OSTEOTIDE

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

Indications

• Menopausal symptoms (e.g., hot flashes, vaginal dryness)
• Hypogonadism
• Thyroid disorders (e.g., hypothyroidism)
• Adrenal insufficiency
• Growth hormone deficiency
• Polycystic ovary syndrome (PCOS)

Dosage

Children: Refer to the BNF for Children for specific paediatric dosing guidelines, as these depend on the type of hormone and the condition being treated.

Adults: Refer to the specific hormone type and formulation for dosing guidance in adults, as dosages may vary significantly based on individual patient needs and specific conditions being treated.

Mechanism of action

Hormones exert their effects through binding to specific receptors on target cells, initiating a cascade of intracellular signaling pathways. This may involve the activation of gene expression, modulation of enzyme activity, or alteration of cell membrane permeability. The specific mechanism varies depending on the type of hormone and its target tissues.

Pharmacodynamics

Hormones have varied effects depending on their class and the target tissues involved. They can influence metabolic pathways, regulate growth and development, and affect mood and cognition. Hormones typically act through either genomic mechanisms, involving changes in gene transcription, or non-genomic pathways, which may involve rapid signaling via second messengers.

Pharmacokinetics

The pharmacokinetics of hormones vary widely based on their chemical structure, route of administration, and formulation. Generally, hormones are absorbed into circulation after administration, with peak plasma concentrations occurring at variable times depending on the specific hormone. They may be metabolized in the liver or other tissues, with elimination typically occurring through renal or biliary excretion. Half-lives can range from minutes to hours, influencing dosing frequency.

Interactions

• antiepileptics (carbamazepine, eslicarbazepine, fosphenytoin, oxcarbazepine, perampanel, phenobarbital, phenytoin, primidone, rufinamide, topiramate) + hormone replacement therapy: Unknown (decreases effects)
• bosentan + hormone replacement therapy: Unknown (decreases effects)
• ritonavir + hormone replacement therapy: Unknown (decreases effects)
• modafinil + hormone replacement therapy: Unknown (decreases effects)
• rifamycins + hormone replacement therapy: Unknown (decreases effects)
• St John's Wort + hormone replacement therapy: Unknown (decreases efficacy)
• etoricoxib + hormone replacement therapy: Unknown (increases exposure)

Dosage

Children: Dosage for human-derived biological products in pediatrics should be determined based on specific product guidelines and the clinical context.

Adults: Dosage for human-derived biological products varies widely. Refer to specific product information for appropriate dosing.

Mechanism of action

Human physiology is governed by complex biological systems involving various cellular and molecular pathways. The mechanisms of action for human-derived biological products vary widely depending on the specific context, including immune response, hormonal regulation, and metabolic processes.

Pharmacodynamics

Pharmacodynamics in humans involves the interaction of drugs with biological systems, resulting in therapeutic effects. This includes receptor binding, signal transduction, and physiological responses. The effects are influenced by genetic factors, existing health conditions, and concurrent medications.

Pharmacokinetics

Pharmacokinetics in humans involves the absorption, distribution, metabolism, and excretion (ADME) of substances. Factors such as age, sex, body weight, and organ function can significantly influence these processes. Drug absorption may occur via oral, intravenous, or other routes, while distribution depends on blood flow and tissue permeability. Metabolism typically occurs in the liver, and excretion primarily takes place through the kidneys.

Pregnancy

There is no specific information available; consult local guidelines.

Breast-feeding

There is no specific information available; consult local guidelines.

Storage

Store in a cool, dry place away from direct sunlight.

Indications

• Hypoparathyroidism
• Osteoporosis (in specific therapeutic formulations)
• Bone disorders associated with low calcium levels

Dosage

Children: Refer to the BNF for Children for specific paediatric dosing recommendations.

Adults: Refer to the BNF for specific adult dosing recommendations.

Mechanism of action

Parathyroid hormone acts primarily on bone and kidney tissues. In bones, it promotes osteoclast activity, leading to increased bone resorption and the release of calcium into the bloodstream. In the kidneys, it enhances tubular reabsorption of calcium, while promoting the excretion of phosphate. Additionally, parathyroid hormone indirectly increases intestinal calcium absorption by stimulating the production of active vitamin D (calcitriol) in the kidneys, which in turn enhances intestinal absorption of calcium.

Pharmacodynamics

Parathyroid hormone increases serum calcium levels through its actions on the bones, kidneys, and intestines. It has a biphasic effect on bone metabolism, stimulating bone resorption at high concentrations while promoting bone formation at lower doses. The hormone's action is finely tuned, as excessive levels can lead to bone loss, while insufficient levels can result in hypocalcemia and related complications.

Pharmacokinetics

Parathyroid hormone is rapidly cleared from the circulation, with a half-life of approximately 5 to 20 minutes. It is mainly metabolized by the liver and kidneys. The pharmacokinetic profile may vary based on factors such as the route of administration and individual patient characteristics. Parathyroid hormone is commonly administered subcutaneously in therapeutic settings, where its absorption is generally consistent.

Interactions

• bisphosphonates: Severe (decreases effects)

Pregnancy

Parathyroid hormone should only be used in pregnancy if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Caution is advised when using parathyroid hormone during breastfeeding; consult a healthcare professional.

Storage

Store in a refrigerator (2 to 8 degrees Celsius). Protect from light.

Indications

• Diabetes mellitus
• Chronic kidney disease-related anemia
• Hemophilia
• Cancer (as targeted therapy)
• Autoimmune diseases (e.g., rheumatoid arthritis)

Dosage

Children: Refer to specific product guidelines for dosing information.

Adults: Refer to specific product guidelines for dosing information.

Mechanism of action

Recombinant drugs function by mimicking the action of naturally occurring proteins in the body. For instance, recombinant insulin binds to insulin receptors on target tissues, facilitating glucose uptake and metabolism. Erythropoietin stimulates erythropoiesis by binding to erythropoietin receptors in the bone marrow, promoting the production of red blood cells.

Pharmacodynamics

The pharmacodynamics of recombinant drugs vary depending on the specific protein or hormone being replaced or supplemented. Generally, they exert their effects at the cellular level by interacting with specific receptors, leading to a cascade of biological responses. The therapeutic effects are usually dose-dependent and can vary based on the patient's biological response and the presence of antibodies against the recombinant product.

Pharmacokinetics

Pharmacokinetics of recombinant drugs include absorption, distribution, metabolism, and excretion (ADME) characteristics that can differ significantly based on the specific drug. Many recombinant proteins have a short half-life and require parenteral administration. They are typically distributed throughout the body via the bloodstream, metabolized by the liver and other tissues, and excreted primarily through the kidneys. The pharmacokinetics may be influenced by the patient's age, weight, and overall health.

Pregnancy

Recombinant proteins should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Caution is advised when administering recombinant proteins during breastfeeding, as the effects on the infant are not well established.

Storage

Store in a refrigerator at 2-8 degrees Celsius. Do not freeze, and protect from light.

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.