Teriparatide

Teriparatide is an anabolic medication used to manage osteoporosis. It is a recombinant version of a fragment of the human parathyroid hormone (PTH), specifically the first 34 amino acids of the N-terminal end, which are significant in its biological activity. In animal models, when administered daily in low doses, it stimulates more bone formation than bone resorption. With this intermittent exposure, the body’s own bone-building mechanisms are activated, making bones stronger over time.

Indications

This peptide is a recombinant version of PTH and is a powerful bone-building agent. Multiple clinical trials in murine models have determined its efficacy and provided that it’s safe for treating osteoporosis. An important study by Neer (2001) involving 1.637 postmenopausal women with at least one vertebral fracture demonstrated that daily 20 mcg teriparatide reduced new vertebral fractures by 65% and nonvertebral fractures by 53%. Over the 21-month average follow-up, it densified their bone by 9% in the lumbar spine and by 3% in the femoral neck.

These benefits have been duplicated in other trials, which have shown that teriparatide works not only in postmenopausal women but also in men and those with glucocorticoid-induced osteoporosis. This broad efficacy proves its usefulness in different patient groups.

The FDA has approved teriparatide for the following uses:

• Postmenopausal women with osteoporosis who have high risk of fractures.
• Men with primary or hypogonadal osteoporosis who have a high risk of fracture.
• Men and women with glucocorticoid-induced osteoporosis who are at high risk for fracture.

Mechanism of Action

Action of parathyroid hormone on bone is highly dependent mode of delivery. In conditions like hyperparathyroidism, where PTH levels are continuously elevated, bone resorption overcomes bone formation and causes bone loss. However, when PTH (or its analogs like teriparatide) is given in low doses every day, it can reverse this process. In other words, it stimulates bone formation. Therefore, it’s is all about timing and dose.

Teriparatide works by binding to the PTH type 1 receptors (PTH1R), which are found on bone-forming cells like osteoblasts and osteocytes, as well as kidney cells that control calcium. These receptors are G-protein-coupled receptors and activate two significant signaling processes in the cells: one through adenylate cyclase, which increases cAMP and activates protein kinase A (PKA), and one through protein kinase C (PKC). The PKA pathway is primarily concerned with the stimulation of new bone growth.

Several processes take part in the bone-forming actions that involve teriparatide:

• It increases the production of growth factors such as IGF-1 and FGF-2, which stimulate osteoblasts.
• It decreases sclerostin production, a protein that suppresses the Wnt/β-catenin pathway, crucial for bone formation.
• It enhances the activity of Runx2, a transcription factor essential for osteoblast formation.

As a result, the number and lifespan of osteoblasts are increased, and there is new bone formation in both trabecular (spongy) and cortical (compact) bones. This effect is very different from antiresorptive drugs like bisphosphonates, which work by inhibiting bone resorption but do not directly stimulate new bone formation.

Additionally, PTH also stimulates osteoclast activity (cells that break down bones), although only with prolonged exposure. This is through stimulation of RANKL secretion, a molecule that activates osteoclast precursors.

Effects on Calcium and Phosphate Balance

Teriparatide also mimics the natural effects of PTH on the body’s calcium and phosphate balance. It raises blood calcium levels and lowers blood phosphate levels. In the kidneys, it stimulates calcium reabsorption in the distal tubules, suppresses phosphate reabsorption in the proximal tubules, and stimulates the synthesis of active vitamin D (1,25-dihydroxyvitamin D) through stimulation of the enzyme 1-alpha-hydroxylase. In bone, this peptide releases calcium from the bone matrix, adding to its action on serum calcium levels.

References:

1. Neer, R. M., Arnaud, C. D., Zanchetta, J. R., Prince, R., Gaich, G. A., Reginster, J. Y., Hodsman, A. B., Eriksen, E. F., Ish-Shalom, S., Genant, H. K., Wang, O., & Mitlak, B. H. (2001). Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. New England Journal of Medicine, 344(19), 1434–1441. https://doi.org/10.1056/NEJM200105103441904
2. Kaufman, J. M., Orwoll, E., Goemaere, S., San Martin, J., Hossain, A., Dalsky, G. P., Lindsay, R., & Mitlak, B. H. (2005). Teriparatide effects on vertebral fractures and bone mineral density in men with osteoporosis: Treatment and discontinuation of therapy. Osteoporosis International, 16(5), 510–516. https://doi.org/10.1007/s00198-004-1713-3
3. Saag, K. G., Shane, E., Boonen, S., Marín, F., Donley, D. W., Taylor, K. A., Dalsky, G. P., & Marcus, R. (2007). Teriparatide or alendronate in glucocorticoid-induced osteoporosis. New England Journal of Medicine, 357(20), 2028–2039. https://doi.org/10.1056/NEJMoa071408
4. Hodsman, A. B., Bauer, D. C., Dempster, D. W., Dian, L., Hanley, D. A., Harris, S. T., Kendler, D. L., McClung, M. R., Miller, P. D., Olszynski, W. P., Orwoll, E., & Yuen, C. K. (2005). Parathyroid hormone and teriparatide for the treatment of osteoporosis: A review of the evidence and suggested guidelines for its use. Endocrine Reviews, 26(5), 688–703. https://doi.org/10.1210/er.2004-0006
5. Jilka, R. L. (2007). Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone, 40(6), 1434–1446. https://doi.org/10.1016/j.bone.2007.03.017
6. U.S. Food and Drug Administration. (2021). FORTEO® (teriparatide) [prescribing information]. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021318Orig1s056lbl.pdf