Transient elevations in parathyroid hormone levels after subcutaneous injection of Preotact stimulates new bone formation on trabecular and cortical bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. Effects on serum calcium concentrations
Parathyroid hormone is the principal regulator of serum calcium hemostasis. In response to subcutaneous doses of Preotact (100 micrograms), serum total calcium levels increase gradually and reach peak concentration at approximately 6 to 8 hours after dosing. In general, serum calcium levels return to normal within 24 hours. Clinical efficacy
In an 18-month double-blind, placebo controlled study, the effects of Preotact on the fracture incidence in 2532 women with postmenopausal osteoporosis was studied. Approximately 19% of patients had a prevalent vertebral fracture at baseline and the mean lumbar T-score of -3.0 in both active and placebo arm. Compared to the placebo group, there was a 61% relative risk reduction of a new vertebral fracture at month 18 for the women in the Preotact group. To prevent one or more new vertebral fractures, 48 women had to be treated for a median of 18 months for the total population. For patients who were already fractured, the number needed to treat was 21. Effect on bone mineral density
In the same study mentioned above, Preotact increased bone mineral density in the lumbar spine after 18 months treatment by 6.5% compared with a reduction by 0.3% in the placebo group. The difference was statistically significant.
The increase of bone mineral density in the hip was also statistically significant compared to placebo, but only around 1.0% at study endpoint. Continued treatment up to 24 months lead to a continued increase in bone mineral density. Pharmacokinetics
Absorption
Subcutaneous administration of parathyroid hormone into the abdomen produces a rapid increase in plasma parathyroid hormone levels which reach peak at 1 to 2 hours after dosing. The mean half-life is approximately 1.5 hours. The absolute bioavailability of 100 micrograms of Preotact after subcutaneous administration in the abdomen is 55%. Distribution
The volume of distribution at steady-state following intravenous administration is approximately 5.4 liters. Intersubject variability is about 40%. Biotransformation
Parathyroid hormone is efficiently removed from the blood by a receptor-mediated process in the liver and is broken down into smaller peptide fragments. The fragments derived from the amino-terminus are further degraded within the cell while the fragments derived from the carboxy-terminus are released back into the blood and cleared by the kidney. These carboxy-terminal fragments are thought to play a role in the regulation of parathyroid hormone activity. Under normal physiological conditions full-length parathyroid hormone H constitutes only 5-30% of the circulating forms of the molecule, while 70-95% is present as carboxy-terminal fragments. Following administration of Preotact, carboxy-terminal fragments make up about 60-90% of the circulating forms of the molecule. Intersubject variability in systemic clearance is about 15%. Elimination
Parathyroid hormone is metabolised in the liver and to a lesser extent in the kidney. It is not excreted from the body in its intact form.