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We report an atypical case of fibroblast growth factor-23 (FGF23)-mediated hypophosphatemic osteomalacia without a pathogenic variant (PV) of PHEX, who improved biochemically, clinically and radiologically post burosumab treatment. We present a narrative review of FGF23-mediated hypophosphatemic osteomalacia and propose a roadmap for investigating the etiology of hypophosphatemia to guide therapy. A 29-yr-old female with FGF23-mediated hypophosphatemic osteomalacia experienced multiple insufficiency fractures, including bilateral femoral diaphyseal fractures and delayed healing. This occurred on a background of juvenile enthesitis-related arthritis, narcolepsy, and brittle dentition since her early teens. Whole-body magnetic resonance imaging and gallium-68 DOTATATE PET scans were unremarkable, making tumor-induced osteomalacia highly unlikely. No hypophosphatemic PVs were found using massively parallel sequencing. Despite phosphate and calcitriol therapy, mild hypophosphatemia persisted with minimal improvement in fracture healing or pain. One dose of 60 mg burosumab, an anti-FGF23 antibody, led to hyperphosphatemia requiring dose titration and 3 doses of burosumab normalized renal tubular maximum reabsorption rate of phosphate relative to glomerular filtration rate. Burosumab led to fracture healing with callus formation corresponding with improved pain at fracture sites. Hypophosphatemic osteomalacia manifests with varus deformity of the lower limbs, gait disturbance, muscle weakness, enthesopathy, and dental necrosis. Evaluation of the etiology is crucial and requires an algorithmic approach to determine whether hypophosphatemia is renally-mediated, FGF23-mediated, acquired or inherited. The most common inherited cause of FGF23-mediated hypophosphatemic osteomalacia is X-linked hypophosphatemia (XLH) secondary to a PV of the PHEX gene. However, the absence of a PHEX PVs does not exclude a diagnosis of hereditary FGF23-mediated hypophosphatemic osteomalacia. Other inherited causes of this disorder include autosomal dominant and autosomal recessive hypophosphatemic rickets, fibrous dysplasia-McCune-Albright syndrome, cutaneous skeletal hypophosphatemia syndrome and osteoglophonic dysplasia. Burosumab significantly improves serum phosphate and fracture healing in XLH and may effectively treat other forms of FGF23-mediated hypophosphatemia.

X-linked hypophosphatemia (XLH) is a rare, X-linked dominant condition with a high burden of both physical and psychosocial disease. This study aimed to describe the experience and burden of disease for children and adults living with XLH in Australia by inviting affected individuals and their carers to complete an online questionnaire. Of the 46 responses, half were completed by a person with XLH, and half by carers. Thirty percent were male, 33% were aged less than 18 yr. Median age at diagnosis was 2 yr (IQR 1.5-3.0). There was a high burden of surgical intervention: 59% reported 5 or more surgeries and 33% (15) had major dental procedures. Bone deformities and painful bones/joints were rated as the most impactful symptoms for both children and adults with XLH with 54% of participants rating emotional and physical burden of disease as equally impactful. Participants reported experiencing many psychosocial and financial challenges, including mental health disorders (including depression, anxiety, suicidal ideation, and self-harm), discrimination, and social isolation. Seventy percent reported it was difficult or very difficult living with XLH. Over 80% percent strongly agreed that lack of XLH awareness impacts on support services and health funding and agreed or strongly agreed that it is hard living with a condition that most Australians have never heard of. X-linked hypophosphatemia imparts a high physical, emotional, psychosocial, and mental toll on affected individuals. While the most impactful reported symptoms were musculoskeletal features, this survey emphasizes the degree of social and psychological challenges that individuals with XLH face. Some of these difficulties appear to be worsened by a lack of awareness. Patient advocacy and improving knowledge of rare diseases such as XLH is a key role of health professionals and should improve overall experience for affected individuals.

Fragility fractures are among the most serious complications of osteoporosis, associated with high morbidity, mortality, and long-term disability. Fracture liaison service (FLS) programs have demonstrated effectiveness in improving osteoporosis evaluation and reducing refracture and mortality rates. However, patient nonattendance remains a critical and underappreciated barrier to program success. At our institution, a hip FLS initiative showed a nonattendance rate of 68%, with only 7 patients initiating antiresorptive therapy. We review the multifactorial causes of nonattendance and propose targeted strategies to overcome these barriers, aiming to achieve effective secondary fracture prevention for all high-risk patients.

Adult hypophosphatasia (HPP) is caused by genetic variations in the ALPL gene causing a loss-of-function, leading to disruptions in normal skeletal mineralization processes. However, the impact of adult HPP extends beyond the skeletal system, as the ubiquitous expression and involvement of the affected enzyme in the body's metabolic processes result in a broad spectrum of symptoms. Consequently, individuals with HPP mostly experience a diminished quality of life (QoL). The severity and presentation of the disease are highly heterogeneous. Despite this variability, the underlying reasons and contributing factors remain poorly understood. This study aims to get a better understanding of HPP patients QoL and identify parameters that correlate with their QoL. To address this, our study retrospectively analyzed 146 adult patients diagnosed with HPP. Health-related quality of life was assessed using the Short Form Health Survey version 1.0 (SF-36 v1), and pain levels were assessed using the brief pain inventory. Our findings indicate that HPP compromises not only physical health but also significantly impacts mental well-being, with a Physical Component Summary of 39.9 and a Mental Component Summary of 39.3. Moreover, we observed that patients' QoL was inversely associated with factors such as obesity, lower concentrations of alkaline phosphatase (ALP) and bone-specific alkaline phosphatase (BAP). Additionally, indicators of physical status demonstrated a strong correlation with QoL. These results underscore the need for a systematic approach to monitoring both somatic parameters and mental health in adult HPP patients to help evaluate disease progression, treatment effects, and overall patient condition. Clinicians can utilize objective criteria, namely physical status indicators, ALP and BAP concentrations, and BW as additional tools in assessing patients' conditions, as these factors are linked to QoL in HPP. This may help clinicians estimate patients disease status and may help to assess and monitor the impact of therapy on QoL.

Loss of muscle quantity and quality with age has been related to fracture risk independent of areal BMD (aBMD) assessed by DXA. Automated approaches to assess muscle on CT images make it more feasible to assess associations of muscle quantity (cross-sectional area) and quality (density) of multiple anatomical regions on fracture risk. We investigated whether automated analysis of muscle area and density at the trunk (L1 and L3) and proximal thigh (right and left) predicted 10-yr fracture risk (any clinical, clinical spine, and non-spine) independent of DXA aBMD as well as CT vBMD and muscle function in older men from the Osteoporotic Fractures in Men (MrOS) study. Men with CT imaging and complete covariate measures were included (n = 3237, 73.7 ± 5.9 yr). Fractures were centrally adjudicated. Proportional hazards models assessed relationships, adjusting for DXA FN aBMD, CT FN vBMD, CT LS vBMD, and muscle function. For any fracture, a 10%-25% and 8%-12% risk reduction was observed per 1-SD increment in muscle area and density, respectively, across anatomical locations, though HR estimates only reached significance for muscle area at the thigh and muscle density at the Trunk-L3 (p > .05), despite overlapping 95% CIs across anatomical sites. Similar reductions were seen for non-spine fractures. For spine fracture, only Trunk-L3 muscle density had a significant 31% risk reduction. For hip fracture, muscle area at the right (40%) and left thigh (35%) and muscle density at Trunk-L3 (25%) were associated with reduced risk (p < .05). Results remained unchanged or slightly attenuated after adjusting for muscle function and BMD, respectively. Automated measures of muscle area and density on CT images may enhance fracture risk assessment in older men that does not vary substantially across different anatomic locations. The relative importance of muscle area and density for fracture risk prediction varies across fracture types.

Medication-related osteonecrosis of the jaw (MRONJ) is an uncommon but potentially serious complication associated with antiresorptive and antiangiogenic therapies, such as bisphosphonates and denosumab. Despite increasing clinical awareness, the pathophysiology of MRONJ remains poorly understood, and no universally accepted preventive strategies are currently available. Preclinical animal studies have served as a cornerstone for investigating potential preventive and therapeutic approaches, offering valuable insights into disease onset, progression, and intervention timing. This narrative, scoping-style review critically examines and maps the available preclinical evidence on preventive and therapeutic strategies aimed at mitigating MRONJ risk, with an emphasis on animal models that simulate clinical conditions. We methodologically explore and compare a wide range of proposed interventions, including laser and photobiomodulation therapies, ozone application, antibiotics, anti-inflammatory agents, natural compounds, and biologics such as BMPs, mesenchymal stem cells (MSCs), and platelet-rich plasma. The efficacy of these interventions is discussed in relation to their impact on inflammation, angiogenesis, bone remodeling, microbial control, and soft tissue healing. Among the most promising strategies, low-level laser therapy and the use of MSCs consistently demonstrated improved healing outcomes and reduced necrotic bone exposure in rodent models. Anti-inflammatory medications and natural compounds, such as resveratrol, showed favorable modulation of the inflammatory microenvironment, while some antibiotics were effective in reducing bacterial burden when administered at appropriate doses and timings. However, discrepancies in study design, animal species, drug administration protocols, and outcome measures often limit direct comparisons and translational conclusions. Taken together, the animal literature supports the potential of multimodal preventive strategies, particularly when interventions are applied before or immediately after dentoalveolar trauma. Nonetheless, further standardization of experimental models and validation in clinical settings are urgently needed. This review highlights the strengths and limitations of current preclinical evidence and proposes directions for future research to bridge the gap between bench and bedside in the management of MRONJ.

Increased bone fragility despite preserved or elevated BMD in type 2 diabetes mellitus (T2DM) is linked to nonenzymatic collagen crosslinking via advanced glycation end-products (AGEs). However, there is no noninvasive method clinically available to probe these collagen alterations in the bone. We examined the potential of ultrashort echo time quantitative magnetization transfer (UTE-qMT) MRI for detecting AGE-induced collagen crosslinking in bones. Rat tibial bones were subject to ribosylation ex vivo to induce AGE accumulation. UTE-qMT MRI was performed to quantify the magnetization exchange rate (k_ba) and macromolecular fraction (MMF), which were compared to mechanical properties from 3-point bending tests and AGE concentrations from fluorometric assays. Ribosylation significantly increased AGE crosslinking, confirmed by a 3-fold rise in AGE fluorescence intensity. UTE-qMT MRI revealed a significantly higher k_ba and MMF in ribosylated bones, whereas BMD did not show significant differences. A 3-point bending test showed that ribosylation reduced post-yield displacement, fracture displacement, and work-to-fracture from load-displacement curves, indicating reduced bone ductility and toughness. Importantly, k_ba and MMF correlated significantly with these mechanical properties, whereas BMD showed no significant correlations. These findings demonstrate that UTE-qMT MRI is a novel noninvasive tool sensitive to AGE-mediated collagen crosslinking and its critical role in predicting bone fragility.

Denosumab is an anti-resorptive therapy that effectively reduces fracture risk and increases BMD in women with postmenopausal osteoporosis. In this study, we focused on the less well-investigated cortical remodeling process and its transition from erosion to formation after denosumab treatment, using a histomorphometric classification of intracortical pores. Cortical bone is more prominent in non-vertebral bones, where denosumab is less effective in fracture reduction. In iliac crest biopsies from the FREEDOM-study, where postmenopausal osteoporotic women were treated with placebo (n = 43) or denosumab (n = 43) for 2-3 yr, the cortical microstructure and remodeling stage and type of intracortical pores were analyzed. Cortical thickness was unaffected in the denosumab group vs placebo (P = .9). Mean pore diameter was significantly decreased in the denosumab group vs placebo (P < .002) with no change in the number of pores per tissue area (P = .83). However, the cortical porosity was not decreased in the denosumab vs placebo group (P < .077). When stratifying the pores according to their remodeling stage, the eroded pores had an increased contribution to the total pore area in the denosumab vs placebo group (P = .001). Eroded-formative and formative pores had a decreased contribution to the total pore area (P < .001). The contribution of quiescent pores was unchanged. The increased contribution of eroded pores and the concomitant reduced contribution of eroded-formative and formative pores indicate that the transition from erosion to formation is largely limited, while pores with ongoing bone formation at the time of initiation of denosumab treatment are refilled.

Tissue-nonspecific alkaline phosphatase (gene: ALPL; protein: TNAP) is a mineralization-associated enzyme that catalyzes several physiological substrates and is widely expressed in skeletal and nonskeletal tissues indicating diverse physiological actions. Loss-of-function mutations in ALPL cause hypophosphatasia (HPP), an inherited skeletal dysplasia featuring rickets and osteomalacia. Hypophosphatasia is also associated with dentoalveolar abnormalities, including dentin defects and acellular cementum hypoplasia, resulting in premature tooth loss. Some reports indicate HPP causes enamel defects. We conditionally ablated Alpl in enamel organ by crossing Krt14^Cre and Alpl^fl/fl mice to generate Krt14^Cre ;Alpl^fl/fl conditional KO (cKO) mice. Control (CTR) and cKO mice were analyzed at 14 and 60 d postnatal using micro-CT, histology, scanning electron microscopy, and an ex vivo caries induction model. In situ hybridization of the incisor revealed Alpl mRNA was expressed in stratum intermedium and maturation stage ameloblasts, but not preameloblasts or secretory stage ameloblasts. Compared to CTR, cKO mice showed no differences in body weight, circulating alkaline phosphatase, or cranial and appendicular bone parameters. By gross observation, cKO incisors showed discoloration, surface irregularities, and blunted tips; however, these alterations were evident in only male cKO mice. Micro-CT analysis indicated enamel hypomineralization in male cKO vs CTR incisors. Scanning electron microscopy showed intact rod-interrod pattern but less mineralized, thinner crystals in male cKO vs CTR incisors. Histology of male cKO incisors revealed impaired prematuration stage ameloblasts due to ameloblast/enamel detachment near the enamel-dentin junction, aberrant proliferating cell nuclear antigen immunostaining, and disorganized multicellular layers. Immunohistochemistry revealed disrupted enamel matrix proteins in cKO incisors. Conditional Alpl ablation in enamel epithelium revealed enamel phenotypes and suggests potential role(s) in maintaining ameloblast integrity, proper initial enamel matrix secretion, and enamel mineralization. Collectively, these findings confirm a role for TNAP in amelogenesis and point to direct effects of HPP on enamel formation, improving our understanding of amelogenesis.

The prevalence of both osteoporosis and sarcopenia increases with age and about 60% of elderly sarcopenia patients also develop osteoporosis. However, the co-occurrence of osteoporosis and sarcopenia remains unclear. We performed single-cell 5' RNA-seq on human skeletal muscle tissues and investigated the enrichment of heritability for musculoskeletal traits in cell type specific cis-regulatory regions. We found the fibroblast-specific cis-regulatory regions are highly enriched in the heritability of bone mineral density (BMD). Using genome-wide association study, we identified estrogen receptor α (ESR1) as a common transcription factor that correlated with both BMD and lean mass. We hypothesized that deficiency of estrogen signaling in fibroblast may attenuate musculoskeletal homeostasis. Therefore, we generated mice lacking Esr1 in PDGFRα (a fibroblast marker) + cells (Esr1^ΔPα ). Although muscle mass and grip strength were not different between groups, distal femoral BMD and cortical thickness were significantly lower in Esr1^ΔPα compared to control. Bone histomorphometry showed that cortical bone in Esr1^ΔPα exhibited a high turnover bone phenotype. Bulk RNA-seq using PDGFRα+ cells revealed that insulin-like growth factor-binding protein 5 (Igfbp5) expression was significantly higher in Esr1^ΔPα compared to control. Furthermore, serum IGFBP5 level was significantly higher in Esr1^ΔPα . IGFBP5 treatment in vitro significantly suppressed osteoblast differentiation and facilitated osteoclast differentiation. These results suggest that estrogen signaling in PDGFRα+ cells suppresses Igfbp5 expression, then maintains bone mass, indicating that estrogen signaling in PDGFRα+ cells plays a significant role in bone metabolism.