Ch. 48 Drugs for Bone and Joint Disorders

Calcium

• primary mineral responsible for bone formation and for maintaining bone health throughout the lifespan

• Critical for proper functioning of the nervous, muscular, and cardiovascular systems

• Adequate levels in body necessary to

  • Transmit nerve impulses

  • Prevent muscle spasms

  • Provide stability and movement

• Also important for blood coagulation and myocardial activity

• Absorption of calcium is increased in the presence of vitamin D & inhibited by vitamin D deficiency

Calcium balance

•  is regulated to maintain homeostasis by parathyroid hormone (PTH), calcitonin, and vitamin D

  • regulate the rate of absorption of calcium from the gastrointestinal (GI) tract, the excretion of calcium from the kidney, and the movement of calcium into and out of bone.

Role of Parathyroid Hormone in Calcium Balance

• Parathyroid—secretes PTH

  • Stimulates bone cells (osteoclasts), accelerating bone resorption/demineralization causing breakdown of bone

  • Break down increases calcium in blood where needed

    • Calcium ion influences the excitability of all neurons

Roles of Parathyroid Hormone and Calcitonin in Calcium Balance

• Calcitonin, secreted by the thyroid gland, stimulates bone deposition/ bone building done by osteoblasts

  • This removes calcium from the blood to be placed in bone

• Together PTH and calcitonin control calcium homeostasis

• PTH and calcitonin influence three targets: bones, kidneys, and gastrointestinal tract

Role of Vitamin D in Calcium Balance

• Vitamin D is synthesized from precursor molecules and aids absorption of calcium

• Cholecalciferol (inactive form) is converted to an intermediate form, calcifediol, then it is metabolized to calcitriol (active form)

Recommended Dietary Allowance (RDA) of Calcium

• For adults RDA is 800–1200 mg/day

• Increased amounts of calcium required for:

  • Pregnant women

  • Growing children

  • Menopausal women

• Normal serum calcium range is 4.5–5.5 mE q/L or 8.5–10.m g/d L

• Serum calcium levels exceeding 5.5 mE q/L result in hypercalcemia

• Hypocalcemia results from serum calcium levels below 4.5 m E q/L

Role of Calcium in Maintaining Homeostasis

• Too high (hypercalcemia) calcium levels lead to:

  • Decreased sodium permeability across cell membranes—a dangerous state

• Too low (hypocalcemia) calcium levels cause:

  • Cell membranes to become hyperexcitable

  • If severe, can lead to Convulsions or muscle spasms

Hypocalcemia

• Many causes:

  • Lack of sufficient dietary calcium or vitamin D (common)

  • CKD

  • GI causes (vomiting, malabsorption disorders)

  • decreased secretion of PTH

  • Drugs (blood transfusions, anticonvulsants, corticosteroids)

    • daily supplements of calcium and vitamin D to prevent

• Minor - moderate asymptomatic, s/s include:

  • Nerve & muscle excitability (twitching, tremor, abdominal cramping), numbness, tingling, convulsions, confusion, abnormal behavior

  • Associated w/ cardiac dysrhythmias

Pharmacotherapy of Hypocalcemia

• Nutritional adjustments: dairy products, fortified orange juice, cereals, green leafy veggies (not spinach)

• Calcium supplements consist of complexed calcium in salts such as carbonate, lactate, or phosphate

Calcium Salts

• Calcium supplement

• Hypocalcemia agent

• for supplementation of calcium

  • prevents & treats hypocalcemia

• AE: hypercalcemia ( lethargy, weakness, anorexia, nausea, vomiting, confusion, renal stones, increased urination, and dehydration), Acute hypercalcemia (serious symptoms such as syncope, coma, dysrhythmias, and cardiac arrest)

• C: v.fib, bone cancer, renal calculi, hypercalcemia

• I: digoxin, magnesium, tetracyclines, zinc rich foods, alcohol, caffeine, carbonated beverages,

• OD: treat hypercalcemia

Metabolic Bone Diseases

• general term referring to a cluster of disorders that have in common defects in the structure of bone.

• caused by abnormal amounts of the minerals or hormones required for proper bone homeostasis

• Some have genetic etiology or drug/therapy causes

Osteoporosis

• Most common metabolic bone disease (MBD)

• Related to bone deterioration—bone resorption (lost) outpaces bone deposition (gained)

  • Lack of dietary calcium and vitamin D

  • Disrupted bone homeostasis

Risk Factors for Osteoporosis

• Onset of menopause: most common risk factor

• High alcohol consumption

• Anorexia nervosa

• Tobacco use

• Physical inactivity/immobilization

• Personal or family history

• Gonadal hormone deficiency

• Low vitamin D or calcium in the diet

• Drugs that lower calcium in blood

  • Corticosteroids, anticonvulsants, immunosuppressants

• White or Asian race

Pharmacotherapy of Osteoporosis

• Calcium and vitamin D therapy

• Bisphosphonates

• Selective estrogen receptor modulators (SERMs)

• Calcitonin

• Miscellaneous

  • Oral calcium modifier (calcium mimic), monoclonal antibody denosumab, human PTH teriparatide

Osteomalacia

• MBD characterized by softening of bones due to demineralization

• Most frequent cause is deficiency of vitamin D and calcium in the diet

• Most prevalent in the older adult, in premature infants, and in individuals on strict vegetarian or vegan diets

• Known as rickets in children

  • Bowlegs, pigeon breasts, slight fever, restless at night

• s/s hypocalcemia, muscle weakness, muscle spasms, and diffuse bone pain

Pharmacotherapy of Osteomalacia

• Calcium supplements and vitamin D

  • Calcitriol is useful in treating rickets

  • Calcitriol usually prescribed in combination with calcium supplements

• Recommendations

  • Daily calcium and vitamin D

  • Adequate exposure to sunlight

Paget’s Disease – osteitis deformans

• MBD characterized by accelerated remodeling of the skeleton, producing enlarged and softened bones

• processes of bone resorption and bone deposition occur simultaneously

• Unknown cause

Vitamin D for MBD

• Drug therapy for adults and children

  • Along with calcium

• Daily needs depend on received sunlight

• Recommended intake increases after age 70

• Fat soluble vitamin

  • Excess consumption can cause hypercalcemia

Bisphosphonates for MBD

• For Osteoporosis

  • Most common treatment

  • Block bone resorption by inhibiting osteoclast activity, increase bone density

  • Benefits plateau after 2 to 3 years

• Preferred drug for treating Paget’s Disease

  • Goal

    • Slow the rate of bone reabsorption and encourage deposit of strong bone

  • No effect on tumors, only given as palliative care

  • Administered until ALP levels normal, then again when levels elevate

  • Most common adverse effects

    • Nausea, vomiting, abdominal pain, and esophageal irritation

  • More rare adverse effect – osteonecrosis of the jaw

Selective Estrogen Receptor Modulators (SERMs) for MBD

• For Osteoporosis prophylaxis & treatment

  • Decrease bone resorption and increase bone mass and density

  • May be either estrogen agonists or antagonists, depending on the drug or tissue involved

Other Drugs for Metabolic Bone Disease

• Denosumab (Prolia, Xgeva)

  • Treat postmenopausal women at high risk for fracture (Prolia)

  • & Prevention of skeletal-related events in patients with bone metastases with solid tumors

• Teriparatide (Forteo) – Human PTH

  • Treatment of osteoporosis in men and postmenopausal women

• Calcitonin

  • calcitonin-salmon (Miacalcin) is obtained from salmon and is approved to treat osteoporosis in women who are more than 5 years postmenopausal, hypercalcemia, and Paget’s disease.

  • Increases bone density and reduces the risk of vertebral fractures

Calcitriol (Calcijex, Rocaltrol)

• Vitamin D

• Bone resorption inhibitor

• promotes the intestinal absorption of calcium and elevates serum levels of calcium, reduces bone absorption

• AE: hypercalcemia ( weakness, confusion, anorexia, nausea, and vomiting, increased urination, dysrhythmias, dehydration, and weight loss)

  • DC at first signs of

• C: hypercalcemia

• I: Thiazide diuretics, magnesium, calcium-rich foods

• OD: treat hypercalcemia, hypercalciuria, and hyperphosphatemia

Alendronate (Fosamax)

• Drug for osteoporosis

• Bisphosphonate; bone resorption inhibitor

• lowers ALP, the enzyme associated with bone turnover

• indicated for:

  • Prevention and treatment of osteoporosis in postmenopausal women

  • Treatment of corticosteroid-induced osteoporosis in both women and men

  • Treatment to increase bone mass in men with osteoporosis

  • Treatment of symptomatic Paget disease in both women and men.

• take on empty stomach w/ water before first food of the day

• remain upright for 30 minutes

• ≠ pregnancy, lactation

• AE: diarrhea, constipation, flatulence, nausea, vomiting, metallic taste, hypocalcemia, hypophosphatemia, abdominal pain, dyspepsia, arthralgia, myalgia, headache, and rash, pathologic fractures

• C: osteomalacia, CKD, HF, liver disease

• I: Calcium, iron, antacids, alcohol

• OD: treat Hypocalcemia

Raloxifene (Evista)

• Drug for osteoporosis prevention

• Selective estrogen receptor modulator

• decreases bone resorption and increases bone mass and density by acting through the estrogen receptor

• prevention of osteoporosis in postmenopausal women

• ≠ pregnancy, lactation

• AE: hot flashes, leg cramps, and weight gain, fever, arthralgia, depression, insomnia, chest pain, peripheral edema, decreased serum cholesterol, nausea, vomiting, flatulence, cystitis, migraines, flulike symptoms, endometrial disorder, breast pain, and vaginal bleeding

• BBW: increases the risk of venous thromboembolism and death from strokes

• I: warfarin, high protein-bound drugs, black cohosh

Joint Disorders

• Osteoarthritis

• Rheumatoid arthritis

• Gout

• Joint pain common symptom

  • Analgesics and anti-inflammatory drugs common component of therapy

Osteoarthritis (OA)

• Progressive degenerative, age-onset disease

• Characterized by wearing away of cartilage at articular joint surfaces

• Symptoms

  • Localized pain and stiffness

  • Joint and bone enlargement

  • Reduced range of motion

• Etiology poorly understood

  • Thought to be due to excessive wear of weight-bearing joints

    • Hip, knee, spine

• Most common type of joint disease

• Considered by some a normal part of aging

Pharmacotherapy of Osteoarthritis (OA)

• Goal is reduction of pain and inflammation

  • Acetaminophen

  • NSAIDs (including aspirin)

  • Topical medications (capsaicin cream, prescription diclofenac [Pennsaid])

• If OTC drugs don’t succeed

  • Sodium hyaluronate (Hyalgan) injections into joint

    • replaces or supplements the body’s natural hyaluronic acid that deteriorated because of the inflammation of OA

    • Provides a barrier to prevent friction & further inflammation

Rheumatoid Arthritis (RA)

• Systemic autoimmune chronic, progressive disorder

• Characterized by disfigurement and inflammation of multiple joints

• Autoimmune etiology

  • Autoantibodies (rheumatoid factors) attack self, activate inflammatory response in joints

• Extra-articular systemic manifestations may develop

  • Infections, pulmonary disease, pericarditis, blood abnormalities, metabolic dysfunction

Pharmacotherapy for Rheumatoid Arthritis (RA)

• Goal: control inflammation, reduce pain, and minimize physical disability.

• NSAIDs initially

• Corticosteroids for severe inflammation or flare-ups

• Disease-modifying antirheumatic drugs (DMARDs)

  • Slowing/modification of progression of tissue damage through immune & inflammatory response

  • Nonbiologic, biologic (TNF antagonists, non-TNF antagonists)

  • Selection of depends on experiences of the healthcare provider and the response of the patient to therapy

• Several months may be needed before therapeutic results are achieved

Adalimumab (Humira)

• DMARD, drug for psoriasis, drug for inflammatory bowel disease

• TNF antagonist

• Slowing/modification of progression of tissue damage through immune & inflammatory response

• AE: injection site pain, upper respiratory infection, increased creatine phosphate, headache, and rash

• BBW: increased risk for the development of serious infections and malignancies (Leukemias, lymphomas, hepatosplenic T-cell lymphoma)

• I: live vaccines, immunosuppressants, Echinacea

Gout

• A form of acute arthritis caused by a buildup of uric acid (urate) crystals in the joints and other body tissues

• Primary gout due to hereditary defect in uric acid metabolism

• Secondary gout due to

  • Certain drugs (thiazide diuretics, aspirin, cyclosporine, or chronic use of alcohol)

  • Diseases that affect uric acid metabolism (diabetic ketoacidosis, kidney failure, leukemia, hemolytic anemia, others)

• Symptoms of acute attacks

  • Red, swollen tissue

  • Often in big toes, ankles, fingers, wrists, knees, elbows

• Triggered by ingestion of alcohol, dehydration, injury, or other stress

• Attacks often occur at night

• Acute gouty arthritis - occurs when needlelike uric acid crystals accumulate in joints, resulting in extremely painful, red, and inflamed tissue.

Hyperuricemia

• elevated blood level of uric acid

Treatment of Acute Gout

• Goals 

  • Termination of acute attacks; prevention of future attacks

• NSAIDs preferred for pain and inflammation

• Corticosteroids for more severe pain and inflammation

• Prophylactic therapy & chronic gout

  • Uricosurics increase excretion of uric acid by blocking reabsorption in the kidney

    • probenecid (Probalan) and sulfinpyrazone (Anturane)

  • Drugs that inhibit formation of uric acid

    • allopurinol (Lopurin, Zyloprim) or febuxostat (Uloric)

  • Drugs that convert uric acid into a less toxic form

    • rasburicase (Elitek) or pegloticase (Krystexxa)

Allopurinol (Lopurin, Zyloprim)

• Drug for gout

• Xanthine oxidase inhibitor

• used to control the hyperuricemia that causes severe gout and to reduce the risk of acute gout attacks

• give w/or after meals

• ≠ pregnancy

• AE: micropapular rash, fatal toxic epidermal necrolysis, Stevens-Johnson syndrome, hypersensitivity syndrome (skin rash, fever, hepatitis, leukocytosis, and progressive CKD), drowsiness, headache, vertigo, nausea, vomiting, abdominal discomfort, malaise, diarrhea, retinopathy, and thrombocytopenia, ototoxicity

• C: impaired liver or kidney function, history of peptic ulcers, lower GI tract disease, bone marrorw depression

• I: alcohol, warfarin, amoxicillin, cyclosporine, thiazides, ACE inhibitors, Aluminum antacids, anticancer drugs, high purine foods