Severe hypophosphataemia and hypocalcaemia following intravenous ferric derisomaltose and denosumab administration.

Serum calcium and phosphorus levels are tightly regulated by the calciotropic hormone parathyroid hormone, fibroblast growth factor 23 and 1,25(OH) vitamin D. Commonly prescribed therapies for iron-deficiency anaemia (IDA) such as ferric carboxymaltose and ferric derisomaltose (FDM) have been shown to disrupt phosphorus homeostasis, resulting in hypophosphataemia. Similarly, denosumab use can result in hypocalcaemia due to the inhibition of osteoclastic maturation, activity and survival.

PTHrP Regulates Fatty Acid Metabolism via Novel lncRNA in Breast Cancer Initiation and Progression Models.

Parathyroid hormone-related peptide (PTHrP) is the primary cause of malignancy-associated hypercalcemia (MAH). We previously showed that PTHrP ablation, in the MMTV-PyMT murine model of breast cancer (BC) progression, can dramatically prolong tumor latency, slow tumor growth, and prevent metastatic spread. However, the signaling mechanisms using lineage tracing have not yet been carefully analyzed.

SCF-SKP2 E3 ubiquitin ligase links mTORC1/ER stress/ISR with YAP activation in murine renal cystogenesis.

The Hippo pathway nuclear effector Yes-associated protein (YAP) potentiates the progression of polycystic kidney disease (PKD) arising from ciliopathies. The mechanisms underlying the increase in YAP expression and transcriptional activity in PKD remain obscure. We observed that in kidneys from mice with juvenile cystic kidney (jck) ciliopathy, the aberrant hyperactivity of mechanistic target of rapamycin complex 1 (mTORC1), driven by ERK1/2 and PI3K/AKT cascades, induced ER proteotoxic stress.

Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1).

Context: Autosomal recessive hypophosphatemic rickets (ARHR) are rare, heritable renal phosphate-wasting disorders that arise from overexpression of the bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23) leading to impaired bone mineralization (rickets and osteomalacia). Inactivating mutations of Dentin matrix protein 1 (DMP1) give rise to ARHR type 1 (ARHR1). Short stature, prominent bowing of the legs, fractures/pseudofractures, and severe enthesopathy are prominent in this patient population.

Role of PTHrP nuclear localization and carboxyl terminus sequences in postnatal spinal cord development.

Parathyroid hormone-related peptide (PTHrP) acts under physiological conditions to regulate normal development of several tissues and organs. The role of PTHrP in spinal cord development has not been characterized. Pthrp knock in (Pthrp KI) mice were genetically modified to produce PTHrP in which there is a deficiency of the nuclear localization sequence (NLS) and C-terminus.

Parathyroid Hormone-Related Protein (PTHrP): An Emerging Target in Cancer Progression and Metastasis.

PTHrP was first discovered as the most common mediator of malignancy-associated hypercalcemia. Subsequently, the discovery of its ubiquitous expression in normal tissues unraveled its role as a physiological autocrine/paracrine regulator. The significance of PTHrP in cancer is not confined to malignancy-associated hypercalcemia, and sufficient evidence now also supports its role in skeletal metastasis through its modulation of bone turnover.

DNA damage checkpoint pathway modulates the regulation of skeletal growth and osteoblastic bone formation by parathyroid hormone-related peptide.

We previously demonstrated that parathyroid hormone-related peptide (PTHrP) 1-84 knockin ( KI) mice, which lacked a PTHrP nuclear localization sequence (NLS) and C-terminus, displayed early senescence, defective osteoblastic bone formation, and skeletal growth retardation. However, the mechanism of action of the PTHrP NLS and C-terminus in regulating development of skeleton is still unclear. In this study, we examined alterations of oxidative stress and DNA damage response-related molecules in KI skeletal tissue.

Defective interplay between mTORC1 activity and endoplasmic reticulum stress-unfolded protein response in uremic vascular calcification.

Vascular calcification increases the risk of cardiovascular disease and death in patients with chronic kidney disease (CKD). Increased activity of mammalian target of rapamycin complex 1 (mTORC1) and endoplasmic reticulum (ER) stress-unfolded protein response (UPR) are independently reported to partake in the pathogenesis of vascular calcification in CKD. However, the association between mTORC1 activity and ER stress-UPR remains unknown.

The parathyroid hormone regulates skin tumour susceptibility in mice.

Using a forward genetics approach to map loci in a mouse skin cancer model, we previously identified a genetic locus, Skin tumour modifier of MSM 1 (Stmm1) on chromosome 7, conferring strong tumour resistance. Sub-congenic mapping localized Parathyroid hormone (Pth) in Stmm1b. Here, we report that serum intact-PTH (iPTH) and a genetic polymorphism in Pth are important for skin tumour resistance.

Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis.

Background: Romosozumab is a monoclonal antibody that binds to and inhibits sclerostin, increases bone formation, and decreases bone resorption.

Methods: We enrolled 4093 postmenopausal women with osteoporosis and a fragility fracture and randomly assigned them in a 1:1 ratio to receive monthly subcutaneous romosozumab (210 mg) or weekly oral alendronate (70 mg) in a blinded fashion for 12 months, followed by open-label alendronate in both groups. The primary end points were the cumulative incidence of new vertebral fracture at 24 months and the cumulative incidence of clinical fracture (nonvertebral and symptomatic vertebral fracture) at the time of the primary analysis (after clinical fractures had been confirmed in ≥330 patients).

A Case of Male Osteoporosis: A 37-Year-Old Man with Multiple Vertebral Compression Fractures.

While the contributing role of testosterone to bone health is rather modest compared to other factors such as estradiol levels, male hypogonadism is associated with low bone mass and fragility fractures. Along with stimulating physical puberty by achieving virilization and a normal muscle mass and improving psychosocial wellbeing, the goals of testosterone replacement therapy in male hypogonadism also include attainment of age-specific bone mineral density. We report on a 37-year-old man who presented with multiple vertebral compression fractures several years following termination of testosterone replacement therapy for presumed constitutional delay in growth and puberty.

FGF23 Is Not Required to Regulate Fetal Phosphorus Metabolism but Exerts Effects Within 12 Hours After Birth.

Loss of fibroblast growth factor-23 (FGF23) causes hyperphosphatemia, extraskeletal calcifications, and early mortality; excess FGF23 causes hypophosphatemia with rickets or osteomalacia. However, FGF23 may not be important during fetal development. FGF23 deficiency (Fgf23 null) and FGF23 excess (Phex null) did not alter fetal phosphorus or skeletal parameters.

Fibroblast Growth Factor 23 Regulation by Systemic and Local Osteoblast-Synthesized 1,25-Dihydroxyvitamin D.

Circulating levels of fibroblast growth factor 23 (FGF23) increase during the early stages of kidney disease, but the underlying mechanism remains incompletely characterized. We investigated the role of vitamin D metabolites in regulating intact FGF23 production in genetically modified mice without and with adenine-induced uremia. Exogenous calcitriol (1,25-dihydroxyvitamin D) and high circulating levels of calcidiol (25-hydroxyvitamin D) each increased serum FGF23 levels in wild-type mice and in mice with global deficiency of the Cyp27b1 gene encoding 25-hydroxyvitamin D 1-α-hydroxylase, which produces 1,25-hydroxyvitamin D.

The Role of Parathyroid Hormone-Related Protein (PTHrP) in Osteoblast Response to Microgravity: Mechanistic Implications for Osteoporosis Development.

Prolonged skeletal unloading through bedrest results in bone loss similar to that observed in elderly osteoporotic patients, but with an accelerated timeframe. This rapid effect on weight-bearing bones is also observed in astronauts who can lose up to 2% of their bone mass per month spent in Space. Despite the important implications for Spaceflight travelers and bedridden patients, the exact mechanisms involved in disuse osteoporosis have not been elucidated.

Overexpression of Bmi1 in Lymphocytes Stimulates Skeletogenesis by Improving the Osteogenic Microenvironment.

To investigate whether overexpression of Bmi1 in lymphocytes can stimulate skeletogenesis by improving the osteogenic microenvironment, we examined the skeletal phenotype of EμBmi1 transgenic mice with overexpression of Bmi1 in lymphocytes. The size of the skeleton, trabecular bone volume and osteoblast number, indices of proliferation and differentiation of bone marrow mesenchymal stem cells (BM-MSCs) were increased significantly, ROS levels were reduced and antioxidative capacity was enhanced in EμBmi1 mice compared to WT mice. In PTHrP1-84 knockin (Pthrp(KI/KI)) mice, the expression levels of Bmi1 are reduced and potentially can mediate the premature osteoporosis observed.

PTHrP Nuclear Localization and Carboxyl Terminus Sequences Modulate Dental and Mandibular Development in Part via the Action of p27.

To determine whether the action of the PTHrP nuclear localization sequence and C terminus is mediated through p27 in modulating dental and mandibular development, compound mutant mice, which are homozygous for both p27 deletion and the PTHrP1-84 knock-in mutation (p27(-/-)Pthrp(KI/KI)), were generated. Their teeth and mandibular phenotypes were compared with those of p27(-/-), Pthrp(KI/KI), and wild-type mice. At 2 weeks of age, the mandibular mineral density, alveolar bone volume, osteoblast numbers, and dental volume, dentin sialoprotein-immunopositive areas in the first molar were increased significantly in p27(-/-) mice and decreased dramatically in both Pthrp(KI/KI) and p27(-/-) Pthrp(KI/KI) mice compared with wild-type mice; however, these parameters were partly rescued in p27(-/-) Pthrp(KI/KI) mice compared with Pthrp(KI/KI) mice.

CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders.

CYP24A1 (hereafter referred to as CYP24) enzymatic activity is pivotal in the inactivation of vitamin D metabolites. Basal renal and extrarenal CYP24 is usually low but is highly induced by its substrate 1,25-dihydroxyvitamin D. Unbalanced high and/or long-lasting CYP24 expression has been proposed to underlie diseases like chronic kidney disease, cancers, and psoriasis that otherwise should favorably respond to supplemental vitamin D.

Deficiency of the parathyroid hormone-related peptide nuclear localization and carboxyl terminal sequences leads to premature skin ageing partially mediated by the upregulation of p27.

We previously reported that deficiency of the PTHrP nuclear localization sequence (NLS) and C-terminus in PTHrP knockin (PTHrP KI) mice resulted in premature ageing of skin. P27, a cyclin-dependent kinase inhibitor, was upregulated in PTHrP KI mice and acted as a downstream target of the PTHrP NLS to regulate the proliferation of vascular smooth muscle cells. To determine the effects of p27 deficiency on premature skin ageing of PTHrP KI mice, we compared the skin phenotypes of PTHrP KI mice to those of p27 knockout (p27(-/-) ) mice and to those of double homozygous p27-deficient and PTHrP KI (p27(-/-) PTHrP KI) mice at 2 weeks age.

Bone Is a Major Target of PTH/PTHrP Receptor Signaling in Regulation of Fetal Blood Calcium Homeostasis.

The blood calcium concentration during fetal life is tightly regulated within a narrow range by highly interactive homeostatic mechanisms that include transport of calcium across the placenta and fluxes in and out of bone; the mechanisms of this regulation are poorly understood. Our findings that endochondral bone-specific PTH/PTHrP receptor (PPR) knockout (KO) mice showed significant reduction of fetal blood calcium concentration compared with that of control littermates at embryonic day 18.5 led us to focus on bone as a possibly major determinant of fetal calcium homeostasis.

The p27 Pathway Modulates the Regulation of Skeletal Growth and Osteoblastic Bone Formation by Parathyroid Hormone-Related Peptide.

Parathyroid hormone-related peptide (PTHrP) 1-84 knock-in mice (Pthrp KI) develop skeletal growth retardation and defective osteoblastic bone formation. To further examine the mechanisms underlying this phenotype, microarray analyses of differential gene expression profiles were performed in long bone extracts from Pthrp KI mice and their wild-type (WT) littermates. We found that the expression levels of p27, p16, and p53 were significantly upregulated in Pthrp KI mice relative to WT littermates.

Deletion of the nuclear localization sequences and C-terminus of PTHrP impairs embryonic mammary development but also inhibits PTHrP production.

Parathyroid hormone-related protein (PTHrP) can be secreted from cells and interact with its receptor, the Type 1 PTH/PTHrP Receptor (PTHR1) in an autocrine, paracrine or endocrine fashion. PTHrP can also remain inside cells and be transported into the nucleus, where its functions are unclear, although recent experiments suggest that it may broadly regulate cell survival and senescence. Disruption of either the PTHrP or PTHR1 gene results in many abnormalities including a failure of embryonic mammary gland development in mice and in humans.

Bisphosphonates for treatment of osteoporosis: expected benefits, potential harms, and drug holidays.

Objective: To outline the efficacy and risks of bisphosphonate therapy for the management of osteoporosis and describe which patients might be eligible for bisphosphonate "drug holiday."

Quality Of Evidence: MEDLINE (PubMed, through December 31, 2012) was used to identify relevant publications for inclusion. Most of the evidence cited is level II evidence (non-randomized, cohort, and other comparisons trials).

Neither absence nor excess of FGF23 disturbs murine fetal-placental phosphorus homeostasis or prenatal skeletal development and mineralization.

Fibroblast growth factor-23 (FGF23) controls serum phosphorus largely through actions on the kidneys to excrete phosphorus and reduce calcitriol. Although these actions are well established in adults and children, the role that FGF23 plays in regulating fetal phosphorus metabolism has not been previously studied. We used several mouse models to study the effect of endogenous deficiency or excess of FGF23 on fetal phosphorus metabolism.