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Pharmacology: Pharmacodynamics: Mechanism of action: Endogenous 84-amino-acid parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidney. FORTEO (rhPTH (1-34)) is the active fragment (1-34) of endogenous human parathyroid hormone. Physiological actions of PTH include stimulation of bone formation by direct effects on bone forming cells (osteoblasts) indirectly increasing the intestinal absorption of calcium and increasing the tubular re-absorption of calcium and excretion of phosphate by the kidney.
Pharmacodynamic Effects: FORTEO is a bone formation agent to treat osteoporosis. The skeletal effects of FORTEO depend upon the pattern of systemic exposure. Once-daily administration of FORTEO increases apposition of new bone on trabecular and cortical bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity.
Clinical Efficacy: Risk Factors: Independent risk factors, for example, low BMD, age, the existence of previous fracture, family history of hip fractures, high bone turnover and low body mass index should be considered in order to identify women and men at increased risk of osteoporotic fractures who could benefit from treatment.
Premenopausal women with glucocorticoid-induced osteoporosis should be considered at high risk for fracture if they have a prevalent fracture or a combination of risk factors that place them at high risk for fracture (e.g., low bone density [e.g., T score ≤−2], sustained high dose glucocorticoid therapy [e.g., ≥7.5 mg/day for at least 6 months], high underlying disease activity, low sex steroid levels).
Postmenopausal women: Postmenopausal women: The pivotal study included 1637 postmenopausal women (mean age 69.5 years). At baseline, ninety percent of the patients had one or more vertebral fractures and on average, vertebral BMD was 0.82 g/cm2 (equivalent to a T-score = -2.6). All patients were offered 1000 mg calcium per day and at least 400 IU vitamin D per day. Results from up to 24 months (median: 19 months) treatment with FORTEO demonstrate statistically significant fracture reduction (Table 1). To prevent one or more new vertebral fractures, 11 women had to be treated for a median of 19 months. (See Table 1.)
Click on icon to see table/diagram/imageAfter 19 months (median) treatment, bone mineral density (BMD) had increased in the lumbar spine and total hip, respectively, by 9% and 4% compared with placebo (p<0.001).
Post-treatment management: Following treatment with FORTEO, 1262 postmenopausal women from the pivotal trial enrolled in a post-treatment follow-up study. The primary objective of the study was to collect safety data of FORTEO. During this observational period, other osteoporosis treatments were allowed and additional assessment of vertebral fractures was performed.
During a median of 18 months following discontinuation of FORTEO, there was a 41% reduction (p=0.004) compared with placebo in the number of patients with a minimum of one new vertebral fracture.
Male osteoporosis: 437 patients (mean age 58.7 years) were enrolled in a clinical trial for men with hypogonadal (defined as low monitoring free testosterone or an elevated FSH or LH) or idiopathic osteoporosis. Baseline spinal and femoral neck bone mineral density mean T-scores were -2.2 and -2.1, respectively. At baseline, 35% of patients had a vertebral fracture and 59% had a non-vertebral fracture.
All patients were offered 1000 mg calcium per day and at least 400 IU vitamin D per day. Lumbar spine BMD significantly increased by 3 months. After 12 months, BMD had increased in the lumbar spine and total hip by 5% and 1%, respectively, compared with placebo. However, no significant effect on fracture rates was demonstrated.
Glucocorticoid-induced osteoporosis: The efficacy of FORTEO in men and women (N=428) receiving sustained systemic glucocorticoid therapy (equivalent to 5 mg or greater of prednisone for at least 3 months) was demonstrated in an 18-month, randomised, double-blind, comparator-controlled study (alendronate 10 mg/day). Twenty-eight percent of patients had one or more radiographic vertebral fractures at baseline. All patients were offered 1000 mg calcium per day and 800 IU vitamin D per day.
This study included postmenopausal women (N=277), premenopausal women (N=67), and men (N=83). At baseline, the postmenopausal women had a mean age of 61 years, mean lumbar spine BMD T score of -2.7, median prednisone equivalent dose of 7.5 mg/day, and 34% had one or more radiographic vertebral fractures; premenopausal women had a mean age of 37 years, mean lumbar spine BMD T score of -2.5, median prednisone equivalent dose of 10 mg/day, and 9% had one or more radiographic vertebral fractures; and men had a mean age of 57 years, mean lumbar spine BMD T score of -2.2, median prednisone equivalent dose of 10 mg/day, and 24% had one or more radiographic vertebral fractures.
Sixty-nine percent of patients completed the 18-month study. At endpoint, FORTEO significantly increased lumbar spine BMD (7.2%) compared with alendronate (3.4%) (p<0.001). FORTEO increased BMD at the total hip (3.6%) compared with alendronate (2.2%) (p<0.01), as well as at the femoral neck (3.7%) compared with alendronate (2.1%) (p<0.05).
A preliminary analysis of 336 spinal X-rays showed that 10 patients in the alendronate group (6.1%)had experienced a new vertebral fracture compared with 1 patient in the FORTEO group (0.6%). In addition, 9 patients in the alendronate group (4.2%) had experienced a nonvertebral fracture compared with 12 patients in the FORTEO group (5.6%).
In premenopausal women, the increase in BMD from baseline to endpoint was significantly greater in the FORTEO group compared with the alendronate group at the lumbar spine (4.2% versus -1.9%; p<0.001) and total hip (3.8% versus 0.9%; p=0.005). However, no significant effect on fracture rates was demonstrated.
Pharmacokinetics: FORTEO is eliminated through hepatic and extra-hepatic clearance (approximately 62 l/hr in women and 94 l/hr in men). After subcutaneous injection, teriparatide has an absolute bioavailability of 95%. The volume of distribution is approximately 1.7 l/kg. The half-life of FORTEO is approximately 1 hour when administered subcutaneously, which reflects the time required for absorption from the injection site. No metabolism or excretion studies have been performed with FORTEO but the peripheral metabolism of parathyroid hormone is believed to occur predominantly in liver and kidney.
Patient characteristics: Geriatrics: No differences in FORTEO pharmacokinetics were detected with regard to age (range 31 to 85 years). Dosage adjustment based on age is not required.
Gender: Systemic exposure to teriparatide is approximately 20% to 30% lower in men than in women. There were, however, no gender differences with respect to safety, tolerability, or pharmacodynamic responses. Dosage adjustment based upon gender is not required.
Renal Impairment: No clinically relevant pharmacokinetic or safety differences were identified in patients with mild, moderate, or severe chronic renal insufficiency administered a single dose of teriparatide. Patients with renal impairment had reduced calcemic and calciuric responses to teriparatide. Dosage adjustment based on renal function is not required. Long-term safety and efficacy have not been evaluated in patients with significant renal impairment.
Heart Failure: No clinically relevant pharmacokinetic, blood pressure, pulse rate, or other safety differences were identified in patients with stable heart failure (New York Heart Association Class I to III and additional evidence of cardiac dysfunction) after the administration of two 20 micrograms doses of teriparatide. Dosage adjustment based on the presence of mild or moderate heart failure is not required.
Toxicology: Preclinical safety data: Teriparatide was not genotoxic in a standard battery of tests. It produced no teratogenic effects in rats, mice or rabbits.
Rats treated with near-life time daily injections had dose-dependent exaggerated bone formation and increased incidence of osteosarcoma most probably due to an epigenitic mechanism. Teriparatide did not increase the incidence of any other type of neoplasia in rats. Due to the differences in bone physiology in rats and humans, the clinical relevance of these findings is probably minor. No bone tumors were observed in ovariectomised monkeys treated for 18 months. In addition, no osteosarcomas have been observed in clinical trials or during the post treatment follow-up study.
Animal studies have shown that severely reduced hepatic blood flow decreases exposure of PTH to the principal cleavage system (Kupffer cells) and consequently clearance of PTH (1-84).
