The first biosimilar approved for the treatment of osteoporosis: results of a comparative pharmacokinetic/pharmacodynamic study.

To demonstrate the clinical comparability between RGB-10 (a biosimilar teriparatide) and the originator, a comparative pharmacokinetic trial was conducted. The study was successful in establishing bioequivalence. Marketing authorisation for RGB-10 (Terrosa®) was granted by the European Medicines Agency in 2017. INTRODUCTION: Teriparatide, the first bone anabolic agent, is the biologically active fragment of human parathyroid hormone. The imminent patent expiry of the originator will open the door for biosimilars to enter the osteology market, thereby improving access to a highly effective, yet prohibitively expensive therapy. METHODS: Subsequent to establishing comparability on the quality and non-clinical levels between RGB-10, a biosimilar teriparatide, and its reference product (Forsteo®), a randomised, double-blind, 2-way cross-over comparative study (duration: four days) was conducted in 54 healthy women (ages: 18 to 55 years) to demonstrate the pharmacokinetic/pharmacodynamic (PK/PD) equivalence and comparable safety of these products. Extents of exposure (AUC0-tlast) and peak exposure (Cmax), as measured by means of ELISA, were evaluated as co-primary PK endpoints, and serum calcium levels, as measured using standard automated techniques, were assessed for PD effects. Safety was monitored throughout the study. RESULTS: The 94.12% CIs for the ratio of the test to the reference treatments, used due to the two-stage design (85.20-98.60% and 85.51-99.52% for AUC0-tlast and Cmax, respectively), fell within the 80.00-125.00% acceptance range. The calcium PD parameters were essentially identical with geometric mean ratios (GMRs) of 99.93% and 99.87% for AUC and Cmax, respectively. Analysis of the safety data did not reveal any differences between RGB-10 and its reference. CONCLUSION: Based on the high level of similarity in the preclinical data and the results of this clinical study, marketing authorisation for RGB-10 (Terrosa®) was granted by the European Medicines Agency (EMA) in 2017.

Calcium-Triggered Pulsatile Delivery of Parathyroid Hormone from Microbeads for Osteoporosis Treatment.

Recombinant human parathyroid hormone 1-34 (rhPTH 1-34) is the most potent anabolic drug recommended for patients with osteoporosis who do not respond to conventional treatment. However, subcutaneous intermittent injection is the only effective regimen due to its unusual action of mechanism. This regimen is inconvenient and is a big hurdle in clinical applications. In this study, we designed polyelectrolyte microbeads that can deliver rhPTH 1-34 in response to Ca2+ concentration, which indicates the osteoporotic status. Dextran photopolymer was synthesized, mixed with anionic monoacrylate, and photopolymerized by passing through capillary microfluidics to obtain the microbeads. The anionic property of microbeads was confirmed by toluidine blue staining. One microbead, loaded with a 1 day dose of rhPTH 1-34 (23.4 ± 0.9 µg), released rhPTH 1-34 in a triggered manner following the addition of Ca2+ ion. In vitro cell study demonstrated that rhPTH 1-34 released in a pulsatile manner from the microbeads induced osteogenic markers (ALP, RUNX2, and OPN) and precipitated mineral disposition more effectively.

Relative bioavailability between two teriparatide formulations in healthy volunteers.

OBJECTIVE: To compare the pharmacokinetics, relative bioavailability (RB), immunogenicity, and safety after a single dose of test or reference formulation of teriparatide in healthy human volunteers in order to demonstrate whether both products are similar. RESEARCH DESIGN AND METHODS: We compared pharmacokinetic parameters, immunogenicity, and safety after a single dose of two formulations (Osteofortil® and Forteo®) of teriparatide in a randomizedsequence, open-label, two-period crossover study in 24 healthy volunteers. The washout period between formulations was 7 days. Blood samples were collected at baseline and 0, 5, 10, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150 minutes, and 3 and 4 hours after administration. Teriparatide concentrations were determined using ELISA. Adverse events were monitored. RESULTS: Geometric mean (90% CI) Cmax for test and reference formulations were 165.86 (153.35 - 212.13) and 175.37 (164.04 - 221.04) pg/mL, the AUC0-t was 14,932 (5,275 - 15,752) and 14,153 (1,861 - 16,875) pg×min/mL, and the AUC0-∞ was 16,147 (15,047 - 18,799) and 15,467 (14,473 - 18,126) pg×min/mL, respectively. The test/reference ratios (90% CI) for Cmax, AUC0-t, and AUC0-∞ were 94.58% (85.29 - 104.87), 105.5% (97.77 - 113.84), and 104.4% (96.97 - 112.39), respectively No subject reported adverse events. CONCLUSION: Test formulation met pharmacokinetic criteria for bioequivalence.

[Relationship of pharmacokinetics, changes of bone turnover markers and BMD/fractures efficacy during treatment with anabolic agents;Teriparatide daily and once weekly subcutaneous injections.]

Teriparatide(recombinant human PTH1-34, 20 µg daily subcutaneous injection)has been approved for osteoporosis patients at high risk of fracture in many countries including Japan. Teriparatide daily injection therapy has been reported to increase BMD, improve microarchitecture of bone, and reduce the risk of new vertebral fractures and that of non-vertebral fractures. Pharmakokinetic(PK)study after a single Teriparatide injection of the daily dose in healthy Japanese postmenopausal women(n=18)revealed very rapid achievement of peak blood level(median of tmax=0.25 hr)followed by fast disappearance from the blood(mean t1/2=0.708 hr, n=17). Consistent with these PK characteristics, a rapid increase in bone formation marker and later increase in bone resorption marker has previously been observed, which was described as a bone anabolic window. More recently, once weekly subcutaneous injection of teriparatide acetate(56.5 µg)has been reported to reduce the risk of new vertebral fractures compared with placebo and has been approved in Japan. PK study after injection of the higher weekly dose in healthy Japanese postmenopausal women(n=10)revealed a relatively slow achievement of the peak blood level(mean tmax=0.875 hr)compared to daily injections, followed by relatively slow disappearance from the blood(mean t1/2=1.295 hr). Consistent with these PK characteristics, an initial(<24 hr)transient decrease of bone formation markers(serum osteocalcin and P1NP)and transient increase of bone resorption markers(serum NTX and urinary CTX)were observed. However, afterword, the bone formation and resorption markers were increased and decreased, respectively, for longer than 1 week from the baseline levels. The relationship of pharmacokinetics, changes of bone turnover markers and BMD/fractures efficacy during daily versus weekly teriparatide treatment needs to be clarified.

Pharmacokinetics of teriparatide after subcutaneous administration to volunteers with renal failure: a pilot study.

BACKGROUND AND OBJECTIVE: Teriparatide acetate was developed in the form of a synthetic analogue of the Nterminal peptide (1-34) of human parathyroid hormone for the treatment of osteoporosis; it is administered subcutaneously once weekly. However, it is not known whether the pharmacokinetics (PK) of this drug is affected by renal impairment, and this study was conducted to look into this question. METHODS: A multi-center study was conducted at six hospitals in Japan. Subjects were enrolled and grouped on the basis of renal function stratified as: normal function to mild renal impairment (estimated GFR(e-GFR): ≥ 60.0 mL/min/1.73 m2) (8 subjects), moderate impairment (eGFR: 30.0 - 59.9 mL/min/1.73 m2) (5 subjects), and severe impairment (eGFR: 15.0 - 29.9 mL/min/1.73 m2) (5 subjects). The PK parameters, blood and urine electrolytes concentrations, and safety profiles were assessed following a single subcutaneous injection of teriparatide acetate (56.5 µg as teriparatide). RESULTS: The elimination half-life (t1/2) and the mean residence time extrapolated to infinity were significantly prolonged in the group with severe renal impairment (t1/2: 5.0 hours) compared with normal to mild and moderate impairment groups (t1/2: 1.5 hours and 1.2 hours, respectively). However, virtually all of the teriparatide was eliminated from the blood after 24 hours. Given that the drug is administered once weekly, it appeared highly unlikely that accumulation of the drug in the body would become a problem even with repeated administration. There were no particular problems with safety or tolerability. CONCLUSIONS: In treatment with teriparatide acetate once-per week formulation, prescription at the usual dosage appears to be appropriate even in renally impaired patients.

Biosimilarity Assessment of the Biosimilar Teriparatide Candidate and the Reference Drug in Healthy Subjects.

SAL001, a recombinant form of parathyroid hormone, is a biosimilar drug to teriparatide and is planned to be used in osteoporosis treatment. A single-dose, randomized, open-label, 2-way crossover trial was conducted in healthy subjects to compare the pharmacokinetics (PK) and safety between SAL001 and the reference drug. Sixty-four subjects were enrolled in the study, and 61 subjects completed the study. In each period, 20 µg of the test or reference formulation was administered subcutaneously. SAL001 was administered by autoinjector pen, whereas the reference drug was administered by a self-matched injection pen. Serial blood samples were obtained for the analyses of PK and serum calcium concentration. Geometric mean ratios with 90%CIs for the maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) were estimated. The safety of these 2 formulations was also evaluated. Overall, the 90%CIs for the geometric mean ratios of Cmax , AUC from time 0 to the last quantifiable time point, and AUC from time 0 extrapolated to infinity of the test or reference product were within 80.0%-125.0% of biosimilarity criteria. Other PK parameters, serum calcium concentration, and safety profiles had no significant differences between the 2 formulations. SAL001 demonstrated PK similarity to the reference drug, and the serum calcium concentration and safety profiles of SAL001 were also considered comparable to the reference drug.

Effects of teriparatide in Japanese and non-Japanese populations: bridging findings on pharmacokinetics and efficacy.

Teriparatide is an anabolic therapy for osteoporosis approved in the United States since 2002 and European Union since 2003; however, approval in Japan lagged significantly. This report describes analyses based on International Conference on Harmonisation (ICH) E-5 guidelines that support bridging between Japanese studies and the large Fracture Prevention Trial (FPT). We analyzed data from single teriparatide doses in healthy Japanese and Caucasian postmenopausal women (J-PK) and from studies of 6 months [Phase 2, dose ranging (J-Ph2)] and 12 months [Phase 3, efficacy and safety (J-Ph3)] of randomized, placebo-controlled, once-daily treatment in Japanese subjects with osteoporosis. In J-PK, apparent teriparatide area-under-the-curve (AUC) and peak concentration (C (max)) were up to 40% higher in Japanese versus Caucasian women; however, body weight-adjusted values were comparable between populations; these findings were supported by population pharmacokinetic analyses. Between the FPT and Japanese studies, baseline demographic characteristics were similar but bone mineral density (BMD) at lumbar spine (L1-L4) and body weight were lower for Japanese subjects. With teriparatide 20 µg/day, significant increases in BMD were observed compared to placebo at 12 months in both the FPT and J-Ph3 study, and percent change and actual change in BMD were comparable between studies. Dose response at 6 months was also comparable across populations. No novel safety signals were identified in Japanese subjects. These analyses show that teriparatide clinical data met ICH E-5 criteria for bridging. Findings from foreign trials such as the FPT can thus be extrapolated to Japanese subjects treated with teriparatide 20 µg/day.

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.

Parathyroid hormone (1-34)-coated microneedle patch system: clinical pharmacokinetics and pharmacodynamics for treatment of osteoporosis.

OBJECTIVES: To evaluate the clinical PK/PD of PTH(1-34) delivered by a novel transdermal drug-coated microneedle patch system (ZP-PTH) for the treatment of osteoporosis. METHODS: Phase 1 PK studies evaluated the effect of site of administration, patch wear time and dose in normal volunteers, ages 40-85 yrs. Phase 2 was conducted in post-menopausal women with osteoporosis to determine the patch dose response compared to placebo patch and FORTEO® injection. RESULTS: Phase 1 ZP-PTH patch delivery demonstrated a rapid PTH plasma pulse profile with T(max) 3 times shorter and apparent T(1/2) 2 times shorter than FORTEO®. In Phase 2, ZP-PTH 20, 30 and 40 µg doses showed a proportional increase in plasma PTH AUC. Inter-subject and intra-subject AUC variability was similar for all patch doses and comparable to injection. All patch doses produced a significant increase in spine bone mineral density. Unexpectedly, ZP-PTH also produced an early increase in hip bone mineral density, an effect not observed with the injection. CONCLUSIONS: These studies suggest that this novel ZP-PTH patch system can deliver a consistent and therapeutically relevant PTH PK profile. Based on encouraging Phase 2 safety and efficacy data, the program is advancing into a pivotal Phase 3 clinical study.

Oral Delivery of Parathyroid Hormone Using a Triple-Padlock Nanocarrier for Osteoporosis via an Enterohepatic Circulation Pathway.

Intermittent subcutaneous (S.C.) injection of teriparatide [PTH (1-34)] is one of the effective therapies to cure osteoporosis. However, a long-term repeated administration of teriparatide by S.C. to the patients is highly challenging. Herein, a triple padlock nanocarrier prepared by a taurocholic acid-conjugated chondroitin sulfate A (TCSA) is designed to develop an oral dosage form of recombinant human teriparatide (rhPTH). Oral administration of TCSA/rhPTH to the bilateral ovariectomized (OVX) rats resulted in the recovery of the bone marrow density and healthy serum bone parameters from the severe osteoporotic conditions. Also, it enhanced new bone formation in the osteoporotic tibias. This triple padlock oral delivery platform overcame the current barriers associated with teriparatide administration and exhibited a promising therapeutic effect against osteoporosis.

Pharmacokinetics of teriparatide (rhPTH[1-34]) and calcium pharmacodynamics in postmenopausal women with osteoporosis.

Teriparatide (rhPTH[1-34]) affects calcium metabolism in a pattern consistent with the known actions of endogenous parathyroid hormone (PTH). This report describes the pharmacokinetics and resulting serum calcium response to teriparatide in postmenopausal women with osteoporosis. Pharmacokinetic samples for this analysis were obtained from 360 women who participated in the Fracture Prevention Trial. Postmenopausal women with osteoporosis received daily subcutaneous injections of either teriparatide 20 µg (4.86 µmol) or placebo, median 21 months' treatment. Serum teriparatide and calcium concentrations were measured throughout the study. An indirect-response model was developed to describe the pharmacokinetic-pharmacodynamic relationship between teriparatide concentrations and serum calcium response. The pharmacokinetics of teriparatide were characterized by rapid absorption (maximum concentration achieved within 30 min) and rapid elimination (half-life of 1 h), resulting in a total duration of exposure to the peptide of approximately 4 h. Teriparatide transiently increased serum calcium, with the maximum effect observed at approximately 4.25 h (median increase 0.4 mg/dl [0.1 mmol/l]). Calcium concentrations returned to predose levels by 16-24 h after each dose. Persistent hypercalcemia was not observed; one teriparatide 20 µg-treated patient had a predose serum calcium value above the normal range but <11.0 mg/dl (2.75 mmol/l). Following once-daily subcutaneous administration, teriparatide produces a modest but transient increase in serum calcium, consistent with the known effects of endogenous PTH on mineral metabolism. The excursion in serum calcium is brief, due to the short length of time that teriparatide concentrations are elevated.

Safety Profiles, Pharmacokinetics, and Changes in Bone Turnover Markers After Twice-Weekly Subcutaneous Administration of Teriparatide in Healthy Japanese Postmenopausal Women: A Single-Blind Randomized Study.

Once-weekly injection of 56.5-µg teriparatide formulation is a potent therapeutic agent for osteoporosis treatment. However, this treatment has an issue of difficulty in continuing the treatment by its adverse side effects including nausea, vomiting, and headaches. To reduce these adverse side effects, we conducted a randomized, single-blind, placebo-controlled study to examine the pharmacokinetics, changes in bone turnover markers, and safety profiles of twice-weekly 28.2-µg teriparatide injections. Different dosing intervals of the twice-weekly 28.2-µg injections were also studied. A total of 100 healthy Japanese postmenopausal women were enrolled in this multiple-dosing study. The systemic exposure of teriparatide acetate in the twice-weekly 28.2-µg injection was half that of the once-weekly 56.5-µg injection. Changes in bone turnover markers in the twice-weekly 28.2-µg injection were comparable to those in the once-weekly 56.5-µg injection. Incidences of adverse events including nausea, vomiting, and headaches were lower in the twice-weekly 28.2-µg injections than those in the once-weekly 56.5-µg injection. Findings were similar in the twice-weekly 28.2-µg injections regardless of the dosing interval. Thus, the new dosing regimen using twice-weekly 28.2-µg injections maintained comparable efficacy to the once-weekly 56.5-µg injections; however, it improved the safety profile and contributed to better continuity of care with teriparatide.

Treatment of osteoporosis with parathyroid hormone and teriparatide.

Nowadays osteoporosis treatment is based primarily on therapy with antiresorptive agents, like the bisphosphonates. Parathyroid hormone (Preotact) and human recombinant parathyroid hormone peptide 1-34 (Teriparatide) are relatively new for the treatment of osteoporosis and belong to the group of anabolic agents. Both agents demonstrated an increase in bone mineral density and a significant reduction in vertebral fractures in postmenopausal women with osteoporosis when given for 18-24 months. Data on nonvertebral fractures are, however, not clear-cut, and so far only bisphosphonates and strontium ranelate have been demonstrated to reduce all types of fractures and therefore remain the front-line option for treatment of osteoporosis. As the safety, tolerability, and cost of the therapy also influence the choice of therapy, Preotact and Teriparatide might be useful additions to the armamentarium for (second-line) treatment of osteoporosis.

Current Treatments and New Developments in the Management of Glucocorticoid-induced Osteoporosis.

Glucocorticoids (GCs) are often used for improvement of quality of life, particularly in the elderly, but long-term GC use may cause harm; bone loss and fractures are among the most devastating side effects. Fracture risk is particularly high in patients with a severe underlying disease with an urgent need for treatment with high-dose GCs. Moreover, it is important to realize that these patients suffer from an augmented background fracture risk as these patients have a high presence of traditional risk factors for osteoporosis, such as high age, low body mass index (BMI), smoking and relatives with osteoporosis or hip fractures. It is thus crucial for prevention of osteoporotic fractures to use the lowest dose of GC for a short period of time to prevent fractures. Another important task is optimal treatment of the underlying disease; for instance, fracture risk is higher in patients with active rheumatoid arthritis than in patients in whom rheumatoid arthritis is in remission. Thus, fracture risk is generally highest in the early phase, when GC dosage and the disease activity of the underlying disease are high. Finally, some of the traditional risk factors can be modulated, e.g., smoking and low BMI. Life-style measures, such as adequate amounts of calcium and vitamin D and exercise therapy are also crucial. In some patients, anti-osteoporotic drugs are also indicated. In general, oral bisphosphonates (BPs) are the first choice, because of their efficacy and safety combined with the low cost of the drug. However, for those patients who do not tolerate oral BPs, alternatives ("second-line therapies") are available: BP intravenously (zoledronic acid), denosumab (Dmab), and teriparatide. Both zoledronic acid and Dmab have been proven to be superior to oral bisphosphonates like risedronate in improvement of bone mineral density. For teriparatide, vertebral fracture reduction has been shown in comparison with alendronate. Thus, to reduce the global burden of GC use and fracture risk, fracture risk management in GC users should involve at least involve life-style measures and the use of the lowest possible dose of GC. In high-risk patients, anti-osteoporotic drugs should be initiated. First choice drugs are oral BPs; however, in those with contraindications and those who do not tolerate oral BPs, second-line therapies should be started. Although this is a reasonable treatment algorithm, an unmet need is that the most pivotal (second-line) drugs are not used in daily clinical practice at the initial phase, usually characterized by high-dose GC and active underlying disease, when they are most needed. In some patients second-line drugs are started later in the disease course, with lower GC dosages and higher disease activity. As this is a paradox, we think it is a challenge for physicians and expert committees to develop an algorithm with clear indications in which specific patient groups second-line anti-osteoporotic drugs should or could be initiated as first-choice treatment.

In vitro and preclinical assessment of an intranasal spray formulation of parathyroid hormone PTH 1-34 for the treatment of osteoporosis.

Osteoporosis treatment with PTH 1-34 injections significantly reduces the incidence of bone fracture. Potential further reductions in fracture rate should be observed through nasal spray delivery to address the poor compliance associated with patient dislike of repeated PTH 1-34 subcutaneous injections. In vitro human osteoblast-like Saos-2 cell intracellular cAMP levels were used to define PTH 1-34 nasal spray formulation bioactivity. The chemically synthesised PTH 1-34 had an EC50 of 0.76nM. Absorption enhancers polyethylene glycol (15)-hydroxystearate (Solutol® HS15), poloxamer 407, chitosan or sodium hyaluronate did not diminish the bioactivity of PTH 1-34 within an in vitro cell culture model (p >0.05). We also demonstrated the effectiveness of the transmucosal absorption enhancer Solutol® HS15 in a nasal spray formulation using a preclinical pharmacokinetic model. In Sprague-Dawley rats without the absorption enhancer the uptake of PTH 1-34 into the blood via intranasal delivery produced a Cmax of 2.1±0.5ng/ml compared to 13.7±1.6ng/ml with Solutol® HS15 enhancer (p=0.016) and a Cmax14.8±8ng/ml in subcutaneous injections. Together these data illustrate that the nasal spray formulation bioactivity in vitro is not affected by the nasal spray absorption enhancers investigated, and the Solutol® HS15 nasal spray formulation had an equivalent pharmacokinetic profile to subcutaneous injection in the rat model. The Solutol® HS15 formulation therefore demonstrated potential as a PTH 1-34 nasal spray formulation for the treatment of osteoporosis.

Pharmacokinetics and safety of recombinant human parathyroid hormone (1-34) (teriparatide) after single ascending doses in Chinese healthy volunteers.

The pharmacokinetics and safety of recombinant human parathyroid hormone (1-34) [rhPTH (1-34)] after single ascending doses were evaluated in Chinese healthy volunteers. Nine healthy volunteers (five male and four female) were recruited for an open label, randomized, three multiply three crossover, single ascending dose (10, 20, and 40 microg) study. Using a validated radioimmunoassay, we determined the plasma concentrations of rhPTH (1-34). The mean peak plasma concentration (Cmax) were 123.6, 195.6, and 318.2 pg x mL(-1) respectively, and were reached from 25.6 to 36.1 min after subcutaneous administration. After Cmax was reached, the plasma drug level decreased quickly, with elimination halflife (t(1/2)) of 53.9 to 64.1 min. The mean AUC(0-infinity) (the area under the plasma concentration versus time curve from time zero to infinite) of rhPTH (1-34) were 11794.2 +/- 974.8, 21606.7 +/- 4753.9, 33877.0 +/- 8374.4 pg x min x mL(-1), respectively. The mean AUC(0-t) (the area under the plasma concentration versus time curve from time zero to the last quantifiable concentration) of rhPTH (1-34) were 9034.4 +/- 1073.9, 17883.3 +/- 4597.1, 31693.5 +/- 6574.8 pg x min x mL(-1), respectively. Dose-related linear trend were observed for AUC(o-t) and Cmax of rhPTH (1-34). t(1/2) and Tmax (time to Cmax) of rhPTH (1-34) were independent of administered dose. rhPTH (1-34) was safe and well tolerated by all volunteers.

Population Pharmacokinetic and Exposure-Response Analysis of Weekly Teriparatide in Osteoporosis Patients.

Teriparatide is a potent therapeutic agent for the treatment of osteoporosis. One of the aims of this analysis was to develop a population pharmacokinetic (PPK) model to understand the pharmacokinetic characteristics of the once-weekly formulation of teriparatide. Another aim was to develop an exposure-response model to describe the relationship between change in bone mineral density (BMD) and teriparatide exposure after weekly subcutaneous administration. The PPK analysis showed that apparent total body clearance was significantly influenced by estimated creatinine clearance and the presence of osteoporosis. A data set consisting of lumbar spine BMD values for 513 osteoporosis patients whose area under the concentration-time curve (AUC) of teriparatide acetate was estimated by the developed PPK model was then compiled. Exposure-response analysis showed that the percentage change from baseline of BMD was well described by a function of the AUC of teriparatide acetate, time, and coadministration of alfacalcidol and a calcium preparation. The analysis indicated that AUC is an important parameter for predicting BMD response to once-weekly teriparatide in osteoporosis patients.

[Effect of drugs for osteoporosis on cardiovascular diseases and effect of cardio vascular drugs on osteoporosis]. / Effet des médicaments de l'ostéoporose sur les maladies cardiovasculaires et effet des médicaments à visée cardiovasculaire sur l'ostéoporose.

Osteoporosis and cardiovascular diseases are epidemiologically associated. Calcification phenomena of atherosclerotic plaque involve cytokines and growth factors also involved in bone remodeling. Drugs given for either of these two conditions could act on these mechanisms. Can osteoporosis drugs have an influence on the occurrence of cardiovascular events? Conversely, can the treatment of hypertension alter the course of osteoporosis? It is possible that administration of high doses of calcium (1g/day) in patients who already have important dietary intake can increase the risk of myocardial infarction. Epidemiological studies show links between low serum vitamin D levels and cardiovascular disease but interventional studies show that vitamin D administration in moderately deficient subjects vitamin D does not prevent the occurrence of cardiovascular events. Cohort studies show a beneficial effect of beta-blockers and thiazides administered to hypertensive patients: they reduce by 20% risk of fracture of the proximal femur. Should we focus on these anti-hypertensive treatments for our patients with 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.

The Effectiveness of Human Parathyroid Hormone and Low-Intensity Pulsed Ultrasound on the Fracture Healing in Osteoporotic Bones.

Osteoporotic fracture has become a major public health problem, and until today, the treatments available are not satisfactory. While there is growing evidence to support the individual treatment of parathyroid hormone (PTH) administration and low-intensity pulsed ultrasound (LIPUS) exposure as respectively systemic and local therapies during osteoporotic fracture healing, their effects have not yet been investigated when introduced concurrently. This study aimed to evaluate the effects of combined treatment with PTH (1-34) and LIPUS on fracture healing in ovariectomized (OVX) rats. Thirty-two, 12-week-old female Sprague-Dawley rats were OVX to induce osteoporosis. After 12 weeks, the rats underwent surgery to create bilateral mid-diaphyseal fractures of proximal tibiae. All animals were randomly divided into 4 groups (n = 8 for each): control group as placebo, PTH group, LIPUS group, and combined group. PTH group had PTH administration at a dose of 30 µg/kg/day for 3 days/week for 6 weeks. LIPUS group received ultrasound 5 days/week for 20 min/day for 6 weeks and combined group had both PTH administration and LIPUS exposure for 6 weeks. Fracture healing was observed weekly by anteroposterior radiography and micro-CT. Five weeks after the fracture, the tibia were harvested to permit histological assessments and at week 6, for mechanical property of the fracture callus. Micro-CT showed that the PTH and combined groups exhibited significantly higher BMD and trabecular bone integrity than control group at weeks 4-6. Radiography, fracture healing score and mean callus area indicated that the combined group revealed better healing processes than the individual groups. Mechanically, bending moment to failure was significantly higher in LIPUS, PTH and combined groups than in control group. These data suggest that the combined treatment of PTH and LIPUS have been shown to accelerate fracture bone healing and enhance bone properties rather than single agent therapy, and may be considered as a treatment remedy for fracture healing in postmenopausal osteoporosis.