Effect of ONO‐5334 on Bone Mineral Density and Biochemical Markers of Bone Turnover in Postmenopausal Osteoporosis: 2‐Year Results From the OCEAN Study

Cathepsin K inhibitors, such as ONO‐5334, are being developed for the treatment of postmenopausal osteoporosis. However, their relative effects on bone resorption and formation, and how quickly the effects resolve after treatment cessation, are uncertain. The aim of this study was to examine the efficacy and safety of 24‐month treatment with ONO‐5334 and to assess the effect of treatment cessation over 2 months. We studied 197 postmenopausal women with osteoporosis or osteopenia with one fragility fracture. Patients were randomized to ONO‐5334 50 mg twice daily, 100 mg or 300 mg once daily, alendronate 70 mg once weekly (positive control), or placebo for 24 months. After 24 months, all ONO‐5334 doses were associated with increased bone mineral density (BMD) for lumbar spine, total hip, and femoral neck (p < 0.001). ONO‐5334 300 mg significantly suppressed the bone‐resorption markers urinary (u) NTX and serum and uCTX‐I throughout 24 months of treatment and to a similar extent as alendronate; other resorption marker levels remained similar to placebo (fDPD for ONO‐5334 300 mg qd) or were increased (ICTP, TRAP5b, all ONO‐5334 doses). Levels of B‐ALP and PINP were suppressed in all groups (including placebo) for approximately 6 months but then increased for ONO‐5334 to close to baseline levels by 12 to 24 months. On treatment cessation, there were increases above baseline in uCTX‐I, uNTX, and TRAP5b, and decreases in ICTP and fDPD. There were no clinically relevant safety concerns. Cathepsin K inhibition with ONO‐5334 resulted in decreases in most resorption markers over 2 years but did not decrease most bone formation markers. This was associated with an increase in BMD; the effect on biochemical markers was rapidly reversible on treatment cessation. © 2014 American Society for Bone and Mineral Research.     

Incidence of Hip and Subtrochanteric/Femoral Shaft Fractures in Postmenopausal Women With Osteoporosis in the Phase 3 Long-Term Odanacatib Fracture Trial

We prospectively assessed, with predefined criteria, the location and rates of all femur fractures (hip, subtrochanteric/femoral shaft [ST/FS], including atypical [AFF] and distal fractures) in women at increased fracture risk during treatment with the cathepsin K inhibitor, odanacatib (ODN), or placebo over 5 years in the Long-Term ODN Fracture Trial (LOFT and LOFT Extension [NCT00529373, EudraCT 2007-002693-66]). ODN was an investigational antiresorptive agent previously in development as an osteoporosis treatment that, unlike bisphosphonates, reduces bone formation only transiently. Women aged ≥65 years with a bone mineral density (BMD) T-score ≤−2.5 at the total hip (TH) or femoral neck (FN) or with a radiographic vertebral fracture and T-scores ≤−1.5 at the TH or FN were randomized (1:1) to receive ODN 50 mg/week or placebo. All patients received vitamin D₃ (5600 IU/week) and calcium (total 1200 mg/d); the analysis included 16,071 women. Rates of all adjudicated low-energy femoral fractures were 0.38 versus 0.58/100 patient-years for ODN and placebo, respectively (hazard ratio [HR] = 0.65; 95% confidence interval [CI] 0.51–0.82; nominal p < .001), and for low-energy hip fractures were 0.29 versus 0.56/100 patient-years, respectively (HR = 0.52; 95% CI 0.40–0.67; p < .001). The cumulative incidence of combined hip and ST/FS or hip fractures alone in the ODN group was consistently lower than in the placebo group (1.93% versus 3.11% for combined fractures and 1.53% versus 3.03% for hip fractures at 5 years, respectively). However, low-energy ST/FS fractures were more frequent in ODN-treated women than in placebo-treated women (24 versus 6, respectively). Among these, 12 fractures were adjudicated as AFF in 10 patients treated with ODN (0.03/100 patient-years) compared with none in the 6 placebo-treated women (estimated difference 0.03; 95% CI 0.02–0.06). These results provide insight into possible pathogeneses of AFF, suggesting that the current criteria for diagnosing these fractures may need to be reconsidered. © 2021 American Society for Bone and Mineral Research (ASBMR)..     

Treatment with Zoledronate Subsequent to Denosumab in Osteoporosis: a Randomized Trial

Discontinuing denosumab is associated with bone loss and possibly increased fracture risk. We investigated if treatment with zoledronate (ZOL) could prevent bone loss and if the timing of the ZOL infusion influenced the outcome. We report on a 2-year randomized, open label, interventional study including 61 patients with osteopenia, discontinuing denosumab after 4.6 ± 1.6 years. We administrated ZOL 6 months (6M group, n = 20) or 9 months (9M group, n = 20) after the last denosumab injection or when bone turnover had increased (OBS group, n = 21). We monitored the patients with DXA and bone turnover markers. Our primary endpoints were change in lumbar spine BMD (LSBMD) 6 months after ZOL and the proportion of patients who failed to maintain BMD. The study is ongoing ( clinicaltrials.gov ; NCT03087851). We included 61 participants and 59 patients completed follow-up 12 months after ZOL. Six months after ZOL, LSBMD had decreased significantly by (mean ± SE) 2.1% ± 0.9%, 4.3% ± 1.1%, and 3.0% ± 1.1% in the 6M, 9M, and OBS groups, respectively, and by 4.8% ± 0.7%, 4.1% ± 1.1%, and 4.7% ± 1.2% 12 months after ZOL in the 6M, 9M, and OBS groups, respectively (p < .02, no between-group differences). BMD loss above the least significant change was seen in all groups; at the spine: 6M, n = 6 (30%); 9M, n = 9 (45%); and OBS, n = 9 (47%); and at the total hip: 6M, n = 1 (5%); 9M, n = 5 (25%); and OBS, n = 2 (11%). In the 6M group p-crosslinked C-terminal telopeptide (p-CTX) decreased initially, but increased rapidly thereafter, and 6 months after ZOL, p-CTX was 0.60 ± 0.08 g/L. p-CTX increased rapidly in the 9M and OBS groups, was suppressed by ZOL but increased again thereafter; p-CTX was 0.47 ± 0.05 μg/L and 0.47 ± 0.05 μg/L in the 9M and OBS groups 6 months after ZOL, respectively. Incident vertebral fractures were seen in two women in the 9M group. Treatment with ZOL irrespective of the timing did not fully prevent loss of BMD in patients discontinuing denosumab. © 2020 American Society for Bone and Mineral Research.     

Denosumab Prevents Early Periprosthetic Bone Loss After Uncemented Total Hip Arthroplasty: Results from a Randomized Placebo-Controlled Clinical Trial

Implant loosening is the most common indication for revision surgery after total hip arthroplasty (THA). Although bone resorption around the implants plays a pivotal role in the pathophysiology of loosening, it is unknown whether potent early inhibition of osteoclasts could mitigate this process and thus reduce the need for revision surgery. We performed a randomized, double-blind, placebo-controlled phase 2 trial in 64 patients aged 35 to 65 years with unilateral osteoarthritis of the hip. They underwent surgery with an uncemented THA and were randomized to either two subcutaneous doses of denosumab (n = 32) or placebo (n = 32) given 1 to 3 days and 6 months after surgery. Patients were followed for 24 months. Primary outcome was periprosthetic bone mineral density (BMD) of the hip at 12 months as measured by dual-energy X-ray absorptiometry (DXA). In addition, [¹⁸F] sodium fluoride positron emission tomography/CT (F-PET) was performed in half of the patients for analysis of periprosthetic standardized uptake value (SUV). Analyses were made according to intention-to-treat principles. The trial was registered at ClinicalTrials.gov 2011-001481-18, NCT01630941. Denosumab potently inhibited early periprosthetic bone loss. After 12 months, BMD in the denosumab group was 32% (95% confidence interval [CI] 22–44) higher in Gruen zone 7 and 11% (95% CI 8–15) higher in zones 1 to 7. After 24 months, the difference in BMD between groups had decreased to 15% (95% CI 4–27) in zone 7 and 4% (95% CI 0–8) in zones 1 to 7. In both groups, SUV increased after surgery, but the increase was less pronounced in the denosumab group. Biochemical markers of bone metabolism decreased in the denosumab group in the first 12 months, but a rebound effect with marker concentrations above baseline was observed after 24 months. Denosumab potently prevents early periprosthetic bone loss after uncemented THA; however, the effect diminishes after discontinuation of treatment. Further research is needed to determine whether this bone loss will prove to be of clinical importance and, if so, whether the positive effect observed in this study could be preserved by either prolonged treatment with denosumab or additional antiresorptive treatment. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.     

The Effect of 6 versus 9 Years of Zoledronic Acid Treatment in Osteoporosis: A Randomized Second Extension to the HORIZON‐Pivotal Fracture Trial (PFT)

While bisphosphonates reduce fracture risk over 3 to 5 years, the optimal duration of treatment is uncertain. In a randomized extension study (E1) of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly?Pivotal Fracture Trial (HORIZON?PFT), zoledronic acid (ZOL) 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers (BTMs) compared with discontinuation after 3 years. To investigate the longer‐term efficacy and safety of ZOL, a second extension (E2) was conducted to 9 years in which women on ZOL for 6 years in E1 were randomized to either ZOL (Z9) or placebo (Z6P3) for 3 additional years. In this multicenter, randomized, double‐blind study, 190 women were randomized to Z9 (n = 95) and Z6P3 (n = 95). The primary endpoint was change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Other secondary endpoints included fractures, BTMs, and safety. From year 6 to 9, the mean change in total hip BMD was ?0.54% in Z9 vs. ?1.31% in Z6P3 (difference 0.78%; 95% confidence interval [CI]: ?0.37%, 1.93%; p = 0.183). BTMs showed small, non‐significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias (combined serious and non‐serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest almost all patients who have received six annual ZOL infusions can stop medication for up to 3 years with apparent maintenance of benefits. © 2015 American Society for Bone and Mineral Research.     

Treatment With Zoledronate Subsequent to Denosumab in Osteoporosis: A 2-Year Randomized Study

Increased bone turnover and rapid bone loss follow discontinuation of denosumab. We investigated the long-term efficacy of zoledronate (ZOL) in maintaining bone mineral density (BMD) after discontinuation of denosumab. In this randomized, open-label, interventional study, we included 61 postmenopausal women and men older than 50 years discontinuing denosumab after 4.6 ± 1.6 years. We administered ZOL 6 months (6 M) or 9 months (9 M) after the last denosumab or when bone turnover had increased (observation group [OBS]). ZOL was readministrated if p-cross-linked C-terminal telopeptide (p-CTX) increased ≥1.26 μg/L or BMD decreased ≥5%. The results after 12 months have previously been published; here we report the outcome after 24 months (ClinicalTrials NCT03087851). Fifty-eight patients completed the study. From 12 to 24 months after the initial ZOL, lumbar spine (LS) BMD was maintained: 0.9 ± 0.9%, 0.4 ± 0.8%, and 0.3 ± 0.7% in the 6 M, 9 M, and OBS groups, respectively (p > .05, no between-group differences). Similarly, total hip (TH) and femoral neck (FN) BMD did not change in any group during year 2. From baseline to 24 months after ZOL, LS BMD decreased by 4.0 ± 0.8%, 4.1 ± 0.8%, and 4.3 ± 1.5% in the 6 M, 9 M, and OBS groups, respectively (p < .001, no between-group differences). Significant bone loss (LS, TH, or FN) was found in all groups 24 months after ZOL: 6 M group: n = 12 (60%), 9 M group: n = 7 (37%), and OBS group: n = 10 (53%). P-CTX did not change significantly during the second year (p > .05, no between-group differences). No patient fulfilled the CTX or fracture criteria for retreatment during year 2; however, 9 patients were retreated at M24 due to BMD loss ≥5%. Two patients sustained a non-vertebral fracture during year 2. Treatment with ZOL subsequent to long-term denosumab did not fully prevent increased bone turnover and bone loss during the first year; however, CTX remained with the reference range and BMD was maintained during the second year. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Effect of Surgery Versus Observation: Skeletal 5‐Year Outcomes in a Randomized Trial of Patients With Primary HPT (the SIPH Study)

Mild primary hyperparathyroidism (PHPT) is known to affect the skeleton, even though patients usually are asymptomatic. Treatment strategies have been widely discussed. However, long‐term randomized studies comparing parathyroidectomy to observation are lacking. The objective was to study the effect of parathyroidectomy (PTX) compared with observation (OBS) on bone mineral density (BMD) in g/cm² and T‐scores and on biochemical markers of bone turnover (P1NP and CTX‐1) in a prospective randomized controlled study of patients with mild PHPT after 5 years of follow‐up. Of 191 patients with mild PHPT randomized to either PTX or OBS, 145 patients remained for analysis after 5 years (110 with validated DXA scans). A significant decrease in P1NP (p < 0.001) and CTX‐1 (p < 0.001) was found in the PTX group only. A significant positive treatment effect of surgery compared with observation on BMD (g/cm²) was found for the lumbar spine (LS) (p = 0.011), the femoral neck (FN) (p < 0.001), the ultradistal radius (UDR) (p = 0.042), and for the total body (TB) (p < 0.001) but not for the radius 33% (Rad33), where BMD decreased significantly also in the PTX group (p = 0.012). However, compared with baseline values, there was no significant BMD increase in the PTX group, except for the lumbar spine. In the OBS group, there was a significant decrease in BMD (g/cm²) for all compartments (FN, p < 0.001; Rad33, p = 0.001; UDR, p = 0.006; TB, p < 0.001) with the exception of the LS, where BMD was stable. In conclusion, parathyroidectomy improves BMD and observation leads to a small but statistically significant decrease in BMD after 5 years. Thus, bone health appears to be a clinical concern with long‐term observation in patients with mild PHPT. © 2017 American Society for Bone and Mineral Research.     

Potential Usefulness of BMD and Bone Turnover Monitoring of Zoledronic Acid Therapy Among Women With Osteoporosis: Secondary Analysis of Randomized Controlled Trial Data

We aimed to compare the clinical validity and the detectability of response of short‐term changes in bone mineral density (BMD; hip and spine) and bone turnover markers (serum PINP and CTX) through secondary analysis of trial data. We analyzed data on 7765 women with osteoporosis randomized to 5‐mg once‐yearly infusions of zoledronic acid or placebo in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (HORIZON‐PFT; trial ran from 2002 to 2006) and the first extension trial (trial ran from 2006 to 2009). We assessed the clinical validity and detectability of response for 1‐year measurements of the following monitoring tests: total hip and lumbar spine BMD, serum N‐terminal propeptide of type I collagen (sPINP), and serum C‐telopeptide of type I collagen (sCTX; 6‐month measurement used). Clinical validity was assessed by examining prediction of clinical fracture in Cox models; detectability of response to treatment was assessed by the ratio of signal to noise, estimated from the distributions of change in zoledronic acid and placebo groups. Baseline measurements were available for 7683 women with hip BMD, 558 with spine BMD, 1246 with sPINP, and 517 women with sCTX. Hip BMD and sPINP ranked highly for prediction of clinical fracture, whereas sPINP and sCTX ranked highly for detectability of response to treatment. Serum PINP had the highest overall ranking. In conclusion, serum PINP is potentially useful in monitoring response to zoledronic acid. Further research is needed to evaluate the effects of monitoring PINP on treatment decisions and other clinically relevant outcomes. © 2016 American Society for Bone and Mineral Research.     

A Randomized,Double‐Blind Phase 2 Clinical Trial of Blosozumab,a Sclerostin Antibody,in Postmenopausal Women with Low Bone Mineral Density

Sclerostin, a SOST protein secreted by osteocytes, negatively regulates formation of mineralized bone matrix and bone mass. We report the results of a randomized, double‐blind, placebo‐controlled multicenter phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin, in postmenopausal women with low bone mineral density (BMD). Postmenopausal women with a lumbar spine T‐score –2.0 to –3.5, inclusive, were randomized to subcutaneous blosozumab 180 mg every 4 weeks (Q4W), 180 mg every 2 weeks (Q2W), 270 mg Q2W, or matching placebo for 1 year, with calcium and vitamin D. Serial measurements of spine and hip BMD and biochemical markers of bone turnover were performed. Overall, 120 women were enrolled in the study (mean age 65.8 years, mean lumbar spine T‐score –2.8). Blosozumab treatment resulted in statistically significant dose‐related increases in spine, femoral neck, and total hip BMD as compared with placebo. In the highest dose group, BMD increases from baseline reached 17.7% at the spine, and 6.2% at the total hip. Biochemical markers of bone formation increased rapidly during blosozumab treatment, and trended toward pretreatment levels by study end. However, bone specific alkaline phosphatase remained higher than placebo at study end in the highest‐dose group. CTx, a biochemical marker of bone resorption, decreased early in blosozumab treatment to a concentration less than that of the placebo group by 2 weeks, and remained reduced throughout blosozumab treatment. Mild injection site reactions were reported more frequently with blosozumab than placebo. In conclusion, treatment of postmenopausal women with an antibody targeted against sclerostin resulted in substantial increases in spine and hip BMD. These results support further study of blosozumab as a potential anabolic therapy for osteoporosis. © 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR)     

The Effect of an Exercise Intervention Program on Bone Health After Bariatric Surgery: A Randomized Controlled Trial

Exercise has been suggested as a therapeutic approach to attenuate bone loss induced by bariatric surgery (BS), but its effectiveness remains unclear. Our aim was to determine if an exercise-training program could induce benefits on bone mass after BS. Eighty-four patients, submitted to gastric bypass or sleeve gastrectomy, were randomized to either exercise (EG) or control group (CG). One month post-BS, EG underwent a 11-month supervised multicomponent exercise program, while CG received only standard medical care. Patients were assessed before BS and at 1, 6, and 12 months post-BS for body composition, areal bone mineral density (BMD), bone turnover markers, calciotropic hormones, sclerostin, bone material strength index, muscle strength, and daily physical activity. A primary analysis was conducted according to intention-to-treat principles and the primary outcome was the between-group difference on lumbar spine BMD at 12 months post-BS. A secondary analysis was also performed to analyze if the exercise effect depended on training attendance. Twelve months post-BS, primary analysis results revealed that EG had a higher BMD at lumbar spine (+0.024 g∙cm⁻² [95% confidence interval (CI) 0.004, 0.044]; p = .015) compared with CG. Among total hip, femoral neck, and 1/3 radius secondary outcomes, only 1/3 radius BMD improved in EG compared with CG (+0.013 g∙cm⁻² [95% CI 0.003, 0.023]; p = .020). No significant exercise effects were observed on bone biochemical markers or bone material strength index. EG also had a higher lean mass (+1.5 kg [95% CI 0.1, 2.9]; p = .037) and higher number of high impacts (+51.4 [95% CI 6.6, 96.1]; p = .026) compared with CG. In addition, secondary analysis results suggest that exercise-induced benefits may be obtained on femoral neck BMD but only on those participants with ≥50% exercise attendance compared with CG (+5.3% [95% CI 2.0, 8.6]; p = .006). Our findings suggest that an exercise program is an effective strategy to ameliorate bone health in post-BS patients. © 2020 American Society for Bone and Mineral Research (ASBMR).     

The Impact of Vitamin D,Calcium, Protein Supplementation,and Physical Exercise on Bone Metabolism After Bariatric Surgery: The BABS Study

Laparoscopic Roux‐en‐Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are common and effective methods to treat severe obesity, but these procedures can adversely influence bone metabolism and areal bone mineral density (aBMD). This was a prospective 24‐month single‐center interventional two‐arm study in 220 women and similarly aged men (median age 40.7 years) with a body mass index (BMI) >38 kg/m² after RYGB and SG procedures. Patients were randomized into: 1) an intervention group receiving: 28,000 IU cholecalciferol/wk for 8 weeks before bariatric surgery, 16,000 IU/wk and 1000 mg calciummonocitrate/d after surgery, daily BMI‐adjusted protein supplementation and physical exercise (Nordic walking, strength perseverance, and equipment training); 2) a non‐intervention group: no preoperative loading, nutritional supplementation, or obligatory physical exercise. At study endpoint, when comparing the intervention group to the non‐intervention group, the relative percentage changes of serum levels of sclerostin (12.1% versus 63.8%), cross‐linked C‐telopeptide (CTX, 82.6% versus 158.3%), 25‐OH vitamin D (13.4% versus 18.2%), phosphate (23.7% versus 32%, p < 0.001 for all), procollagen type 1 amino‐terminal propeptide (P1NP, 12% versus 41.2%), intact parathyroid hormone (iPTH, –17.3% versus –7.6%), and Dickkopf‐1 (–3.9% versus –8.9%, p < 0.05 for all) differed. The decline in lumbar spine, total hip and total body aBMD, changes in BMI, lean body mass (LBM), as well as changes in trabecular bone score (TBS) values (p < 0.005 for all) were less, but significantly, pronounced in the intervention group. We conclude that vitamin D loading and ongoing vitamin D, calcium, and BMI‐adjusted protein supplementation in combination with physical exercise decelerates the loss of aBMD and LBM after bariatric surgery. Moreover, the well‐known increases of bone turnover markers are less pronounced. © 2015 American Society for Bone and Mineral Research.     

Effects of Romosozumab Compared With Teriparatide on Bone Density and Mass at the Spine and Hip in Postmenopausal Women With Low Bone Mass

Romosozumab, a monoclonal antibody that binds sclerostin, has a dual effect on bone by increasing bone formation and reducing bone resorption, and thus has favorable effects in both aspects of bone volume regulation. In a phase 2 study, romosozumab increased areal BMD at the lumbar spine and total hip as measured by DXA compared with placebo, alendronate, and teriparatide in postmenopausal women with low bone mass. In additional analyses from this international, randomized study, we now describe the effect of romosozumab on lumbar spine and hip volumetric BMD (vBMD) and BMC at month 12 as assessed by QCT in the subset of participants receiving placebo, s.c. teriparatide (20 µg once daily), and s.c. romosozumab (210 mg once monthly). QCT measurements were performed at the lumbar spine (mean of L₁ and L₂ entire vertebral bodies, excluding posterior processes) and hip. One year of treatment with romosozumab significantly increased integral vBMD and BMC at the lumbar spine and total hip from baseline, and compared with placebo and teriparatide (all p < 0.05). Trabecular vertebral vBMD improved significantly and similarly from baseline (p < 0.05) with both romosozumab (18.3%) and teriparatide (20.1%), whereas cortical vertebral vBMD gains were larger with romosozumab compared with teriparatide (13.7% versus 5.7%, p < 0.0001). Trabecular hip vBMD gains were significantly larger with romosozumab than with teriparatide (10.8% versus 4.2%, p = 0.01), but were similar for cortical vBMD (1.1% versus –0.9%, p = 0.12). Cortical BMC gains were larger with romosozumab compared with teriparatide at both the spine (23.3% versus 10.9%, p < 0.0001) and hip (3.4% versus 0.0%, p = 0.03). These improvements are expected to result in strength gains and support the continued clinical investigation of romosozumab as a potential therapy to rapidly reduce fracture risk in ongoing phase 3 studies. © 2016 American Society for Bone and Mineral Research.     

Skeletal Changes After Hematopoietic Stem Cell Transplantation in Osteopetrosis

Osteopetrosis is a rare skeletal dysplasia resulting from an osteoclast defect leading to increased bone mass and density. Hematopoietic stem cell transplantation can rescue the disease phenotype and prevent complications. However, little is known about the skeletal changes hematopoietic stem cell transplantation induces in patients with this disease. The purpose of this study was to describe the skeletal changes after hematopoietic stem cell transplantation in a retrospective cohort of patients diagnosed with osteopetrosis in one medical center over 13 years. For this purpose, all available epidemiological, hematological, biochemical, and radiographic data were collected and quantitatively analyzed. We found a significant early change in bone metabolism markers coinciding with hematopoietic recovery after stem cell transplantation. Hematopoietic stem cell transplantation induced a later significant improvement in both skeletal mineral distribution and morphology but did not lead to complete radiological normalization. Presumably, changes in bone metabolism, skeletal mineral distribution, and morphology were the result of renewed osteoclast function enabling bone remodeling. We propose that biochemical bone metabolism markers and radiological indices be routinely used to evaluate response to hematopoietic stem cell transplantation in patients with osteopetrosis. © 2020 American Society for Bone and Mineral Research.     

A Novel Splice Mutation in PLS3 Causes X‐linked Early Onset Low‐Turnover Osteoporosis

Genetic factors play an important role in the development of osteoporosis. Several monogenic forms of osteoporosis have been recognized, most recently an X‐chromosomal form resulting from mutations in the gene encoding plastin 3 (PLS3). PLS3 is a protein involved in actin bundle formation in the cytoskeleton. We present a large family with early onset osteoporosis and X‐linked inheritance. Phenotyping was performed on 19 family members and whole‐exome sequencing on 7 family members (5 with a diagnosis of early onset osteoporosis and 2 with normal bone parameters). Osteoporosis had its onset in childhood and was characterized by recurrent peripheral fractures, low bone mineral density (BMD), vertebral compression fractures, and significant height loss in adulthood. Males were in general more severely affected than females. Bone histomorphometry findings in 4 males and 1 female showed severe trabecular osteoporosis, low amount of osteoid, and decreased mineral apposition rate, indicating impaired bone formation; resorption parameters were increased in some. All affected subjects shared a single base substitution (c.73‐24T > A) in intron 2 of PLS3 on Xq23. The mutation, confirmed by Sanger sequencing, segregated according to the skeletal phenotype. The mutation introduces a new acceptor splice site with a predicted splice score of 0.99 and, thereby, as confirmed by cDNA sequencing, induces the insertion of 22 bases between exons 2 and 3, causing a frameshift and premature termination of mRNA translation (p.Asp25Alafs*17). The mutation affects the first N‐terminal calcium‐binding EF‐hand domain and abolishes all calcium‐ and actin‐binding domains of the protein. Our results confirm the role of PLS3 mutations in early onset osteoporosis. The mechanism whereby PLS3 affects bone health is unclear, but it may be linked to osteocyte dendrite function and skeletal mechanosensing. Future studies are needed to elucidate the role of PLS3 in osteoporosis and to define optimal treatment. © 2014 American Society for Bone and Mineral Research.     

Identification of Hip BMD Loss and Fracture Risk Markers Through Population‐Based Serum Proteomics

Serum proteomics analysis may lead to the discovery of novel osteoporosis biomarkers. The Osteoporotic Fractures in Men (MrOS) study comprises men ≥65 years old in the US who have had repeated BMD measures and have been followed for incident fracture. High‐throughput quantitative proteomic analysis was performed on baseline fasting serum samples from non‐Hispanic white men using a multidimensional approach coupling liquid chromatography, ion‐mobility separation, and mass spectrometry (LC‐IMS‐MS). We followed the participants for a mean of 4.6 years for changes in femoral neck bone mineral density (BMD) and for incident hip fracture. Change in BMD was determined from mixed effects regression models taking age and weight into account. Participants were categorized into three groups: BMD maintenance (no decline; estimated change ≥0 g/cm², n = 453); expected loss (estimated change 0 to 1 SD below the estimated mean change, –0.034 g/cm² for femoral neck, n = 1184); and accelerated loss (estimated change ≥1 SD below mean change, n = 237). Differential abundance values of 3946 peptides were summarized by meta‐analysis to determine differential abundance of each of 339 corresponding proteins for accelerated BMD loss versus maintenance. Using this meta‐analytic standardized fold change at cutoffs of ≥1.1 or ≤0.9 (p < 0.10), 20 proteins were associated with accelerated BMD loss. Associations of those 20 proteins with incident hip fracture were tested using Cox proportional hazards models with age and BMI adjustment in 2473 men. Five proteins were associated with incident hip fracture (HR between 1.29 and 1.41 per SD increase in estimated protein abundance). Some proteins have been previously associated with fracture risk (eg, CD14 and SHBG), whereas others have roles in cellular senescence and aging (B2MG and TIMP1) and complement activation and innate immunity (CO7, CO9, CFAD). These findings may inform development of biomarkers for future research in bone biology and fracture prediction. © 2017 American Society for Bone and Mineral Research.     

Men and Women in Space: Bone Loss and Kidney Stone Risk After Long‐Duration Spaceflight

Bone loss, a key concern for long‐duration space travelers, is typically considered a female issue. The number of women who have flown long‐duration space missions is now great enough to allow a quantitative comparison of changes in bone and renal stone risk by sex. Participants were 42 astronauts (33 men and 9 women) on long‐duration missions to the International Space Station. Bone mineral density (by dual‐energy X‐ray absorptiometry) and biochemical markers of bone metabolism (from blood and urine samples) were evaluated before and after flight. Data were analyzed in two groups, based on available resistance exercise equipment. Missions were 49 to 215 days in duration, flown between 2000 and 2012. The bone density response to spaceflight was the same for men and women in both exercise groups. The bone mineral density response to flight was the same for men and women, and the typical decrease in bone mineral density (whole body and/or regional) after flight was not observed for either sex for those using an advanced resistive exercise device. Biochemical markers of bone formation and resorption responded similarly in male and female astronauts. The response of urinary supersaturation risk to spaceflight was not significantly different between men and women, although risks were typically increased after flight in both groups, and risks were greater in men than in women before and after flight. The responses of men and women to spaceflight with respect to these measures of bone health were not different. © 2014 American Society for Bone and Mineral Research.     

Burosumab Improved Histomorphometric Measures of Osteomalacia in Adults with X-Linked Hypophosphatemia: A Phase 3, Single-Arm,International Trial

In adults with X-linked hypophosphatemia (XLH), excess FGF23 impairs renal phosphate reabsorption and suppresses production of 1,25-dihydroxyvitamin D, resulting in chronic hypophosphatemia and persistent osteomalacia. Osteomalacia is associated with poor bone quality causing atraumatic fractures, pseudofractures, delayed fracture healing, and bone pain. Burosumab is a fully human monoclonal antibody against FGF23. UX023-CL304 is an ongoing, open-label, single-arm, phase 3 study investigating the efficacy of subcutaneous burosumab, 1.0 mg/kg administered every 4 weeks, in improving osteomalacia in adults with XLH who have not been treated for at least 2 years before enrollment. The primary endpoint was improvement in osteoid volume/bone volume assessed by transiliac bone biopsies obtained at baseline and week 48. Additional assessments included serum phosphorus, markers of bone turnover, fracture/pseudofracture healing, and safety. Fourteen subjects enrolled, 13 completed 48 weeks, and 11 completed paired biopsies. All osteomalacia-related histomorphometric measures improved significantly at week 48 (mean percent change: osteoid volume/bone volume, –54%, osteoid thickness, –32%, osteoid surface/bone surface, –26%, [median] mineralization lag time, –83%). Mean serum phosphorus concentration averaged across the mid-point of the dose cycle between weeks 0 and 24 was 3.3 mg/dL, a 50% increase from 2.2 mg/dL at baseline. Markers of bone formation and resorption increased at week 48 (least squares [LS] mean increase: P1NP, +77%; CTx, +36%; both p < 0.0001). All subjects had one or more treatment-emergent adverse event (AE). Most AEs were mild to moderate in severity. Two subjects experienced serious AEs (migraine; paresthesia) that were unrelated to treatment and resolved. Eleven subjects had 18 biopsy procedure-related AEs: 14 for pain, two for itch, and one each for headache and bandage irritation. No deaths or incidents of hyperphosphatemia occurred. In conclusion, by normalizing phosphate homeostasis, burosumab significantly improved osteomalacia in adults with XLH, which likely explains the improved fracture healing and amelioration of skeletal complications. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

Effect of Low‐Magnitude Mechanical Stimuli on Bone Density and Structure in Pediatric Crohn's Disease: A Randomized Placebo‐Controlled Trial

Pediatric Crohn's Disease (CD) is associated with low trabecular bone mineral density (BMD), cortical area, and muscle mass. Low‐magnitude mechanical stimulation (LMMS) may be anabolic. We conducted a 12‐month randomized double‐blind placebo‐controlled trial of 10 minutes daily exposure to LMMS (30 Hz frequency, 0.3 g peak‐to‐peak acceleration). The primary outcomes were tibia trabecular BMD and cortical area by peripheral quantitative CT (pQCT) and vertebral trabecular BMD by QCT; additional outcomes included dual‐energy X‐ray absorptiometry (DXA) whole body, hip and spine BMD, and leg lean mass. Results were expressed as sex‐specific Z‐scores relative to age. CD participants, ages 8 to 21 years with tibia trabecular BMD <25th percentile for age, were eligible and received daily cholecalciferol (800 IU) and calcium (1000 mg). In total, 138 enrolled (48% male), and 121 (61 active, 60 placebo) completed the 12‐month trial. Median adherence measured with an electronic monitor was 79% and did not differ between arms. By intention‐to‐treat analysis, LMMS had no significant effect on pQCT or DXA outcomes. The mean change in spine QCT trabecular BMD Z‐score was +0.22 in the active arm and –0.02 in the placebo arm (difference in change 0.24 [95% CI 0.04, 0.44]; p = 0.02). Among those with >50% adherence, the effect was 0.38 (95% CI 0.17, 0.58, p < 0.0005). Within the active arm, each 10% greater adherence was associated with a 0.06 (95% CI 0.01, 1.17, p = 0.03) greater increase in spine QCT BMD Z‐score. Treatment response did not vary according to baseline body mass index (BMI) Z‐score, pubertal status, CD severity, or concurrent glucocorticoid or biologic medications. In all participants combined, height, pQCT trabecular BMD, and cortical area and DXA outcomes improved significantly. In conclusion, LMMS was associated with increases in vertebral trabecular BMD by QCT; however, no effects were observed at DXA or pQCT sites. © 2016 American Society for Bone and Mineral Research.