Drugs affecting Calcium levels and Bone mineralization

calcium is absorbed in the

small intestine

absorption is increased by

PTH, vitamin D

what decreases calcium aborpstion

glucocorticoids, insoluble fiber (quinoa, brown rice, green beans) phytic acid (whole grain cereals, wheat bread) and oxalates like spinach , Swiss chard, beet greens can interfere with calcium absorption

calcium is excreted in the; and what determines the loss of calcium

renal; amount loss determined by GFR and tubular resabsorption

what reduces excretion of calcium

PTH

vitamin D

thiazide diuretics (hydrochlorothiazide)

what increases the excretion of calcium

loop diuretics like furosemide

calcitonin

loading with sodium (high amount of sodium)

Calcium Salts

Parenteral: calcium chloride and calcium gluconate

oral calcium salts: calcium acetate, calcium carbonate, calcium citrate, calcium glubionate, calcium gluconate, calcium lactate, tricalcium phosphate

USE: dietary supplement; treats mild hypocalcemia (oral); severe hypocalcemia (parenteral)

PK: oral or parenteral

AE: hypercalcemia (too much Ca+ 3-4g.day); IV calcium irritating; IM calcium: necrosis and sloughing; bradycardia (if Ca+ given with digoxin)

DI: PPI (reduced absorption of calcium by increasing gastric pH); glucocorticoids: reduces absorption of oral calcium; Ca+ decrease absorption of: tetracycline and quinolone antibiotics, thyroid hormone, phenytoin and bisphoantes; thiazide diuretics (decreases renal calcium excretion=hypercalcemia); loop diuretics (increases calcium excretion=hypocalcemia); digoxin (digoxin toxicity; effects are additive, Ca+ and dig increase intracellular Ca+ in cardiac myocytes); compounds like phosphate, carbonates, sulfates, tartrates can cause precipitation=dont add in calcium solutions

FOOD Interactions: surpasses calcium absorption: oxalic acid (spinach, rhubarb, Swiss chard, beets), phytic acid and insoluble fiber (bran and whole grain)- dont give oral calcium with these food

L: calcium levels; ECG; albumin (tells you the total calcium); phosphate and magnesium (if low won’t be able to fix calcium)

CI: hypercalcemia, renal calculi, hypophosphatemia

range for serum calcium

8.4-10.2mg/dl

patient education: with calcium salts

switching calcium preparation can alter the amount of calcium obtained

take calcium salt with large glass of water

taking it with meal or shortly after increased absorption

avoid eating: spinach, Swiss chard, beets, bran, whole grain cereals

s/s of hypercalcemia- nausea, vomiting, constipation, frequent urination, lethargy, depression

calcium bins to tetracyclines and quinolones- decreasing absorption (take them at least one hour apart)

calcium interrupts absorption of thyroid hormone; seperate these two for several hours

no more than ___mg should be consumed of calcium to ensure adequate absorption

600

bioavailability of calcium citrate is better absorbed with

PPI

calcium carbonate has the highest percentage of __

calcium

taking calcium with meals can

increase absorption by promoting acid production

Vitamin D

ergocalciferol (vitamin d2) & cholecalciferol (vitamin d3) [naturally in humans when skin exposed to sun], calcitriol, (paricalcitol (this one treats hyperparathyroidism 2/2 chronic renal dialysis) and doxercalciferol [are synthetics]) ** vitamin d 3 is more effective bc it raises blood levels of 25-OH D the active form of vitamin D is the body

USE: vitamin D deficiency, rickets (disease of growing children where the bone and growth plate cartilage fail to mineralize=disturbance in Ca+ and phosphate homeostasis/insuffiencet calcium and phosphate to harden newly formed tissue=soft weak bone and disorganized with widened growth plate), osteomalacia (softening of bone; defective mineralization of newly formed bone matrix), hypoparathyroidism

PK: orally, absorbed in the small intestine; bile is needed for absorption, in the absence of bile give it IM; excreted in the bile; gets activated in the liver

AE: hypervitaminosis D (vitamin D exceeding 1000iu/day in infants, >50,000 IU/day in adults); poisoning is common in children due to accidental ingestion or excessive dosing of vitamin D by parents

DI:

L: monitor 25(OH) D, calcium, phosphorus, alkaline phosphatase (monitors bone formation/osteobast activity), 24 urinary calcium determination

CI: hypercalcemia, hypertvitaminosis D, malabsorption syndrome, caution with digoxin (hypercalcemia can cause digoxin cardiac toxicity

vitamin d patient education

swallow oral preparation intact -without crushing or chewing

therapeutic response to vitamin d need adequate calcium intake-eat more calcium rich foods like - milk yogurt, hard cheese

too much vitamin d can cause

decalcification [loss of or removal of caclium] of bone = osteoporosis (too much vitamin d can drive calcium out)

vitamin d regulates

calcium and phosphorus

vitamin d rich foods are

cereals

milk

yogurt

cheese

OJ

if there is vitamin d toxicity what should you tell the patient

stop taking/ DC vitamin d immediately and increase fluid intake and eat low calcium diet (avoid milk, yogurt, cheese(

Cinacalet

MOA: mimics calcium at the parathyroid hormone receptor - reducing PTH secretion

USE: manages hyperparathyroidism; hypercalcemia caused by hyperthyroidism treats secondary hyperthyroidism caused by CKD (secondary hyperthyroidism- failing kidney disrupt calcium, phosphate and vitamin D balance all of which drive the parathyroid gland to overproduce PTH—kidney pts can’t excrete phosphate so it builds up=stimuate PTH secretion and also lowers ionized calcium further triggering PTH; the kidney is where vitamin D is activated, as kidney tissue is lost calcitriol falls, low calcitriol means less intestinal calcium absorption —> hypocalcemia

AE: nausea, vomiting, diarrhea, hypocalcemia (cramping, convulsion, myalgias, paresthesias, tetany—should be reported)

DI: ketoconazole, itraconazole, erythromycin (cinacalcet is metabolized by P450 isoenzyme 3A4; these increase cinaclcet levels, decrease cinacalcet)—if strong CYP34 INHIBITOR- CAN INCRASE CINACALCET

L: iPTH and serum calcium; measure serum calcium within 1 week of the first dose and each dose change for parathyroid carcinoma; after maintenance dosage has been established measure serum calcium every 2 months; in secondary hyperparathyroidism, measure serum calcium and phosphorus within 1 week of the first dose and each dosage change and measure PTH within 4 weeks of the first dose and each dose change. after maintenance has been established measure calcium and phosphorus monthly and PTH every 1-3 months

Calcitonin- not really a drug of choice for hypercalcemia

Calcitonin, intranasal (Miacalcin)

MOA: inhibits osteoclasts=decreasing bone resorption; inhibits tubular resorption of calcium= increasing calcium excretion (decreases alkaline phosphatase in blood and increases hydroxyproline (measures bone breakdown that excreted in the urine)

USE: established not for prevention of postmenopausal osteoporosis, Paget disease (disorganized bone remodeling; excessive abnormal bone turnover= producing weak enlarged deformed bones), hypercalcemia (from hyperparathyroidism, vitamin D toxicity, and cancer)

PK: nasal spray, injection

AE: nasal dryness and irritation (most common); increased malignancies; after parenteral- nausea (diminished over time); inflammatory reactions at the injection site; flushing of the face and hands; neutralizing antibodies (anti drug antibodies that bind the hormone and block its biologic activity; meaning they lose response to the drug) that bind to pathogen or after 1 yr or longer taking it

DI

L: monitor bone mineral density (BMD); check axial (spine and hip) dual energy X-ray absorptiome-try (DXA)[check 1-2 years until stable then very 2 years]; serum calcium levels & phosphorus; alkaline phosphatase and 25 (OH)D [active form of vitamin d] ; check height annually; if increased back pain get spinal radiographs to see if there is fractures.

CI: allergies to fish

• for osteoporosis BMD should increase or remains constant and fractures are prevented. For Paget decreased bone pain

• if nasal ulceration occurs dc the drug especially if heavy bleeding

patient education: calcitonin Miacalcon

to prime the metered dose pump for first use by hold the upright and depressing the two white sidearms towards the bottle six times= production a faint initial spray

drug is given by placing the nozzle in the nostril then depressing the pump handle

if injection subq rotate sites

Bisphosphonates

MOA: inhibits bone resorption by decreasing the activity of osteoclasts

USE: postemenopausal osteoporosis, osteoporosis in men, glucocorticoid-induced osteoporosis, Paget disease of bone and hypocalcemia of malignancy & help prevent and treat bone metastases in patients with cancer.

Alendronate (bisphosphonate) (Fosamax, Fosamax Plus D, Binosto)

USE: prevention and treatment of osteoporosis in postmenopausal patients, decreasing bone resorption by osteoclasts or osteoporosis in any gender; first choice of drug for prevention and treatment of GIOP (common complication of glucocorticoids); Paget disease; alendronate is taken up rapidly by the bone (incorporation into bone and then inhibits bone resorption by decreasing activity of osteoclasts); reduces the number of osteoclasts;

PK: oral

AE: indigestion, esophagitis, musculoskeletal pain, ocular inflammation (conjunctives, scleritis, blurred vision and eye pain-due to drug induced release of inflammatory cytokines), atypical femur fractures, osteonecrosis of the jaw (ONJ) [seen with IV bisphosphonates; avoid invasive dental procedures or get them done before starting the drug) (AE increase with long term use), esophageal cancer; hyperparathyroidism (pagets disease- inhibiting accelerated bone resorption, this drug causes blood levels of calcium to fall= increase PTH; take calcium supplements to avoid this); atrial fibrillation (IV)

DI: absorption is decreased with food or drinks; calcium, magnesium and iron bind with alendronate and other bisphosphoante (take at least 2 hours after administration before taking calcium products, mineral supplements or antacids)

L: DXA, height, serum calcium and 25(OH)D, serum creatine level for renal functions, pregnancy test

Education: reduce dosing frequency (weekly vs daily), taking the drug with full glass of water and staying up right for 30-60 minutes after dosing, report any vision changes or eye pain; take medication in the morning before breakfast on an empty stomach, then no food or drink other than water should be consumed at least 30 minutes after administration; after dosing, postpone ingesting anything OJ, juice, coffee, antacids, and calcium iron or mag for attest 30-60 minutes

CI: esophageal disorders that could impeded swelling , unable to sit or stand for at least 30-60 minutes; patients at low risk for osteoporosis related fractures (atypical fractures); upper GI problems; creatine clearance <30-35, real failure; caution in OA or dehydrated and with chronic renal impairment and nephrotoxic drug

= increases BMD, reduces vertebral fracture and decreases loss of height; in GIOP helps restore lost bone and may reduce risk for fractures

if patients need alternative treatment can suggest raloxifene or teriparatide for Osteoporosis of the spine and normal BMD (or only moderately reduced) of the femoral neck or hip

if pain persist use calcitonin, teriparatide or raloxifene

IV zoledronic acid can damage the kidney = acute renal failure; give zoledronic acid slowly over 30 min or more

do annual reevaluate of treatment if taking more than 5 years

estrogen in osteoporosis

MOA: stop osteoclast proliferation and can suppress resorption

• intact uterus should also take progestin like medroxyprogesterone to minimize risk for estrogen induced endometrial cancer

Black box warning: estrogen

increased risk for endometrial cancer in patients with uterus who take unopposed estrogen + increased risk for venous thromboembolic events (DVTS, PE); increases dementia in women 65 or older

Selective Estrogen Receptor Modulators: Raloxifine

USE: preserves BMD and reduces plasma levels of cholesterol; protect against breast and endometrium; prevention and treatment of osteoporosis in postmenopausal patients, and protection against estrogen receptor- positive breast cancer ( because it can block or mimic action estrogen)

**primarily reduces the risk of spinal fractures but does not reduce the risk for fractures at other sites

**protects against estrogen receptor + breast cancer; approved for reducing the risk for invasive breast cancer in postmenopausal patients who have osteoporosis or at high risk for breast cancer even if they dont have osteoporosis

MOA: mimics the effect of estrogen on bone, lipid metabolism, and blood clotting and block estrogen effects in breast and endometrium

AE: thromboembolic events: DVT, PE, & stroke (should dc raloxifene for at least 72 hours before prolonged immobilization (s/p surgery and extended bed rest) and should not resume the drug until full mobility has been restored; fetal harm; weight gain; hot flashes;

L: axial DXA (1 to 2 years until stable then every 2 years or less) and height (annually) , serum calcium, 25 (OH) D, mammogram (annually), pregnancy test; spinal radiographs if increased back pain ; check weight

CI: history of venous thrombotic events; pregnant; prolonged inactivity

raloxifene black box warning

associated with an increased risk for VTE like DVT and PE

increased risk for death from stroke when given to postmenopausal patients who have hx or risk for coronary heart disease

patient education: raloxifene

ensure adequate intake of calcium and vitamin D

DC raloxifene at least 72 hrs before prolonged immobilization

terparatide and abaloparatide are the only medications that

increase bone formation

Recombinant Parathyroid Hormone and Parathyroid Analog: Teriparatide

MOA: increases bone resorption by osteoclasts and increased bone deposition (laying down new bone) by osteoblasts

*lifetime limit of two years

USE: from of PTH: txt for osteoporosis in postmenopausal women, osteoporosis in men and treatment of GIOP

**daily subq for 18 most showed increased BMD of lumbar spine and femoral neck and reduced th risk of vertebral fracture

AE: nausea, headache, arthralgia, back pain, leg cramps, injection site discomfort, orthostatic hypotension and dizziness can happen within 4 hours of injection, risk of osteosarcoma with prolonged use; urinary calculi; on antihypertensives may increase OH; urinary calculi

PK: pen injector, store in 36-46 degrees F, only take it out when about to make injection

L: axial DXA every 1-2 years until stable then every 2 years or less; spinal radiographs to determine vertebral fractures; calcium and 25(OH)D levels; uric acid level; pregnancy test

E: ensure adequate intake of calcium and vitamin D; report development of weakness, excessive tiredness, confusion or bone pain because it can be due significant rise in calcium levels; s/s of kidney stones (2/2 increase calcium levels);ensure to lie down if OH occurs since it can happen 4 Hours after injections

NSAIDs for arthralgia and discomfort or ketorolac

Recombinant Parathyroid Hormone and Parathyroid Analog: abaloparatide

USE: approved for treatment of postmenopausal osteoporosis and osteoporosis in men

MOA:analog of PTH that acts asa PTH agonist at PTH1 receptors = this activation situates osteoblast activity; osteoblasts build bone=bone mass is increased

AE: nausea, headache, arthralgia, back pain, leg cramps, injection site discomfort, orthostatic hypotension and dizziness can happen within 4 hours of injection, risk of osteosarcoma with prolonged use ; increased uric acid, hypercalcemia, erythema at injection site, antibody development increase (where you have response to the medication but then it stops) did not do a significant impact on safety or efficacy; urinary calculi

L: axial DXA every 1-2 years until stable then every 2 years or less; spinal radiographs to determine vertebral fractures; check height; calcium and 25(OH)D levels; uric acid level; pregnancy test

E:ensure adequate intake of calcium and vitamin D; report development of weakness, excessive tiredness, confusion or bone pain because it can be due significant rise in calcium levels; s/s of kidney stones (2/2 increase calcium levels); ensure to lie down if OH occurs since it can happen 4 Hours after injections

NSAIDs for arthralgia and discomfort or ketorolac

Drugs for osteoporosis

Bisphosphonates- Alendronate (Binosto and Fosamax), Risedronate (Actonel), Ibandronate, Zoledronic acid

Recombinant Parathyroid hormone and parathyroid hormone analog: terparatide (Forteo) and abaloparatide (Tymlos)

Calcitonin: Calcitonin, intranasal, Calcitonin, injection

Monoclonal antibodies: Denosumab (Prolia, Xgeva) & Romosozumab (Evenity)

Selective estrogen receptor modulators: Raloxifine

Monoclonal antibodies: Denosumab (Prolia, Xgeva)

first in class receptor activator of nuclear factor kappa-B ligand (RANKL)

Prolia for high risk fractures or who have bone loss due to glucocorticoids therapy

Xgeva used for bone metastases

USE: treatment of osteoporosis in men and postmenopausal women at high risk for fractures, treatment of bone loss in men and women who are on anticancer therapy (androgen deprivation therapy for prostate cancer and aromatase inhibitor for breast cancer); GIOP; prevention of skeletal related events in pts which bone metastases form solid tumors

MOA: monoclonal antibody, that decreases formation and function of osteoclasts(breakdown bone)=decreasing bone resorption and increasing BMD and bone strength; prevents the activation of receptor called “receptor activator in nuclear factor kappa (RANK),”, found on the surface of osteoclasts and their precursor cells.

in normal conditions, RANK is activated by binding with endogenous compound called “RANK ligand” (RANKL). When activated by RANKL, RANK stimulated the formation and activity of osteoclasts. Denosumab bind with RANKL and prevents it from activity RANK

AE: back pain, pain in extremities, Muscoloskeletal pain, hypercholesterolemia, urinary bladder infection; in CA pts with bone metastases: fatigue, hypophosphatemia (due to less Ca+ and phosphate from the bone, PTH increase=phosphate loss) and nausea; 2/2 suppression of bone turn over=delay fracture healing and increase risk for new fractures and ONJ. can worsen preexisting hypocalcemia= 2/2 reduced osteoclast activity; serious infection (endocarditis, serious skin infections, infection of abdomen, UTI, ear); dermatologic reactions (dermatitis, eczema, rashes DC IF SEVERE RXN OCCURS); Osteonecrosis of the jaw

PK: refrigerated and then warmed before use (room temp for 15-30 minutes), all preparations should be clear and colorless (or pale yellow)

L: monitor levels of calcium, magnesium, phosphorus; DXA every 1-2 yrs until stable then every 2 years or less. check height annually. monitor for back pain, get radiographs for vertebral fractures. check serum calcium, serum creatine and serum magnesium within the first two weeks of therapy

CI: caution with impaired renal function (increases the risk of hypocalcemia) and hx of hypoparathyroidism , thyroid sx, malabsorption syndrome, or excision of small intestine (risk for hypocalcemia); caution with immunocompromised patient (HIV or treatment with immunosuppressant

E: to prevent hypocalcemia when taking denosumab, patients should take 1000 mg of calcium every day and atlas 400 IU of vitamin D/day; may decrease ability to fight infections, avoid contact with people who have contagious disease and practice good hygiene , report dental surgery, maintain routing plan for excellent dental hygiene. report jaw pain and s/s of infection; avoid stopping denosumab without first talking to dr; risk for bone fracture is increased after denosuman is DC’d

NSAIDs especially ketorolac can help with bone pain

renal patients are at risk for hypocalcemia because the decreased kidney cannot make enough active vitamin d = decreasing calcium intestinal absorption

drugs for hypercalcemia

lasix- promotes excretion of calcium (useful for treating hypercalcemic emergencies, plus (0.9% NaCL) isotonic saline IV must be given before lasix)

glucocorticoids- reduces intestinal absorption of calcium (for severe hypercalcemia, parenteral glucocorticoid)

bisphosphonates- Pamidronate, etidronate, zoledronic acid: approved for hypercalcemia of malignancy

inorganic phosphates; reduces plasma levels of calcium (IV for for lifethreatening; can be taken orally-dont give to renal impaired pts (can cause toxicity) or elevated phosphate; dont give with antacids that have aluminum, magnesium or calcium nc it binds to phosphate and prevent abosrptiomn

Edetate disodium: chelating agent that binds to calcium in the blood - renal excretion of calcium (can be dangerous= profound hypocalcemia=tetany, convulsions, dysrythmias, death; severe nephrotoxicity; reserved for life threatening events)

Osteoporosis common fractures

common fractures are vertebrae, distal forearm (wrist) and femoral neck (hip)

osteoporosis is

low bone mass, altered bone architecture, increased bone fragility