes
N18.1 - N18.5 Chronic kidney disease (CKD)

The above policy is based on the following references:

  1. Llach F, Yudd M. Pathogenic, clinical, and therapeutic aspects of secondary hyperparathyroidism in chronic renal failure. Am J Kidney Dis. 1998;32(2 Suppl 2):S3-S12.
  2. Dabbagh S. Renal osteodystrophy. Curr Opin Pediatr. 1998;10(2):190-196.
  3. Felsenfeld AJ. Considerations for the treatment of secondary hyperparathyroidism in renal failure. J Am Soc Nephrology. 1997;8(6):993-1004.
  4. Fukazawa M, Kuroki K. Pathogenesis and medical treatment of secondary hyperparathyroidism. Semen Surg Oncol. 1997;13(2):73-77.
  5. Tominaga Y, Johansson H, Johansson H, et al. Secondary hyperparathyroidism: Pathophysiology, histopathology, and medical and surgical management. Surg Today. 1997;27(9):787-792.
  6. Fernandez E, Llach F. Guidelines for dosing of intravenous calcitriol in dialysis patients with hyperparathyroidism. Nephrol Dial Transplant. 1996;11(Suppl 3):96-101.
  7. Daisley-Kydd RE, Mason NA. Calcitriol in the management of secondary hyperparathyroidism of renal failure. Pharmacotherapy. 1996;16(4):619-630.
  8. Martin K, Gonzalez E, Gellens M, et al. 19-nor-1-alpha-25-dihydroxyvitamin D2 (Paricalcitol) safely and effectively reduces the levels of intact parathyroid hormone in patients on hemodialysis. J Am Soc Nephrol. 1998;9(8):1427-1432.
  9. Andress DL. Intravenous versus oral vitamin d therapy in dialysis patients: What is the question? Am J Kidney Dis. 2001;38(5 Suppl 5):S41-S44.
  10. Martin KJ, Gonzalez EA. Vitamin D analogues for the management of secondary hyperparathyroidism. Am J Kidney Dis. 2001;38(5 Suppl 5):S34-S40.
  11. Sanchez CP. Prevention and treatment of renal osteodystrophy in children with chronic renal insufficiency and end-stage renal disease. Semin Nephrol. 2001;21(5):441-450.
  12. Brown AJ. Therapeutic uses of vitamin D analogues. Am J Kidney Dis. 2001;38(5 Suppl 5):S3-S19.
  13. Sprague SM, Lerma E, McCormmick D, et al. Suppression of parathyroid hormone secretion in hemodialysis patients: Comparison of paricalcitol with calcitriol. Am J Kidney Dis. 2001;38(5 Suppl 5):S51-S56.
  14. Slatopolsky E, Brown AJ. Vitamin d analogs for the treatment of secondary hyperparathyroidism. Blood Purif. 2002;20(1):109-112.
  15. Turk U, Akbulut M, Yildiz A, et al. Comparative effect of oral pulse and intravenous calcitriol treatment in hemodialysis patients: The effect on serum IL-1 and IL-6 levels and bone mineral density. Nephron. 2002;90(2):188-194.
  16. Morosetti M, Jankovic L, Cetani F, et al. High doses of intravenous calcitriol in the treatment of severe secondary hyperparathyroidism. J Nephrol. 2004;17(1):95-100.
  17. Baskin E, Ozen S, Karcaaltincaba M, et al. Beneficial role of intravenous calcitriol on bone mineral density in children with severe secondary hyperparathyroidism. Int Urol Nephrol. 2004;36(1):113-118.
  18. Beer TM, Myrthue A, Eilers KM. Rationale for the development and current status of calcitriol in androgen-independent prostate cancer. World J Urol. 2005;23(1):28-32.
  19. Tartaglia F, Giuliani A, Sgueglia M, et al. Randomized study on oral administration of calcitriol to prevent symptomatic hypocalcemia after total thyroidectomy. Am J Surg. 2005;190(3):424-429.
  20. Robinson DM, Scott LJ. Paricalcitol: A review of its use in the management of secondary hyperparathyroidism. Drugs. 2005;65(4):559-576.
  21. Koeffler HP, Aslanian N, O'Kelly J. Vitamin D(2) analog (Paricalcitol; Zemplar) for treatment of myelodysplastic syndrome. Leuk Res. 2005;29(11):1259-1262.
  22. Rosery H, Bergemann R, Marx SE, et al. Health-economic comparison of paricalcitol, calcitriol and alfacalcidol for the treatment of secondary hyperparathyroidism during haemodialysis. Clin Drug Investig. 2006;26(11):629-638.
  23. Johnson CS, Muindi JR, Hershberger PA, Trump DL. The antitumor efficacy of calcitriol: Preclinical studies. Anticancer Res. 2006;26(4A):2543-2549.
  24. Beer TM, Myrthue A. Calcitriol in the treatment of prostate cancer. Anticancer Res. 2006;26(4A):2647-2651.
  25. Greenbaum LA, Benador N, Goldstein SL, et al. Intravenous paricalcitol for treatment of secondary hyperparathyroidism in children on hemodialysis. Am J Kidney Dis. 2007;49(6):814-823.
  26. Sowery RD, So AI, Gleave ME. Therapeutic options in advanced prostate cancer: Present and future. Curr Urol Rep. 2007;8(1):53-59. 
  27. Cozzolino M, Galassi A, Gallieni M, Brancaccio D. Pathogenesis and treatment of secondary hyperparathyroidism in dialysis patients: The role of paricalcitol. Curr Vasc Pharmacol. 2008;6(2):148-153.
  28. Tu SM, Lin SH. Current trials using bone-targeting agents in prostate cancer. Cancer J. 2008;14(1):35-39.
  29. Niino M, Fukazawa T, Kikuchi S, Sasaki H. Therapeutic potential of vitamin D for multiple sclerosis. Curr Med Chem. 2008;15(5):499-505.
  30. Smolders J, Damoiseaux J, Menheere P, Hupperts R. Vitamin D as an immune modulator in multiple sclerosis, a review. J Neuroimmunol. 2008;194(1-2):7-17.
  31. Abdul Gafor AH, Saidin R, Loo CY, et al. Intravenous calcitriol versus paricalcitol in haemodialysis patients with severe secondary hyperparathyroidism. Nephrology (Carlton). 2009;14(5):488-492.
  32. Haiyang Zhou, Chenggang Xu. Comparison of intermittent intravenous and oral calcitriol in the treatment of secondary hyperparathyroidism in chronic hemodialysis patients: A meta-analysis of randomized controlled trials. Clin Nephrol. 2009;71(3):276-285.
  33. Muindi JR, Johnson CS, Trump DL, et al. A phase I and pharmacokinetics study of intravenous calcitriol in combination with oral dexamethasone and gefitinib in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2009;65(1):33-40.
  34. Chiang KC, Chen TC. Vitamin D for the prevention and treatment of pancreatic cancer. World J Gastroenterol. 2009;15(27):3349-3354.
  35. de Zeeuw D, Agarwal R, Amdahl M, et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): A randomised controlled trial. Lancet. 2010;376(9752):1543-1551.
  36. Soloway B. Vitamin D receptor activation reduces albuminuria in patients with diabetic nephropathy. Summary and Comment. JWatch Gen Med. 2010 Nov 24.
  37. Chadha MK, Tian L, Mashtare T, et al. Phase 2 trial of weekly intravenous 1,25 dihydroxy cholecalciferol (calcitriol) in combination with dexamethasone for castration-resistant prostate cancer. Cancer. 2010;116(9):2132-2139.
  38. Nuijten M, Andress DL, Marx SE, et al. Cost Effectiveness of Paricalcitol versus a non-selective vitamin D receptor activator for secondary hyperparathyroidism in the UK: A chronic kidney disease markov model. Clin Drug Investig. 2010;30(8):545-557.
  39. Reis FN. The unsolved cyclosporine-induced kidney injury: Is paricalcitol a feasible new renoprotective option? Kidney Int. 2010;77(12):1055-1057.
  40. Henderson RC, Lester G. Vitamin D levels in children with cystic fibrosis. South Med J. 1997;90(4):378-383.
  41. Ferguson JH, Chang AB. Vitamin D supplementation for cystic fibrosis. Cochrane Database Syst Rev. 2009;(4):CD007298.
  42. Tamez H, Zoccali C, Packham D, et al. Vitamin D reduces left atrial volume in patients with left ventricular hypertrophy and chronic kidney disease. Am Heart J. 2012;164(6):902-909.
  43. Thadhani R, Appelbaum E, Pritchett Y, et al. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: The PRIMO randomized controlled trial. JAMA. 2012;307(7):674-684.
  44. Gonzalez-Parra E, Rojas-Rivera J, Tunon J, et al. Vitamin D receptor activation and cardiovascular disease. Nephrol Dial Transplant. 2012;27 Suppl 4:iv17-iv21.
  45. Cozzolino M, Stucchi A, Rizzo MA, et al. Vitamin D receptor activation and prevention of arterial ageing. Nutr Metab Cardiovasc Dis. 2012;22(7):547-552.
  46. Ramnath N, Daignault-Newton S, Dy GK, et al. A phase I/II pharmacokinetic and pharmacogenomic study of calcitriol in combination with cisplatin and docetaxel in advanced non-small-cell lung cancer. Cancer Chemother Pharmacol. 2013;71(5):1173-1182.
  47. Coyne DW, Goldberg S, Faber M, et al. A randomized multicenter trial of paricalcitol versus calcitriol for secondary hyperparathyroidism in stages 3-4 CKD. Clin J Am Soc Nephrol. 2014;9(9):1620-1626.
  48. Joergensen C, Tarnow L, Goetze JP, Rossing P. Vitamin D analogue therapy, cardiovascular risk and kidney function in people with Type 1 diabetes mellitus and diabetic nephropathy: A randomized trial. Diabet Med. 2015;32(3):374-381.
  49. Trillini M, Cortinovis M, Ruggenenti P, et al. Paricalcitol for secondary hyperparathyroidism in renal transplantation. J Am Soc Nephrol. 2015;26(5):1205-1214.
  50. Leaf DE, Raed A, Donnino MW, et al. Randomized controlled trial of calcitriol in severe sepsis. Am J Respir Crit Care Med. 2014;190(5):533-41.
  51. Chokhandre MK, Mahmoud MI, Hakami T, et al. Vitamin D & its analogues in type 2 diabetic nephropathy: A systematic review. J Diabetes Metab Disord. 2015;14:58.
  52. Chen Y, Wan JX, Jiang DW, et al. Efficacy of calcitriol in treating glucocorticoidinduced osteoporosis in patients with nephrotic syndrome: An open-label, randomized controlled study. Clin Nephrol. 2015;84(11):262-269.
  53. Uyanıkgil Y, Solmaz V, Cavusoglu T, et al. Inhibitor effect of paricalcitol in rat model of pentylenetetrazol-induced seizures. Naunyn Schmiedebergs Arch Pharmacol. 2016;389(10):1117-1122.
  54. Donate-Correa J, Henriquez-Palop F, Martín-Nunez E, et al. Effect of paricalcitol on FGF-23 and Klotho in kidney transplant recipients. Transplantation. 2016;100(11):2432-2438.
  55. Deng J, Zheng X, Xie H, Chen L. Calcitriol in the treatment of IgA nephropathy with non-nephrotic range proteinuria: A meta-analysis of randomized controlled trials. Clin Nephrol. 2017;87(1):21-27.
  56. Ersan S, Celik A, Tanrisev M, et al. Pretreatment with paricalcitol attenuates level and expression of matrix metalloproteinases in a rat model of renal ischemia-reperfusion injury. Clin Nephrol. 2017;88(11):231-238.
  57. Oblak M, Mlinsek G, Kandus A, et al. Effects of paricalcitol on biomarkers of inflammation and fibrosis in kidney transplant recipients: Results of a randomized controlled trial. Clin Nephrol. 2017 Supplement 1;88(13):119-125.
  58. Block GA, Bushinsky DA, Cunningham J, et al. Effect of etelcalcetide vs placebo on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism: Two randomized clinical trials. JAMA. 2017a;317(2):146-155.
  59. Block GA, Bushinsky DA, Cheng S, et al. Effect of etelcalcetide vs cinacalcet on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism: A randomized clinical trial. JAMA. 2017b;317(2):156-164.
  60. Food and Drug Administration. Parsabiv (etelcalcetide) Injection. FDA: Silver spring, MD. February 7, 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208325Orig1s000TOC.cfm. Accessed October 24, 2017.
  61. KAI Pharmaceuticals, Inc. Parsabiv (etelcalcetide) injection, for intravenous use. Prescribing Information. Thousand Oaks, CA: KAI Pharmaceuticals; revised February 2017.
  62. Donate-Correa J, Henríquez-Palop F, Martín-Nunez E, et al. Anti-inflammatory profile of paricalcitol in kidney transplant recipients. Nefrologia. 2017;37(6):622-629.
  63. Shigematsu T, Fukagawa M, Yokoyama K, et al; ONO-5163 Study Group. Long-term effects of etelcalcetide as intravenous calcimimetic therapy in hemodialysis patients with secondary hyperparathyroidism. Clin Exp Nephrol. 2018;22(2):426-436.
  64. Quarles LD, Berkoben M. Management of secondary hyperparathyroidism in dialysis patients. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2017.
  65. Kidney Disease Improving Global Outcomes (KDIGO). KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD-MBD). Available at: http://kdigo.org/wp-content/uploads/2017/02/2017-KDIGO-CKD-MBD-GL-Update.pdf. Accessed March 13, 2018.
  66. Ketteler M, Block GA, Evenepoel P, et al. Executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update: what's changed and why it matters. Kidney Int. 2017;92(1):26-36.
  67. Waheed S, Dorjbal B, Hamilton CA, et al. Progesterone and calcitriol reduce invasive potential of endometrial cancer cells by targeting ARF6, NEDD9 and MT1-MMP. Oncotarget. 2017;8(69):113583-113597.
  68. Shen Y, Yu D, Qi P, et al. Calcitriol induces cell senescence of kidney cancer through JMJD3 mediated histone demethylation. Oncotarget. 2017;8(59):100187-100195.
  69. Gilzad-Kohan H, Sani S, Boroujerdi M. Calcitriol reverses induced expression of efflux proteins and potentiates cytotoxic activity of gemcitabine in capan-2 pancreatic cancer cells. J Pharm Pharm Sci. 2017;20(0):295-304.
  70. Bothou C, Alexopoulos A, Dermitzaki E, et al. Successful treatment of severe atopic dermatitis with calcitriol and paricalcitol in an 8-year-old girl. Case Rep Pediatr. 2018;2018:9643543.
  71. Nicolas S, Bolzinger MA, Jordheim LP, et al. Polymeric nanocapsules as drug carriers for sustained anticancer activity of calcitriol in breast cancer cells. Int J Pharm. 2018;550(1-2):170-179.
  72. Schroll MM, Ludwig KR, Bauer KM, Hummon AB. Calcitriol supplementation causes decreases in tumorigenic proteins and different proteomic and metabolomic signatures in right versus left-sided colon cancer. Metabolites. 2018;8(1).
  73. Ferronato MJ, Alonso EN, Salomón DG, et al. Antitumoral effects of the alkynylphosphonate analogue of calcitriol EM1 on glioblastoma multiforme cells. J Steroid Biochem Mol Biol. 2018;178:22-35.
  74. Srivastava AK, Rizvi A#, Cui T, et al. Depleting ovarian cancer stem cells with calcitriol. Oncotarget. 2018;9(18):14481-14491.
  75. Ye J, Deng G, Gao F. Theoretical overview of clinical and pharmacological aspects of the use of etelcalcetide in diabetic patients undergoing hemodialysis. Drug Des Devel Ther. 2018;12:901-909.
  76. Oblak M, Mlinšek G, Kandus A, et al. Paricalcitol versus placebo for reduction of proteinuria in kidney transplant recipients: A double-blind, randomized controlled trial. Transpl Int. 2018;31(12):1391-1404.