Journal of Bone and Mineral Research最新文献

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.

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.

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.

Tumor-induced osteomalacia (TIO) is an ultrarare paraneoplastic syndrome of abnormal phosphate and vitamin D metabolism secondary to the overproduction of fibroblast growth factor 23 by small-sized mesenchymal tumors typically located in soft tissues and bone. The tumor has adverse effects on bone and patients complain of skeletal symptoms and in severe cases they suffer multiple devastating fractures. Specific features may characterize the histology of tumors located in bone with respect to those found in extra-skeletal sites. Indeed, the matrix may contain foci resembling primitive cartilage and osteoid. Light microscopy of bone biopsy samples reveal accumulation of osteoid due to thickening of osteoid seams and, if tetracyclines were sequentially administrated, fluorescence microscopy reveals prolongation of the mineralization lag time. Areal bone mineral density assessed by DXA is significantly lower at both the lumbar and femoral sites in patients with TIO and values of trabecular bone score are significantly reduced with respect to healthy individuals. Patients with TIO are also characterized by significant impairment in bone quality at both the trabecular and cortical compartment when evaluated by high-resolution peripheral quantitative computed tomography. Successful surgical removal of the causative tumor completely reverts biochemical abnormalities. Bone mineral density accrual is impressive in the short term at the central (spine and hip) level but may take longer to improve, together with microstructural parameters, at peripheral sites (radius and tibia). Future studies should address effects of long-term treatment on quality-of-life outcomes related to irreversible events, such as vertebral fractures. This is particularly important in patients with a heavy burden due to a long-standing disease.

Osteoporosis is the most prevalent metabolic bone disease globally, characterized by decreased bone mass and microarchitectural deterioration, leading to an increased risk of fractures. While its pathogenesis is multifactorial, including hormonal changes, aging and inflammatory processes, and thus far incompletely understood, 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 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. VRACs 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 therapeutic opportunities, as evidenced by studies showing that targeting TREK-1 and Piezo1 can alter macrophage polarization and reduce osteoclast-mediated bone resorption. 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.

Abdominal aortic calcification (AAC), a marker of subclinical cardiovascular disease, has previously shown to be associated with low bone mineral density (BMD) and fracture. However, it remains unclear whether AAC is associated with trabecular bone score (TBS), a gray-level textural measure, or whether it predicts fracture risk independent of this measure. Here, we examined the cross-sectional association of AAC scored using a validated machine learning algorithm (ML-AAC24) with TBS, and their simultaneous associations with incident fractures in 7,691 individuals (93.4% women) through the Manitoba BMD Registry (mean age 75.3 years). The association between ML-AAC24 and TBS was tested using generalised linear regression. Cox proportional hazards models tested the simultaneous relationships of ML-AAC24 and TBS with incident fractures. At baseline, 41.3% of the study cohort had low (<2), 32.4% had moderate (2 to <6) and 26.3% had high (≥6) ML-AAC24. Compared to low ML-AAC24, high ML-AAC24 was associated with a 0.81% lower TBS in the multivariable-adjusted model. Independent of each other and multiple established fracture risk factors, ML-AAC24 and TBS were each associated with an increased risk of incident fractures. Specifically, high ML-AAC24 (HR 1.41 95%CI 1.15-1.73, compared to low ML-AAC24) and lower TBS (HR 1.13 95%CI 1.05-1.22, per SD decrease) were associated with increased relative hazards for any incident fracture. High ML-AAC24 and lower TBS were also associated with incident major osteoporotic fracture (HR 1.48 95%CI 1.18-1.87 and HR 1.15 95%CI 1.06-1.25, respectively) and hip fracture (HR 1.56 95%CI 1.05-2.31 and HR 1.25 95%CI 1.08-1.44, respectively). In conclusion, high ML-AAC24 is associated with lower TBS in older adults attending routine osteoporosis screening. Both measures were associated with incident fractures. The findings of this study highlight high ML-AAC24, seen in more than 1 in 4 of the study cohort, and lower TBS provide complementary prognostic information for fracture risk.