PTH(1-34) and zoledronic acid have differing longitudinal effects on juvenile mouse femur strength and morphology.

Treatment of secondary pediatric osteoporosis-particularly that due to chronic diseases, immobilization, and necessary medical treatments-is currently limited by a poor understanding of the long-term efficacy and safety of skeletal metabolism modifying drugs. This study aimed to characterize longitudinal effects of representative anabolic (parathyroid hormone, PTH) and anti-catabolic (zoledronic acid, ZA) drugs on skeletal morphology, mechanical strength, and growth in juvenile mice. BALB/cJ mice aged 4 weeks were given PTH(1-34) or vehicle (control) daily for 8 weeks, or 4 weekly doses of ZA, and evaluated at time points 0-26 weeks after treatment initiation. There were no enduring differences in body length or mass between treatment groups. ZA increased femur size as early as week 0, including increased distal femur bone volume and diaphyseal cross-sectional area, persisting through week 26. PTH treatment only transiently increased bone size, including distal femur volume at weeks 4-12. ZA decreased diaphyseal cortical tissue mineral density (TMD) at 12-26 weeks versus controls; PTH decreased TMD only at 2 weeks (vs. controls). ZA increased bending strength at 0-12 weeks and flexural strength at week 4 (vs. controls), but decreased flexural strength and modulus at week 26. PTH treatment increased bending strength only at 4 weeks, and did not affect flexural strength. Overall, ZA rapidly and persistently increased femur strength and size, but compromised bone material quality long-term. In healthy juvenile mice, limited-duration PTH treatment did not exert a strong anabolic effect, and had no adverse effects on femur strength, morphology, or growth. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1707-1715, 2017.

Unexpected radiographic lucency following grafting of bone defects with calcium sulfate/tricalcium phosphate bone substitute.

OBJECTIVE: To report the development of unexpected radiographic lucency (URL) corresponding to the use of a commercially available calcium sulfate/tricalcium phosphate composite used to treat benign osseous lesions. MATERIALS AND METHODS: This is a retrospective comparative study of patients with and without URL after treatment with curettage and grafting with calcium sulfate/tricalcium phosphate. The charts of 87 patients meeting the inclusion criteria were reviewed for demographic, clinical, and radiographic data. The group with URL was compared to those with more typical patterns of graft incorporation. RESULTS: Thirteen of 87 cases (15%) showed URL. There was no difference with respect to the pathologic subtype, anatomic location, or specific bone for the presence of URL. Of patients with URL, one (7.7%) required reoperation and regrafting, whereas among patients without URL, five (6.7%) had clinical complications, with one requiring reoperation and regrafting, and one requiring radiofrequency ablation. CONCLUSIONS: The majority of patients treated with calcium sulfate/tricalcium phosphate cementing after curettage of low-grade bone lesions go on to uneventful healing in our series. In a minority of patients, URL occurs in lieu of the more typical pattern of centripetal incorporation. However, there is no increase in complications associated with URL. Based on these findings, patients should be informed of the possibility of this risk, although there appears to be little risk of clinically relevant adverse consequences. Physicians should be aware of this complication in order to avoid mistaking it for recurrence of the primary lesion.

Concurrent administration of zoledronic acid and irradiation leads to improved bone density, biomechanical strength, and microarchitecture in a mouse model of tumor-induced osteolysis.

BACKGROUND AND OBJECTIVES: Bone metastases are typically treated with bisphosphonates as adjuncts to radiation therapy. The goal of this study was to determine whether radiotherapy combined with a bisphosphonate could restore bone density, microarchitecture, and biomechanical strength of a tumor-burdened bone to normal. MATERIALS AND METHODS: Breast cancer cells were injected into the right femur of 30 female nude mice. Mice were divided into three treatment groups (0 Gy, 20 Gy, and 20 Gy + ZA). Left limbs served as non-operated normal bones. Tumor-bearing femora were irradiated 3 weeks later. ZA (100 microg/kg SC) was administered once weekly for 6 weeks. Mice were euthanized at 9 weeks or earlier if severe lameness or pathology occurred. RESULTS: Mice treated with 20 Gy/ZA exhibited higher bone density, bone volume, fractional trabecular bone volume, and biomechanical strength compared to mice treated with 20 Gy only (P < 0.05). Statistical analysis revealed that mice treated with 20 Gy/ZA were not significantly different from normal bones with respect to bone density and strength. Micro-CT reconstructions showed improved microarchitecture in the 20 Gy/ZA group compared to 20 Gy. CONCLUSIONS: Treatment of an osteolytic bone with radiation therapy plus zoledronic acid restores normal bone qualities with respect to bone density, microarchitecture, and biomechanical strength.

Combinations of radioprotectants spare radiation-induced damage to the physis.

Radiotherapy used in the treatment of bone and soft tissue sarcomas in pediatric patients often results in undesirable growth plate damage. Radioprotectants may hold promise in the selective protection of growth plate tissue in this setting. In an animal model, the hypothesis tested was that pentoxifylline, selenium, or misoprostol, used in combination with amifostine, would significantly reduce longitudinal growth loss during one radiation dose exposure to a greater extent than the protection provided by only amifostine without increased morbidity or mortality or adverse effects on bone mineral density. Amifostine alone and in combination with each of the other radioprotectants resulted in limb discrepancy reduction to levels significantly less than radiated controls. The tibial length discrepancy in the selenium and amifostine group was 12.1 +/- 0.8%, less than the 15.5 +/- 2.6% tibial length discrepancy in the animals treated with amifostine alone, and less than the mean 18.8% tibial length discrepancy in the radiated limbs without radioprotection. There were no adverse effects on bone density in any group, but the selenium and amifostine group showed some increased mortality. Combinations of amifostine with these radioprotectants show efficacy in growth plate radioprotection and therefore warrant additional study in a clinically relevant fractionated model.

Sequential histomorphometric analysis of the growth plate following irradiation with and without radioprotection.

BACKGROUND: The availability of radioprotectant drugs that selectively protect normal cells but not tumor cells has rekindled interest in the effects of irradiation on the growth plate. The purpose of the present study was to quantitatively examine the sequential histomorphometric effects of irradiation and pretreatment with a free radical scavenger radioprotectant, amifostine, on the growth plate over time. METHODS: Sixty four-week-old male Sprague-Dawley rats were randomized into five groups of twelve animals that were to be killed at 0.5, one, two, three, or four weeks after irradiation. One-half of the animals also received amifostine (100 mg/kg) prior to irradiation. In all animals, the right knee was treated with a single 17.5-Gy dose of radiation. End points were assessed with quantitative histomorphometric analysis of the growth plate, BrdU labeling for evidence of proliferation, evaluation of chondroclast cellularity, and determination of growth rates by means of oxytetracycline labeling. RESULTS: The mean lengths of the femur, tibia, and hind limb continued to increase at each time-interval following treatment, but by one week the mean limb length was 4% less on the irradiated side than on the control side, and this difference remained significant for four weeks (p < 0.05). The proximal tibial growth rate decreased during the first week to 18% of the control level. Nevertheless, growth continued even at the earliest time-periods, began to return toward normal at two weeks, and ultimately returned to at least 80% of normal by four weeks after irradiation. The area fraction of matrix in the hypertrophic zone increased initially and returned to control levels at three and four weeks. The administration of the radioprotectant resulted in significant increases in growth, growth rate, growth plate height, hypertrophic zonal height, and chondroclast profiles compared with the values for limbs in which irradiation had not been preceded by treatment with amifostine. CONCLUSIONS: We found an initially profound but transient direct inhibitory effect of irradiation on growth plate chondrocytes. Recovery of growth plate function after irradiation corresponded temporally with the appearance of newly formed islands of proliferating chondrocytes. Accumulation of matrix led to a transient increase in overall growth plate height, which was most pronounced in the hypertrophic zone. This was due, in part, to the sensitivity of chondroclasts to irradiation. The radioprotectant amifostine reduced these effects on growth rate, growth plate height, matrix accumulation, and limb length.