Metaphyseal fracture healing in a sheep model of low turnover osteoporosis induced by hypothalamic–pituitary disconnection (HPD)

Abstract

ABSTRACT:We recently established a large animal model of osteoporosis in sheep using hypothalamic-pituitary disconnection (HPD). As central regulation is important for bone metabolism, HPD-sheep develop severe osteoporosis because of low bone turnover. In this study we investigated metaphyseal fracture healing in HPD-sheep. To elucidate potential pathomechanisms, we included a treatment group receiving thyroxine T4 and 17b-estradiol. Because clinically osteoporotic fractures often occur in the bone metaphysis, HPDsheep and healthy controls received an osteotomy in the distal femoral condyle. Half of the HPD-sheep were systemically treated with thyroxine T4 and 17b-estradiol during the healing period. Fracture healing was evaluated after 8 weeks using pQCT, mCT, and histomorphometrical analysis. Bone mineral density (BMD) and bone volume/total volume (BV/TV) were considerably reduced by 30% and 36%, respectively, in the osteotomy gap of the HPD-sheep compared to healthy sheep. Histomorphometry also revealed a decreased amount of newly formed bone (À29%) and some remaining cartilage in the HPD-group, suggesting that HPD disturbed fracture healing. Thyroxine T4 and 17b-estradiol substitution considerably improved bone healing in the HPD-sheep. Our results indicate that fracture healing requires central regulation and that thyroxine T4 and 17b-estradiol contribute to the complex pathomechanisms of delayed metaphyseal bone healing in HPD-sheep. Keywords: osteoporosis; low turnover; central control; hypothalamic-pituitary disconnection (HPD); metaphyseal fracture healing Osteoporosis predominantly affects postmenopausal women, but also older men, and is characterized by an imbalance between bone formation and resorption. The resulting bone loss is associated with fragility fractures, which frequently involve the spine and metaphyseal bone at the hip and wrist.1 Osteoporotic fractures are often associated with complications, leading to disability, increased mortality and socioeconomic burden.2 Complications are caused by poor primary stability of the fracture fixation in the fragile bone, which results in unfavorable mechanical healing conditions, or by comorbidities.3 Whether the osteoporotic bone itself possesses reduced healing capacity is under ongoing discussion.4 Clinical 5,6 and preclinical reports [7][8][9] indicate that the regenerative capacity of the bone is highly likely to be affected by osteoporosis. The underlying pathomechanisms are under extensive research to develop effective treatments to improve bone healing in osteoporotic patients.Most fracture healing studies were performed in small animal models of ovariectomy-induced osteoporosis. 7,9,10 To identify specific genes playing a role in osteoporotic bone healing, fracture healing is increasingly studied in genetically modified mice.11,12 However, small animal models have important drawbacks.The small size of the skeleton makes it impossible to prove orthopedic implants or to adequately study metaphyseal fracture healing. To address these issues, lar...

Review of Animal Models of Comorbidities in Fracture‐Healing Research

“…Cortical bone loss was 25% after 12 months and sustained over a period of 24 months after HPD . Furthermore, HPD sheep displayed significantly delayed metaphyseal fracture healing, indicated by an increased amount of soft tissue and cartilage, but less bone in the fracture area . This demonstrated the relevance of this large animal model for osteoporotic fracture healing research, although the HPD procedure clearly leads to an artificially generated type of osteoporosis.…”

A metaphyseal fracture rat model for mechanistic studies of osteoporotic bone healing

“…Despite the evidence, most pre-clinical studies have concentrated on healing of osteoporotic diaphyseal fractures with intramedullary fixation based on the classic model described by Bonnarens and Einhorn (1984). Few experimental studies have been performed on osteoporotic metaphyseal osteotomies on rats (Kolios et al, 2010;Komrakova et al, 2015;Stuermer et al, 2013), goats (Cheung et al, 2016) and sheep (Bindl et al, 2013). Amongst these limited studies, many are clinically inadequate, with www.ecmjournal.org over-simplified models including drill-hole defects and partial osteotomy models (Wong et al, 2018).…”

Preclinical testing of drug delivery systems to bone

“…This osteoporotic phenotype is sustained for at least two years [250]. Indeed, long bone defects can be investigated in this model [251]. On the other hand, this model is also suitable for maxillofacial surgeons as the mandibular bone shows bone loss similar as seen in osteoporotic patients [252].…”