Journal of Bone and Mineral Research最新文献

Little is known about the associations of plasma fatty acids (FAs) with bone mineral accrual, and the evidence is mostly based on cross-sectional data. In this observational study, we investigated for the first time the longitudinal associations of plasma FA composition as well as desaturase and elongase enzyme activities with BMD from childhood to adolescence. Altogether, 480 children (227 girls) aged 7-9 yr attending baseline examinations were included in the current analyses. The longitudinal associations of the proportions of FAs in plasma phospholipids, analyzed by gas chromatography, as well as estimated desaturase and elongase activities with total body less head BMD, measured by dual-energy X-ray absorptiometry, were analyzed by linear mixed-effects models using values from baseline, 2-yr, and 8-yr follow-up and adjusted for sex, maturity offset, follow-up time, and lean mass (LM) or fat mass (FM). Decreased proportion of linoleic acid (standardized regression coefficient β = -.023, p = .001), increased proportion of dihomo-gamma-linolenic acid (β = .029, p < .001), and Δ6-desaturase activity (β = .032, p < .001) were associated with increased BMD independent of sex, maturity offset, follow-up time, LM, and FM. Increased proportions of nervonic acid (β = .018, p = .012), arachidonic acid (β = .019, p = .017), and docosapentaenoic acid (β = .020, p = .013) were associated with increased BMD, and these associations were partly explained by LM. Increased proportions of arachidic acid (β = .022, p = .005), behenic acid (β = .018, p = .010), lignoceric acid (β = .015, p = .040), and palmitoleic acid (β = .016, p = .013), increased stearoyl-CoA-desaturase activity (β = .017, p = .009), and decreased elongase activity (β = -.017, p = .023) were associated with increased BMD, and these associations were partly explained by FM. Single plasma saturated, monounsaturated, and polyunsaturated FAs have divergent longitudinal associations with BMD from childhood to adolescence. Plasma FA composition predicts bone mineral accrual from childhood to adolescence, implying that FA metabolism is important for healthy bone development since childhood.

Increased fracture risk has been reported in patients using selective serotonin reuptake inhibitors (SSRIs). However, prior studies have had limited information regarding BMD and symptoms of depression, both potentially important confounders. We examined a longitudinal cohort of women who initiated SSRIs, other antidepressant (AD) medications, or no AD to estimate the risk of fracture associated with start of SSRIs. The Study of Women's Health Across the Nation (SWAN) is a longitudinal cohort of diverse women from across the US transitioning across the menopause. Study visits are approximately yearly, with reporting of medication use, fracture incidence (any and non-traumatic), mental health scales (CES-D), and BMD (the latter occurring in selected SWAN sites). We estimated fracture incidence and relative risk among women starting SSRIs or other AD, and compared them with women not starting SSRIs or other AD. Multivariable Cox regression models with increasing adjustment were constructed. As well, secondary analyses focused on non-traumatic fractures and women with BMD measurements. The Study of Women's Health Across the Nation includes 3302 total women, of which 286 were excluded because of prevalent AD use and 1167 because they did not have adequate follow-up time, had a fracture prior to start of an AD, or could not be matched; this left 1849 women for analysis. The incidence rates for any fracture (per 100 person-years) for SSRI users was 2.64 (95% CI: 1.82-3.71), other AD users 0.80 (95% CI: 0.22-2.04), and non-users 1.21 (95% CI: 1.07-1.36). Fully adjusted regression models found an increased hazard ratio for any fracture among women starting SSRIs compared with no AD (HR 1.77, 95% CI: 1.15-2.74). These results were consistent for non-traumatic fractures and in subgroups with BMD included as a covariate. Initiation of SSRI among women in mid-life was associated with an increased risk of fracture.

Pseudohypoparathyroidism (PHP) was first described as a syndrome characterized by PTH resistance combined with skeletal abnormalities known as Albright's hereditary osteodystrophy (AHO). Studies have since focused on genetic or epigenetic alterations underlying PHP and related disorders. The α-subunit of the stimulatory G protein (Gsα) mediates the signaling of G protein-coupled receptors that stimulate cAMP generation. The Gsα-cAMP cascade is pivotal for human skeletal growth, as evidenced by pathogenic mutations converging on this signaling pathway in a spectrum of skeletal dysplasias that overlap with AHO. The gene encoding Gsα, GNAS, is subject to genomic imprinting, an epigenetic mechanism governing allele-specific gene expression through differential methylation. Parental allele contribution to Gsα expression differs among tissues. While Gsα is biallelically transcribed in most tissues, including bone and cartilage, the paternal Gsα allele is suppressed in a limited number of cells/tissues, including the proximal renal tubule, where PTH exerts critical actions. Therefore, Gsα mutations cause distinct clinical manifestations according to the affected parental allele. While maternal mutations result in PHP type 1A, which consists of PTH resistance and AHO, paternal mutations lead to pseudo-pseudohypoparathyroidism (PPHP), that is, AHO without hormone resistance. Epigenetic alterations of GNAS cause PHP type 1B (PHP1B), defined by PTH resistance in the absence of AHO. Thus, genomic imprinting plays a key role in the phenotypes associated with GNAS alterations. Investigations on the genetic cause of PHP1B have identified crucial imprinting control regions of GNAS, whose functions were elucidated only recently using human embryonic stem cells to model imprinting regulatory mechanisms in the early embryo. We herein review the current understanding of the genetic and epigenetic basis of PHP and related disorders, focusing on their skeletal manifestations.

Dentin, the primary hard tissue of teeth, is formed through the differentiation of dental mesenchymal progenitor cells into odontoblasts. Primary cilia, essential organelles on the surface of mesenchymal cell populations, are dynamically regulated in length and play a crucial role in dentinogenesis. However, the specific role of primary cilia length stability, in the regulation of cell function and dentin formation and repair, remains to be fully elucidated. Through spatial transcriptome analysis combined with mouse molar development studies, we found that ciliary membrane gene Arl13b specifically maintains cilia length homeostasis by suppressing cilia decapitation. ARL13B deficiency, which results in cilia shortening, would interfere with the differentiation fate of dental mesenchymal progenitor cells. Mechanistically, the abnormally shortened cilia disrupt intraflagellar transport (IFT)-mediated SHH signaling within cilia, thereby inhibiting the odontoblastic differentiation, and ultimately affecting tertiary dentin formation during injury repair. These findings indicate that the maintenance of primary cilia length homeostasis is crucial for the repair and regeneration of dentin.

Parathyroid hormone (PTH), produced by the parathyroid glands, plays a critical role in the regulation of calcium and phosphate homeostasis, acting primarily on bone and kidney to maintain serum calcium levels within a narrow range. Parathyroid hormone also plays important roles in bone remodeling by directly stimulating osteoblasts and osteocytes, integrating its calcemic response with stimulation of bone formation. Through the RANK/RANK-ligand system, these cells activate osteoclasts, promoting a balanced process of bone formation and resorption that maintains bone density and strength. Dysregulation of PTH, as seen in disorders such as hyper- and hypoparathyroidism, can lead to significant clinical complications. In recent years, major advancements have been made in the development of PTH analogs, aimed at leveraging PTH's physiological effects on bone to treat conditions such as osteoporosis and hypoparathyroidism. While PTH promotes both bone formation and bone resorption, the net outcome may be a gain or loss of bone mass, depending largely on the administration pattern of PTH or its analogs. When PTH is given intermittently (eg, as once-daily subcutaneous injection), bone formation is favored. Continuous administration of PTH or chronic elevation of blood PTH levels as seen in primary hyperparathyroidism tend to promote bone resorption. Parathyroid hormone analogs, such as teriparatide (PTH(1-34)) and the PTHrP analog abaloparatide, administered once daily, have significant efficacy in stimulating bone formation, making them valuable options for the treatment of osteoporosis. Given this capacity to improve bone structure, these analogs hold broader therapeutic potential for other skeletal disorders, including fracture healing and oral bone repair, which expands the scope of PTH-based therapies beyond osteoporosis. Long-acting PTH analogs have applications in treating hypoparathyroidism, offering an alternative to conventional treatment with calcium and active vitamin D. This article reviews the molecular mechanisms of approved and emerging PTH-based medicines, their clinical applications, and recent advances in optimizing their therapeutic potential. We also discuss ongoing research aimed at developing next-generation PTH analogs with improved efficacy for skeletal and metabolic disorders.

Hypochondroplasia is a rare genetic form of skeletal dysplasia, caused by gain-of-function pathogenic variants in the FGF receptor 3 (FGFR3). It is characterized by disproportionate short stature and has a wide spectrum of clinical features. Currently, there are no precision therapeutic options approved for hypochondroplasia. Infigratinib is an orally bioavailable FGFR1-3 selective tyrosine kinase inhibitor in development for achondroplasia and hypochondroplasia. Infigratinib acts directly at the source of the pathophysiological cause of both conditions by inhibiting the phosphorylation of FGFR3 and attenuating both main downstream signaling pathways that are involved in the conditions. Results from a phase 2 study support the concept that infigratinib has a potential to improve bone growth in achondroplasia. We report results of a step-wise evaluation of the therapeutic relevance of infigratinib for hypochondroplasia: in silico assessment of infigratinib with hypochondroplasia associated FGFR3 variants suggest strong interaction; in vitro, infigratinib showed potent inhibitory effect; in a mouse model of hypochondroplasia (Fgfr3N534K/+), infigratinib resulted in significant improvement in skeletal growth. These data in addition to the clinical results from the phase 2 study conducted in children with achondroplasia provide support for the development of infigratinib in the treatment of hypochondroplasia.

Inactivity has been associated with increased bone marrow adipose tissue (BMAT) and bone loss. Artificial gravity (AG) may prevent these complications. This randomized controlled trial investigated the effectiveness of AG at 2 g at the feet to prevent lumbar vertebral BMAT accumulation and bone loss. Twenty-four participants (16 male, 8 female) were bedridden for 60 d at 6° head down tilt. They were randomly assigned to bedrest only (n = 8), continuous supine centrifugation (cAG; 30 min/d), or intermittent supine centrifugation (iAG; 6 bouts of 5 min/d). Serial 3T magnetic resonance (MR) measured BMAT while DXA measured BMD in the lumbar vertebrae before, during, and after bedrest. After 60 d of bedrest, vertebral BMAT was higher in controls, +3.93% (95% CI: -0.28 to 8.14), compared to cAG and iAG interventions. After 60 d of bedrest, male controls BMAT increased 5.81% (95% CI: 2.01 to 9.61) compared to -1.35% (95% CI: -5.74 to 3.04) and 1.23% (95% CI: -1.53 to 3.99) for male cAG and iAG participants, respectively. This difference between interventions was significant: X2(2) = 8.487, p = .014. In addition, while control male participants showed decreased BMD after 60 d of bedrest (-0.02 g/cm2; 95% CI: -0.05 to 0.00), the male participants receiving iAG showed no decrease in BMD during bedrest (0.00 g/cm2; 95% CI: -0.04 to 0.05). The modulation of BMAT was inversely correlated with BMD at the same vertebrae. Recreating an axial force vector mechanically on horizontalized participants prevented BMAT accumulation and demineralization. These findings suggest exploring technological advances to translate these clinical benefits to populations at risk of acute or chronic bone loss.

Individuals with dementia have a heightened hip fracture and fall risk but whether markers of brain injury are associated with hip fracture and falls is unknown. We tested the hypothesis that higher circulating brain injury markers were associated with increased risk of hip fracture and fall hospitalizations. Brain injury markers were measured in 2141 participants (mean age 77.9 years 60% women). Brain Injury markers included neurofilament light chain (NfL), a marker of axonal injury; glial fibrillary acidic protein (GFAP), a marker of astrocytic injury; total Tau, whose many functions include neuron microtubule stabilization; and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a major protein of neurons. Incident hip fractures and hospitalizations for falls were identified through participant report and confirmed with medical records or Medicare claims. Hazard ratios were computed for a doubling exposure (log2 transformed brain injury marker) using multivariable-adjusted Cox models. After a median follow-up of 11 years, 304 incident hip fractures and 284 incident fall hospitalizations occurred. Doubling of GFAP and NfL were associated with a 22% (p=0.048) and 42% (p<0.001) higher risk of hip fracture, respectively. Additional adjustment for cognitive function, gait speed, grip strength, inflammatory markers, and depressive symptoms had no effect on results. Models that adjusted for all 4 brain markers showed that only NfL was independent of the other markers. NfL was also associated with a 47% increase risk of hospitalization for falls. There was no association of total Tau or UCH-L1 with hip fracture or falls. GFAP was also unrelated to fall hospitalizations. NfL, was independently associated with an incident risk of hip fracture and fall hospitalizations. These results suggest that subclinical degrees of brain injury may contribute to falls and hip fracture. Future research is needed to test whether the association between NfL and hip fracture is independent of falls.

Combined treatment with parathyroid hormone (PTH) receptor stimulation (teriparatide 20-μg) and RANKL inhibition (denosumab 60-mg) increases spine and hip bone mineral density (BMD) and improves estimates of bone strength to a greater extent than either monotherapy. The mechanisms underlying the enhanced efficacy of this combination, however, are not fully defined. In this randomized, three-arm interventional trial, postmenopausal women with osteoporosis were randomized to receive denosumab 60-mg (n=9), teriparatide 20-μg (n=13), or both (n=12) for 3 months. Participants received double fluorochrome labeling and underwent a single iliac crest bone biopsy at month 3. A total of 26 bone biopsies were suitable for histomorphometry. Fluorescence microscopy was utilized to differentiate remodeling-based from modeling-based bone formation in the cancellous and endocortical envelopes by identifying the morphology of underlying cement lines as either scalloped or smooth, respectively. Within-subject three-month changes from baseline were compared among the three treatment groups using one way ANOVA. At 3 months, teriparatide significantly increased histomorphometric indices of bone formation (BFR/BS, MS/BS, and dLS/BS) compared to denosumab or combination therapy, consistent with its greater effect on bone formation markers. Although both remodeling- and modeling-based bone formation increased in the combination group, denosumab attenuated the teriparatide-induced increases bone in formation, except for modeling-based bone formation in the endocortical envelope. These findings suggest that the greater increases in BMD observed with combined denosumab and teriparatide in the DATA study may result from the net effect of denosumab-mediated remodeling suppression which leads to a reduction in cortical porosity and enables secondary mineralization of the preserved bone volume and teriparatide-induced bone formation.