What are the differences between teriparatide (recombinant parathyroid hormone) and normal parathyroid hormone (PTH) in terms of body effects and chemistry?

Differences Between Teriparatide and Normal PTH in Body Effects and Chemistry

Teriparatide is a recombinant form of the biologically active N-terminal fragment (amino acids 1-34) of the full-length 84-amino acid human parathyroid hormone, retaining the same biological activity but with distinct pharmacokinetic properties and clinical applications compared to endogenous PTH. 1

Chemical Structure and Composition

• Teriparatide consists of only the first 34 amino acids of the full-length 84-amino acid human parathyroid hormone, representing the biologically active region 1
• The molecular formula of teriparatide is C181H291N55O51S2 with a molecular weight of 4117.8 daltons 1
• Teriparatide is manufactured using recombinant DNA technology with a strain of Pseudomonas fluorescens, while endogenous PTH is naturally produced by the chief cells of the parathyroid glands 1
• Endogenous PTH is synthesized as a 115-amino acid peptide precursor (pre-proPTH), which is cleaved to proPTH and finally to the 84-amino acid biologically active hormone 2

Receptor Binding and Biological Activity

• Both teriparatide and the 34 N-terminal amino acids of natural PTH bind to PTH1R receptors with the same affinity and have the same physiological actions on bone and kidney 1
• The first 34 amino acids and the formation of an alpha helix are crucial for biological activity in both molecules 2
• Both hormones exert their effects through interaction with the PTH1R receptor on target tissues 2, 1

Metabolism and Circulation

• Natural PTH circulates as both full-length 84-amino acid peptide and multiple fragments, particularly C-terminal fragments that arise from liver metabolism and direct secretion from the parathyroid gland 2
• The plasma half-life of full-length PTH is very short (2-4 minutes), while C-terminal fragments have a half-life 5-10 times longer with normal kidney function 2
• C-terminal fragments of natural PTH accumulate in patients with kidney disease as they are primarily cleared by the kidneys 2
• Teriparatide is not expected to accumulate in bone or other tissues, unlike some fragments of natural PTH 1
• Teriparatide disappears from blood faster after oral administration than after subcutaneous injection 3

Physiological Effects and Clinical Differences

• Both natural PTH and teriparatide regulate calcium and phosphate metabolism in bone and kidney 2, 1
• The skeletal effects of teriparatide depend on the pattern of systemic exposure - once-daily administration stimulates new bone formation by preferentially stimulating osteoblastic activity over osteoclastic activity 1
• In contrast, continuous excess of endogenous PTH (as in hyperparathyroidism) may be detrimental to the skeleton because bone resorption may be stimulated more than bone formation 1
• Teriparatide has been shown to improve trabecular microarchitecture and increase bone mass and strength by stimulating new bone formation in both cancellous and cortical bone 1
• Teriparatide increases bone mineral density and reduces fracture risk in osteoporotic patients when administered intermittently 4, 5
• Teriparatide has a dose-dependent effect on serum calcium, with peak concentrations occurring 4-6 hours after dosing 1

Clinical Applications and Limitations

• Teriparatide is FDA-approved for the treatment of osteoporosis, while natural PTH is not used therapeutically 4
• Teriparatide therapy is not recommended for more than 2 years, partly due to concerns about osteosarcoma risk observed in rat models 4
• Teriparatide is administered as a daily subcutaneous injection (20 mcg), creating an intermittent exposure pattern that favors bone formation 1, 4
• Teriparatide may have potential applications in fracture healing, though this remains an off-label use 6

Measurement and Monitoring Considerations

• PTH assays differ in the antibodies used and consequently measure different fragments and isoforms of PTH in addition to biologically active PTH 2
• Standardization of PTH assays is ongoing, and lack of standardization leads to differences in PTH concentrations measured in different laboratories 2
• Teriparatide therapy requires monitoring of serum calcium, with measurements recommended after 1 month of treatment 4

The key distinction between teriparatide and natural PTH lies in their administration pattern and resulting effects on bone metabolism - intermittent teriparatide administration promotes bone formation, while continuous elevation of natural PTH (as in hyperparathyroidism) favors bone resorption 1, 7.