A Systematic Review and Meta-analysis of Efficacy and Safety of Calcimimetic Agents in the Treatment of Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease.

BACKGROUND: Some reports have pointed out that calcimimetics agents are effective in the treatment of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) patients, but there is no detailed description of the advantages and disadvantages of calcimimetics agents of SHPT in CKD patients. We tried to pool the published data to verify the effectiveness of calcimimetics agents and to compare the advantages and disadvantages of cinacalcet compared with control in the treatment of SHPT in CKD patients. METHODS: We included eligible studies of published papers from January 1st, 2000 to December 31st, 2020 in Medline, Pubmed and Web of science databases, and the data were extracted for this meta-analysis. RESULTS: Twenty-seven studies were eligible, and all the included studies were randomized controlled trials (RCT) including patients treated with long-term dialysis. The results indicated that calcimimetic agents can reduce the parathyroid hormone (PTH, pg/ml) level (WMD = -178.22, 95% CI: -238.57, -117.86, P < 0.00001), calcium (Ca, mg/dl) level (WMD = -0.71, 95% CI: -0.86, -0.55, P < 0.00001), phosphorus (P, mg/dl) level (WMD = -0.32, 95% CI: -0.55, -0.08, P = 0.008), calcium-phosphorus product level (WMD = -7.73, 95% CI: -9.64, -5.82, P < 0.00001). Calcimimetic agents increased the bone alkaline phosphatase (BSAP, ng/ml) levels and rate of achieving target PTH, and reduced osteocalcin levels and the rate of parathyroidectomy. Calcimimetic agents increased the total adverse events' rate, the rate of hypocalcemia and gastrointestinal side effects (nausea, vomiting, abdominal pain and diarrhea), but there was no significant difference in serious adverse events between the calcimimetic agent group and control group. CONCLUSION: Calcimimetic agents can reduce the PTH level, Ca level, P level, calcium-phosphorus product level and do not increase serious adverse events.

Tenofovir-induced osteopenia and hyperparathyroidism: A case report and literature review.

Tenofovir disoproxil fumarate is the first-line antiviral therapy for chronic viral hepatitis B, but long-term use is associated with renal failure and hypophosphatemic osteomalacia. Tenofovir disoproxil fumarate-induced osteoporosis and secondary hyperparathyroidism are less commonly reported. Herein, we describe the case of a patient with bone and multijoint pain who was initially misdiagnosed as having normocalcemic primary hyperparathyroidism associated with prolonged exposure to tenofovir disoproxil fumarate. The patient's 24-h urinary calcium and phosphorus excretion levels and serum calcium levels were at the lower end of the normal range. After reviewing these findings, the diagnosis was amended to osteoporosis and secondary hyperparathyroidism caused by tenofovir disoproxil fumarate. In this report, we describe the differences in clinical and laboratory manifestations of hyperparathyroidism induced by tenofovir disoproxil fumarate and normocalcemic primary hyperparathyroidism. We also discuss relevant pathophysiological mechanisms and propose a feasible treatment strategy.

Early response of the parathyroid gland to withdrawal of a calcimimetic compound in uremic rats.

Little is known about changes in parathyroid cells when calcimimetics are withdrawn. We examined the response of parathyroid glands to cinacalcet (Cina) withdrawal in uremic Sprague-Dawley rats fed a high-phosphate diet to develop secondary hyperparathyroidism and divided into groups treated with vehicle (UC), Cina, and Cina and maxacalcitol (Maxa), a vitamin D receptor activator (CiNa + Maxa). After 2 wk of treatment, vehicle and Cina were withdrawn and Maxa was continued. Rats were analyzed immediately (day 0) and 7 days (day 7) after withdrawal. The Cina and CiNa + Maxa groups had significantly lower parathyroid hormone (PTH) than the UC group on day 0, although PTH in the Cina group reached UC levels on day 7. On day 0, there were significantly more proliferating cell nuclear antigen-positive cells in the UC group compared with normal controls, and this increase was significantly suppressed in the Cina and CiNa + Maxa groups. On day 7, the Cina group, but not the CiNa + Maxa group, showed a significant increase in proliferating cell nuclear antigen-positive cells compared with the UC group. This increase was related to parathyroid cell diameter regression to UC levels, whereas combination treatment maintained diameter suppression. These results indicate that parathyroid growth activity is stimulated by Cina withdrawal, although the PTH level was not further increased. Continuous administration of Cina may be required for optimal control of secondary hyperparathyroidism, and simultaneous use of a vitamin D receptor activator may be advisable during Cina withdrawal.

Activation of the calcium sensing receptor attenuates TRPV6-dependent intestinal calcium absorption.

Plasma calcium (Ca2+) is maintained by amending the release of parathyroid hormone and through direct effects of the Ca2+ sensing receptor (CaSR) in the renal tubule. Combined, these mechanisms alter intestinal Ca2+ absorption by modulating 1,25-dihydroxy vitamin D3 production, bone resorption, and renal Ca2+ excretion. The CaSR is a therapeutic target in the treatment of secondary hyperparathyroidism and hypocalcemia a common complication of calcimimetic therapy. The CaSR is also expressed in intestinal epithelium, however, a direct role in regulating local intestinal Ca2+ absorption is unknown. Chronic CaSR activation decreased expression of genes involved in Ca2+ absorption. In Ussing chambers, increasing extracellular Ca2+ or basolateral application of the calcimimetic cinacalcet decreased net Ca2+ absorption across intestinal preparations acutely. Conversely, Ca2+ absorption increased with decreasing extracellular Ca2+ concentration. These responses were absent in mice expressing a non-functional TRPV6, TRPV6D541A. Cinacalcet also attenuated Ca2+ fluxes through TRPV6 in Xenopus oocytes when co-expressed with the CaSR. Moreover, the phospholipase C inhibitor, U73122, prevented cinacalcet-mediated inhibition of Ca2+ flux. These results reveal a regulatory pathway whereby activation of the CaSR in the basolateral membrane of the intestine directly attenuates local Ca2+ absorption via TRPV6 to prevent hypercalcemia and help explain how calcimimetics induce hypocalcemia.

Nitrite-induced acute kidney injury with secondary hyperparathyroidism: Case report and literature review.

RATIONALE: Acute kidney injury (AKI) with hyperparathyroidism caused by nitrite was rare, and renal function and parathyroid hormone (PTH) decreased to normal range after therapy. PATIENT CONCERNS: Acute kidney injury was diagnosed in a 40-year-old male with hyperparathyroidism and cyanosis of his hands and both forearms. DIAGNOSES: The patient ate some recently pickled vegetables, and he experienced nausea, vomiting and diarrhoea without oliguria or anuria; Additionally, his hands and both forearms had a typical blue ash appearance. After admission, the laboratory findings indicated theincreasing serum creatinine (Scr) and parathyroid hormone (PTH). He was diagnosed as acute kidney injury with hyperparathyroidism caused by nitrite. INTERVENTIONS: The patient stopped eating the pickled vegetables and was given rehydration, added calories and other supportive therapy without any glucocorticoids. OUTCOMES: According to his clinical manifestations, laboratory findings and imaging results, the patient was diagnosed with acute kidney injury with secondary hyperparathyroidism. He was given symptomatic supportive care therapy. After one week, the serum creatinine, parathyroid hormone (PTH), hypercalcemia, hyperphosphatemia, proteinuria, and urine red blood cell values decreased to normal range. LESSONS: Nitrite-induced acute kidney injury with secondary hyperparathyroidism was relatively rare. After therapy, the function of the kidney and parathyroid returned to normal. This case suggests that detailed collection of medical history, physical examination and correct symptomatic treatment is very important.

Successful Reversal of Furosemide-Induced Secondary Hyperparathyroidism With Cinacalcet.

Secondary hyperparathyroidism (SHPT) is a rare complication of furosemide therapy that can occur in patients treated with the loop diuretic for a long period of time. We report a 6-month-old 28-weeks premature infant treated chronically with furosemide for his bronchopulmonary dysplasia, who developed hypocalcemia and severe SHPT, adversely affecting his bones. Discontinuation of the loop diuretic and the addition of supplemental calcium and calcitriol only partially reversed the SHPT, bringing serum parathyroid hormone level down from 553 to 238 pg/mL. After introduction of the calcimimetic Cinacalcet, we observed a sustained normalization of parathyroid hormone concentration at 27 to 63 pg/mL and, with that correction, of all biochemical abnormalities and healing of the bone disease. No adverse effects were noted. We conclude that in cases of SHPT due to furosemide in which traditional treatment fails, there may be room to consider the addition of a calcimimetic agent.

Furosemide Increases the Risk of Hyperparathyroidism in Chronic Kidney Disease.

BACKGROUND: Diuretics are widely used in patients with chronic kidney disease (CKD). While thiazide-like diuretics limit urinary calcium excretion, loop diuretics (LD) promote calcium wasting, which might facilitate the development of secondary hyperparathyroidism (HPT2). We sought to investigate, in CKD patients not on dialysis, the influence of either hydrochlorothiazide (Hydro) or furosemide (Furo) on circulating parathyroid hormone (PTH) and whether such actions are determined by the effects of these compounds on calcium excretion. METHODS: Electronic charts of all nephrology outpatients (CKD stages 2-5) who were given Hydro or Furo were included. We assessed estimated glomerular filtration rate (eGFR), biochemical parameters and 24-hour calcium excretion. Hyperparathyroidism was defined as PTH >65 pg/ml. RESULTS: Out of 275 patients, 108 (29%) were taking Hydro and 167 (61%) Furo. Patients on Hydro were younger, mostly female and had higher eGFR. The median 24-hour urinary calcium excretion in the overall cohort was 41 (22, 76), being lower in Furo than in Hydro patients (37 (16, 68) vs. 47 (26, 88) mg/24 h, respectively, p = 0.016). Logistic regression showed that, after adjustment for eGFR, calcium excretion rate was found not to increase the risk ratio for HPT2, whereas Furo was a strong predictor of HPT2. CONCLUSION: Furo increased the risk of HPT2 among CKD patients compared to Hydro. This effect was independent of eGFR or calcium excretion. The use of LD in CKD, currently preferred in advanced stages, should be reappraised.

Changes of Serum Total and Free Testosterone Concentrations in Male Chronic Hemodialysis Patients with Secondary Hyperparathyroidism in Response to Cinacalcet Treatment.

BACKGROUND/AIMS: Calcium sensing receptor (CaSR) is expressed, among others also in testis. Cinacalcet binds to the CaSR, increases sensitivity of CaSR to serum calcium and is used in the treatment of secondary hyperparathyroidism (sHPT) in chronic hemodialysis patients (HDP). In most of male HDP, serum testosterone concentration is lower than in healthy males. The aim of this study was to assess the influence of six-month treatment with cinacalcet on the serum total and free testosterone concentration in male HDP with sHPT. METHODS: 38 male, hemodialysed CKD patients with sHPT (PTH>300 pg/ml) were enrolled into the study. In each patient serum PTH, total testosterone (TT) and free testosterone (FT) concentrations were assessed before the first dose of cinacalcet and then after 3 and 6 months of treatment. The results are presented as means with 95% confidence interval. RESULTS: In 33 patients who completed the study cinacalcet treatment caused significant decrease of serum PTH from 1143 pg/ml (828 - 1458 pg/ml) at the baseline, to 809 pg/ml (487 - 1132 pg/ml) after 3 month of treatment (p = 0.002), and to 607 pg/ml (281 - 934 pg/ml; p < 0.0001) after 6 months of treatment. Serum TT concentration also decreased from 4.95 ng/ml (4.23 - 5.67 ng/ml) to 4.45 ng/ml (3.85 - 5.06 ng/ml) and to 4.39 ng/ml (3.75 - 5.03 ng/ml), respectively (p for trend = 0.009). Moreover, serum FT concentration decreased from 6.95 pg/ml (5.54 - 8.36 pg/ml) to 5.98 pg/ml (5.00-6.94 pg/ml); p = 0.14 and to 5.60 pg/ml (4.63 - 6.57 pg/ml); p = 0.034, respectively (p for trend = 0.012). CONCLUSION: Treatment with cinacalcet decreases serum total and free testosterone concentration in male hemodialysed patients with chronic kidney disease and secondary hyperparathyroidism.

Impact of phosphorus restriction and vitamin D-substitution on secondary hyperparathyroidism in a proteinuric mouse model.

BACKGROUND/AIMS: Since the discovery of FGF23, secondary hyperparathyroidism (SHPT) in renal disease has been considered to result primarily from phosphorus retention rather than vitamin D deficiency. However, the impact of phosphorus restriction and vitamin D supplementation on SHPT is still ill defined. METHODS: We investigated the development of SHPT in a doxorubicin-induced proteinuric mouse model and tested different treatment strategies including a low phosphorus diet and substitution with native or active vitamin D in 129 S1/SvImJ wild-type mice. RESULTS: Development of SHPT at day 30 was strongly related to the magnitude of induced proteinuria. In mice with a proteinuria <100 mg/mg creatinine, SHPT was mild (PTH increase 2.4-fold), and serum levels of FGF23, phosphate and urea remained almost stable, whereas mice with heavy proteinuria (>100 mg/mg creatinine) developed marked SHPT (PTH increase 10.1-fold) accompanied by massive increase in FGF23 (27.0-fold increase), hyperphosphatemia (1.8-fold increase), renal failure (7.3-fold urea increase) and depletion of both 25-OH vitamin D and 1,25-OH vitamin D. Substitution with native or active vitamin D was unable to suppress SHPT, whereas a low-phosphorus diet (Pi content 0.013%) completely suppressed SHPT in mice with both mild and heavy proteinuria. CONCLUSIONS: The development of SHPT resulted from phosphate retention in this proteinuric model and could completely be suppressed with a low-phosphorus diet.

[Citrate anticoagulation in acute renal replacement therapy : Method of choice]. / Zitratantikoagulation in der akuten Nierenersatztherapie : Methode der Wahl.

BACKGROUND: Anticoagulation is prerequisite for efficient continuous renal replacement therapy (CRRT). Premature clotting of the extracorporeal system leads to therapy interruptions, is costly, and causes relevant blood losses. REGIONAL ANTICOAGULATION: Regional citrate anticoagulation (RCA) achieves reliable coagulation inhibition and is clearly superior to heparin with regard to filter survival time. Due to its mode of action, a bleeding risk can be excluded. RCA with the commercial machine solutions is safe and has been promoted as the new standard anticoagulant for CRRT. Bioincompatibility reactions like leukocyte degranulation and complement system activation are ameliorated under RCA. DISCUSSION: An assumed survival advantage of RCA could not be confirmed. In case of severe liver insufficiency and lactic acidosis, RCA can lead to metabolic complications. Despite calcium supplementation, the calcium net balance of RCA is often negative. Long treatment durations can therefore cause secondary hyperparathyroidism and in extreme cases osteomalacia. RCA is also a valuable option in intermittent hemodialysis.

Osteomalacia in a patient with Paget's bone disease treated with long-term etidronate.

A 93 year-old woman with Paget's disease of bone had been treated with etidronate without interruption during 20 years. The daily dose was usual (5mg/kg/day) but this prescription had never been stopped by her physicians. Two fractures had already occurred in pagetic (right tibia) and non pagetic bones (right fibula) within the last 2 years, and she presented rib fractures, another right tibia fracture and right femur fracture during hospitalization time. X-rays films showed major osteolysis of left ulna and right tibia. Blood samples and technetium bone scan brought no evidence for sarcoma or lytic evolution of the disease. A transiliac bone biopsy on non pagetic bone site confirmed the diagnosis of osteomalacia (increased osteoid parameters), with secondary hyperparathyroidism (hook resorption). In Paget's disease of bone, continuous treatment by etidronate may induce generalized osteomalacia, and increase the risk of fracture in both pagetic and non-pagetic bones. Whereas physicians and pharmaceutical industry try to improve the observance of those drugs, this striking observation also points out that a prescription always needs to be updated.

Licorice-related rhabdomyolysis: a big price for a sweet tooth.

UNLABELLED: A 50-year-old lady on hydrochlorothiazide (HCTZ) presented to the hospital after 4 days of generalized muscle aches and dark urine. She admitted to consuming one and a half bags of black licorice bites containing 2% natural licorice during the past 3 weeks. Examination showed high blood pressure, while labs revealed elevated creatine kinase, hypokalemia, hypocalcemia and hypophosphatemia with low aldosterone and plasma renin levels and high intact PTH. The active component of licorice is glycyrrhizic acid, which inhibits an enzyme required to convert cortisol to a less active metabolite, cortisone. This causes excess cortisol, simulating syndrome of apparent mineralocorticoid excess (AME), thus resulting in hypertension, hypokalemia and metabolic alkalosis. In our patient, licorice induced hypokalemia resulted in rhabdomyolysis. The rhabdomyolysis along with the effect of licorice led to secondary hypocalcaemia, which in turn triggered secondary hyperparathyroidism. This might have had a phosphaturic effect that caused hypophosphatemia, further worsening rhabdomyolysis. CONCLUSION: This case illustrates the complex relationship of various electrolytes, which can lead to self perpetuation of the disease, hence demanding more vigilance.

Prognostic role of serum parathyroid hormone levels in advanced prostate cancer patients undergoing zoledronic acid administration.

BACKGROUND: Secondary hyperparathyroidism is frequent in prostate cancer patients with bone metastases, and this condition is worsened by the administration of potent bisphosphonates. Serum parathyroid hormone (PTH) elevation can impair the efficacy of these drugs in terms of survival. METHODS: The prognostic role of elevated serum PTH levels at baseline and after 3 months of zoledronic acid administration was assessed prospectively in 643 bone metastatic prostate cancer patients enrolled in a prospective randomized, placebo-controlled study. RESULTS: On multivariate analysis, after adjusting for major prognostic factors and bone turnover markers, elevated baseline serum PTH level was negatively associated with overall survival (hazard ratio [HR], 1.448; 95% confidence interval [CI], 1.045-2.006; p < .03) in zoledronic acid-treated patients but not in placebo-treated patients. In patients with normal baseline PTH levels, there was a trend but insignificant association between zoledronic acid administration and a better survival outcome than with placebo (HR, 0.81; 95% CI, 0.65-1.01; p = .065), whereas a trend in the opposite direction was observed in patients with elevated PTH levels (HR, 1.45; 95% CI, 0.87-2.39; p = .151); interaction test, p = .040. Elevated serum PTH level after 3 months of zoledronic acid treatment was not significantly associated with survival outcome. CONCLUSIONS: Secondary hyperparathyroidism has a negative prognostic impact in metastatic prostate cancer patients undergoing zoledronic acid administration. Counteracting elevated PTH levels by adequate doses of vitamin D may improve the efficacy of this drug.

Secondary hyperparathyroidism but stable bone-mineral density in patients with chronic myeloid leukemia treated with imatinib.

Imatinib is currently the standard treatment for chronic myeloid leukemia(CML). Previous studies have shown that imatinib affects bone metabolism in CML patients. However, these effects are not well-studied prospectively. The authors studied bone-mineral density (BMD) and bone metabolism in 17 CML patients and matched controls in 2007 and now repeated the analyses prospectively in 2011. All CML patients were in complete cytogenetic remission during this 4-year period and treated with 400 mg imatinib q.d. (n 5 15) or 600 mg imatinib q.d. (n 5 2). Mean treatment duration was 102 months (range 69­129) in 2011. The authors found that serum levels of parathyroid hormone increased significantly in the patients between 2007 and 2011, and seven out of 17 patients had secondary hyperparathyroidism in 2011. However, the mean areal and volumetric BMDs were stable in the CML patients over the 4-year-observation period. Moreover, the CML patients had significantly higher volumetric BMD in the cortical compartment when compared with controls in 2011 and 2007. Thus, despite a high incidence of secondary hyperparathyroidism,there were no signs of osteoporosis or osteomalacia in imatinib-treated CML patients as suggested earlier.

The impact of dietary induced hyperparathyroidism on healthy and diseased periodontia: an experimental study in rats.

BACKGROUND AND OBJECTIVE: Nutrition may be a potential modifying factor in periodontal conditions. The present study investigated this phenomenon for dietary induced hyperparathyroidism (dHPT) by revealing the histopathological and histomorphometrical profiles of healthy and diseased periodontia in dHPT. METHODS: Dietary induced hyperparathyroidism was induced in 12 rats by dietary calcium/phosphorous imbalance and 12 rats were fed standard diet (SD). Periodontitis was induced on the right mandibular molar teeth (mmt) of these rats by injecting an endotoxin + saline solution whereas injecting pure saline to the left mmt. Thus, four study groups were created: dHPT + saline (group 1), dHPT + endotoxin (group 2), SD + endotoxin (group 3) and SD + saline (group 4). Histological sections were obtained from the second mmt and examined using light microscope. RESULTS: Group 1 demonstrated inflammatory and degenerative alterations in periodontium without pocket formation. Periodontitis was evident in groups 2 and 3. Group 2 revealed the highest amounts of gingival inflammatory cell and vessel counts (group 2 > group 3 > group 1 > group 4), attachment and bone losses (group 2 > group 3 > groups 1 > group 4) and osteoclast count (group 2 > group 3 > group 1 > group 4) (p < 0.05). CONCLUSION: These results propose that dHPT may impair the health status of periodontium and may worsen the pathobiology of periodontal diseases.

Secondary hyperparathyroidism in HIV patients: is there any responsibility of highly active antiretroviral therapy?

Secondary hyperparathyroidism may develop in the presence of hypovitaminosis D in order to maintain calcium homeostasis. We conducted a cross-sectional analysis in a cohort of 371 patients, identifying secondary hyperparathyroidism in 65 patients. This high prevalence (17.5%) was in part justified by the high prevalence of hypovitaminosis D (77.4%) in the whole sample, but we also identified an independent association with the use of tenofovir.

[Chronic use of proton pump inhibitors: is the risk of osteoporosis and fractures real?]. / ¿Es real el riesgo de osteoporosis y riesgo de fracturas con el uso crónico de inhibidores de la bomba de protones?

Proton pump inhibitors (PPI) are one of the most widely used groups of drugs and their potential toxicity is periodically reviewed, emphasizing aspects originally considered secondary. The present review analyzes the physiological and pharmacological bases and the scarce clinical evidence for a potential association between the continued administration of PPI and the development of osteoporosis and bone fractures. Both disorders are clearly related to calcium homeostasis and are highly important in elderly patients due to their poor general prognosis and disabling consequences.