Concurrent Denosumab and Parenteral Iron Therapy Precipitating Severe Hypocalcemia and Hypophosphatemia.

Denosumab-induced hypocalcemia and iron infusion-related hypophosphatemia are both well described. We describe a case of severe hypocalcemia and hypophosphatemia following sequential denosumab and parenteral iron administration. This resulted in respiratory failure due to muscle weakness and cardiac arrhythmia, requiring noninvasive ventilation and urgent intravenous electrolyte replacement. This case highlights the severe dysregulation in calcium and phosphate homeostasis that can occur with denosumab and iron infusions when administered in quick succession. Given that these drugs are among the most common therapies prescribed across a range of specialties, we hope to alert clinicians to this potential serious drug-drug interaction and suggest strategies for monitoring and management of the electrolyte derangement.

Hypervitaminosis D Secondary to a CYP24A1 Loss-of-Function Mutation: An Unusual Cause of Hypercalcemia in Two Siblings.

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.

Bone Mineral Density Compared to Trabecular Bone Score in Primary Hyperparathyroidism.

Individuals with primary hyperparathyroidism (PHPT) have reduced bone mineral density (BMD) according to dual X-ray absorptiometry at cortical sites, with relative sparing of trabecular BMD. However, fracture risk is increased at all sites. Trabecular bone score (TBS) may more accurately describe their bone quality and fracture risk. This study compared how BMD and TBS describe bone quality in PHPT. We conducted a retrospective cross-sectional study with a longitudinal component, of adults with PHPT, admitted to a tertiary hospital in Australia over ten years. The primary outcome was the TBS at the lumbar spine, compared to BMD, to describe bone quality and predict fractures. Secondary outcomes compared changes in TBS after parathyroidectomy. Of 68 included individuals, the mean age was 65.3 years, and 79% were female. Mean ± SD T-scores were -1.51 ± 1.63 at lumbar spine and mean TBS was 1.19 ± 0.12. Only 20.6% of individuals had lumbar spine BMD indicative of osteoporosis, while 57.4% of TBS were ≤1.20, indicating degraded architecture. There was a trend towards improved fracture prediction using TBS compared to BMD which did not reach statistical significance. Comparison of 15 individuals following parathyroidectomy showed no improvement in TBS.

Bilateral atypical femoral fractures during denosumab therapy in a patient with adult-onset hypophosphatasia.

SUMMARY: Hypophosphatasia (HPP) is a rare and under-recognised genetic defect in bone mineralisation. Patients presenting with fragility fractures may be mistakenly diagnosed as having osteoporosis and prescribed antiresorptive therapy, a treatment which may increase fracture risk. Adult-onset HPPhypophosphatasia was identified in a 40-year-old woman who presented with bilateral atypical femoral fractures after 4 years of denosumab therapy. A low serum alkaline phosphatase (ALP) and increased serum vitamin B6 level signalled the diagnosis, which was later confirmed by identification of two recessive mutations of the ALPL gene. The patient was treated with teriparatide given the unavailability of ALP enzyme-replacement therapy (asfotase alfa). Fracture healing occurred, but impaired mobility persisted. HPP predisposes to atypical femoral fracture (AFF) during antiresorptive therapy; hence, bisphosphonates and denosumab are contraindicated in this condition. Screening patients with fracture or 'osteoporosis' to identify a low ALP level is recommended. LEARNING POINTS: Hypophosphatasia (HPP) is a rare and under-recognised cause of bone fragility produced by impaired matrix mineralisation that can be misdiagnosed as a fragility fracture due to age-related bone loss. Antiresorptive therapy is contraindicated in HPP. Low serum alkaline phosphatase (ALP) provides a clue to the diagnosis. Elevated serum vitamin B6 (an ALP substrate) is indicative of HPP, while identification of a mutation in the ALPL gene is confirmatory. Enzyme therapy with recombinant ALP (asfotase alfa) is currently prohibitively costly. Treatment with anabolic bone agents such as teriparatide has been reported, but whether normally mineralized bone is formed requires further study.

Hyponatraemia due to the syndrome of inappropriate antidiuretic hormone secretion in adults with respiratory syncytial virus infection.

We present a case of severe hyponatraemia due to syndrome of inappropriate antidiuretic hormone (SIADH) in a patient with respiratory syncytial virus (RSV) infection. A retrospective analysis of all patients admitted to our hospital with RSV in the preceding 3-year period revealed hyponatraemia in 41 (28%) cases, of which 13 (8.9%) were moderate or severe. SIADH was explored and confirmed in five (3.4%) patients, raising this as an important, previously unrecognised, complication of RSV infection in adults. Physician awareness of SIADH as a potential complication of RSV will facilitate early diagnosis and treatment of this potentially fatal disorder.

High parathyroid hormone levels are associated with osteosarcopenia in older individuals with a history of falling.

OBJECTIVES: The combination of osteopenia/osteoporosis and sarcopenia (osteosarcopenia) defines a diagnostic subset of individuals at higher risk of falls, fractures and institutionalization. In this study we aimed to assess the potential role of high serum levels of parathyroid hormone (PTH) in osteosarcopenia. We hypothesized that a high PTH level is one of the major determinants of this syndrome. STUDY DESIGN: Cross-sectional study in 400 subjects (mean age = 79, 65% women) assessed between 2009 and 2014 at the Falls and Fractures Clinic, Nepean Hospital (Penrith, Australia). MAIN OUTCOME MEASURES: Medical history, physical examination, bone densitometry, body composition, posturography, grip strength, gait parameters, and blood tests for nutrition and secondary causes of sarcopenia and osteoporosis. Patients were assigned to one of four groups: 1) osteopenic/osteoporotic; 2) sarcopenic; 3) osteosarcopenic; or 4) non-sarcopenic/non-osteopenic. Patients with abnormal corrected calcium levels were excluded from analysis. Between-group differences were assessed using one-way analysis of variance and chi-squared tests. Multivariable linear regression was used to evaluate the association between the groups and PTH levels adjusted for age, vitamin D, renal function and albumin. RESULTS: 24% of the subjects had a high serum PTH level with normal corrected calcium level. These subjects were older, reported more falls per year, and had lower grip strength, limits of stability, BMD, and gait velocity. Subjects with high PTH levels were more likely to be in the osteosarcopenia group than in the non-sarcopenic/non-osteopenic group (OR 6.88; CI: 1.9-9.2). CONCLUSIONS: We reported an independent association between high PTH levels and osteosarcopenia. Our results suggest an important role of PTH in osteosarcopenia that deserves further exploration.