Effects of continual intermittent administration of parathyroid hormone on implant stability in the presence of osteoporosis: an in vivo study using resonance frequency analysis in a rabbit model

Abstract Objective: This study aimed to evaluate the effects of continual intermittent administration of parathyroid hormone (PTH) on implant stability in the presence of osteoporosis, using rabbit models. Material and Methods: Fifteen female New Zealand white rabbits underwent ovariectomy and were administered glucocorticoids to induce osteoporosis, following which they were divided into three groups. The first group received intermittent subcutaneous PTH for 4 weeks until implant placement (PTH1), while the second and third groups received PTH (PTH2) and saline (control), respectively, for 4 weeks before and after implant placement. After intermittent administration of PTH or saline, titanium implants were inserted into the left femoral epiphyses of all animals, and the implant stability quotient (ISQ) was measured immediately after placement to assess the primary stability and at 2 and 4 weeks after implant placement to assess osseointegration. At 4 weeks after implant placement, histological and histomorphometric evaluations were conducted and the bone area around the implant socket was measured as a ratio of the total bone area to the total tissue area. Results: Regarding primary stability, the ISQ values for the PTH1 and PTH2 groups were significantly higher than those for the control group (p<0.05). Concerning osseointegration, the ISQ values at 2 and 4 weeks were significantly higher for the PTH2 group than for the PTH1 and control (p<0.05) groups. Histological assessments showed a thicker and more trabecular bone around the implant sockets in the PTH2 specimens than in the PTH1 and control specimens. The bone area around the implant socket was significantly greater in the PTH2 group than in the PTH1 and control groups (p<0.05). Conclusions: Our results suggest that continual intermittent PTH administration before and after dental implant placement is effective for the achievement of favorable stability and osseointegration in the presence of osteoporosis.


Introduction
Successful implant therapy depends on the achievement of favorable implant stability, which can be divided into primary stability and secondary stability or osseointegration 9 . Both primary stability and osseointegration are affected by different factors, including bone quantity and quality, implant design, and surgical protocols 24 . In particular, the most important factor is the condition of the bone at the site of implant placement 19 . Primary stability decreases at sites with a low bone density, which may result in implant failure 25 .
Osteoporosis is a skeletal disease that causes the systematic loss of bone regarding density and quantity. As mentioned above, the condition of the bone at the implant placement site is strongly correlated with the implant failure rate. Patients with osteoporosis who undergo implant treatment show less favorable outcomes compared with patients exhibiting healthy bone 28 . The most common secondary form of osteoporosis is that induced by glucocorticoid autoimmune disorders 17 . Glucocorticoids affect the bone quality mainly by decreasing bone formation by a decrease in osteoblastogenesis and an increase in osteoblast and osteocyte apoptosis. Therefore, glucocorticoid-induced osteoporosis is an unfavorable factor regarding implant stability. In a previous study, we showed that glucocorticoid-induced osteoporosis decreased the primary stability of implants and the mechanical strength of the femur in a rabbit model 23 .
The phenomenon of poorly primary stability was caused by reduction of cortical bone thickness and mechanical strength.
Currently, the intermittent administration of parathyroid hormone (PTH) for enhancing bone formation and improving bone quantity is clinically approved. Some animal studies have reported that intermittent PTH administration is effective in promoting bone remodeling and increasing the trabecular bone mass 10,11 . PTH affects cancellous bone remodeling by promoting the formation of osteoblasts and suppressing their apoptosis 2,16 . Furthermore, it increases the thickness of not only trabecular bone, but also cortical bone 15 . Therefore, intermittent PTH administration can be effective in improving the bone density at the implant placement site and achieving favorable primary stability and osseointegration in patients with severe osteoporosis, including that induced by glucocorticoids. Corsini, et al. 5 (2008) reported that intermittent PTH administration enhanced secondary stability in normal healthy rabbits. Almagro, et al. 1 (2013) reported that osseointegration could be improved by intermittent PTH administration in rabbit models with osteoporosis.
In these studies, however, intermittent PTH administration was initiated after implant placement; furthermore, only secondary implant stability or osseointegration was evaluated. Therefore, the effects on primary stability remained unclear, considering the bone quality at the implant placement site was not improved by prior intermittent PTH administration.
On the other hand, our previous study assessed the effects of intermittent PTH administration initiated before implant placement in rabbit models with osteoporosis 21 . Thus, the bone condition was improved before implant placement and favorable primary stability was achieved. However, secondary stability was not evaluated. Therefore, few studies have evaluated the effects of PTH therapy on osseointegration after the achievement of favorable primary stability. This study aimed to evaluate the effects of continual intermittent PTH administration before and after dental implant placement on primary stability and secondary stability in the presence of osteoporosis induced in rabbit models by ovariectomy and glucocorticoid administration.    The socket is created in the distal epiphysis (knee joint) of the left femur. After the knee joint was exposed, an implant surgical system with a rotary speed not exceeding 800 rpm was used for consecutive applications of a 2.0-mm round drill, 2.0-mm twist drill, 3.0-mm pilot drill, 3.0-mm twist drill, and countersink drill. Following the socket preparation procedures, implants were inserted until the color indicator was level with the bone ridge     The bone area around the implant socket was than in the PTH1 (30.8±7.7%) and control groups (25.5±3.8%; Table 1).

Discussion
Low bone density, such as that observed in patients with osteoporosis, results in poor primary implant stability because of decreased mechanical bone strength at the placement sites. Furthermore, osseointegration is barely achieved at such sites because of the suppression of bone remodeling. In this study, we found that continual intermittent PTH administration before and after implant placement can improve both primary stability and secondary stability, as determined by ISQ values.
suppressing bone formation through the inhibition of osteoblastogenesis and promotion of osteoblast and osteocyte apoptosis 2,16 . In our study, ISQ   the appropriate dosage of PTH for achieving such an effect 5,29 . In our study, the PTH dose rate was set at is within the range used for in vivo rabbit studies 21 .
In conclusion, the results of our study suggest that continual intermittent PTH administration is effective for achieving favorable primary and secondary stability in the presence of osteoporosis. It is the authors' intention to conduct further studies comparing normal healthy models to investigate the detailed effects of PTH on implant stability.
The authors declare no competing financial interests.