Journal of Bone and Mineral Research最新文献

Hypophosphatasia (HPP) is a genetic disorder caused by loss-of-function mutations in the ALPL gene that encodes tissue-nonspecific alkaline phosphatase (TNAP), an enzyme essential for physiological skeletal/dental mineralization. In HPP, TNAP deficiency leads to the accumulation of extracellular pyrophosphate (PPi), a potent inhibitor of calcification, resulting in skeletal and dental hypomineralization, with disease severity varying from the life-threatening perinatal and infantile forms to the milder later-onset forms that manifest in adulthood or only affect the dentition. Enzyme-replacement therapy based on recombinant mineral-targeted alkaline phosphatase (asfotase alfa) has been approved multinationally since 2015 for the treatment of pediatric-onset HPP, remarkably increasing the lifespan, their skeletal condition, and the quality of life of patients affected by the severe forms of HPP. However, non-skeletal symptoms remain an important clinical concern. As its moniker implies, TNAP is expressed in a large variety of tissues and cell types, and TNAP may be engaged in distinct metabolic pathways in each tissue. A better understanding of the cells expressing TNAP physiologically, the metabolic pathways involved, and the natural substrates of TNAP in each tissue will help design improved and/or alternative therapies to prevent/correct known or yet to be discovered non-skeletal manifestations of HPP.

The early postmenopausal period is characterized by rapid bone loss, accompanied by a decline in lean mass and an increase in fat mass, highlighting the importance of understanding how these changes influence bone health. This study aimed to assess the cross-sectional and longitudinal associations between body composition and bone characteristics in early postmenopausal women using linear mixed models for repeated measures. A total of 223 Swedish women, aged 50-60 and within 1-4 yr postmenopause, were followed for 2 yr as part of the ELBOW II clinical trial. Body composition-body weight, appendicular lean mass (ALM), and fat mass-was assessed by DXA. Bone outcomes included areal BMD at the TH, FN, LS (DXA), as well as tibia bone microarchitecture and volumetric BMD (vBMD), measured by HR-pQCT. Higher baseline body weight, BMI, fat mass, and ALM were significantly associated with greater cortical area, cortical vBMD, and total vBMD. Baseline body weight, BMI, and fat mass, but not ALM, were positively associated with TH BMD. Longitudinally, increases in ALM were significantly associated with favorable changes in TH BMD, LS BMD, total vBMD, trabecular bone volume fraction, and cortical area. Changes in body weight and BMI were associated with multiple bone outcomes, while fat mass change was linked only with cortical area. In exploratory group comparisons, women with low baseline fat mass (28.14%) and greater ALM loss (∆% ALM: -2.87 kg) experienced 2.4-fold and 5.2-fold greater reductions in TH BMD and tibia total vBMD, respectively, compared to those with high fat mass and maintained ALM. These findings underscore the importance of maintaining or increasing lean mass and preserving overall body weight to mitigate bone loss and reduce skeletal fragility in early postmenopausal women.

Osteoporosis is the most prevalent metabolic bone disease globally, leading to an increased risk of fractures. Recent advances in ion channel research have shed light on the importance of mechanosensitive ion channels as novel players in these pathophysiological processes. This perspective discusses the involvement of the mechanosensitive ion channels TREK-1, Piezo, and volume-regulated anion channels (VRACs) as potential novel pharmacological targets for the treatment of osteoporosis. TREK-1, a mechanosensitive K2P channel is important for maintaining the resting membrane potential in many cells, including osteoblasts and osteoclasts. K2P channels regulate osteoblast proliferation and differentiation, as well as osteoclast activity, potentially modulating bone remodeling in osteoporosis. Piezo channels influence osteoblast differentiation and osteoclast activity by modulating calcium influx, which is crucial for osteogenic signaling pathways, such as Wnt/β-catenin and ERK1/2. Piezo1 activation promotes bone formation, while its deficiency leads to impaired osteogenesis and increased bone resorption. Volume-regulated anion channels have been shown to be involved in osteoblast adaptation to mechanical stress and macrophage polarization, which indicates their importance for bone homeostasis. Chronic inflammation is a major contributor to osteoporosis progression. Evidence of ion channel involvement in this process has emerged in recent years. Specifically, macrophage function in osteoporosis seems to be linked to ion channel activity. Inflammatory polarization of macrophages is a key player in inflammation-induced bone loss and can be driven by mechanosensitive ion channels. Modulating these ion channels may provide new therapeutic opportunities. Given the complexity of ion channel interactions in bone cells and their regulatory role in bone remodeling, understanding their precise function in osteoporosis is essential. Targeted modulation of mechanosensitive ion channels holds promise as a novel therapeutic approach to mitigate inflammation-driven bone loss and improve bone density. Further research into their role in osteoclasts and macrophage-driven bone degradation will aid in developing innovative osteoporosis treatments.

Hypophosphatasia (HPP) is a heritable multisystem disorder caused by pathogenic variants in the tissue nonspecific alkaline phosphatase (ALP)-coding gene ALPL. The genotype-phenotype correlation in heterozygous adults with HPP remains incompletely understood. In this genotype-based study, we aimed to measure the prevalence of pathogenic or likely-pathogenic ALPL variants and to test the hypothesis that HPP penetrance is low in adult carriers. A total of 37 147 genomes from unselected individuals visiting a tertiary care, academic medical center were investigated. Variants classified as pathogenic or likely-pathogenic were observed with a prevalence of 0.3% (n = 109) or 1/341. Variant c.571G>A was most frequent (67.9%). A subset of 70 individuals had linked electronic health records (EHRs) and were termed ALPL+. All 70 ALPL+ individuals showed mild, mainly neurological, symptoms often reported in adults with HPP. However, low serum ALP, a hallmark of HPP, was found in only 65.7% (38/70) of ALPL+ individuals, and 12.9% (9/70) met the diagnostic criteria for HPP based on consensus guidelines, thus complete penetrance was low. Compared to controls lacking pathogenic or likely-pathogenic variants (ALPL-), the ALPL+ individuals had a higher probability of progression for mobility issues (median age 73 yr ALPL+ vs 82 yr ALPL-, p = .03), as well as a similar probability of progression for fatigue, arthritis, or dental problems. Unexpectedly, 3.4% (5/148) of individuals in the ALPL- group met the diagnostic criteria for HPP, possibly due to unidentified variants or non-ALPL genetic factors. Overall, the data support our hypothesis and aids the management of carriers of pathogenic ALPL variants.

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.

Although preclinical studies suggest that omega-3 fatty acids may benefit skeletal health, there are few randomized controlled trials investigating effects of supplemental omega-3 on bone outcomes. This VITamin D and OmegA-3 TriaL (VITAL) ancillary study investigated effects of marine omega-3 (1 g/d; EPA+DHA in a 1.2:1 ratio) vs placebo supplements on fracture risk and bone density/structure. VITAL is a 2 × 2 factorial randomized placebo-controlled trial that studied effects of supplemental marine omega-3 fatty acids and/or vitamin D3 vs placebo on cancer and cardiovascular events. The intervention took place from November 2011 through December 2017; median follow-up was 5.3 yr. The study included 25 871 U.S. men (aged ≥50) and women (aged ≥55) without baseline cancer or cardiovascular disease, not selected for low bone density or fracture history. Primary outcomes were adjudicated incident total, nonvertebral, and hip fractures in the overall cohort. In a subcohort of 771 individuals, we measured 2-yr changes in areal BMD (aBMD) by DXA, and volumetric BMD (vBMD), cortical thickness, and bone strength indices at the radius and tibia by peripheral QCT. Supplemental omega-3 vs placebo had no effect on total (HR, 1.02; 95% CI, 0.92-1.13; p = .73), nonvertebral (HR, 1.01; 95% CI, 0.91-1.12; p = .80), or hip fractures (HR, 0.89; 95% CI, 0.61-1.30; p = .55). In the subcohort, omega-3 supplementation resulted in a small increase in whole body aBMD (+0.03% vs -0.41%, p = .006) and no effect on aBMD at the spine or hip, or vBMD or bone strength indices at the radius or tibia. No serious adverse effects were observed. Supplementation with marine omega-3 fatty acids did not reduce incident fracture risk. It led to a small increase in whole body aBMD but had no other effects on BMD or bone strength measures compared to placebo in generally healthy midlife and older adults.

Impact and resistance exercise have potent osteogenic effects and may positively affect cartilage through tissue deformation. These effects may be mediated through inhibitors of Wnt signaling, such as sclerostin and Dickkopf WNT signaling pathway inhibitor 1 (DKK1), which may also play a role in cartilage metabolism. This study evaluated the effect of acute bouts of impact and resistance exercise on biomarkers of bone turnover, signaling, and cartilage metabolism. Healthy young men completed impact or resistance exercise and a control trial in random order. Impact exercise involved 120 maximum-effort multidirectional jumps and hops. Resistance exercise involved 120 high load lower limb lifts. Jumps and lifts were interspersed with 1-3 s pauses. In control trial, participants rested in a supine position for same duration as exercise trial. Blood samples were taken before, immediately, and 24 h post-exercise/rest and analyzed for sclerostin, DKK1, C-terminal telopeptide of type I collagen (CTX-I), procollagen I N-terminal propeptide (PINP), procollagen II C-terminal propeptide (PIICP), and cartilage oligomeric matrix protein. Repeated measures ANOVA compared time points, trials, and their interaction. Participants were 26 men, mean (SD) age 23.4 (2.9) yr. Impact exercise increased PINP immediately post-exercise (by mean [95% CI] + 10.8[4.8, 17.2]%, p = .002) and 24 h later (+7.4 [0.0, 15.3]%, p = .05), whereas resistance exercise had no effect. A transient increase in sclerostin immediately post-exercise occurred in the impact exercise trial only (+36.3 [24.6, 49.3]%, p < .001). Both exercise modes transiently increased DKK1 immediately post-exercise (impact +32.4 [23.1, 42.4]%, p < .001; resistance +30.3 [22.8, 38.4]%, p < .001). Cartilage oligomeric matrix protein increased immediately after resistance exercise only (+36.2 [16.0, 59.8]%, p < .001). Neither form of exercise affected CTX-I. Impact and resistance exercise transiently increased Wnt signaling inhibitors. Resistance exercise increased a marker of cartilage turnover but did not affect markers of bone turnover. Impact exercise did not affect cartilage turnover markers. Increases in bone formation but not resorption markers may reflect positive adaptation to impact loading.