Teriparatide: A bone formation treatment for osteoporosis

Teriparatide is the recombinant human N-terminal fragment (1-34) of endogenous human parathyroid hormone, and it is the first bone anabolic agent for the treatment of osteoporosis. When given as once-daily subcutaneous injections, teriparatide can reverse the course of osteoporosis by stimulating formation of new bone and restoring lost architecture. Teriparatide (20 microg) treatment of osteoporosis in postmenopausal women rapidly increased markers of bone formation and reduced the incidence of vertebral fractures by 65% and of nonvertebral fragility fractures by 53%. In addition, treatment with this compound increased spine bone mineral density by 10% and hip bone mineral density by 3% at study endpoint. Teriparatide is well tolerated and is not associated with any serious side effects. The compound has been approved in Europe and in the US for the treatment of osteoporosis. Duration of treatment is 18-24 months and the dose does not need to be adjusted for age or gender.     

A review of teriparatide and its clinical efficacy in the treatment of osteoporosis

Until recently, antiresorptive medications such as bisphosphonates and raloxifene represented the main pharmacological treatment options for patients with osteoporosis. With the introduction of teriparatide (rhPTH_(1–34)), a recombinant formulation of parathyroid hormone (PTH) consisting of the first 34 amino acids of the N-terminal region, bone-forming therapy has now become possible. Preclinical, as well as human studies, have shown increases in trabecular as well as cortical bone mass with subsequent improvements in bone microstructure and cortical thickness. The subcutaneous daily dose of teriparatide 20 μg has been shown to decrease the occurrence of new vertebral fractures in caucasian women (70 years of age) by 65%, in a large randomised, double-blind placebo-controlled trial. Moderate-to-severe fractures or multiple vertebral fractures could be reduced by 90 and 77%, respectively. There was also a significant beneficial effect on new nonvertebral fractures (-35%) by the end of the 21-month treatment period. The reduction in nonvertebral fractures became evident after ～ 8 – 12 months of treatment. Smaller studies in men with low bone mass showed similar effects on bone mineral density and changes in bone turnover markers when compared to the results obtained in postmenopausal women. Recent data suggest that teriparatide is best given as monotherapy and not in combination with a bisphosphonate. Previous bisphosphonate treatment is also likely to diminish the bone anabolic potential of teriparatide. In order to preserve bone mass gained during the recommended 18- to 24-month treatment period, antiresorptive medication should be prescribed following teriparatide treatment. Studies so far have not shown serious PTH-related side effects. Hypercalcaemia is usually mild and transient and the osteosarcoma risk reported in rat toxicology studies is very unlikely to be predictive of a similar risk in humans. As teriparatide is expensive, its use at the moment should be limited to patients with more severe forms of osteoporosis, usually with the presence or history of one or more fractures because of those patients’ high risk for subsequent fractures.     

A review of teriparatide and its clinical efficacy in the treatment of osteoporosis

Until recently, antiresorptive medications such as bisphosphonates and raloxifene represented the main pharmacological treatment options for patients with osteoporosis. With the introduction of teriparatide (rhPTH (1-34) ), a recombinant formulation of parathyroid hormone (PTH) consisting of the first 34 amino acids of the N -terminal region, bone-forming therapy has now become possible. Preclinical, as well as human studies, have shown increases in trabecular as well as cortical bone mass with subsequent improvements in bone microstructure and cortical thickness. The subcutaneous daily dose of teriparatide 20 microg has been shown to decrease the occurrence of new vertebral fractures in caucasian women (70 years of age) by 65%, in a large randomised, double-blind placebo-controlled trial. Moderate-to-severe fractures or multiple vertebral fractures could be reduced by 90 and 77%, respectively. There was also a significant beneficial effect on new nonvertebral fractures (-35%) by the end of the 21-month treatment period. The reduction in nonvertebral fractures became evident after approximately 8 - 12 months of treatment. Smaller studies in men with low bone mass showed similar effects on bone mineral density and changes in bone turnover markers when compared to the results obtained in postmenopausal women. Recent data suggest that teriparatide is best given as monotherapy and not in combination with a bisphosphonate. Previous bisphosphonate treatment is also likely to diminish the bone anabolic potential of teriparatide. In order to preserve bone mass gained during the recommended 18- to 24-month treatment period, antiresorptive medication should be prescribed following teriparatide treatment. Studies so far have not shown serious PTH-related side effects. Hypercalcaemia is usually mild and transient and the osteosarcoma risk reported in rat toxicology studies is very unlikely to be predictive of a similar risk in humans. As teriparatide is expensive, its use at the moment should be limited to patients with more severe forms of osteoporosis, usually with the presence or history of one or more fractures because of those patients' high risk for subsequent fractures.     

Prevention of glucocorticoid-induced osteoporosis

Glucocorticoid-induced osteoporosis is the most common cause of secondary osteoporosis. The role of the Wnt signaling pathway in bone formation and the ratio of receptor activator for NF-κB ligand versus osteoprotegerin in bone resorption are exciting new insights. The absolute fracture risk helps both clinicians and patients to interpret the results of bone density measurement, which may have a positive influence on adherence to therapy. The bisphosphonates alendronate and risedronate are the first-line treatment in the prevention of glucocorticoid-induced osteoporosis, because both increase the bone mineral density of the spine and hips and reduce the vertebral fracture rate. Treatment with the anabolic agent parathyroid hormone (1 – 34) strongly stimulates bone turnover, and seems to be superior to treatment with alendronate. It might be attractive for glucocorticoid-treated patients with new vertebral fractures during treatment with bisphosphonates, and/or with severe fracture risk.     

Severe hypercalcemia due to teriparatide

Osteoporosis that is by far the most common metabolic bone disease, has been defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Anabolic therapy with teriparatide, recombinant human parathyroid hormone (PTH 1-34), stimulates bone formation and resorption and improves trabecular and cortical microarchitecture. Teriparatide is indicated for the treatment of men and postmenopausal women with osteoporosis who are at high risk for fracture, including those who have failed or are intolerant of previous osteoporosis therapy. In conclusion, although teriparatide seems quite effective in the treatment of osteoporosis, it may cause life-threatening hypercalcemia. Therefore, patients should be closely monitored if symptoms of hypercalcemia are present during teriparatide treatment. Sustained hypercalcemia due to teriparatide treatment can not be seen in literature so we wanted to emphasize that severe hypercalcemia may develop due to teriperatide.     

Parathyroid hormone as an anabolic skeletal therapy

The quest for effective treatment for osteoporosis merits great attention because of the widespread prevalence of this disease, which is not only associated with fragility fractures, but also with significant morbidity and mortality. The efficacy of the antiresorptive drugs in this disease is achieved by reducing bone turnover, increasing bone density and improving other aspects of bone quality. This article concentrates on another approach to the treatment of osteoporosis, namely the use of anabolic therapy, which has even greater prospects for improving bone quality.Parathyroid hormone (PTH) is currently available only as the recombinant amino-terminal fragment, PTH(1-34), known as teriparatide. The full-length molecule, human PTH(1-84), is currently being investigated, as are other PTH molecules. Teriparatide improves bone quality through actions on bone turnover, bone density, bone size and bone microarchitecture. In postmenopausal women with osteoporosis, teriparatide reduces the incidence of vertebral and nonvertebral fractures. In individuals who have previously been treated with an antiresorptive agent, the subsequent actions of teriparatide on bone density are transiently delayed if bone turnover has been markedly suppressed. Combination therapy with teriparatide or PTH(1-84) and an antiresorptive agent does not appear, at this time, to offer advantages over the use of PTH or an antiresorptive agent alone. However, in order to maintain the densitometric gains in bone density obtained with PTH, it is important to follow its use with that of an antiresorptive agent.     

Teriparatide for postmenopausal osteoporosis

Teriparatide (Forsteo - Eli Lilly) is the first parathyroid hormone derivative to be licensed for the treatment of women with postmenopausal osteoporosis. It is described as a "bone-formation agent", in contrast to established treatments, such as bisphosphonates, raloxifene, calcitriol and calcitonin, which reduce bone resorption. Here we consider whether teriparatide offers any worthwhile advantages over these other options.     

The role of the liver and kidneys in the pharmacokinetics of subcutaneously administered teriparatide acetate in rats

Teriparatide acetate, a synthetic polypeptide fragment consisting of human parathyroid hormone residues 1-34 [hPTH(1-34)], is a bone anabolic agent used to treat osteoporosis. The present study was conducted to characterise the pharmacokinetics of teriparatide acetate in rats after subcutaneous administration. Teriparatide was rapidly absorbed into the circulation and eliminated immediately. No intact teriparatide was detected in the urine. To elucidate the mechanism of teriparatide metabolism, we performed in vivo and in vitro studies using the radiolabelled bioactive analogue, [(125)I]-[Nle(8,18),Tyr(34)]-hPTH(1-34). After subcutaneous administration, the concentration of analogue metabolites increased in the plasma time-dependently. The concentration in the kidneys was more than 3-fold the concentration in the liver. In vitro analyses suggested that kidney radioactivity was associated with degraded bioactive analogue. In model rats, renal failure, but not hepatic failure, affected the pharmacokinetics of teriparatide acetate, which accounted for the decrease in the clearance of teriparatide. In conclusion, our results suggest that after subcutaneous administration of teriparatide acetate, teriparatide is rapidly absorbed and distributed to the liver or kidneys, where it is immediately degraded. The kidneys play a particularly important role in the distribution and metabolism of teriparatide, but not its excretion.     

Present and future pharmacotherapy for osteoporosis

Although neither calcium nor vitamin D has been shown to prevent osteoporosis in postmenopausal women alone, the combination does. Both calcium and vitamin D are commonly used in the treatment of osteoporosis. The estrogens and raloxifene both prevent bone loss in postmenopausal women, and the estrogens probably also decrease the risk of first fracture. There is good evidence that raloxifene prevents further fractures in postmenopausal women who have already had fractures and some evidence that estrogen does as well. Calcitonin increases bone mineral density in early postmenopausal women and men with idiopathic osteoporosis, and also reduces the risk of new fractures in osteoporotic women. The bisphosphonate alendronate prevents bone loss and reduces fractures in healthy and osteoporotic postmenopausal women, and in osteoporotic men. Risedronate is more potent and has fewer upper gastrointestinal side effects than alendronate, and reduces the incidence of fractures in osteoporotic women. Intermittent use of the potent bisphosphonate zoledronate also increases bone mineral density and may become an alternative in the prevention and treatment of osteoporosis. All of the agents discussed above prevent bone resorption, whereas teriparatide increases bone formation and is effective in the treatment of osteoporotic women and men. In the treatment of secondary osteoporosis associated with the use of glucocorticoids to treat inflammation or prevent rejection after transplantation, the bisphosphonates are effective. The agents that have undergone some clinical trialing as new or alternative drugs for the treatment of osteoporosis include tibolone, new SERMs, androgens, growth hormone, insulin-like growth factor-1 and stontium ranelate. The targets/drugs that are being developed to inhibit bone resorption include the OPG/ RANKL/RANK system, cathepsin K inhibitors, vitronectin receptor antagonists, estren, the interleukin-6 and gp130 system, cytokines and growth factors. New drugs/targets to promote bone formation include the commonly used lipid-lowering statins and the calcilytic release of PTH.     

Development of an algorithm for using PINP to monitor treatment of patients with teriparatide

INTRODUCTION: Teriparatide effects are mediated via the preferential stimulation of osteoblastic activity over osteoclastic activity. Amino-terminal propeptide of type I procollagen (PINP) is an indicator of osteoblastic activity. OBJECTIVE: Develop an algorithm using PINP as an aid in the management of patients with postmenopausal osteoporosis treated with teriparatide. RESEARCH DESIGN AND METHODS: For inclusion in this post-hoc analysis, trials had to be investigations of teriparatide 20 microg/day in postmenopausal women with osteoporosis having measurements of PINP at 3 months and bone mineral density (BMD) at 12 months. Signal-to-noise ratio was calculated for a series of markers of bone turnover in the Fracture Prevention Trial. An algorithm was developed to monitor patients treated with teriparatide using PINP. RESULTS: Three trials met inclusion criteria and included the Fracture Prevention, Forteo-Alendronate Comparator and Anabolic After Antiresorptive trials. PINP had the highest signal-to-noise ratio of all bone-turnover markers. Positive PINP responses defined as increases > 10 microg/L were observed in 77-79% of teriparatide- and in 6% of placebo-treated patients after 3 months of study drug. Mean lumbar spine BMD increases after 12 months of teriparatide in patients having PINP changes > 10 microg/L ranged from 8.3% to 9.5% and in patients with PINP changes < or = 10 microg/L ranged from 5.9% to 7.6%.In the algorithm, PINP is measured at baseline and after 1-3 months of therapy. Patients with PINP increases > 10 microg/L are given a positive message. Patients with PINP increases < or = 10 microg/L are assessed for adherence, teriparatide administration and storage techniques, and for the presence of medical conditions that might limit their therapeutic response, and these issues are addressed as appropriate. Patients without these issues and with PINP increases < or = 10 microg/L should be given a neutral message because BMD may significantly increase with continued therapy. CONCLUSIONS: The PINP algorithm provides information regarding the anabolic response to teriparatide therapy and has the potential to identify patients requiring help with issues of adherence, injection technique, teriparatide storage, and medical problems limiting therapeutic responsiveness to teriparatide treatment. Data assessing the relationship of changes in PINP to fracture risk reduction are not available. We recommend physicians audit the use of the algorithm in practice so that improvements can be made.     

Antifracture efficacy of currently available therapies for postmenopausal osteoporosis

Osteoporosis is a systemic bone disease characterized by low bone mass and bone mineral density, and deterioration of the underlying structure of bone tissue. These changes lead to an increase in bone fragility and an increased risk for fracture, which are the clinical consequences of osteoporosis. The classical triad for consideration in osteoporosis is morbidity, mortality and cost. Vertebral fracture is an important source of morbidity in terms of pain and spinal deformity. On the other hand, hip fracture is associated with the worst outcomes and is widely regarded as a life-threatening event in the elderly; it is the source of the bulk of the cost of the disease in contemporary healthcare. The prevention of osteoporosis-associated fracture should include fall prevention, calcium supplementation and lifestyle advice, as well as pharmacological therapy using agents with proven antifracture efficacy. The most commonly used osteoporosis treatments in Europe are the bisphosphonates alendronate, risedronate, ibandronate and zoledronic acid; the selective estrogen receptor modulator (SERM) raloxifene; teriparatide; and strontium ranelate. Recent additions include the biological therapy denosumab and the SERM bazedoxifene. In this review, we explore the antifracture efficacy of these agents with the aim of simplifying treatment decisions. These treatments can be broadly divided according to their mode of action. The antiresorptive agents include the bisphosphonates, the SERMs and denosumab, while the bone-forming agents include parathyroid hormone and teriparatide. Strontium ranelate appears to combine both antiresorptive and anabolic activities. We collated data on vertebral and hip fracture efficacy from the pivotal 3-year phase III trials, all of which had a randomized, double-blind, placebo-controlled design. The relative reductions in risk in the osteoporosis trials range from 30% to 70% for vertebral fracture and 30% to 51% for hip fracture. This translates into 3-year number needed to treat values of between 9 and 21 for vertebral fracture and from 48 upwards for hip fracture. International guidelines agree that agents that have been shown to decrease vertebral, nonvertebral and hip fractures should be used preferentially over agents that only demonstrate vertebral antifracture efficacy. This is the case for alendronate, risedronate, zoledronic acid, denosumab and strontium ranelate. Finally, therapeutic decisions should be based on a balance between benefits and risks of treatment, which must be carefully considered in each particular case both by the physician and the patient. Indeed, no single agent is appropriate for all patients and, therefore, treatment decisions should be made on an individual basis, taking into account all measures of treatment effect and risk before making informed judgments about the best individual treatment option.     

Does the combination of alendronate and parathyroid hormone give a greater benefit than either agent alone in osteoporosis?

In osteoporosis, both the bisphosphonate alendronate and parathyroid hormone (1-34) (PTH (1-34) ) have been shown to reduce the incidence of fractures. As bisphosphonates and PTH have different mechanisms, it has been proposed that their effects in osteoporosis may be additive. However, a major clinical trial of PTH (1-84) and alendronate in postmenopausal women demonstrated that their effects were not additive. A further trial in men with osteoporosis showed that alendronate impaired the ability of PTH (1-34) to increase bone mineral density. The combination of alendronate and PTH does not have greater benefit than either agent alone, and may even be detrimental, thus should not be used.     

特立帕肽联合阿仑膦酸钠治疗绝经后骨质疏松症的临床研究

目的探讨特立帕肽联合阿仑膦酸钠治疗绝经后骨质疏松症的临床疗效。方法选取2014年1月—2015年6月天津中医药大学第一附属医院收治的绝经后骨质疏松症患者140例,随机分为对照组和治疗组,每组各70例。对照组患者口服阿仑膦酸钠片,1片/次,1次/d。治疗组在对照组治疗基础上皮下注射特立帕肽注射液,20μg/次,1次/d。两组患者均连续治疗6个月。观察两组患者治疗前后骨密度和骨代谢指标的变化情况。结果治疗组治疗3个月时腰椎骨密度相对于治疗前有明显上升,全髋与股骨颈骨密度则无明显变化,治疗组治疗6个月时腰椎、全髋、股骨颈骨密度均明显上升,同组治疗前后差异具有统计学意义(P0.05);对照组治疗3个月各部位骨密度均未出现明显上升,治疗6个月腰椎骨密度较治疗前有明显上升(P0.05)。治疗组治疗6个月时腰椎、全髋、股骨颈骨密度改善情况明显优于对照组,两组比较差异有统计学意义(P0.05)。治疗组治疗3、6个月血清骨钙素(OC)水平逐渐上升,均明显高于治疗前,同组治疗前后差异具有统计学意义(P0.05);对照组则逐渐下降,均明显低于治疗前(P0.05);治疗组治疗3、6个月血清Ⅰ型胶原羧基端肽交联(β-CTX)水平逐渐下降,对照组也逐渐下降,对照组下降幅度则明显大于治疗组(P0.05)。结论特立帕肽联合阿仑膦酸钠治疗绝经后骨质疏松症具有较好的临床疗效,可增加患者的骨密度,可有效改善骨代谢,具有一定的临床推广应用价值。     

特立帕肽在行腰椎融合术骨质疏松患者中的应用

近年来行腰椎融合术的老年患者不断增加,老年患者常合并有骨质疏松,是椎体融合的不利因素,会增加骨科术后并发症的发生风险.特立帕肽即重组人甲状旁腺激素1-34,可促进骨形成,临床用于治疗有骨折高风险的重度骨质疏松患者.有研究表明,特立帕肽可提高行腰椎融合术骨质疏松患者的腰椎植骨融合率、缩短融合时间,并可增加内植物稳定性,且...     

Osteosarcoma in Sprague-Dawley rats after long-term treatment with teriparatide (human parathyroid hormone (1-34))

Teriparatide, a therapeutic agent for osteoporosis, has been reported to increase the incidences of bone neoplasms such as osteosarcoma when administered subcutaneously to Fischer 344 (F344) rats for a long term, but its non-carcinogenic dose level following 2-year daily administration has not been established. Here we report detailed studies on the carcinogenicity of teriparatide following long-term administration. When teriparatide was administered subcutaneously to male and female Sprague-Dawley (SD) rats daily for 2 years, the incidence of osteosarcoma was increased at 13.6 μg/kg/day. The non-carcinogenic dose level was 4.5 μg/kg/day for both males and females. The development of osteosarcoma in SD rats depends on the dose level of, and treatment duration with, teriparatide. Responses of the bones to teriparatide were similar between F344 and SD rats in many aspects. These results suggested that the carcinogenic potential of teriparatide in SD rats is essentially the same as in F344 rats.     

Teriparatide: new preparation. Osteoporosis: less well evaluated than alendronic acid

(1) Oral alendronic acid is the reference drug for women with osteoporosis and a previous vertebral fracture. In a placebo-controlled trial in women who were also taking calcium and vitamin D, treatment with alendronic acid for three years reduced the incidence of symptomatic vertebral fractures (2.3% versus 5%) and wrist fractures (2.2% versus 4.1%) and, albeit with a lower level of evidence, the incidence of hip fractures (1.1% versus 2.2%). (2) Teriparatide, a biotech drug, reproduces the 34 N-terminal amino acids of parathormone. It is marketed in Europe for subcutaneous treatment of "proven" postmenopausal osteoporosis. (3) The cornerstone of the clinical evaluation dossier is a randomised placebo-controlled double-blind trial in 1637 women also taking calcium and vitamin D. The two doses of teriparatide (20 micrograms/day and 40 micrograms/day), given for a median of 19 months, reduced the risk of new radiologically documented vertebral fractures (about 4% versus 14% in the placebo group) and spinal pain (about 16% versus 23% in the placebo group), but not the risk of hip fracture. (4) In a double-blind trial in 146 postmenopausal women also taking calcium and vitamin D, 40 micrograms/day teriparatide given subcutaneously for 14 months increased spinal mineral bone density significantly more than 10 mg/day alendronic acid given orally. The trial was not designed to show a difference in clinical outcome (fractures). (5) The main adverse effects of teriparatide reported to date are nausea, headache, cramp, hypercalcemia and hyperuricemia. (6) A rat study showed an increased risk of osteosarcoma. This tumour is rare in humans, and the number of patients so far enrolled in clinical trials is insufficient to document a possible increase in risk associated with teriparatide. (7) The need for daily subcutaneous injections and for refrigeration of the prefilled syringes are two notable disadvantages of teriparatide therapy. (8) In practice, alendronic acid is better assessed and remains the reference treatment, combined with calcium and vitamin D, for secondary prevention of osteoporotic fracture in postmenopausal women.     

Combination antiresorptive and osteoanabolic therapy for osteoporosis: we are not there yet

Osteoanabolic therapy is theoretically and practically an appealing therapeutic option for men and postmenopausal women with osteoporosis because bone formation is directly stimulated, an action that is not shared by any antiresorptive agent. Parathyroid hormone (PTH), in the form of the full-length molecule (PTH[1-84]) and its fully active but truncated amino-terminal fragment teriparatide (PTH[1-34]), belong to this osteoanabolic class. Both formulations of PTH increase bone mineral density, increase biochemical markers of bone turnover, and reduce fracture incidence. They improve skeletal microstructure. While antiresorptive agents are considered by most to be first line for the treatment of osteoporosis, there are situations when anabolic therapy could be reasonably considered as first line. In most situations, however, treatment with PTH follows a course of antiresorptive therapy. Simultaneous combination therapy with PTH and an antiresorptive drug does not appear to provide any advantages over monotherapy. After the recommended 2-year period of PTH treatment, an antiresorptive should be used to maintain densitometric gains. The drugs are well tolerated. Early safety concerns about osteosarcoma in rats have not been borne out after almost 9 years experience with human subjects.     

The novel non-steroidal selective androgen receptor modulator S-101479 has additive effects with bisphosphonate, selective estrogen receptor modulator, and parathyroid hormone on the bones of osteoporotic female rats

We have studied non-steroidal selective androgen receptor modulators (SARMs) to develop anti-osteoporosis drugs for males and females. Many SARMs have been studied for their anabolic effects on bone or muscle with reduced virilizing effects in male animals. However, the tissue selectivities of these agents in female animals have not been fully evaluated. We evaluated the novel SARM S-101479 from tetrahydroquinoline libraries in ovariectomized (OVX) rats. S-101479 preferentially bound to the androgen receptor with nanomolar affinity among nuclear receptors. It increased the bone mineral density (BMD) of femurs and diminished the effects on the uterus and clitoral gland in OVX rats. We then compared the effect of S-101479 on bone with those of commercial anti-osteoporosis drugs such as alendronate, raloxifene, and teriparatide. Furthermore, we evaluated the effects of combination treatments with these agents in OVX rats. After 16-week treatment, all agents significantly increased BMD, but the magnitude of bone mineral content (BMC) and/or bone size (projected bone area) were different. Alendronate, raloxifene, and teriparatide maintained BMC and bone size in this experimental dose. Only S-101479 increased BMC with bone size on single treatments. In combination treatment, S-101479 significantly increased BMC and bone size compared with single treatments of other agents. S-101479, like natural androgen, may have showed periosteal bone formation of the cortical area and indicated additive effects with commercial anti-osteoporosis drugs. These results indicate that S-101479 may be a useful anti-osteoporosis drug, particularly for patients with established severe osteoporosis.     

Degradation of teriparatide by gastro-intestinal proteolytic enzymes

Teriparatide, a recombinant parathyroid hormone (1-34) is the first approved agent for the treatment of osteoporosis that stimulates new bone formation. Currently, the drug is administered daily by s.c. injection. Because of the obvious advantages of oral teriparatide administration, the development of such a delivery system would be of great benefit. Besides other barriers, the enzymatic barrier caused by gastro-intestinal (GI) proteolytic enzymes is believed to be responsible for negligible teriparatide oral bioavailability. It was therefore the aim of the study to evaluate the stability of teriparatide towards a variety of GI proteases under physiological conditions. Results indicate that teriparatide is entirely degraded by trypsin, chymotrypsin and pepsin within 5 min. In contrast, even after 3 h of incubation with elastase about 85% of undegraded teriparatide could still be detected. Within an incubation period of 3 h in the presence of rat small intestinal mucosa, approximately half of the teriparatide was degraded. Experiments with isolated aminopeptidase N demonstrated that this membrane bound peptidase is primarily involved in the degradation process. Results gained from and recorded in this study provide a precise characterisation of the enzymatic barrier for oral teriparatide administration and represents a prerequisite for the development of oral teriparatide delivery systems.