Longitudinal assessment of physical function in adults with X-linked hypophosphatemia following initiation of burosumab therapy.

We assessed multiple components of muscle function in ten adults with X-linked hypophosphatemia (XLH) receiving burosumab treatment. Lower limb power (+ 9%), short physical performance battery (SPPB) score (+ 1.2 points), and physical activity (+ 65%) increased following 6 months of treatment, and hand grip increased (+ 10%) between 6 and 12 months of treatment. PURPOSE: X-linked hypophosphatemia (XLH) is a rare genetic disorder of phosphate metabolism. Burosumab is a monoclonal antibody treatment shown to improve phosphate homeostasis and improve symptoms as well as fracture healing when used as a therapy for XLH in adults. However, little is known about its effects on the large deficits in multiple components of physical function previously reported in XLH. METHODS: Ten adults (6 females, age 41.1 ± 15.7 y) were recruited from specialist centres in London and Bristol. During clinical visits for initial burosumab treatment and at 6-month and 12-month follow-up, physical function, and physical activity (PA) assessments were performed. In detail, lower limb power was assessed by mechanography via a countermovement jump, mobility by short physical performance battery (SPPB), functional capacity by 6-min walk test (6MWT), upper limb strength by hand grip dynamometry, and PA via an International Physical Activity Questionnaire (IPAQ). Differences between baseline and 6-month follow-up, and in a subset of 5 patients between 6- and 12-month follow-up, were assessed. RESULTS: Lower limb power increased by 9% (P = 0.049) from baseline to 6 months, as did SPPB score (+ 1.2 points, P = 0.033) and total PA (+ 65%, P = 0.046) although hand grip and 6MWT did not differ. Only for hand grip was a significant improvement (+ 10%, P = 0.023) seen between 6 and 12 months. CONCLUSIONS: Burosumab treatment is associated with improved lower limb function and mobility at 6 months, with improvement in hand grip strength at 12 months. Future studies should explore the underlying mechanisms and describe on function and other patient outcomes.

Garetosmab in fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial.

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n = 20) or placebo (n = 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n = 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths (5 of 44; 11.4%) occurred in the open-label period and, while considered unlikely to be related, causality cannot be ruled out. The primary efficacy end point in period 1 (total lesion activity by PET-CT) was not met (P = 0.0741). As the development of new HO lesions was suppressed in period 1, the primary efficacy end point in period 2 was prospectively changed to the number of new HO lesions versus period 1. No placebo patients crossing over to garetosmab developed new HO lesions (0% in period 2 versus 40.9% in period 1; P = 0.0027). Further investigation of garetosmab in FOP is ongoing. ClinicalTrials.gov identifier NCT03188666 .

The prevalence of musculoskeletal pain and therapy needs in adults with Osteogenesis Imperfecta (OI) a cross-sectional analysis.

BACKGROUND: Osteogenesis Imperfecta affects approximately 1 in every 10,000 people. Musculoskeletal disorders and pain are common in adults with Osteogenesis Imperfecta, but specific knowledge of the problems people have is lacking. Access to therapy services for adults with Osteogenesis Imperfecta is variable. We designed this analysis to better understand the musculoskeletal disorders and consequent therapy needs for adults with Osteogenesis Imperfecta.  METHODS: This study was a cross-sectional analysis of outpatients with Osteogenesis Imperfecta. Adults attending a newly established multidisciplinary clinic at a tertiary centre in 2019 were included. A highly specialist physiotherapist worked within the clinic to offer therapy input if required and to refer patients to appropriate therapy as needed. People over the age of 18 were included if they had a diagnosis of Osteogenesis Imperfecta. Data were collected over a five month period using routinely collected clinical information and patient reported outcomes. RESULTS: Over five months 50 patients attended the clinic. Musculoskeletal pain was a significant feature reported by 84% of patients. Over 50% of patients reported persistent pain for longer than one year duration and the most common site of pain was in the spine (46%). No difference in pain between types of OI and age. Forty five per cent (n = 19) of patients reported moderate to severe problems with mobility on the EQ-5D with over half reporting problems with self-care and ability to carry out usual activities. Over 50% of patients in clinic also reported anxiety (EQ-5D). During the consultation 70% of patients received therapy input which was either advice in clinic or an onward referral to the appropriate service. The referral rate to specialist out-patient rehabilitation services at a tertiary centre was 30%. CONCLUSIONS: This analysis highlights the high prevalence of MSK pain in adults with OI and the effect on physical function and emotional wellbeing. This study demonstrates the diverse needs of the adult Osteogenesis Imperfecta population and the need for suitable multidisciplinary therapy services.

Patient-Reported Complications, Symptoms, and Experiences of Living With X-Linked Hypophosphatemia Across the Life-Course.

CONTEXT: X-linked hypophosphatemia (XLH) is a rare, genetic phosphate-wasting disease resulting in bone, muscular, and dental problems, beginning in childhood and increasing in adulthood. OBJECTIVE: This qualitative analysis aimed to explore patient-reported symptoms, complications, and experiences of XLH over the life-course, using data from a large multinational online survey. METHODS: Responses to 2 open-ended questions from 209 adults and 86 children/adolescents (proxy report) with self-reported XLH were analyzed in 8 age groups. Two researchers independently coded and analyzed the responses, using thematic analysis, with differences settled among a multidisciplinary group. Six themes were identified, with age subgroup analysis conducted on the 3 most common, according to coding frequency. RESULTS: Within theme 1, "Clinical Signs and Symptoms of XLH," "Pain" was a dominant subtheme across the life-course, but "Skeletal Pathology" dominated the responses of children/adolescents. Within theme 2, "Impacts of Clinical Signs and Symptoms," interference with "Physical Exertion" and "Emotional Wellbeing" (comprising depression/anxiety in adults and lack of self-esteem in children/adolescents) was reported across all ages. For theme 3, "Negative Treatment Experiences," "Medication" was problematic for children, with adults reporting lack of "Access to Appropriate Treatment." Three further themes were identified: "Resilience," "Positive Treatment Experiences," and "Information Needs." CONCLUSION: The multiple burdens imposed on people with XLH throughout their lifetime encompassed the physical, emotional, and social, although the most challenging symptoms or complications differed between ages. Burden was further exacerbated by adults' lack of access to appropriate treatment, illustrating the need for age-appropriate multidisciplinary care.

Teriparatide and vertebral fracture healing in Ankylosing Spondylitis.

Patients with Ankylosing Spondylitis (AS) are four times more likely to sustain spinal fractures. Due to the associated risk of neurological complications treatment is complex. We present the case of a 56-year-old Caucasian gentleman with AS who sustained a fracture of T2 vertebra following a traumatic hyperextension injury. He declined surgery in fear of complications and started treatment with subcutaneous Teriparatide at a dose of 20 mg daily for six months. There was complete healing of the vertebral fracture at 6 months without any complications. This case is unique as complete healing was achieved without preceding surgical intervention. Further exploration of the use of Teriparatide in spinal fractures in patients with AS is recommended to support the theories generated by this and other existing cases in the literature.

Atypical Femur Fractures in Patients Treated with Bisphosphonates: Identification, Management, and Prevention.

Osteoporosis is a common condition with significant health care costs. First-line therapy is with bisphosphonates, which have proven anti-fracture efficacy. Around 10 years after the introduction of bisphosphonates reports began to be published of atypical femoral fractures (AFFs) that may be associated with this therapy. These fractures are associated with significant morbidity although lower mortality than the more common osteoporotic neck-of-femur fractures. A case definition has been described to allow identification of this class of fracture. Further work has established a high relative risk of AFFs in patients treated with bisphosphonates, but a low absolute risk in comparison to that of osteoporotic fractures. Proposed pathological mechanisms include low bone turnover states leading to stress/insufficiency fractures. Clinicians should be aware of the risk of AFFs and in particular the high rate of prodromal thigh/groin pain that warrants investigation in a patient receiving a bisphosphonate. If an incomplete fracture is diagnosed then bisphosphonate therapy needs to be stopped and prophylactic surgery may be considered. Due to these rare side effects patients on bisphosphonates require regular review, and this is particularly advised after 5 years of oral or 3 years of intravenous therapy.

Molecular analysis of DMP1 mutants causing autosomal recessive hypophosphatemic rickets.

We previously demonstrated that the mutations Met1Val (M1V) and the deletion of nucleotides 1484-1490 (1484-1490del) in Dentin matrix protein-1 (DMP1) cause the novel disorder autosomal recessive hypophosphatemic rickets (ARHR), which is associated with elevated fibroblast growth factor-23 (FGF23). To further understand the role of DMP1 in ARHR, we undertook molecular genetic and in vitro expression studies. First, we examined a kindred with a severe hypophosphatemic rickets phenotype and recessive inheritance. Analyses of this family demonstrated that the affected members had elevated serum FGF23 and carried a large, biallelic deletion that removed the majority of DMP1. At a minimum, this deletion encompassed 49 kb between DMP1 exon 3 and an intergenic region 5' to the next telomeric gene, integrin-binding sialoprotein (IBSP). We next performed immunofluorescent studies in cells to understand the effects of the known ARHR mutations on DMP1 cellular processing. These analyses showed that the M1V DMP1 mutant was not sorted to the trans-Golgi network (TGN) and secretory pathway, but filled the entire cytoplasm. In contrast, the 1484-1490del mutant localized to the TGN and was secreted, similar to wild type DMP1. The 1484-1490del mutation replaces the DMP1 18 C-terminal amino acids with 33 non-native residues. Truncation of wild type DMP1 by these native 18 residues followed by Western blot and confocal microscopic analyses demonstrated a wild type expression pattern when compared with the 1484-1490del mutant, indicating that the last 18 residues are not critical for cellular trafficking, but that the 33 additional residues arising from the 1484-1490del mutation likely compromise DMP1 processing. The relationship between DMP1 and FGF23 is unclear. To test endogenous DMP1 response to serum metabolites that also regulate FGF23, UMR-106 cells were treated with 1,25(OH)(2) vitamin D (1x10(-7) M) and showed a 12-fold increase in DMP1 mRNA and protein at 24 h. In summary, we have identified a novel DMP1 deletion as the cause of ARHR, as well as demonstrated that the ARHR mutations alter DMP1 cellular processing, and that DMP1 can be regulated by vitamin D. Taken together, this work expands our understanding of the genetic and molecular mechanisms associated with DMP1 alterations causing ARHR.

Clinical management and algorithms in osteoporosis.

The aim of management in osteoporosis is to reduce the risk of fractures. Case-finding strategies are currently recommended to identify subjects at high risk of future fracture who will benefit most from therapy. This article reviews these approaches and discusses the current and future treatment options that are available for patients with osteoporosis.