NON-HORMONAL AGENTS

Bisphosphonates
• Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar
diseases.
• They are the most commonly prescribed drugs used to treat osteoporosis.
• They are called bisphosphonates because they have two phosphonate (PO(OH)2) groups.
• They are thus also called diphosphonates (bis- or di- + phosphonate).
• Evidence shows that they reduce the risk of fracture in post-menopausal women with osteoporosis.
• Bone tissue undergoes constant remodeling and is kept in balance (homeostasis) by osteoblasts creating bone
and osteoclasts destroying bone.
• Bisphosphonates inhibit the digestion of bone by encouraging osteoclasts to undergo apoptosis, or cell death,
thereby slowing bone loss.
• The uses of bisphosphonates include the prevention and treatment of osteoporosis, Paget's disease of bone,
bone metastasis (with or without hypercalcemia), multiple myeloma, primary hyperparathyroidism,
osteogenesis imperfecta, fibrous dysplasia, and other conditions that exhibit bone fragility.

Pharmacokinetics
• of the bisphosphonate that is resorbed (from oral preparation) or infused (for intravenous drugs), about 50% is
excreted unchanged by the kidney.
• The remainder has a very high affinity for bone tissue, and is rapidly adsorbed onto the bone surface.
• Once bisphosphonates are in bone, they have a very long elimination half-life that can exceed ten years.

Mechanism of action
• Bisphosphonates are structurally similar to pyrophosphate, but with a central carbon that can have up to two
substituents (R1 and R2) instead of an oxygen atom.
• Because a bisphosphonate group mimics the structure of pyrophosphate, it can inhibit activation of enzymes that
utilize pyrophosphate.
• The specificity of bisphosphonate-based drugs comes from the two phosphonate groups (and possibly a hydroxyl
at RI) that work together to coordinate calcium ions.
• Bisphosphonate molecules preferentially bind to calcium ions.
• The largest store of calcium in the human body is in bones, so bisphosphonates accumulate to a high concentration
only in bones
• Bisphosphonates, when attached to bone tissue, are released by osteoclasts, the bone cells that break down bone
tissue.
• Bisphosphonate molecules then attach to and enter osteoclasts where they disrupt intracellular enzymatic
functions needed for bone resorption.
There are two classes of bisphosphonate compounds:
non-nitrogenous (no nitrogen in R2)
nitrogenous (R2 contains nitrogen).
• The two types of bisphosphonates work differently in killing osteoclasts.

Non-nitrogenous
• The non-nitrogenous bisphosphonates (diphosphonates) are metabolized in the cell to compounds that replace
the terminal pyrophosphate moiety of ATP, forming a non- functional molecule that competes with adenosine
triphosphate (ATP) in the cellular energy metabolism.
• The osteoclast initiates apoptosis and dies, leading to an overall decrease in the breakdown of bone.
• This type of bisphosphonate has overall more negative effects than the nitrogen containing group, and is
prescribed far less often.
Non-nitrogenous
➢ Etidronate (Didronel)
➢ Clodronate (Bonefos, Loron)
➢ Tiludronate (Skelid)

Nitrogenous
• Nitrogenous bisphosphonates act on bone metabolism by binding and blocking the enzyme farnesyl diphosphate
synthase (FPPS) in the HMG-CoA reductase pathway (also known as the mevalonate pathway).
• Bisphosphonates that contain isoprene chains at the R1 or R2 position can impart specificity for inhibition of
GGPS1.
• Geranylgeranyl pyrophosphate synthase is an enzyme that in humans is encoded by the GGPS 1 gene.
Nitrogenous
➢ Pamidronate (APD, Aredia) Neridronate (Nerixia)
➢ Olpadronate
➢ Alendronate (Fosamax)
➢ Ibandronate (Boniva - US, Bonviva - Asia)
➢ Risedronate (Actonel)
➢ Zoledronate (Zometa, Aclasta)
Calcimimetics
• Calcimimetics are a new class of compounds that bind to the parathyroid calcium sensing receptor, increase its
sensitivity to ionized calcium by allosteric modification, and dose dependently decrease plasma PTH levels by up
to 80%.
• Calcimimetics define a new class of pharmaceuticals with proven safety and efficacy in treating secondary HPT in
patients on dialysis and in certain patients with primary HPT.
• Calcimimetics reduce levels of parathyroid hormone and serum calcium.
• The main regulator of the parathyroid formation and release is calcium-sensing receptors on the cells of the
parathyroid gland.
• Calcimimetics act to increase the sensitivity of the calcium-sensing receptor to extracellular calcium and therefore
there is a decrease in parathyroid hormone and a decrease in serum calcium levels.

List of Calcimimetics
• Sensipar (Pro)
Generic name: cinacalcet
• Parsabiv (Pro)
Generic name: etelcalcetid

Cinacalcet
• Cinacalcetis a calcium sensing receptor agonist used to treat secondary hyperparathyroidism in chronic kidney
disease and hypercalcemia in parathyroid carcinoma.
• Brand Names:
Mimpara
Sensipar
• Generic Name :
Cinacalcet
Background:
• Cinacalcet is a calcimimetic sold by Amgen under the trade name Sensipar in North America and Australia and as
Mimpara in Europe. It is used to treat hyperparathyroidism due to parathyroid tumors or renal failure.
Indication
• For the treatment of secondary hyperparathyroidism in patients with Chronic Kidney Disease who are on
hemodialysis or peritoneal dialysis. Also for the treatment of hypercalcemia in patients with parathyroid
carcinoma.
Associated Conditions:
Hypercalcemia
Secondary Hyperparathyroidism! (SHPT)
Pharmacodynamics
• Cinacalcet is a drug that acts as a calcimimetic (.e.it mimics the action of calcium on tissues). Secondary
hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) is a progressive disease, associated with
increases in parathyroid hormone (PTH) levels and derangements in calcium and phosphorus metabolism.
Increased PTH stimulates osteoclastic activity resulting in cortical bone resorption and marrow fibrosis. The goals
of treatment of secondary hyperparathyroidism are to lower levels of PTH, calcium, and phosphorus in the blood,
in order to prevent progressive bone disease and the systemic consequences of disordered mineral

Cinacalcet
• In CKD patients on dialysis with uncontrolled secondary HPT, reductions in PTH are associated with a favorable
impact on bone- specific alkaline phosphatase (BALP), bone turnover and bone fibrosis. Cinacalcet reduces calcium
levels by increasing the sensitivity of the calcium sensing receptor to extracellular calcium.
Mechanism of action:
• Cinacalcet directly lowers parathyroid hormone levels by increasing the sensitivity of the calcium sensing
receptors to activation by extracellular calcium, resulting in the inhibition of PTH secretion.
• The reduction in PTH is associated with a concomitant decrease in serum calcium levels
Absorption:
• Rapidly absorbed following oral administration.
PRODUCT IMAGE

Calcimimetics
Medical conditions associated with calcimimetics:
Hypercalcemia of Malignancy
Hyperparathyroidism Secondary to Renal Impairment
Primary Hyperparathyroidism
Secondary Hyperparathyroidism
• Calcimimetics are used to treat mineral and bone disorder by reducing parathyroid hormone (PTH), calcium (Ca),
and phosphorus (Phos).
• A calcimimeticis a pharmaceutical drug that mimics the action of calcium on tissues, by allosteric activation of the
calcium-sensing receptor that is expressed in various human organ tissues. Calcimimetics are used to treat
secondary hyperparathyroidism (SHPT).
Plicamycin
• Plicamycinis an antineoplastic antibiotic produced by Streptomyces plicatus. It has been used in the treatment of
testicular cancer, Paget's disease of bone, and, rarely, the management of hypercalcemia.
• The manufacturer discontinued plicamycin in 2000.
• Plicamycin is an antibiotic isolated from the bacterium Streptomyces plicatus with antineoplastic activity.
• Plicamycin, also known as mithramycin, binds to the minor groove of DNA at GC-rich sites, resulting in inhibition
of RNA synthesis; this agent also inhibits mRNA expression, resulting in a reduction in protein synthesis.
• In addition, plicamycin may inhibit bone resorption by down regulating transcription of C- src, an oncogene
involved in bone metabolism and resorption.
• Plicamycin, which was formerly known as mithramycin, is an antibiotic that is used as an anticancer agent in the
therapy of testicular and germ cell cancers.
• Plicamycin causes acute hepatic injury that arises within days of starting therapy, but is usually transient and
asymptomatic and rarely leads to jaundice.
• Plicamycin has not been approved for use as cancer chemotherapy in the United States, but continues to be used
on an investigational basis
• Plicamycin (INN, also known as mithramycin; trade name Mithracin) is an antineoplastic antibiotic produced by
Streptomyces plicatus.
• It is an RNA synthesis inhibitor.
• The manufacturer discontinued production in 2000. Several different structures are currently reported in different
places all with the same chromomycin core, but with different stereochemistry in the glycoside chain, a 1999 study
has re-investigated the compound and proposed a revised structure.
Uses
• Plicamycin has been used in the treatment of testicular cancer, Paget's disease of bone, and, rarely, the
management of hypercalcemia.
• Plicamycin has been tested in chronic myeloid leukemia.
• Plicamycin is currently used in multiple areas of research, including cancer cell apoptosis and as a metastasis
inhibitor.
• One elucidated pathway shows it interacts by cross- binding chromatin GC-rich promoter motifs, thereby

Thiazides
• Thiazide refers to both a class of sulfur- containing organic molecules and a class of diuretics based on the chemical
structure of benzothiadiazine.
• The thiazide drug class was discovered and developed at Merck and Co. in the 1950s.
• The first approved drug of this class, chlorothiazide, was marketed under the trade name Diuril beginning in 1958.
• In most countries, thiazides are the least expensive antihypertensive drugs available
• Thiazide organic molecules are bi-cyclic structures that contain adjacent sulfur and nitrogen atoms on one ring.
• Confusion sometimes occurs because thiazide-like diuretics such as indapamide are referred to as thiazides
despite not having the thiazide chemical structure.
• When used this way, "thiazide" refers to a drug which acts at the thiazide receptor
• The thiazide receptor is a sodium-chloride transporter that pulls NaCl from the lumen in the distal convoluted
tubule.
• Thiazide diuretics inhibit this receptor, causing the body to release NaCl and water into the lumen, thereby
increasing the amount of urine produced each day.
An example of a molecule that is chemically a thiazide but not used as a diuretic is methylchloroisothiazolinone, often
found as an antimicrobial in cosmetics.

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CI
• Thiazides reduce the clearance of uric acid since they compete for the same transporter, and therefore raise the
levels of uric acid in the blood. Hence, they are prescribed with caution in patients with gout or hyperurice'mia.
• Chronic administration of thiazides is associated with the increase of insulin resistance which can lead to
hyperglycemia.
• Thiazides cause loss of blood potassium, while conserving blood calcium.
• Thiazides can decrease placental perfusion and adversely affect the fetus, so should be avoided in pregnancy,

Fluoride
• Fluoride is a form of the chemical element fluorine.
• It is used as medicine.
• Fluoride is most commonly used to prevent cavities, and to treat tooth plaque, a mild form of gum disease
(gingivitis), and weak and brittle bones (osteoporosis).
• Fluoride protects teeth from the bacteria in plaque.
• It also promotes new bone formation.
• This is different than most medicines used for weak bones (osteoporosis), which fight osteoporosis by keeping
bone from being broken down.
• Fluoride is an inorganic, monatomic anion of fluorine, with the chemical formula F, whose salts are typically white
or colorless.
• Fluoride salts typically have distinctive bitter tastes, and are odorless.