Sclerostin Depletion Induces Inflammation in the Bone Marrow of Mice

Romosozumab, a humanized monoclonal antibody specific for sclerostin (SOST), has been approved for treatment of postmenopausal women with osteoporosis at a high risk for fracture. Previous work in sclerostin global knockout (Sost−/−) mice indicated alterations in immune cell development in the bone marrow (BM), which could be a possible side effect in romosozumab-treated patients. Here, we examined the effects of short-term sclerostin depletion in the BM on hematopoiesis in young mice receiving sclerostin antibody (Scl-Ab) treatment for 6 weeks, and the effects of long-term Sost deficiency on wild-type (WT) long-term hematopoietic stem cells transplanted into older cohorts of Sost−/− mice. Our analyses revealed an increased frequency of granulocytes in the BM of Scl-Ab-treated mice and WT®Sost−/− chimeras, indicating myeloid-biased differentiation in Sost-deficient BM microenvironments. This myeloid bias extended to extramedullary hematopoiesis in the spleen and was correlated with an increase in inflammatory cytokines TNFα, IL-1α, and MCP-1 in Sost−/− BM serum. Additionally, we observed alterations in erythrocyte differentiation in the BM and spleen of Sost−/− mice. Taken together, our current study indicates novel roles for Sost in the regulation of myelopoiesis and control of inflammation in the BM.

Gender-Related Impact of Sclerostin Antibody on Bone in the Osteogenesis Imperfecta Mouse

Osteogenesis imperfecta (OI), which is most often due to a collagen type 1 gene mutation, is characterized by low bone density and bone fragility. In OI patients, gender-related differences were reported, but data in the literature are not convergent. We previously observed that sclerostin antibody (Scl-Ab), which stimulates osteoblast Wnt pathway via sclerostin inactivation, improved spine and long-bone parameters and biomechanical strength in female oim/oim mice, a validated model of human type 3 OI. Here, we wanted to highlight the effect of Scl-Ab on male oim/oim bones in order to identify a possible distinct therapeutic effect from that observed in females. According to the same protocol as our previous study with female mice, male wild-type (Wt) and oim/oim mice received vehicle or Scl-Ab from 5 to 14 weeks of age. Clinimetric and quantitative bone parameters were studied using X-rays, peripheral quantitative computed tomography, microradiography, and dynamic histomorphometry and compared to those of females. Contrary to Wt mice, male oim/oim had significantly lower weight, snout–sacrum length, and bone mineral content than females at 5 weeks. No significant difference in these clinimetric parameters was observed at 14 weeks, whereas male oim showed significantly more long-bone fractures than females. Scl-Ab improved bone mineral density and bone volume/total volume ratio (BV/TV) of vertebral body in Wt and oim/oim, without significant difference between male and female at 14 weeks. Male vehicle oim/oim had a significantly lower cortical thickness (Ct.Th) and BV/TV of tibial diaphysis than female and showed a higher number of fractures at 14 weeks. Scl-Ab increased midshaft periosteal apposition rate in such a way that tibial Ct.Th of male oim/oim was not significantly different from the female one at 14 weeks. The number of fractures was lower in male than female oim/oim after 14 weeks of Scl-Ab treatment, but this difference was not significant. Nevertheless, Scl-Ab–treated oim/oim male and female mice remained smaller than the Wt ones. In conclusion, our results highlighted differences between male and female oim/oim at 4 and 14 weeks of age, as well as some male-specific response of cortical bone to Scl-Ab. These gender-related particularities of oim/oim should be considered when testing experimental treatments.

Low Level of Serum Sclerostin in Adult Patients with Tumor-induced Osteomalacia Comparing with X-linked Hypophosphatemia

Context Sclerostin is an inhibitor of Wnt-β-catenin signaling to regulate bone formation. Circulating sclerostin levels were reported to be elevated in patients with X-linked hypophosphatemia (XLH), and sclerostin antibody (Scl-Ab) has been shown to increase bone mass and normalize circulating phosphate levels in Hyp mice. However, circulating sclerostin level in acquired hypophosphatemic patients with tumor-induced osteomalacia (TIO) remains rare reported. Objectives This study was designed to evaluate serum sclerostin levels in TIO patients comparing them with age-, sex- matched healthy controls and XLH patients, and analyze correlation of circulating sclerostin with BMD and laboratory parameters. Design, Setting and Participants 190 individuals including 83 adult TIO patients, 83 adult healthy controls and 24 adult XLH patients were enrolled in this cross-sectional study. Main outcome measures Serum sclerostin levels were determined in TIO patients, healthy controls and XLH patients. Results TIO patients (43 male and 40 female) aged 44.3 ± 8.7 (mean ± SD) years had lower levels of circulating sclerostin than healthy controls (94.2 ± 45.8 vs 108.4 ± 42.3 pg/mL, p = 0.01) with adjustment for age, gender, BMI and diabetes rate. Sclerostin levels were positively associated with age (r = 0.238, p = 0.030). Male patients had higher sclerostin level than female patients (104.7 ± 47.3 vs 83.0 ± 41.8 pg/mL, p = 0.014) and postmenopausal patients had higher tendency of sclerostin level than premenopausal patients (98.4 ± 48.8 vs 71.6 ± 32.3 ng/ml, p = 0.05). Sclerostin levels were positively associated with BMD of L1-4 (r = 0.255, p = 0.028), femoral neck (r = 0.242, p = 0.039) and serum calcium (r = 0.231, p = 0.043). TIO subgroup patients (n=24, 35.9 ± 7.3 years old) comparing with age-, sex-matched adult XLH patients and healthy controls revealed significant difference of sclerostin levels (XLH, TIO and healthy control were 132.0 ± 68.8, 68.4 ± 31.3 and 98.6 ± 41.1 pg/mL, respectively, p < 0.001). Conclusions Circulating sclerostin levels were decreased in TIO patients but increased in XLH patients, which might be result of histological abnormality and bone mass.

Bilateral Atypical Femoral Fracture(AFF) After Teriparatide and Subsequent Anti-Resorptive Therapy: A Management Dilemma

Introduction: Femoral fractures carry devastating morbidity for long term ambulation. Atypical femoral fractures (AFF) are uncommon, and bilateral AFFs are more rare with added post-fracture limitations. We report two patients with bilateral AFFs despite receiving teriparatide (TPTD). Case 1: A 72 y.o. Filipino lady with osteoporosis since late 1990 was treated with bisphosphonates (BP) intermittently over 25 years with drug holidays for dental work. She stopped alendronate in mid-2013 and continued raloxifene. She suffered a spontaneous left mid-femur AFF in June, 2015 that was treated with intramedullary (IM) rod and nailing. In July, 2015 she started TPTD 20 mcg daily for 23 months until May, 2017. Alendronate was restarted weekly. In December, 2018 she developed right thigh and hip prodromal pain without x-ray changes. In April, 2019 (46 months after the left AFF and 23 months after TPTD), she sustained a spontaneous right sub-trochanteric AFF. BP was stopped. After IM rod and nailing, she began a second course of TPTD. Case 2: 72 y.o Caucasian lady with osteoporosis since 2000 was treated with alendronate until April, 2006. She was switched to daily TPTD for 22 months from May, 2006 to March, 2008. Oral BP was resumed in April, 2008. She suffered a left AFF in November, 2009; BP was stopped in March, 2010. In July, 2010 she sustained a right AFF (9 months after the left AFF and 28 months post-TPTD). Each spontaneous AFF occurred after prodromal pain, and each was treated with IM rod placement with nailing. She received BP infusion in 2011 and TPTD from March, 2012 to March, 2014. DXA scan in 2020 showed lumbar spine osteopenia. She currently takes calcium and Vit D supplementation. Discussion: TPTD is reported as a potential treatment for enhancing AFF healing, bone mineral density and pain resolution. The expectation is that it might prevent contralateral AFF. No randomized studies of prevention of AFF with TPTD exist. Available reports show variable results. Prolonged presence of BP in bone may contribute to this variation. We identified 7 reported AFF patients treated with TPTD who then developed a contralateral AFF. We found 2 patients with new AFF after TPTD as in our Case 2. In all cases there was previous exposure to BP. Perhaps the 28–30% risk of a contralateral AFF within 4 years in the setting of BP is irremediable. Conclusion: TPTD increases healing of AFF in some reports, but prevention of an initial or further AFF has not been well documented. Our 2 patients and 9 others reported suggest a possible subset with increased sensitivity to the effect of BP and increased AFF risk. The best choice after TPTD is unclear, but it may include permanent removal of anti-resorptive agents. The anti-sclerostin antibody romosozumab also has been associated with AFF. Choices are limited for these patients other than excellent surgical care, adequate calcium/vitamin D intake, and periodic imaging as symptoms dictate.