Proposed diagnostic criteria for the diagnosis of hypophosphatasia in children and adolescents: results from the HPP International Working Group.

Hypophosphatasia (HPP) is a rare inborn error of metabolism that presents variably in both age of onset and severity. HPP is caused by pathogenic variants in the ALPL gene, resulting in low activity of tissue nonspecific alkaline phosphatase (TNSALP). Patients with HPP tend have a similar pattern of elevation of natural substrates that can be used to aid in diagnosis. No formal diagnostic guidelines currently exist for the diagnosis of this condition in children, adolescents, or adults. The International HPP Working Group is a comprised of a multidisciplinary team of experts from Europe and North America who have expertise in the diagnosis and management of patients with HPP. This group reviewed 93 papers through a Medline, Medline In-Process, and Embase search for the terms "HPP" and "hypophosphatasia" between 2005 and 2020 and that explicitly address either the diagnosis of HPP in children, clinical manifestations of HPP in children, or both. Two reviewers independently evaluated each full-text publication for eligibility and studies were included if they were narrative reviews or case series/reports that concerned diagnosis of pediatric HPP or included clinical aspects of patients diagnosed with HPP. This review focused on 15 initial clinical manifestations that were selected by a group of clinical experts.The highest agreement in included literature was for pathogenic or likely pathogenic ALPL variant, elevation of natural substrates, and early loss of primary teeth. The highest prevalence was similar, including these same three parameters and including decreased bone mineral density. Additional parameters had less agreement and were less prevalent. These were organized into three major and six minor criteria, with diagnosis of HPP being made when two major or one major and two minor criteria are present.

The challenge of hypophosphatasia diagnosis in adults: results from the HPP International Working Group Literature Surveillance.

Hypophosphatasia (HPP) is an inborn error of metabolism caused by reduced or absent activity of the tissue non-specific alkaline phosphatase (TNSALP) enzyme, resulting from pathogenic variants in the ALPL gene. Clinical presentation of HPP is highly variable, including lethal and severe forms in neonates and infants, a benign perinatal form, mild forms manifesting in adulthood, and odonto-HPP. Diagnosis of HPP remains a challenge in adults, as signs and symptoms may be mild and non-specific. Disease presentation varies widely; there are no universal signs or symptoms, and the disease often remains underdiagnosed or misdiagnosed, particularly by clinicians who are not familiar with this rare disorder. The absence of diagnosis or a delayed diagnosis may prevent optimal management for patients with this condition. Formal guidelines for the diagnosis of adults with HPP do not exist, complicating efforts for consistent diagnosis. To address this issue, the HPP International Working Group selected 119 papers that explicitly address the diagnosis of HPP in adults through a Medline, Medline In-Process, and Embase search for the terms "hypophosphatasia" and "HPP," and evaluated the pooled prevalence of 17 diagnostic characteristics, initially selected by a group of HPP clinical experts, in eligible studies and in patients included in these studies. Six diagnostic findings showed a pooled prevalence value over 50% and were considered for inclusion as major diagnostic criteria. Based on these results and according to discussion and consideration among members of the Working Group, we finally defined four major diagnostic criteria and five minor diagnostic criteria for HPP in adults. Authors suggested the integrated use of the identified major and minor diagnostic criteria, which either includes two major criteria, or one major criterion and two minor criteria, for the diagnosis of HPP in adults.

Romosozumab Treatment in Postmenopausal Women with Osteoporosis.

BACKGROUND: Romosozumab, a monoclonal antibody that binds sclerostin, increases bone formation and decreases bone resorption. METHODS: We enrolled 7180 postmenopausal women who had a T score of -2.5 to -3.5 at the total hip or femoral neck. Patients were randomly assigned to receive subcutaneous injections of romosozumab (at a dose of 210 mg) or placebo monthly for 12 months; thereafter, patients in each group received denosumab for 12 months, at a dose of 60 mg, administered subcutaneously every 6 months. The coprimary end points were the cumulative incidences of new vertebral fractures at 12 months and 24 months. Secondary end points included clinical (a composite of nonvertebral and symptomatic vertebral) and nonvertebral fractures. RESULTS: At 12 months, new vertebral fractures had occurred in 16 of 3321 patients (0.5%) in the romosozumab group, as compared with 59 of 3322 (1.8%) in the placebo group (representing a 73% lower risk with romosozumab; P<0.001). Clinical fractures had occurred in 58 of 3589 patients (1.6%) in the romosozumab group, as compared with 90 of 3591 (2.5%) in the placebo group (a 36% lower risk with romosozumab; P=0.008). Nonvertebral fractures had occurred in 56 of 3589 patients (1.6%) in the romosozumab group and in 75 of 3591 (2.1%) in the placebo group (P=0.10). At 24 months, the rates of vertebral fractures were significantly lower in the romosozumab group than in the placebo group after each group made the transition to denosumab (0.6% [21 of 3325 patients] in the romosozumab group vs. 2.5% [84 of 3327] in the placebo group, a 75% lower risk with romosozumab; P<0.001). Adverse events, including instances of hyperostosis, cardiovascular events, osteoarthritis, and cancer, appeared to be balanced between the groups. One atypical femoral fracture and two cases of osteonecrosis of the jaw were observed in the romosozumab group. CONCLUSIONS: In postmenopausal women with osteoporosis, romosozumab was associated with a lower risk of vertebral fracture than placebo at 12 months and, after the transition to denosumab, at 24 months. The lower risk of clinical fracture that was seen with romosozumab was evident at 1 year. (Funded by Amgen and UCB Pharma; FRAME ClinicalTrials.gov number, NCT01575834 .).

[Hypophosphatasia]. / Hypophosphatasie de l'adulte.

Hypophosphatasia (HPP) is an inborn metabolic bone disorder caused by loss-of-function mutations in the gene encoding tissue nonspecific alkaline phosphatase (TNSALP). The adult form can be mistaken with common osteoporosis and/or present recurrent metatarsal fractures, skeletal and muscular pain. Subtrochanteric femoral pseudofractures resembling bisphosphonate-associated atypical femoral fractures can also be present, and Bps are therefore contraindicated in HPP. Early tooth loss and renal calcifications can orient towards the diagnosis. The diagnosis is based on low serum ALP levels (< 40 U/L) and high ALP substrate levels, such as vitamin B6 (pyridoxin), eventually on genetic testing. Recent development of an enzyme replacement therapy offers new therapeutic perspectives in severe cases.

L'hypophosphatasie (HPP) est une maladie rare due à une perte de fonction du gène de la phosphatase alcaline (ALP). La forme adulte peut être facilement confondue avec une ostéoporose banale. Elle se manifeste aussi par des fractures de stress, des douleurs osseuses et des myalgies. Des pseudofractures des fémurs proximaux ressemblent aux fractures atypiques par bisphosphonates, qui sont donc contre-indiqués en cas d'HPP. La perte précoce des dents et des calcifications rénales peuvent mettre sur la piste d'une HPP. Le diagnostic est fondé sur l'histoire clinique et des valeurs basses d'ALP (< 40 U/l), hautes de ses substrats, notamment la vitamine B6, et finalement sur les tests génétiques. Le développement récent d'un substitut enzymatique offre de nouvelles perspectives thérapeutiques dans les cas sévères.

Denosumab in the Treatment of Osteoporosis: 10 Years Later: A Narrative Review.

The fully human monoclonal antibody denosumab was approved for treatment of osteoporosis in 2010 on the basis of its potent antiresorptive activity, which produces clinically meaningful increases in bone mineral density (BMD) and reduces fracture risk at key skeletal sites. At that time, questions remained regarding the long-term safety and efficacy of this receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor; and with clinical experience, new questions have arisen regarding its optimal use. Here, we examine these questions through the lens of data from the FREEDOM trial program and other studies to determine where denosumab fits in the osteoporosis treatment landscape. Clinical consensus and evidentiary support have grown for denosumab as a highly effective anti-osteoporosis therapy for patients at high risk of fracture. In the 10-year FREEDOM Extension study, denosumab treatment produced progressive incremental increases in BMD, sustained low rates of vertebral fracture, and further reduction in nonvertebral fracture risk without increased risk of infection, cancer, or immunogenicity. There was no evidence that suppression of bone turnover or mineralization was excessive, and rates of osteonecrosis of the jaw (ONJ) and atypical femoral fracture (AFF) were very low. It is now recognized, however, that transitioning to another anti-osteoporosis therapy after denosumab discontinuation is essential to mitigate a transient rebound of bone turnover causing rapid BMD loss and increased risk of multiple vertebral fractures (MVFs). Taken together, the available data show that denosumab has a favorable benefit/risk profile and is a versatile agent for preventing osteoporotic fractures in the short and long term. Video abstract: Denosumab in the Treatment of Osteoporosis-10 Years Later (MP4 62727 KB).

Regeneration of Craniofacial Bone Induced by Periosteal Pumping.

A variety of surgical techniques and tissue engineering strategies utilizing osteogenic potential of the periosteum have been developed for the repair of extended bone deficiencies. The aim of the present study was to assess the impact of an alternating protocol of periosteal distraction osteogenesis (PDO) on bone regeneration in an intraoral model. Eight adult, male Beagle dogs were used for the study. Two distraction devices were placed on each side of the mandible. After a 7-day latency period, distraction devices in all animals were manipulated at the rate of 0.5 mm for a total of 8 days. The pumping protocol in two test groups proceeded twice daily by alternating activation with relaxation. In the periosteal pumping/distraction (PPDO) group, the distraction screws were activated two times (at 12 and 24 h) and then turned back (at 36 h), and in the periosteal pumping (PP) group repeatedly activated and turned back (at 12 h). In the PDO group, only activation was performed once daily (positive control). Devices were left inactivated in the negative control (NC) group. The samples were harvested after 8 weeks of consolidation period and investigated by micro-CT and histological analysis. New mature, lamellar bone was formed over the pristine bone in all groups. PPDO and PDO groups showed more new bone area (NBA) compared to the PP (p < 0.001 and p < 0.001, respectively) and to the NC group (p = 0.032 and p = 0.031, respectively). Furthermore, greater NBA was found in the PP group than the NC group (p = 0.006). PDO demonstrated higher relative connective tissue area than the PPDO group (p = 0.005) and lower relative new bone volume than the NC group (p = 0.025). Pumping protocol of periosteal distraction may successfully induce the endogenous regeneration of the mandibular bone in dogs. Impact Statement Repair of extended bone defects impose a significant challenge to oral and maxillofacial surgeons. In this article, a principle of distraction osteogenesis was applied to stimulate bone regeneration in the mandible. A periosteum-based regeneration approach may represent a valuable step toward creating a significant volume of hard and soft tissues, without need for autogenous bone harvesting or application of biomaterials.

The matricellular protein periostin is required for sost inhibition and the anabolic response to mechanical loading and physical activity.

Periostin (gene Postn) is a secreted extracellular matrix protein involved in cell recruitment and adhesion and plays an important role in odontogenesis. In bone, periostin is preferentially expressed in the periosteum, but its functional significance remains unclear. We investigated Postn(-/-) mice and their wild type littermates to elucidate the role of periostin in the skeletal response to moderate physical activity and direct axial compression of the tibia. Furthermore, we administered a sclerostin-blocking antibody to these mice in order to demonstrate the influence of sustained Sost expression in their altered bone phenotypes. Cancellous and cortical bone microarchitecture as well as bending strength were altered in Postn(-/-) compared with Postn(+/+) mice. Exercise and axial compression both significantly increased bone mineral density and trabecular and cortical microarchitecture as well as biomechanical properties of the long bones in Postn(+/+) mice by increasing the bone formation activity, particularly at the periosteum. These changes correlated with an increase of periostin expression and a consecutive decrease of Sost in the stimulated bones. In contrast, mechanical stimuli had no effect on the skeletal properties of Postn(-/-) mice, where base-line expression of Sost levels were higher than Postn(+/+) and remained unchanged following axial compression. In turn, the concomitant injection of sclerostin-blocking antibody rescued the bone biomechanical response in Postn(-/-) mice. Taken together, these results indicate that the matricellular periostin protein is required for Sost inhibition and thereby plays an important role in the determination of bone mass and microstructural in response to loading.

Favorable skeletal benefit/risk of long-term denosumab therapy: A virtual-twin analysis of fractures prevented relative to skeletal safety events observed.

Antiresorptive therapies reduce fracture risk; however, long-term bone turnover inhibition may raise concerns about rare, but serious, skeletal adverse events-atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ). Denosumab, a fully human monoclonal antibody against RANKL, has demonstrated sustained low vertebral and nonvertebral fracture rates with low skeletal adverse event rates in the 3-year FREEDOM trial and its 7-year Extension (in which all subjects received open-label denosumab). In this analysis, we aimed to estimate fractures prevented relative to skeletal adverse events observed with 10 years of denosumab therapy. We modeled a hypothetical placebo group using the virtual-twin method, thereby allowing calculation of fractures prevented with denosumab treatment (relative to the virtual-placebo group) in the context of AFF or ONJ events observed in the long-term denosumab group. Estimated virtual-placebo and observed long-term denosumab exposure-adjusted fracture rates per 100,000 subject-years were calculated for fractures classified as clinical (3180 and 1777, respectively), major osteoporotic (2699 and 1525), vertebral (1879 and 901), and nonvertebral (2924 and 1528), and compared with observed AFF and ONJ in the long-term denosumab group (5 and 35 per 100,000 subject-years, respectively). The skeletal benefit/risk ratio (fractures prevented per adverse event observed) for clinical fractures was 281 (AFF) and 40 (ONJ). Based on this model, denosumab treatment for up to 10 years has a favorable skeletal benefit/risk profile when comparing fractures prevented per skeletal adverse event observed. Clinical trial registration: NCT00089791, NCT00523341.

Further Nonvertebral Fracture Reduction Beyond 3 Years for Up to 10 Years of Denosumab Treatment.

CONTEXT: Evidence for further nonvertebral fracture (NVF) reductions with long-term antiresorptive therapy in osteoporosis is lacking. OBJECTIVE: To evaluate NVF risk reduction in subjects receiving ≤10 years of denosumab treatment. DESIGN: Phase 3, randomized, placebo-controlled, 3-year Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial (NCT00089791) and its open-label 7-year extension (NCT00523341). SETTING: One hundred seventy-two study centers worldwide. PATIENTS: Women 60 to 90 years, lumbar spine or total hip bone mineral density T-scores <-2.5 (≥-4.0 at both). INTERVENTIONS: Subjects randomly assigned 1:1 denosumab 60 mg SC Q6M (long-term) or placebo (crossover) in FREEDOM; eligible subjects could enroll in the extension to receive denosumab 60 mg SC Q6M. MAIN OUTCOME MEASURES: NVF Exposure-adjusted subject incidence (per 100 subject-years) during denosumab treatment years 1 to 3 and 4 to 7 (all subjects) and years 4 to 10 (long-term only), and rate ratios (RRs) for years 4 to 7 or 4 to 10 vs 1 to 3. RESULTS: Among 4074 subjects (2343 long-term, 1731 crossover), NVF rates (95% CI) in all subjects were 2.15 (1.90 to 2.43) during years 1 to 3 and 1.53 (1.34 to 1.75) during years 4 to 7 of denosumab treatment [RR (95% CI) = 0.72 (0.61 to 0.86); P < 0.001]; in long-term only were 1.98 (1.67 to 2.34) during years 1 to 3 and 1.44 (1.24 to 1.66) during years 4 to 10 [RR = 0.74 (0.60 to 0.93); P = 0.008]. combined osteonecrosis of the jaw and atypical femoral fracture rate was 0.06. CONCLUSIONS: Long-term denosumab treatment, >3 and ≤10 years, was associated with further reductions in NVF rates compared with the first 3 years.

Periostin action in bone.

Periostin is a highly conserved matricellular protein that shares close homology with the insect cell adhesion molecule fasciclin 1. Periostin is expressed in a broad range of tissues including the skeleton, where it serves both as a structural molecule of the bone matrix and a signaling molecule through integrin receptors and Wnt-beta-catenin pathways whereby it stimulates osteoblast functions and bone formation. The development of periostin null mice has allowed to elucidate the crucial role of periostin on dentinogenesis and osteogenesis, as well as on the skeletal response to mechanical loading and parathyroid hormone. The use of circulating periostin as a potential clinical biomarker has been explored in different non skeletal conditions. These include cancers and more specifically in the metastasis process, respiratory diseases such as asthma, kidney failure, renal injury and cardiac infarction. In postmenopausal osteoporosis, serum levels have been shown to predict the risk of fracture-more specifically non-vertebral- independently of bone mineral density. Because of its preferential localization in cortical bone and periosteal tissue, it can be speculated that serum periostin may be a marker of cortical bone metabolism, although additional studies are clearly needed.

Zoledronate effects on systemic and jaw osteopenias in ovariectomized periostin-deficient mice.

Osteoporosis and periodontal disease (PD) are frequently associated in the elderly, both concurring to the loss of jaw alveolar bone and finally of teeth. Bisphosphonates improve alveolar bone loss but have also been associated with osteonecrosis of the jaw (ONJ), particularly using oncological doses of zoledronate. The effects and therapeutic margin of zoledronate on jaw bone therefore remain uncertain. We reappraised the efficacy and safety of Zoledronate (Zol) in ovariectomized (OVX) periostin (Postn)-deficient mice, a unique genetic model of systemic and jaw osteopenia. Compared to vehicle, Zol 1M (100 µg/kg/month) and Zol 1W (100 µg/kg/week) for 3 months both significantly improved femur BMD, trabecular bone volume on tissue volume (BV/TV) and cortical bone volume in both OVX Postn(+/+) and Postn(-/-) (all p<0.01). Zol 1M and Zol 1W also improved jaw alveolar and basal BV/TV, although the highest dose (Zol 1W) was less efficient, particularly in Postn(-/-). Zol decreased osteoclast number and bone formation indices, i.e. MAR, MPm/BPm and BFR, independently in Postn(-/-) and Postn(+/+), both in the long bones and in deep jaw alveolar bone, without differences between Zol doses. Zol 1M and Zol 1W did not reactivate inflammation nor increase fibrous tissue in the bone marrow of the jaw, whereas the distance between the root and the enamel of the incisor (DRI) remained high in Postn(-/-) vs Postn(+/+) confirming latent inflammation and lack of crestal alveolar bone. Zol 1W and Zol 1M decreased osteocyte numbers in Postn(-/-) and Postn(+/+) mandible, and Zol 1W increased the number of empty lacunae in Postn(-/-), however no areas of necrotic bone were observed. These results demonstrate that zoledronate improves jaw osteopenia and suggest that in Postn(-/-) mice, zoledronate is not sufficient to induce bone necrosis.