FORTEO

Indications

• Osteoporosis in postmenopausal women
• Osteoporosis in men at high risk of fracture
• Glucocorticoid-induced osteoporosis

Dosage

Children: Not established; refer to the BNF for Children for specific guidance

Adults: The recommended dosage for adults is 20 micrograms administered subcutaneously once daily.

Mechanism of action

Teriparatide acts by binding to the PTH type 1 receptors (PTH1R) on osteoblasts, which are bone-forming cells. This interaction activates downstream signaling pathways (PKA and PKC) that promote osteoblastic activity, leading to increased new bone formation. Unlike continuous exposure to PTH, which can lead to bone resorption, the intermittent dosing of teriparatide promotes net bone gain, enhancing both trabecular and cortical bone through stimulation of osteoblastic activity over osteoclastic activity.

Pharmacodynamics

As a PTH analog, teriparatide stimulates bone formation and increases markers of bone turnover. It has been shown to increase bone mineral density (BMD) and reduce the risk of vertebral and non-vertebral fractures. Teriparatide also influences calcium and phosphate metabolism, causing transient increases in serum calcium and urinary calcium excretion, as well as mild reductions in serum phosphorus levels. Its anabolic effects on bone contribute significantly to improved skeletal strength.

Pharmacokinetics

Teriparatide is administered via subcutaneous injection, with peak plasma concentrations typically occurring within 30 minutes post-injection. The elimination half-life is approximately 1 hour, and it is primarily metabolized by the liver. Teriparatide's pharmacokinetic profile allows for once-daily dosing, which is essential for its efficacy in stimulating bone formation. Renal function can impact teriparatide clearance, and caution is advised in patients with significant renal impairment.

Contra-indications

• Hypersensitivity to teriparatide or any of its excipients
• Uncontrolled hypercalcemia
• Pregnancy
• Severe renal impairment (creatinine clearance less than 30 mL/min)
• History of osteosarcoma or other skeletal malignancies

Adverse effects

• Nausea
• Dizziness
• Headache
• Muscle cramps
• Arthralgia
• Palpitations
• Fatigue
• Hypercalcemia
• Peripheral edema
• Constipation
• Diarrhea
• Vomiting
• Insomnia
• Anxiety
• Rare allergic reactions such as angioedema and urticaria

Interactions

• Strontium ranelate - avoid concurrent use
• Diuretics - may increase the risk of hypercalcemia
• Thiazide diuretics - may increase calcium levels
• Other medications affecting calcium metabolism

Precautions

• Caution in patients with cardiovascular disease, cerebrovascular disease or peripheral arterial disease
• Monitor for signs of hypercalcemia
• Caution in patients with renal impairment
• Consider monitoring for osteosarcoma in patients with Paget's disease or prior radiation therapy

Pregnancy

Manufacturer advises to avoid use during pregnancy due to potential toxicity as indicated by animal studies.

Breast-feeding

Manufacturer advises to avoid use during breastfeeding due to the presence of teriparatide in human milk.

Storage

Store in a refrigerator (2°C to 8°C). Do not freeze. Protect from light. After first use, the solution can be stored at room temperature for up to 28 days.

Formulations

• Teriparatide 250 micrograms per 1 mL solution for injection in a pre-filled disposable pen
• Teriparatide 20 micrograms/80 microlitres solution for injection in a pre-filled cartridge

Mechanism of action

Parathyroid hormone (PTH) is an endogenous hormone that regulates calcium and phosphate metabolism in bone and kidney. It regulates bone metabolism, renal tubular reabsorption of calcium and phosphate, and intestinal calcium absorption. It mediates its physiological actions by binding to the PTH receptors. Excess PTH - such as in certain disease states like hyperparathyroidism - can cause increased osteoclast activity and accelerated bone resorption. Interestingly, the effects of PTH depend on the dose and pattern of exposure of PTH to the bone. Continuous exposure to PTH promotes bone resorption, whereas intermittent exposure to low-dose PTH can induce bone formation more favourably than bone resorption. Similarly, teriparatide's skeletal effects depend upon the systemic exposure pattern. Once-daily administration of teriparatide stimulates new bone formation on trabecular and cortical (periosteal and/or endosteal) bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. Teriparatide mediates its osteoanabolic actions by binding to the N-terminal moiety to PTH type 1 receptors (PTH type 1R), which are G-protein coupled receptors expressed on various cells, including osteoblasts, osteocytes, and renal tubular cells. Binding of teriparatide to PTH receptors on osteoblasts activates the downstream PKA- and PKC-dependent signaling pathways that promotes anabolic effects on bone. For example, teriparatide increases expression of pro-osteoclastogenic cytokines like receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor. It also upregulates transcriptional expression of pro-osteoblastogenic growth factors like insulin-like growth factor 1 (IGF1) and fibroblast growth factor 2 (FGF2). Teriparatide also downregulates the synthesis of sclerostin, which is a negative regulator of bone formation. It also promotes the differentiation of osteoblasts. The skeletal effects of teriparatide depend upon the pattern of systemic exposure. Once-daily administration of teriparatide stimulates new bone formation on trabecular and cortical (periosteal and/or endosteal) bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. In monkey studies, teriparatide improved trabecular microarchitecture and increased bone mass and strength by stimulating new bone formation in both cancellous and cortical bone. In humans, the anabolic effects of teriparatide are manifest as an increase in skeletal mass, an increase in markers of bone formation and resorption, and an increase in bone strength. By contrast, continuous excess of endogenous PTH, as occurs in hyperparathyroidism, may be detrimental to the skeleton because bone resorption may be stimulated more than bone formation. Endogenous 84-amino-acid parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidney. Physiological actions of PTH include regulation of bone metabolism, renal tubular reabsorption of calcium and phosphate, and intestinal calcium absorption. The biological actions of PTH and teriparatide are mediated through binding to specific high-affinity cell-surface receptors. Teriparatide and the 34 N-terminal amino acids of PTH bind to these receptors with the same affinity and have the same physiological actions on bone and kidney. Teriparatide is not expected to accumulate in bone or other tissues.

Pharmacodynamics

Teriparatide is a PTH analog that works to stimulate bone formation in both men and women. It increases skeletal mass, increases markers of bone formation such as bone-specific alkaline phosphatase (BSAP) and procollagen I carboxy-terminal propeptide (PICP), and increases bone strength. Like endogenous PTH, teriparatide affects calcium and phosphate homeostasis. It causes a transient increase in serum calcium levels and increases urinary calcium excretion. In clinical trials, it also produced transient phosphaturia and mild transient reductions in serum phosphorus concentration.