Bone turnover and mineral metabolism in adult patients with hypophosphatasia treated with asfotase alfa

Seefried, Lothar; Rak, Dominik; Petryk, Anna; Genest, Franca

doi:10.1007/s00198-021-06025-y

Cited by 15 publications

(13 citation statements)

References 35 publications

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“…Certainly, the osteoblast production of alkaline phosphatase is compromised and it would be of interest to know what serum calcium and serum PTH levels are in the mutant mice. Adult humans with hypophosphatasia have levels of PTH 1-84 levels in the normal range [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that the anabolic actions of PTH which are particularly prominent in growing mice may be restrained by alkaline phosphatase under normal conditions. Interestingly, a recent study of asfotase alfa enzyme replacement (Strensiq®) in human adults with hypophosphatasia found enzyme replacement therapy led to transient increases in PTH 1-84 levels [ 33 ]. Anabolic PTH is well known to increase P1NP levels and is a marker of the effective increase in bone formation evoked by PTH.…”

Section: Discussionmentioning

confidence: 99%

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Anabolic actions of parathyroid hormone in a hypophosphatasia mouse model

et al. 2022

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Hypophosphatasia, the rare heritable disorder caused by TNAP enzyme mutations, presents wide-ranging severity of bone hypomineralization and skeletal abnormalities. Intermittent PTH (1-34) increased long bone volume in Alpl -/mice but did not alter the skull phenotype. PTH may have therapeutic value for adults with TNAP deficiency-associated osteoporosis. Introduction Hypophosphatasia is the rare heritable disorder caused by mutations in the tissue non-specific alkaline phosphatase (TNAP) enzyme leading to TNAP deficiency. Individuals with hypophosphatasia commonly present with bone hypomineralization and skeletal abnormalities. The purpose of this study was to determine the impact of intermittent PTH on the skeletal phenotype of TNAP-deficient Alpl -/mice. Methods Alpl-/-and Alpl+/+ (wild-type; WT) littermate mice were administered PTH (1-34) (50 µg/kg) or vehicle control from days 4 to 12 and skeletal analyses were performed including gross measurements, micro-CT, histomorphometry, and serum biochemistry. Results Alpl -/mice were smaller with shorter tibial length and skull length compared to WT mice. Tibial BV/TV was reduced in Alpl -/mice and daily PTH (1-34) injections significantly increased BV/TV and BMD but not TMD in both WT and Alpl -/tibiae. Trabecular spacing was not different between genotypes and was decreased by PTH in both genotypes. Serum P1NP was unchanged while TRAcP5b was significantly lower in Alpl -/vs. WT mice, with no PTH effect, and no differences in osteoclast numbers. Skull height and width were increased in Alpl -/vs. WT mice, and PTH increased skull width in WT but not Alpl -/mice. Frontal skull bones in Alpl -/mice had decreased BV/TV, BMD, and calvarial thickness vs. WT with no significant PTH effects. Lengths of cranial base bones (basioccipital, basisphenoid, presphenoid) and lengths of synchondroses (growth plates) between the cranial base bones, plus bone of the basioccipitus, were assessed. All parameters were reduced (except lengths of synchondroses, which were increased) in Alpl -/vs. WT mice with no PTH effect. Conclusion PTH increased long bone volume in the Alpl -/mice but did not alter the skull phenotype. These data suggest that PTH can have long bone anabolic activity in the absence of TNAP, and that PTH may have therapeutic value for individuals with hypophosphatasia-associated osteoporosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Anabolic actions of parathyroid hormone in a hypophosphatasia mouse model

et al. 2022

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“…Asfotase alfa also seems to be beneficial for adult patients with pediatric-onset HPP, improving the biochemical characteristics of the disease: it increases TNSALP activity and lowers both PLP and PPi levels [67][68][69], with no significant difference between the ALPL variant states [70]. When a group of adolescents and adults with childhood-onset HPP, treated with asfotase alfa, was compared to an untreated control group, after 6 months of therapy, there was found a higher TNSALP activity, lower PLP and PPi levels and significant improvement in the 6-minute-walk test [67].…”

Section: Asfotase Alfa: Recombinant Enzyme Replacement Therapy In Hppmentioning

confidence: 99%

“…Lumbar spine BMD T-scores continued to increase throughout the follow up. They concluded that asfotase alfa mediates bone mineralization and bone turnover on previously inaccessible bone [69] (▶Fig. 3).…”

Section: Asfotase Alfa: Recombinant Enzyme Replacement Therapy In Hppmentioning

confidence: 99%

Novel Therapeutic Agents for Rare Diseases of Calcium and Phosphate Metabolism

et al. 2022

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The last decade has been revolutionary regarding the management of rare bone diseases caused by impaired calcium and phosphate metabolism. Elucidation of the underlying genetic basis and pathophysiologic alterations has been the determinant factor for the development of new, disease-specific treatment agents. The phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) possesses a critical role in the pathogenesis of various hypophosphatemic disorders. Among them, the genetic disorder of X-linked hypophosphatemia and the acquired syndrome of tumor-induced osteomalacia, although very rare, have attracted the scientific community’s attention towards designing an FGF23-inhibitor as a potential specific therapy. The monoclonal antibody burosumab was approved for the treatment of children and adult patients with X-linked hypophosphatemia and recently for tumor-induced osteomalacia patients, demonstrating benefits regarding their symptoms, biochemical profile and bone mineralization status. Asfotase alfa is a hydroxyapatite-targeted recombinant alkaline phosphatase, an enzymatic replacement therapy, substituting the defective activity of tissue non-specific alkaline phosphatase, in patients suffering from hypophosphatasia. Promising data regarding its favorable effect on survival rate, bone quality, fracture healing, muscle strength, mobility, respiratory function, and general quality of life have led to the approval of the drug for the treatment of childhood-onset hypophosphatasia. Given the high costs of treatment for both agents and their limited clinical use until now, more data are needed to define patients’ characteristics that make them ideal candidates for therapy. Long-term safety issues also need to be clarified.

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“…Similarly favorable results were reported in several case reports in adults with HPP [ 102 , 103 , 104 , 105 , 106 ]. In addition, Seefried et al [ 107 ] reported the 24-month effect of asfotase alfa on bone turnover markers and BMD in 21 adults with paediatric-onset HPP. Serum osteocalcin, procollagen-1 N-terminal peptide and PTH increased at 3 and 6 months and returned to baseline at 12 months, while tartrate-resistant acid phosphatase 5b increased at 3 months and returned to baseline thereafter.…”

Section: Managementmentioning

confidence: 99%

Hypophosphatasia

Tournis

Yavropoulou

Polyzos

et al. 2021

JCM

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Hypophosphatasia (HPP) is an inherited metabolic disease caused by loss-of-function mutations in the tissue non-specific alkaline phosphatase (TNAP) gene. Reduced activity of TNAP leads to the accumulation of its substrates, mainly inorganic pyrophosphate and pyridoxal-5΄-phosphate, metabolic aberrations that largely explain the musculoskeletal and systemic features of the disease. More than 400 ALPL mutations, mostly missense, are reported to date, transmitted by either autosomal dominant or recessive mode. Severe disease is rare, with incidence ranging from 1:100,000 to 1:300,000 live births, while the estimated prevalence of the less severe adult form is estimated to be between 1:3100 to 1:508, in different countries in Europe. Presentation largely varies, ranging from death in utero to asymptomatic adults. In infants and children, clinical features include skeletal, respiratory and neurologic complications, while recurrent, poorly healing fractures, muscle weakness and arthropathy are common in adults. Persistently low serum alkaline phosphatase is the cardinal biochemical feature of the disease. Management requires a dedicated multidisciplinary team. In mild cases, treatment is usually symptomatic. Severe cases, with life-threating or debilitating complications, can be successfully treated with enzyme replacement therapy with asfotase alfa.

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Bone turnover and mineral metabolism in adult patients with hypophosphatasia treated with asfotase alfa

Cited by 15 publications

References 35 publications

Anabolic actions of parathyroid hormone in a hypophosphatasia mouse model

Anabolic actions of parathyroid hormone in a hypophosphatasia mouse model

Novel Therapeutic Agents for Rare Diseases of Calcium and Phosphate Metabolism

Hypophosphatasia

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