Focal radiotherapy is frequently associated with skeletal damage within the radiation field. Our previous in vitro study showed that activation of Wnt/β-catenin pathway can overcome radiation-induced DNA damage and apoptosis of osteoblastic cells. Neutralization of circulating sclerostin with a monoclonal antibody (Scl-Ab) is an innovative approach for treating osteoporosis by enhancing Wnt/β-catenin signaling in bone. Together with the fact that focal radiation increases sclerostin amount in bone, we sought to determine whether weekly treatment with Scl-Ab would prevent focal radiotherapy-induced osteoporosis in mice. Micro-CT and histomorphometric analyses demonstrated that Scl-Ab blocked trabecular bone structural deterioration after radiation by partially preserving osteoblast number and activity. Consistently, trabecular bone in sclerostin null mice was resistant to radiation via the same mechanism. Scl-Ab accelerated DNA repair in osteoblasts after radiation by reducing the number of γ-H2AX foci, a DNA double-strand break marker, and increasing the amount of Ku70, a DNA repair protein, thus protecting osteoblasts from radiation-induced apoptosis. In osteocytes, apart from using similar DNA repair mechanism to rescue osteocyte apoptosis, Scl-Ab restored the osteocyte canaliculi structure that was otherwise damaged by radiation. Using a lineage tracing approach that labels all mesenchymal lineage cells in the endosteal bone marrow, we demonstrated that radiation damage to mesenchymal progenitors mainly involves shifting their fate to adipocytes and arresting their proliferation ability but not inducing apoptosis, which are different mechanisms from radiation damage to mature bone forming cells. Scl-Ab treatment partially blocked the lineage shift but had no effect on the loss of proliferation potential. Taken together, our studies provide proof-of-principle evidence for a novel use of Scl-Ab as a therapeutic treatment for radiation-induced osteoporosis and establish molecular and cellular mechanisms that support such treatment.

Cancer radiotherapy is often complicated by a spectrum of changes in the neighboring bone from mild osteopenia to osteoradionecrosis. We previously reported that parathyroid hormone (PTH, 1–34), an anabolic agent for osteoporosis, reversed bone structural deterioration caused by multiple microcomputed tomography (microCT) scans in adolescent rats. To simulate clinical radiotherapy for cancer patients and to search for remedies, we focally irradiated the tibial metaphyseal region of adult rats with a newly available small animal radiation research platform (SARRP) and treated these rats with intermittent injections of PTH1–34. Using a unique 3D image registration method that we recently developed, we traced the local changes of the same trabecular bone before and after treatments, and observed that, while radiation caused a loss of small trabecular elements leading to significant decreases in bone mass and strength, PTH1–34 preserved all trabecular elements in irradiated bone with remarkable increases in bone mass and strength. Histomorphometry demonstrated that SARRP radiation severely reduced osteoblast number and activity, which were impressively reversed by PTH treatment. In contrast, suppressing bone resorption by alendronate failed to rescue radiation-induced bone loss and to block the rescue effect of PTH1–34. Furthermore, histological analyses revealed that PTH1–34 protected osteoblasts and osteocytes from radiation-induced apoptosis and attenuated radiation-induced bone marrow adiposity. Taken together, our data strongly support a robust radioprotective effect of PTH on trabecular bone integrity through preserving bone formation and shed light on further investigations of an anabolic therapy for radiation-induced bone damage.

Background:Primary adhesive capsulitis is mainly characterized by spontaneous chronic shoulder pain and the gradual loss of shoulder motion. The main treatment for adhesive capsulitis is a trial of conservative therapies, including analgesia, exercise, physiotherapy, oral nonsteroidal anti-inflammation drugs, and intra-articular corticosteroid injections. Previously, it was reported that intra-articular corticosteroid lead to fast pain relief and improvement of range of motion (ROM). The objective of this study was to determine whether corticosteroid injections would lead to better pain relief and greater improvement in ROM.Methods:We searched PubMed, Medline, and the Cochrane library. We included 5 articles of the 1166 articles identified. Totally injection group included 115 patients and placebo group included 110 patients. We calculated the weighted mean differences to evaluate the pain relief as the primary outcome. We determined the ROM as the secondary outcome. Study quality was evaluated using the 12-item scale. We also used the criteria of the Grading of Recommendations Assessment, Development and Evaluation to evaluate the quality of evidence.Results:In total, 5 studies were included, 4 of which were randomized clinical trials, with a sample size of 225 patients with adhesive capsulitis of the shoulders. The overall pooled data demonstrated that, compared with placebo as control treatment, intra-articular corticosteroid injections were more effective in reducing the pain score at 0 to 8 weeks, but there was no difference between the injection group and the control group at 9 to 24 weeks. Improvement of ROM in the injection group was greater than that of the control group both at 0 to 8 and 9 to 24 weeks.Conclusions:Intra-articular corticosteroid injections were more effective in pain relief in the short term, but this pain relief did not sustain in the long term. Intra-articular corticosteroid injection resulted in greater improvement in passive ROM both in the short and the long terms.