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The SUNFLOWER study was initiated in Japan and South Korea to clarify the course of X-linked hypophosphatemic rickets/osteomalacia (XLH); delineate its physical, mental, and financial burdens; and collect information on treatment. Here, we report cross-sectional data at the time of patient enrollment to better understand the real-world management and complications in patients with XLH and examine the effect of XLH on quality of life (QOL). This is an ongoing, longitudinal, observational cohort study of patients with a diagnosis of XLH. Data from 147 patients (118 in Japan and 29 in South Korea) were evaluated. In total, 77 children (mean age, 9.7 yr; 67.5% female) and 70 adults (mean age, 37.6 yr; 65.7% female) were enrolled. PHEX gene mutations were confirmed in 46/77 (59.7%) children and 37/70 (52.9%) adults. Most patients in both age groups were receiving a combination of phosphate and active vitamin D at baseline. The mean height Z-score was −2.21 among adults (male: −2.34; female: −2.14). The mean Rickets Severity Score in children was 1.62. Whereas children appeared to have low pain levels (mean revised faces pain scale score, 1.3), adults reported mild-to-moderate pain (mean Brief Pain Inventory pain severity, 2.02). Mean QOL in children (assessed using the 10-item short-form health survey for children) was low, with a score below normative level for physical functioning. In adults, results from the Western Ontario and McMaster Universities osteoarthritis index indicated the presence of pain, stiffness, and decreased physical function. The respective mean total days/year of work/school non-attendance due to symptoms/complications and management of XLH were 0.7 and 3.0 among adults, and 6.4 and 6.1 among children. Our findings reconfirmed a relationship between disease and QOL in patients with XLH. We anticipate that these data will be important in enabling clinicians to understand the daily reality of patients with XLH. Lay Summary: X-linked hypophosphatemic rickets/osteomalacia (XLH) is a rare, PHEX gene mutation-linked disorder that causes weak bones and bone deformities. The ongoing SUNFLOWER study aims to collect information on Japanese and South Korean patients with XLH to better understand how this disease progresses over time, its impact on quality of life (QOL), and how it is currently being treated. Data from 147 patients (77 children and 70 adults) were evaluated. Over half of the adults and children included in this study had a confirmed PHEX gene mutation. Although most patients were receiving conventional therapy for XLH, laboratory tests revealed that they had underlying issues with bone health and that their growth rates were still being negatively affected. Bone-related complications were more common among adults than children. Children reported low levels of pain, whereas adults reported mild-to-moderate pain. Children with XLH scored low for physical functioning on QOL tests. Adults with XLH reported pain, stiffness, and decreased physical function on QOL tests. XLH had a larger impact on children's school attendance than adults' work attendance. Our findings will help improve understanding of the daily reality of XLH patients in Japan and South Korea. [ABSTRACT FROM AUTHOR]

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare disorder caused by deficient FGF23 signaling and resultant ectopic calcification. Here, we systematically characterized and quantified macro- and micro-calcification in a HFTC cohort using CT and 18F-sodium fluoride PET/CT (18F-NaF PET/CT). Fourier-transform infrared (FTIR) spectroscopy was performed on 4 phenotypically different calcifications from a patient with HFTC, showing the dominant component to be hydroxyapatite. Eleven patients with HFTC were studied with CT and/or 18F-NaF PET/CT. Qualitative review was done to describe the spectrum of imaging findings on both modalities. CT-based measures of volume (eg, total calcific burden and lesion volume) and density (Hounsfield units) were quantified and compared to PET-based measures of mineralization activity (eg, mean standardized uptake values—SUVs). Microcalcification scores were calculated for the vasculature of 6 patients using 18F-NaF PET/CT and visualized on a standardized vascular atlas. Ectopic calcifications were present in 82% of patients, predominantly near joints and the distal extremities. Considerable heterogeneity was observed in total calcific burden per patient (823.0 ± 670.1 cm3, n = 9) and lesion volume (282.5 ± 414.8 cm3, n = 27). The largest lesions were found at the hips and shoulders. 18F-NaF PET offered the ability to differentiate active vs quiescent calcifications. Calcifications were also noted in multiple anatomic locations, including brain parenchyma (50%). Vascular calcification was seen in the abdominal aorta, carotid, and coronaries in 50%, 73%, and 50%, respectively. 18F-NaF-avid, but CT-negative calcification was seen in a 17-year-old patient, implicating early onset vascular calcification. This first systematic assessment of calcifications in a cohort of patients with HFTC has identified the early onset, prevalence, and extent of calcification. It supports 18F-NaF PET/CT as a clinical tool for distinguishing between active and inactive calcification, informing disease progression, and quantification of ectopic and vascular disease burden. Lay Summary: Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare disorder in which patients develop sometimes large debilitating calcifications of soft tissues and blood vessels. It is caused by deficient fibroblast growth factor-23 that leads to high phosphate levels, which contributes to the calcifications. The calcifications and manifestations of this disorder have not been well characterized. We determined the mineral composition of the calcifications to be hydroxyapatite. Capitalizing on the fact fluoride can be integrated into hydroxyapatite, we used radiolabeled sodium fluoride PET/CT scans (18F-NaF PET/CT) to characterize and quantify the calcifications in 11 patients. Eighty-two percent of the patients had calcifications, with the largest located at the hips and shoulders. Micro-calcifications were found in the blood vessels of most patients, including children. The technique also enabled us to differentiate between active vs stable calcifications. This first systematic assessment of calcifications in patients with HFTC showed the utility of 18F-NaF PET/CT as a tool to identify and quantify calcifications, as well as distinguish between active and stable calcifications. This approach will inform disease progression and may prove useful for measuring response to treatment. Graphical Abstract [ABSTRACT FROM AUTHOR]

A 63-yr-old woman with end-stage CKD secondary to glomerulonephritis, on hemodialysis therapy, presented with scoliosis, back pain, and progressive loss of physical function for which corrective surgery was planned. Optimization of bone health was requested by the surgeon as a DXA scan had revealed osteoporosis at spine, hip, and forearm. Due to previous subtotal parathyroidectomy and normal parathyroid hormone and bone-specific alkaline phosphatase levels, a low bone turnover state was suspected. An iliac bone biopsy was performed and revealed low bone turnover, a mineralization defect, and severe osteoporosis. The patient was treated with calcium and intensified vitamin D supplementation, followed by a 2-yr course of teriparatide. Monitoring of bone turnover markers indicated a bone anabolic response to therapy, and a repeat DXA showed increases in BMD at spine and hip. A repeat biopsy at end of treatment showed normal bone turnover and mineralization. This case demonstrates the complicated bone health of patients with advanced CKD. As there are no randomized trials for fracture pretention in patients with CKD, care must be individualized and is often based on expert opinion. The use of bone biopsy is safe and informative in guiding therapy. [ABSTRACT FROM AUTHOR]

Calcitriol circulates at low levels in normal human and rodent fetuses, in part due to increased 24-hydroxylation of calcitriol and 25-hydroxyvitamin D by 24-hydroxylase (CYP24A1). Inactivating mutations of CYP24A1 cause high postnatal levels of calcitriol and the human condition of infantile hypercalcemia type 1, but whether the fetus is disturbed by the loss of CYP24A1 is unknown. We hypothesized that loss of Cyp24a1 in fetal mice will cause high calcitriol, hypercalcemia, and increased placental calcium transport. The Cyp24a1+/− mice were mated to create pregnancies with wildtype, Cyp24a1+/− , and Cyp24a1 null fetuses. The null fetuses were hypercalcemic, modestly hypophosphatemic (compared to Cyp24a1+/− fetuses only), with 3.5-fold increased calcitriol, 4-fold increased fibroblast growth factor 23 (FGF23), and unchanged parathyroid hormone. The quantitative RT-PCR confirmed the absence of Cyp24a1 and 2-fold increases in S100g , sodium–calcium exchanger type 1, and calcium-sensing receptor in null placentas but not in fetal kidneys; these changes predicted an increase in placental calcium transport. However, placental 45Ca and 32P transport were unchanged in null fetuses. Fetal ash weight and mineral content, placental weight, crown-rump length, and skeletal morphology did not differ among the genotypes. Serum procollagen 1 intact N-terminal propeptide and bone expression of sclerostin and Blgap were reduced while calcitonin receptor was increased in nulls. In conclusion, loss of Cyp24a1 in fetal mice causes hypercalcemia, modest hypophosphatemia, and increased FGF23, but no alteration in skeletal development. Reduced incorporation of calcium into bone may contribute to the hypercalcemia without causing a detectable decrease in the skeletal mineral content. The results predict that human fetuses bearing homozygous or compound heterozygous inactivating mutations of CYP24A1 will also be hypercalcemic in utero but with normal skeletal development. [ABSTRACT FROM AUTHOR]

A 38-yr-old woman with chronic non-surgical hypoparathyroidism, managed elsewhere, presented to our practice with symptomatic hypocalcemia. At the age of 17, she began to suffer from muscle cramps, paresthesia, and ongoing diffuse pain. It took years before she was correctly diagnosed with hypoparathyroidism. Her symptoms were severe enough that she required emergency room visits several times a year. After she was properly diagnosed and started on calcium and calcitriol therapy, she continued to experience frequent episodes of severe hypocalcemia. She saw multiple healthcare providers who each introduced a new regimen. In addition, poor communication led to her discontinuing her medications altogether. As a result, her calcium levels remained consistently low, and she lost confidence in her prospect for better health. At the time of her visit to our clinic, she had discontinued calcitriol, was taking a large amount of oral calcium daily all at once, and had hypocalcemia. We addressed her concerns, and the challenges she faces with adherence to her medication regimen. We provided her with detailed information about the disease and the reasoning behind her treatment plan. Treatment was initiated with calcium carbonate 600 mg 3 times daily and calcitriol 0.5 mcg once daily. One week after treatment initiation, her test results showed improvement in her albumin-adjusted calcium, phosphorus, and 24-h urine calcium which were all within target range. [ABSTRACT FROM AUTHOR]

Two months after her first pregnancy, a 35-yr-old exclusively breastfeeding woman bent to move her baby in the car seat and experienced sudden, severe pain from 5 spontaneous vertebral compression fractures. Genomic screen was negative but she had mild ankylosing spondylitis previously well controlled on etanercept. She was vegetarian with a high phytate intake. A lactation consultant had advised her to pump and discard milk between feeds, leading her to believe she produced twice as much milk as her baby ingested. She presented with a LS Z score of −3.6 and a TH Z score of −1.6. After 6 mo postweaning, she was treated with teriparatide (14 mo intermittently over 18 mo) and ultimately achieved a 50% increase in LS bone density and an 8% increase in TH bone density. Her fragility is explained by normal lactational bone loss amplified by excessive milk production and phytate-induced impairment of intestinal calcium absorption, ankylosing spondylitis, and the bend-and-lift maneuver. The marked increase in bone density resulted from the combined effects of spontaneous recovery and pharmacotherapy. Spontaneous recovery of bone mass and strength should occur during 12 mo after weaning in all women, including those who have fractured. [ABSTRACT FROM AUTHOR]

Introduction: Tumor-induced osteomalacia (TIO), is a rare acquired paraneoplastic syndrome characterized by defective bone mineralization, caused by the overproduction of fibroblast growth factor 23 (FGF23) by a tumor. Material and methods: We conducted a systematic review to identify all case reports of TIO, focusing on those associated with mesenchymal tumors. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) consensus, and we included patients with a diagnosis of TIO and histological confirmation of phosphaturic mesenchymal tumors or resolution of the condition after treatment of the tumor. Bibliographical searches were carried out until December 2023 in the Cochrane Library, Medline and Embase, as well as congress abstracts online. Results: We identified 769 articles with 1979 cases reported. Most patients were adults, with a higher incidence on men. Disease duration before diagnosis is a mean of 4.8 years. Most tumors were histologically classified as PMT. Lower limbs were the predominant location. Hypophosphatemia was present in 99.8 % of patients. The FGF23 was elevated at diagnosis in 95.5 %. Resection of the tumor was the treatment of choice in most of patients. After resection, there was a clinical improvement in 97.6 % of cases, and serum phosphorus and FGF23 levels returned to normal ranges in 91.5 % and 81.4 % of the patients, respectively. Conclusion: TIO is usually misdiagnosed with rheumatological or musculoskeletal disorders. The diagnosis should be suspected in patients with hypophosphatemic osteomalacia, and the measurement of serum FGF23 can be useful for diagnosis and management.

A 47-year-old postmenopausal woman with osteoporosis was treated with denosumab, which was discontinued due to side effects. She was therefore transitioned to a yearly intravenous infusion of zoledronic acid. An increase in bone turnover markers together with bone loss at the lumbar spine was observed before the second infusion, suggesting an overshooting of bone resorption due to denosumab discontinuation. On physical examination, the patient was restless and reported having lost about 10 kg since the last visit. A solitary left inferior thyroid nodule was noted on neck palpation. Circulating thyroid hormone levels were elevated, with suppressed thyroid-stimulating hormone. A thyroid scan showed increased uptake in the left inferior nodule with suppression of the remainder of the thyroid gland. A diagnosis of hyperthyroidism due to toxic adenoma was made. The patient was treated with radioactive iodine ablation, with consequent complete normalization of thyroid function. She continued yearly treatment with zoledronic acid. She remained clinically well with no further fractures. Bone turnover markers were appropriately suppressed and bone mineral density increased in the spine and hip. This case illustrates how the overshooting phenomenon following denosumab discontinuation may be compounded by the development of secondary conditions, which can result in suboptimal response to antiresorptive osteoporosis medications. [ABSTRACT FROM AUTHOR]

Hypervitaminosis D as a cause of hypercalcemia may be due to vitamin D intoxication, granulomatous diseases, or abnormalities of vitamin D metabolism. The CYP24A1 gene encodes for the 24‐hydroxylase enzyme, which is responsible for the catabolism of 25‐hydroxyvitamin D (25(OH)D) and 1,25‐dihydroxyvitamin D (1,25(OH)2D). Mutations in CYP24A1 can result in elevated 1,25(OH)2D causing parathyroid hormone (PTH)‐independent hypercalcemia, hypercalciuria, nephrolithiasis, and nephrocalcinosis. We present the cases of two siblings exhibiting hypercalcemia secondary to a CYP24A1 loss‐of‐function mutation. Case 1 presented initially with PTH‐dependent hypercalcemia, with localization of a left upper parathyroid adenoma on parathyroid technetium sestamibi (99mTc‐MIBI) uptake study. Despite parathyroidectomy (180 mg adenoma), hypercalcemia, hypercalciuria, and low normal PTH levels persisted. A repeat parathyroid 99mTc‐MIBI uptake study localized a second adenoma and a right inferior parathyroidectomy was performed (170 mg adenoma). PTH subsequently became undetectable, however hypercalcemia and hypercalciuria persisted. A new presentation of PTH‐independent hypercalcemia found to be secondary to a CYP24A1 loss‐of‐function mutation in his sibling, Case 2, signaled the underlying cause. Cascade testing confirmed both siblings were homozygous for the pathogenic variant c.1186C>T, p.Arg396Trp (R396W) of CYP24A1 (NM_000782.5). In clinical practice CYP24A1 loss‐of‐function mutations should be considered in patients presenting with PTH‐independent hypercalcemia, hypercalciuria, and 1,25(OH)2D levels in the upper normal or elevated range. Although in our case assays of 24,25(OH)2D were not available, calculation of the 25(OH)D:24,25(OH)2D ratio can assist in the diagnostic process. Possible treatments to manage the risk of hypercalcemia in patients with a CYP24A1 loss‐of‐function mutation include avoidance of vitamin D oversupplementation and excessive sun exposure. Hydration and bisphosphonate therapy can be useful in managing the hypercalcemia. Although not utilized in our cases, treatment with ketoconazole, fluconazole, and rifampicin have been described as potential therapeutic options. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

ABSTRACT Degenerative osteoarthritis (OA) is recognized as an early‐onset comorbidity of X‐linked hypophosphatemia (XLH), contributing to pain and stiffness and limiting range of motion and activities of daily living. Here, we extend prior findings describing biochemical and cellular changes of articular cartilage (AC) in the phosphate‐wasting environment of XLH to determine the impact of these changes on the biomechanical properties of AC in compression and potential role in the etiology of OA. We hypothesize that despite increased proteoglycan biosynthesis, disruption of the mineralized zone of AC impacts the mechanical properties of cartilage that function to accommodate loads and that therapeutic restoration of this zone will improve the mechanical properties of AC. Data were compared between three groups: wild type (WT), Hyp, and Hyp mice treated with calcitriol and oral phosphate. EPIC microCT confirmed AC mineral deficits and responsiveness to therapy. MicroCT of the Hyp subchondral bone plate revealed that treatment improved trabecular bone volume (BV/TV) but remained significantly lower than WT mice in other trabecular microstructures (p

ABSTRACT Hypervitaminosis D as a cause of hypercalcemia may be due to vitamin D intoxication, granulomatous diseases, or abnormalities of vitamin D metabolism. The CYP24A1 gene encodes for the 24‐hydroxylase enzyme, which is responsible for the catabolism of 25‐hydroxyvitamin D (25(OH)D) and 1,25‐dihydroxyvitamin D (1,25(OH)2D). Mutations in CYP24A1 can result in elevated 1,25(OH)2D causing parathyroid hormone (PTH)‐independent hypercalcemia, hypercalciuria, nephrolithiasis, and nephrocalcinosis. We present the cases of two siblings exhibiting hypercalcemia secondary to a CYP24A1 loss‐of‐function mutation. Case 1 presented initially with PTH‐dependent hypercalcemia, with localization of a left upper parathyroid adenoma on parathyroid technetium sestamibi (99mTc‐MIBI) uptake study. Despite parathyroidectomy (180 mg adenoma), hypercalcemia, hypercalciuria, and low normal PTH levels persisted. A repeat parathyroid 99mTc‐MIBI uptake study localized a second adenoma and a right inferior parathyroidectomy was performed (170 mg adenoma). PTH subsequently became undetectable, however hypercalcemia and hypercalciuria persisted. A new presentation of PTH‐independent hypercalcemia found to be secondary to a CYP24A1 loss‐of‐function mutation in his sibling, Case 2, signaled the underlying cause. Cascade testing confirmed both siblings were homozygous for the pathogenic variant c.1186C>T, p.Arg396Trp (R396W) of CYP24A1 (NM_000782.5). In clinical practice CYP24A1 loss‐of‐function mutations should be considered in patients presenting with PTH‐independent hypercalcemia, hypercalciuria, and 1,25(OH)2D levels in the upper normal or elevated range. Although in our case assays of 24,25(OH)2D were not available, calculation of the 25(OH)D:24,25(OH)2D ratio can assist in the diagnostic process. Possible treatments to manage the risk of hypercalcemia in patients with a CYP24A1 loss‐of‐function mutation include avoidance of vitamin D oversupplementation and excessive sun exposure. Hydration and bisphosphonate therapy can be useful in managing the hypercalcemia. Although not utilized in our cases, treatment with ketoconazole, fluconazole, and rifampicin have been described as potential therapeutic options. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Chronic kidney disease (CKD) is characterized by kidney damage and loss of renal function. CKD mineral and bone disorder (CKD–MBD) describes the dysregulation of mineral homeostasis, including hyperphosphatemia and elevated parathyroid hormone (PTH) secretion, skeletal abnormalities, and vascular calcification. CKD–MBD impacts the oral cavity, with effects including salivary gland dysfunction, enamel hypoplasia and damage, increased dentin formation, decreased pulp volume, pulp calcifications, and altered jaw bones, contributing to clinical manifestations of periodontal disease and tooth loss. Underlying mechanisms are not fully understood, and CKD mouse models commonly require invasive procedures with high rates of infection and mortality. We aimed to characterize the dentoalveolar effects of an adenine diet (AD)‐induced CKD (AD–CKD) mouse model. Eight‐week‐old C57BL/6J mice were provided either a normal phosphorus diet control (CTR) or adenine and high‐phosphorus diet CKD to induce kidney failure. Mice were euthanized at 15 weeks old, and mandibles were collected for micro–computed tomography and histology. CKD mice exhibited kidney failure, hyperphosphatemia, and hyperparathyroidism in association with porous cortical bone in femurs. CKD mice showed a 30% decrease in molar enamel volume compared to CTR mice. Enamel wear was associated with reduced ductal components, ectopic calcifications, and altered osteopontin (OPN) deposition in submandibular salivary glands of CKD mice. Molar cusps in CKD mice were flattened, exposing dentin. Molar dentin/cementum volume increased 7% in CKD mice and pulp volume decreased. Histology revealed excessive reactionary dentin and altered pulp‐dentin extracellular matrix proteins, including increased OPN. Mandibular bone volume fraction decreased 12% and bone mineral density decreased 9% in CKD versus CTR mice. Alveolar bone in CKD mice exhibited increased tissue‐nonspecific alkaline phosphatase localization, OPN deposition, and greater osteoclast numbers. AD–CKD recapitulated key aspects reported in CKD patients and revealed new insights into CKD‐associated oral defects. This model has potential for studying mechanisms of dentoalveolar defects or therapeutic interventions. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Recombinant human parathyroid hormone (1‐84), rhPTH(1‐84), is an approved adjunctive treatment to oral calcium and active vitamin D for adult patients with hypoparathyroidism; however, there is limited information on the effect of twice daily (BID) dosing of rhPTH(1‐84). This was a phase I, open‐label, randomized, crossover, multicenter study conducted in adult patients with chronic hypoparathyroidism. The primary objective was to assess the pharmacokinetic profile and pharmacodynamic effects of 1 day of treatment with rhPTH(1‐84) administered subcutaneously at 25 μg BID, 50 μg BID, and 100 μg once daily (QD) with or without supplemental oral calcium. Safety and tolerability were evaluated as secondary objectives. In total, 33 patients with chronic hypoparathyroidism completed the study. Treatment with rhPTH(1‐84), both BID and QD, over the short‐term maintained serum calcium, lowered serum phosphorus, decreased urinary calcium excretion, and increased urinary phosphorus excretion. The decrease in urinary calcium excretion was numerically greater for BID than QD. Generally, baseline‐adjusted pharmacokinetic parameters including area under the curve and maximum observed concentration increased with increasing rhPTH(1‐84) dose, although this effect was not dose proportional. No new safety findings were observed. Our study revealed no differences thought to be clinically meaningful in pharmacokinetic or pharmacodynamic parameters with BID versus QD rhPTH(1‐84) dosing. Future long‐term studies are warranted to further elucidate the effects of alternative dosing strategies. © 2023 Takeda Development Center Americas, Inc and The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Lipids play a crucial role in signaling and metabolism, regulating the development and maintenance of the skeleton. Membrane lipids have been hypothesized to act as intermediates upstream of orphan phosphatase 1 (PHOSPHO1), a major contributor to phosphate generation required for bone mineralization. Here, we spatially resolve the lipid atlas of the healthy mouse knee and demonstrate the effects of PHOSPHO1 ablation on the growth plate lipidome. Lipids spanning 17 subclasses were mapped across the knee joints of healthy juvenile and adult mice using matrix‐assisted laser desorption ionization imaging mass spectrometry (MALDI‐IMS), with annotation supported by shotgun lipidomics. Multivariate analysis identified 96 and 80 lipid ions with differential abundances across joint tissues in juvenile and adult mice, respectively. In both ages, marrow was enriched in phospholipid platelet activating factors (PAFs) and related metabolites, cortical bone had a low lipid content, whereas lysophospholipids were strikingly enriched in the growth plate, an active site of mineralization and PHOSPHO1 activity. Spatially‐resolved profiling of PHOSPHO1‐knockout (KO) mice across the resting, proliferating, and hypertrophic growth plate zones revealed 272, 306, and 296 significantly upregulated, and 155, 220, and 190 significantly downregulated features, respectively, relative to wild‐type (WT) controls. Of note, phosphatidylcholine, lysophosphatidylcholine, sphingomyelin, lysophosphatidylethanolamine, and phosphatidylethanolamine derived lipid ions were upregulated in PHOSPHO1‐KO versus WT. Our imaging pipeline has established a spatially‐resolved lipid signature of joint tissues and has demonstrated that PHOSPHO1 ablation significantly alters the growth plate lipidome, highlighting an essential role of the PHOSPHO1‐mediated membrane phospholipid metabolism in lipid and bone homeostasis. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

ABSTRACT Recombinant human parathyroid hormone (1‐84), rhPTH(1‐84), is an approved adjunctive treatment to oral calcium and active vitamin D for adult patients with hypoparathyroidism; however, there is limited information on the effect of twice daily (BID) dosing of rhPTH(1‐84). This was a phase I, open‐label, randomized, crossover, multicenter study conducted in adult patients with chronic hypoparathyroidism. The primary objective was to assess the pharmacokinetic profile and pharmacodynamic effects of 1 day of treatment with rhPTH(1‐84) administered subcutaneously at 25 μg BID, 50 μg BID, and 100 μg once daily (QD) with or without supplemental oral calcium. Safety and tolerability were evaluated as secondary objectives. In total, 33 patients with chronic hypoparathyroidism completed the study. Treatment with rhPTH(1‐84), both BID and QD, over the short‐term maintained serum calcium, lowered serum phosphorus, decreased urinary calcium excretion, and increased urinary phosphorus excretion. The decrease in urinary calcium excretion was numerically greater for BID than QD. Generally, baseline‐adjusted pharmacokinetic parameters including area under the curve and maximum observed concentration increased with increasing rhPTH(1‐84) dose, although this effect was not dose proportional. No new safety findings were observed. Our study revealed no differences thought to be clinically meaningful in pharmacokinetic or pharmacodynamic parameters with BID versus QD rhPTH(1‐84) dosing. Future long‐term studies are warranted to further elucidate the effects of alternative dosing strategies. © 2023 Takeda Development Center Americas, Inc and The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Hypoparathyroidism (HypoPT) is a rare disorder characterized by hypocalcemia in the presence of a low or inappropriately normal parathyroid hormone level. HypoPT is most commonly seen after neck surgery, which accounts for approximately 75% of cases, whereas approximately 25% have HypoPT due to nonsurgical causes. In both groups of patients, conventional therapy includes calcium and active vitamin D analogue therapy aiming to maintain serum calcium concentration in the low normal or just below the normal reference range and normalize serum phosphorus, magnesium concentrations, and urine calcium levels. The limitations of conventional therapy include wide fluctuations in serum calcium, high pill burden, poor quality of life, and renal complications. Parathyroid hormone (PTH) replacement therapy may improve the biochemical profile in those in whom conventional therapy proves unsatisfactory. Based on a systematic review and meta‐analysis of the literature, the panel made a graded recommendation suggesting conventional therapy as first line therapy rather than administration of PTH (weak recommendation, low quality evidence). When conventional therapy is deemed unsatisfactory, the panel considers use of PTH. Because pregnancy and lactation are associated with changes in calcium homeostasis, close monitoring is required during these periods with appropriate adjustment of calcium and active vitamin D analogue therapy to ensure that serum calcium remains in the mid to low normal reference range in order to avoid maternal and fetal complications. Emerging therapies include molecules with prolonged PTH action as well as different mechanisms of action that may significantly enhance drug efficacy and safety. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

The approach utilized a systematic review of the medical literature executed with specifically designed criteria that focused on the etiologies and pathogenesis of hypoparathyroidism. Enhanced attention by endocrine surgeons to new knowledge about parathyroid gland viability are reviewed along with the role of intraoperative parathyroid hormone (ioPTH) monitoring during and after neck surgery. Nonsurgical etiologies account for a significant proportion of cases of hypoparathyroidism (~25%), and among them, genetic etiologies are key. Given the pervasive nature of PTH deficiency across multiple organ systems, a detailed review of the skeletal, renal, neuromuscular, and ocular complications is provided. The burden of illness on affected patients and their caregivers contributes to reduced quality of life and social costs for this chronic endocrinopathy. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

The complications and symptoms of hypoparathyroidism remain incompletely defined. Measuring serum parathyroid hormone (PTH) and calcium levels early after total thyroidectomy may predict the development of chronic hypoparathyroidism. The study aimed (i) to identify symptoms and complications associated with chronic hypoparathyroidism and determine the prevalence of those symptoms and complications (Part I), and (ii) to examine the utility of early postoperative measurements of PTH and calcium in predicting chronic hypoparathyroidism (Part II). We searched Medline, Medline In‐Process, EMBASE, and Cochrane CENTRAL to identify complications and symptoms associated with chronic hypoparathyroidism. We used two predefined criteria (at least three studies reported the complication and symptom and had statistically significantly greater pooled relative estimates). To estimate prevalence, we used the median and interquartile range (IQR) of the studies reporting complications and symptoms. For testing the predictive values of early postoperative measurements of PTH and calcium, we used a bivariate model to perform diagnostic test meta‐analysis. In Part I, the 93 eligible studies enrolled a total of 18,973 patients and reported on 170 complications and symptoms. We identified nine most common complications or symptoms probably associated with chronic hypoparathyroidism. The complications or symptoms and the prevalence are as follows: nephrocalcinosis/nephrolithiasis (median prevalence among all studies 15%), renal insufficiency (12%), cataract (17%), seizures (11%), arrhythmia (7%), ischemic heart disease (7%), depression (9%), infection (11%), and all‐cause mortality (6%). In Part II, 18 studies with 4325 patients proved eligible. For PTH measurement, regarding the posttest probability, PTH values above 10 pg/mL 12–24 hours postsurgery virtually exclude chronic hypoparathyroidism irrespective of pretest probability (100%). When PTH values are below 10 pg/mL, posttest probabilities range from 3% to 64%. Nine complications and symptoms are probably associated with chronic hypoparathyroidism. A PTH value above a threshold of 10 pg/mL 12–24 hours after total thyroidectomy is a strong predictor that the patients will not develop chronic hypoparathyroidism. Patients with PTH values below the threshold need careful monitoring as some will develop chronic hypoparathyroidism. © 2022 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

This clinical practice guideline addresses the prevention, diagnosis, and management of hypoparathyroidism (HypoPT) and provides evidence‐based recommendations. The HypoPT task forces included four teams with a total of 50 international experts including representatives from the sponsoring societies. A methodologist (GG) and his team supported the taskforces and conducted the systematic reviews. A formal process following the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology and the systematic reviews provided the structure for seven of the guideline recommendations. The task force used a less structured approach based on narrative reviews for 20 non‐GRADEd recommendations. Clinicians may consider postsurgical HypoPT permanent if it persists for >12 months after surgery. To predict which patients will not develop permanent postsurgical HypoPT, we recommend evaluating serum PTH within 12 to 24 hours post total thyroidectomy (strong recommendation, moderate quality evidence). PTH > 10 pg/mL (1.05 pmol/L) virtually excludes long‐term HypoPT. In individuals with nonsurgical HypoPT, genetic testing may be helpful in the presence of a positive family history of nonsurgical HypoPT, in the presence of syndromic features, or in individuals younger than 40 years. HypoPT can be associated with complications, including nephrocalcinosis, nephrolithiasis, renal insufficiency, cataracts, seizures, cardiac arrhythmias, ischemic heart disease, depression, and an increased risk of infection. Minimizing complications of HypoPT requires careful evaluation and close monitoring of laboratory indices. In patients with chronic HypoPT, the panel suggests conventional therapy with calcium and active vitamin D metabolites as first‐line therapy (weak recommendation, low‐quality evidence). When conventional therapy is deemed unsatisfactory, the panel considers the use of PTH. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Dietary phosphorus restriction and phosphorus binders are commonly prescribed for patients with chronic kidney disease (CKD). However, occurrences of non‐adherence to these interventions are common. As low‐phosphorus (LP) diets have been consistently experimentally shown in vitro to increase intestinal phosphorus absorption efficiency, a bout of non‐adherence to diet or binders may cause an unintended consequence of enhanced intestinal phosphorus absorption. Thus, we aimed to determine the effect of a single bout of high‐phosphorus (HP) intake after acclimation to a LP diet. Male Sprague Dawley rats with 5/6 nephrectomy (n = 36) or sham operation (n = 36) were block‐randomized to 1 of 3 diets: LP (0.1% P w/w), HP (1.2%), or LP followed by acute HP (LPHP 0.1% then 1.2%). Phosphorus absorption tests were conducted using 33P radioisotope administrated by oral gavage or intravenously (iv). Although the overall two‐way ANCOVA model for intestinal fractional phosphorus absorption was non‐significant, exploratory comparisons showed intestinal fractional phosphorus absorption efficiency tended to be higher in rats in the LP compared with HP or LPHP groups. Rats in the HP or LPHP groups had higher plasma phosphorus compared with rats in the LP group, but the LPHP group was not different from the HP group. Gene expression of the major intestinal phosphate transporter, NaPi‐2b, was lower in the jejunum of rats in the LPHP group compared with rats in the HP group but not different in the duodenum. These results demonstrate that an acute HP load after acclimation to a LP diet does not lead to enhanced intestinal fractional phosphorus absorption efficiency in 5/6 nephrectomized male rats. These data provide evidence against the notion that dietary phosphorus restriction or binder use adversely increases absorption efficiency after a single instance of dietary or binder non‐adherence. However, other adverse consequences of fluctuating dietary phosphorus intake cannot be ruled out. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Inactivating mutations of the gene coding for phosphate‐regulating endopeptidase homolog X‐linked (PHEX) cause X‐linked hypophosphatemia (XLH). A novel PHEX variant, c.*231A>G; exon 13–15 duplication, has emerged as a common cause of XLH in North America, emphasizing the importance of delineating its clinical presentation. Here, a comprehensive description of a five‐generation American kindred of 22 treatment‐naïve individuals harboring the c.*231A>G; exon 13–15 duplication is provided. After XLH was diagnosed in the proposita, pro‐active family members used social media to facilitate a timely assessment of their medical history. Most had normal height and 50% were normophosphatemic. Thirteen had been given a diagnosis other than XLH, most commonly ankylosing spondylitis, and XLH was only established after genetic testing. The prevalent phenotypic characteristics of c.*231A>G; exon 13–15 duplication were disorders of dentition (68.2%), enthesopathies (54.5%), fractures/bone and joint conditions (50%), lower‐limb deformities (40.9%), hearing loss/tinnitus (40.9%), gait abnormalities (22.7%), kidney stones/nephrocalcinosis (18.2%), chest wall disorders (9.1%), and Chiari/skull malformation (4.5%). More affected males than females, respectively, had gait abnormalities (42.9% versus 13.3%), lower‐limb deformities (71.4% versus 26.7%), and enthesopathies (85.7% versus 40%). Single phenotypes, observed exclusively in females, occurred in 22.7% and multiple phenotypes in 77.3% of the cohort. However, as many as six characteristics could develop in either affected males or females. Our findings will improve diagnostic and monitoring protocols for XLH. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Albumin-corrected serum calcium (cSCa) decline at late stages of chronic kidney disease and rise after dialysis initiation. Although hypercalcemia is associated with higher mortality in end-stage renal disease (ESRD), there are scarce data on the impact of pre-ESRD cSCa on post-ESRD mortality. Therefore, we used a large national cohort of 21,826 US veterans who transitioned to dialysis in all US Department of Veterans Affairs health care facilities over 2009 to 2014 to examine the associations with all-cause and cause-specific post-ESRD mortality of (1) cSCa concentrations averaged over the last 6 months and (2) its rate of decline during the last 12 months before dialysis initiation. Mean concentrations and median rate of decline of cSCa were 9.3 ± 0.7 mg/dL and -0.15 (interquartile range -0.39 to 0.07) mg/dL/year, respectively. A total of 9596 patients died during the follow-up period (mean 1.9 years; total 41,541 patient-years) with an incidence rate of 23.1 per 100 patient-years. There was an independent linear association between higher cSCa with higher mortality (ptrend < 0.001). The mortality risk associated with cSCa ≥9.0 mg/dL was attenuated among active vitamin D users (pinteraction < 0.001). Patients with faster decline in cSCa showed lower mortality irrespective of baseline cSCa concentrations. These cSCa-mortality associations were stronger for noncardiovascular versus cardiovascular death. In conclusion, lower pre-ESRD cSCa and faster decline in cSCa were consistently and linearly associated with better post-ESRD survival among US veterans, especially for noncardiovascular death. Further studies are needed to determine if correcting hypocalcemia is beneficial or harmful and which intervention is preferred when indicated among patients transitioning to ESRD. © 2018 American Society for Bone and Mineral Research.

ABSTRACT Inactivating mutations of the gene coding for phosphate‐regulating endopeptidase homolog X‐linked (PHEX) cause X‐linked hypophosphatemia (XLH). A novel PHEX variant, c.*231A>G; exon 13–15 duplication, has emerged as a common cause of XLH in North America, emphasizing the importance of delineating its clinical presentation. Here, a comprehensive description of a five‐generation American kindred of 22 treatment‐naïve individuals harboring the c.*231A>G; exon 13–15 duplication is provided. After XLH was diagnosed in the proposita, pro‐active family members used social media to facilitate a timely assessment of their medical history. Most had normal height and 50% were normophosphatemic. Thirteen had been given a diagnosis other than XLH, most commonly ankylosing spondylitis, and XLH was only established after genetic testing. The prevalent phenotypic characteristics of c.*231A>G; exon 13–15 duplication were disorders of dentition (68.2%), enthesopathies (54.5%), fractures/bone and joint conditions (50%), lower‐limb deformities (40.9%), hearing loss/tinnitus (40.9%), gait abnormalities (22.7%), kidney stones/nephrocalcinosis (18.2%), chest wall disorders (9.1%), and Chiari/skull malformation (4.5%). More affected males than females, respectively, had gait abnormalities (42.9% versus 13.3%), lower‐limb deformities (71.4% versus 26.7%), and enthesopathies (85.7% versus 40%). Single phenotypes, observed exclusively in females, occurred in 22.7% and multiple phenotypes in 77.3% of the cohort. However, as many as six characteristics could develop in either affected males or females. Our findings will improve diagnostic and monitoring protocols for XLH. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ABSTRACT Dietary phosphorus restriction and phosphorus binders are commonly prescribed for patients with chronic kidney disease (CKD). However, occurrences of non‐adherence to these interventions are common. As low‐phosphorus (LP) diets have been consistently experimentally shown in vitro to increase intestinal phosphorus absorption efficiency, a bout of non‐adherence to diet or binders may cause an unintended consequence of enhanced intestinal phosphorus absorption. Thus, we aimed to determine the effect of a single bout of high‐phosphorus (HP) intake after acclimation to a LP diet. Male Sprague Dawley rats with 5/6 nephrectomy (n = 36) or sham operation (n = 36) were block‐randomized to 1 of 3 diets: LP (0.1% P w/w), HP (1.2%), or LP followed by acute HP (LPHP 0.1% then 1.2%). Phosphorus absorption tests were conducted using 33P radioisotope administrated by oral gavage or intravenously (iv). Although the overall two‐way ANCOVA model for intestinal fractional phosphorus absorption was non‐significant, exploratory comparisons showed intestinal fractional phosphorus absorption efficiency tended to be higher in rats in the LP compared with HP or LPHP groups. Rats in the HP or LPHP groups had higher plasma phosphorus compared with rats in the LP group, but the LPHP group was not different from the HP group. Gene expression of the major intestinal phosphate transporter, NaPi‐2b, was lower in the jejunum of rats in the LPHP group compared with rats in the HP group but not different in the duodenum. These results demonstrate that an acute HP load after acclimation to a LP diet does not lead to enhanced intestinal fractional phosphorus absorption efficiency in 5/6 nephrectomized male rats. These data provide evidence against the notion that dietary phosphorus restriction or binder use adversely increases absorption efficiency after a single instance of dietary or binder non‐adherence. However, other adverse consequences of fluctuating dietary phosphorus intake cannot be ruled out. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Fibroblast growth factor‐23 (FGF23) measurement is a critical tool in the evaluation of patients with disordered phosphate homeostasis. Available laboratory reference ranges for blood FGF23 were developed using samples from normophosphatemic individuals. Reliance on such values can lead to misdiagnosis in patients with FGF23‐mediated hypophosphatemia, such as X‐linked hypophosphatemia (XLH) and tumor‐induced osteomalacia (TIO), in whom pathology‐driving FGF23 levels can be in the "normal range." To determine FGF23 levels that are diagnostic for the identification of patients with FGF23‐mediated hypophosphatemic disorders, we studied 149 patients with various disorders of FGF23‐mediated and FGF23‐independent hypophosphatemia and defined cut‐off levels for both intact FGF23 (iFGF23) and C‐terminal FGF23 (cFGF23) that can accurately distinguish between FGF23‐mediated and FGF23‐independent hypophosphatemia. In addition, to demonstrate the relationship between FGF23 and phosphate across the spectrum of human physiology, we assessed blood levels of FGF23 and phosphate in 434 patients with various forms of hypophosphatemia, hyperphosphatemia, and normophosphatemia. An intact FGF23 cut point of 27 pg/mL was 100% sensitive and specific in distinguishing FGF23‐mediated from FGF23‐independent hypophosphatemia, and a cFGF23 cut point of 90 RU/mL was 100% sensitive and specific in distinguishing specifically TIO from FGF23‐independent hypophosphatemia. There was overlap in the cFGF23 range of 45–90 RU/mL between genetic forms of FGF23 excess and FGF23‐independent hypophosphatemia, substantiating the superiority of iFGF23 over cFGF23 in making the diagnosis of FGF23‐mediated hypophosphatemia. In this cohort, using the laboratory upper limit of normal for cFGF23 (180 RU/mL) would result in a misdiagnosis in more than half of patients with FGF23‐mediated hypophosphatemia. In this, the largest study of FGF23 in chronic hypophosphatemia to date, we established iFGF23 and cFGF23 cut‐off values to assist in the evaluation and diagnosis of hypophosphatemic conditions. © 2022 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

To develop guidelines for hypoparathyroidism and primary hyperparathyroidism, the panel assembled a panel of experts in parathyroid disorders, general endocrinologists, representatives of the Hypoparathyroidism Association, and systematic review and guideline methodologists. The guideline panel referred to a formal process following the Recommendations, Assessment, Development, and Evaluation Working Group (GRADE) methodology to issue GRADEd recommendations. In this approach, panelists and methodologists formatted the questions, conducted systematic reviews, evaluated risk of bias, assessed certainty of evidence, and presented a summary of findings in a transparent fashion. For most recommendations, the task forces used a less structured approach largely based on narrative reviews to issue non‐GRADEd recommendations. The panel issued Eight GRADEd recommendations (seven for hypoparathyroidism and one for hyperparathyroidism). Each GRADEd recommendation is linked to the underlying body of evidence and judgments regarding the certainty of evidence and strength of recommendations, values and preferences, and costs, feasibility, acceptability and equity. This article summarizes the methodology for issuing GRADEd and non‐GRADEd recommendations for patients with hypoparathyroidism or hyperparathyroidism. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Since the last international guidelines were published in 2014 on the evaluation and management of primary hyperparathyroidism (PHPT), new information has become available with regard to evaluation, diagnosis, epidemiology, genetics, classical and nonclassical manifestations, surgical and nonsurgical approaches, and natural history. To provide the most current summary of these developments, an international group, consisting of over 50 experts in these various aspects of PHPT, was convened. This paper provides the results of the task force that was assigned to review the information on the management of PHPT. For this task force on the management of PHPT, two questions were the subject of systematic reviews using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology. The full report addressing surgical and nonsurgical management of PHPT, utilizing the GRADE methodology, is published separately in this series. In this report, we summarize the results of that methodological review and expand them to encompass a much larger body of new knowledge that did not specifically fit the criteria of the GRADE methodology. Together, both the systematic and narrative reviews of the literature, summarized in this paper, give the most complete information available to date. A panel of experts then considered the last set of international guidelines in light of the newer data and assessed the need for their revision. This report provides the evidentiary background to the guidelines report. In that report, evidence from all task forces is synthesized into a summary statement and revised guidelines for the evaluation and management of PHPT. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Both medical and surgical therapy represent potential management options for patients with asymptomatic primary hyperparathyroidism (PHPT). Because uncertainty remains regarding both medical and surgical therapy, this systematic review addresses the efficacy and safety of medical therapy in asymptomatic patients or symptomatic patients who decline surgery and surgery in asymptomatic patients. We searched Medline, Embase, Cochrane Central Register of Controlled Trials, and PubMed from inception to December 2020, and included randomized controlled trials in patients with PHPT that compared nonsurgical management with medical therapy versus without medical therapy and surgery versus no surgery in patients with asymptomatic PHPT. For surgical complications we included observational studies. Paired reviewers addressed eligibility, assessed risk of bias, and abstracted data for patient‐important outcomes. We conducted random‐effects meta‐analyses to pool relative risks and mean differences with 95% confidence intervals and used Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) to assess quality of evidence for each outcome. For medical therapy, 11 trials reported in 12 publications including 438 patients proved eligible: three addressed alendronate, one denosumab, three cinacalcet, two vitamin D, and two estrogen therapy. Alendronate, denosumab, vitamin D, and estrogen therapy all increased bone density. Cinacalcet probably reduced serum calcium and parathyroid hormone (PTH) levels. Cinacalcet and vitamin D may have a small or no increase in overall adverse events. Very‐low‐quality evidence raised the possibility of an increase in serious adverse events with alendronate and denosumab. The trials also provided low‐quality evidence for increased bleeding and mastalgia with estrogen therapy. For surgery, six trials presented in 12 reports including 441 patients proved eligible. Surgery achieved biochemical cure in 96.1% (high quality). We found no convincing evidence supporting an impact of surgery on fracture, quality of life, occurrence of kidney stones, and renal function, but the evidence proved low or very low quality. Surgery was associated with an increase in bone mineral density. For patients with symptomatic and asymptomatic PHPT, who are not candidates for parathyroid surgery, cinacalcet probably reduced serum calcium and PTH levels; anti‐resorptives increased bone density. For patients with asymptomatic PHPT, surgery usually achieves biochemical cure. These results can help to inform patients and clinicians regarding use of medical therapy and surgery in PHPT. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

X‐linked hypophosphatemia (XLH) is a rare genetic disorder that disrupts skeletal and dental mineralization. In addition to rickets in children, XLH patients also have frequent spontaneous dental abscesses that increase the risk of tooth loss and may lead to facial cellulitis. Hypomineralized and hypoplastic dentin is the main driver of these infections. Conventional treatment (CT) of XLH improves this tissue defect and reduces the occurrence of dental abscesses. Burosumab is a recent treatment for XLH that targets excess circulating fibroblast growth factor 23 (FGF23), and its benefits on rickets have been demonstrated. It is not yet known whether burosumab improves dental manifestations of XLH. The main objective of our study was to compare the incidence of dental abscesses with XLH treated with either CT or burosumab. In this monocentric retrospective study, we measured and compared the incidence of dental abscess in children with XLH treated with either CT or burosumab, followed at our dental center for at least 1 year. The primary endpoint was the number of dental abscesses per month of dental follow‐up. A total of 71 children were included in the study, with a mean ± standard deviation (SD) age at the start of dental follow‐up of 7.86 ± 3.76. Thirty‐eight children were treated with CT (53.5%) and 33 with burosumab (46.5%). All children treated with burosumab had previously been treated with CT. The mean number of dental abscesses per month of dental follow‐up was significantly reduced in the burosumab group compared with the CT group (0.01 versus 0.04; p = 0.04). Burosumab treatment appears to be associated with a reduction in the number of dental abscesses in XLH children, compared with CT. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Inactivation of 24-hydroxylase (CYP24A1) causes mild hypercalcemia in humans that becomes severe and life-threatening during pregnancy through unclear mechanisms. We studied Cyp24a1 null mice during pregnancy, lactation, and post-weaning. We hypothesized that Cyp24a1 nulls have a much greater increase in calcitriol during pregnancy and lactation, leading to markedly increased intestinal calcium absorption and reduced lactational bone loss. WT and Cyp24a1 null sisters were mated to Cyp24a1+/- males. Timepoints included baseline (BL), late pregnancy (LP), mid-lactation (ML), late lactation (LL), and weekly x4 weeks of post-weaning recovery (R1-4). Assessments included intestinal calcium absorption (IntCaAbs) by gavage of 45Ca, bone mineral content (BMC) by DXA, microCT of femurs, 3-point bending tests of tibias, serum hormones, serum and urine minerals, milk analysis, and intestinal gene expression. At LP, whole body BMC increased equally by ~12% in null and WT. Calcitriol was 2.5-fold higher in nulls vs WT, accompanied by 3-fold increased IntCaAbs, hypercalcemia, hypercalciuria, and 6.5-fold higher FGF23. PTH was suppressed in both. Twenty percent of null dams died during delivery but their serum calcium at LP did not differ from Cyp24a1 nulls that survived. At ML, calcitriol, IntCaAbs, and FGF23 declined in both genotypes but remained higher than BL values in Cyp24a1 nulls. By LL, nulls were still hypercalcemic vs WT, and had lost less mean whole body BMC (11% vs. 21%, P<.02), but by micro-CT there were no differences from WT in cortical or trabecular bone mass. Lactational losses in BMC, cortical thickness, and trabecular number were restored by R4 in both genotypes. In summary, ablation of Cyp24a1 increased IntCaAbs and caused hypercalcemia during pregnancy and lactation, late gestational mortality in some nulls, and reduced lactational BMC loss. Treating women with gestational hypercalcemia from CYP24A1 mutations should focus on reducing calcitriol or IntCaAbs, since increased bone resorption is not the cause., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Objectives: To estimate the prevalence of chondrocalcinosis and calcium pyrophosphate dihydrate deposition disease (CPPD) in patients with low alkaline phosphatase (ALP) levels and a positive ALPL genetic study (+GT) for hypophosphatasia (HPP) compared to those with the same biochemical abnormality and a negative genetic test (-GT). As a secondary objective, to analyze the biochemical factors associated with its presence in subjects with ALPL variants., Methods: Seventy-eight subjects with persistently low ALP levels and ALPL genetic test were included. Baseline and 24-mo knee ultrasounds were performed in 42 + GT and 36 -GT subjects, in whom the fibrocartilage, hyaline cartilage of menisci, tendons, and synovial fluid were scanned to detect calcium pyrophosphate deposits. A MyLabTwice ultrasound machine (Esaote) with a multifrequency linear array transducer (4-13 MHz) was used., Results: A higher percentage of chondrocalcinosis was observed in the +GT group [9/42 (21.4%)] compared to the -GT group [2/36 (5.6%), p =.045)]. Two patients (4.76%), both in the +GT group, had arthritis secondary to CPPD. No new cases were identified at the 24-mo control. When comparing +GT patients with and without chondrocalcinosis, ALP levels were lower, and pyridoxal-5'-phosphate (PLP) and phosphate levels were higher in the former group ( p <.05). Logistic regression analysis revealed that higher PLP levels are associated with the presence of chondrocalcinosis (OR: 1.1; 95% confidence interval, CI, 1.001-1.012)., Conclusions: Chondrocalcinosis was a frequent ultrasonographic finding in HPP. Arthritis secondary to calcium pyrophosphate deposits, however, proved less prevalent. Genetic causes, such as HPP, should be considered when evaluating patients with chondrocalcinosis in clinical practice., Competing Interests: P.A. and C.T. have received fees for advisory board participation from Alexion Pharmaceuticals and have been recipients of a research grant from this biopharmaceutical company, but not for this original manuscript. The rest of authors declare that they do not have any other conflict of interest regarding the publication of this article., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Context: The adverse skeletal effects of type 1 diabetes (T1D) include deficient bone accrual and lifelong increased fracture risk. The contributors to impaired bone accrual in people with T1D are incompletely understood., Objective: To determine if urinary calcium excretion is associated with impaired bone accrual in youth with T1D and to characterize the contribution of glycemic control and markers of bone mineral metabolism to urinary calcium excretion., Design: Observational study., Participants: 50 participants with T1D aged 6-20 years completed a 12-month longitudinal study of bone accrual. A second cohort of 99 similarly aged participants with T1D completed cross-sectional 24-hr urine and blood collections., Main Outcome Measure: Whole body less head bone mineral content (WBLH BMC) velocity Z-score and fractional excretion of calcium (FeCa)., Results: Participants in the bone accrual cohort had lower WBLH BMC velocity compared to a healthy reference dataset (Z-score -0.3 ± 1.0, p=0.03). FeCa was negatively associated with WBLH BMC velocity Z-score, ρ= -0.47, p=0.001. In the urinary calcium excretion cohort, intact parathyroid hormone (β= -0.4, p=0.01), beta c-telopeptide (β=0.35, p=0.007), and either hemoglobin A1c (HbA1c, β=0.08, p=0.03) or urine fractional glucose excretion (β=0.07, p=0.03) were associated with FeCa in multivariable regression models that included known determinants of urinary calcium excretion., Conclusions: Urinary calcium excretion was negatively associated with bone accrual in this cohort of youth with T1D. Mechanistic studies are needed to determine if interventions to reduce urinary calcium excretion could increase bone accrual and reduce skeletal fragility in people with T1D., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

ABSTRACT X‐linked hypophosphatemia (XLH) is a rare genetic disorder that disrupts skeletal and dental mineralization. In addition to rickets in children, XLH patients also have frequent spontaneous dental abscesses that increase the risk of tooth loss and may lead to facial cellulitis. Hypomineralized and hypoplastic dentin is the main driver of these infections. Conventional treatment (CT) of XLH improves this tissue defect and reduces the occurrence of dental abscesses. Burosumab is a recent treatment for XLH that targets excess circulating fibroblast growth factor 23 (FGF23), and its benefits on rickets have been demonstrated. It is not yet known whether burosumab improves dental manifestations of XLH. The main objective of our study was to compare the incidence of dental abscesses with XLH treated with either CT or burosumab. In this monocentric retrospective study, we measured and compared the incidence of dental abscess in children with XLH treated with either CT or burosumab, followed at our dental center for at least 1 year. The primary endpoint was the number of dental abscesses per month of dental follow‐up. A total of 71 children were included in the study, with a mean ± standard deviation (SD) age at the start of dental follow‐up of 7.86 ± 3.76. Thirty‐eight children were treated with CT (53.5%) and 33 with burosumab (46.5%). All children treated with burosumab had previously been treated with CT. The mean number of dental abscesses per month of dental follow‐up was significantly reduced in the burosumab group compared with the CT group (0.01 versus 0.04; p = 0.04). Burosumab treatment appears to be associated with a reduction in the number of dental abscesses in XLH children, compared with CT. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Fibrous dysplasia (FD) is a rare mosaic disorder resulting in fractures, pain, and disability. Bone lesions appear during childhood and expand during skeletal growth. The rate at which FD lesions progress and the biochemical determinants of FD lesion formation have not been established, making it difficult to investigate and implement preventative therapies. The purpose of this study was to characterize FD lesion progression in children, and to identify clinical variables associated with progressive disease. Clinical data and imaging from an ongoing natural history study at the National Institutes of Health (NIH) were reviewed. 99m‐Technetium methylene diphosphonate (99Tc‐MDP) scans were used to determine Skeletal Burden Score (SBS), a validated quantitative scoring system. FD progression rate was determined by the change in the SBS in each patient per year. Thirty‐one children had serial 99Tc‐MDP scans, with a median age at first scan of 6 years (interquartile range [IQR] 4–8, range 2–10), and median follow‐up 1.1 years (IQR 1.1–2.1, range 0.7–11.2). The median FD progression rate for the total group was 2.12 SBS units/year (IQR 0.81–2.94, range 0.05–7.81). FD progression rates were highest in children under age 8 years and declined with age (p = 0.03). Baseline disease severity was associated with subsequent disease progression (p = 0.009), with the highest FD progression rates in patients with moderate disease (baseline SBS 16–30), and lowest progression rates in those with severe disease (SBS ≥50). Serum levels of the bone formation marker osteocalcin were positively correlated with subsequent FD progression rate (p = 0.01, R = 0.58). There was no association between FD progression and baseline endocrinopathies, fractures, or surgery rates. FD lesions progress during childhood, particularly in younger children and those with moderate involvement. Osteocalcin may potentially serve as a biomarker for progressive disease. These findings may allow clinicians to investigate preventative therapies, and to identify children with FD who are candidates for early interventions. Published 2022. This article is a U.S. Government work and is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

Conventional albumin-corrected calcium is inaccurate in predicting ionized calcium, and hidden hypercalcemia, characterized as high ionized calcium with normal total calcium, is associated with higher mortality in hemodialysis patients. By using a national cohort of hemodialysis patients in the Unites States, a novel laboratory-specific prediction equation composed of total calcium, albumin, and phosphorus was derived from 242 patients in the South Atlantic division (adjusted R2  = 0.80 versus 0.71 for the conventional equation) and then validated among 566 patients in the other divisions (adjusted R2  = 0.79 versus 0.68 for the conventional equation). Compared with the conventional equation, the novel equation showed a greater correlation with intact parathyroid hormone. Its relative performance against the conventional equation was consistent across subgroups based on medications related to calcium metabolism. The novel equation also had a higher sensitivity (57% versus 34%) and an equivalent specificity (99% versus 100%) against ionized hypercalcemia at a cut-off value of 10.2 mg/dL. Sensitivity and specificity at 9.4 mg/dL was 94% and 76% (versus 87% and 82% for the conventional equation), respectively. A survival analysis in 87,779 incident hemodialysis patients showed that among patients who were categorized as having a high-normal calcium status (ie, >9.4 to 10.2 mg/dL) by the conventional equation, there appeared a trend toward higher adjusted mortality risk across higher calcium status defined according to the novel equation. Meanwhile, the mortality risk was consistent across calcium strata defined according to the conventional equation within the categories defined by the novel equation. In conclusion, in comparison to the conventional equation, a novel laboratory-specific correction equation derived for correction of total calcium performs significantly better in ascertaining hidden hypercalcemia in hemodialysis patients, and aids in identifying patients at higher risk for mortality. © 2016 American Society for Bone and Mineral Research.

X-linked hypophosphatemia (XLH) is a genetic disease that results in excessive FGF23, chronic hypophosphatemia, and musculoskeletal abnormalities, with affected patients experiencing symptoms such as bone pain, bone deformity, fracture, and pseudofracture. Burosumab is a fully human monoclonal antibody that binds to FGF23, improving lowered serum 1,25(OH)2D and phosphate levels in patients with XLH. There are insufficient data on the use of burosumab, its safety, and the outcomes of treated patients in a real-world setting. The SUNFLOWER (Study of longitUdinal observatioN For patients with X-Linked hypOphosphatemic rickets/osteomalacia in collaboration With Asian partnERs) study is an ongoing longitudinal, observational cohort study of patients with XLH in Japan and South Korea. Enrollment occurred between April 2018 and December 2020. This interim analysis compared the background characteristics of patients who received burosumab with those who did not, and assessed improvements in biomarkers, physical and motor function, health-related quality-of-life (HRQOL) and other patient-reported outcome (PRO) measures, as well as the safety of burosumab treatment in 143 Japanese patients from 15 institutions over 6 mo. The patients had a median [interquartile range] age of 17.5 [11.0, 38.8] yr and 98 (68.5%) were female. Among patients aged <18 and ≥18 yr, 40/73 (54.8%) and 25/70 (35.7%) received burosumab, respectively. More patients aged ≥18 who received burosumab had bone pain at baseline vs those not treated with burosumab (6/25, 24.0% vs 2/45, 4.4%, p=.021). Patients treated with burosumab had improved serum phosphate and 1,25(OH)2D levels; moreover, rickets severity and HRQOL/PRO measures, such as pain, appeared to improve over 6 mo of burosumab treatment, and no new safety concerns were identified. This study identified trends in the background characteristics of patients with XLH who receive burosumab in real-world clinical practice. Furthermore, the results support the use of burosumab therapy in real-world settings. [ABSTRACT FROM AUTHOR]

Skeletal disorders, including both isolated and syndromic brachydactyly type E, derive from genetic defects affecting the fine tuning of the network of pathways involved in skeletogenesis and growth‐plate development. Alterations of different genes of this network may result in overlapping phenotypes, as exemplified by disorders due to the impairment of the parathyroid hormone/parathyroid hormone‐related protein pathway, and obtaining a correct diagnosis is sometimes challenging without a genetic confirmation. Five patients with Albright's hereditary osteodystrophy (AHO)‐like skeletal malformations without a clear clinical diagnosis were analyzed by whole‐exome sequencing (WES) and novel potentially pathogenic variants in parathyroid hormone like hormone (PTHLH) (BDE with short stature [BDE2]) and TRPS1 (tricho‐rhino‐phalangeal syndrome [TRPS]) were discovered. The pathogenic impact of these variants was confirmed by in vitro functional studies. This study expands the spectrum of genetic defects associated with BDE2 and TRPS and demonstrates the pathogenicity of TRPS1 missense variants located outside both the nuclear localization signal and the GATA ((A/T)GATA(A/G)‐binding zinc‐containing domain) and Ikaros‐like binding domains. Unfortunately, we could not find distinctive phenotypic features that might have led to an earlier clinical diagnosis, further highlighting the high degree of overlap among skeletal syndromes associated with brachydactyly and AHO‐like features, and the need for a close interdisciplinary workout in these rare patients. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) both influence blood phosphate levels by regulating urinary phosphate reabsorption. Clinical data suggest that adequate renal phosphate handling requires the presence of both FGF23 and PTH, but robust evidence is lacking. To investigate whether the phosphaturic effects of PTH and FGF23 are interdependent, 11 patients with hypoparathyroidism, which features high blood phosphate in spite of concomitant FGF23 elevation, and 1 patient with hyperphosphatemic familial tumoral calcinosis (HFTC), characterized by deficient intact FGF23 action and resulting hyperphosphatemia, were treated with synthetic human PTH 1–34 (hPTH 1–34). Biochemical parameters, including blood phosphate, calcium, intact FGF23 (iFGF23), nephrogenic cAMP, 1,25(OH)2 vitamin D (1,25D), and tubular reabsorption of phosphate (TRP), were measured at baseline and after hPTH 1–34 treatment. In patients with hypoparathyroidism, administration of hPTH 1–34 increased nephrogenic cAMP, which resulted in serum phosphate normalization followed by a significant decrease in iFGF23. TRP initially decreased and returned to baseline. In the patient with HFTC, hPTH 1–34 administration also increased nephrogenic cAMP, but this did not produce changes in phosphate or TRP. No changes in calcium were observed in any of the studied patients, although prolonged hPTH 1–34 treatment did induce supraphysiologic 1,25D levels in the patient with HFTC. Our results indicate that PTH and FGF23 effects on phosphate regulation are interdependent and both are required to adequately regulate renal phosphate handling. Published 2021. This article is a U.S. Government work and is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

Tumor‐induced osteomalacia (TIO) is a rare paraneoplastic disease characterized by frequent fractures, bone pain, muscle weakness, and affected gait. The rarity of TIO and similar presentation to other phosphate‐wasting disorders contribute to a high misdiagnosis rate and long time to correct diagnosis. TIO is curable by tumor resection, so accurate diagnosis has significant impact on patients' emotional and economic burden. Current diagnostics for TIO rely on decades‐old literature with poor phenotypic validation. Here, we identify salient clinical differences between rigorously validated cohorts of patients with TIO (n = 9) and X‐linked hypophosphatemia (XLH; n = 43), a frequent misdiagnosis for patients with TIO. The TIO cohort had significantly elevated FGF23 (365 versus 95 RU/mL, p < 0.001) and alkaline phosphatase (282.8 versus 118.5 IU/L, p < 0.01) but significantly reduced phosphorus (1.4 versus 2.2 mg/dL, p < 0.05) and 1,25(OH)2 D (16.6 versus 59.8 pg/mL, p < 0.01). By contrast, total vitamin D was similar between the two groups. Dual‐energy X‐ray absorptiometry (DXA) scans reveal lower Z‐scores in the hip (−1.6 versus 0.050, p < 0.01) and spine (0.80 versus 2.35, p < 0.05). TIO patients were more likely to have prior clinical diagnosis of osteoporosis (67% versus 0%), use assistive devices in daily living (100% versus 14%), and have received a knee arthroplasty (33% versus 7%). TIO patients lost an average of 1.5 cm over their disease course and had sustained an average of 8 fractures each, whereas fractures were rare in XLH. The XLH cohort had higher incidence of osteotomy (19% versus 0%), spinal stenosis (12% versus 0%), secondary dental abnormalities (95% versus 44%, p < 0.001), and depression and anxiety (46.5% versus 11%). These results deepen our understanding of the subtle differences present between diseases of phosphate wasting. They suggest several biochemical, clinical, and historical features that effectively distinguish TIO from XLH. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

1,25(OH)2D3, the biologically active form of vitamin D3, is a major regulator of mineral and bone homeostasis and exerts its actions through binding to the vitamin D receptor (VDR), a ligand‐activated transcription factor that can directly modulate gene expression in vitamin D‐target tissues such as the intestine, kidney, and bone. Inactivating VDR mutations or vitamin D deficiency during development results in rickets, hypocalcemia, secondary hyperparathyroidism, and hypophosphatemia, pointing to the critical role of 1,25(OH)2D3‐induced signaling in the maintenance of mineral homeostasis and skeletal health. 1,25(OH)2D3 is a potent stimulator of VDR‐mediated intestinal calcium absorption, thus increasing the availability of calcium required for proper bone mineralization. However, when intestinal calcium absorption is impaired, renal calcium reabsorption is increased and calcium is mobilized from the bone to preserve normocalcemia. Multiple cell types within bone express the VDR, thereby allowing 1,25(OH)2D3 to directly affect bone homeostasis. In this review, we will discuss different transgenic mouse models with either Vdr deletion or overexpression in chondrocytes, osteoblasts, osteocytes, or osteoclasts to delineate the direct effects of 1,25(OH)2D3 on bone homeostasis. We will address the bone cell type–specific effects of 1,25(OH)2D3 in conditions of a positive calcium balance, where the amount of (re)absorbed calcium equals or exceeds fecal and renal calcium losses, as well as during a negative calcium balance, due to selective Vdr knockdown in the intestine or triggered by a low calcium diet. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

ABSTRACT Tumor‐induced osteomalacia (TIO) is a rare paraneoplastic disease characterized by frequent fractures, bone pain, muscle weakness, and affected gait. The rarity of TIO and similar presentation to other phosphate‐wasting disorders contribute to a high misdiagnosis rate and long time to correct diagnosis. TIO is curable by tumor resection, so accurate diagnosis has significant impact on patients' emotional and economic burden. Current diagnostics for TIO rely on decades‐old literature with poor phenotypic validation. Here, we identify salient clinical differences between rigorously validated cohorts of patients with TIO (n = 9) and X‐linked hypophosphatemia (XLH; n = 43), a frequent misdiagnosis for patients with TIO. The TIO cohort had significantly elevated FGF23 (365 versus 95 RU/mL, p

ABSTRACT In 1980, Farfel and colleagues (NEJM, 1980;303:237–42) provided first evidence for two distinct variants of pseudohypoparathyroidism (PHP) that present with hypocalcemia and impaired parathyroid hormone (PTH)‐stimulated urinary cAMP and phosphate excretion, either in the presence or absence of Albright's hereditary osteodystrophy (AHO). An “abnormal allele” and an “unexpressed allele” were considered as underlying defects, predictions that turned out to be correct for both forms of PHP. Patients affected by the first variant (now referred to as PHP1A) were later shown to be carriers of inactivating mutations involving the maternal GNAS exons encoding Gsα. Patients affected by the second variant (now referred to as PHP1B) were shown in the current study to carry a maternal 3‐kb STX16 deletion, the most frequent cause of autosomal dominant PHP1B, which is associated with loss of methylation at GNAS exon A/B that reduces or abolishes maternal Gsα expression. However, the distinct maternal mutations leading to either PHP1A or PHP1B are disease‐causing only because paternal Gsα expression in the proximal renal tubules is silenced, ie, “unexpressed.” Our findings resolve at the molecular level carefully conducted investigations reported some 41 years ago that had provided first clues for the existence of two distinct PHP variants. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ABSTRACT Hypophosphatasia (HPP) is caused by loss‐of‐function mutations in ALPL resulting in decreased alkaline phosphatase (ALP) activity. Metatarsal stress fracture (MSF) is a common clinical feature of hypophosphatasia in adults. In this study, the primary objectives were to determine whether new cases of ALPL variants could be identified in patients with MSF and who also had serum ALP concentration below the reference range and to phenotype their clinical course. Electronic health records were queried for adult patients with MSF using International Classification of Disease codes (ICD‐9, ICD‐10CM) and ALP measurements. Patients with ALP levels below the normal limit were invited to receive mutational analysis of ALPL and to complete the following surveys: the Short Form 36 version 2 (SF36v2), the Brief Pain Inventory‐Short Form (BPI), and the Health Assessment Questionnaire Disability Index (HAQ‐DI). Cases with and controls without ALPL pathogenic variants were compared by survey scores and clinical variables relevant to fracture. In 1611 patients with MSF presenting to a podiatry clinic (10/1/2011–10/1/2017), 937 had ALP measurement, of whom 13 (1.4%) had ALP levels below the lower normal limit. In eight patients consenting to participate, two had heterozygous pathogenic ALPL variants. ALPL variants were found in 2 of 1611 patients (0.12%) with MSF, 2 patients of 937 (0.21%) in those with MSF and any ALP measurement, and 2 of 13 patients (15%) in MSF and decreased ALP level. Cases versus controls rated lower scores on eight of eight SF36v2 scales (range, 0–100); higher scores for worst pain (8.0 vs. 0.8) and average pain (6.0 vs. 0.7) on the BPI (range, 0–10); and higher standard disability score (1.4 vs. 0) on the HAQ‐DI (range, 0–3). These data provide proof‐of‐concept for HPP case identification in patients presenting to a podiatry clinic with MSF, suggesting a search for historically low ALP levels may be a useful step for consideration of HPP diagnosis, and supports a prospective study to determine an optimal case‐finding strategy. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ABSTRACT Patients with chronic inflammatory diseases (CID) experience accelerated loss of bone mineral density, which is often accompanied by increased vascular calcification. These disturbances can be attenuated by therapies for inflammation, such as the tumor necrosis factor inhibitor infliximab. Calciprotein particles (CPP) are circulating colloidal aggregates of calcium and phosphate together with the mineral‐binding protein fetuin‐A, which have emerged as potential mediators of vascular calcification. The precise origins of serum CPP are unclear, but bone turnover may be an important source. In this longitudinal observational study, we studied patients with CID undergoing treatment with infliximab to assess the temporal relationship between bone turnover and circulating CPP. Ten patients with active CID receiving infliximab induction therapy and an additional 3 patients with quiescent CID on maintenance infliximab therapy were studied for 8 weeks with repeated measures of bone turnover markers as well as CPP (calciprotein monomers [CPM], primary CPP [CPP‐I], and secondary CPP [CPP‐II]). Therapeutic response was appraised using validated disease activity scores. At baseline, those with active CID had elevated markers of bone resorption and suppressed bone formation markers as well as higher CPM and CPP‐I compared with those with quiescent CID. In responders, there was an early but transient reduction in resorption markers by week 1, but a more sustained increase in bone formation markers compared with non‐responders at week 8. This was accompanied by reductions in CPM (β = −6.5 × 103 AU [95% CI −11.1, −1.8], p = 0.006) and CPP‐I (β = −23.4 × 104 particles/mL [95% CI −34.8, −11.9], p

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the major enzyme that cleaves extracellular adenosine triphosphate (ATP) to generate pyrophosphate (PPi), an inorganic metabolite with potent anticalcification activity. Loss‐of‐function mutations cause hypopyrophosphatemia and lead to a state of ENPP1 deficiency, which has an acute infantile phase known as generalized arterial calcification of infancy (GACI) and a pediatric to adult phase known as autosomal‐recessive hypophosphatemic rickets type 2 (ARHR2). ENPP1 deficiency manifests as ectopic calcification of multiple tissues, neointimal proliferation, premature mortality, impaired growth, and bone deformities. INZ‐701, a human ENPP1‐Fc protein, is in clinical development as an enzyme replacement therapy for the treatment of ENPP1 deficiency. The pharmacokinetic and pharmacodynamic profile and therapeutic effect of INZ‐701 were investigated in Enpp1asj/asj mice, a murine model of ENPP1 deficiency. Enpp1asj/asj mice have undetectable plasma PPi, lower plasma phosphate, and higher FGF23 levels compared with wild‐type (WT) mice. Enpp1asj/asj mice on the acceleration diet, containing high phosphate and low magnesium, quickly develop clinical signs, including dehydration, rough hair coat, pinned ears, stiffed legs, and hunched back. Enpp1asj/asj mice treated with vehicle had aforementioned clinical signs plus severe ectopic calcification in multiple tissues and bone defects, characteristics of the clinical phenotype observed in GACI and ARHR2 patients. Our results showed a durable PPi response for more than 3 days after a single dose of INZ‐701. Treatment of ENPP1‐deficient mice every other day with INZ‐701 for 8 weeks restored circulating levels of PPi, prevented pathological calcification in all the tested organs, restored growth parameters, corrected bone defects, improved clinical signs, and decreased mortality in Enpp1asj/asj mice, demonstrating the potential of INZ‐701 to treat ENPP1 deficiency. © 2021 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

In 1980, Farfel and colleagues (NEJM, 1980;303:237–42) provided first evidence for two distinct variants of pseudohypoparathyroidism (PHP) that present with hypocalcemia and impaired parathyroid hormone (PTH)‐stimulated urinary cAMP and phosphate excretion, either in the presence or absence of Albright's hereditary osteodystrophy (AHO). An "abnormal allele" and an "unexpressed allele" were considered as underlying defects, predictions that turned out to be correct for both forms of PHP. Patients affected by the first variant (now referred to as PHP1A) were later shown to be carriers of inactivating mutations involving the maternal GNAS exons encoding Gsα. Patients affected by the second variant (now referred to as PHP1B) were shown in the current study to carry a maternal 3‐kb STX16 deletion, the most frequent cause of autosomal dominant PHP1B, which is associated with loss of methylation at GNAS exon A/B that reduces or abolishes maternal Gsα expression. However, the distinct maternal mutations leading to either PHP1A or PHP1B are disease‐causing only because paternal Gsα expression in the proximal renal tubules is silenced, ie, "unexpressed." Our findings resolve at the molecular level carefully conducted investigations reported some 41 years ago that had provided first clues for the existence of two distinct PHP variants. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Hypophosphatasia (HPP) is caused by loss‐of‐function mutations in ALPL resulting in decreased alkaline phosphatase (ALP) activity. Metatarsal stress fracture (MSF) is a common clinical feature of hypophosphatasia in adults. In this study, the primary objectives were to determine whether new cases of ALPL variants could be identified in patients with MSF and who also had serum ALP concentration below the reference range and to phenotype their clinical course. Electronic health records were queried for adult patients with MSF using International Classification of Disease codes (ICD‐9, ICD‐10CM) and ALP measurements. Patients with ALP levels below the normal limit were invited to receive mutational analysis of ALPL and to complete the following surveys: the Short Form 36 version 2 (SF36v2), the Brief Pain Inventory‐Short Form (BPI), and the Health Assessment Questionnaire Disability Index (HAQ‐DI). Cases with and controls without ALPL pathogenic variants were compared by survey scores and clinical variables relevant to fracture. In 1611 patients with MSF presenting to a podiatry clinic (10/1/2011–10/1/2017), 937 had ALP measurement, of whom 13 (1.4%) had ALP levels below the lower normal limit. In eight patients consenting to participate, two had heterozygous pathogenic ALPL variants. ALPL variants were found in 2 of 1611 patients (0.12%) with MSF, 2 patients of 937 (0.21%) in those with MSF and any ALP measurement, and 2 of 13 patients (15%) in MSF and decreased ALP level. Cases versus controls rated lower scores on eight of eight SF36v2 scales (range, 0–100); higher scores for worst pain (8.0 vs. 0.8) and average pain (6.0 vs. 0.7) on the BPI (range, 0–10); and higher standard disability score (1.4 vs. 0) on the HAQ‐DI (range, 0–3). These data provide proof‐of‐concept for HPP case identification in patients presenting to a podiatry clinic with MSF, suggesting a search for historically low ALP levels may be a useful step for consideration of HPP diagnosis, and supports a prospective study to determine an optimal case‐finding strategy. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Patients with chronic inflammatory diseases (CID) experience accelerated loss of bone mineral density, which is often accompanied by increased vascular calcification. These disturbances can be attenuated by therapies for inflammation, such as the tumor necrosis factor inhibitor infliximab. Calciprotein particles (CPP) are circulating colloidal aggregates of calcium and phosphate together with the mineral‐binding protein fetuin‐A, which have emerged as potential mediators of vascular calcification. The precise origins of serum CPP are unclear, but bone turnover may be an important source. In this longitudinal observational study, we studied patients with CID undergoing treatment with infliximab to assess the temporal relationship between bone turnover and circulating CPP. Ten patients with active CID receiving infliximab induction therapy and an additional 3 patients with quiescent CID on maintenance infliximab therapy were studied for 8 weeks with repeated measures of bone turnover markers as well as CPP (calciprotein monomers [CPM], primary CPP [CPP‐I], and secondary CPP [CPP‐II]). Therapeutic response was appraised using validated disease activity scores. At baseline, those with active CID had elevated markers of bone resorption and suppressed bone formation markers as well as higher CPM and CPP‐I compared with those with quiescent CID. In responders, there was an early but transient reduction in resorption markers by week 1, but a more sustained increase in bone formation markers compared with non‐responders at week 8. This was accompanied by reductions in CPM (β = −6.5 × 103 AU [95% CI −11.1, −1.8], p = 0.006) and CPP‐I (β = −23.4 × 104 particles/mL [95% CI −34.8, −11.9], p < 0.001). In contrast, no significant changes in any markers were observed in non‐responders or those receiving maintenance therapy. Thus, CPP have a dynamic association with changes in bone turnover in response to infliximab therapy, adding to accumulating evidence of the role of bone as a determinant of systemic levels. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

ABSTRACT Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive disorder caused by mutations in FGF23, GALNT3, KLOTHO, or FGF23 autoantibodies. Prominent features include high blood phosphate and calcific masses, usually adjacent to large joints. Dental defects have been reported, but not systematically described. Seventeen patients with HFTC followed at the National Institutes of Health underwent detailed clinical, biochemical, molecular, and dental analyses. Studies of teeth included intraoral photos and radiographs, high‐resolution μCT, histology, and scanning electron microscopy (SEM). A scoring system was developed to assess the severity of tooth phenotype. Pulp calcification was found in 13 of 14 evaluable patients. Short roots and midroot bulges with apical thinning were present in 12 of 13 patients. Premolars were most severely affected. μCT analyses of five HFTC teeth revealed that pulp density increased sevenfold, whereas the pulp volume decreased sevenfold in permanent HFTC teeth compared with age‐ and tooth‐matched control teeth. Histology revealed loss of the polarized odontoblast cell layer and an obliterated pulp cavity that was filled with calcified material. The SEM showed altered pulp and cementum structures, without differences in enamel or dentin structures, when compared with control teeth. This study defines the spectrum and confirms the high penetrance of dental features in HFTC. The phenotypes appear to be independent of genetic/molecular etiology, suggesting hyperphosphatemia or FGF23 deficiency may be the pathomechanistic driver, with prominent effects on root and pulp structures, consistent with a role of phosphate and/or FGF23 in tooth development. Given the early appearance and high penetrance, cognizance of HFTC‐related features may allow for earlier diagnosis and treatment. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

ABSTRACT Treatment with asfotase alfa has transformed the prognosis of hypophosphatasia in children and improves the bone and muscle signs in adults. The doses used in adults are the same as in children, whereas bone remodeling is different between them. We report on the cases of two patients treated with 1 mg/kg/day of asfotase alfa who developed spinal cord compression from spinal ossifications during treatment. The first patient, 50 years old, presented after 2 years of treatment with quadraparesis secondary to an increase in ossifications of the cervical vertebral ligaments. The neurological damage was resolved after laminectomy, and the patient was then treated for 18 months with doses of 80 mg per week, without recurrence of the bone and muscle signs. The second patient, 26 years old, 78 kg, developed pain and cervical stiffness with pyramidal tract irritation secondary to ossifications of the vertebral ligaments. This improved with a reduction of doses to 80 mg/week, which then, after 6 months of follow‐up, enabled maintained improvement of the bone and muscle pain that was initially obtained. To our knowledge, these are the first reported cases of increased spinal ligamentous ossifications with neurological complications. Biological monitoring in adults does not seem to enable asfotase alfa doses to be adjusted. The levels of serum alkaline phosphatase (ALP) while on the recommended treatment of 1 mg/kg/day are significantly supraphysiological (5000 to 20,000 IU) and the assays of pyrophosphate and pyridoxal phosphate are not correlated with clinical efficacy. In both of our patients, the treatment with 80 mg of asfotase alfa per week, which was proposed after the occurrence of spinal complications, seemed as effective, after a follow‐up of 18 months and 6 months, as the initial treatment for improving the bone and muscle signs, and could be provided as “attack” doses after healing of the pseudoarthroses. © 2021 American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.