Drugs Affecting Calcium Levels and Bone Mineralization Chapter 75 Drugs Affecting Calcium Levels and Bone Mineralization 1

Calcium Physiology Functions and daily requirements Body stores Critical to function of the skeletal, nervous, muscular, and cardiovascular systems Body stores Bones: More than 98% stored in the bones Blood: Total serum calcium = 10 mg/dL Absorption Occurs in the small intestine Increased by parathyroid hormone and vitamin D Glucocorticoids decrease absorption Excretion Calcitonin augments calcium elimination 2

Calcium Physiology Regulation of calcium levels Absorption from the small intestine Excretion by the kidney Resorption in bone Regulated by Parathyroid hormone Vitamin D Calcitonin 3

Calcium Physiology Parathyroid hormone Promotes calcium resorption from bone Promotes tubular reabsorption of calcium that had been filtered by the kidney glomerulus Promotes activation of vitamin D, and thereby promotes increased absorption of calcium from the intestine 4

Calcium Physiology Vitamin D Increases calcium resorption from bone Decrease calcium excretion by the kidney Increases calcium absorption from the intestine 5

Calcium Physiology Calcitonin Released from the thyroid gland when calcium levels in the blood rise too high Lowers calcium levels by inhibiting resorption of calcium from bone and increasing calcium excretion by the kidney Does not influence calcium absorption 6

Hypercalcemia Usually asymptomatic If symptoms are present: Kidney, gastrointestinal (GI) tract, CNS Causes Cancer Hyperparathyroidism Vitamin D intoxication Sarcoidosis Use of thiazide diuretics 7

Hypercalcemia Treatment Drugs that promote urinary excretion of calcium Drugs that decrease mobilization of calcium from bone Drugs that decrease intestinal absorption of calcium Drugs that form complexes with free calcium in the blood IV saline Then diuresis with a loop diuretic 8

Hypercalcemia Drugs Edetate disodium Glucocorticoids Calcitonin Bisphosphonates Gallium nitrate Cinacalcet (Sensipar): Suppresses parathyroid hormone (PTH) secretion; used for hypercalcemia associated with hyperparathyroidism 9

Hypocalcemia Increases neuromuscular excitability Clinical presentation Tetany, convulsions, and spasm of the pharynx Causes Deficiency of PTH Deficiency of vitamin D Deficiency of calcium Chronic renal failure Long-term use of certain medications, such as magnesium-based laxatives, and drugs used to manage osteoporosis (for example, bisphosphonates and denosumab) 10

Hypocalcemia Treatment Intravenous calcium supplementation (calcium gluconate) Once calcium levels have been restored: Calcium citrate for maintenance Vitamin D 11

Other Disorders Involving Calcium Rickets (usually children) Vitamin D deficiency results in reduced calcium absorption PTH is released PTH restores serum calcium by promoting calcium resorption from bone, thereby causing bones to soften Stress on softened bones caused by bearing weight results in deformity Treatment: Vitamin D replacement therapy 12

Other Disorders Involving Calcium Osteomalacia (adult counterpart of rickets) Absence of vitamin D Impaired mineralization of bone Bowing of the legs Fractures of the long bones Kyphosis (“hunchback” curvature of the spine) Diffuse, dull, aching bone pain Treatment: Vitamin D replacement therapy 13

Other Disorders Involving Calcium Osteoporosis: Most common disorder of calcium metabolism Paget’s disease of bone Increased bone resorption and replacement of resorbed bone with abnormal bone Pelvis, femur, spine, skull, tibia Pain, skeletal deformity, fracture Treatment: Pain management and bisphosphonates to suppress bone resorption 14

Other Disorders Involving Calcium Hypoparathyroidism Cause: Inadvertent removal of parathyroid glands during surgery on the thyroid gland Lack of PTH: Hypocalcemia, paresthesias, tetany, skeletal muscle spasm, laryngospasm, convulsions Treatment: Calcium supplements 15

Other Disorders Involving Calcium Primary hyperparathyroidism Cause: Usually results from a benign parathyroid adenoma Increase in PTH secretion: Hypercalcemia and hypophosphatemia Skeletal muscle weakness, constipation, CNS symptoms, renal calculi, bone abnormalities Treatment: Surgical resection of parathyroid glands; calcium-lowering drugs – cinacalcet [Sensipar] 16

Other Disorders Involving Calcium Secondary hyperparathyroidism Cause: Common complication of chronic kidney disease (CKD) High levels of PTH and disturbances of calcium and phosphorus homeostasis Treatment Vitamin D sterol (for example, paricalcitol) and calcium-containing phosphate-binding agents Cinacalcet [Sensipar]: Can reduce PTH and has a positive effect on calcium and phosphorus levels 17

Drugs for Disorders Involving Calcium Calcium salts Oral Mild hypocalcemia, dietary supplements PMS Colorectal adenoma Adverse effects: Hypercalcemia Drug interactions: Corticosteroids, tetracycline, fluoroquinolone, thyroid hormone, phenytoin, bisphosphonates, loop diuretics, thiazide diuretics 18

Drugs for Disorders Involving Calcium Calcium salts (Cont.) Parenteral: Calcium chloride and calcium gluconate Adverse effects: Highly irritating; do not give IM; can cause IV extravasation Drug interaction: Digoxin 19

Drugs for Disorders Involving Calcium Vitamin D Important regulator of calcium and phosphorus homeostasis Health benefits Vitamin D deficiency Activation of vitamin D Vitamin D as a hormone 20

Drugs for Disorders Involving Calcium Vitamin D toxicity Early symptoms: Weakness, fatigue, nausea, vomiting, anorexia, abdominal cramping, constipation Later symptoms: Kidney function is affected, resulting in polyuria, nocturia, and proteinuria Neurologic: Seizures, confusion, ataxia Cardiac dysrhythmia Coma Calcium deposition in soft tissues Decalcification of bone 21

Drugs for Disorders Involving Calcium Calcium salts Vitamin D Calcitonin-salmon [Calcimar, Miacalcin, Fortical] Bisphosphonates Alendronate, risedronate, ibandronate, tiludronate, etidronate, zoledronate, pamidronate 22

Drugs for Disorders Involving Calcium Vitamin D Ergocalciferol [Calciferol Drops, Drisdol] Cholecalciferol (Vitamin D3) Calcitriol (1,25-Dihydroxy-D3)  Doxercalciferol [Hectorol] Paricalcitol [Zemplar] Calcitonin-salmon 23

Drugs for Disorders Involving Calcium Calcitonin Inhibits the activity of osteoclasts Decreases bone resorption Inhibits tubular resorption of calcium Increases calcium excretion Therapeutic uses: Osteoporosis, Paget’s disease, hypercalcemia Adverse effects 24

Drugs for Disorders Involving Calcium Bisphosphonates Structural analogs of pyrophosphate Incorporate into bone: Inhibit bone resorption by decreasing activity of osteoclasts Indications: Postmenopausal osteoporosis, osteoporosis in men, glucocorticoid-induced osteoporosis, Paget’s disease of bone, hypercalcemia of malignancy May also help prevent and treat bone metastases in patients with cancer Adverse effects: May include ocular inflammation, osteonecrosis of the jaw (ONJ), atypical femur fractures, atrial fibrillation (A-fib) 25

Bisphosphonates Alendronate [Fosamax, Fosamax Plus D] Most widely used oral bisphosphonate Uses: Postmenopausal osteoporosis, male osteoporosis, glucocorticoid-induced osteoporosis, Paget’s disease of bone Oral bioavailability: Poor Adverse effects: Generally safe; esophageal ulceration, atypical femoral fracture, esophageal cancer, musculoskeletal pain, ocular problems, ONJ, hyperparathyroidism, A-fib 26

Bisphosphonates Risedronate [Actonel] Uses: Postmenopausal osteoporosis, male osteoporosis, glucocorticoid-induced osteoporosis, Paget’s disease of bone Adverse effects: Arthralgia, diarrhea, headache, rash, nausea, flulike syndrome, esophagitis, atypical femoral fractures, ocular problems, musculoskeletal pain 27

Bisphosphonates Ibandronate [Boniva] Uses: Prevention and treatment of postmenopausal osteoporosis Dosing: Once a month or once every 3 months Adverse effects: GI effects, including esophagitis, dyspepsia, abdominal pain; ocular inflammation; atypical fractures; ONJ; renal damage if IV administered too rapidly 28

Bisphosphonates Tiludronate [Skelid] Use: Paget’s disease of bone Adverse effects: Nausea, diarrhea, dyspepsia, esophagitis, ocular problems, musculoskeletal pain, possibly esophageal cancer, chest pain, edema, paresthesias, hyperparathyroidism, vomiting, flatulence 29

Selective Estrogen Receptor Modulator (SERM) Raloxifene [Evista] Structurally similar to estrogen and binds to estrogen receptors Comparison to estrogen Therapeutic uses Osteoporosis Breast cancer Adverse effects Thromboembolic events, such as deep vein thrombosis (DVT), pulmonary embolism, and stroke, and fetal harm 30

Teriparatide [Forteo] Form of PTH Produced by recombinant DNA Only drug that increases bone formation Generally well tolerated Nausea, headache, back pain, leg cramps 31

Denosumab [Prolia, Xgeva] First-in-class RANKL inhibitor with three indications: Osteoporosis in postmenopausal women and in men at high risk for fractures Bone loss in women and men receiving certain anticancer therapy Prevention of skeletal-related events in patients with bone metastases from solid tumors RANKL, Receptor activator of nuclear factor kappa-B ligand.

Denosumab [Prolia, Xgeva] Adverse effects Hypocalcemia Serious infections Dermatologic reactions Osteonecrosis of the jaw

Cinacalcet [Sensipar] Calcimimetic drug Approved for primary hyperparathyroidism and secondary hyperparathyroidism (caused by CKD) Increases the sensitivity of calcium-sensing receptors to activation by extracellular calcium Suppresses PTH secretion 34

Cinacalcet [Sensipar] Adverse effects: Nausea, vomiting, diarrhea, hypocalcemia Interactions Monitoring 35

Drugs for Hypercalcemia Furosemide Glucocorticoids Gallium nitrate Bisphosphonates Inorganic phosphates Edetate disodium 36

Osteoporosis Most common disorder of calcium metabolism Low bone mass and increased bone fragility Primary prevention Calcium, vitamin D, lifestyle Diagnosis Measurement of bone mineral density (BMD) Dual-energy x-ray absorptiometry (DEXA) 37

Treating Osteoporosis in Women Agents that decrease bone resorption: Estrogen, raloxifene, bisphosphonates, calcitonin, denosumab; sufficient calcium and vitamin D are important Agent that promotes bone formation: Teriparatide (Forteo) Agents that reduce fractures: Teriparatide, denosumab, zoledronate 38

Treating Osteoporosis in Men Five drugs have been approved for osteoporosis treatment in men: Alendronate [Fosamax] Risedronate [Actonel] Zoledronate [Reclast] Teriparatide [Forteo] Denosumab [Prolia] 39

Case Study A nurse has been asked to present a talk on drug therapy for osteoporosis to a group of adults. When preparing the talk, what should the nurse include for the mechanism of action and the adverse effects of the bisphosphonates? Bisphosphonates help decrease the breakdown of the microstructure of bone. Side effects of bisphosphonates include stomach pain, difficulty swallowing, esophageal inflammation, esophageal reflux, and ulcer formation. 40

Case Study What information should the nurse include to reduce adverse effects of bisphosphonates? To reduce adverse effects of bisphosphonates, the patient should avoid using aspirin, nonsteroidal anti-inflammatory agents, and antacids when taking bisphosphonates. In addition, the patient should not sit or lie down for 30 minutes after taking the bisphosphonate. 41

Case Study Along with the use of drugs for the treatment of osteoporosis, what other measures can help prevent the development of osteoporosis? The nurse should inform the group that adequate calcium and vitamin D intake, as well as not smoking, avoiding alcohol, and performing weight-bearing exercises, can prevent the development of osteoporosis. 42

Question 1 The nurse should advise patients who are taking calcium to avoid consumption of which food? A. Spinach B. Lettuce C. Tomatoes D. Squash Answer: A Rationale: Calcium absorption is reduced by consumption of foods containing oxalic acid (spinach, rhubarb, Swiss chard, and beets) and phytic acid (bran and whole-grain cereals).

Question 2 A patient with hyperparathyroidism has a calcium level of 13.2 mg/dL. What medication does the nurse anticipate being prescribed? A. Alendronate [Fosamax] B. Calcium acetate [PhosLo] C. Salmon calcitonin [Calcimar] D. Raloxifene [Evista] Answer: C Rationale: Salmon calcitonin is administered for hypercalcemia related to hyperparathyroidism. Calcium levels are lowered by inhibition of bone resorption and increased excretion of calcium by the kidneys.

Question 3 When preparing to administer intravenous calcium chloride, the nurse should do what? A. Warm the solution to body temperature. B. Inject 5 mL over 1 minute. C. Increase the calcium chloride dose if the patient is also taking digoxin. D. Evaluate the patient for an increase in tetany as an indication that the drug is exerting its therapeutic effect. Answer: A Rationale: Calcium solutions should be warmed to body temperature before IV dosing. Perform IV injections of calcium chloride slowly (0.5 to 2 mL/min). Parenteral calcium may cause severe bradycardia in patients taking digoxin; infuse calcium slowly and cautiously in these patients. Evaluate the patient for reductions in tetany, muscle spasm, laryngospasm, paresthesias, and other symptoms of severe hypocalcemia.