Parathyroid hormone--a drug for orthopedic surgery?

Whereas continuous exposure to PTH results in bone resorption, administration at intermittent doses results in bone formation by increasing osteoblast number and activity. The anabolic action of PTH has also been demonstrated in clinical trials, in which PTH increased the bone mass and reduced fracture rate in patients with osteoporosis. In animal models of fracture healing and fixation of orthopedic implants, PTH increases the bone density in a dose-dependent manner, leading to faster repair and better fixation. The effect appears to be stronger on the new forming bone than on pre-existing bone. Based on these preclinical studies, we suggest that intermittent PTH treatment may also benefit fracture healing and implant fixation in patients.     

Present and future scope of recombinant parathyroid hormone therapy in orthopaedics

Parathyroid Hormone (PTH) has a significant role in calcium metabolism. Its intermittent administration has an anabolic effect on bone mineralization. Teriparatide (PTH 1-34), a recombinant form of parathyroid hormone, is useful in the treatment of osteoporosis, fracture healing, non-union, stress fracture, augmentation of implant fixation with bone, and chondroprotection in osteoarthritis. The present review article will elaborate on the potential approved uses of recombinant PTH in orthopedics and its evolving role in the management of fracture osteosynthesis and other common challenging bone pathologies.     

Mechanisms for the enhancement of fracture healing in rats treated with intermittent low-dose human parathyroid hormone (1-34).

Recent reports have demonstrated that intermittent treatment with parathyroid hormone (1-34) [PTH(1-34)] increases callus formation and mechanical strength in experimental fracture healing. However, little is known about the optimal dose required for enhancement of fracture repair or the molecular mechanisms by which PTH regulates the healing process. In this study, we analyzed the underlying molecular mechanisms by which PTH affects fracture healing and tested the hypothesis that intermittent low-dose treatment with human PTH(1-34) can increase callus formation and mechanical strength. Unilateral femoral fractures were produced and a daily subcutaneous injection of 10 microg/kg of PTH(1-34) was administered during the entire healing period. Control animals were injected with vehicle solution alone. The results showed that on day 28 and day 42 after fracture, bone mineral content (BMC), bone mineral density (BMD), and ultimate load to failure of the calluses were significantly increased in the PTH-treated group compared with controls (day 28, 61, 46, and 32%; day 42, 119, 74, and 55%, respectively). The number of proliferating cell nuclear antigen (PCNA)-positive subperiosteal osteoprogenitor cells was significantly increased in the calluses of the PTH-treated group on day 2, and TRAP+ multinucleated cells were significantly increased in areas of callus cancellous bone on day 7. The levels of expression of type I collagen (COLlA1), osteonectin (ON), ALP, and osteocalcin (OC) mRNA were increased markedly in the PTH-treated group and accompanied by enhanced expression of insulin-like growth factor (IGF)-I mRNA during the early stages of healing (days 4-7). The increased expression of COL1A1, ON, ALP, and OC mRNA continued during the later stages of healing (days 14-21) despite a lack of up-regulation of IGF-I mRNA. These results suggest that treatment of fractures with intermittent low dose PTH(1-34) enhances callus formation by the early stimulation of proliferation and differentiation of osteoprogenitor cells, increases production of bone matrix proteins, and enhances osteoclastogenesis during the phase of callus remodeling. The resultant effect to increase callus mechanical strength supports the concept that clinical investigations on the ability of injectable low-dose PTH(1-34) to enhance fracture healing are indicated.     

Recent Advances Toward the Clinical Application of PTH (1-34) in Fracture Healing

PTH 1-34, an active form of parathyroid hormone, has been shown to enhance osteoblastic bone formation when administered as a daily subcutaneous injection. The effect of the intermittent administration of PTH (1-34) is an uncoupling of bone turnover with an increase in bone mass and density and decrease in risk of vertebral and nonvertebral fractures. While PTH (1-34) has been used clinically to increase bone mass and reduce fracture risk in postmenopausal women with osteoporosis, there is increasing evidence that PTH (1-34) may promote fracture healing. Animal studies have demonstrated accelerated callus formation with enhanced remodeling and biomechanical properties of the healing fracture. Given these effects, PTH (1-34) will likely be used clinically to enhance fracture union in poor healing situations such as osteoporosis and recalcitrant nonunions.     

Human parathyroid hormone (1-34) accelerates natural fracture healing process in the femoral osteotomy model of cynomolgus monkeys

Several studies in rats have demonstrated that parathyroid hormone accelerates fracture healing by increasing callus formation or stimulating callus remodeling. However the effect of PTH on fracture healing has not been tested using large animals with Haversian remodeling system. Using cynomolgus monkey that has intracortical remodeling similar to humans, we examined whether intermittent treatment with human parathyroid hormone [hPTH(1–34)] accelerates the fracture healing process, especially callus remodeling, and restores geometrical shapes and mechanical properties of osteotomized bone.

Seventeen female cynomolgus monkeys aged 18–19 years were allocated into three groups: control (CNT, n = 6), low-dose PTH (0.75 μg/kg; PTH-L, n = 6), and high-dose PTH (7.5 μg/kg; PTH-H, n = 5) groups. In all animals, twice a week subcutaneous injection was given for 3 weeks. Then fracture was produced surgically by transversely cutting the midshaft of the right femur and fixing with stainless plate. After fracture, intermittent PTH treatment was continued until sacrifice at 26 weeks after surgery. The femora were assessed by soft X-ray, three-point bending mechanical test, histomorphometry, and degree of mineralization in bone (DMB) measurement. Soft X-ray showed that complete bone union occurred in all groups, regardless of treatment. Ultimate stress and elastic modulus in fractured femur were significantly higher in PTH-H than in CNT. Total area and percent bone area of the femur were significantly lower in both PTH-L and PTH-H than in CNT. Callus porosity decreased dose-dependently following PTH treatment. Mean DMB of callus was significantly higher in PTH-H than in CNT or PTH-L. These results suggested that PTH decreased callus size and accelerated callus maturation in the fractured femora.

PTH accelerates the natural fracture healing process by shrinking callus size and increasing degree of mineralization of the fracture callus, thereby restoring intrinsic material properties of osteotomized femur shaft in cynomolgus monkeys although there were no significant differences among the groups for structural parameters.     

Triweekly administration of parathyroid hormone (1–34) accelerates bone healing in a rat refractory fracture model

Background

Some reports have shown that intermittent parathyroid hormone (PTH) (1–34) treatment for patients with delayed union or nonunion have led to successful healing. In this study, we investigated whether systemic intermittent administration of PTH (1–34) has a beneficial effect on bone healing in a rat refractory fracture model.

Methods

We created a refractory femoral fracture model in 32 rats with periosteal cauterization that leads to atrophic nonunion at 8 weeks after surgery. Half the rats received subcutaneous intermittent human PTH (1–34) injections at a dosage of 100 μg/kg, thrice a week for 8 weeks. The other half received the vehicle only. At 8 weeks after fracture, radiographic, histological and mechanical assessments were performed.

Results

Radiographic assessments showed that the union rate was significantly higher in the PTH group than in the control group (P?<?0.05). The degree of fracture repair as scored using the Allen grading system in histological assessment was significantly greater in the PTH group than in the control group (P?<?0.05). The ultimate stress and stiffness measurements were significantly greater in the PTH group than in the control group (p?<?0.05).

Conclusions

We demonstrated that triweekly administration of PTH (1–34) increased union rate and accelerated bone healing in a rat refractory fracture model, suggesting that systemic administration of PTH (1–34) could become a novel and useful therapy for accelerating fracture healing in patients at high risk of delayed union or nonunion.

     

The influence of parathyroid hormone on the process of fracture healing

The influence of parathyroid hormone (PTH) on the process of fracture healing was examined using the fractured rats which were parathyroidectomized or given synthetic PTH. The biochemical and histological changes were studied. The results were as follows: I) Parathyroidectomized rats (PTX rats) showed decreased serum Ca, increased serum P and decreased serum PTH as observed in hypoparathyroidism. The fracture healing was impaired due to delay of both chondroclasis at the phase of endochondral ossification and secondary remodeling of primary cancellous bone. II) In rats treated with PTH (PTH rats) both serum Ca and P levels were increased at the early stage. Bone resorption as well as formation was also promoted at the early stage. At the late stage only bone formation remained good with poor bone resorption, indicating that secondary bone remodeling is decreased. The union of callus was impaired. Fracture healing was consequently delayed in both PTX and PTH rats. It is therefore suggested that PTH may be one of the important factors in fracture healing.     

Intermittent parathyroid hormone (PTH) treatment and age-dependent effects on rat cancellous bone and mineral metabolism.

In recent years, intermittent PTH treatment has been investigated extensively for its efficacy in preventing osteoporotic fractures and to improve fracture healing and implant fixation. Although these tasks concern patients of all ages, very little is known about whether aging impacts the bone anabolic response to PTH. Female Sprague-Dawley rats of 1, 3, and 13 months of age were either treated by hPTH-(1-34) or by vehicle solution (CTR) for 1 week. As main outcome measures, we determined the effects on static and dynamic histomorphometry of cancellous bone. In addition, we measured gene expression in femur and serum parameters reflecting bone turnover and mineral metabolism. There was a profound decrease in bone formation rate (BFR) with aging in CTR rats, whereas PTH treatment resulted in a significant relative 1.5-, 3-, and 4.7-fold increase in BFR, without altering indices of bone resorption. Aging decreased and PTH increased mRNA levels for bone matrix proteins and growth factors in a gene-specific manner. In younger animals, PTH-induced a marked stimulation in the mineral apposition rate with no effect on osteoblast number, whereas the latter was increased in older animals (1.0-, 1.7-, and 3.1-fold). Treatment with PTH in young rats led to a significant increase in trabecular number (1.6-2.6/mm, p < 0.05), whereas older rats demonstrated increases in trabecular thickness only (52.8-77.8 microm, p < 0.001). Although PTH increased bone formation at all ages, we found significant age-related differences in the cellular and molecular mechanisms involved in the bone anabolic response to the hormone.     

Role of parathyroid hormone in the mechanosensitivity of fracture healing.

The mechanical environment at a fracture site can influence the course of healing. Intermittent parathyroid hormone (PTH) has been shown to accelerate fracture healing. Intact bone models show that mechanical loading and PTH have a synergistic beneficial effect on osteogenesis. We hypothesized that PTH and mechanical loading would have a similar synergistic effect on fracture healing. Eighty mice underwent surgical osteotomy and intramedullary nailing of the tibia. The mice were divided into four groups: one underwent daily loading, one received daily subcutaneous PTH injections (30 microg/kg/day), one received both loading and PTH, and a control group received sham loading and vehicle injection. Daily loading was applied to the ends of the tibia with an external loading device for 2 weeks. Fracture healing was assessed by microcomputed tomography, histology, and biomechanical testing. The group with both loading and PTH had increased osteoblast and osteoclast activity and was the only group with a significantly larger callus mineral density and bone volume fraction. The PTH only group had significantly more osteoid in the callus compared to the control group, indicating enhanced early osteoblast activity. This group also had a significantly higher bone mineral content and total bone volume compared to controls. The group that received loading as the only intervention had significantly greater osteoclast activity versus controls. The contribution of loading and PTH administration to the fracture healing cascade indicates a synergistic effect. This finding may be of potential clinical utility when weight bearing is utilized to stimulate lower extremity fracture healing.     

Sequential Treatment with Intermittent Low-Dose Human Parathyroid Hormone (1-34) and Bisphosphonate Enhances Large-Size Skeletal Reconstruction by Vascularized Bone Transplantation

Vascularized bone transplantation enables reconstruction of large skeletal defects, but this process needs a long time. Since short-term intermittent parathyroid hormone (PTH) enhances rat fracture healing, we investigated the effects of 4-week intermittent low-dose (10 μg/kg/day) or high-dose (100 μg/kg/day) PTH followed by 4-week vehicle, low-dose or high-dose intermittent PTH, or zoledronic acid (ZOL, 2 μg/kg/week), a potent bisphosphonate, on large skeletal reconstruction by vascularized tibial grafting in rats. Compared to 8-week vehicle, 8-week low-dose PTH did not significantly increase the serum osteocalcin level as well as the urinary deoxypyridinoline level, while 4-week low-dose or high-dose PTH followed by 4-week ZOL decreased both of these levels. Eight-week PTH increased the bone mass of the graft and strength of the reconstructed skeleton in a dose-dependent manner; notably, the reconstructed skeleton showed an obviously higher response to PTH compared to the contralateral nonoperated femur. In contrast, 4-week PTH followed by 4-week vehicle reduced these effects and caused local bone loss at the host-graft junctions. Four-week PTH followed by 4-week ZOL did not induce such bone loss; however, 4-week high-dose PTH followed by 4-week ZOL caused a large callus in the distal cortical junction. Four-week PTH followed by 4-week ZOL increased the bone mass and strength similarly to 8-week PTH. These preliminary findings suggest, for the first time, that sequential treatment with short-term intermittent low-dose PTH and bisphosphonate as well as long-term intermittent low-dose PTH treatment enhance large skeletal reconstruction by vascularized bone transplantation, though early timing of sequential antiresorptive treatment could result in delay of bone repair.     

Enhancement of graft bone healing by intermittent administration of human parathyroid hormone (1-34) in a rat spinal arthrodesis model

Bone grafting is commonly used to treat skeletal disorders associated with large bone defect or unstable joint. It can take several months, however, to achieve a solid union and bony fusion sometimes delays or fails especially in osteoporosis patients. Therefore, we used a rat spinal arthrodesis model to examine whether intermittent administration of human PTH(1-34) accelerates bone graft healing. Eighty-two male Sprague-Dawley rats underwent posterolateral spinal arthrodesis surgery using autologous bone grafts. Animals were given daily subcutaneous injections of hPTH(1-34) (40 microg/kg/day PTH group) or 0.9% saline vehicle (control group) from immediately after surgery till death. Five rats each were killed 2, 4, 7, and 14 days after the surgery, and mRNA expression analysis was performed on harvested grafted bone. Seven rats each were killed 14, 28, and 42 days after the surgery, and the lumbar spine, which contained the grafted spinal segment, was subjected to fusion assessment, microstructural analysis using three-dimensional micro-computed tomography, and histologic examination. Serum bone metabolism markers were analyzed. The results indicated that PTH administration decreased the time required for graft bone healing and provided a structurally superior fusion mass in the rat spinal arthrodesis model. PTH administration increased the fusion rate on day 14 (14% in the control group and 57% in the PTH group), accelerated grafted bone resorption, and produced a larger and denser fusion mass compared to control. mRNA expression of both osteoblast- and osteoclast-related genes was upregulated by PTH treatment, and serum bone formation and resorption marker levels were higher in the PTH group than in the control group. Histologically calculated mineral apposition rate, mineralized surface and osteoclast surface were also higher in the PTH group than in the control group. These findings suggest that intermittent administration of PTH(1-34) enhanced bone turn over dominantly on bone formation at the graft site, leading to the acceleration of the spinal fusion. Based on the results of this study, intermittent injection of hPTH(1-34) might be an efficient adjuvant intervention in spinal arthrodesis surgery and all other skeletal reconstruction surgeries requiring bone grafts.     

Promotion of peri-implant bone healing by systemically administered parathyroid hormone (1-34) and zoledronic acid adsorbed onto the implant surface

Summary

The effect of human parathyroid hormone 1-34 (PTH) and zoledronic acid (ZA) alone or in combination on bone healing in osteoporotic settings was tested using implants inserted in tibiae of ovariectomized (OVX) rats. Combination therapy promoted bone healing more than each treatment alone 12 weeks after implant insertion.

Introduction

PTH and ZA have been demonstrated to be effective on implant fixation. However, reports about the combined use of PTH and ZA for promotion of bone healing around implant in osteoporotic settings are still limited. This study aims to investigate effects of PTH+ZA on implant stabilization in OVX rats.

Methods

Twelve weeks after bilateral ovariectomy, OVX rats randomly received implants without or with ZA (by immersion in 1 mg/ml ZA solution for 24 h). Subsequently, half of the animals from each group also received subcutaneous injections of PTH (60 μg/kg, three times a week) for 12 weeks. Thus, there were four groups: control, PTH, ZA, and PTH+ZA.

Results

All treatments promoted bone healing around implant compared to control, but PTH+ZA treatment showed significantly stronger effects than PTH or ZA alone in histological, micro-CT, and biomechanical tests.

Conclusion

The results indicated the additive effects of PTH and ZA on implant fixation in OVX rats; it was suggested that the anabolic effect of PTH was potent and not blunted by ZA during bone healing around implant when used concurrently.     

Systemic intermittent parathyroid hormone treatment improves osseointegration of press-fit inserted implants in cancellous bone

Background and purpose Intermittent administration of parathyroid hormone (PTH) has an anabolic effect on bone, as confirmed in human osteoporosis studies, distraction osteogenesis, and fracture healing. PTH in rat models leads to improved fixation of implants in low-density bone or screw insertion transcortically. Material and methods We examined the effect of human PTH (1-34) on the cancellous osseointegration of unloaded implants inserted press-fit in intact bone of higher animal species. 20 dogs were randomized to treatment with human PTH (1-34), 5 μg/kg/day subcutaneously, or placebo for 4 weeks starting on the day after insertion of a cylindrical porous coated plasma-sprayed titanium alloy implant in the proximal metaphyseal cancellous bone of tibia. Osseointegration was evaluated by histomorphometry and fixation by push-out test to failure. Results Surface fraction of woven bone at the implant interface was statistically significantly higher in the PTH group by 1.4 fold with (median (interquartile range) 15% (13-18)) in the PTH group and 11% (7-13) in control. The fraction of lamellar bone was unaltered. No significant difference in bone or fibrous tissue was observed in the circumferential regions of 0-500, 500-1,000, and 1,000-2,000 μm around the implant. Mechanically, the implants treated with PTH showed no significant differences in total energy absorption, maximum shear stiffness, or maximum shear strength. Interpretation Intermittent treatment with PTH (1-34) improved histological osseointegration of a prosthesis inserted press-fit at surgery in cancellous bone, with no additional improvement of the initial mechanical fixation at this time point.     

The effect of PTH(1‐34) on fracture healing during different loading conditions

Parathyroid hormone (PTH) and PTH(1‐34) have been shown to promote bone healing in several animal studies. It is known that the mechanical environment is important in fracture healing. Furthermore, PTH and mechanical loading has been suggested to have synergistic effects on intact bone. The aim of the present study was to investigate whether the effect of PTH(1‐34) on fracture healing in rats was influenced by reduced mechanical loading. For this purpose, we used female, 25‐week‐old ovariectomized rats. Animals were subjected to closed midshaft fracture of the right tibia 10 weeks after ovariectomy. Five days before fracture, half of the animals received Botulinum Toxin A injections in the muscles of the fractured leg to induce muscle paralysis (unloaded group), whereas the other half received saline injections (control group). For the following 8 weeks, half of the animals in each group received injections of hPTH(1‐34) (20 µg/kg/day) and the other half received vehicle treatment. Fracture healing was assessed by radiology, dual‐energy X‐ray absorptiometry (DXA), histology, and bone strength analysis. We found that unloading reduced callus area significantly, whereas no effects of PTH(1‐34) on callus area were seen in neither normally nor unloaded animals. PTH(1‐34) increased callus bone mineral density (BMD) and bone mineral content (BMC) significantly, whereas unloading decreased callus BMD and BMC significantly. PTH(1‐34) treatment increased bone volume of the callus in both unloaded and control animals. PTH(1‐34) treatment increased ultimate force of the fracture by 63% in both control and unloaded animals and no interaction of the two interventions could be detected. PTH(1‐34) was able to stimulate bone formation in normally loaded as well as unloaded intact bone. In conclusion, the study confirms the stimulatory effect of PTH(1‐34) on fracture healing, and our data suggest that PTH(1‐34) is able to promote fracture healing, as well as intact bone formation during conditions of reduced mechanical loading. © 2013 American Society for Bone and Mineral Research.     

Parathyroid Hormone and Bone Healing

Fracture healing is a complex process, and a significant number of fractures are complicated by impaired healing and non-union. Impaired healing is prevalent in certain risk groups, such as the elderly, osteoporotics, people with malnutrition, and women after menopause. Currently, no pharmacological treatments are available. There is therefore an unmet need for medications that can stimulate bone healing. Parathyroid hormone (PTH) is the first bone anabolic drug approved for the treatment of osteoporosis, and intriguingly a number of animal studies suggest that PTH could be beneficial in the treatment of fractures and could thus be a potentially new treatment option for induction of fracture healing in humans. Furthermore, fractures in animals with experimental conditions of impaired healing such as aging, estrogen withdrawal, and malnutrition can heal in an expedited manner after PTH treatment. Interestingly, fractures occurring at both cancellous and cortical sites can be treated successfully, indicating that both osteoporotic and nonosteoporotic fractures can be the target of PTH-induced healing. Finally, the data suggest that PTH partly prevents the delay in fracture healing caused by aging. Recently, the first randomized, controlled clinical trial investigating the effect of PTH on fracture healing was published, indicating a possible clinical benefit of PTH treatment in inducing fracture healing. The aim of this article is therefore to review the evidence for the potential of PTH in bone healing, including the underlying mechanisms for this, and to provide recommendations for the clinical testing and use of PTH in the treatment of impaired fracture healing in humans.     

Increases in callus formation and mechanical strength of healing fractures in old rats treated with parathyroid hormone

We studied the effects of intermittent administration of parathyroid hormone (PTH(1-34)) on callus formation and mechanical strength of tibial fractures in 27-month-old rats after 3 and 8 weeks of healing. 200 microg PTH(1-34)/kg was administered daily during both periods of healing, and control animals with fractures were given vehicle. At 3 weeks, PTH treatment increased maximum load and external callus volume by 160% and 208%; at 8 weeks, by 270% and 135%. It also enhanced callus bone mineral content (BMC) by 190% and 388% (3 and 8 weeks). From week 3 to week 8, callus BMC increased by 60% in the vehicle-injected animals, and by 169% in the PTH-treated animals. In the contralateral intact tibia, PTH treatment increased BMC by 18% and 21% (3 and 8 weeks). No differences in body weight were found between the vehicle-injected and the PTH-treated animals during the experiment. In conclusion, PTH treatment enhances fracture strength, callus volume and callus BMC after 3 and 8 weeks of healing.     

Increases in callus formation and mechanical strength of healing fractures in old rats treated with parathyroid hormone

We studied the effects of intermittent administration of parathyroid hormone (PTH(1-34)) on callus formation and mechanical strength of tibial fractures in 27-month-old rats after 3 and 8 weeks of healing. 200 &#119 g PTH(1-34)/kg was administered daily during both periods of healing, and control animals with fractures were given vehicle. At 3 weeks, PTH treatment increased maximum load and external callus volume by 160% and 208%; at 8 weeks, by 270% and 135%. It also enhanced callus bone mineral content (BMC) by 190% and 388% (3 and 8 weeks). From week 3 to week 8, callus BMC increased by 60% in the vehicle-injected animals, and by 169% in the PTH-treated animals. In the contralateral intact tibia, PTH treatment increased BMC by 18% and 21% (3 and 8 weeks). No differences in body weight were found between the vehicle-injected and the PTH-treated animals during the experiment. In conclusion, PTH treatment enhances fracture strength, callus volume and callus BMC after 3 and 8 weeks of healing.     

Mice expressing a constitutively active PTH/PTHrP receptor in osteoblasts show reduced callus size but normal callus morphology during fracture healing

Background The parathyroid hormone-/parathyroid hormone-related protein (PTH/PTHrP) receptor plays a crucial role in endochondral bone formation and possibly also in fracture healing. Patients with Jansen's metaphysial chondrodysplasia (JMC) have a gain-of-function mutation in the PTH/PTHrP receptor. Transgenic mice expressing JMC PTH/PTHrP receptor mutants in osteoblasts are characterized by increased trabecular bone formation and reduced osteoblastic activity at periosteal sites. We have analyzed the bone phenotype and studied the fracture healing process in this model.

Methods We performed bone density analysis of tibiae from 17-week-old transgenic mice and controls. Also, tibial fractures were produced in 14-week-old mice. Fracture healing was examined by radiographic and histological analysis.

Results Transgenic mice had a lower total bone mineral content (BMC), by a factor of one-third. The changes were bone compartment-specific with an increase in trabecular bone volume and a decrease in cortical thickness. The calluses in the transgenic mice were smaller, with a reduction in BMC and mean crosssectional area by a factor of one-half. Despite the smaller size, however, the morphology and progression through the healing process were similar in both transgenic and wild-type littermates.

Interpretation We conclude that the constitutively active PTH/PTHrP receptor has compartment-specific effects on bone formation when expressed in osteoblasts. During fracture healing, however, both the periosteal and the endochondral processes are activated, leading to fracture healing that is temporally and morphologically normal, although the callus tissue is less prominent.     

Optimal mechanical environment of the healing bone fracture/osteotomy

The aim of this paper is to review recent experimental and clinical publications on bone biology with respect to the optimal mechanical environment in the healing process of fractures and osteotomies. The basic postulates of bone fracture healing include static bone compression and immobilisation/fixation for three weeks and intermittent dynamic loading treatment afterwards. The optimal mechanical strain should be in the range of 100–2,000 microstrain, depending on the frequency of the strain application, type of bone and location in the bone, age and hormonal status. Higher frequency of mechanical strain application or larger number of repetition cycles result in increased bone mass at the healing fracture site, but only up to a certain limit, values beyond which no additional benefit is observed. Strain application and transition period from non-load-bearing to full load-bearing can be modified by implants allowing dynamisation of compression and generating strains at the fracture healing site in a controlled manner.     

Implant fixation enhanced by intermittent treatment with parathyroid hormone

The intermittent administration of parathyroid hormone (PTH) increases the formation of bone by stimulating osteoblastic activity. Our study evaluates the possibility that intermittent treatment with PTH (1-34) may also enhance the implant-bone fixation of stainless-steel screws. Twenty-eight rats received one screw in either one (n = 8) or in both (n = 20) proximal tibiae. We administered either PTH (1-34) in a dosage of 60 microg/kg/day (n = 14) or vehicle (n = 14) over a period of four weeks. At the end of this time, the degree of fixation was assessed by measuring the removal torque on one screw in each rat (n = 28) and the pull-out strength on the contralateral screw (n = 20). PTH increased the mean removal torque from 1.1 to 3.5 Ncm (p = 0.001) and the mean pull-out strength from 66 to 145 N (p = 0.002). No significant differences in body-weight or ash weight of the femora were seen. Histological examination showed that both groups had areas of soft tissue at the implant-bone interface, but these appeared less in the PTH group. These results indicate that intermittent treatment with PTH may enhance the early fixation of orthopaedic implants.