Resumen de Synthetic Parathyroid Hormone May Augment Bone Volume in Autogenous Grafts: A Study in Rats
Rodrigo A. B. dos Santos, Marcelo S. Ferreira, Carlos Eduardo S. Mafra, Marinella Holzhausen, Luiz Antonio Pugliesi Alves de Lima, Claudio Pannuti, João Batista César-Neto
Background: Synthetic parathyroid hormone [PTH(1–34)] has been investigated for its benefits on bone healing and osteoporosis treatment; however, there is little information regarding bone grafts. This study therefore investigates the effect of PTH(1–34) on autogenous bone graft healing.
Methods: Bone grafts were harvested from the calvarium of rats with a trephine bur (3-mm internal diameter) and placed on the cortex near the mandible angle with a titanium screw. Animals were randomly assigned to group 1 (control): subcutaneous injections of saline solution, three times a week (n = 15); group 2: 2 μg/kg PTH(1–34), three times a week (n = 15); and group 3: 40 μg/kg PTH(1–34), three times a week (n = 15). Thirty days postoperatively, the animals were killed, and specimens (implant + bed + graft) were removed and used for undecalcified sections. The following histometric parameters were evaluated: total bone thickness (TT) (bed + gap + graft), graft thickness (GT) (adjacent to the implant), bone-to-implant contact (BIC), and bone area (BA) (within the limits of the threads). Five additional animals were sacrificed immediately after surgery (zero hour) to register bed and graft sizes before healing.
Results: Group 3 showed significantly greater bone gain compared with groups 1 and 2 (TT and GT, P <0.05). In relation to initial thickness (zero hour), groups 1 and 2 showed a total decrease in volume of 15.91% and 20.83%, respectively, whereas group 3 showed a slight bone gain (1.21%). Data analysis revealed a significant difference for group 3 compared with groups 1 and 2 (P <0.01). No differences were observed for BIC and BA (P >0.05).
Conclusion: Systemic administration of PTH(1–34) augmented bone volume in autogenous grafts.
Long-term studies have reported a high degree of predictability in the osseointegration process and high success rates in clinical prosthetic rehabilitation with titanium implants.1,2 However, some factors have been related to dental implant failure, such as general health, bone quantity and quality, degree of surgical trauma, smoking, and bacterial contamination.3 Alveolar bone resorption is often observed after tooth extraction, which can alter the thickness and the height of the bone.4 The resorption can directly affect bone volume and architecture, and consequently, the prognosis of a site candidate for implant surgery.5 Such biologic events may result in the need for bone augmentation procedures to allow the installation of implant-supported prostheses.6 Satisfactory results have been reported with bone grafts, guided bone regeneration, and osteogenesis distraction, allowing bone gain and the placement of implants in areas of previously resorbed bone.4,7 In contrast, sometimes the bone volume obtained is not enough to install the recommended implant size. Furthermore, these techniques have some limitations, such as low predictability gain in bone height and the need for a second surgery, that include a significant period of time (≈6 months) between the procedure of bone reconstruction and implant placement. So far, there is a lack of studies investigating systemically administered drugs with the objective of optimizing bone augmentation procedure outcomes in the oral cavity. Such approaches may aim at an increase in the healing pattern, and consequently, a decrease in the interval between reconstruction and implant placement.
Parathyroid hormone (PTH) has been extensively investigated for its properties demonstrated in osteoporosis treatment.8-11 This hormone is a major regulator of organic calcium and phosphate metabolism, and controls (by bone remodeling) the flow of these minerals in bones and kidneys.12 When administered continuously, it promotes bone resorption, but its intermittent use is highly anabolic to bone tissue.13 Animal studies revealed that intermittent administration of synthetic PTH [PTH(1–34)] significantly decreased the bone loss from ligature-induced periodontitis when promoted in normal14 and ovariectomized15 animals. The effect of PTH(1–34) on bone tissue, after placing titanium implants into the tibia of ovariectomized rats, has been evaluated in previous studies.16,17 The results suggest that intermittent application of PTH(1–34) can avoid trabecular bone resorption around implants, as well as provide additional bone volume that was lost after ovariectomy.16 PTH appears to have an effect by acting on osteoblast stimulation.17 It is also considered more effective in the treatment of osteoporosis than bone resorption inhibitors such as alendronate, risedronate, etidronate, and raloxifene.9 It has been reported that PTH(1–34) does not increase the incidence of tumors and has no mutagenic and toxic effects or side effects.12,18 This was also confirmed in studies involving ≈1,000 patients treated with PTH(1–34) for 3 years.10 A study evaluating injections of PTH(1–34) in young and aged rats showed that this substance promotes an intense osteogenic effect, which increases bone volume around titanium implants.19 Also, PTH(1–34) administered in 40 μg/kg/day dosages increased the healing rate of bone grafts used for spinal fusion in rats.20 A study of two different doses of PTH(1–34) (10 versus 100 μg/kg/day) in an extensive reconstruction of the tibia, including bone grafts transplanted with a syngeneic animal model, showed a positive effect of PTH(1–34) (proportional to concentration) on bone graft healing.21 Despite these interesting findings, animal studies have used dosages based on studies of carcinogenesis in rats,22,23 which are about 100 to 200 times higher than those used clinically in humans. Clinical studies have used daily applications of 209 or 4011 μg PTH(1–34) (≈0.3 to 0.7 μg/kg/day).
Thus, the aim of the present study is to evaluate the osteogenic potential for lower doses of PTH(1–34) than those used previously in studies on rats, closer to those administered clinically in patients, in the repair of healing bone grafts obtained from rat calvaria and fixed by titanium mini-implants in the mandibular angle of the same animal.
