• Sign Up

Teriparatide


Teriparatide

Article Author:
Hacen Vall
Article Editor:
Mayur Parmar
Updated:
6/4/2020 8:55:13 AM
For CME on this topic:
Teriparatide CME
PubMed Link:
Teriparatide

Indications

Teriparatide is a recombinant fragment of human parathyroid hormone consisting of its first amino(N)-terminal 34 amino acids, and a potent osteoanabolic agent. It has undergone multiple clinical trials that proved its safety and efficacy for the treatment of osteoporosis. In a seminal randomized placebo-controlled trial (n = 1637) by Neer et al (2001) in postmenopausal women with at least one prior vertebral fracture (the Fracture  Prevention Trial) , 20 mcg teriparatide administered  daily (i.e. the currently approved dose for prescription) decreased the risk for new vertebral fractures by 65% (RR = 0.35; 95% CI = 0.22-0.55) and nonvertebral fragility fractures by 53% (RR = 0.47;  95% CI = 0.25-0.88) and increased bone mineral density (BMD) at lumbar spine by 9% and at femoral neck by 3% over a median follow-up period of 21 months.[1] Not only do other subsequent trials corroborate these effects in head-to-head comparison trails to available therapies such as alendronate and risedronate in postmenopausal women but also replicate them in men and patients with different etiology for osteoporosis such as glucocorticoid-induced osteoporosis, indicating activity independently of sex and through primary and secondary osteoporotic etiologies.[2][3][4][5][6][7][8][9] 

 It has FDA approval for the following indications  :

  • Treatment of osteoporosis in postmenopausal women with a high risk for fracture;
  • Increase of bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture;
  • Treatment of men and women with systemic glucocorticoid-induced osteoporosis at high risk for fracture

‘’High risk for fracture’’ is defined in the FDA drug label as a history of osteoporotic fracture, multiple risk fracture factors, failure, or intolerance to other available osteoporosis therapy (e.g., bisphosphonates). 

To preserve the increments of BMD acquired with teriparatide, therapy with an antiresorptive agent (e.g., bisphosphonates) should restart after teriparatide discontinuation.[10] However, while bisphosphonates help retain BMD gains that tend to regress after cessation of teriparatide, concomitant use with teriparatide is to be avoided because they may blunt its anabolic effect.[10]

Given the availability of safe, effective and less expensive therapies for osteoporosis, the exigence of high risk for fracture or intolerance or nonavailability of other therapies points to that PTH analogs should be used as ‘’last resort’’ treatment and reserved for severe osteoporosis ( defined by WHO as BMD of T-score 2.5 or less plus at least one fragility fracture) because patients with severe osteoporosis have significant risk for fracture.  In a meta-analysis of cohort studies of 15259 men and 44902 women with prior fracture, a personal history of previous fragility fracture increased the risk of any subsequent fracture by more than 86% compared to individuals without prior fracture (RR = 1.86; 95% CI = 1.75-1.98).[11] The high risk for fracture associated with severe osteoporosis makes these patients likely to derive the most clinical benefit from this therapy.  

Other than the approved indications for osteoporosis, studies and reports indicate possible benefits of teriparatide in fracture healing, hypoparathyroidism, osteonecrosis of the jaw, and periodontal disease.[12]

Mechanism of Action

  • Effects on Bone Metabolism

In disease states associated with excess parathyroid hormone (PTH) in the blood, such as primary hyperparathyroidism, increased osteoclast activity, and accelerated bone resorption occurs. It may, therefore, comes as paradoxical that parathyroid hormone or its analogs can be a treatment for osteoporosis, a disease associated with accelerated bone loss. It turns out that the difference in PTH effects on the bone stem from differences in the dose and pattern of exposure of bone to it. When under continuous exposure to PTH (e.g., hyperparathyroidism), bone undergoes resorption more than formation, while intermittent exposure to low-dose PTH (like daily administration of teriparatide) induces bone formation more than resorption. Although The underlying molecular mechanisms that undergird this variation in effect (i.e., catabolic effect with sustained exposure vs. anabolic effect with intermittent exposure) are largely unknown, some involved molecular signaling mechanisms have been elucidated.[13][14][15]

Teriparatide is an analog of PTH binds through the N-terminal moiety to PTH type 1 receptors (PTH type 1R). PTH type 1R are G-protein coupled receptors (GPCR) expressed on surfaces of various cells, the most important of which in respect to the classical physiological actions of PTH on calcium and phosphate homeostasis and bone metabolism are osteoblasts, osteocytes, and renal tubular cells. Following ligand binding to the receptor, both Gs–mediated activation of adenylate cyclase and Gq-mediated-activation of protein kinase C (PKC) occur.[15][16] Adenylate cyclase catalyzes the generation of the secondary messenger cAMP, which ultimately activates protein kinase A (PKA).  Although PTH activates both PKA- and PKC-dependent signaling pathways, the PKA-dependent pathway is the primarily used one for its anabolic and catabolic effects on bone.[16] The anabolic effects of (intermittent) PTH are mediated by (1) upregulated transcriptional expression of pro-osteoblastogenic growth factors like insulin-like growth factor 1 (IGF1), fibroblast growth factor 2 (FGF2); (2) modulation of the wnt/beta-catenin osteoanabolic signaling pathway by down-regulating the synthesis of the wnt-antagonist sclerostin, and (3) increased expression and activity of Runx2 - a transcription factor essential for differentiation of osteoblasts.[13][15][16] These pathways lead to an increased osteoblast survival and number, which results in the new growth of trabecular and cortical bones. This mode of action stands in stark contrast to that of antiresorptive agents (i.e., bisphosphonates, long-term estrogen, raloxifene, and nasal calcitonin). These agents inhibit osteoclast-mediated bone resorption, and by doing so, also inhibit new bone formation because the two processes of resorption and formation are tightly coupled together.[10] To exert its catabolic effects, PTH acts on the same receptors in osteoblasts and osteocytes, increasing expression of pro-osteoclastogenic cytokines like receptor activator of nuclear factor kappa-B ligand (RANKL), and macrophage colony-stimulating factor.[15][16] RANKL interacts with its receptor (RANK) on osteoclast hematopoietic precursor cells, promoting osteoclastic differentiation and activation.  It is worth mentioning that two FDA-approved therapies for osteoporosis target these complex signaling mechanisms to bring about their effects: denosumab is a RANKL inhibitor and the recently approved romosozumab as a sclerostin antagonist. 

  • Effects on Calcium and Phosphate Homeostasis

Teriparatide has the same actions of endogenous PTH on calcium and phosphate homeostasis (i.e., increases serum calcium and lowers serum phosphate). These effects are generated through the well-known effects of PTH on kidney and bone. In the kidney, PTH stimulates distal tubular calcium reabsorption, inhibits proximal tubular phosphate reabsorption, and activates 1-alpha-hydroxylase enzyme in proximal tubules, which subsequently converts the filtered 25-hydroxyvitamin D to 1,25-dihydroxy vitamin D, the most active vitamin D metabolite. In bone, it mobilizes calcium from the bone matrix into circulation.

Administration

Teriparatide administration is via subcutaneous injection into the abdominal wall or anterior thigh.

The dosage is 20 micrograms per day. Pens containing 28 day supply of pre-filled 20 mcg doses are available.

The administration should be at a site where the patient can sit or lie down in case orthostatic hypotension develops.

The maximum duration of usage is limited to 2 years because of a theoretical risk of osteosarcoma.

Patients should also be prescribed supplemental calcium and vitamin d during the duration of the treatment.

Adverse Effects

Teriparatide is a well-tolerated drug. Short term side effects reported by patients include nausea, headache, dizziness, and orthostatic hypotension.  Alterations of calcium metabolism are common, with hypercalcemia and hypercalciuria being the two most frequent side effects.[12] Hypercalcemia seen is most commonly mild and transient, and rarely ( 3% of patients taking 20 microgram/day) does it become persistent and requires dose reduction or discontinuation of treatment.[14][10] Although it increased renal calcium excretion from baseline, significant hypercalcemia or its renal sequelae like nephrolithiasis and nephrosclerosis have not been reported.[10]

The most concerning adverse effect of teriparatide therapy is the risk of skeletal carcinogenicity, most notably osteosarcoma. Researchers detected the carcinogenic effect in Fisher rats subjected to the treatment of relatively high doses ranging from 5 to 75 mcg/kg/day for a 2-yr period. It is considered to be minimal and nonsignificant in humans because of several lines of evidence: differences between rat and human skeletal physiologies, the fact that two years represent almost 90% of the rats' lifespan while representing only 2 to 3 % of that of humans and the doses used are three to 58-fold the prescribed human dose, the detection of only 3 cases of osteosarcoma with unproven causality in over 1 million patients treated with teriparatide, and an ongoing post-marketing surveillance study of teriparatide use in humans showing no incident risk of osteosarcoma at 8-year interim analysis.[14][10][17][18][19] It bears mentioning that the FDA limited approval to 2 years based on the Fisher rats toxicity study because of the uncertain relevance of rat osteosarcoma findings to humans, as mentioned in the FDA drug label, and that much of the available evidence regarding teriparatide-related osteosarcoma risk in humans was not available at the time of approval in 2002. 

Contraindications

Teriparatide is contraindicated in patients with :

  • Hypersensitivity to teriparatide or its excipients.
  • Increased basal risk for osteosarcoma like Paget disease of bone, history of primary or secondary skeletal malignancy, history of ionizing radiation involving the skeleton, pediatric and young patients with open epiphyses
  • Hypercalcemia
  • Hypercalciuria and/or urolithiasis because it causes hypercalciuria, which promotes urinary stones.

Monitoring

Patients who are on teriparatide therapy should be monitored by serum calcium measurements at one month of treatment, with subsequent follow-up intervals according to serum calcium level and the physician’s discretion. If hypercalcemia is present, the dose of supplemental calcium should be reduced fist; if it does not return to baseline, treatment should be administered every other day; if it persists, treatment should be discontinued, and the patient should undergo diagnostic investigation for the cause of hypercalcemia.[10]

BMD requires evaluation 1-year post first dose.

Before starting treatment, serum and urinary calcium should be measured because both hypercalcemia and hypercalciuria constitute contraindications to recombinant PTH therapy.

Toxicity

Overdose symptoms are transient and are the same as the most commonly reported side effects associated with therapeutic dose: nausea, vomiting, dizziness, orthostatic hypotension. There have been no fatalities reported.

Enhancing Healthcare Team Outcomes

Recombinant parathyroid hormone falls in a new category of osteoporosis therapy called anabolic therapy. It is the first approved drug of this category and has shown to improve outcomes for patients with osteoporosis. Like any therapy, Teriparatide also comes with potential side effects, most notably, a theoretical risk of osteosarcoma. Healthcare providers should be aware of the evidence related to this side effect and communicate it effectively to their patients in a manner that assists the patient in making the best-informed decision and acknowledges both the worrisome nature of an osteosarcoma risk and the clinical benefit of this therapy (reduction in vertebral and nonvertebral (e.g., hip) fractures and strengthening of bones). Orthostatic hypotension should also be a concern, and patients need to be informed about how to prevent and manage it. This issue is a high priority, especially in this osteoporotic patient population, where a slight fall might result in a catastrophic fracture.


References

[1] Neer RM,Arnaud CD,Zanchetta JR,Prince R,Gaich GA,Reginster JY,Hodsman AB,Eriksen EF,Ish-Shalom S,Genant HK,Wang O,Mitlak BH, Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. The New England journal of medicine. 2001 May 10;     [PubMed PMID: 11346808]
[2] Body JJ,Gaich GA,Scheele WH,Kulkarni PM,Miller PD,Peretz A,Dore RK,Correa-Rotter R,Papaioannou A,Cumming DC,Hodsman AB, A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1-34)] with alendronate in postmenopausal women with osteoporosis. The Journal of clinical endocrinology and metabolism. 2002 Oct;     [PubMed PMID: 12364430]
[3] Wang YK,Qin SQ,Ma T,Song W,Jiang RQ,Guo JB,Li K,Zhang YM, Effects of teriparatide versus alendronate for treatment of postmenopausal osteoporosis: A meta-analysis of randomized controlled trials. Medicine. 2017 May;     [PubMed PMID: 28538396]
[4] Liu CL,Lee HC,Chen CC,Cho DY, Head-to-head comparisons of bisphosphonates and teriparatide in osteoporosis: a meta-analysis. Clinical and investigative medicine. Medecine clinique et experimentale. 2017 Jun 26;     [PubMed PMID: 28653616]
[5] Kendler DL,Marin F,Zerbini CAF,Russo LA,Greenspan SL,Zikan V,Bagur A,Malouf-Sierra J,Lakatos P,Fahrleitner-Pammer A,Lespessailles E,Minisola S,Body JJ,Geusens P,Möricke R,López-Romero P, Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial. Lancet (London, England). 2018 Jan 20;     [PubMed PMID: 29129436]
[6] Kurland ES,Cosman F,McMahon DJ,Rosen CJ,Lindsay R,Bilezikian JP, Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral density and bone markers. The Journal of clinical endocrinology and metabolism. 2000 Sep;     [PubMed PMID: 10999788]
[7] Orwoll ES,Scheele WH,Paul S,Adami S,Syversen U,Diez-Perez A,Kaufman JM,Clancy AD,Gaich GA, The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2003 Jan;     [PubMed PMID: 12510800]
[8] Saag KG,Shane E,Boonen S,Marín F,Donley DW,Taylor KA,Dalsky GP,Marcus R, Teriparatide or alendronate in glucocorticoid-induced osteoporosis. The New England journal of medicine. 2007 Nov 15;     [PubMed PMID: 18003959]
[9] Saag KG,Zanchetta JR,Devogelaer JP,Adler RA,Eastell R,See K,Krege JH,Krohn K,Warner MR, Effects of teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: thirty-six-month results of a randomized, double-blind, controlled trial. Arthritis and rheumatism. 2009 Nov;     [PubMed PMID: 19877063]
[10] Hodsman AB,Bauer DC,Dempster DW,Dian L,Hanley DA,Harris ST,Kendler DL,McClung MR,Miller PD,Olszynski WP,Orwoll E,Yuen CK, Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use. Endocrine reviews. 2005 Aug;     [PubMed PMID: 15769903]
[11] Kanis JA,Johnell O,De Laet C,Johansson H,Oden A,Delmas P,Eisman J,Fujiwara S,Garnero P,Kroger H,McCloskey EV,Mellstrom D,Melton LJ,Pols H,Reeve J,Silman A,Tenenhouse A, A meta-analysis of previous fracture and subsequent fracture risk. Bone. 2004 Aug;     [PubMed PMID: 15268886]
[12] Cheng ML,Gupta V, Teriparatide - Indications beyond osteoporosis. Indian journal of endocrinology and metabolism. 2012 May;     [PubMed PMID: 22629497]
[13] Canalis E, MANAGEMENT OF ENDOCRINE DISEASE: Novel anabolic treatments for osteoporosis. European journal of endocrinology. 2018 Feb;     [PubMed PMID: 29113980]
[14] Cipriani C,Irani D,Bilezikian JP, Safety of osteoanabolic therapy: a decade of experience. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2012 Dec;     [PubMed PMID: 23165426]
[15] Jilka RL, Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone. 2007 Jun;     [PubMed PMID: 17517365]
[16] Lee M,Partridge NC, Parathyroid hormone signaling in bone and kidney. Current opinion in nephrology and hypertension. 2009 Jul;     [PubMed PMID: 19395963]
[17] Minisola S,Cipriani C,Grotta GD,Colangelo L,Occhiuto M,Biondi P,Sonato C,Vigna E,Cilli M,Pepe J, Update on the safety and efficacy of teriparatide in the treatment of osteoporosis. Therapeutic advances in musculoskeletal disease. 2019;     [PubMed PMID: 31632472]
[18] Vahle JL,Sato M,Long GG,Young JK,Francis PC,Engelhardt JA,Westmore MS,Linda Y,Nold JB, Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety. Toxicologic pathology. 2002 May-Jun;     [PubMed PMID: 12051548]
[19] Gilsenan A,Harding A,Kellier-Steele N,Harris D,Midkiff K,Andrews E, The Forteo Patient Registry linkage to multiple state cancer registries: study design and results from the first 8 years. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2018 Oct;     [PubMed PMID: 29978254]