Efficacy of anti-sclerostin monoclonal antibody BPS804 in adult patients with hypophosphatasia

Seefried, Lothar; Baumann, Juliane; Hemsley, Sarah; Hofmann, Christine; Kunstmann, Erdmute; Kiese, Beate; Huang, Yue; Chivers, Simon; Valentin, Marie‐Anne; Borah, Babul; Roubenoff, Ronenn; Junker, Uwe; Jakob, Franz

doi:10.1172/jci83731

Cited by 68 publications

(39 citation statements)

References 41 publications

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“…A recent publication reports the treatment of 8 adult patients with HPP with a monoclonal anti‐sclerostin antibody (BPS804) in a phase IIA escalating‐dose trial . Treatment for 29 weeks increased bone formation markers as well as a transient decrease in the bone resorption marker C‐telopeptide.…”

Section: Treatment Of Hpp In Adultsmentioning

confidence: 99%

Hypophosphatasia in Adults: Clinical Assessment and Treatment Considerations

Shapiro

Lewiecki

2017

Journal of Bone and Mineral Research

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Hypophosphatasia (HPP) is a rare inherited disorder of bone affecting approximately 500 to 600 known individuals in the United States. HPP is the result of mutations involving the gene for tissue nonspecific alkaline phosphatase. Five clinical types of HPP are recognized. The clinical presentation of HPP varies from devastating prenatal intrauterine disease to mild manifestations in adulthood. In adults, main clinical involvement includes early loss of primary or secondary teeth, osteoporosis, bone pain, chondrocalcinosis, and fractures. Treatment for HPP is limited. Asfotase alfa is a subcutaneously administered synthetic human alkaline phosphatase that is approved for treatment of patients, including adults, with perinatal/infantile- and juvenile-onset HPP. However, guidelines for the treatment of adults with HPP are not available. This discussion addresses diagnostic and treatment considerations for adults with HPP. © 2017 American Society for Bone and Mineral Research.

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Section: Treatment Of Hpp In Adultsmentioning

confidence: 99%

Hypophosphatasia in Adults: Clinical Assessment and Treatment Considerations

Shapiro

Lewiecki

2017

Journal of Bone and Mineral Research

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“…Bone anabolic treatment, such as treatment with recombinant human parathyroid hormone analogs yielded debatable efficacy. 26 Asfotase alfa (Strensiq, Alexion), a bone-targeted enzyme replacement therapy, was approved for the long-term treatment of pediatric-onset HPP in the United States, Europe, Canada, and Japan. However, there are no guidelines for selecting adult patients for treatment, evaluating the results of treatment, or determining the optimal duration of treatment at this time.…”

Section: Discussionmentioning

confidence: 99%

Ionomycin ameliorates hypophosphatasia via rescuing alkaline phosphatase deficiency-mediated L-type Ca2+ channel internalization in mesenchymal stem cells

Dong

et al. 2020

Bone Res

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The loss-of-function mutations in the ALPL result in hypophosphatasia (HPP), an inborn metabolic disorder that causes skeletal mineralization defects. In adults, the main clinical features are early loss of primary or secondary teeth, osteoporosis, bone pain, chondrocalcinosis, and fractures. However, guidelines for the treatment of adults with HPP are not available. Here, we show that ALPL deficiency caused a reduction in intracellular Ca 2+ influx, resulting in an osteoporotic phenotype due to downregulated osteogenic differentiation and upregulated adipogenic differentiation in both human and mouse bone marrow mesenchymal stem cells (BMSCs). Increasing the intracellular level of calcium in BMSCs by ionomycin treatment rescued the osteoporotic phenotype in alpl +/− mice and BMSC-specific (Prrx1-alpl −/−) conditional alpl knockout mice. Mechanistically, ALPL was found to be required for the maintenance of intracellular Ca 2+ influx, which it achieves by regulating L-type Ca 2+ channel trafficking via binding to the α2δ subunits to regulate the internalization of the L-type Ca 2+ channel. Decreased Ca 2+ flux inactivates the Akt/GSK3β/β-catenin signaling pathway, which regulates lineage differentiation of BMSCs. This study identifies a previously unknown role of the ectoenzyme ALPL in the maintenance of calcium channel trafficking to regulate stem cell lineage differentiation and bone homeostasis. Accelerating Ca 2+ flux through L-type Ca 2+ channels by ionomycin treatment may be a promising therapeutic approach for adult patients with HPP.

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“…Recent reports on the clinical trials of Scl-Ab aimed at treatment for bone fragility diseases such as osteoporosis demonstrate promising results (3,4) . Scl-Ab may also play a therapeutic role in many sclerostin-mediated diseases other than osteoporosis, such as rheumatoid arthritis (18) , hypophosphatasia (19) , osteogenesis imperfecta (20) and bone rebuilding in multiple myeloma (21) . However, the impacts of Scl-Ab therapy on the immune system have not yet been examined.…”

Section: Discussionmentioning

confidence: 99%

Sclerostin Deficiency Alters Peripheral B Lymphocyte Responses in Mice

Chow

Mason

Coney

et al. 2018

Preprint

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Understanding how changes in bone physiology and homeostasis affect immune responses will inform how to retain strong immunity in patients with bone disease and in aged individuals. We previously identified sclerostin (Sost) as a mediator of cell communication between the skeletal and the immune system. Elevated bone mineral density in Sost-knockout (Sost -/-) mice contributes to an altered bone marrow microenvironment and adversely affects B cell development. B cells originate from hematopoietic stem cells within the bone marrow and mature in peripheral lymphoid organs to produce antibodies in response to infection and/or vaccination. In this study, we investigated whether the aberrant B cell development observed in the bone marrow of Sost -/mice extends to peripheral B cells in the spleen during immune challenge, and if these changes were age-dependent. Concomitant with more severe changes in bone architecture, B cell development in the bone marrow and in the spleen worsened with age in Sost -/mice. B cell responses to T-independent antigens were enhanced in young Sost -/mice, whereas responses to T-dependent antigens were impaired. Our results support the hypothesis that the adverse effects of B cell development in the Sost-deficient bone marrow microenvironment extends to the peripheral B cell immune response to protein antigens, and suggest that the B cell response to routine vaccinations should be monitored regularly in patients being treated with sclerostin antibody therapy. In addition, our results open the possibility that Sost regulates the T-independent B cell response, which might be applicable to the improvement of vaccines towards non-protein antigens.

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Efficacy of anti-sclerostin monoclonal antibody BPS804 in adult patients with hypophosphatasia

Cited by 68 publications

References 41 publications

Hypophosphatasia in Adults: Clinical Assessment and Treatment Considerations

Hypophosphatasia in Adults: Clinical Assessment and Treatment Considerations

Ionomycin ameliorates hypophosphatasia via rescuing alkaline phosphatase deficiency-mediated L-type Ca2+ channel internalization in mesenchymal stem cells

Sclerostin Deficiency Alters Peripheral B Lymphocyte Responses in Mice

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