The primary aetiology of periodontal diseases and chronic inflammation around dental implants is a bacterial infection [1]. In essence, a gram negative infection is necessary, but not sufficient to induce periodontal disease initiation or progression. Ultimately, it is the host’s reaction to the presence of the bacteria that mediates tissue destruction. Therefore, it is logical to consider therapeutic approaches that manipulate the host response, in addition to antibacterial approaches in the management of periodontitis and peri-implant disease.
This concept of host response modulation was introduced to dentistry by Williams and Golub [2]. Williams, in 1990, concluded that, “There are compelling data from animal and human trials which indicate that pharmacologic agents that modulate the host responses and are believed to be involved in the pathogenesis of periodontal destruction may be effective in slowing progression of periodontal disease” [3].
Various Host Modulatory Therapies (HMT) have been developed or proposed, with the goal of reducing tissue destruction and stabilizing or even regenerating the periodontium, by modifying or downregulating destructive aspects of host response and upregulating protective or regenerative responses.
Over the past two decades, a variety of pharmacological agents have been studied for their possible roles as host modulators in the management of periodontal disease. Three categories of host-modulating agents have been investigated in the periodontal therapy [4]:
Antiproteinases (which are represented by tetracyclines),
Anti-inflammatory drugs (Non-steroidal anti-inflammatory drugs, Statins, omega 3 fatty acids) and
Bone-sparing drugs (which are represented by antiresorptive agents such as bisphosphonates).
Recently, a fourth category has been postulated, namely, the ‘bone-forming drugs’, which includes teriparatide.
Teriparatide (Forsteo® or ForteoA®, Eli Lilly), a biosynthetic human parathyroid hormone, which consists of the first 34 amino acids of parathyroid hormone, is an anabolic agent. It has been known since 1932, that parathyroid hormone has anabolic effects on bone[5], but interest in its action lay dormant for almost 50 years until synthetic manufacturing of parathyroid hormone became possible in 1974. Multiple clinical trials have shown that teriparatide is associated with increased Bone Mineral Density (BMD). This review has focused on the mechanism of action of teriparatide and its potential role in periodontal regeneration.
Mechanism of Action
Endogenous Parathyroid Hormone (PTH), an 84-amino acid peptide, plays a central role in calcium and phosphate metabolism in the bone and kidney. Its physiological effects include stimulation of bone formation by directly affecting bone-forming cells (osteoblasts) and increasing renal tubular re-absorption of calcium and excretion of phosphate, and by indirectly increasing intestinal absorption of calcium via its effects on 1,25-dihydroxyvitamin D production [6].
Teriparatide and PTH mediate their biological effects via specific, G-protein-dependent, high-affinity membrane cell-surface receptors which are expressed on osteoblasts and renal tubular cells; both these molecules bind to the receptors with the same affinity and exert the same physiological effects on bone and kidney. It has been suggested that ligand binding induces a cascade that activates protein kinase-1, cyclic adenosine monophosphate, protein kinase C and phospholipase C. The activation of these pathways results in an increase in the number of active osteoblasts, a decrease in osteoblast apoptosis and probably, recruitment of bone lining cells as newly formed osteoblasts, thereby increasing bone strength, mass and diameter, and bone structural integrity, as well as increasing serum and urinary levels of markers of bone formation and resorption [6].
Other factors may also play a role in the anabolic effect of teriparatide. Basic fibroblast growth factor 2 (bFGF-2) is also up-regulated in teriparatide treated individuals [7]. Since bFGF-2 regulates the proliferation and differentiation of osteoblast progenitors, this cytokine could play an important role in the bone formative response to teriparatide therapy [8]. Also, the osteocytic Sclerostin (SOST) gene may be transcriptionally suppressed by PTH. As a result, reductions in sclerostin, a potent inhibitor of bone formation, could account for part of the anabolic response to PTH [9].
Continuous vs. Intermittent Debate
It has now been widely accepted that intermittent teriparatide is anabolic and that continuous endogenous PTH is catabolic. Although several mechanisms have been postulated for this observation, the exact mechanisms for these differential effects remain incompletely understood. Intermittent and low dosages of PTH, such as those which are achieved with a daily subcutaneous teriparatide administration, are believed to form, what has been termed as an ‘anabolic window’, a time during which bone formation is stimulated before a secondary increase in bone resorption occurs, resulting in an overall anabolic period [10]. In contrast, a continuous PTH infusion leads to a persistently and a markedly enhanced bone resorption and suppression of bone formation which results from its discordant effects on 1,25(OH)2 vitamin D, increased receptor activator of nuclear factor kappa-B ligand (RANKL) and decrease in osteoprotegerin (OPG) expression [10].
The effect of an intermittent teriparatide treatment not only increases trabecular thickness, but it also increases trabecular connectivity, as was verified by microcomputer tomography of transiliac bone biopsies [11].
Pharmacokinetic Properties
The bioavailability of teriparatide is approximately 95% after its subcutaneous administration. Maximum serum levels are achieved after approximately 30 min and its half-life is approximately 75 min as compared to a half-life of approximately 10 min. after an intravenous administration. Its serum levels are 20-30% lower in men as compared to those in women after the administration of subcutaneous injections. Teriparatide is metabolized in the liver and kidneys [12].
Outcomes of Various Preclinical Studies
Teriparatide increases the structural integrity of trabecular bone (Shen et al., 1993) [13] and it increases bone strength. (Mosekilde et al., 1991) [14]. The anabolic effects are pronounced in the trabecular bone and on the endosteal surface of cortical bone. In rat, cortical bone mass and strength are increased (Ejersted et al. 1993; Oxlund et al., 1993) [15,16]. In some species such as rat, little remodelling of cortical bone is seen. In contrast, a remodelling does occur in species such as monkeys, dogs, and rabbits and in these species, parathyroid hormone treatment increases cortical bone porosity, however, due to the concomitant increase in bone diameter (i.e. an anabolic effect on the periosteal surface), bone strength seems to be unaffected by the increased porosity (Mashiba et al., 2001) [17].
With the help of tissue engineering, teriparatide has been fused with various biomaterials like polyethylene glycol that are used to enhance bone generation and implant osseintegration. A study which was carried out on the acute defects which were created around dental implants in dogs at 2 weeks of healing, to evaluate the effect of PTH 1-34 which was covalently bound with a synthetic Polyethylene Glycol-based hydrogel, showed promising results [18].
Also, experimental studies which were done on rats have shown that teriparatide accelerates tooth movement during orthodontic tooth movements, by causing a three-fold increase in osteoclast number on the compression side and causing bone deposition on the tension side (Soma et al 1999) [19]. But previous studies do not support the use of this drug in orthodontic treatment, as no osteoclast mediated bone resorption was seen to produce any impact on tooth movement. (Schmidt et al 1995) [20].
Clinical Studies
Bashutski et al., in 2010, conducted a study to evaluate the effect of daily administration of teriparatide in conjuction with oral surgical procedures, on periodontal regeneration in men and women with severe periodontal disease. A total of 40 patients with severe periodontitis underwent periodontal surgeries and they received daily injections of teriparatide (20 μg) or placebo, along with calcium and vitamin D supplementation for a 6 week period. Significantly improved clinical and radiographic outcomes were achieved in patients who received teriparatide [21].
Another case which was reported by Bashutski in 2012, demonstrated that teriparatide administration, in conjunction with periodontal surgery, resulted in improved clinical and radiographic outcomes that were sustained for 4 years [22]. Another recent study assessed the osteogenic effect of teriparatide on various parts of the human skeleton and found that the mandible had one of the highest activity rates [23]. This may suggest as to why a systemic teriparatide administration resulted in such a high clinical success when it was used as an adjunct to an oral surgical procedure. Additionally, this suggests that the oral cavity may be one of the most receptive sites in the body to develop a response to teriparatide .
In conformation with the ‘anabolic window’, results from clinical trials showed that after commencing treatment with teriparatide, markers of bone formation were significantly increased sooner (from 1 month) than markers of bone resorption (from month 3) [24], thus indicating overall bone remodeling, with the net balance in favour of bone formation [25].
Other clinical trial which was conducted by using teriparatide at doses of 20 μg or 40 μg showed statistically significant results which were associated with the improved quality of non-vertebral cortical bone and improved geometry and distribution of the trabeculae within the bone. However, the effect of PTH on effective bone remodeling and stimulation of osteoblasts gradually wanes between 18 to 24 months, thus suggesting an ideal course of treatment at around 6-12 months [26].
Comparison with Other Drugs
Teriparatide (40μg/day i.e., a dosage which is higher than the approved dose) was compared head to head with alendronate (10mg/day) in a randomized, double blind trial. After 14 months of treatment, the increase in BMD, which was significantly higher in the teriparatide group, was more effective than alendronate in increasing bone formation marker levels from baseline (Body et al ., 2002) [27]. The higher rates of bone formation and resorption may be attributed to a large number of multicellular unit forming new bones, whereas alendronate therapy reduces both bone formation and resorption, thereby preserving the bone [28].
Hwang et al., compared teriparatide with calcitonin and concluded that BMD was significantly greater in patients who took teriparatide [29].Similar outcomes were obtained in various other studies (Kung et al.) [30].
Recker et al., compared the effects of 20μg/daily teriparatide and 2gm strontum ranelate on Procollagen type I N-terminal propeptide (PINP), a serum biomarker of bone formation. PINP levels increased significantly in the teriparatide group at 1 month and they increased till 6 months [31].
Sequential and Combined Treatment
Loss of bone mass which was gained during teriparatide treatment is the principal concern, following cessation of anabolic therapy. Teriparatide treatment is time restricted due to concerns which are related to osteosarcoma risk. Studies suggest that the bone loss which results after teriparatide cessation can be attenuated with antiresorptive treatment [32]. Patients who received at least 24 months of treatment with bisphosphonates during the 30 month post-teriparatide phase of the Fracture Prevention Trial, demonstrated further increases in BMD. In contrast, those who did not receive anti-resorptive treatment during the 30 month post-teriparatide treatment phase, demonstrated a reduction in BMD, that was not different from placebo (p < 0.05) [33]. Similar improvements in BMD were demonstrated in 2 studies which were done by using teriparatide, followed by raloxifene as compared to those which were done by using teriparatide, followed by placebo [34,35].
Adverse Effects
The FDA has issued a black-box warning because of the drug’s association with an increased incidence of osteosarcoma (a malignant bone tumour) in male and female rats. The effect was dependent on the dose and treatment durations and it was observed at systemic exposures to teriperatide which ranged from three to 60 times the exposure in humans who were given a 20-micro grams dose [36]. It should not be prescribed for patients who are at an increased risk for osteosarcoma at baseline, including those with Paget’s disease of bone or unexplained elevations of alkaline phosphatase, open epiphyses, or a previous radiation therapy which involved the skeleton.
Adverse drug events (ADEs) which are associated with teriparatide use include—but are not limited to—headache, asthenia, neck pain, hypertension, angina pectoris, syncope, nausea, constipation, dizziness, depression, insomnia, vertigo, hyperuricaemia, and hypercalcaemia. ADEs appear to increase with higher dosages.
According to the study of Body et al., significantly fewer patients who took teriparatide (5.5%) had a new or worsened back pain as compared to patients who took alendronate (19.2%), although six patients who took teriparatide and none who took alendronate reported leg cramps. In this study, 28 women who took teriparatide and two who received alendronate had elevated four-hour to six-hour post-dose serum calcium levels at least once, and one woman discontinued teriparatide treatment because of an increase in her serum calcium levels after taking the injection. The women with elevated serum calcium levels were asymptomatic, and these increases were not associated with clinically significant adverse outcomes [27].
Future Prospects
Periodontitis is a localized disease as compared to osteoporosis, and so, future strategies which are undertaken to optimize teriparatide administration could include local concentration at sites of osseous wound healing, to maximize benefits and to minimize systemic effects. However, it is challenging to develop a local delivery system that is able to deliver teriparatide at low and intermittent doses, which is what is required to achieve anabolic effects. Several local delivery systems have been developed already and they have been tested in preclinical animal models, with varying rates of success. In foxhounds, an arginine–glycine–aspartic acid modified polyethylene glycol-based matrix which contained covalently bound peptides of PTH, resulted in significantly more new bone formation but not more bone-to-implant contact after 4 and 12 weeks [37]. In contrast, a systemic PTH administration in a rat model was found to stimulate local bone formation, whereas a local delivery of PTH by using β-tricalcium phosphate did not [38]. There is a clear need for improved therapeutics that can target localized osseous healing as desired, to get periodontal regenerative outcomes.
Conclusion
The introduction of these anabolic agents has widened our treatment armamentarium in the management of periodontitis. Using systemic teriparatide as an adjunct to a periodontal surgery may project it as a promising host modulating agent, to promote osseous regeneration with long-term results. However, future large-scale clinical trials are needed in humans, to fine tune the indications and to answer questions which are related to safety, efficacy, optimum dosing and feasibility of local drug delivery systems and their optimum durations of use. Clarification of these important aspects could further improve the effectiveness of this drug.
[1]. Socransky SS, Haffajee AD, Evidence of bacterial etiology: A historical perspective Periodontol 2000 5:7-25.1994 [Google Scholar]
[2]. Kornman KS, Host modulation as a therapeutic strategy in the treatment of periodontal disease Clin Infec Dis 1999 28:520-24. [Google Scholar]
[3]. Williams RC, Periodontal disease N Engl J Med 1990 322:373-82. [Google Scholar]
[4]. Elavarasu S, Sekar S, Murugan T, Host modulation by therapeutic agents J Pharm Bioallied Sci 2012 4:S256-59. [Google Scholar]
[5]. Selye H, On the stimulation of new bone formation with parathyroid extract and irradiated ergosterol Endocrinology 1932 16:547-58. [Google Scholar]
[6]. Blick SK, Dhillon S, Keam SJ, Teriparatide: a review of its use in osteoporosis Drugs 2008 68:2709-37. [Google Scholar]
[7]. Hurley M, Yao W, Lane NE, Changes in serum fibroblast growth factor 2 in patients with glucocorticoid-induced osteoporosis treated with human parathyroid hormone (1-34) Osteoporos Int 2005 16:2080-84. [Google Scholar]
[8]. Mayahara H, Ito T, Nagai H, Miyajima H, Tsukuda R, In vivo stimulation of endosteal bone formation by basic fibroblast growth factor in rats Growth Factors 1993 9:73-80. [Google Scholar]
[9]. Kramer I, Keller H, Leupin O, Kneissel M, Does osteocytic SOST suppression mediate PTH bone anabolism? Trends Endocrinol Metab 2010 21:237-44. [Google Scholar]
[10]. Dhillon RS, Schwarz EM, Teriparatide therapy as an adjuvant for tissue engineering and integration of biomaterials Materials 2011 4:1117-31. [Google Scholar]
[11]. Jiang Y, Zhao JJ, Mitlak BH, Wang O, Genant HK, Recombinant human parathyroid hormone (1-34) [teriparatide] improves both cortical and cancellous bone structure J Bone Miner Res 2003 18:1932-41. [Google Scholar]
[12]. Brixen KT, Christensen PM, Ejersted C, Langdahl BL, Teriparatide (biosynthetic human parathyroid hormone 1-34): a new paradigm in the treatment of osteoporosis Basic Clin Pharmacol Toxicol 2004 94:260-70. [Google Scholar]
[13]. Shen V, Dempster DW, Birchman R, Xu R, Lindsay R, Loss of cancellous bone mass and connectivity in ovariectomized rats can be restored by combined treatment with parathyroid hormone and estradiol J Clin Invest 1993 91:2479-87. [Google Scholar]
[14]. Mosekilde L, Sogaard CH, Danielsen CC, Torring O, The anabolic effects of human parathyroid hormone (hPTH) on rat vertebral body mass are also reflected in the quality of bone, assessed by biomechanical testing: a comparison study between hPTH-(1–34) and hPTH-(1-84) Endocrinology 1991 129:421-28. [Google Scholar]
[15]. Ejersted C, Andreassen TT, Oxlund H, Jorgensen PH, Bak B, Human parathyroid hormone (1-34) and (1-84) increase the mechanical strength and thickness of cortical bone in rats J Bone Miner Res 1993 8:1097-101. [Google Scholar]
[16]. Oxlund H, Ejersted C, Andreassen TT, Torring O, Nilsson MH, Parathyroid hormone (1-34) and (1-84) stimulate cortical bone formation both from periosteum and endosteum Calcif Tissue Int 1993 53:394-99. [Google Scholar]
[17]. Mashiba T, Burr DB, Turner CH, Sato M, Cain RL, Effects of human parathyroid hormone (1–34), LY333334, on bone mass, remodeling, and mechanical properties of cortical bone during the first remodeling cycle in rabbits Bone 2001 28:538-47. [Google Scholar]
[18]. Valderrama P, Jung ER, Thoma SD, Jones AA, Cochran LD, Evaluation of parathyroid hormone bound to a synthetic matrix for guided bone regeneration around dental implants: a histomorphometric study in dogs J Periodontol 2010 81:737-47. [Google Scholar]
[19]. Soma S, Iwamoto M, Higuchi Y, Kurisu K, Effects of continuous infusion of PTH on experimental tooth movement in rats J Bone Miner Res 1999 14:546-54. [Google Scholar]
[20]. Schmidt IU, Dobnig H, Turner RT, Intermittent parathyroid hormone treatment increases osteoblast number, steady state messenger ribonucleic acid levels for osteocalcin, and bone formation in tibial metaphysis of hypophysectomized female rats Endocrinology 1995 136:5127-34. [Google Scholar]
[21]. Bashutski JD, Eber RM, Kinney JS, Benavides E, Maitra S, Teriparatide and Osseous Regeneration in the Oral Cavity N Engl J Med 2010 363:2396-405. [Google Scholar]
[22]. Bashutski JD, Kinney JS, Benavides E, Maitra S, Braun TM, Systemic Teriparatide Administration Promotes Osseous Regeneration of an Intrabony Defect: A Case Report Clin Adv Periodontics 2012 2:66-71. [Google Scholar]
[23]. Moore AE, Blake GM, Taylor KA, Assessment of regional changes in skeletal metabolism following 3 and 18 months of teriparatide treatment J Bone Miner Res 2010 25:960-67. [Google Scholar]
[24]. Deal C, Omizo M, Schwartz EN, Combination teriparatide and raloxifene therapy for postmenopausal osteoporosis: results from a 6-month double-blind placebo-controlled trial. and cancellous bone structure J Bone Miner Res 2005 20:1905-11. [Google Scholar]
[25]. Chen P, Satterwhite JH, Licata AA, Early changes in biochemical markers of bone formation predict BMD response to teriparatide in postmenopausal women with osteoporosis J Bone Miner Res 2005 20:962-70. [Google Scholar]
[26]. Aggarwal P, Zavras A, Parathyroid hormone and its effects on dental tissues Oral Dis 2012 18:48-54. [Google Scholar]
[27]. Body JJ, Gaich GA, Scheele WH, Kulkarni PM, Miller PD, A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1–34)] with alendronate in postmenopausal women with osteoporosis J Clin. Endocrinol Metab 2002 87:4528-35. [Google Scholar]
[28]. Arlot M, Meunier PJ, Boivin G, Haddock L, Tamayo J, Differential effects of teriparatide and alendronate on bone remodeling in postmenopausal women assessed by histomorphometric parameters J Bone Miner Res 2005 20:1244-53. [Google Scholar]
[29]. Hwang JS, Tu ST, Yang TS, Teriparatide vs. calcitronin in the treatment of Asian postmenopausal women with established osteoporosis Osteoporos Int 2006 17:373-78. [Google Scholar]
[30]. Kung AWC, Pasion EG, Sofiyan M, A comparison of teriparatide and calcitronin therapy in postmenopausal Asian women with osteoporosis: a 6 month study Curr Med Res Opin 2006 22:929-37. [Google Scholar]
[31]. Recker RR, Marin F, Ish-Shalom S, Möricke R, Hawkins F, Comparative effects of teriparatide and strontium ranelate on bone biopsies and biochemical markers of bone turnover in postmenopausal women with osteoporosis J Bone Miner Res 2009 24:1358-68. [Google Scholar]
[32]. Inderjeet CA, Chan K, Giendenning P, Teriparatide: its use in the treatment of osteoporosis. Clinical Medicine Insights Therapeutics 2011 3:67-80. [Google Scholar]
[33]. Sipos PR, Hosain AA, Sustained nonvertebral fragility fracture risk reduction after discontinuation of teriparatide treatment J Bone Miner Res 2005 20:1507-13. [Google Scholar]
[34]. Adami S, Martin JS, Munoz-Torres M, Effect of raloxifene after recombinant teriparatide [hTPTH (1-34)] treatment in post-menopausal women with osteoporosis Osteoporos Int 2008 19:87-94. [Google Scholar]
[35]. Minne H, Audran M, Simoes ME, Bone density after teriparatide in patients with or without prior antiresorptive treatment: one-year results from EUROFORS study Curr Med Res Opin 2008 24:3117-28. [Google Scholar]
[36]. Subbiah V, Madsen VS, Raymond AK, Benjamin RS, Ludwig JA, Of mice and men: Divergent risks of teriparatide-induced osteosarcoma Osteoporos Int 2010 21:1041-45. [Google Scholar]
[37]. Jung RE, Cochran DL, Domken O, The effect of matrix bound parathyroid hormone on bone regeneration Clin Oral Implants Res 2007 18:319-25. [Google Scholar]
[38]. Yun JI, Wikesjo UM, Borke JL, Effect of systemic parathyroid hormone (1-34) and a beta-tricalcium phosphate biomaterial on local bone formation in a critical-size rat calvarial defect model J Clin Periodontol 2010 37:419-26. [Google Scholar]