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Romosozumab is a potent treatment for osteoporosis, with significant effects on bone density and fracture prevention. This study evaluated the cardiovascular safety of romosozumab in a real-world cohort of postmenopausal women at high fracture risk. We retrospectively evaluated postmenopausal women who initiated treatment with romosozumab between January 1, 2020, and June 30, 2023. We examined the occurrence of a major adverse cardiovascular event (MACE) across two distinct segments during the treatment period and after its conclusion. After applying inclusion and exclusion criteria, 847 women were followed for a median of 729 days (IQR: 445-1060). The incidence rate of MACE was 24.0 (95% CI 17.7-32.5) per 1000 person-years during the study period. The change in the rate of MACE from 0-90 days and 90-365 days post-treatment initiation was 0.04 and 0.06 events per 1000 days, respectively. The difference in the rate between these intervals was not statistically significant (p = .09). After 1 yr of treatment, the slope of MACE increased to 0.10, differing significantly from the preceding 12 mo on treatment (p<.001). The incidence of MACE was higher in those with a background of previous cardiovascular disease or diabetes at all timepoints, as expected. The consistency in event rates during treatment suggests that romosozumab is not associated with an increase in MACE in postmenopausal women. This finding challenges reports suggesting an increase in cardiovascular events within the first year of romosozumab treatment.

Osteogenesis imperfecta (OI) is an uncommon bone disorder caused by mutations in type I collagen involved in bone matrix leading to increased fracture risk. There are several sub-categories within OI, with OI type I being the most common and mildest form. Women with OI considering pregnancy need to be aware of bone loss and fracture risk, particularly with lactation. We report the first case of a female with twin pregnancy and OI type I who presented with multiple vertebral fractures following delivery and postpartum lactation. Following endocrine review, she weaned breast-feeding but represented within weeks with further pain and magnetic resonance imaging (MRI) demonstrating new T12 and L1 fractures. Even after receiving intravenous zoledronic acid, she experienced further thoracic pain after lifting, and MRI demonstrated a further T7 fracture. Following modification of her treatment regimen to daily teriparatide injections for 12 months, repeat dual-energy X-ray absorptiometry scan showed a significant improvement in bone mineral density at the lumbar spine and left hip. Bone loss with lactation is an important consideration for women with OI considering pregnancy. Women with OI should be assessed by an endocrinologist prior to conception to optimize bone health and have an individualized plan to mitigate bone loss and fracture risk during pregnancy and the postpartum period.

Costal cartilage plays an important functional role in the rib cage, but its mechanical properties have not been well characterized. The objective of this study is to characterize the properties of human costal cartilage and examine the effects of age, sex, rib level, and degree of calcification. We obtained cadaveric costal cartilage samples of ribs 3-6 with intact perichondrium from 24 donors (12 females and 12 males) evenly distributed by age (range 47-94 yr). Peripheral QCT scans were used to quantify geometric properties (area moments) and tissue calcification (as volume, length, and classified as central, peripheral, and mixed). Four-point bending tests were performed on each sample, and bending stiffness and modulus outcomes were evaluated by fitting data from mechanical testing with non-linear pseudo-elastic models (composed of linear and cubic components, separated into loading and unloading regimes). Effects of sex, age, rib level, and cartilage calcification on bending stiffness and modulus outcomes were assessed with mixed-effects regression models. Cartilage size (area moment) was larger in males than females and positively associated with age, while there was more calcification volume in cartilage of females than males. During loading, stiffness (linear and cubic) was larger in males, while modulus (linear and cubic) was larger in females. Linear stiffness and modulus were both negatively associated with age, positively associated with calcification, and varied between rib levels. Cubic (nonlinear) components of stiffness and modulus were positively associated with calcification and varied by rib, while modulus (but not stiffness) was negatively associated with age. During unloading, the linear stiffness and modulus values were much lower, though some similar associations were found. Overall, this study adds to our understanding of the behavior of costal cartilage as a nonlinear visco-elastic material, and the effects of sex, aging, and calcification on mechanical behavior.

Hormonal agents administered for metastatic castration-resistant prostate cancer (mCRPC) may lead to osteoporosis, skeletal events, reduced quality of life, and even reduced overall survival (OS). Bone-modifying agents may prevent those events but their effect on cancer-control outcomes remains uncertain. Relying on our institutional tertiary-care database, we explored the effect of bone-modifying agents (bisphosphonates such as zoledronic acid and denosumab) on OS and progression-free survival in patients with mCRPC with at least 1 bone metastasis using Kaplan-Meyer estimates and Cox regression models. Of 420 patients with mCRPC, 60% received bone-modifying agents who were younger (68 vs 69 years), with more systemic treatment lines for mCRPC (3 vs 2), and a higher proportion of initial de novo metastatic disease (72% vs 62%, all p ≤ .04) than patients without bone-modifying agents. In progression-free survival analyses, no significant differences were observed between both groups. In OS analyses, significant median OS differences were observed in favor of patients with bone-modifying agents (58 vs 45 months; hazard ratio [HR]: 0.66), even after multivariable adjustment (HR: 0.37; both p ≤ .01). In bone-modifying agent-stratified analyses, 57% received denosumab vs 43% bisphosphonates, with a significantly higher rate of Eastern Cooperative Oncology Group status of ≥2 in the bisphosphonates group. In progression-free and OS analyses, no significant differences were observed between bisphosphonates and denosumab patients, with numerically better results in progression-free survival analysis for denosumab after adjusting for covariates. The cumulative rate of osteonecrosis of the jaw at any treatment time was 12% in both groups and significantly decreased over time. Real-world data suggest a relatively low administration rate of bone-modifying agents in patients with osseous mCRPC. However, real-world data also suggest an OS benefit when bone-modifying agents are used, even after controlling for possible confounding patient and tumor characteristics.

Calciphylaxis, also known as calcific uremic arteriolopathy (CUA), is a rare disorder with many unknown treatment and diagnostic aspects. It is characterized by calcification and thrombosis of small blood vessels. This disease leads to progressive skin calcification, necrotizing ulcers, and infections and is associated with a high mortality rate. Although primarily affected sites tend to be on skin, those affecting bones are also significant. We report a case of CUA complicated with rapidly progressing multiple vertebral fractures and severe osteoporosis. The patient experienced a series of five vertebral fractures within 5 months after hospitalization, and blood tests revealed abnormally high levels of bone resorption marker bone-type tartrate-resistant acid phosphatase (TRACP-5b). Consequently, intravenous sodium thiosulfate and hyperbaric oxygen therapy were administered for the treatment of skin lesions caused by calciphylaxis, and brace therapy and denosumab treatment were initiated for vertebral fractures. This approach rapidly decreased TRACP-5b levels and arrested the chain of vertebral fractures. We concluded that to maintain the quality of life of patients with CUA, early treatment of primary skin lesions as well as comorbid conditions is essential.

Recent studies have linked pain and the resultant nociception-induced neural inflammation (NINI) to trauma-induced heterotopic ossification (THO). It is postulated that nociception at the injury site stimulates the transient receptor potential vanilloid-1 (the transient receptor potential cation channel subfamily V member 1) receptors on sensory nerves within the injured tissues resulting in the expression of neuroinflammatory peptides, substance P (SP), and calcitonin gene-related peptide (CGRP). Additionally, BMP-2 released from fractured bones and soft tissue injury also selectively activates TRVP1 receptors, resulting in the release of SP and CGRP and causing neuroinflammation and degranulation of mast cells causing the breakdown the blood-nerve barrier (BNB), leading to release of neural crest derived progenitor cells (NCDPCs) into the injured tissue. Parallel to this process BMP-2 initiates the NCDPCs toward osteogenic differentiation. CGRP has direct osteogenic effects on osteoprogenitor cells/mesenchymal stem cells, by activating BMP-2 via canonical Wnt/β-catenin signaling and cAMP-cAMP-response element binding protein signaling. BMP-2 binds to TGF-βRI and activates TGF-β-activated kinase 1 (TAK1) leading to phosphorylation of SMAD1/5/8, which binds to the co-activator SMAD4 and translocates to the nucleus to serve as transcription factor for BMP responsive genes critical in osteogenesis such as Runx2 and others. Thus, NINI phenotypes, and specifically CGRP induction, play a crucial role in THO initiation and progression through the activation of the BMP pathway, breakdown of the BNB, leading to the escape of NCDPCs, and the osteogenic differentiation of the latter.

Retinoids are metabolic derivatives of vitamin A and play crucial roles in the regulation of various tissues and organs during prenatal and postnatal development. Active retinoids, like all-trans-retinoic acid, are synthesized in the cytoplasm and subsequently interact with nuclear retinoic acid receptors (RARα, RARβ, and RARγ) to enhance transcription of specific genes. In the absence of retinoids, RARs can still bind to response elements of target genes but repress their transcription. Chondrogenic cell differentiation and cartilage maturation in the growth plate require the absence of retinoid signaling and transcriptional repression by unliganded RARs. This led to the hypothesis that synthetic retinoid agonists may be pharmacological agents to inhibit those cellular processes and counter the excessive formation of cartilage and bone in conditions like heterotopic ossification (HO). HO can be instigated by diverse culprits including trauma, invasive surgeries, inflammatory disorders, or genetic conditions. One such genetic disease is fibrodysplasia ossificans progressiva (FOP), a rare disorder driven by activating mutations in the ACVR1 gene. Patients with FOP have severe and progressive HO formation in soft tissues, leading to extensive permanent loss of mobility and increased mortality. Synthetic retinoid agonists selective for RARα or RARγ showed efficacy against injury-induced and genetic HO in mouse models. The RARγ agonists showed the highest effectiveness, with palovarotene being selected for clinical trials in patients with FOP. Post hoc analyses of phase II and phase III clinical trials showed that palovarotene has significant disease-modifying effects for FOP, but with significant risks such as premature growth plate closure in some younger subjects. This review provides an overview of retinoid and RAR roles in skeletal development and discusses the identification of palovarotene as a potential FOP therapy, the clinical data supporting its regulatory approval in some countries, and the potential applications of this drug for other relevant disorders besides FOP.

X-linked hypophosphatemic rickets (XLH), the most common form of hereditary rickets, is characterized by renal phosphate wasting and abnormal vitamin D metabolism due to elevated circulating levels of the phosphatonin fibroblast growth factor 23 (FGF23). Dominant inactivating variants of the phosphate regulating endopeptidase homolog, X-linked (PHEX), gene are present in patients with XLH, and more than half of affected patients carry de novo variants. We report on 3 families in whom affected members had highly unusual PHEX pathogenic variants. In 1 family we identified a previously described deep intronic PHEX variant (c.1768 + 173A>G) in the proband and her affected son. This variant is also near a previously reported PHEX variant (c.1768 + 177_1768 + 180dupGTAA) and is predicted to affect splicing by SpliceAI (delta score: 0.95) through creation of a new donor splice site. In a second proband we identified 2 pathogenic de novo and novel PHEX variants, c.2083delT (p.Ser695Profs*45) and c.2085delC (p.Tyr696Thrfs*44), that were present on different alleles, consistent with mosaicism for 3 PHEX alleles. The third proband also carried 2 PHEX variants (c.755 T>C [p.Phe252Ser] and c.759G>A [p.Met253Ile]), but in this case both variants were present on the same PHEX allele. These studies expand the molecular catalog of pathogenic PHEX variants in XLH and emphasize the importance of deep intronic sequencing and comprehensive family studies. Conventional approaches to genetic diagnosis may not be adequate to identify or characterize the disease-causing variants in the PHEX gene in some patients with likely XLH.

Germline and somatic pathogenic variants in the CDC73 gene, encoding the nuclear protein parafibromin, increase the risk for parathyroid carcinoma and cause hereditary primary hyperparathyroidism (PHPT) syndromes known as familial isolated hyperparathyroidism (FIHP) and hyperparathyroidism-jaw tumor syndrome (HPT-JT). The identification of pathogenic germline variants in PHPT-susceptibility genes can influence surgical planning for parathyroidectomy, guide screening for potential syndromic manifestations, and identify/exonerate at-risk family members. Numerous types of pathogenic germline variants have been described for CDC73-related conditions, including deletion, truncating, missense, and splice site mutations. Here, we report identification of a non-coding germline CDC73 variant (CDC73 c.1155-3A > G), previously categorized as a variant of uncertain significance (VUS), in a family with HPT-JT. This variant, found in two family members with PHPT, altered CDC73 splicing in peripheral blood cells and disrupted parafibromin immunostaining in associated parathyroid adenomas, strongly evidencing its pathogenicity. Sestamibi scintigraphy yielded nondiagnostic localization results for both patients' parathyroid adenomas, consistent with prior studies suggesting lower sensitivity for small or cystic lesions. Our findings demonstrate key aspects of CDC73-related disorders, highlight the diagnostic value of RNA testing, and exemplify the importance of obtaining a thorough, three-generational family history.

The present study was designed to evaluate the influence of a high-protein diet under conditions of calorie restriction (CR) in the muscle, adipose tissue, bone, and marrow adipose tissue (MAT). It included three groups of 20 female Wistar Hannover rats, fed with the following diets for 8 wk: control group (C) fed with an AIN93M diet, CR group (R) fed with an AIN-93M diet modified to 30% CR, and CR + high-protein group (H) fed with an AIN-93M diet modified to 30% CR with 40% protein. Body composition was determined by DXA. The femur was used for histomorphometry and the estimation of adipocytes. Microcomputed tomography (μCT) was employed to analyze the bone structure. Hematopoietic stem cells from the bone marrow were harvested for osteoclastogenesis. Body composition revealed that the gain in lean mass surpassed the increase in fat mass only in the H group. Bone histomorphometry and μCT showed that a high-protein diet did not mitigate CR-induced bone deterioration. In addition, the number of bone marrow adipocytes and the differentiation of hematopoietic stem cells into osteoclasts were higher in H than in the other groups. These results indicated that under CR, a high-protein diet was beneficial for muscle mass. However, as the μCT scanning detected significant bone deterioration, this combined diet might accentuate the detrimental effect on the skeleton caused by CR. Remarkably, the H group rats exhibited greater MAT expansion and elevated hematopoietic stem cell differentiation into osteoclasts than the CR and control counterparts. These data suggest that a high protein may not be an appropriate strategy to preserve bone health under CR conditions.