Jacques P. Brown

We describe a family with 11 members affected by oral, facial and digital findings, as well as adult‐onset multiple long bone insufficiency fractures mimicking atypical femur fractures (AFF) on radiographs. The analysis of the pedigree of this family suggested an X‐linked dominant inheritance. We performed whole‐exome sequencing in this family. A rare novel variant, p.Ala642Asp (NM_003611, c.1925C>A, hg19) of the OFD1 gene was the only candidate on the X chromosome segregating with the phenotype within the family. The OFD1 gene targeted sequencing was carried out on 49 patients with AFF and 100 healthy controls. We detected another rare variant, p.Lys668Asn (NM_003611, c.2004G>C, hg19) of the OFD1 gene, in a woman with AFF. The structure of OFD1 protein has been predicted by AlphaFold 3 (AF3). According to the AF3 model of OFD1, the destabilization of the dimerization of OFD1 by the p.Ala642Asp variant and the breaking of ionic bond by the p.Lys668Asn variant could be pathogenic. This family demonstrates that such insufficiency fractures of long bones may occur in patients with oral‐facial‐digital syndrome and provides novel insight into the pathophysiology of these fractures and their association with dental and facial hypoplasia.

Paget's disease of bone (PDB) is a focal, late-onset, chronic disorder of bone metabolism. Although the prevalence of PDB is stable in Quebec, the incidence and clinical severity of PDB have decreased over time. In this study, we determined the temporal trend of mortality associated with PDB in a large population-based retrospective cohort over 20 yr from the medico-administrative data of the Régie de l'assurance maladie du Québec, compared with the general population. For each fiscal year, the age-standardized rate of all-cause mortality was determined from 2000/2001 to 2020/2021 in individuals aged ≥55 with PDB and in the general population. The population size was 1 706 015 in 2000/2001 and 2 913 820 in 2019/2020. The case definition was based on 1 hospitalization or 2 claims from physicians with the diagnosis code of PDB. We determined the adjusted relative risk (aRR) of mortality in men and women, as well as by age categories. A total of 99% CIs have been calculated. We described the percentage of death for each main cause of death. Between 2000-2001 and 2020/2021, the all-cause age-standardized mortality rate (ASMR) in PDB individuals significantly increased from 47.1/1000 to 54.2/1000, respectively (JoinPoint analysis p < .01). The all-cause ASMR significantly decreased from 27.6/1000 to 22.3/1000 in the general population (JoinPoint analysis p < .01), respectively. Over the study period, compared with the general population, the PDB aRR of mortality rate has increased from 1.06 (0.95-1.19) to 1.16 (1.06-1.27), with a significant increase of mortality observed between 2016/2017 and 2019/2020. We observed an increase in the aRR of mortality in the age category of 65-74 yr from 1.15 (0.84-1.57) to 1.26 (0.97-1.64). The increased mortality in the endocrine and cardiovascular systems may be related to the aging of the pagetic cohort but also to the presence of vascular calcifications.

Paget's Disease of Bone (PDB) is a chronic, late-onset skeletal disorder characterized by highly localized regions of increased bone resorption, accompanied by excessive and abnormal new bone formation. Consequently, PDB serves as a crucial model for elucidating the genetic and molecular mechanisms governing both abnormal osteoclast formation and osteoclast-induced osteoblast/osteocyte activities. This narrative review based on the available indexed literature examines the genetics of PDB and its connections with the pathophysiology of the disease, focusing on interactions with bone cells, environmental factors, clinical presentation, and complications. PDB research highlights the importance of genetic studies, and the need for further research especially in families not linked to SQSTM1 pathogenic variants. Enhancing education for health care professionals is critical, given PDB's rarity and its exclusion from medical curricula, which leads to diagnostic delays and mismanagement. Further exploration of gene-environmental interactions and the role of bone cells in lesion formation remains a priority. Advances in precision medicine may soon allow genetic testing to predict the risk of PDB using polygenic risk scores, leading to targeted prevention strategies. Future treatments may involve SQSTM1 gene inhibitors, such as siRNA, offering a personalized approach to early prevention and management of PDB.

Early increases in bone turnover markers (BTMs) in response to anabolic therapy correlate with 18-mo BMD increases in postmenopausal women with osteoporosis; however, this relationship has not been assessed in men. In this analysis, the correlation between changes from baseline in fasting intact serum procollagen type I N propeptide (PINP) and serum CTX at 1, 3, 6, and 12 mo and percent increase from baseline in BMD at 12 mo in men from the randomized phase 3 ATOM study (NCT03512262) were evaluated using Pearson’s correlation coefficients. The uncoupling index (UI), a measure of the balance between markers of bone formation (PINP) and bone resorption (CTX), with positive UI favoring bone formation, was calculated. Results in men were compared to 12-mo results for women from the ACTIVE study using the z score test after Fisher’s Z transformation. In abaloparatide-treated men, PINP increases at 1 mo (r = 0.485), 3 mo (r = 0.614), 6 mo (r = 0.632), and 12 mo (r = 0.521) were highly correlated (p < .0001) with 12-mo LS BMD increases. The mean UI for abaloparatide-treated men was greater than placebo as early as 1 mo (2.26 vs −0.25). At month 3, the mean UI for men was greater (1.32) than for women (0.88) (p < .001). There was a significant correlation between 3-mo UI and LS BMD at 12 mo in both men (r = 0.453; p < .001) and women (r = 0.252; p < .01). UI at months 6 and 12 were also significantly correlated with 12-mo LS BMD in men and women, but the correlation was stronger in men than women. These data support that early changes in BTMs in men treated with abaloparatide are associated with subsequent changes in BMD similar to what has been reported in women.

Background: In 2021, an EULAR task force published a definition of difficult-to-treat rheumatoid arthritis (D2T RA). Our current knowledge of D2T RA with the EULAR definition is based on European and Asian cohorts, and no North American cohort has yet to be published. The aim of this study was to compare D2T RA patients to non-D2T RA who are good responders to advanced therapy, and to describe their evolution in an university health center patient cohort. Methods: This is a retrospective single centre study of the medical records of all adults with RA on at least one biologic or target synthetic DMARD (b/tsDMARD). D2T RA group was defined according to the EULAR definition of D2T RA. The non-D2T RA group was defined as a b/tsDMARD good responder who had low-disease activity or remission for at least one year on 1 or 2 b/tsDMARD mechanism of action. We compared the patients’ comorbidities, and history of b/tsDMARD use. Descriptive statistics and proportions were calculated. Kaplan-Meier analysis with log-rank test was used to estimate and compare median survival. Results: Among the 417 patients, 101 (24%) were D2T RA and 316 (76%) were non-D2T RA. D2T RA group was slightly younger (63 ± 9 years versus 65 ± 12 years, p = 0.045), more likely to have concomitant non-inflammatory pain (28% versus 8%, p < 0.0001) and to discontinue at least one b/tsDMARD due to intolerance (39% versus 10%, p < 0.0001). In the D2T RA group, JAK inhibitors were associated with longer drug continuation when used as the third b/tsDMARD. Fewer patients were using corticosteroid at their most recent follow-up in this Canadian cohort compared to others (16% versus from 29 to 74%). Conclusion: Concomitant non-inflammatory pain was more prevalent in D2T RA patients compared to b/tsDMARD good responder non-D2T RA patients. Steroid-sparing strategies is possible even in D2T RA patients. Future prospective research may compare JAK inhibitors with other mechanisms of action in D2T RA.

Bone turnover markers (BTMs) have emerged as promising tools in the management of osteoporosis as they provide dynamic information regarding skeletal status that is independent from, and often complementary to, BMD measurements. Despite remaining issues with reference intervals and assays harmonization, BTMs have been useful in elucidating the pharmacodynamics and effectiveness of osteoporosis medications in clinical trials. ¹ Serum procollagen type I N-propeptide (sPINP) and serum C-telopeptide cross-linked type I collagen (sCTX) have been identified as the most promising markers of bone formation and resorption, respectively, in osteoporosis. Among individuals not receiving osteoporosis treatment, resorption and formation rates are tightly linked and positively highly correlated (r = 0.6-0.8). ¹ Early changes (3 mo) in sPINP correlate with the percentage change in LS BMD after 18 mo of treatment with both abaloparatide and teriparatide, although the correlation with abaloparatide was greater. ² Although absolute levels of sPINP and sCTX were lower with abaloparatide than teriparatide, suggesting a lower turnover, the balance (uncoupling index) between the formation and resorption marker was similar. ²

Romosozumab treatment results in a transient early increase in bone formation and sustained decrease in bone resorption. Histomorphometric analyses revealed that the primary bone-forming effect of romosozumab is a transient early stimulation of modeling-based bone formation on cancellous and endocortical surfaces. Furthermore, preclinical studies have demonstrated that romosozumab may affect changes in the remodeling unit, resulting in positive bone balance. To further investigate the effects of romosozumab on bone balance, mo 12 (M12) and mo 2 (M2) (to analyze early effects) unpaired bone biopsies from the FRAME clinical trial were analyzed using remodeling site reconstruction to assess whether positive changes in bone balance on cancellous/endocortical surfaces may contribute to the progressive improvement in bone mass/structure and reduced fracture risk in osteoporotic women at high fracture risk. At M12, bone balance was higher with romosozumab vs placebo on cancellous (+6.1 vs +1.5 μm; P = .012) and endocortical (+5.2 vs −1.7 μm; P = .02) surfaces; higher bone balance was due to lower final erosion depth (40.7 vs 43.7 μm; P = .05) on cancellous surfaces and higher completed wall thickness (50.8 vs 47.5 μm; P = .037) on endocortical surfaces. At M2, the final erosion depth was lower on the endocortical surfaces (42.7 vs 50.7 μm; P = .021) and was slightly lower on the cancellous surfaces (38.5 vs 44.6 μm; P = .11) with romosozumab vs placebo. Sector analysis of early endocortical formative sites revealed higher osteoid thickness (29.9 vs 19.2 μm; P = .005) and mineralized wall thickness (18.3 vs 11.9 μm; P = .004) with romosozumab vs placebo. These evolving bone packets may reflect the early stimulation of bone formation that contributes to the increase in completed wall thickness at M12. These data suggest that romosozumab induces a positive bone balance due to its effects on bone resorption and formation at the level of the remodeling unit, contributing to the positive effects on bone mass, structure, and fracture risk. Romosozumab treatment has a dual effect on bone, adding new bone and reducing bone loss. In the FRAME clinical trial, romosozumab increased the bone mass and strength and reduced fracture risk in postmenopausal women with osteoporosis. Addition of new bone occurs early in treatment and rapidly on cancellous and endocortical bone surfaces where bone resorption is not ongoing. However, it remains unclear if romosozumab affects bone loss or gain in areas where bone resorption is ongoing (remodeling units), contributing to a further positive bone balance. Here, we examined whether changes at the remodeling unit occur early (2 mo) and/or late (12 mo) in treatment by using bone biopsies from patients treated with romosozumab or placebo in FRAME. At M2, a combination of lower bone resorption and higher bone gain on endocortical surfaces resulted in a positive bone balance with romosozumab vs placebo. At M12, the bone balance was positive with romosozumab vs placebo due to lower bone resorption on cancellous surfaces and greater bone gain on endocortical surfaces. This demonstrates that romosozumab induces a positive bone balance at remodeling units early in treatment, leading to overall gains observed later, contributing to the positive effects of romosozumab on bone mass and structure.

Postfracture survival rates provide prognostic information but are rarely reported along with other mortality outcomes in adults aged ≥50 yr. The timing of survival change following a fracture also needs to be further elucidated. This population-based, matched-cohort, retrospective database study examined 98 474 patients (73% women) aged ≥66 yr with an index fracture occurring at an osteoporotic site (hip, clinical vertebral, proximal non-hip non-vertebral [pNHNV], and distal non-hip non-vertebral [dNHNV]) from 2011 to 2015, who were matched (1:1) to nonfracture individuals based on sex, age, and comorbidities. All-cause 1- and 5-yr overall survival and relative survival ratios (RSRs) were assessed, and time trends in survival changes were characterized starting immediately after a fracture. In both sexes, overall survival was markedly decreased over 6 yr of follow-up after hip, vertebral, and pNHNV fractures, and as expected, worse survival rates were observed in older patients and males. The lowest 5-yr RSRs were observed after hip fractures in males (66–85 yr, 51.9%–63.9%; ≥86 yr, 34.5%), followed by vertebral fractures in males (66–85 yr, 53.2%–69.4%; ≥86 yr, 35.5%), and hip fractures in females (66–85 yr, 69.8%–79.0%; ≥86 yr, 52.8%). Although RSRs did not decrease as markedly after dNHNV fractures in younger patients, relatively low 5-yr RSRs were observed in females (75.9%) and males (69.5%) aged ≥86 yr. The greatest reduction in survival occurred within the initial month after hip, vertebral, and pNHNV fractures, indicating a high relative impact of short-term factors, with survival-reduction effects persisting over time. Therefore, the most critical period for implementing interventions aimed at improving post-fracture prognosis appears to be immediately after a fracture; however, considering the immediate need for introducing such interventions, primary fracture prevention is also crucial to prevent the occurrence of the initial fracture in high-risk patients.