Die Dual-Röntgen-Absorptiometrie (DXA) an der Lendenwirbelsäule und am proximalen Femur beidseits ist gemäß den aktuellen Leitlinien das empfohlene Standardverfahren zur quantitativen Bestimmung der Knochendichte. Der ermittelte T‑Score gibt an, um wie viele Standardabweichungen die gemessene Knochendichte vom Mittelwert einer jungen, gesunden Referenzpopulation abweicht. Die operationale Definition einer Osteoporose der Weltgesundheitsorganisation (WHO) basiert dabei auf einem T‑Score ≤−2,5 am Schenkelhals, wenngleich im Alltag andere Messorte analog interpretiert werden. Umfangreiche Studien zeigen, dass eine Abnahme der Knochendichte mit einem exponentiellen Anstieg des Frakturrisikos einhergeht. Dennoch reicht die isolierte Betrachtung der Knochendichte nicht aus, um das tatsächliche Frakturrisiko adäquat abzuschätzen. Die DXA-Messung sollte daher stets im Kontext zusätzlicher klinischer Risikofaktoren interpretiert werden. Ergänzende DXA-Verfahren und erweiterte Analysen können die diagnostische Aussagekraft erheblich verbessern.

Hypophosphatasia is a rare genetic disease caused by deficient alkaline phosphatase (AP) activity. In adults, this causes functional limitations, substantial disability with pain and reduced quality of life. This Phase 1b, single-center, open-label trial investigated ilofotase alfa, a fully human recombinant protein intended as enzyme replacement therapy, in adults with hypophosphatasia. Changes in plasma levels of AP substrates inorganic pyrophosphate and pyridoxal-5′-phosphate were evaluated. Participants were randomized 1:1 to receive at 0.8 or 3.2 mg/kg ilofotase alfa intravenously over 1 h. Twelve participants were enrolled and completed the trial. At baseline, all participants had reduced AP activity and elevated pyridoxal-5′-phosphate. The greatest reduction in inorganic pyrophosphate and pyridoxal-5′-phosphate occurred 2 h after start of dosing in both treatment groups. Across the 10-d follow-up period, inorganic pyrophosphate values returned to baseline levels more rapidly in the 0.8 mg/kg group compared with the 3.2 mg/kg group. Mean circulating AP activity peaked 24 h after dosing and subsequently declined but remained above the lower limit of normal throughout the study. A dose-proportional increase in ilofotase alfa was observed, reaching peak concentration 1-h post-infusion. Eight treatment-emergent adverse events occurred, all classified as mild. These data demonstrate that single-dose ilofotase alfa enhances AP activity and results in dose-dependent reductions in primary disease-specific biomarkers without undesired effects on mineral homeostasis. Clinical trial registration number: ClinicalTrials.gov number: NCT05890794.

Hypophosphatasia (HPP) is a genetically determined systemic disorder characterized by reduced activity of tissue-nonspecific alkaline phosphatase (TNSALP). The resulting accumulation of its unhydrolyzed substrates leads to impaired bone mineralization and may also cause muscular, neurological, gastrointestinal or nonspecific systemic symptoms. In adults, the condition may present with chronic pain, fatigue, reduced muscle strength, pseudofractures or, in some cases, delayed fracture healing, while asymptomatic courses may occur despite detectable genetic variants. Since 2015, asfotase alfa has been available as the first causal therapy for patients with pediatric-onset HPP and significant skeletal involvement, improving bone mineralization, fracture healing, mobility and quality of life. In contrast, mild or late-onset forms predominantly require multimodal, symptom-oriented management, including physiotherapy, physical medicine interventions and structured pain therapy. Osteoanabolic treatment strategies may be considered only in cases of concomitant osteoporosis and are not established options for treating the underlying disease. Surgical procedures require careful preoperative planning and metabolic optimization due to impaired mineralization. Overall, the long-term management of adults with HPP relies on a coordinated, interdisciplinary approach to maintain function, mobility and health-related quality of life.

Hypophosphatasia (HPP) is the rare metabolic disorder caused by variants in the ALPL gene, resulting in deficient activity of tissue-nonspecific alkaline phosphatase (ALP). This leads to accumulation of substrates contributing to impaired bone mineralization. Hypophosphatasia manifests with a broad clinical spectrum; however, an increasing number of individuals with ALPL variants have been identified presenting the hallmark biochemical feature of HPP of low serum ALP activity, with or without elevated serum pyridoxal-5-phosphate (PLP) or urine phosphoethanolamine (PEA), while remaining asymptomatic. These ALPL carriers may represent a distinct subgroup within the HPP continuum, prompting the need for clearer classification. Using data from the Global ALPL Gene Variant Database, we identified 43 subjects who fulfilled the following criteria: low ALP (adjusted for age/sex), at least one ALPL variant, and no overt or reported HPP-related symptoms. Their median age was 29 yr (range 0-64); 23 were female. Serum ALP activity was reduced in all cases, with 76% of subjects showing levels less than 50% below the lower limit of normal. In 19 of 43 individuals, PLP or PEA was also elevated. Thirty distinct genotypes were observed; 79% of subjects were heterozygous, while 21% harbored homozygous or compound heterozygous variants. The identified variants were largely missense (77%), mostly affecting regions without a specific domain (38%). Five variants showed a dominant-negative effect in vitro, yet produced no clinical manifestations. Some identified genotypes were also linked to adult, childhood, or odontohypophosphatasia phenotypes, underscoring significant genotype-phenotype variability. These findings refine our understanding of the HPP spectrum, identifying a cohort of asymptomatic ALPL carriers with biochemical phenotype of HPP. Recognizing this group is important for improving diagnostic criteria and preventing overdiagnosis and unnecessary treatment. Longitudinal studies are needed to clarify follow-up strategies and determine whether these individuals develop clinical manifestations later in life or remain asymptomatic.

The XLH Matters 2024 GCC Edition meeting convened 51 physicians from 6 Gulf countries to discuss the diagnosis and management of patients with X-linked hypophosphatemia (XLH). This was the first XLH Matters meeting held in the Gulf Cooperation Council (GCC) region, reflecting the unique healthcare structure, cultural context, and patient needs. The key themes of the meeting included: challenges faced by GCC clinicians in diagnosing and treating XLH, the importance of multi-disciplinary care, the psychosocial impact, and the principles of effective transition of patients from pediatric to adult care. Participants emphasized the importance of raising awareness of XLH among primary care physicians, pediatricians, and dentists to facilitate early diagnosis in the region. Genetic testing was highlighted as the key tool supporting diagnosis, but wider access to this is needed across the GCC. A structural, progressive, and personalized model for pediatric-to-adult transition was proposed, based on the individual needs of the patient and including patient empowerment and continuity of care. The meeting underscored the need for regional collaboration, awareness initiatives, and implementation of recent clinical guidelines to improve outcomes for people with XLH in the GCC region.

Denosumab is a monoclonal antibody targeting the receptor activator of nuclear factor kappa-b ligand widely used for the prevention of skeletal-related events in patients with bone metastases. This Phase 1 randomized, double-blind, two-arm, parallel-group study assessed the equivalence in pharmacokinetics (PK) and compared the pharmacodynamics (PD), safety, and immunogenicity of the proposed biosimilar RGB-14-X and reference denosumab in healthy males. Participants were randomized 1:1 to a single subcutaneous 60 mg dose of RGB-14-X or reference denosumab, with 252 days of follow-up. Primary PK endpoints were maximum observed serum concentration (Cmax) and area under the concentration-time curve from time 0 to last quantifiable concentration (AUC0-last) and extrapolated to infinity (AUC0-inf). Secondary objectives were to compare additional PK parameters, safety and tolerability, PD and immunogenicity between groups. Of 165 participants randomized, 162 (98.2%) completed the study. The geometric mean ratios and corresponding 90% confidence intervals of RGB-14-X versus reference denosumab for Cmax, AUC0-last, and AUC0-inf were within the pre-specified range of 0.80-1.25, demonstrating equivalence. No notable differences were observed in secondary PK or PD parameters between groups; maximum reduction in concentration of the bone resorption marker serum C-terminal telopeptide of type I collagen (CTX) and the extent and duration of reduction in CTX levels over time were similar. RGB-14-X was well tolerated with a similar safety profile to reference denosumab. No anti-drug or neutralizing antibodies were detected in either group. RGB-14-X demonstrated biosimilarity to reference denosumab, with equivalent PK and similar PD, safety, and immunogenicity outcomes in healthy males.

To evaluate the efficacy of somatostatin receptor (SSTR)-directed PET/CT in localizing phosphaturic mesenchymal tumors (PMT) in patients with suspected tumor-induced osteomalacia (TIO) and to explore relationships between imaging parameters and biochemical markers. This retrospective analysis included 20 patients with suspected TIO, undergoing SSTR-directed PET/CT. Imaging findings and laboratory markers were assessed. SSTR-positive tumors were resected, while patients without detectable tumor, but persistent renal phosphate wasting, continued on medical treatment. Follow-up assessments included laboratory values and clinical examinations. PMT were detected on PET in 12 patients (60

Dual-energy X‑ray absorptiometry (DXA) assessing the lumbar spine and bilateral proximal femurs is the current guideline-recommended standard method for quantitative measurement of bone density. The output of DXA-the T score-reflects the number of standard deviations by which the measured bone density differs from the average of a healthy young reference population. The operational World Health Organization (WHO) definition of osteoporosis is based on a T score ≤-2.5 at the femoral neck, although other measurement locations are interpreted analogously in clinical routine. Numerous studies have shown that a decrease in bone density is associated with an exponential increase in the fracture risk. However, consideration of the bone density in isolation is inadequate to predict the real fracture risk. Therefore, DXA results must always be interpreted within the context of other clinical risk factors. Additional DXA methods and further analyses can significantly improve the diagnostic accuracy.

To establish the therapeutic equivalence of RGB-14-P and reference denosumab (RD) in postmenopausal women with osteoporosis through demonstrating equivalent efficacy and similar safety, pharmacodynamics (PD), and immunogenicity when transitioning from RD to RGB-14-P. Patients (n = 188) who had received two 60-mg doses of RGB-14-P or RD (day 1 and week 26) in a randomised, blinded, controlled phase 3 study were re-randomised 1:1:1 at week 52 to continue RGB-14-P (n = 63) or RD (n = 63) or transition from RD to RGB-14-P (n = 62) and followed to week 78. Gains in lumbar spine, hip, and femoral neck bone mineral density (BMD) observed in the first 52 weeks of treatment were further improved up to week 78 in all three groups, including patients who transitioned from RD to RGB-14-P. Incidences of new fragility fractures were comparable. Changes from baseline in serum PD markers (serum C-telopeptide of type I collagen and procollagen type I N-terminal propeptide) were maintained. The transition did not induce a discernible immunological reaction, and there were no clinically meaningful between-group differences in safety. Treatment responses to RGB-14-P or RD seen during the first 52 weeks of treatment further improved to week 78; transitioning from RD to RGB-14-P had no discernible impact on efficacy, PD, immunogenicity, or safety. The totality of the evidence on the proposed biosimilar RGB-14-P available to date demonstrated structural and functional similarity as well as PK, PD, and therapeutic equivalence to reference denosumab, which suggests that RGB-14-P can be considered for long-term treatment, as well as a continuation of denosumab treatment.

Hypophosphatasia (HPP) is a rare inherited metabolic disorder characterized by deficient activity of tissue-nonspecific alkaline phosphatase (TNAP) caused by variants in the ALPL gene. Disease manifestations encompass skeletal hypomineralization with rickets and lung hypoplasia, vitamin B6-dependent seizures, craniosynostosis, and premature loss of deciduous teeth. The clinical presentation can comprise failure to thrive with muscular hypotonia, delayed motor development, and gait disturbances later in childhood. In adults, pseudofractures are a characteristic indicator of severely compromised enzyme activity, but non-canonical symptoms like generalized musculoskeletal pain, weakness, and fatigue, frequently accompanied by neuropsychiatric and gastrointestinal issues are increasingly recognized as key findings in patients with HPP. The diagnosis is based on clinical manifestations in combination with persistently low alkaline phosphatase (ALP) activity, elevated levels of ALP substrates, specifically inorganic pyrophosphate (PPi), pyridoxal 5'-phosphate (PLP) or urine phosphoethanolamine (PEA), and genetic confirmation of a causative ALPL variant. Considering the wide range of manifestations, treatment must be multimodal and tailored to individual needs. The multidisciplinary team for comprehensive management of HPP patients should include expertise to ensure disease state metabolic and musculoskeletal treatment, dental care, neurological and neurosurgical surveillance, pain management, physical therapy, and psychological care. Asfotase alfa as first-in-class enzyme replacement therapy (ERT) for HPP has been shown to improve survival, rickets, and functional outcomes in severely affected children, but further research is needed to refine how enzyme replacement can also address emerging manifestations of the disease. Prospectively, further elucidating the pathophysiology behind the diverse clinical manifestations of HPP is instrumental for improving diagnostic concepts, establishing novel means for substituting enzyme activity, and developing integrative, multimodal care.

• In women with postmenopausal osteoporosis, proposed denosumab biosimilar RGB-14-P demonstrated equivalent efficacy and pharmacodynamics, and similar immunogenicity and safety to reference denosumab. • RGB-14-P comprehensively replicates the therapeutic benefit of denosumab in a clinical setting. • Denosumab biosimilars, such as RGB-14, have potential to provide lower-cost alternatives to denosumab with comparable efficacy and safety. To demonstrate the equivalence of the proposed denosumab biosimilar RGB-14-P and the reference denosumab (hereafter denosumab) in women with postmenopausal osteoporosis. In this multicentre, double-blind, Phase 3 study (EudraCT 2020-006017-38; NCT05087030), participants were randomised 1:1 to subcutaneous RGB-14-P or denosumab 60 mg every 6 months, on Day 1 and Week 26, with follow-up to Week 52. Primary endpoints were percentage change from baseline (

Purpose:Hypophosphatasia (HPP) is a rare disease characterized by skeletal and nonskeletal manifestations that can increase patient disability. The 6-Minute Walk Test (6MWT) is frequently used to assess mobility in patients with HPP, although the test is laborious to conduct in clinical practice. The purpose of the current study was to determine correlations between time to complete the 6MWT, time to complete the Chair-Rise Test (CRT), and scores on the Lower Extremity Functional Scale (LEFS) in adults with HPP. Methods:Pearson correlations between time to complete outcomes on the 6MWT and CRT, time to complete the 6MWT and scores on the LEFS, and time to complete the CRT and scores on the LEFS were calculated using de-identified data from adults with HPP who had first onset of symptoms in childhood. All patients were enrolled in the previously conducted, observational EmPATHY study. Results:Pearson correlation analyses showed inverse correlations between 6MWT and CRT outcomes (r = -0.584) and between CRT and LEFS outcomes (r = -0.596) and a direct correlation between 6MWT and LEFS outcomes (r = 0.808). Conclusions:Time to complete the 6MWT was correlated with time to complete the CRT and scores on the LEFS in adults with HPP. CRT and LEFS may be suitable, expeditious options to amend or substitute 6MWT when assessing functional status in patients with HPP.