Calcium Pharmacology & Parathyroid Disorders

• 99% of bodily calcium is stored in bone, while 1% circulates in serum
• Serum calcium is crucial for muscle contraction, neuronal function, blood clotting, metabolic processes, and cell adhesion
• Serum calcium is regulated by parathyroid hormone, Vitamin D, and calcitonin

Calcium Pharmacology: Key Drug Treatments

• Focus is on drugs for hypo- and hyperparathyroidism and osteoporosis

Learning Objectives: Parathyroid Disorders

• Understanding the relationship between serum calcium and parathyroid hormone (PTH) under normal and disease states is important
• Pharmacologic interventions for hyperparathyroidism, hypercalcemia of malignancy, hypoparathyroidism, and chronic kidney disease are key
• Important drug therapies include bisphosphonates, calcimimetics, calcitonin, calcitriol, and sevelamer

Drugs to Know - Parathyroid Treatments:

• Alendronate is an oral bisphosphonate used for primary hyperparathyroidism
• Cinacalcet is a calcimimetic for primary hyperparathyroidism
• Miacalcin (calcitonin-salmon) addresses severe hypercalcemia
• Zoledronic acid is an IV bisphosphonate used for severe hypercalcemia
• Sevelamer is a resin that binds dietary phosphate in the GI tract
• Calcitriol is the active form of Vitamin D3, which is 1,25-dihydroxyvitamin D3

PTH's Actions to Elevate Serum Calcium

• PTH's main goal is to increase serum calcium
• PTH decreases urinary calcium excretion
• PTH stimulates Ca2+ reabsorption in the distal tubule within minutes of secretion
• PTH increases bone resorption
• PTH mobilizes calcium from bone rapidly
• PTH increases intestinal calcium absorption
• PTH stimulates 1α-hydroxylase expression in the kidney, which converts 25(OH)D to the active form of vitamin D

PTH Secretion Regulation

• PTH secretion from the parathyroid gland is inversely related to serum calcium
• A minor drop in blood ionized calcium leads to a surge in PTH serum
• Increased PTH raises serum calcium
• The minute-by-minute control of ionized calcium (Ca2+) is primarily managed through PTH changes

Calcium-Sensing Receptors (CaSRs)

• Serum calcium regulates PTH through calcium-sensing receptors (CaSR) in the parathyroid gland
• Parathyroid gland CaSRs identify the concentration of extracellular calcium
• Activation of CaSRs by small increases in serum calcium halts PTH secretion
• When serum calcium decreases, CaSRs are deactivated, prompting PTH secretion
• CaSRs are dimeric GPCRs in calcium-regulating tissues like parathyroid glands and kidneys
• CaSRs regulate PTH production and release inversely in the parathyroid glands
• CaSR activation decreases PTH release, which lowers serum calcium

PTH, Calcium and Disease

• Primary hyperparathyroidism involves a noncancerous tumor (adenoma) on a parathyroid gland
• Surgery is typically advised, but alendronate (oral bisphosphonate) and cinacalcet can also be used if patient is not a surgery candidate
• Alendronate inhibits bone resorption to offset excess PTH, while cinacalcet enhances CaSR activation to reduce PTH secretion
• Hypercalcemia of malignancy affects patients with nonmetastatic solid tumors that secrete PTHrP or in 20% of cases, bone metastasis
• Severe hypercalcemia requires IV fluids and pharmacologic agents
• Calcitonin reduces serum Ca2+ by inhibiting osteoclast activity; miacalcin is favored
• Bisphosphonates (typically IV zoledronic acid) act more slowly than calcitonin, but are used concurrently
• Hypoparathyroidism is characterized by lacking or having poor thyroid hormone, leading to a low calcium serum
• First-line treatments for Hypoparathyroidism include calcium with active vitamin D supplements
• NATPARA is recombinant PTH can be used to control serum calcium in hypoparathyroidism if first-line treatments fail
• Secondary hyperparathyroidism is associated with chronic kidney disease (CKD)
• Kidney dysfunction results in hyperphosphatemia and deficiencies in Calcitriol resulting in hypocalcemia
• This situation will chronically increase PTH secretion in an attempt to fix it
• Phosphate-lowering treatments can fix the original problem
• Patients vitamin D deficiency needs to be treated to maintain serum calcium in normal ranges
• Cinacalcet can combat hyperparathyroidism at normal serum calcium levels

Osteoporosis Drugs to Know:

• Bisphosphonates work via inhibiting osteoclasts
• Denosumab works targeting RANKL mAbs
• Teriparatide is a PTH analog
• Abaloparatide is a PTHrP analog
• Romosozumab is a sclerostin mAb
• Vitamin D and Calcium are adjunct agents for all therapies

Osteoporosis Guideline Update

• Low-to-moderate risk patients should be given bisphosphonates
• High-to-very high risk patients on the other hand should get bisphosphonates, denosumab, teriparatide or abaloparatide, romosozumab etc

Bisphosphonates

• Bisphosphonates are primarily used for osteoporosis treatment and prevention, also Paget's disease, and bone cancers
• Bone mineral density in postmenopausal women increases with these drugs
• Commonly prescribed ones include an alendronate (Fosamax PO once a week) and zoledronic acid (Reclast -IV once-a-year)
• Bisphosphonates closely resemble pyrophosphate and exhibit charges in both acidic and neutral pH conditions
• Orally, bisphosphonates are best taken on an empty stomach with plenty of water
• Of bisphosphonate molecules that are absorbed, 70% are filtered through the kidney with 60 minutes, and 30% accumulates in bone tissue until active osteoclasts eat it up
• Bisphosphonates work by inhibiting bone resorption and osteoclast survival, which induces apoptosis
• Major bisphosphonates include nitrogenous molecules like alendronate and zoledronic acid
• Adverse effects can include osteonecrosis and femoral shaft fractures

Denosumab (Prolia)

• It is a regulator made by osteoblasts to activate osteoclasts
• Denosumab halts formation, activation, migration, and survival of osteoclasts and is often recommended for initial treatment of osteoporosis
• Administered via injection every 6 months

Teriparatide (Forteo)

• Teriparatide is a synthetic form of PTH
• It increases bone mass via daily doses
• It is approved for high risks of fractures, by those that have Osteoporosis , or from steroid treatments, amongst others
• Administered daily subcutaneously

Abaloparatide

• Similar to teriparatide in action
• FDA considers this like the above, to treat osteoporosis under the same guidlines

Managing with Anabolic and Anti-resorptive Agents

• The impact is short-term with only 12 months with decreased risk of fractures if therapy continues for 24 months
• Mineral density can deplete quickly making combinations of treatment more ideal

Romosozumab

• Romosozumab inhibits sclerostin, also known as a regulatory factor

Romosozumab (Evenity)

• Approved for osteoporosis treatment, but has limited use of up to 12 doses

Calcium and Vitamin D

• Postmenopausal women with low bone mineral density should take a joint supplement as needed
• 1,000mg if over 50 years old
• 600 IU of vitamin D
• The active form of vitamin form is D3 rather than D or D2
• Dietary intakes need to be hydroxylated sequentially from the liver and then the kidney to be activated
• It is a major stimulant for intestinal calcium and improves the gradient