Journal of Bone and Mineral Research

Blank, Robert D

2024 Journal of Bone and Mineral Research

doi: 10.1093/jbmr/zjae129pmid: 39258753

Sims, Natalie A

2024 Journal of Bone and Mineral Research

doi: 10.1093/jbmr/zjae110pmid: 38990205

Coupling, the mechanism that controls the sequence of events in bone remodeling, is a fundamental theory for understanding the way the skeleton changes throughout life. This review is an adapted version of the Louis V Avioli lecture, delivered at the Annual Scientific Meeting of the American Society of Bone and Mineral Research in 2023. It outlines the history of the coupling concept, details how coupling is thought to occur within trabecular and cortical bone, and describes its multiple contexts and the many mechanisms suggested to couple bone-forming osteoblasts to the prior action of osteoclasts on the same bone surface. These mechanisms include signals produced at each stage of the remodeling sequence (resorption, reversal, and formation), such as factors released by osteoclasts through their resorptive action and through protein synthesis, molecules deposited in the cement line during the reversal phase, and potential signals from osteocytes within the local bone environment. The review highlights two examples of coupling factors (Cardiotrophin 1 and EphrinB2:EphB4) to illustrate the limited data available, the need to integrate the many functions of these factors within the basic multicellular unit (BMU), and the multiple origins of these factors, including the other cell types present during the remodeling sequence (such as osteocytes, macrophages, endothelial cells, and T-cells).

Bok, Seoyeon; Sun, Jun; Greenblatt, Matthew B

2024 Journal of Bone and Mineral Research

doi: 10.1093/jbmr/zjae109pmid: 39052334

Only in the past decade have skeletal stem cells (SSCs), a cell type displaying formal evidence of stemness and serving as the ultimate origin of mature skeletal cell types such as osteoblasts, been defined. Here, we discuss a pair of recent reports that identify that SSCs do not represent a single cell type, but rather a family of related cells that each have characteristic anatomic locations and distinct functions tailored to the physiology of those sites. The distinct functional properties of these SSCs in turn provide a basis for the diseases of their respective locations. This concept emerges from one report identifying a distinct vertebral skeletal stem cell driving the high rate of breast cancer metastasis to the spine over other skeletal sites and a report identifying 2 SSCs in the calvaria that interact to mediate both physiologic calvarial mineralization and pathologic calvarial suture fusion in craniosynostosis. Despite displaying functional differences, these SSCs are each united by shared features including a shared series of surface markers and parallel differentiation hierarchies. We propose that this diversity at the level of SSCs in turn translates into a similar diversity at the level of mature skeletal cell types, including osteoblasts, with osteoblasts derived from different SSCs each displaying different functional and transcriptional characteristics reflecting their cell of origin. In this model, osteoblasts would represent not a single cell type, but rather a family of related cells each with distinct functions, paralleling the functional diversity in SSCs.

Cosman, Felicia; Lewiecki, E Michael; Eastell, Richard; Ebeling, Peter R; Jan De Beur, Suzanne; Langdahl, Bente; Rhee, Yumie; Fuleihan, Ghada El-Hajj; Kiel, Douglas P; Schousboe, John T; Borges, Joao Lindolfo; Cheung, Angela M; Diez-Perez, Adolfo; Hadji, Peyman; Tanaka, Sakae; Thomasius, Friederike; Xia, Weibo; Cummings, Steven R

2024 Journal of Bone and Mineral Research

doi: 10.1093/jbmr/zjae119pmid: 39073912

The overarching goal of osteoporosis management is to prevent fractures. A goal-directed approach to long-term management of fracture risk helps ensure that the most appropriate initial treatment and treatment sequence is selected for individual patients. Goal-directed treatment decisions require assessment of clinical fracture history, vertebral fracture identification (using vertebral imaging as appropriate), measurement of bone mineral density (BMD), and consideration of other major clinical risk factors. Treatment targets should be tailored to each patient’s individual risk profile and based on the specific indication for beginning treatment, including recency, site, number and severity of prior fractures, and BMD levels at the total hip, femoral neck, and lumbar spine. Instead of first-line bisphosphonate treatment for all patients, selection of initial treatment should focus on reducing fracture risk rapidly for patients at very high and imminent risk, such as in those with recent fractures. Initial treatment selection should also consider the probability that a BMD treatment target can be attained within a reasonable period of time and the differential magnitude of fracture risk reduction and BMD impact with osteoanabolic versus antiresorptive therapy. This position statement of the ASBMR/BHOF Task Force on Goal-Directed Osteoporosis Treatment provides an overall summary of the major clinical recommendations about treatment targets and strategies to achieve those targets based on the best evidence available, derived primarily from studies in older postmenopausal women of European ancestry.

Goldsweig, Bracha; Turk Yilmaz, Rukiye Sena; Ravindranath Waikar, Apoorva; Brownstein, Catherine; Carpenter, Thomas O

2024 Journal of Bone and Mineral Research

doi: 10.1093/jbmr/zjae137pmid: 39163488

VignetteFamilial hypocalciuric hypercalcemia (FHH) is typically a benign condition characterized by elevated serum calcium, low urinary calcium excretion, and non-suppressed circulating levels of parathyroid hormone (PTH), usually requiring no intervention. FHH is inherited in an autosomal-dominant manner. Three subtypes are described, representing variants in genes with critical roles in extracellular calcium-sensing. FHH1, due to heterozygous inactivating variants in the calcium-sensing receptor gene (CASR), accounts for the majority of cases. FHH2, due to variants in GNA11, encoding the α-subunit of the downstream signaling protein, G11, is the rarest form of FHH. FHH3, resulting from variants in AP2S1, may present with a more pronounced phenotype than FHH1 or FHH2. We describe herein a newborn girl presenting with in utero femoral fractures, hypercalcemia, hypophosphatemia, and elevated circulating PTH. She was diagnosed with mild hyperparathyroidism and provided supplemental phosphate upon hospital discharge. However, serum calcium and PTH remained elevated at 5 mo of age. The combination of low-calcium formula and cinacalcet improved the biochemical profile. No pathogenic variants in the coding region of CASR were identified; subsequent whole exome sequencing revealed a G- > T transition at c.44 (p.R15L) in AP2S1. Family studies identified this variant in the father and an affected brother. The mother was unexpectedly found to be hypocalcemic and was diagnosed with idiopathic hypoparathyroidism. This case demonstrates successful treatment of FHH3 using a low-calcium formula to limit dietary calcium availability and cinacalcet to modify PTH levels.

Dahir, Kathryn M; Shannon, Amy; Dunn, Derek; Voegtli, Walter; Dong, Qunming; Hasan, Jawad; Pradhan, Rajendra; Pelto, Ryan; Pan, Wei-Jian

2024 Journal of Bone and Mineral Research

doi: 10.1093/jbmr/zjae128pmid: 39135540

Hypophosphatasia (HPP) is a rare, inherited metabolic disease caused by deficient activity of tissue-nonspecific alkaline phosphatase (TNSALP). Efzimfotase alfa (ALXN1850) is a second-generation TNSALP enzyme replacement therapy in development for HPP. This first-in-human open-label, dose-escalating phase 1 trial evaluated efzimfotase alfa safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity. Fifteen adults (5/cohort) with HPP received efzimfotase alfa in doses of 15 mg (cohort 1), 45 mg (cohort 2), or 90 mg (cohort 3) as one intravenous (i.v.) dose followed by 3 weekly subcutaneous (s.c.) doses. The primary objective was to assess safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics of ALP substrates known to be biomarkers of disease (inorganic pyrophosphate [PPi] and pyridoxal 5′-phosphate [PLP]) and immunogenicity. Treatment-emergent adverse events (TEAEs) occurred in 12 (80%) participants. Eight (53%) participants had injection site reactions (ISRs), observed after 10 of 41 (24%) s.c. injections. Most ISR TEAEs were mild and resolved within 1–2 d. Peak and total exposures of efzimfotase alfa increased in a greater-than-dose proportional manner over the range of 15–90 mg after i.v. and s.c. dosing. The arithmetic mean elimination half-life was approximately 6 d; absolute bioavailability was 28.6%–36.8% over the s.c. dose range of 15–90 mg. Dose-dependent reductions in plasma concentrations of PPi and PLP relative to baseline reached nadir in the first week after i.v. dosing and were sustained for 3–4 wk after the last s.c. dose. Four (27%) participants tested positive for antidrug antibodies (ADAs), 3 of whom were ADA positive before the first dose of efzimfotase alfa. ADAs had no apparent effect on efzimfotase alfa pharmacokinetics/pharmacodynamics. No participants had neutralizing antibodies. Efzimfotase alfa demonstrated acceptable safety, tolerability, and pharmacokinetic profiles and was associated with sustained reductions in biomarkers of disease in adults with HPP, supporting further evaluation in adult and pediatric patients.Registration: ClinicalTrials.gov NCT04980248 (https://clinicaltrials.gov/study/NCT04980248).

Keaveny, Tony M; Adams, Annette L; Orwoll, Eric S; Khosla, Sundeep; Siris, Ethel S; McClung, Michael R; Bouxsein, Mary L; Fatemi, Shireen; Lee, David C; Kopperdahl, David L

2024 Journal of Bone and Mineral Research

doi: 10.1093/jbmr/zjae090pmid: 38861422

Randomized trials have not been performed, and may never be, to determine if osteoporosis treatment prevents hip fracture in men. Addressing that evidence gap, we analyzed data from an observational study of new hip fractures in a large integrated healthcare system to compare the reduction in hip fractures associated with standard-of-care osteoporosis treatment in men versus women. Sampling from 271,389 patients aged ≥ 65 who had a hip-containing CT scan during care between 2005 and 2018, we selected all who subsequently had a first hip fracture (cases) after the CT scan (start of observation) and a sex-matched equal number of randomly selected patients. From those, we analyzed all who tested positive for osteoporosis (DXA-equivalent hip BMD T-score ≤ −2.5, measured from the CT scan using VirtuOst). We defined “treated” as at least six months of any osteoporosis medication by prescription fill data during follow-up; “not-treated” was no prescription fill. Sex-specific odds ratios of hip fracture for treated vs not-treated patients were calculated by logistic regression; adjustments included age, BMD T-score, BMD-treatment interaction, BMD, race/ethnicity, and seven baseline clinical risk factors. At two-year follow-up, 33.9% of the women (750/2,211 patients) and 24.0% of the men (175/728 patients) were treated primarily with alendronate; 51.3% and 66.3%, respectively, were not-treated; and 721 and 269, respectively, had a first hip fracture since the CT scan. Odds ratio of hip fracture for treated vs not-treated was 0.26 (95% confidence interval: 0.21–0.33) for women and 0.21 (0.13–0.34) for men; the ratio of these odds ratios (men:women) was 0.81 (0.47–1.37), indicating no significant sex effect. Various sensitivity and stratified analyses confirmed these trends, including results at five-year follow-up. Given these results and considering the relevant literature, we conclude that osteoporosis treatment prevents hip fracture similarly in both sexes.

Vilaca, Tatiane; Schini, Marian; Lui, Li-Yung; Ewing, Susan K; Thompson, Austin R; Vittinghoff, Eric; Bauer, Douglas C; Eastell, Richard; Black, Dennis M; Bouxsein, Mary L

2024 Journal of Bone and Mineral Research

doi: 10.1093/jbmr/zjae126pmid: 39127916

There is a strong association between total hip bone mineral density (THBMD) changes after 24 mo of treatment and reduced fracture risk. We examined whether changes in THBMD after 12 and 18 mo of treatment are also associated with fracture risk reduction. We used individual patient data (n = 122 235 participants) from 22 randomized, placebo-controlled, double-blind trials of osteoporosis medications. We calculated the difference in mean percent change in THBMD (active-placebo) at 12, 18, and 24 mo using data available for each trial. We determined the treatment-related fracture reductions for the entire follow-up period, using logistic regression for radiologic vertebral fractures and Cox regression for hip, non-vertebral, “all” (combination of non-vertebral, clinical vertebral, and radiologic vertebral) fractures and all clinical fractures (combination of non-vertebral and clinical vertebral). We performed meta-regression to estimate the study-level association (r2 and 95% confidence interval) between treatment-related differences in THBMD changes for each BMD measurement interval and fracture risk reduction. The meta-regression revealed that for vertebral fractures, the r2 (95% confidence interval) was 0.59 (0.19, 0.75), 0.69 (0.32, 0.82), and 0.73 (0.33, 0.84) for 12, 18, and 24 mo, respectively. Similar patterns were observed for hip: r2 = 0.27 (0.00, 0.54), 0.39 (0.02, 0.63), and 0.41 (0.02, 0.65); non-vertebral: r2 = 0.27 (0.01, 0.52), 0.49 (0.10, 0.69), and 0.53 (0.11, 0.72); all fractures: r2 = 0.44 (0.10, 0.64), 0.63 (0.24, 0.77), and 0.66 (0.25, 0.80); and all clinical fractures: r2 = 0.46 (0.11, 0.65), 0.64 (0.26, 0.78), and 0.71 (0.32, 0.83), for 12-, 18-, and 24-mo changes in THBMD, respectively. These findings demonstrate that treatment-related THBMD changes at 12, 18, and 24 mo are associated with fracture risk reductions across trials. We conclude that BMD measurement intervals as short as 12 mo could be used to assess fracture efficacy, but the association is stronger with longer BMD measurement intervals.

Carballido-Gamio, Julio; Marques, Elisa A; Sigurdsson, Sigurdur; Siggeirsdottir, Kristin; Jensen, Alexandria; Sigurdsson, Gunnar; Aspelund, Thor; Gudnason, Vilmundur; Lang, Thomas F; Harris, Tamara B

2024 Journal of Bone and Mineral Research

doi: 10.1093/jbmr/zjae132pmid: 39151035

A better understanding of how age-related bone loss affects the fracture-prone regions of the proximal femur could lead to more informed fracture-prevention strategies. Therefore, the aim of this work was to assess the spatio-temporal distribution of bone deterioration in older men and women with aging. A subset of 305 men (74.87 ± 4.76 years; mean ± SD) and 371 age-matched women (74.84 ± 4.71 years) with no history of fracture was randomly selected from the Age, Gene/Environment Susceptibility-Reykjavik study. Quantitative computed tomography (QCT) scans of the left proximal femur obtained at baseline and at 5.2 ± 0.4 years follow-up were processed to assess local changes in volumetric bone mineral density (vBMD), cortical bone thickness (Ct.Th), and internal bone structure using voxel-based morphometry (VBM), surface-based statistical parametric mapping (surf-SPM), and tensor-based morphometry (TBM). Local parametric changes within each sex and sex differences in these changes were statistically assessed using linear mixed effects models allowing for baseline and time-varying covariates, yielding Student’s t-test and p-value statistical maps of the proximal femur. The statistical maps indicated regions with significant parametric changes in each sex and with significant different parametric changes between older men and older women with aging. Older women manifested significantly larger losses in vBMD, (Ct.Th), and structure than older men, and they did so in regions where deficiency in these parameters has been associated with incident hip fracture. Using longitudinal QCT scans of the proximal femur and Computational Anatomy, we provided new insights into the higher fracture rates of the proximal femur in older women compared with men of similar age providing new information on the pathophysiology of osteoporosis.

Johannesdottir, Fjola; Tedtsen, Trinity; Cooke, Laura M; Mahar, Sarah; Zhang, Meng; Nustad, Jordan; Garrahan, Margaret A; Gehman, Sarah E; Yu, Elaine W; Bouxsein, Mary L

2024 Journal of Bone and Mineral Research

doi: 10.1093/jbmr/zjae134pmid: 39151032

Adults with type 1 diabetes (T1D) have increased hip fracture risk, yet no studies have assessed volumetric bone density or structure at the hip in older adults with T1D. Here, we used previously collected 3D CT scans of the proximal femur from older adults with longstanding T1D and non-diabetic controls to identify bone deficits that may contribute to hip fracture in T1D. In this retrospective cohort study, we identified 101 adults with T1D and 181 age-, sex-, and race-matched non-diabetic controls (CON) who received abdominal or pelvis CT exams from 2010 to 2020. Among adults with T1D, 33 (33%) had mild-to-moderate nephropathy, 61 (60%) had neuropathy, and 71 (70%) had retinopathy. Within the whole cohort, adults with T1D tended to have lower FN density, though differences did not reach statistical significance. The subset of the T1D group who were diagnosed before age 15 had lower total BMC (−14%, TtBMC), cortical BMC (−19.5%, CtBMC), and smaller Ct cross-sectional area (−12.6, CtCSA) than their matched controls (p<.05 for all). Individuals with T1D who were diagnosed at a later age did not differ from controls in any bone outcome (p>.21). Furthermore, adults with T1D and nephropathy had lower FN aBMD (−10.6%), TtBMC (−17%), CtBMC (−24%), and smaller CtCSA (−15.4%) compared to matched controls (p<.05 for all). Adults with T1D and neuropathy had cortical bone deficits (8.4%–12%, p<.04). In summary, among older adults with T1D, those who were diagnosed before the age of 15 yr, as well as those with nephropathy and neuropathy had unfavorable bone outcomes at the FN, which may contribute to the high risk of hip fractures among patients with T1D. These novel observations highlight the longstanding detrimental impact of T1D when present during bone accrual and skeletal fragility as an additional complication of microvascular disease in individuals with T1D.