Abstract
Osteoporosis often leads to fragility fractures of the hip, resulting in impaired quality of life and increased mortality. Augmenting the proximal femur could be an attractive option for prevention of fracture or fixation device failure. We describe a tissue engineering based strategy to enhance long-term bone formation in the femoral neck of osteoporotic rats by locally delivering bioactive molecules; recombinant human bone morphogenic protein-2 (rhBMP-2), and zoledronic acid (ZA) by using a calcium sulfate/hydroxyapatite (CaS/HA) biomaterial. A defect was created by reaming the femoral neck canal of osteoporotic (OVX) rats and they were treated as follows: G1. Empty, G2. CaS/HA, G3. CaS/HA+Systemic ZA, G4. CaS/HA+Local ZA, and G5. CaS/HA+Local ZA+rhBMP-2. Bone formation was evaluated 6 months after treatment. Further, radioactively labeled 14C-ZA was used to study the bioavailability of ZA at the defect location, which was determined by using scintillation counting. Micro-CT indicated significantly higher bone volume in groups G4 and G5 compared with the other treatment groups. This was confirmed qualitatively by histological assessment. Addition of rhBMP-2 gave no additional benefit in this model. Local delivery of ZA performed better than systemic administration of ZA. Mechanical testing showed no differences between the groups, likely reflecting that the addition of bioactive molecules had limited effect on cortical bone or the choice of mechanical testing setup was not optimal. Scintillation counting revealed higher amounts of 14C-ZA present in the treated leg of G4 compared with its contralateral control and compared with G3, indicating that local ZA delivery can be used to achieve high local concentrations without causing a systemic effect. This long-term study shows that local delivery of ZA using a CaS/HA carrier can regenerate cancellous bone in the femoral neck canal and has clear implications for enhancing implant integration and fixation in fragile bone.Impact statementThis long-term study shows a promising method to enhance bone formation in the femoral neck canal of osteoporotic rats. The approach involves a ceramic carrier that facilitates bone regeneration via sustained delivery of bioactive molecules locally in the femoral neck. Further, the carrier acts as a local depot for bioactive molecule delivery for as long as 6 months with overall positive effect on bone regeneration. The results from this model can potentially be translated into the clinics for reinforcing the femoral neck or for enhancing implant anchorage in poor-quality osteoporotic bone, which presents a real clinical challenge in fragility fractures.
Highlights
Fragility fractures of the hip are on the rise and with the current age quake the worldwide numbers are estimated to exceed 2.5 million by 2025 and double by 2050.1,2 Apart from patient morbidity and societal impact, the mortality rate 1 year after hip fracture is a staggering 30%.3 More than half of the patients never return to their prefracture level mobility, a disastrous outcome in old age.[4]Prevention of osteoporotic fractures has hitherto focused on pharmacological intervention with bisphosphonates or more recently by using biological drugs targeting osteoclasts with anti-RANKL treatment.[5]
We have recently developed an animal model to study this phenomenon in the femoral neck canal of osteoporotic rats[10] and augmentation led to new bone formation, which could possibly enhance the mechanical strength of the bone or improve bone-implant anchorage in osteoporotic patients
Treated leg: A similar effect on bone volume (BV)/tissue volume (TV) was observed in both Region of interests (ROIs)
Summary
Fragility fractures of the hip are on the rise and with the current age quake the worldwide numbers are estimated to exceed 2.5 million by 2025 and double by 2050.1,2 Apart from patient morbidity and societal impact, the mortality rate 1 year after hip fracture is a staggering 30%.3 More than half of the patients never return to their prefracture level mobility, a disastrous outcome in old age.[4]Prevention of osteoporotic fractures has hitherto focused on pharmacological intervention with bisphosphonates or more recently by using biological drugs targeting osteoclasts with anti-RANKL treatment.[5]. Fragility fractures of the hip are on the rise and with the current age quake the worldwide numbers are estimated to exceed 2.5 million by 2025 and double by 2050.1,2 Apart from patient morbidity and societal impact, the mortality rate 1 year after hip fracture is a staggering 30%.3. More than half of the patients never return to their prefracture level mobility, a disastrous outcome in old age.[4]. We have recently developed an animal model to study this phenomenon in the femoral neck canal of osteoporotic rats[10] and augmentation led to new bone formation, which could possibly enhance the mechanical strength of the bone or improve bone-implant anchorage in osteoporotic patients
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