Small Molecules as Modulators of Voltage-Gated Calcium Channels in Neurological Disorders: State of the Art and Perspectives.

Voltage-gated calcium channels (VGCCs) are widely expressed in the brain, heart and vessels, smooth and skeletal muscle, as well as in endocrine cells. VGCCs mediate gene transcription, synaptic and neuronal structural plasticity, muscle contraction, the release of hormones and neurotransmitters, and membrane excitability. Therefore, it is not surprising that VGCC dysfunction results in severe pathologies, such as cardiovascular conditions, neurological and psychiatric disorders, altered glycemic levels, and abnormal smooth muscle tone. The latest research findings and clinical evidence increasingly show the critical role played by VGCCs in autism spectrum disorders, Parkinson's disease, drug addiction, pain, and epilepsy. These findings outline the importance of developing selective calcium channel inhibitors and modulators to treat such prevailing conditions of the central nervous system. Several small molecules inhibiting calcium channels are currently used in clinical practice to successfully treat pain and cardiovascular conditions. However, the limited palette of molecules available and the emerging extent of VGCC pathophysiology require the development of additional drugs targeting these channels. Here, we provide an overview of the role of calcium channels in neurological disorders and discuss possible strategies to generate novel therapeutics.

Probenecid Improves Cardiac Function in Subjects with a Fontan Circulation and Augments Cardiomyocyte Calcium Homeostasis.

Subjects with functionally univentricular circulation who have completed staged single ventricle palliation, with the final stage culminating in the Fontan procedure, are often living into adulthood. However, high morbidity and mortality remain prevalent in these patients, as diastolic and systolic dysfunction of the single systemic ventricle are linked to Fontan circulatory failure. We presently investigated the effects of probenecid in post-Fontan patients. Used for decades for the treatment of gout, probenecid has been shown in recent years to positively influence cardiac function via effects on the Transient Receptor Potential Vanilloid 2 (TRPV2) channel in cardiomyocytes. Indeed, we observed that probenecid improved cardiac function and exercise performance in patients with a functionally univentricular circulation. This was consistent with our findings from a retrospective cohort of patients with single ventricle physiology where TRPV2 expression was increased. Experiments in isolated cardiomyocytes associated these positive actions to augmentation of diastolic calcium homeostasis.

CACNA1S haploinsufficiency confers resistance to New World arenavirus infection.

Understanding the genetics of susceptibility to infectious agents is of great importance to our ability to combat disease. Here, we show that voltage-gated calcium channels (VGCCs) are critical for cellular binding and entry of the New World arenaviruses Junín and Tacaribe virus, suggesting that zoonosis via these receptors could occur. Moreover, we demonstrate that α1s haploinsufficiency renders cells and mice more resistant to infection by these viruses. In addition to being more resistant to infection, haploinsufficient cells and mice required a lower dosage of VGCC antagonists to block infection. These studies underscore the importance of genetic variation in susceptibility to both viruses and pharmaceutics.

Calcitriol ameliorated autonomic dysfunction and hypertension by down-regulating inflammation and oxidative stress in the paraventricular nucleus of SHR.

The hypothalamic paraventricular nucleus (PVN) plays crucial roles in central cardiovascular regulation. Increasing evidence in humans and rodents shows that vitamin D intake is important for achieving optimal cardiovascular function. The purpose of this study was to investigate whether calcitriol, an active form of vitamin D, improves autonomic and cardiovascular function in hypertensive rats and whether PVN oxidative stress and inflammation are involved in these beneficial effects. Male spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto (WKY) rats were treated with either calcitriol (40 ng/day) or vehicle (0.11 µL/h) through chronic PVN infusion for 4 weeks. Blood pressure and heart rate were recorded continuously by radiotelemetry. PVN tissue, heart and plasma were collected for molecular and histological analysis. Compared to WKY rats, SHR exhibited increased systolic blood pressure, sympathetic drive, and cardiac hypertrophy and remodeling. These were associated with higher mRNA and protein expression levels of high mobility box 1 (HMGB1), receptor for advanced glycation end products (RAGE), toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB), proinflammatory cytokines, NADPH oxidase subunit in the PVN. In addition, increased norepinephrine in plasma, elevated reactive oxygen species levels and activation of microglia in the PVN were also observed in SHR. Chronic calcitriol treatment ameliorated these changes but not in WKY rats. Our results demonstrate that chronic infusion of calcitriol in the PVN ameliorates hypertensive responses, sympathoexcitation and retains cardiovascular function in SHR. Reduced inflammation and oxidative stress within the PVN are involved in these calcitriol-induced effects.

Anxiolytic effects of the novel α2δ ligand mirogabalin in a rat model of chronic constriction injury, an experimental model of neuropathic pain.

RATIONALE: Psychiatric disorders such as anxiety and depression are frequently observed in neuropathic pain patients, and negatively impact their quality of life. Mirogabalin is a novel ligand for the α2δ subunit of voltage-gated calcium channels and has unique binding characteristics to α2δ subunits and potent and long-lasting analgesic effects in neuropathic pain models. OBJECTIVES: To provide further information on the pharmacological profile of mirogabalin and its utility for chronic pain therapy, we investigated its anxiolytic effects in an experimental animal model for neuropathic pain. METHODS: In chronic constriction injury (CCI) model rats, mechanical hypersensitivity was determined by the von Frey test. Anxiety- and depression-related behaviours were evaluated using the elevated plus maze test and forced swimming test, respectively. RESULTS: CCI model rats showed sustained tactile allodynia followed by anxiety-related behaviours, not depression-related behaviours. The tactile allodynia (significant decreases in paw withdrawal threshold) developed within 2 weeks after model preparation, whereas the anxiety-related behaviours (significant decreases in the number of entries and time spent in open arms and significant increases in time spent in closed arms) were observed at 5 weeks but not 4 weeks after model preparation. Single oral administration of mirogabalin (3 or 10 mg/kg) dose-dependently alleviated the above-mentioned anxiety-related behaviours and tactile allodynia. CONCLUSIONS: CCI model rats showed anxiety-related behaviours in a time-dependent manner in the elevated plus maze test. Mirogabalin alleviated both the anxiety-related behaviours and tactile allodynia in CCI model rats. Mirogabalin may provide effective anxiety relief as well as pain relief in patients with neuropathic pain.

Anti-schistosomal action of the calcium channel agonist FPL-64176.

Subversion of parasite neuromuscular function is a key strategy for anthelmintic drug development. Schistosome Ca2+ signaling has been an area of particular interest for decades, with a specific focus on L-type voltage-gated Ca2+ channels (Cavs). However, the study of these channels has been technically challenging. One barrier is the lack of pharmacological probes that are active on flatworms, since the dihydropyridine (DHP) based ligands typically used to study Cavs are relatively ineffective on schistosomes. Here, we have characterized the effect of a structurally distinct putative L-type Cav agonist, FPL-64176, on schistosomes cultured ex vivo and in an in vivo murine model of infection. Unlike DHPs, FPL-64176 evokes rapid and sustained contractile paralysis of adult Schistosoma mansoni reminiscent of the anthelmintic praziquantel. This is accompanied by tegument disruption and an arrest of mitotic activity in somatic stem cells and germ line tissues. Interestingly, this strong ex vivo phenotype was temperature dependent, with FPL-64176 treatment being less potent at 37 °C than 23 °C. However, FPL-64176 caused intra-tegument lesions at the basement membrane of worms cultured ex vivo under both conditions, as well as an in vivo hepatic shift of parasites from the mesenteric vasculature of infected mice to the liver. Gene expression profiling of worms harvested following in vivo FPL-64176 exposure reveals differences in transcripts associated with muscle and extracellular matrix function, as well as female reproduction, which is consistent with the worm phenotypes observed following ex vivo drug treatment. These data advance FPL-64176 as a useful tool to study schistosome Ca2+ signaling, and the benzoyl pyrrole core as a hit compound that may be optimized to develop new parasite-selective leads.

Combination of ascorbic acid and calcitriol attenuates chronic asthma disease by reductions in oxidative stress and inflammation.

Airway inflammation and oxidative stress are the two major characteristics of asthma pathogenesis. Therefore, this study evaluated the protective effects of ascorbic acid in combination with calcitriol on the oxidative damages and inflammation in asthma model. All animals, except in the control group, were sensitized and challenged with ovalbumin. One day after the last challenge, samples of bronchoalveolar lavage fluid was collected for the assessment of total white blood cell counts and differential count of white blood cell and plasma was used for the measurement of pro-oxidant/antioxidant balance level. Lung tissue samples were also stored for examining peribronchial inflammatory cell infiltration, phosphorylated nuclear factor-kappa B expression and measurement of malondialdehyde level. Induction of asthma caused significant increases in total white blood cell counts, percentage of neutrophils and eosinophils and a decrease in the percentage of lymphocytes. Moreover, asthma resulted in significant increases of peribronchial inflammatory cell infiltration, phosphorylated nuclear factor-kappa B expression and malondialdehyde level. However, no significant changes were observed in pro-oxidant/antioxidant balance level with the induction of asthma. Co-administration of low doses of ascorbic acid and calcitriol returned all to the levels measured before sensitization and challenge. Combination of low doses of ascorbic acid with calcitriol improves mouse asthma model by a possible additive effects through the decrease of oxidative stress and inflammation.

Brown tumor of the thoracic spine presenting with paraplegia in a patient with peritoneal dialysis.

Secondary and tertiary hyperparathyroidism is an important problem of chronic kidney disease. Brown tumor is a benign, unusual, reactive lesion as a result of disturbed bone remodeling, from long-standing increase in parathyroid hormone level. Brown tumors may cause morbidity due to pressure symptoms on neural structures and spontaneous bone fractures. Herein, we presented a peritoneal dialysis patient with tertiary hyperparathyroidism under calcand calcitriol treatment for 4 years due to refusing of the parathyroidectomy operation. She admitted to hospital for sudden onset back pain with difficulty in gait and walking, and imaging studies showed an expansile mass lesion in the thoracic spine. She was operated for mass and diagnosed with brown tumor. After operation, she lost the ability of walking than become paraplegic and she underwent rehabilitation program. Preventive measures including calcitriol and cinacalcet may cause a modest decrease in parathyroid hormone levels but it should be remembered for the development of bone complications such as brown tumor formation in patients with moderate elevated PTH levels, especially those with tertiary hyperparathyroidism. Parathyroidectomy should be performed without delay in these cases.

Anticancer Activity of Euplotin C, Isolated from the Marine Ciliate Euplotes crassus, Against Human Melanoma Cells.

Cutaneous melanoma is the most serious type of skin cancer, so new cytotoxic weapons against novel targets in melanoma are of great interest. Euplotin C (EC), a cytotoxic secondary metabolite of the marine ciliate Euplotes crassus, was evaluated in the present study on human cutaneous melanoma cells to explore its anti-melanoma activity and to gain more insight into its mechanism of action. EC exerted a marked cytotoxic effect against three different human melanoma cell lines (A375, 501Mel and MeWo) with a potency about 30-fold higher than that observed in non-cancer cells (HDFa cells). A pro-apoptotic activity and a decrease in melanoma cell migration by EC were also observed. At the molecular level, the inhibition of the Erk and Akt pathways, which control many aspects of melanoma aggressiveness, was shown. EC cytotoxicity was antagonized by dantrolene, a ryanodine receptor (RyR) antagonist, in a concentration-dependent manner. A role of RyR as a direct target of EC was also suggested by molecular modelling studies. In conclusion, our data provide the first evidence of the anti-melanoma activity of EC, suggesting it may be a promising new scaffold for the development of selective activators of RyR to be used for the treatment of melanoma and other cancer types.

Effect of calcitriol on serum hepcidin in individuals with chronic kidney disease: a randomized controlled trial.

BACKGROUND: Anemia is highly prevalent in chronic kidney disease (CKD). Elevated hepcidin concentrations are an important mediator of disordered iron metabolism, a key mechanism underlying anemia of CKD. Vitamin D was recently shown to reduce serum hepcidin concentrations in healthy individuals. We examined whether treatment with calcitriol reduces serum hepcidin in individuals with CKD. METHODS: A total of 40 participants with stage 3 or 4 CKD (eGFR 15-60 ml/min/1.73m2) were randomized to receive either oral calcitriol 0.5 mcg daily or identically-matched placebo for 6 weeks. The primary outcome variable was change in serum hepcidin concentrations. Secondary outcomes variables included the change in iron parameters, calcium, phosphorus, intact parathyroid hormone and hemoglobin concentrations. Study samples were drawn at baseline, 3 days, 1 week, 4 weeks and 6 weeks after randomization. Repeated measures analysis was used to examine differences in outcome variables over time in the two groups. RESULTS: There were no significant differences in the baseline characteristics between the placebo and calcitriol arms. Over 6 weeks of follow-up there were no significant differences in the change in serum hepcidin, iron parameters, or hemoglobin between the two groups. Serum calcium and phosphorus significantly increased and PTH significantly decreased after 6 weeks in calcitriol group whereas these analytes did not change in the placebo group. CONCLUSION: Calcitriol did not reduce serum hepcidin concentrations among individuals with mild to moderate CKD. Future studies are needed to assess if nutritional forms of vitamin D affect hepcidin concentrations in CKD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01988116 . Registered: November 4, 2013.

Parathyroid Nodular Hyperplasia and Responsiveness to Drug Therapy in Renal Secondary Hyperparathyroidism: An Open Question.

The goal of the pharmacological therapy in secondary hyperparathyroidism (SHPT) is to reduce serum levels of parathyroid hormone and phosphorus, to correct those of calcium and vitamin D, to arrest or reverse the parathyroid hyperplasia. However, when nodular hyperplasia or an autonomous adenoma develops, surgery may be indicated. We reviewed the literature with the aim of defining if the echographic criteria predictive of unresponsiveness of SHPT to calcitriol therapy are valid also in the cinacalcet era and if drug therapy may reverse nodular hyperplasia of parathyroid gland (PTG). The responsiveness to therapy and regression of the nodular hyperplasia of PTG remains an open question in the calcimimetic era as well as the cutoff between medical and surgical therapy. Prospective studies are needed in order to clarify if an earlier use of cinacalcet in moderate SHPT might arrest the progression of parathyroid growth and stabilize SHPT.

Do the benefits of using calcitriol and other vitamin D receptor activators in patients with chronic kidney disease outweigh the harms?

The primary indication for administration of calcitriol or other vitamin D receptor activators (VDRA) in chronic kidney disease (CKD) is secondary hyperparathyroidism (SHPT). Prevention and treatment of SHPT appears important, as imbalances in mineral metabolism are associated with renal osteodystrophy, and higher parathyroid hormone (PTH) levels are associated with increased rates of mortality and morbidity in CKD patients. There is, however, a lack of controlled trial data that show lowering PTH with calcitriol/VDRA equates to improved clinical outcomes. Recent randomized controlled trials have concentrated on potential benefits of calcitriol/VDRA on cardiovascular outcomes and reduction of proteinuria and on possible differences between calcitriol and the various VDRA. Several systematic reviews and meta-analyses have also been published, evaluating the benefits and harms of calcitriol/VDRA. Concerns have been raised about the effectiveness of calcitriol/VDRA for suppression of SHPT in the CKD stages 3-5 population, as well as potential adverse outcomes such as hypercalcaemia and elevation in FGF23 levels, suggesting their routine use to treat SHPT in the pre-dialysis CKD population may not be favourable. Conversely, concerns still exist about the wide PTH range in advanced CKD, and that high values may negatively impact bone quality, result in the progression of parathyroid hyperplasia and decrease the effectiveness of treatments to reduce PTH. We discuss the current controversies relating to the challenges in the management of SHPT in patients with CKD stages 3-5 and the need for more evidence to determine the efficacy or harm of using calcitriol/VDRA in this population.

Calcitriol Suppression of Parathyroid Hormone Fails to Improve Skeletal Properties in an Animal Model of Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) leads to complex metabolic changes and an increased risk of fracture. Currently, calcitriol is the standard of care as it effectively suppresses parathyroid hormone (PTH) levels in CKD patients. While calcitriol and its analogs improve BMD and reduce fractures in the general population, the extension of these benefits to patients with advanced kidney disease is unclear. Here, the impact of calcitriol on the skeleton was examined in the setting of reduction in PTH. METHODS: Male Cy/+ rats, a PKD-like CKD model, were treated with either vehicle or calcitriol for 5 weeks. Their normal littermates served as controls. Animals were assessed for changes in mineral metabolism and skeletal parameters (microCT, histology, whole bone mechanics and bone quality). RESULTS: PTH levels were significantly higher (12-fold) in animals with CKD compared to normal controls. CKD animals also exhibited negative changes in bone structural and mechanical properties. Calcitriol treatment resulted in a 60% suppression of PTH levels in animals with CKD. Despite these changes, it had no impact on bone volume (cortical or cancellous), bone turnover, osteoclast number or whole bone mechanical properties. CONCLUSIONS: These data indicate that while calcitriol effectively lowered PTH in rats with CKD, it did little to prevent the negative effects of secondary hyperparathyroidism on the skeleton.

Calcitriol attenuates cardiac remodeling and dysfunction in a murine model of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a complex reproductive and metabolic disorder affecting 10 % of reproductive-aged women, and is well associated with an increased prevalence of cardiovascular risk factors. However, there are few data concerning the direct association of PCOS with cardiac pathologies. The present study aims to investigate the changes in cardiac structure, function, and cardiomyocyte survival in a PCOS model, and explore the possible effect of calcitriol administration on these changes. PCOS was induced in C57BL/6J female mice by chronic dihydrotestosterone administration, as evidenced by irregular estrous cycles, obesity and dyslipidemia. PCOS mice progressively developed cardiac abnormalities including cardiac hypertrophy, interstitial fibrosis, myocardial apoptosis, and cardiac dysfunction. Conversely, concomitant administration of calcitriol significantly attenuated cardiac remodeling and cardiomyocyte apoptosis, and improved cardiac function. Molecular analysis revealed that the beneficial effect of calcitriol was associated with normalized autophagy function by increasing phosphorylation levels of AMP-activated protein kinase and inhibiting phosphorylation levels of mammalian target of rapamycin complex. Our findings provide the first evidence for the presence of cardiac remodeling in a PCOS model, and vitamin D supplementation may be a potential therapeutic strategy for the prevention and treatment of PCOS-related cardiac remodeling.

Synchronous Diaphragmatic Flutter Secondary to Primary Hypoparathyroidism in a Dog.

A 3 yr old, spayed, female miniature mchnauzer was presented for rhythmic, spontaneous contractions of the abdominal wall and across the costal arches. The rate of contractions coincided with the heart rate and increased during exercise. The dog was diagnosed with primary hypoparathyroidism based on low plasma ionized calcium and serum parathyroid hormone (PTH) concentrations. Fluoroscopic exam confirmed the diagnosis of a synchronous diaphragmatic flutter. Treatment of the hypocalcemia led to resolution of the diaphragmatic flutter.

Magnesium Modifies the Impact of Calcitriol Treatment on Vascular Calcification in Experimental Chronic Kidney Disease.

Chronic kidney disease (CKD) patients are commonly treated with vitamin D analogs, such as calcitriol. Recent epidemiologic evidence revealed a significant interaction between vitamin D and magnesium, since an inverse relationship between vitamin D levels and mortality mainly occurs in patients with a high magnesium intake. The aim of the study was to assess the mechanisms involved by determining whether magnesium alone or combined with calcitriol treatments differentially impacts vascular calcification (VC) in male Sprague-Dawley rats with adenine-induced CKD. Treatment with moderate doses of calcitriol (80 µg/kg) suppressed parathyroid hormone to near or slightly below control levels. Given alone, this dose of calcitriol increased the prevalence of VC; however, when magnesium was given in combination, the severity of calcification was attenuated in the abdominal aorta (51% reduction), iliac (44%), and carotid arteries (46%) compared with CKD controls. The decreases in vascular calcium content were associated with a 20-50% increase in vascular magnesium. Calcitriol treatment alone significantly decreased TRPM7 protein (↓ to ∼11%), whereas the combination treatment increased both mRNA (1.7×) and protein (6.8×) expression compared with calcitriol alone. In summary, calcitriol increased VC in certain conditions, but magnesium prevented the reduction in TRPM7 and reduced the severity of VC, thereby increasing the bioavailable magnesium in the vascular microenvironment. These findings suggest that modifying the adverse effect profile of calcitriol with magnesium may be a plausible approach to benefiting the increasing number of CKD patients being prescribed calcitriol.

The Impact of Hypoparathyroidism Treatment on the Kidney in Children: Long-Term Retrospective Follow-Up Study.

CONTEXT: Adults with hypoparathyroidism have significant rates of nephrocalcinosis and impaired renal function. Little is known about the impact of hypoparathyroidism treatment on renal function in children. OBJECTIVES: To determine the prevalence and predictors for renal abnormalities (nephrocalcinosis and decreased estimated glomerular filtration rate [eGFR]) in children with treated hypoparathyroidism. DESIGN AND SETTING: A retrospective chart review of patients with permanent hypoparathyroidism at the Hospital for Sick Children, Toronto, between 1996 and 2013. PATIENTS: Data of 29 patients (15 males) followed for at least 1 year with documented hypoparathyroidism were analyzed. Mean duration of follow up was 7.4 ± 5 years. MAIN OUTCOME MEASURES: The presence or absence of nephrocalcinosis as detected on ultrasound and eGFR were evaluated. RESULTS: Time-weighted average serum measurements were calculated for all biochemical variables. Mean total and ionized serum calcium were 8.9 ± 0.8 and 4.6 ± 0.5 mg/dL, respectively. Nephrocalcinosis was observed in 38% of the subjects, with the most significant predictors being the degree of relative hypercalcemia and hyperphosphatemia (R(2) = 0.47, P < .01). Although all patients had an eGFR greater than 60, in 45% of the children, the eGRF was between 60 and 90 mL/min per 1.73 m(2). Higher calcium concentrations (r = -0.42, P = .02) and a greater proportion of time with relative hypercalcemia (r = -0.41, P = .03) were associated with lower eGFR. CONCLUSIONS: Our results establish that children with hypoparathyroidism treated with calcitriol and calcium supplements are at risk for nephrocalcinosis and decreased eGFR. Because hypoparathyroidism is most commonly a life-long condition, careful monitoring and management of calcium abnormalities has important future implications.

Determinants of coronary artery calcification in maintenance hemodialysis patients.

In addition to the well-known traditional risk factors, uremia-related so-called novel risk factors and medications appear to affect coronary artery calcification in hemodialysis patients. This study was performed to evaluate coronary artery calcification score (CACS) in maintenance hemodialysis (MHD) patients, and to identify significantly related factors. We assessed CACS using Agatston Score by MDCT, sex, age, dialysis vintage, presence of diabetes mellitus, smoking history, presence of ≥100 ml urine volume/day, normalized protein catabolic rate, geriatric nutritional risk index, administration of active vitamin D3, cinacalcet, phosphate binders or antihypertensive agents, and circulation parameters including creatinine, albumin, corrected calcium and phosphate in 207 MHD patients. Coronary artery calcifications were observed in 192 patients (92.8%). In multivariate analysis, CACS showed direct associations with age (p < 0.001), dialysis vintage (p < 0.001) and presence of diabetes mellitus (p < 0.01), and an inverse association only with active vitamin D3 administration (p < 0.001) in MHD patients. Patients with active vitamin D3 showed significantly lower CACS than in those without it (1349.6 ± 1635.0 vs. 2475.6 ± 2646.6 H, p < 0.05). Older age, longer duration of dialysis and diabetes mellitus are risk factors and administration of active vitamin D3 is protective factor for coronary artery calcification in MHD patients.

Suppression of murine experimental autoimmune encephalomyelitis development by 1,25-dihydroxyvitamin D3 with autophagy modulation.

Multiple sclerosis (MS) has been associated with a history of sub-optimal exposure to ultraviolet light, implicating vitamin D3 as a possible protective agent. We evaluated whether 1,25(OH)2D3 attenuates the progression of experimental autoimmune encephalomyelitis (EAE), and explored its potential mechanisms. EAE was induced in C57BL/6 mice via immunization with MOG35-55, and some mice received 1,25(OH)2D3. 1,25(OH)2D3 inhibited EAE progression. Additionally, 1,25(OH)2D3 reduced inflammation, demyelination, and neuron loss in the spinal cord. The protective effect of 1,25(OH)2D3 was associated with significantly elevated expression of Beclin1, increased Bcl-2/Bax ratio, and decreased LC3-II accumulation. Thus, 1,25(OH)2D3 may represent a promising new MS treatment.

Oral manifestations of hyperparathyroidism secondary to familial hypophosphatemic rickets.

A 14-year-old male with familial hypophosphatemic rickets, being treated with oral phosphate and calcitriol therapy, presented to the Division of Pediatric Dentistry, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, Pa. A panoramic radiograph showed multifocal, multilocular lesions in the mandible leading to surgical exploration and biopsy. Histopathological evaluation of the largest lesion showed features consistent with central giant cell granuloma. Given the patient's history, hyperparathyroidism was suspected. Laboratory data showed an elevated parathyroid hormone of 152 pg/ml (normal range equals nine to 69). This confirmed the diagnosis of multiple brown tumors in the mandible associated with secondary hyperparathyroidism, which was attributed to high-dose phosphate treatment. After endocrinology consultation, calcitriol therapy was increased. Improvement of the patient's brown tumors is expected with medical therapy. The purpose of this case report was to raise awareness among pediatric dentists about the maxillofacial ramifications of secondary hyperparathyroidism.