ORTHOCOLE 5 600

Indications

• Primary prevention of vitamin D deficiency
• Treatment of vitamin D deficiency
• Renal osteodystrophy
• Established postmenopausal osteoporosis

Dosage

Adults: For the primary prevention of vitamin D deficiency: 400 units daily. For treatment of vitamin D deficiency: loading dose of 50

Mechanism of action

Colecalciferol is converted in the liver to 25-hydroxyvitamin D and subsequently in the kidneys to 1,25-dihydroxyvitamin D, its active form. These metabolites enhance the intestinal absorption of calcium and phosphorus, increase serum calcium and phosphate levels, and mobilize these minerals from bone. The synthesis of active metabolites requires 10 to 24 hours after administration, and the regulation of this metabolism is influenced by parathyroid hormone.

Pharmacodynamics

The pharmacological effects of colecalciferol are primarily mediated through its active metabolites, which promote the absorption of calcium and phosphate in the gastrointestinal tract, enhance renal reabsorption of calcium, and mobilize calcium from bones. This results in increased serum calcium levels, which are essential for various physiological functions, including bone mineralization. The action of colecalciferol is closely tied to parathyroid hormone levels, which regulate calcium homeostasis.

Pharmacokinetics

Colecalciferol is well absorbed from the gastrointestinal tract, particularly when taken with food. Its bioavailability can be affected by factors such as fat intake and gastrointestinal health. After absorption, colecalciferol is transported in the bloodstream, primarily bound to vitamin D-binding protein. Its distribution is widespread, and it is stored in adipose tissues. The half-life of colecalciferol is approximately 19 to 25 hours, but this can vary based on individual factors such as body fat and metabolic health.

Adverse effects

• Urinary tract infection
• Abdominal pain
• Dehydration
• Drowsiness
• Fever
• Growth retardation
• Muscle weakness
• Paralytic ileus
• Polydipsia
• Psychiatric disorders
• Sensory disorders
• Thirst
• Urinary disorders

Precautions

• Monitor plasma-calcium, phosphate, and creatinine concentrations regularly, particularly during dose titration.
• In patients with renal impairment, avoid unless advised by the manufacturer.
• Monitor calcium levels closely during treatment, especially if doses are adjusted.

Pregnancy

Colecalciferol can be used during pregnancy, but doses should be evaluated carefully to avoid excess vitamin D.

Breast-feeding

Colecalciferol is considered safe during breastfeeding, but supplementation should be monitored.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Capsules
• Tablets
• Oral solution
• Oral suspension

Indications

• Osteoporosis in postmenopausal women
• Osteoporosis in men
• Paget's disease of bone
• Glucocorticoid-induced osteoporosis

Dosage

Children: Safety and efficacy in children have not been established, thus specific pediatric dosing for alendronate is not available. Refer to the BNF for Children for further guidance.

Adults: For the treatment of osteoporosis, the usual dose is 10 mg once daily or 70 mg once weekly. For Paget's disease, the recommended dose is 40 mg once daily for 6 months.

Mechanism of action

Alendronic acid binds to bone hydroxyapatite. Bone resorption causes local acidification, releasing alendronic acid, which is taken into osteoclasts by fluid-phase endocytosis. This process leads to the apoptosis of osteoclasts, resulting in decreased bone resorption, as evidenced by reduced levels of urinary calcium and collagen degradation products.

Pharmacodynamics

Alendronic acid has very low oral bioavailability and distributes into soft tissues and bone. It does not undergo metabolism and is primarily excreted unchanged in urine. Its effects on bone density become apparent after sustained administration, as it preferentially accumulates at sites of active bone resorption.

Pharmacokinetics

After oral administration, alendronic acid has a very low bioavailability, with most of the drug being absorbed in the gastrointestinal tract. It subsequently distributes to bone and soft tissues. The drug is excreted in urine as unchanged alendronic acid, and it does not undergo significant metabolic transformation.

Adverse effects

• Gastrointestinal irritation
• Osteonecrosis of the jaw
• Atypical femoral fractures
• Abdominal pain
• Constipation
• Diarrhea
• Nausea
• Esophageal irritation
• Headache

Interactions

• aspirin+alendronate: Unknown (increases risk of gastrointestinal irritation)
• nsaids+alendronate: Unknown (increases risk of gastrointestinal irritation)
• oralmagnesium+alendronate: Unknown (decreases absorption)
• oralzinc+alendronate: Unknown (decreases absorption)

Precautions

• Use with caution in patients with renal impairment.
• Monitor for signs of gastrointestinal irritation.
• Assess dental health prior to initiation to minimize risk of osteonecrosis of the jaw.

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Alendronate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether alendronate is excreted in human milk. Caution should be exercised when administering to a nursing woman.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Alendronate sodium 10 mg tablet
• Alendronate sodium 70 mg tablet
• Alendronate sodium 70 mg/75 mL oral solution

Indications

• Osteoporosis in postmenopausal women
• Osteoporosis in men
• Paget's disease of bone
• Prevention of osteoporosis in patients receiving glucocorticoids

Dosage

Children: Refer to the BNF for Children for specific dosing information, as alendronic acid is not commonly used in pediatric populations.

Adults: Refer to the BNF for specific dosing information as it varies based on the condition treated.

Mechanism of action

Alendronic acid acts by inhibiting the enzyme farnesyl pyrophosphate synthase in the mevalonate pathway. This inhibition decreases the activity of osteoclasts, the cells responsible for bone resorption, leading to a net increase in bone density and strength.

Pharmacodynamics

The pharmacodynamic effects of alendronic acid include increased bone density and reduced incidence of vertebral and hip fractures. The drug preferentially accumulates in areas of high bone turnover, exerting its effects primarily on cortical and trabecular bone.

Pharmacokinetics

Alendronic acid is poorly absorbed from the gastrointestinal tract, with bioavailability estimated at 0.5% to 1%. After oral administration, peak plasma concentrations occur within 1 to 3 hours. The drug has a long half-life, with a terminal elimination half-life of approximately 10 years due to its strong binding to bone. It is primarily excreted unchanged in urine.

Contra-indications

• Hypersensitivity to alendronic acid or any excipients
• Abnormalities of the esophagus which delay esophageal emptying
• Inability to stand or sit upright for at least 30 minutes
• Hypocalcemia
• Severe renal impairment (creatinine clearance less than 35 mL/min)

Adverse effects

• Gastrointestinal disturbances (nausea, abdominal pain, dyspepsia)
• Esophageal irritation or ulceration
• Osteonecrosis of the jaw
• Atypical femoral fractures
• Musculoskeletal pain
• Hypocalcemia
• Skin rash or reactions
• Flu-like symptoms
• Renal impairment

Interactions

• Calcium supplements, antacids, or other medications containing divalent or trivalent cations may interfere with absorption
• NSAIDs may increase the risk of gastrointestinal adverse effects
• Other medications that affect renal function may enhance the risk of renal adverse effects

Precautions

• Use with caution in patients with a history of gastrointestinal disease
• Monitor renal function periodically during treatment
• Ensure adequate intake of calcium and vitamin D
• Advise patients about the signs and symptoms of osteonecrosis
• Caution in patients with a history of hypocalcemia

Pregnancy

Alendronic acid is not recommended during pregnancy due to potential risks to the fetus.

Breast-feeding

It is not known if alendronic acid is excreted in human breast milk. Caution is advised.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets (e.g., 5 mg, 10 mg, 35 mg, 70 mg)
• Oral solution

Mechanism of action

Alendronic acid binds to bone hydroxyapatite. Bone resorption causes local acidification, releasing alendronic acid which is that taken into osteoclasts by fluid-phase endocytosis. Endocytic vesicles are acidified, releasing alendronic acid to the cytosol of osteoclasts where they induce apoptosis. Inhibition of osteoclasts results in decreased bone resorption which is shown through decreased urinary calcium, deoxypyridinoline and cross-linked N-telopeptidases of type I collagen. Animal studies have indicated the following mode of action. At the cellular level, alendronate shows preferential localization to sites of bone resorption, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment, but it does inhibit osteoclast activity. Studies in mice on the localization of radioactive (3)H-alendronate in bone showed about 10-fold higher uptake on osteoclast surfaces than on osteoblast surfaces. Bones examined 6 and 49 days after (3)H-alendronate administration in rats and mice, respectively, showed that normal bone was formed on top of the alendronate, which was incorporated inside the matrix. While incorporated in bone matrix, alendronate is not pharmacologically active. Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Histomorphometry in baboons and rats showed that alendronate treatment reduces bone turnover (i.e., the number of sites at which bone is remodeled). In addition, bone formation exceeds bone resorption at these remodeling sites, leading to progressive gains in bone mass. Alendronate (alendronate sodium hydrate) is a nitrogen-containing bisphosphonate, which combines with the bone surface and reduces osteoclast-mediated bone resorption. It is a third-generation bisphosphonate compound, specifically distributed on the surface of bone resorption and taken into osteoclasts. Under the closed circumstances which is formed with osteoclast and the bone surface, alendronate becomes detached from the bone surface and taken into osteoclast since acid released from osteoclast leads to pH decrease (acidified). The uptaken alendronate blocks the pathway of mevalonic acid synthesis, which is cholesteric synthesis, inhibits the prenylation of GTP binding protein, and decreases the osteoclast's function by influencing the cytoskeleton. This restraint of alendronate in bone resorption against osteoclasts is reversible, showing no cytotoxicity at more than hundredfold concentration level at which action occurs. ... The differences that exist among individual BPs in terms of mineral binding and biochemical actions may explain differences in their clinical behavior and effectiveness. The classical pharmacological effects of bisphosphonates (BPs) appear to be the result of two key properties: their affinity for bone mineral and their inhibitory effects on osteoclasts. There is new information about both properties. Mineral binding affinities differ among the clinically used BPs and may influence their differential distribution within bone, their biological potency, and their duration of action. The antiresorptive effects of the nitrogen-containing BPs (including alendronate, risedronate, ibandronate, and zoledronate) appear to result from their inhibition of the enzyme farnesyl pyrophosphate synthase (FPPS) in osteoclasts. FPPS is a key enzyme in the mevalonate pathway, which generates isoprenoid lipids utilized for the post-translational modification of small GTP-binding proteins that are essential for osteoclast function. Effects on other cellular targets, such as osteocytes, may also be important. BPs share several common properties as a drug class. However, as with other families of drugs, there are obvious chemical, biochemical, and pharmacological differences among the individual BPs. Each BP has a uniqu

Pharmacodynamics

Alendronic acid tablets have a very low oral bioavialability. After administration it distributes into soft tissue and bone or is excreted in the urine. Alendronic acid does not undergo metabolism.

Mechanism of action

Most individuals naturally generate adequate amounts of vitamin D through ordinary dietary intake of vitamin D (in some foods like eggs, fish, and cheese) and natural photochemical conversion of the vitamin D3 precursor 7-dehydrocholesterol in the skin via exposure to sunlight. Conversely, vitamin D deficiency can often occur from a combination of insufficient exposure to sunlight, inadequate dietary intake of vitamin D, genetic defects with endogenous vitamin D receptor, or even severe liver or kidney disease. Such deficiency is known for resulting in conditions like rickets or osteomalacia, all of which reflect inadequate mineralization of bone, enhanced compensatory skeletal demineralization, resultant decreased calcium ion blood concentrations, and increases in the production and secretion of parathyroid hormone. Increases in parathyroid hormone stimulate the mobilization of skeletal calcium and the renal excretion of phosphorus. This enhanced mobilization of skeletal calcium leads towards porotic bone conditions. Ordinarily, while vitamin D3 is made naturally via photochemical processes in the skin, both itself and vitamin D2 can be found in various food and pharmaceutical sources as dietary supplements. The principal biological function of vitamin D is the maintenance of normal levels of serum calcium and phosphorus in the bloodstream by enhancing the efficacy of the small intestine to absorb these minerals from the diet. At the liver, vitamin D3 or D2 is hydroxylated to 25-hydroxyvitamin D and then finally to the primary active metabolite 1,25-dihydroxyvitamin D in the kidney via further hydroxylation. This final metabolite binds to endogenous vitamin d receptors, which results in a variety of regulatory roles - including maintaining calcium balance, the regulation of parathyroid hormone, the promotion of the renal reabsorption of calcium, increased intestinal absorption of calcium and phosphorus, and increased calcium and phosphorus mobilization of calcium and phosphorus from bone to plasma to maintain balanced levels of each in bone and the plasma. In particular, calcitriol interacts with vitamin D receptors in the small intestine to enhance the efficiency of intestinal calcium and phosphorous absorption from about 10-15% to 30-40% and 60% increased to 80%, respectively. Furthermore, calcitriol binds with vitamin D receptors in osteoblasts to stimulate a receptor activator of nuclear factor kB ligand (or RANKL) which subsequently interacts with receptor activator of nuclear factor kB (NFkB) on immature preosteoclasts, causing them to become mature bone-resorbing osteoclasts. Such mature osteoclasts ultimately function in removing calcium and phosphorus from bone to maintain blood calcium and phosphorus levels. Moreover, calcitriol also stimulates calcium reabsorption from the glomerular filtrate in the kidneys. Additionally, it is believed that when calcitriol binds with nuclear vitamin D receptors, that this bound complex itself binds to retinoic acid X receptor (RXR) to generate a heterodimeric complex that consequently binds to specific nucleotide sequences in the DNA called vitamin D response elements. When bound, various transcription factors attach to this complex, resulting in either up or down-regulation of the associated gene's activity. It is thought that there may be as much as 200 to 2000 genes that possess vitamin D response elements or that are influenced indirectly to control a multitude of genes across the genome. It is in this way that cholecalciferol is believed to function in regulating gene transcription associated with cancer risk, autoimmune disorders, and cardiovascular disease linked to vitamin D deficiency. In fact, there has been some research to suggest calcitriol may also be able to prevent malignancies by inducing cellular maturation and inducing apoptosis and inhibiting angiogenesis, exhibit anti-inflammatory effects by inhibiting foam cell formation and promoting angiogenesis in en

Pharmacodynamics

The in vivo synthesis of the predominant two biologically active metabolites of vitamin D occurs in two steps. The first hydroxylation of vitamin D3 cholecalciferol (or D2) occurs in the liver to yield 25-hydroxyvitamin D while the second hydroxylation happens in the kidneys to give 1, 25-dihydroxyvitamin D. These vitamin D metabolites subsequently facilitate the active absorption of calcium and phosphorus in the small intestine, serving to increase serum calcium and phosphate levels sufficiently to allow bone mineralization. Conversely, these vitamin D metabolites also assist in mobilizing calcium and phosphate from bone and likely increase the reabsorption of calcium and perhaps also of phosphate via the renal tubules. There exists a period of 10 to 24 hours between the administration of cholecalciferol and the initiation of its action in the body due to the necessity of synthesis of the active vitamin D metabolites in the liver and kidneys. It is parathyroid hormone that is responsible for the regulation of such metabolism at the level of the kidneys.