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Hypophosphatasia (HPP) is a rare, inherited, systemic disease characterized by skeletal and systemic manifestations. Asfotase alfa (AA) is the only US Food and Drug Administration-approved treatment for perinatal/infantile- and juvenile-onset HPP. Real-world data are scarce on fracture rates and healthcare resource utilization (HCRU) in patients treated with AA. This retrospective, observational study evaluated fracture-related outcomes and HCRU in patients with HPP treated with AA from January 2016 to December 2022 using the US Medicare Fee-for-Service and Inovalon Medical Outcomes Research for Effectiveness and Economics closed claims databases. Patients (≥2 yr of age) treated with AA (≥1 pharmacy claim for AA between January 2017 and December 2021 [identification period]) and ≥12 mo of continuous enrollment with medical and pharmacy coverage pre- and post-AA initiation were included. Clinical outcomes (change in fractures, types of fractures, and fracture event rates) and HCRU were assessed. Statistical analyses were performed to compare outcomes before and after initiation of AA. One hundred forty-nine patients (65.1% females, 69.1% adults; mean age, 39.6 yr) met the inclusion criteria. The proportion of patients experiencing fractures in the 12 mo following AA initiation significantly decreased compared to the 12 mo prior to treatment (18.1% vs 8.1%; p = .004). The mean fracture rate per patient per year nominally decreased post-AA initiation (0.24 vs 0.14; p = .096). The decrease was significant in fragility fracture rates (0.08 vs 0.02; p = .019). Most prescribed concomitant drugs at baseline were opioid analgesics (36.9%), nonopioid analgesics (34.2%), and antidepressants (34.9%). At baseline, 38.2% of patients were continuously using opioids and 21.8% were using high-dose opioids. Asfotase alfa initiation was associated with a statistically significant reduction in the proportion of patients experiencing fractures and fragility fracture rates, underscoring its potential therapeutic benefits.

Intravenous iron infusions (particularly ferric carboxymaltose) are associated with hypophosphatemia. This is mediated by increased fibroblast growth factor 23 (FGF-23), resulting in decreased activation of 25(OH)vitamin D to 1,25(OH)₂ vitamin D and increased urinary phosphate excretion. Similarly, parenteral antiresorptive agents can lead to hypocalcemia due to reduced bone calcium mobilization, increasing parathyroid hormone (PTH) secretion, and exacerbating kidney phosphate excretion. When given concurrently, electrolyte disturbances can be severe and refractory to treatment, necessitating intravenous replacement, frequent monitoring, and prolonged hospitalization. We describe a case series of six patients with severe hypophosphatemia and hypocalcemia from concurrent administration of intravenous iron and antiresorptive therapy. The average time to hypophosphatemia following iron therapy in the presence of antiresorptives was 17.5 days. This is consistent with the nadir of phosphate 2 weeks following iron infusion and appears to be prolonged and exacerbated by antiresorptive therapy, increasing urinary phosphate loss through increased PTH activity. With the increasing popularity of intravenous iron infusions and parenteral antiresorptive agents, the interplay of these medications is an important consideration for clinicians. The emerging administration of these agents in the community and fragmentation of care across primary and specialist networks create the risk of unintentional concurrent use. Increased awareness of their impact on calcium-phosphate homeostasis is needed to mitigate the risk of severe electrolyte derangements with consideration of alternate iron formulations preferentially in those receiving medications for osteoporosis.

X-linked hypophosphatemia (XLH) is an X-linked dominant condition where fibroblast growth factor-23 (FGF23) excess leads to hypophosphatemic rickets, lower limb bowing, and musculoskeletal pain. Burosumab, a monoclonal antibody against FGF23, has been shown to ameliorate the clinical phenotype of XLH and has recently been approved for use in many countries. This study aimed to evaluate patient and parental/caregiver perception of burosumab therapy and the acceptability of current management practices in Australia. Children with XLH and parents/carers were invited to respond to a survey on clinical and management information including use of telehealth, access to multidisciplinary team members, and perceptions and experience regarding burosumab therapy. This was a multi-centre, cross-sectional survey-based study involving 4 tertiary Australian children's hospitals. A total of 21 survey responses from parents/carers were received between December 2022 and October 2023. Mean (SD) age at time of survey was 12.7 (4.1) yr and median time on burosumab was 42 mo (range 2-100). Reported side effects of burosumab were limited to local skin reactions (38%, n = 8) and injection site pain (5%, n = 1), with the majority (62%, n = 13) reporting no side effects. Logistical issues (availability from the pharmacy or medical centre holiday closure) led to most instances of missed or delayed doses, which were reported by 24% (n = 5). Most participants reported seeing their specialist both face-to-face and via telehealth (64%, n = 14). The majority saw an endocrinologist (100%, n = 21) and orthopaedic surgeon (67%, n = 14), but only a small minority saw a psychologist (10%, n = 2). Answers to Likert scale questions revealed that most parents/carers and children reported a perceived improvement in physical and psychological symptoms and function with burosumab therapy. This study supports the use of recently published local guidelines to manage children with XLH on burosumab due to high satisfaction expressed by children and parents/carers. However, logistical issues leading to delayed or missed doses should be addressed.

X-linked hypophosphatemia (XLH) is a chronic disabling hereditary musculoskeletal disorder associated with inactivating PHEX mutations and elevated circulating FGF-23 concentrations. In a placebo-controlled trial of adults with XLH, burosumab (anti-FGF-23 antibody) demonstrated durable improvements in phosphate concentrations, and self-reported stiffness and physical limitation. However, real-world data regarding burosumab efficacy and tolerability in adults with XLH are lacking. A retrospective audit was performed of patients (age ≥18-years) who commenced 4-weekly subcutaneous burosumab for XLH at Royal North Shore and Westmead Hospitals, Sydney, between January 2021 and June 2024. Patients were managed per standard clinical care and burosumab dose adjusted as necessary according to manufacturer instructions. Electronic medical records were reviewed to collate data regarding patient demographics, XLH-related complications and prior treatment, burosumab dosage and side effects, and pre- and post-burosumab biochemistry and Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores. Of the 13 adults with XLH, all had hypophosphatemia before commencing burosumab (mean 0.64 ± 0.08 mmol/L). Mean WOMAC scores demonstrated baseline impairments in stiffness, pain, and physical limitation. Burosumab was administered for median 15 months during follow-up (median dose 70 mg). Hypophosphatemia resolved in all patients within 3 months of burosumab (mean 1.03 ± 0.38 mmol/L). Two patients developed hyperphosphatemia 2 weeks after commencing burosumab requiring dose reduction. One patient ceased burosumab in the setting of hypercalcemia and constipation secondary to pre-existing tertiary hyperparathyroidism. Adverse events were mild, including transient musculoskeletal discomfort (n = 4), restless legs (n = 2), injection site reaction (n = 2), and headache (n = 1). Repeat WOMAC within 12 months of commencing burosumab (n = 9) demonstrated clinically meaningful improvements in stiffness (-33.3 ± 12.5, p<.001) and physical function (-14.3 ± 16.2, p=.029). This study reports real-world outcomes of adults with XLH treated with burosumab. Clinical experience from 2 centers in Sydney supports trial findings that burosumab is well-tolerated and associated with improved serum phosphate concentrations and self-reported stiffness and physical function.

Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) and generalized arterial calcification of infancy (GACI) occur secondary to biallelic ectonucleotide pyrophosphate/phosphodiesterase 1 (ENPP1) loss-of-function pathogenic variants. GACI is a life-threatening condition, often presenting in the neonatal period with heart failure and hypertension, caused by calcification of the media in large- and medium-sized arteries. ARHR2 typically manifests later in life. Children with ARHR2 commonly exhibit short stature, rachitic skeletal changes, progressive deformities of the lower limbs, skeletal fragility and bone/muscle pain. We present six cases of homozygous pathogenic variants in the ENPP1 gene causing ARHR2 and/or GACI. Case 1: Presented with lower limb deformities and pain with radiological evidence of rickets. Subsequent investigations displayed aortic and pulmonary arterial calcification. Case 2: Presented with lower limb deformities and knee pain. Confirmatory testing was undertaken following her brother's (Case 1) diagnosis. Case 3: The diagnosis was made antenatally. Bisphosphonate treatment was instituted in both the pre- and post-natal periods due to the presence of extensive arterial calcifications. Rickets were noted by two years of age. Case 4: Presented with lower limb deformities and pain. There is neither any current evidence of arterial calcification nor hypertension. Case 5: Presented at 3 mo of age in cardiogenic shock with widespread calcification of large and medium-sized arteries. Bisphosphonate treatment was instituted. Case 6: Presented at 2 wk of age with right shoulder discomfort, with evidence of glenohumeral joint calcification. Further imaging revealed aortic, mediastinal, sternoclavicular joint and vertebral spinous process calcification. Case 1 and 2 were also found to have a heterozygous pathogenic ALPL variant consistent with hypophosphatasia. Clinical features, biochemistry, imaging and genetic analyses assist in the diagnosis of ARHR2 and GACI. Conventional therapy, oral phosphate and calcitriol for ARHR2 and bisphosphonates for GACI, have been utilized for many years. ENPP1 replacement treatment remains an exciting prospect for future management of ARHR2 and GACI secondary to loss of function of ENPP1.

Hypophosphatemia occurring after ferric carboxymaltose or iron polymaltose infusion is common and has been well-characterized. Post-iron infusion hypocalcemia has been documented in case reports, but there is no data on the prevalence of hypocalcemia developing after i.v. iron infusion. In this retrospective cohort study, we sought to characterize integrated daily changes in serum phosphate and corrected calcium levels before and after iron infusion in a real-world inpatient setting. Inpatients who received i.v. iron polymaltose at the Royal Brisbane and Women's Hospital (Queensland, Australia) between January 2020 and September 2021 were included. We extracted all results for serum phosphate and corrected calcium levels for 21 d before and after iron infusion. A total of 741 patients with 8272 blood samples were included. The serum phosphate concentration reduced by an average of 30.6% (95% CI 28.2-32.9) in the 5 d following infusion. Serum phosphate reached a nadir at day 5 before incrementing, but still remained below baseline by the end of the study period. Conversely, serum corrected calcium levels increased within 1 d of iron polymaltose infusion and then dropped over the following 5 d. There was a significant increase in the prevalence of hypophosphatemia developing after iron polymaltose infusion (34% post-infusion vs 8% pre-infusion, p-value < .001). Hypophosphatemia occurred most commonly within the first week after iron infusion, whereas hypocalcemia was more frequently a later occurrence. Our results have enhanced the understanding of the day-to-day biochemical changes occurring after iron infusion as well as the prevalence and timing of post-iron infusion hypophosphatemia and hypocalcemia.

Tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR) is a key diagnostic test for renal phosphate wasting. However, there is a lack of international consensus regarding the reporting of age-related reference intervals. The TmP/GFR Harmonization Working Group, formed by The Australasian Association for Clinical Biochemistry (AACB) and Laboratory Medicine and The Australian and New Zealand Bone and Mineral Society (ANZBMS), aimed to evaluate analytical differences amongst commercial creatinine and phosphate assays, harmonize age-specific cut-offs and compare the ANZBMS TmP/GFR online calculator with existing products. A total of 11 360 results from The Royal College of Pathologists of Australasia Quality Assurance Programs were analyzed to assess creatinine and phosphate assay performance amongst 5 in vitro diagnostic (IVD) companies. Ortho-Clinical Diagnostics analyzers had a positive bias of up to 32% for serum phosphate and up to 29% for TmP/GFR. The other IVD companies produced comparable results and are suitable for harmonized reference intervals. To date, the AACB-ANZBMS TmP/GFR online calculator is the only validated Isotope Dilution Mass Spectrometry-creatinine aligned tool which caters for both pediatric and adult individuals, providing automatic interpretive comments to aid clinicians managing patients with hypophosphatemia.

Iron deficiency is the leading cause of anemia, which affects 1 quarter of the adult population globally. Intravenous iron is a well-established treatment option and is generally well tolerated. However, there is increasing recognition that it can cause hypophosphatemia, which can result in fatigue, nausea, myalgia, weakness, and osteomalacia. We sought to determine the prevalence, natural history, and predictors of hypophosphatemia following iron infusion in a tertiary hospital. All adult patients who received 1 or more iron infusions between January 1, 2019 and December 31, 2021 were included in this retrospective study. A total of 2367 subjects were identified, receiving a total of 7063 infusions over the study period. Hypophosphatemia was defined as a serum phosphate level of <0.75 mmol/L (<2.32 mg/dL), with severity classified as mild 0.65-0.75 mmol/L (2.01-2.31 mg/dL), moderate 0.32-0.64 mmol/L (0.99-1.98 mg/dL), or severe <0.32 mmol/L (<0.99 mg/dL). Prevalence of hypophosphatemia was 48.9%, with the highest prevalence from day 4 to 20 post-iron infusion (39.3%-44.1%). Risk factors were receipt of iron polymaltose (odds ratio [OR] 2.33, CI 1.71-3.19, p < .0001), receipt of ferric carboxymaltose (OR 1.79, CI 1.29-2.48, p = .001), male gender (OR 1.35, CI 1.09-1.66, p = .006), and multiple iron infusions (OR 1.56, CI 1.20-2.03, p = .001). Risk was reduced in recipients with higher baseline phosphate (OR 0.18, CI 0.11-0.28, p < .0001), higher baseline creatinine (OR 0.83, CI 0.74-0.92, p = .001), and increased weight (OR 0.99, CI 0.99-1.00, p = .016). Risk factors for moderate to severe hypophosphatemia were the same, except that gender became nonsignificant, while increasing age (OR 0.99, CI 0.99-1.00, p = .002) was also associated with reduced risk. These findings may aid clinicians in identifying those at greatest risk of developing significant hypophosphatemia, thereby preventing adverse outcomes.

Although hearing impairment is often listed as a nonskeletal complication of X-linked hypophosphatemia (XLH), the prevalence, etiology, pathology, and natural history are poorly described. This review aims to summarize existing literature with a view to guide the clinical management of hearing impairment in XLH. The review was conducted by 2 researchers independently. Four databases (PubMed/Medline, EMBASE, Web of Science, and Cochrane Library) were searched between January 1, 2000 and July 31, 2024, with keywords related to "X-linked hypophosphataemic rickets" and "hearing loss" including synonyms. Identified records were screened for inclusion and exclusion criteria. Human and animal studies were included. Out of 82 records found excluding duplicates, 12 studies met the final criteria and were reviewed. Studies described both conductive and sensorineural hearing loss in 13%-76% of adults with XLH, with sensorineural hearing loss more commonly reported, with impairment developing in adulthood, affecting high and low frequencies, and may be fluctuating. Evidence suggests that endolymphatic hydrops (ELH) may be a major underlying cause of hearing loss in XLH. Individuals with XLH have generalized osteosclerosis with petrous bone thickening and narrowing of the auditory meatus. No studies have looked at burosumab, a monoclonal antibody that inhibits FGF23, and its effect on the development of hearing loss in individuals with XLH. Animal studies of XLH mouse models (Hyp and Gy) describe both conductive and sensorineural hearing impairment. Mouse models demonstrate high Auditory Brainstem Response (ABR) thresholds and signs of osteomalacia of auditory ossicles and ELH. In conclusion, there is an association between hearing loss in XLH and, most commonly, adult-onset sensorineural hearing loss. Pathogenesis of hearing loss in XLH is incompletely understood, but possible contributing factors include thickening of the temporal bones, osteomalacia of the auditory ossicles, and development of ELH. There is currently no evidence that treatment with conventional therapy or burosumab reduces the risk or severity of hearing impairment.