Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by hypophosphatemia, bone mineralization disorders with increased risk of fragility fractures, muscle pain, and progressive weakness. TIO has been associated with increased production of the phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) usually by mesenchymal tumors of soft tissue or bone (Phosphaturic Mesenchymal Tumors-PMTs). In rare cases TIO may be observed in association with other malignancies. We report the case of a 66-year-old woman with an occasional diagnosis of both a PMT and an ovarian cancer during the evaluation of TIO. We also systematically review the literature to discover possible correlations between osteomalacia, FGF23 production, and ovarian cancer. Four studies were eligible for the analysis. Two case reports described an association between TIO development and ovarian cancer, whereas the two case-control studies hypothesized a possible correlation between FGF/FGF receptor axis and cancer development. Although it does not provide conclusive evidence regarding the association between TIO and ovarian cancer, this case report highlights the possibility that in the diagnostic workup of suspected TIO, both FGF23-secreting tumors distinct from PMT and tumors unrelated to the clinical presentation of TIO could be identified. This information is important for guiding successful tumor staging and determining the necessity for surgical intervention and/or eventual adjuvant therapy.

This report describes a case of generalized chronic periodontitis requiring periodontal regenerative therapy. The patient was a 56-year-old woman visiting the Tokyo Dental College Suidobashi Hospital with the chief complaint of swelling in the maxillary right gingiva. An initial examination revealed 34.0% of sites with a probing depth (PD) of ≥4 mm. The prevalence of sites with bleeding on probing was 32.7%. The plaque control record (PCR) score was 65.7%. Radiographic examination revealed angular bone resorption at #18 and 48. Horizontal absorption was also observed in other areas. The percent bone loss/age at #48 was 1.07. A clinical diagnosis of generalized chronic periodontitis (Stage III, Grade C) was made. Based on the clinical diagnosis of severe chronic periodontitis, initial periodontal therapy was performed. An improvement was observed in periodontal conditions at re-evaluation. The PCR score was 16.7%. Periodontal surgery was performed for teeth with a residual PD of ≥4 mm. Periodontal regenerative therapy using rhFGF-2 were performed on intrabony defects in #18 and 48. Open flap debridement was performed on #16, 26, and 27. Following evaluation, oral function was restored using all-ceramic crowns (#46). At 6 months postoperatively, the patient was transitioned to supportive periodontal therapy (SPT). During the 6-month SPT, stable periodontal conditions that facilitated a favourable level of plaque control were maintained.

BACKGROUND: Tumor-induced osteomalacia (TIO) belongs to a rare disease of the paraneoplastic syndrome. Phosphate uric mesenchymal tumor (PMT) is the most common cause of TIO, while the possibility of other tumors cannot be excluded.
METHODS: We present a case of a 36-year-old female patient with systemic skeletal abnormalities. The woman complained of low back pain with mild motor dysfunction for 2 years. Laboratory examination showed abnormalities in markers of bone metabolism, parathyroid hormone (PTH), vitamin D and serum phosphorus. Pooled imaging examination indicated extension abnormalities in the skeletal system and a single lesion in the right femoral head. The lesion of the right femoral was imaging with somatostatin receptor-positive, which was highly suggestive of a single neuroendocrine tumor. CT guided right femoral tumorectomy and bone grafting were performed when medical treatment failed. Postoperative pathological diagnosis was phosphate urinary mesenchymal tumor secreting fibroblast growth factor 23 (FGF23), which accorded with pre-operative expectations. The postoperative symptoms were effectively relieved, and indicators returned to normal.
CONCLUSIONS: The tumors causing TIO exhibited significant heterogeneity in terms of tissue origin, pathological characteristics and biological behavior, but the unique common characteristic is the secretion of FGF23. With significant progress in diagnosis and treatment, the clinical follow-up of most TIO patients shows a good prognosis, but the prognosis of those with malignant tumors is relatively poor.

OBJECTIVE: To examine the prospective association between fibroblast growth factor 21 (FGF21) and risk of gestational diabetes mellitus (GDM) and the modifying effect of overweight/obesity for this association.
METHODS: Serum FGF21 levels were measured at 6-15 weeks of gestation among 332 GDM cases and 664 matched controls. Conditional logistic regression was used to evaluate its association with GDM risk. Interaction analyses on multiplicative and additive scales were conducted to investigate the modifying effect of overweight/obesity.
RESULTS: Elevated FGF21 levels were associated with a higher risk of GDM in multivariable models, but the positive association was attenuated after further adjustment for pre-pregnancy body mass index (BMI). A significant multiplicative interaction was noted between FGF21 (both continuous and dichotomous) and pre-pregnancy BMI (p for interaction = 0.049 and 0.03), and the association was only significant in participants with pre-pregnancy BMI ≥24 kg/m2 . When participants were grouped based on pre-pregnancy BMI (≥24 and <24 kg/m2 ) and FGF21 levels (≥median and CONCLUSIONS: Elevated serum FGF21 levels in early pregnancy were associated with a higher risk of GDM, particularly among those with overweight/obesity.

Although there are a few case reports of patients with small cell lung cancer developing hypophosphatemia, detailed information on this condition is scarce. A 52-year-old patient with advanced stage small cell lung cancer developed hypophosphatemia (1.1 mg/dL) during chemotherapy. A reduced level of the tubular reabsorption of phosphate concomitant with an inappropriately elevated level of fibroblast growth factor (FGF) 23 (48.4 pg/mL) was noted, leading to the diagnosis of FGF23-related hypophosphatemia. Laboratory data also showed hypercortisolemia with an elevated ACTH level and hyponatremia with an inappropriately unsuppressed level of antidiuretic hormone (ADH). These data suggested the overproduction of FGF23 in addition to ACTH and ADH. Because the octreotide loading test did not present a suppressive effect on ACTH or FGF23 levels, the patient was treated with phosphate supplementation, active vitamin D and metyrapone, which partially improved the serum phosphate and cortisol levels. Even after two subsequent courses of chemotherapy, the small cell lung cancer progressed, and the FGF23 level was further elevated (83.7 pg/mL). Although it is very rare, FGF23-related hypophosphatemia is one of the hormonal disturbances that could be observed in patients with small cell lung cancer. This article reviews similar clinical conditions and revealed that advanced states of malignancy seemed to be associated with the development of renal wasting hypophosphatemia, especially in lung cancer and prostate cancer. Therefore, the parameters related to hypophosphatemia should be monitored in patients with advanced small cell lung cancer to prevent the development of hypophosphatemic osteomalacia.

BACKGROUND: Rare tumor-induced osteomalacia (TIO) usually resulted in bone pain, fragility fractures and muscle weakness in clinical, which is caused by the reduced phosphate reabsorption, thus impaired mineralization of the bone matrix and free energy transfer. The specific problems in postsurgical patients are obscure although surgical removal of the tumor is the only definitive treatment. Here, we documented a female TIO patient who suffered more severe bone pain and muscle spasms post-operation. Further, we presented and discussed our explanation for the unexpected symptoms.
METHODS: The main symptoms were whole-body pain and muscle weakness. The patient also presented with osteoporosis and multiple fractures.
METHODS: Elevated serum fibroblast growth factor 23 (FGF23) level and hypophosphatemia indicated the diagnosis of TIO. Positron emission tomography (PET)/computed tomography (CT) with 68 Ga-DOTATATE located the tumor in the dorsolateral part of the left foot. Histopathological examinations confirmed the diagnosis.
METHODS: The tumor was surgically removed immediately after the diagnosis of TIO and localization of the tumor. Postoperatively, calcium carbonate supplement treatment was continued.
RESULTS: Two days after surgery, the serum FGF23 level was decreased to the normal range. Five days after surgery, N-terminal propeptide of type I procollagen and β-CrossLaps (β-CTx) had a remarkable increase. A month after surgery, the patient N-terminal propeptide of type I procollagen and β-CTx levels were decreased obviously, and serum FGF23, phosphate and 24h urinary phosphate were in the normal range.
CONCLUSIONS: We report a female patient who presented with osteoporosis and fractures. She was found with an elevation of FGF23 and diagnosis with TIO after PET/CT scanning. After surgically removing the tumor, the patient experienced more severe bone pain and muscle spasms. Active bone remodeling might be the reason for the symptoms. Further study will reveal the specific mechanism for this abnormal bone metabolism.

Tumor-induced osteomalacia (TIO) due to fibroblast growth factor 23 (FGF23) overexpression is becoming recognized in patients with malignancy. The condition may be underdiagnosed, with a scarce medical literature.
To perform a meta-analysis of case reports to allow a better understanding of malignant TIO and its clinical implications.
Full texts were selected according to strict inclusion criteria. All case reports were included where patients had hypophosphatemia, malignant TIO, and FGF23 blood levels. Thirty-two of 275 eligible studies (n = 34 patients) met inclusion criteria. A list of desired data was extracted and graded for methodological quality.
Prostate adenocarcinoma (n = 9) were the most tumors reported. Twenty-five of 34 patients had a metastatic disease and a poor clinical outcome was reported for 15 of 28 patients. The median levels of blood phosphate and C-terminal FGF23 (cFGF23) were 0.40 mmol/L and 788.5 RU/mL, respectively. For most of patients, blood PTH was elevated or within range, and calcitriol levels were inappropriately low or normal. Alkaline phosphatase concentrations were increased for 20 of 22 patients. The cFGF23 values were significantly higher for patients with a poor clinical outcome when compared to other patients (1685 vs 357.5 RU/mL). In case of prostate cancer, cFGF23 levels were significantly lower (429.4 RU/mL) than for other malignancies (1007.5 RU/mL).
We report for the first time a detailed description of the clinical and biological characteristics of malignant TIO. In this context, FGF23 blood measurement would be of value for the diagnostic workup, prognostication, and follow-up of patients.

X‑linked hypophosphatemia (XLH) is a phosphate wasting disorder. Typical serum constellations include low serum phosphate as well as high alkaline phosphatase (ALP) and fibroblast growth factor 23 (FGF-23 ) levels. Adult XLH patients usually suffer from (pseudo)fractures, enthesopathies, impaired mobility, and osteoarthritis. We report the case of a middle-aged woman with clinically mild disease, relatively balanced laboratory values, but bone non-healing of the femur post-surgery. Transiliac bone biopsy revealed pronounced osteomalacia and severe deterioration of bone microstructure. Due to the lack of XLH-typical symptoms, the patient was not substituted with calcitriol and phosphate in adulthood. Thus, laboratory findings and radiological examinations do not necessarily reflect bone metabolism in XLH. Bone biopsies should be considered in unclear cases or prior to surgery in adults with XLH.

Acquired fibroblast growth factor (FGF) 23-related hypophosphatemic osteomalacia is characterized clinically by muscle weakness, bone pain, and fractures. Its biochemical features include hypophosphatemia, caused by renal phosphate wasting, and inappropriately normal or low 1,25-dihydroxy-vitamin D levels. Recently, burosumab, a fully human monoclonal antibody targeting FGF23, was approved for the treatment of FGF23-related hypophosphatemic rickets and osteomalacia. We report the case of a 75-year-old Japanese woman with decompensated liver cirrhosis and hepatic encephalopathy, caused by primary biliary cholangitis, who complained of back pain and limited mobility resulting from multiple vertebral fractures. She was not receiving iron infusion therapy and denied alcohol consumption. The patient exhibited hypophosphatemia with a low tubular maximum reabsorption of phosphate per unit glomerular filtration rate (TmP/GFR) and a high circulating concentration of FGF23. Conventional therapy with alfacalcidol and oral phosphate slightly improved her serum phosphate concentration and back pain, but she experienced a hip fracture, causing her to become wheelchair-dependent. Burosumab was initiated 8 weeks after the hip fracture, which increased her serum phosphate concentration and TmP/GFR. Her mobility gradually improved, such that she could walk without a cane after 16 weeks of treatment. Her lumbar bone mineral density increased after 48 weeks. Hepatic encephalopathy developed once before the initiation of treatment and twice after the initiation of the therapy, but her liver function was preserved. This is the first study to report the efficacy and safety of burosumab treatment for FGF23-related hypophosphatemic osteomalacia with decompensated liver cirrhosis.

X-linked hypophosphatemia (XLH) is the most prevalent type of heritable fibroblast growth factor 23 (FGF23)-related hypophosphatemic rickets. Recently, anti-FGF23 antibody, burosumab, has become clinically available. We herein report a patient with adult XLH and tertiary hyperparathyroidism.
The serum phosphate level and tubular maximum reabsorption of phosphate per glomerular filtration rate (TmP/GFR) remained low, despite burosumab treatment. While the influence of the relationship between FGF23 and parathyroid hormone (PTH) on the phosphaturic effect is unclear, it was considered that a high level of PTH due to tertiary hyperparathyroidism remains to suppress renal phosphate reabsorption. A calcimimetic, evocalcet, increased the serum phosphate level and TmP/GFR.
Therefore, it is important to evaluate the presence of secondary-tertiary hyperparathyroidism in patients whose serum phosphate level does not increase with burosumab treatment.