Journal of Bone and Mineral Research最新文献

Aromatase contributes to maintenance of bone mass because male patients with loss-of-function mutations of CYP19A1 exhibit bone loss. Treatment with aromatase inhibitor also causes bone loss in men and post-menopausal women, suggesting that part of the anabolic effect of testosterone in men is dependent on estradiol (E2) biosynthesized by aromatase in non-gonadal tissues. It remains unclear how locally biosynthesized E2 contributes to maintenance of bone mass. We examined the function of aromatase in local tissues rather than gonads using cell-type specific aromatase knockout (KO) mice. Because osteoblast-specific aromatase KO mice exhibited no bone phenotype, we focused on adipose tissue, known as a reservoir of steroid hormones and analyzed the bone phenotypes of adipose tissue-specific aromatase KO (AroΔaP2) mice. Sixteen-week-old male AroΔaP2 mice exhibited significantly lower bone mineral density in tibia and femur, especially in trabecular bone, than controls. Bone histomorphometry showed that AroΔaP2 mice exhibited an insufficient calcification bone phenotype with increased osteoid volume and width, and decreased osteoclast area and numbers. Moreover, serum phosphate, renal phosphate reabsorption and FGF23 were significantly lower in AroΔaP2, suggesting that the insufficient calcification phenotype in AroΔaP2 was not caused by excessive FGF23 activities. Finally, we analyzed NaPi2a and NaPi2c, phosphate transporters localized in the kidney and found that protein levels in renal brush border membrane vesicles were lower in AroΔaP2. These results indicate that estrogens locally biosynthesized by aromatase in adipocytes can play a significant role in bone mass maintenance via regulation of phosphate reabsorption in the kidney by NaPi2.

Longevity in African populations is increasing, where deprivation and malnutrition are common; hence fragility fracture incidence is expected to increase. Healthcare systems must adapt to provide for this aging population; however, currently fragility fracture incidence has yet to be determined in any West African setting. This study aimed to determine age- and sex-specific hip fracture incidence rates in adults in The Gambia, compare these with rates from other Southern African countries, and estimate future national hip fracture projections. All hip fracture cases in adults aged ≥40 yr, presenting to a hospital or traditional bone setter (TBS) in the study area over 2-yr, were identified. Age- and sex-specific hip fracture incidence per 100 000 person-years were estimated using the 2024 Gambian Population census. Incidence rate estimates were compared between The Gambia, Zimbabwe, South Africa, and Botswana. In The Gambia, future hip fracture numbers were estimated through to 2054 using United Nations population projections. Over 2-yr, 226 hip fracture patients, mean (standard deviation [SD]) age 71.2(12.5) years, 64.6% female, presented to hospital (184[81.4%]) or TBS (42[18.6%]). Most presented with a fragility fracture (205[90.7%]). High-impact trauma (eg, traffic accidents) was more common in younger men. Delays in presentation were common (68[30.1%]). Incidence rates for adults ≥40 yr in The Gambia were 28.1 and 51.7 per 100 000 person years for men and women, respectively, increasing with age. In those age ≥ 80 yr, incidence rates plateaued in men. The number of hip fractures is estimated to increase from 166 in 2024 to 621 by 2054. Age-specific hip fracture incidence rates were broadly comparable between The Gambia, Zimbabwe, Botswana, and Black South Africans. In summary, fragility fractures in Gambian adults were common, indicative of age-associated osteoporosis. Hip fracture cases will almost quadruple over coming decades; therefore, health service capacity must expand to manage this rising demand.

Adolescent idiopathic scoliosis (AIS) is characterized by decreased bone mineral density (BMD), which is associated with an increased risk of skeletal fragility and poor long-term outcomes. This study explores the role of the CARD14 gene in osteoclast differentiation and its contribution to bone metabolism dysregulation in AIS patients. RNA sequencing of peripheral blood mononuclear cells (PBMCs) from AIS patients identified significantly elevated CARD14 expression compared to controls. Functional in vitro assays demonstrated enhanced osteoclastogenesis in PBMC-derived cells from AIS patients, as evidenced by an increase in TRAP-positive multinucleated cells and resorption pit formation. To further elucidate CARD14's role, adenoviral vectors were constructed to overexpress CARD14 in bone marrow-derived macrophages (BMMs) from C57/B6 mice, leading to markedly increased osteoclast differentiation and activity. Next, we utilized bone marrow-specific Card14 knockout mice to investigate the in vivo role of CARD14. These mice exhibited reduced osteoclast activity, improved trabecular bone microarchitecture, and increased BMD, as evidenced by micro-CT and histological analyses. Additionally, serum biomarkers of bone metabolism further corroborated these findings. Mechanistically, CARD14 was found to interact with MYC and regulate osteoclast differentiation through a MYC-dependent pathway, while simultaneously activating NF-κB and MAPK signaling, which are critical for osteoclastogenesis. AIS patients consistently showed lower BMD and higher osteoclast counts than age-matched controls, establishing a link between abnormal osteoclast function and bone loss in AIS. The results highlight that elevated CARD14 expression promotes osteoclastogenesis and bone resorption, contributing to reduced BMD in AIS. Targeting CARD14 and its associated signaling pathways may represent a novel therapeutic approach to address bone density loss in AIS patients, potentially improving their skeletal health and quality of life.

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.

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.

Autosomal Dominant Osteopetrosis (ADO) is a rare, osteosclerotic disorder usually caused by missense variants in the CLCN7 gene, resulting in impaired osteoclastic bone resorption. Penetrance is incomplete and disease severity varies widely, even among relatives within the same family. Although ADO can cause visual loss, osteonecrosis, osteomyelitis, and bone marrow failure, the most common complication of ADO is fracture. We are conducting a natural history study to characterize disease progression and determinants of disease severity. We hypothesized that baseline bone mineral density and bone turnover markers would correlate with self-reported fracture history. We report cross-sectional analysis of baseline data from the natural history study in 54 individuals (42 adults, 12 children). In adults, Z scores for both volumetric (r = 0.87, p < .001) and areal bone mineral density (aBMD) of the lumbar spine, and Z scores for femoral neck, and total hip aBMD (r = 0.77 to 0.78; p < .001) were correlated with lifetime fracture number. Tartrate resistant acid phosphatase, a marker of osteoclast number, correlated positively with fracture (r = 0.52, p = .004) consistent with an adaptive response of higher numbers of osteoclasts among more severely affected individuals. However, fracture number correlated inversely with the bone resorption markers serum C-telopeptide (r = -0.60, p < .001) and urine N-telopeptide/creatinine ratio (r = -0.35, p = .047), suggesting that ADO subjects who have the most reduced osteoclast activity have a greater tendency to fracture. Correlation coefficients between fractures, BMD and bone turnover markers were similar when limited to the 37 adults with disease causing CLCN7 variants. There were no statistically significant differences between subjects with the most common CLCN7 variant (G215R), the most common variant in our cohort, compared to other CLCN7 variants with respect to fracture, bone density measures or biochemical markers of bone turnover. These data demonstrate that bone density and biochemical bone turnover markers are indicators of ADO severity as defined by fracture number.

Introduction: 3D-modeling of hip DXA scans has been proposed to partition BMD into cortical surface (csBMD) and trabecular "volumetric" (tvBMD). We assessed in a population-based cohort whether such partitioning contributes to fracture risk assessment compared to aBMD alone.

Methods: Participants (N = 4908) from the Rotterdam Study comprised 56% women, mean age 67.4 (SD = 10.1) years. Hip DXA scans were analyzed with enCore (GE Lunar) and 3D Shaper software. Pearson partial correlation was calculated between aBMD, csBMD and tvBMD at the total hip, femoral neck and trochanter. Incident fractures were collected from GP or hospital records. During a mean follow-up of 6.8 (SD = 2.5) years, 171 sustained a hip fracture, and 1019 any-type fractures. Fracture risk estimates were determined as hazard ratios (HR) per SD decrease in BMD, from Cox-regression adjusted for multiple confounders.

Results: High correlation (r= > 0.81; p < .001) was observed between aBMD and the modeled 3D parameters; also, between csBMD and tvBMD (r = 0.85; p < .001 at total hip). Lower aBMD was associated with higher incidence of any-type (HR = 1.60, 95%CI 1.43-1.78) and hip (HR = 2.46, 95%CI 1.90-3.17) fracture; lower csBMD with increased risk of any-type (HR = 1.44, 95%CI 1.30-1.60) and hip (csBMD HR = 1.76, 95%CI 1.39-2.23) fracture, and tvBMD with increased risk of any-type (HR = 1.62, 95%CI 1.45-1.80) and hip fracture (HR = 2.44, 95%CI 1.88-3.15). Inclusion of aBMD in models with tvBMD or csBMD resulted in high multicollinearity and unreliable coefficient parameters (VIF > 5). The effect of csBMD was largely attenuated after inclusion of tvBMD in the same model for both any-type (csBMD HR = 0.96, 95%CI 0.81-1.13; tvBMD HR = 1.67, 95%CI 1.41-1.98) and hip (csBMD HR = 0.83, 95%CI 0.58-1.21, tvBMD HR = 2.82, 95%CI 1.94-4.10) fractures. Similar results were observed at the neck and intertrochanteric regions.

Conclusions: DXA-derived 3D modeled parameters are highly correlated to aBMD and do not provide additional value for the estimation of fracture risk beyond aBMD alone.

Hearing loss is common in conditions caused by ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) deficiency, such as generalized arterial calcification of infancy and autosomal recessive hypophosphatemic rickets type 2. Mechanistically, it is hypothesized that poor mineralization of the auditory ossicles leads to impaired sound transmission in the middle ear. Here we investigated whether enzyme replacement therapy (ERT) improves hearing loss in an Enpp1-deficient mouse model and whether this is associated with corrected bone properties in the ossicles. For this purpose, male Enpp1asj/asj mice were subjected to either a soluble or bone-targeted ERT of ENPP1-Fc. Hearing function and bone properties of the malleus, the first bone of the ossicular chain, were evaluated and compared to untreated Enpp1asj/asj and WT mice at the age of 17 wk. In untreated Enpp1-deficient mice, we found elevated hearing thresholds at stimulus frequencies of 8, 16, and 32 kHz, suggesting a generalized impairment of hearing. The hearing deficits observed in Enpp1asj/asj mice were partially or fully corrected by both soluble and bone-targeted ERT, as evidenced by the restoration of auditory brainstem response thresholds, with dose dependence and generally stronger effect of bone-targeted ERT. This was not only associated with corrected blood plasma markers of mineral metabolism but also improved matrix mineralization and restored osteocyte properties in the malleus. In addition, for the first time in mice, we were able to demonstrate the occurrence of mineralized osteocyte lacunae in Enpp1asj/asj mice, a phenomenon that was corrected by bone-targeted but not soluble ERT, underscoring the need for targeted delivery for effective treatment. In contrast to osteocyte lacunar mineralization in humans (ie, micropetrosis), the intra-lacunar mineral was overall less mineralized than the adjacent bone. In conclusion, our results point toward the potential benefit of correcting ossicular mineralization to prevent hearing loss in ENPP1 deficiency.