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Hypercalcemia is a significant complication in cancer patients, primarily caused by parathyroid hormone-related peptide (PTHrP) and, rarely, by parathyroid hormone (PTH) production from tumors. We report a case of severe hypercalcemia in a woman with uterine cancer who exhibited elevated PTH and PTHrP levels. Surgical intervention revealed dedifferentiated endometrial carcinoma. Postoperatively, PTH and PTHrP levels normalized but subsequently increased due to metastases. A molecular analysis confirmed the expression of the PTH gene and protein within the tumor, indicating ectopic PTH production. In diagnosing and treating cancers, it is necessary to consider not only PTHrP production but also ectopic PTH production.

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We present a case of a PTH-related peptide (PTH-rp) producing uterine myoma, leading to hypercalcemia in pregnancy. Our patient presented with dehydration, hypotension, delirium, and malnutrition. Due to a serum calcium level of 17.9 mg/dL (4.48 mmol/L) (reference range 8.8-11.2 mg/dL; 2.20-2.80 mmol/L), prompt treatment with hydration and calcitonin was initiated. The patient went into labor before we could consider other treatment options. Although uncommon in pregnancy, it is of great importance to identify hypercalcemia since it is related to a high risk of maternal and neonatal morbidity and mortality. Because bisphosphonates are contraindicated in pregnancy, hydration and calcitonin are the cornerstones of treatment for PTH-rp-induced hypercalcemia.

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Calcium plays central roles in numerous biological processes, thereby, its levels in the blood are under strict control to maintain homeostatic balance and enable the proper functioning of living organisms. The regulatory mechanisms ensuring this balance can be affected by pathologies such as cancer, and as a result, hyper- or hypocalcemia can occur. These states, characterized by elevated or decreased calcium blood levels, respectively, have a significant effect on general homeostasis. This article focuses on a particular form of calcium metabolism disorder, which is hypercalcemia in neoplasms. It also constitutes a summary of the current knowledge regarding the diagnosis of hypercalcemia and its management. Hypercalcemia of malignancy is estimated to affect over 40% of cancer patients and can be associated with both solid and blood cancers. Elevated calcium levels can be an indicator of developing cancer. The main mechanism of hypercalcemia development in tumors appears to be excessive production of parathyroid hormone-related peptides. Among the known treatment methods, bisphosphonates, calcitonin, steroids, and denosumab should be mentioned, but ongoing research promotes progress in pharmacotherapy. Given the rising global cancer prevalence, the problem of hypercalcemia is of high importance and requires attention.

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Humoral hypercalcemia of malignancy (HHM) comprises the majority of cases with malignancy-related hypercalcemia and is mediated by elevated parathyroid hormone-related peptide (PTHrP). HHM is rare in cholangiocarcinoma and has been reported only in a few case reports and series. We report a case of a 63-year-old male with a history of locally advanced fibroblast growth factor receptor (FGFR) fusion-positive intrahepatic cholangiocarcinoma who presented with recurrent HHM. The first episode of his hypercalcemia occurred 15 months after the initial diagnosis of cholangiocarcinoma and coincided with disease progression. The hypercalcemia was treated with zoledronic acid, and an FGFR inhibitor was started for the treatment of his malignancy. The second hypercalcemia episode occurred nine months later, with evidence of further disease progression. HHM is associated with poor clinical outcomes; a high index of suspicion should be present to identify and treat this complication in cases of cholangiocarcinoma promptly. With an increased understanding of the molecular alterations underlying cholangiocarcinoma, it will also be necessary to further evaluate its co-occurrence with HHM as the specific molecular alterations in this setting could lay the groundwork for targeted therapies and improve risk stratification for these patients.

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Hypoparathyroidism requires management with both calcium supplementation and active vitamin D to avert a state of hypocalcemia. During late gestation and the postpartum period (specifically lactation), there is an under-recognized, yet intriguing occurrence of apparent 'pseudohyperparathyroidism', whereby supplementation dosages may need to either be reduced or discontinued, to prevent hypercalcemia. The explanation for this apparent phenomenon of improved parathyroid status ('remission' or 'resolution') is incompletely understood; the purpose of this review is to analyze the case reports of this enigma within the medical (and grey) literature, providing an overall pathophysiological explanation and recommendation for the management of such patients. A literature search was conducted through PubMed/Medline, CINAHL, Cochrane Library Database, Scopus, UpToDate, Google Scholar, and the grey literature without a time-restricted period, analyzing all available articles within the literature describing an apparent improvement in parathyroid status in late-gestation and postpartum (lactating) females. Non-hypoparathyroid case reports were also included to further analyze and synthesize an overall likely pathophysiological explanation. Through the literature search, 24 papers were identified covering such a phenomenon in patients with hypoparathyroidism, alongside multiple additional reports of a similar occurrence in patients without underlying hypoparathyroidism. The pathophysiology is believed to occur due to the placental production of parathyroid hormone-related peptide (PTHrP) during gestation, with further production from the lactating mammary glands during the postpartum period. A typical pattern is observed, with increased PTHrP and suppressed PTH throughout both gestation and lactation (present in both normal and hypoparathyroid subjects). The concept of PTHrP-induced hypercalcemia is further demonstrated in patients without hypoparathyroidism, including subjects with placental hypersecretion and mammary gland enlargement. It is evident that patients with hypoparathyroidism may require a dosage reduction during late gestation and lactation, due to the risk for hypercalcemia. In addition to patients with hypoparathyroidism, this pathophysiological phenomenon occurs in unsuspecting patients, demonstrating the need for all clinicians in contact with pregnant females to be aware of this uncommon - yet perilous - occurrence.

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Renal cell carcinoma (RCC) is the most common type of kidney cancer. It typically presents with macroscopic hematuria, weight loss, and or a palpable flank mass. Diagnosis of this disease involves imaging techniques such as abdominal ultrasound and CT scans. Care for RCC can consist of ablation, tumor removal, nephrectomy, and systemic treatment options. Herein, we present a case of a 50-year-old Hispanic male with complaints of rectal bleeding and hematuria. Prior to admission, the patient had been informed twice about high suspicion of renal malignancy. Due to low health literacy and barriers to communication, he failed to understand the magnitude of his diagnosis. Subsequently, he underwent a resection of a considerable 22 cm x 13 cm x 13 cm RCC of his left kidney. This case highlights the need for effective patient health education to prevent emotional distress in patients with low health literacy.

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The superficial zone cells in mandibular condylar cartilage are proliferative. The present purpose was to delineate the relation of calcium-sensing receptor (CaSR) and parathyroid hormone-related peptide nuclear localization sequence (PTHrP87-139 ), and their role in the proliferation behaviors of the superficial zone cells. A gain- and loss-of-function strategy were used in an in vitro fluid flow shear stress (FFSS) model and an in vivo bilateral elevation bite model which showed mandibular condylar cartilage thickening. CaSR and PTHrP87-139 were modulated through treating the isolated superficial zone cells with activator/SiRNA and via deleting CaSR or parathyroid hormone-related peptide (PTHrP) gene in mice with the promoter gene of proteoglycan 4 (Prg4-CreERT2 ) in the tamoxifen-inducible pattern with or without additional injection of Cinacalcet, the CaSR agonist, or PTHrP87-139 peptide. FFSS stimulated CaSR and PTHrP expression, and accelerated proliferation of the Prg4-expressing superficial zone cells, in which process CaSR acted as an up-streamer of PTHrP. Proteoglycan 4 specific knockout of CaSR or PTHrP reduced the cartilage thickness, suppressed the proliferation and early differentiation of the superficial zone cells, and inhibited cartilage thickening and matrix production promoted by bilateral elevation bite. Injections of CaSR agonist Cinacalcet could not improve the phenotype caused by PTHrP mutation. Injections of PTHrP87-139 peptide rescued the cartilage from knockout of CaSR gene. CaSR modulates proliferation of the superficial zone cells in mandibular condylar cartilage through activation of PTHrP nuclear localization sequence. Our data support the therapeutic target of CaSR in promoting PTHrP production in superficial zone cartilage.

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Elaborate bioreactor cultivation or expensive growth factor supplementation can enhance extracellular matrix production in engineered neocartilage to provide sufficient mechanical resistance. We here investigated whether raising extracellular calcium levels in chondrogenic cultures to physiologically relevant levels would provide a simple and inexpensive alternative to enhance cartilage neogenesis from human articular chondrocytes (AC) or bone marrow-derived mesenchymal stromal cells (BMSC). Interestingly, AC and BMSC-derived chondrocytes showed an opposite response to a calcium increase from 1.8 mM to 8 mM by which glycosaminoglycan (GAG) and collagen type II production were elevated during BMSC chondrogenesis but depressed in AC, leading to two-fold higher GAG/DNA values in BMSC-based neocartilage compared to the AC group. According to control treatments with Mg2+ or sucrose, these effects were specific for CaCl2 rather than divalent cations or osmolarity. Importantly, undesired pro-hypertrophic traits were not stimulated by calcium treatment. Specific induction of PTHrP mRNA and protein by 8.0mM calcium only in AC, along with negative effects of recombinant PTHrP1-34 on cartilage matrix production, suggested that the PTHrP pathway contributed to the detrimental effects in AC-based neocartilage. Altogether, raising extracellular calcium levels was discovered as a novel, simple and inexpensive stimulator for BMSC-based cartilage neogenesis without the need for special bioreactors, whereas such conditions should be avoided for AC.

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The local application of drug-loaded bioactive scaffold materials is one of the important directions to solve the clinical problem of osteoporotic (OP) bone defects. This study retains the advantages of drug loading and mechanical properties of natural 3D bioactive scaffolds. The scaffolds are functionally modified through chemical and self-assembly approaches with application of polydopamine (PDA) nanoparticles and parathyroid hormone-related peptide-1 (PTHrP-1) for efficient local drug loading. This study investigates the effects of the novel bioactive scaffolds on ossification, osteoclastogenesis, and macrophage polarization. This work elucidates the effects of the scaffolds in regulating osteoclastic activity and new bone formation in vitro. Further studies on the establishment and repair of OP bone defects in small animals are conducted, and the potential of natural bioactive porous scaffold materials to promote the repair of OP bone defects is initially verified. The preparation of safe and economical anti-OP bone repair material provides a theoretical basis for clinical translational applications.

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A 61-year-old Japanese woman presented with epigastric pain and jaundice. Imaging showed the presence of primary distal cholangiocarcinoma (DCC). A subtotal stomach-preserving pancreaticoduodenectomy was performed, followed by chemotherapy using S-1. However, second-line chemotherapy with gemcitabine and cis-diamminedichloroplatinum was required for the treatment of hepatic metastasis of the DCC 3 months following the surgery. Nine months after the surgery, the serum calcium and parathyroid hormone-related peptide concentrations were high, at 16.5 mg/dL and 28.7 pmol/L, respectively, which suggested the presence of humoral hypercalcemia of malignancy (HHM) secondary to the DCC. Moreover, marked leukocytosis, with a white blood cell count of 40,400/µL, was also present. The patient died 11 months after the diagnosis of DCC. Because hypercalcemia of malignancy is associated with a poor prognosis, and HHM and leukocytosis caused by DCC are very rare, we have presented the present case in detail and provide a review of the existing literature.

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Hypercalcemia - Diagnosis and Management Abstract. The diagnostic workup of hypercalcemia requires a thorough patient history, a focused clinical examination as well as a step-by-step laboratory diagnostic approach. In order to detect the exact aetiology of hypercalcemia an accurate measurement of serum calcium in correlation with the parathyroid hormone level is therefore essential. Primary hyperparathyroidism and malignancy-related hypercalcemia are responsible for about 90% of all hypercalcemia cases. Therefore, these two pathologies should always be considered in the diagnostic approach. The therapeutic procedure is based on the aetiology and severity of the hypercalcemia.

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Hypercalcaemia is common in patients with malignancy, but is rare in seminoma with only eight cases reported in the literature. We present an unusual case of a 36-year-old man who presented with hypercalcaemia and stage 3 acute kidney injury. He presented initially with headache and malaise, and was found to have markedly deranged blood tests. He underwent a renal biopsy before imaging confirmed an unexpected large abdominal mass, which was confirmed histologically to be a seminoma. He was referred to a tertiary oncology centre, and underwent emergency chemotherapy and radical resection with no evidence of recurrence to this date and with return to normocalcaemia.

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Endochondral bone formation is an important pathway in fracture healing, involving the formation of a cartilaginous soft callus and the process of cartilage-to-bone transition. Failure or delay in the cartilage-to-bone transition causes an impaired bony union such as nonunion or delayed union. During the healing process, multiple types of cells including chondrocytes, osteoprogenitors, osteoblasts, and endothelial cells coexist in the callus, and inevitably crosstalk with each other. Hypertrophic chondrocytes located between soft cartilaginous callus and bony hard callus mediate the crosstalk regulating cell-matrix degradation, vascularization, osteoclast recruitment, and osteoblast differentiation in autocrine and paracrine manners. Furthermore, hypertrophic chondrocytes can become osteoprogenitors and osteoblasts, and directly contribute to woven bone formation. In this review, we focus on the roles of hypertrophic chondrocytes in fracture healing and dissect the intermingled crosstalk in fracture callus during the cartilage-to-bone transition.

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Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) regulate extracellular phosphate and calcium homeostasis as well as bone remodeling. PTH is a classic endocrine peptide hormone whose synthesis and negative feedback by multiple factors control release from the parathyroid glands. PTHrP is ubiquitously expressed (pre- and postnatally) and acts in an autocrine/paracrine manner. This review considers the structural pharmacology and actions of PTH and PTHrP, biological consequences of inherited mutations, engineered analogs that illuminate similarities and differences in physiologic actions, and targeted therapeutic opportunities.

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Parathyroid hormone-related peptide (PTHrP) is well-known to play a role in bone formation, and abaloparatide, an analog of PTHrP(1-34), is approved for the treatment of osteoporosis in post-menopausal women. PTHrP has also been reported to have cardiovascular effects, with recent data demonstrating that exogenously administered PTHrP can limit the death of isolated cardiomyocytes subjected to oxidative stress via upregulation of classic 'survival kinase' signaling. Our aim in the current study was to extend this concept and, employing both in vitro and in vivo models, establish whether PTHrP(1-36) and abaloparatide are cardioprotective in the setting of lethal myocardial ischemia-reperfusion injury. We report that preischemic administration of PTHrP(1-36) and abaloparatide attenuated cell death in HL-1 cardiomyocytes subjected to simulated ischemia-reperfusion, an effect that was accompanied by the augmented expression of phospho-ERK and improved preservation of phospho-Akt, and blocked by co-administration of the MEK-ERK inhibitor PD98059. Moreover, using the translationally relevant swine model of acute coronary artery occlusion-reperfusion, we make the novel observation that myocardial infarct size was significantly reduced in pigs pretreated with PTHrP(1-36) when compared with placebo-controls (13.1 ± 3.3% versus 42.0 ± 6.6% of the area of at-risk myocardium, respectively; p < 0.01). Taken together, these data provide the first evidence in support of the concept that pretreatment with PTHrP(1-36) and abaloparatide renders cardiomyocytes resistant to lethal myocardial ischemia-reperfusion injury.

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Humoral hypercalcemia of malignancy (HHM) is a paraneoplastic syndrome caused by elevations in parathyroid hormone-related protein (PTH-rP). HHM often presents in patients with squamous cell carcinomas of the lung, head, and neck, as well as breast, ovarian, renal, and bladder carcinomas. HHM associated with neuroendocrine carcinoma (NEC) is rarely observed. Here, we report a case of NEC-associated HHM refractory to standard calcium-reducing therapies but improved with the off-label addition of cinacalcet. A 31-year-old male with metastatic NEC presented to the emergency department (ED) with symptoms of nausea, emesis, constipation, and progressive weakness. He was being treated via a clinical trial at a tertiary referral center after failing standard therapies. He had recently been admitted at an outside facility for hypercalcemia, which had been managed with denosumab (120 mg subcutaneously) over the previous four weeks. He was admitted from the ED with a serum calcium of 14.6 mg/dL, potassium of 2.9 mmol/L, and phosphate of 1.2 mg/dL; ionized calcium was elevated at 8.0 mg/dL. Despite hydration and aggressive electrolyte replacement, his calcium increased to 15.5 mg/dL. Further laboratory evaluation revealed parathyroid hormone (PTH) of 6 pg/mL (10-65 pg/mL), 25-hydroxyvitamin D of 25 ng/mL (25-80 ng/mL), 1,25-dihydroxyvitamin D of 513 pg/mL (18-64 pg/mL), and PTH-rP of 25 pmol/L (<2.5 pmol/L), consistent with HHM. Calcitonin was avoided due to a prior hypersensitivity reaction. He received prednisone 10 mg daily and pamidronate 90 mg IV, and his calcium improved to 11.5 mg/dL. He was discharged and investigational therapy was resumed. This therapy failed, and he did not qualify for additional cancer therapy due to refractory hypercalcemia. He was started on cinacalcet, and his calcium decreased enough to permit further cancer treatment. He had multiple hospitalizations with fluctuating calcium levels and ultimately died several months later after sustaining a subarachnoid hemorrhage from a fall. In conclusion, we report a rare case of HHM associated with NEC. While many cases of HHM are effectively managed with hydration, calcitonin, antiresorptive therapies, and glucocorticoids, some are refractory. Our patient was refractory and differed from most patients with HHM in at least two ways. As mentioned previously, NEC causing HHM is quite uncommon (~2% of cases); it is unclear, but this malignancy might predispose to refractory hypercalcemia. Our patient's elevated vitamin D may also have made his HHM more resistant to treatment. Ultimately, while not first line, cinacalcet was an effective treatment in our patient. This provides additional evidence that cinacalcet may be considered for refractory hypercalcemia secondary to malignancy.

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BACKGROUND: Parathyroid hormone related peptide (PTHrP) measurements are helpful in the evaluation and management of individuals suspected of humoral hypercalcemia of malignancy (HHM). AIM: To develop a chemiluminescent assay for PTHrP quantitation, establish reference intervals, and evaluate its clinical performance. METHOD: PTHrP 1-86 was measured using a polyclonal rabbit antibody (capture) and an acridinium ester labeled goat polyclonal antibody for chemiluminescent detection. RESULTS: Assay imprecision was < 9% (intra-assay) and < 15% (inter-assay). The analytical measuring range was 0.16-50.5 pmol/L. No significant cross-reactivity was observed for PTH (1-84), PTHrP (107-139), and PTHrP (1-36); whereas PTHrP (38-94) showed 8.3% cross-reactivity. Comparison with the pre-existing Mayo assay showed a positive bias: new assay = 2.24 (pre-existing assay)-0.30 and r2 = 0.96. The reference interval was ≤ 0.7 pmol/L, however, a cut-off of ≤ 4.2 pmol/L yielded increased specificity (98%). Comparison of patients with HHM versus those without HHM resulted in an area under the ROC curve of 0.99. A significant inverse relationship between eGFR and PTHrP was observed (r = 0.738). PTHrP concentrations in patients with Chronic Kidney Disease (CKD) were ≤ 4.2 pmol/L. CONCLUSION: This assay is specific for PTHrP 1-86. A clinical decision limit of 4.2 pmol/L was sensitive and specific for patients with HHM.

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A 24-year-old female presented with nausea, vomiting and abdominal pain. Physical examination was unremarkable. The patient's laboratory studies showed calcium of 17.2 mg/d, white cell count: 9,000/mcL with a normal peripheral blood smear. The patient had low PTH and PTHrp. She was hydrated, given calcitonin of four units/kg every 12 hours subcutaneously for 24 hours and zoledronate IV 4mg given once, with which calcium levels normalized and symptoms resolved. The patient returned one week later, with bone pain and bruises. Platelet count: 51,000/mcL, WBC count: 9,000/mcL, with lymphocytosis. A peripheral smear showed lymphoblasts. Flow cytometry confirmed precursor B-cell acute lymphoblastic leukemia (ALL) with 43% blasts. Hypercalcemic patients may have blasts at presentation, but can be "aleukemic." Unexplained hypercalcemia with bone pain should lead to the suspicion of ALL, and a bone marrow exam should be performed even without peripheral blastosis to diagnose and treat ALL immediately.

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Stromal cells in the tumor microenvironment (TME) can regulate the progression of numerous types of cancer; however, the bone invasion of oral squamous cell carcinoma (OSCC) has been poorly investigated. In the present study, the effect of verrucous SCC­associated stromal cells (VSCC­SCs), SCC­associated stromal cells (SCC­SCs) and human dermal fibroblasts on bone resorption and the activation of HSC­3 osteoclasts in vivo were examined by hematoxylin and eosin, AE1/3 (pan­cytokeratin) and tartrate­resistant acid phosphatase staining. In addition, the expression levels of matrix metalloproteinase (MMP)9, membrane­type 1 MMP (MT1­MMP), Snail, receptor activator of NF­κB ligand (RANKL) and parathyroid hormone­related peptide (PTHrP) in the bone invasion regions of HSC­3 cells were examined by immunohistochemistry. The results suggested that both SCC­SCs and VSCC­SCs promoted bone resorption, the activation of osteoclasts, and the expression levels of MMP9, MT1­MMP, Snail, RANKL and PTHrP. However, SCC­SCs had a more prominent effect compared with VSCC­SCs. Finally, microarray data were used to predict potential genes underlying the differential effects of VSCC­SCs and SCC­SCs on bone invasion in OSCC. The results revealed that IL1B, ICAM1, FOS, CXCL12, INS and NGF may underlie these differential effects. In conclusion, both VSCC­SCs and SCC­SCs may promote bone invasion in OSCC by enhancing the expression levels of RANKL in cancer and stromal cells mediated by PTHrP; however, SCC­SCs had a more prominent effect. These findings may represent a potential regulatory mechanism underlying the bone invasion of OSCC.

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Pregnancy and lactation-related osteoporosis (PLO) is the development of osteoporosis in a premenopausal woman, usually in the third trimester of pregnancy or puerperium. The hormonal changes that allow for the maternal-fetal calcium gradient may be the underlying cause for bone loss, but it is not currently known why some women are affected so severely. Because osteoporosis does not cause symptoms until the condition is advanced, diagnosis is usually made upon the development of an osteoporotic fracture or incidentally when imaging is performed for other reasons. Spontaneous recovery is common once lactation is discontinued, as the underlying hormonal factors that caused the osteoporosis revert to the pre-pregnancy state. We used the research database TriNetX (TriNetX, LLC, Cambridge, MA) to perform a query selecting women between the ages of 10 and 50 years old who experienced an osteoporotic fracture within 12 months of pregnancy. We analyzed the cohort of patients to determine the incidence of fractures at different skeletal locations and evaluated the medications that were utilized in the patients who received treatment.