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The following common bone diseases are discussed within this module:

• Osteoporosis
• Rheumatoid arthritis
• Osteoarthritis
• Gout

OSTEOPOROSIS

Overview

Osteoporosis is the most common disorder of the bone.^1,2 Epidemiologic studies have estimated that in the United States, 8 million women and 2 million men have osteoporosis. The disorder is more common in white and Asian women and the risk of developing osteoporosis increases with age.^3,4  The skeletal system includes 2 types of bone: cortical and trabecular.^4,5 Cortical bone comprises 80% and forms the outer layer of the skeletal system, whereas trabecular bone comprises 20% and forms the inner layer of the skeleton. Remodeling is a dynamic process in which there is a balance between bone resorption and bone formation.^2,4,5 Peak bone mass occurs around 30 years of age.^5,6 After that time, bone mass decreases by 0.3% to 0.5% per year in both sexes.⁵ Due to the loss of estrogen, bone loss occurs at a rate of 2% to 3% yearly in postmenopausal women.  

Osteoporosis is the result of an imbalance in bone remodeling; osteoclast activity (bone resorption) is greater than osteoblast activity (bone formation), which causes decreased bone mineral density (BMD).^1,2,7 Other factors that can contribute to low BMD include genetics, increasing age, low body weight, history of fractures, decreased calcium and vitamin D intake, chronic disease, physical inactivity, smoking, alcohol abuse, medications (e.g., corticosteroids), and hormonal deficiencies.^1-3  Osteoporosis is characterized by a decrease in bone strength, which increases the risk of fractures.^2,3,8 It is considered a "silent disease"; patients are often asymptomatic until a fracture occurs.^2,8 If signs and symptoms occur, they may include pain, lack of mobility, depressed mood due to physical limitations, decreased height (defined as > 1.5 inch loss), and rounding of the spine.^2,4

Clinically, osteoporosis is diagnosed by the measurement of BMD or the presence of a fracture without major trauma.^9,10,11 The dual-energy x-ray absorptiometry (DXA) scan measures bone density at the hip and spine, which may predict the incidence of a future fracture. The DXA score, reported as a T-score, compares the patient's bone density to the peak bone density of a healthy 30 year old adult. On the other hand, a Z-score compares the patient's bone density to that of an individual of the same age, sex, and ethnic background. T-scores are used to diagnose osteoporosis in patients older than 50 years old or postmenopausal women, whereas Z-scores help diagnose osteoporosis in men younger than 50 years old, children, or premenopausal women.^2,9,10 The World Health Organization (WHO) has defined bone density levels which are summarized in Table 1.^10,11 Additionally, the Fracture Risk Assessment Tool (FRAX), developed by the WHO, calculates the estimated risk of fracture based on BMD and individual patient factors.¹²

Table 1. World Health Organization Definitions Based on Bone Density Levels10,11
Level	Definition
Normal	BMD is within 1 SD (T-score +1 or -1) of the young adult mean
Low bone mass (osteopenia)	BMD is between 1 and 2.5 SD below the young adult mean (T-score -1 to -2.5 SD)
Osteoporosis	Bone density is ≥ 2.5 SD below the young adult mean (T-score -2.5 or lower)
Osteoporosis (severe, established)	Bone density is ≥ 2.5 SD below the young adult mean and ≥ 1 fractures
BMD = bone mineral density; SD = standard deviation.

Prevention of loss of BMD and fractures is the primary goal of osteoporosis management.^4,8 The incidence of osteoporosis can be reduced by optimizing skeletal development and peak bone mass early in life. Prevention of age-related and secondary causes of bone loss is also important. Once osteoporosis develops, the goal is to stabilize the skeletal system and improve strength and bone mass.

Treatment Recommendations

The American Academy of Clinical Endocrinologists (AACE), the American College of Rheumatology (ACR), and the National Osteoporosis Foundation (NOF) provide recommendations for the prevention and management of osteoporosis using both lifestyle modifications and pharmacologic therapies.^8,11,13 Maintenance of a bone-healthy lifestyle can reduce the risk of fractures. Specific lifestyle modifications are summarized in Table 2.^4,8,11

Table 2. Osteoporosis Lifestyle Modifications4,6,8,11,14
	Recommendations
Nutrition	Consume a well-balanced diet limited in excess salt, caffeine, and protein
Ensure adequate intake of calcium and vitamin D	Total daily elemental calcium* Women 19 to 50 years – 1000 mg Men 51 to 70 years – 1000 mg Women > 50 years and men > 70 years – 1200 mg Maximum daily dose: 2000 to 2500 mg (depending on age)	Total daily vitamin D Women 19 to 50 years – 600 IU Women/men >50 to 70 years – 600 to 1000 IU Women/men >70 years – 800 to 1000 IU
Regular weight bearing exercises	Walking, jogging, stair climbing, weight machines, free weights, or elastic bands
Avoid tobacco use	Smoking cessation
Limit alcohol consumption	Women < 1 drink daily; men < 2 drinks daily
Fall precautions	Checking/correcting visual or hearing problems; monitor for low blood pressure or heart rate; use proper footwear; replace high-risk medications for falls with safer alternatives; home safety assessment
Hip protectors	For patients with high risk of falls or previous fracture
*Dosages expressed as elemental calcium; calcium carbonate is 40% elemental calcium; calcium citrate is approximately 21% elemental calcium. IU = international units.

Adequate calcium intake is essential for the development of bone mass during childhood and for maintenance of bone mass throughout life.⁴ The primary source of calcium should be obtained through a patient's diet. Supplementation with calcium is recommended when dietary intake is inadequate.^4,11 Calcium intake recommendations are based on the amount of elemental calcium in each product.⁶ For example, calcium carbonate is 40% elemental calcium. Therefore, 1250 mg calcium carbonate contains 500 mg of elemental calcium. Since the dosage of elemental calcium varies between products, it is important to consult the product labeling.

The choice of pharmacologic therapy is based on anti-fracture benefits demonstrated in clinical studies.^8,11 All of the agents approved for osteoporosis reduce the risk of new vertebral fracture; however, select agents have been shown in clinical trials to reduce the risk of non-vertebral or hip fractures. The various agents approved by the Food and Drug Administration (FDA) for the prevention and treatment of osteoporosis are summarized in Table 3.

First-line agents recommended by the AACE include alendronate, risedronate, zoledronic acid, or denosumab.⁸ Ibandronate is considered a second-line agent. Raloxifene is a second- or third-line agent and calcitonin is the last-line agent. For patients with a very high fracture risk, or patients that do not respond to bisphosphonate treatment, teriparatide is the agent of choice, as it has been shown to reduce the risk of vertebral and nonvertebral fractures. Estrogen use is limited for short-term treatment of menopausal symptoms.^15,16

Table 3. Agents Used for the Treatment/Prevention of Postmenopausal Osteoporosis4,15,17,18
Drug	FDA-approved indication in osteoporosis	Dosage	Comments/dosing adjustments
Bisphosphonates (oral)*
Alendronate (Fosamax, Fosamax-D, Binosto, generic)	Treatment	10 mg daily or 70 mg weekly	70 mg dose is also available as an effervescent tablet or combination tablet with 2800 or 5600 units of vitamin D Also available in a 70 mg/75 mL liquid formulation Not recommended in patients with CrCl < 35 mL/min
	Prevention	5 mg orally or 35 mg weekly
Ibandronate (Boniva)	Treatment, prevention	150 mg monthly	Not recommended in patients with CrCl < 30 mL/min
Risedronate (Actonel, Atelvia delayed-release)	Treatment, prevention	5 mg daily, 35 mg weekly, 75 mg on two consecutive days per month,  150 mg monthly	35 mg dose is also available as a delayed-release tablet for treatment Not recommended in patients with CrCl < 30 mL/min
Bisphosphonates (IV)
Ibandronate (Boniva)	Treatment	3 mg IV once every 3 months	Not recommended in patients with CrCl < 30 mL/min
Zoledronic acid (Reclast)	Treatment	5 mg IV once yearly	May premedicate with acetaminophen or NSAIDs to decrease infusion reactions Contraindicated in patients with CrCl < 35 mL/min Also marketed under the brand name Zometa with different dosing for the treatment of hypercalcemia of malignancy, multiple myeloma, and bone metastases in patients with solid tumors
	Prevention	5 mg IV once every 2 years
Selective estrogen receptor modulator
Raloxifene (Evista)	Treatment, prevention	60 mg daily
Conjugated estrogens and selective estrogen receptor modulator
Conjugated estrogens and bazedoxifene (Duavee)	Prevention	0.45 mg/20 mg daily	Not recommended for women older than 75 years Not recommended in patients with renal impairment Contraindicated in patients with hepatic impairment
Anti-RANK ligand antibody
Denosumab (Prolia)	Treatment	60 mg SC every 6 months	Administered by a healthcare professional Prior to administration, correct hypocalcemia Also marketed under the brand name Xgeva for the prevention of skeletal-related events from bone metastases from solid tumors
Calcitonin
Calcitonin (Fortical and Miacalcin nasal sprays)	Treatment	200 units (1 spray) daily	Administer in 1 nostril daily, alternating nostrils each day Refrigerate until opened for daily use, then store at room temperature Prime with first use
(Miacalcin injection)	Treatment	100 units SC or IM daily or every other day	Administer as IM route for injection volumes over 2 mL, otherwise administer as SC route
Parathyroid hormone
Teriparatide (Forteo)	Treatment	20 mcg SC daily
*Oral bisphosphonates should be administered first thing in the morning on an empty stomach with 6 to 8 oz of plain (not mineral) water. After administration, the patient may not eat or drink (except water) and remain upright for at least 30 minutes (60 minutes with ibandronate). CrCl = creatinine clearance; FDA = Food and Drug Administration; IM = intramuscular; IV = intravenous; NSAIDs = nonsteroidal anti-inflammatory drugs; SC = subcutaneous.

Osteoporosis is one of the most significant adverse effects of glucocorticoid therapy.^13,16 The ACR has published guidelines for the treatment of osteoporosis in premenopausal women and men.¹³ All patients should practice a bone-healthy lifestyle. Specific pharmacologic agents are recommended based on age, risk factors, dose, duration of prednisone therapy, and history of fractures. Patients with chronic kidney disease are also at increased risk for osteoporosis.⁴ Treatment is based on the degree of renal dysfunction. Since the majority of patients with stage 3 or 4 disease are deficient in vitamin D, it is recommended that levels be monitored and replacement given as needed. Patients with osteoporosis, and a creatinine clearance (CrCl) > 30 mL/min, should be treated with standard therapy. However, the oral bisphosphonates are not recommended in patients with a CrCl < 30 mL/min. Zoledronic acid is contraindicated in patients with a CrCl < 35 mL/min. Denosumab is not renally eliminated and is an option for patients with chronic kidney disease.

Monitoring Parameters

Table 4 provides a summary of both common and severe adverse effects, as well as monitoring parameters for the agents used for the treatment or prevention of osteoporosis.^4,15,17

Table 4. Monitoring Medications Used in the Treatment/Prevention of Osteoporosis4,15,17
Drug	Adverse drug reactions	Monitoring parameters	Comments
Bisphosphonates
Oral agents	Common: heartburn, esophageal irritation, esophagitis, abdominal pain, nausea, vomiting, diarrhea, transient musculoskeletal pain, headache Rare: GI perforation, ulceration and/or bleeding, osteonecrosis of the jaw, atypical femoral fractures, severe bone, joint, and muscle pain, ocular inflammation, hypocalcemia, atypical femur fractures	BMD Serum calcium and vitamin D levels Fractures
Injectable	Renal failure, acute injectable reactions (low-grade fever, myalgias, arthralgias)		Pregnancy category D for zoledronic acid
Selective estrogen receptor modulator
Raloxifene	Common: hot flashes, leg pain, spasms, cramps, peripheral edema Rare: thromboembolism	BMD Fractures Hot flashes Leg cramps Blood clots	Pregnancy category X Boxed warning: increased risk for VTE and death from stroke
Conjugated estrogens and selective estrogen receptor modulator
Conjugated estrogens/ bazedoxifene	Common: muscle spasm, diarrhea, nausea, dyspepsia, abdominal pain, oropharyngeal pain Rare: thromboembolism, dementia	BMD	Pregnancy category X
Anti-RANK ligand antibody
Denosumab	Common: flatulence, hypocalcemia (especially in patients with decreased renal function), rash, eczema, dermatitis, nausea, arthralgias, dyspnea Rare: osteonecrosis of the jaw, atypical femur fractures	Serum calcium, phosphorus, and magnesium BMD Fractures	Pregnancy category X REMS: medication guide and monitoring due to the risk of serious infections, dermatologic adverse effects, and suppression of bone turnover
Calcitonin
Nasal spray	Common: rhinitis, sinusitis, occasional epistaxis Rare: severe allergic reactions	BMD Fractures	Many experts recommend avoiding calcitonin due to potential serious allergic reactions and increased risk of malignancy
Injectable	Common: nausea and flushing, injection site reactions Rare: severe allergic reactions
Parathyroid hormone
Teriparatide	Common: orthostasis with first few injections, pain at injection site, hypercalcemia, hypercalciuria, nausea, headache, dizziness, leg cramps Rare: increase in uric acid	BMD Fractures Trough serum calcium concentration 1 month after therapy	Boxed warning: potential risk for osteosarcoma
BMD = bone mineral density; GI = gastrointestinal; REMS = Risk Evaluation Mitigation Strategy; VTE = venous thromboembolism.

There are few interactions associated with the drugs used to treat osteoporosis.^4,17 Oral bisphosphonates should not be administered with food or medications. Dosing instructions state that bisphosphonates should be administered first thing in the morning on an empty stomach with 6 to 8 oz of plain (not mineral) water. After administration, the patient may not eat or drink (except water) and remain upright for at least 30 minutes (60 minutes with ibandronate). Coadministration with aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of additive effects of the gastrointestinal (GI) mucosa. Raloxifene is highly protein-bound; therefore, caution should be taken when coadministered with other highly protein-bound agents. Raloxifene can decrease prothrombin time by 10%; therefore, close monitoring is recommended when used with warfarin. Denosumab has minimal drug interactions. The agent may enhance the adverse effects of immunosuppressant agents, specifically the risk of infections. The risk of hypercalcemia due to teriparatide may cause toxicity in patients taking digoxin.

RHEUMATOID ARTHRITIS

Overview

Rheumatoid arthritis (RA) is the most common chronic inflammatory disorder.^19-21 The prevalence is estimated to be 1% worldwide. The disease is more common in women, typically presents in patients between 30 and 40 years of age, and increases in prevalence up to 70 years of age.^19,21  The cause of RA is complex and multi-factorial.^19,21 Genetic predisposition, environmental factors, older age, and immunologic dynamics are thought to be linked to the disease. Factors that initiate the inflammatory process are unknown. Chronic inflammation of the synovial tissue leads to destruction of cartilage, bone, tendons, ligaments, and joints.^20-22 Rheumatoid factors (RFs) are the primary autoantibodies that play a role in the pathogenesis of synovitis.^20,21

Individuals with RA initially present with pain, stiffness, and swelling of multiple joints for > 6 weeks.^21,23,24 Patients may also present with fatigue, low-grade fever, and loss of appetite. The small joints including the fingers, thumbs, and wrists, as well as the joints of the toes, are affected first. Patients may also experience pain in large joints, including the elbows, shoulders, ankles, and knees. A predominant feature of RA is morning stiffness, defined as: "slowness or difficulty moving the joints when getting out of bed or after staying in one position too long, which involves both sides of the body and gets better with movement."²⁵

The diagnosis of RA cannot be made by 1 physical finding or laboratory result.^23,26 The ACR/European League Against Rheumatism (EULAR) provides specific criteria for the diagnosis of RA.^22,23,26  Patients that present with synovitis in at least 1 joint, and the swelling of the joint is not the result of another disease, should be tested for RA. Patients that score ≥ 6 (out of a possible 10) on the ACR/EULAR classification criteria are diagnosed as having RA (Table 5).

Table 5. ACR/EULAR Classification Criteria for Rheumatoid Arthritis*26
Classification criteria	Score
Joint involvement 1 large joint 2 to 10 large joints 1 to 3 small joints‡ 4 to 10 small joints‡ > 10 joints (with ≥ 1 small joint)	0 1          2 3 5
Serology§ Negative RF and negative ACPA Low-positive RF or low-positive ACPA High-positive RF or high-positive ACPA	0 2 3
Acute-phase reactants§ Normal CPR and normal ESR Abnormal CPR or abnormal ESR	0 1
Duration of symptoms (patient self-report) < 6 weeks ≥ 6 weeks	0 1
*Add scores of categories A to D; a score of ≥ 6/10 is needed for classification of definite RA. ‡With or without involvement of large joints. §At least 1 test result is needed for classification. ACPA = anti-citrullinated protein antibody; ACR = American College of Rheumatology; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; EULAR = European League Against Rheumatism; RF = rheumatoid factor.

The primary goal in the treatment of RA is to improve quality of life by reducing pain and maintaining or improving functional abilities.²¹ Ideally, the goal of therapy is disease remission or low disease activity.^21,27 Additional goals include slowing destructive joint damage and delaying disability.²¹ Treatment of RA includes both non-pharmacologic and pharmacologic therapies. An emphasis is placed on aggressive treatment in early RA.^{21,27, 28}

Treatment Recommendations

A nonpharmacologic treatment plan includes rest, occupational or physical therapy, weight loss, and/or surgery.²¹ Engaging in these lifestyle modifications will aid in relieving stress on inflamed joints, decrease pain, and increase or maintain mobility. Surgery, which includes tendon repair or joint replacement, is reserved for patients with severe disease.

The primary medication classes used in the treatment of RA include: NSAIDs, corticosteroids, synthetic disease-modifying anti-rheumatic drugs (DMARDs), and biologic DMARDs, which include tumor necrosis factor (TNF)-α inhibitors and non-TNF agents.^21,27,28 Table 6 provides a summary of agents used in the treatment of RA, with a focus on synthetic and biologic DMARDs.^21,27,29 Corticosteroids and NSAIDs are used for symptomatic relief but have no effect on disease progression.²¹ The ACR guidelines provide pharmacologic recommendations based on disease activity, stage of RA (early vs. established), and degrees of prognosis.^27,28 Generally, in patients with early RA (< 6 months), with low or high disease activity and without features of poor prognosis, DMARD monotherapy is the standard of care. Combination therapy (double or triple) is recommended for patients with any degree of disease activity and the presence of poor prognostic factors. Initially, DMARD monotherapy is the treatment of choice in patients with established RA (≥ 6 months). However, as a result of disease progression or adverse effects, patients will often require a change in therapy from 1 DMARD to another or to a biologic agent or addition of agents. The ACR provides specific recommendations for switching drug regimens. It is also recommended that all patients are vaccinated against influenza, pneumococcal, hepatitis B, human papilloma, and herpes zoster; however, live-attenuated vaccinations are contraindicated in patients receiving biologics such as TNF inhibitors and non-TNF agents  for RA (see Interactions section below).^28,30

Table 6. Common Agents Used for the Treatment of Rheumatoid Arthritis17,21,29,31
Drug	Usual dosage	Comments/dosing adjustments
DMARDS
Methotrexate, oral (Rheumatrex, Trexall, generic)	7.5 to 25 mg orally once weekly	Use with caution and dose adjust in patients with moderate renal dysfunction Not recommended in patients with severe renal dysfunction (CrCl < 10 mL/min)
Methotrexate, injectable (Otrexup, Rasuvo, generic)	7.5 to 25 mg IM or SC once weekly	May be given with folic acid 1 to 5 mg weekly to reduce adverse reactions
Hydroxychloroquine (Plaquenil)	200 to 400 mg orally daily	Avoid in patients with severe renal insufficiency
Sulfasalazine (Azulfidine, Azulfidine EN-tabs, generic)	2 g orally in divided doses	Use extreme caution for patients with renal or hepatic impairment
Leflunomide (Arava, generic)	10 to 20 mg orally daily	Loading dose of 100 mg daily for 3 days is recommended to reduce GI effects Not recommended in liver disease (ALT > 2 X ULN)
Biologic agents – TNF-α inhibitors
Adalimumab (Humira)	40 mg SC every 1 to 2 weeks	Rotate injection sites and do not give injections into areas where the skin is tender, bruised, red, or hard No information regarding dosing in renal or hepatic impairment
Certolizumab pegol (Cimzia)	400 mg SC at 0, 2, and 4 weeks; then 200 mg every other week or 400 mg every 4 weeks	The 400 mg dose is given as 2 SC injections of 200 mg Data are lacking to provide dosing recommendations in patients with moderate and severe renal impairment
Etanercept (Enbrel)	25 mg SC twice weekly or 50 mg SC once weekly	Use caution in patients with moderate to severe alcoholic hepatitis
Golimumab (Simponi)	50 mg SC once monthly	No information regarding dosing in renal or hepatic impairment
Infliximab (Remicade)	3 mg/kg IV at 0, 2, and 6 weeks; then every 8 weeks	Only approved for use in combination with methotrexate Antihistamines, acetaminophen and/or corticosteroids may be administered as premedications to  manage infusion-related reactions
Biologic agents – Non-TNF inhibitors
Abatacept (Orencia)	500, 750, or 1000 mg IV at 0, 2, and 4 weeks; then every 4 weeks IV	IV dose is dependent upon weight: < 60 kg = 500 mg 60 to 100 kg = 750 mg > 100 kg = 1000 mg
	125 mg once weekly SC	SC dose may be initiated with or without an IV loading dose (see above for dosing) If initiating with an IV loading dose, administer 125 mg SC within 24 hours of the IV infusion, followed by 125 mg SC once weekly thereafter
Anakinra (Kineret)	100 mg SC once daily	Consider administering the dose every other day for patients who have severe renal insufficiency or end-stage renal disease (CrCl < 30 mL/min)
Rituximab (Rituxan)	1000 mg IV followed by a second 1000 mg IV dose 2 weeks later Subsequent doses to be given no sooner than 16 weeks	Only approved for use in combination with methotrexate in patients with an inadequate response to at least 1 TNF-α antagonist Methylprednisolone 50 to 100 mg IV infused over 30 minutes is recommended before administration to reduce the incidence and severity of infusion reactions
Tocilizumab (Actemra)	4 to 8 mg/kg IV every 4 weeks	Reduction of dose from 8 to 4 mg/kg is recommended in the settings of elevated LFTs, neutropenia, and thrombocytopenia
	162 mcg SC every week	Administer every other week in patients weighing less than 100 kg Administration modification necessary with elevated LFTs
Tofacitinib (Xeljanz)	5 mg orally twice daily	Dose reduction in patients with moderate to severe renal impairment or moderate hepatic impairment Avoid use in patients with severe hepatic impairment
ALT = alanine aminotransferase; CrCl = creatinine clearance; CYP = cytochrome P450; DMARDs = disease-modifying anti-rheumatic drugs; EN = enteric coated; GI = gastrointestinal; IM = intramuscular; IV = intravenous; LFTs = liver function tests; SC = subcutaneous; TNF = tumor necrosis factor, ULN = upper limit of normal.

Monitoring Parameters

Table 7 provides a summary of both common and serious adverse effects, as well as monitoring parameters for the agents used in the treatment of RA.^21,29,31 Of the medications used in the treatment of RA, methotrexate is associated with the most drug interactions.¹⁷ Drugs that interfere with folate metabolism, such as trimethoprim/sulfamethoxazole, may increase bone marrow suppression caused by methotrexate.^17,31,32 A decrease in the renal clearance of methotrexate, which may increase toxicity, is the result of concomitant therapy with probenecid and NSAIDs; however, clinically these agents have been used together without adverse effects. Oral vancomycin and nystatin have been shown to decrease the absorption of methotrexate.^17,32 A 25% reduction in digoxin concentration may occur with concurrent administration of sulfasalazine and digoxin. Dual therapy with 2 TNF-α inhibitors should be avoided due to an increased risk of serious infections.¹⁷ Drug-herbal interactions have been reported for some of the agents. Dong quai and St. John's Wort should be avoided in patients taking sulfasalazine, as this increases the risk of photosensitivity. Echinacea increases the therapeutic effects of TNF-α inhibitors and the combination should be avoided.

Although it is recommended that patients should be administered needed immunizations after starting therapy with a DMARD or a biologic agent, live vaccinations should be avoided.^17,30,31 Such vaccines include herpes zoster, MMR (measles, mumps, rubella), varicella, and intranasal influenza. If live-attenuated vaccines are necessary in patients with RA, it is recommended that they be given at least 1 month prior to the initiation of therapy or at least 3 months after immunosuppressants.

Table 7. Monitoring Parameters for Common Medications Used in the Treatment of Rheumatoid Arthritis21,29,31
Drug	Adverse drug reactions	Monitoring parameters	Comments
DMARDs
Methotrexate	Common: nausea, diarrhea, stomatitis/mouth ulcers, alopecia, fatigue Serious: hepatotoxicity, myelosuppression, infection, interstitial pneumonitis	Initial: CBC, LFTs, viral hepatitis panel, chest x-ray Routine: CBC, creatinine, LFTs every 2 to 3 months	Pregnancy category X Boxed warning: Deaths have occurred with the use of methotrexate in malignancy, psoriasis, and RA Bone marrow depression may occur and result in anemia, leukopenia, or thrombocytopenia Methotrexate causes hepatotoxicity, fibrosis, and cirrhosis after prolonged use Methotrexate-induced lung disease is a potentially dangerous lesion that may acutely occur at any time Caution if using methotrexate in patients with impaired renal function Diarrhea and ulcerative stomatitis require interruption of therapy Hemorrhagic enteritis and death may occur from intestinal perforation Use only preservative-free formulations and diluents for intrathecal use
Hydroxychloroquine	Common: nausea, diarrhea, headache, rash Serious: irreversible retinal damage, cardiotoxicity, blood dyscrasia	Initial: eye examination if > 40 years of age or prior ocular disease, CBC at baseline and periodically Routine: funduscopic and visual field testing every 12 months
Sulfasalazine	Common: nausea, diarrhea, headache, rash Serious: granulocytopenia, hemolytic anemia (with G6PD deficiency)	Initial: CBC, LFT, G6PD level Routine: CBC every 2 to 4 weeks for the first 2 months; then every 3 months
Leflunomide	Common: alopecia, diarrhea Serious: hepatotoxicity, myelosuppression, infection	Initial: CBC, LFTs, viral hepatitis panel* Routine: CBC, creatinine, LFTs every 2 to 3 months	Pregnancy category X Boxed warning: Severe liver injury, including fatal liver failure, has been reported
Biologic agents
TNF-α inhibitors
Adalimumab	Common: injection site reactions, upper RTI Serious: increase risk of bacterial/fungal infections, reactivation of latent TB, increase risk of lymphoma, drug-induced lupus, neurologic deficits	Initial: PPD skin test Routine: injection site reactions	Boxed warning: Patients are at increased risk of developing serious infections that may lead to hospitalization or death Lymphoma and other malignancies, some fatal, have been reported in children and adolescents treated with TNF-α blockers
Certolizumab pegol
Etanercept
Golimumab
Infliximab	Common: infusion reactions, increased LFTs, nausea, upper RTI Serious: increase risk of bacterial/fungal infections, reactivation of latent TB, increase risk of lymphoma, drug-induced lupus, neurologic deficits	Initial: PPD skin test Routine: LFTs periodically
Non-TNF inhibitors
Abatacept	Common: headache, nausea  Serious: increase risk of bacterial/viral infections	Initial: PPD skin test Routine: infusion reactions
Anakinra	Common: headache, injection site reaction Serious: increase risk of bacterial/viral infections, reactivation of latent TB, neutropenia	Initial: PPD skin test, CBC with differential Routine: CBC every month for 3 months; then every 4 months for 1 year, injection site reactions
Rituximab	Common: rash, fever Serious: increase risk of bacterial/viral infections, infusion reactions, cytopenia, hepatitis B reactivation	Initial: CBC, viral hepatitis panel* Routine: CBC at regular intervals	Boxed warning: Administration can result in serious, or fatal, infusion reactions Severe, including fatal, mucocutaneous reactions can occur HBV reactivation can occur in patients treated with rituximab, in some cases resulting in fulminant hepatitis, hepatic failure, and death John Cunningham virus infection can cause progressive multifocal leukoencephalopathy and death Premedicate with methylprednisolone 100 mg to decrease infusion reactions
Tocilizumab	Common: elevated serum cholesterol (in combination therapy), elevated ALT, AST Serious: risk of infection, infusion reactions, LFT elevation, dyslipidemia, cytopenias	Initial: PPD skin test Routine: CBC and LFTs at regular intervals	Boxed warning: patients are at an increased risk for developing serious infections that may lead to hospitalization or death REMS: to increase awareness of risks for serious infections, GI perforations, allergic reactions, changes in liver function, neutropenia, thrombocytopenia, dyslipidemia, demyelinating disorders, and malignancies
Tofacitinib	Common: respiratory infections, nasopharyngitis, diarrhea, headache Serious: risk of infection, LFT elevation, dyslipidemia, neutropenia	Initial: PPD skin test Routine: CBC, LFTs, and lipids at regular intervals	Boxed warning: Patients are at increased risk of developing serious infections that may lead to hospitalization or death Lymphoma and other malignancies, some fatal, have been reported in patients taking tofacitinib REMS: to increase awareness of risks for serious infections, lymphoma, and other malignancies
*viral hepatitis panel: hepatitis B surface antigen, hepatitis C viral antibody.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBC = complete blood count; DMARDs = disease-modifying anti-rheumatic drugs; G6PD = glucose-6-phosphate dehydrogenase; GI = gastrointestinal; HBV = hepatitis B virus; LFT(s) = liver function test(s); PPD = purified peptide derivative; RA = rheumatoid arthritis; REMS = Risk Evaluation Mitigation Strategy; RTI = respiratory tract infection; TB = tuberculosis; TNF = tissue necrosis factor.

OSTEOARTHRITIS

Overview

Osteoarthritis (OA) is the most common type of arthritis in the United States and the leading cause of disability in the elderly.^33-35 In 2005, the disease was estimated to affect 27 million people.^33,36,37 The incidence is on the rise and it is projected that by the year 2030, over 67 million people will have OA.^33,34 The prevalence of OA increases with age (> 60 years), is higher in females, and affects all race and ethnicities.^33,38 The exact cause of OA is unknown; it is likely to be complex and multifactorial.^33,35  Age, gender, joint trauma, previous joint injury or surgery, occupation, obesity, and muscle weakness are common risk factors.^33,35,36  An improper balance between cartilage formation and destruction leads to loss of cartilage in the joint(s) and damage to the underlying bone. The knees are most commonly affected, as well as the hands (thumb and fingers) and hips.

Frequently, patients with OA have an initial complaint of stiffness in the affected joint.^33-35 This symptom is prevalent in the morning, upon wakening, and during periods of rest. Additional symptoms of pain are described as:

• Deep and aching
• Joint pain increases with activity (e.g., walking up and down stairs)
• Resolves with motion or occurs at rest
• Duration < 30 minutes
• Related to the weather
• Limited joint motion
• Joint instability (joints "giving way")
• Difficulty with previous daily activities (e.g., holding, gripping, or writing with a pen)

The diagnosis of OA is based on symptoms, physical examination, laboratory blood tests, screening autoantibodies (to rule out RA), and radiographic imaging.^33,36 The ACR has established guidelines for the diagnosis of OA of the hand, knee, and hip (Table 8).³⁵

Table 8. Criteria for Diagnosis of Osteoarthritis of Primary Joints35
Hand	Knee	Hip
Hand pain, aching, or stiffness	Knee pain	Hip pain
AND	AND	AND
Hard tissue enlargement of ≥ 2 joints	Radiographic osteophytes	≥ 2 of the following: ESR <10 mm/h Radiographic femoral or acetabular osteophytes Radiographic joint space narrowing
AND	AND
< 3 swollen MCP joints	≥ 1 of the following: age ≥ 50 years morning stiffness < 30 minutes crackling/popping sounds on motion
AND
≥ 2 DIP joints with hard tissue enlargement
OR
Deformity in ≥ 2 select joints (DIP, PIP, and first CMC)
CMC = carpometacarpal; DIP = distal interphalangeal; ESR = erythrocyte sedimentation rate; MCP = metacarpophalangeal; PIP = proximal interphalangeal.

As previously mentioned, OA is the leading cause of disability in the elderly.^33-35 The prognosis of OA depends on the joint(s) affected; it is the leading cause of hip and knee replacements in the United States.^33,36 Goals of therapy are to: decrease pain and stiffness, improve or maintain joint function, reduce disability, and increase quality of life.^33,35,36                 

Treatment Recommendations

The treatment of OA relies heavily on non-pharmacologic therapy as it is simple and effective.^33,35,36 It is the only treatment that delays disease progression and improves joint function.^33,36 It is recommended that patients avoid painful activities.^33,34,36 Additional interventions are summarized in Table 9.

Table 9. Nonpharmacologic Interventions for the Treatment of Osteoarthritis33,34,36,39
Conventional interventions	Unconventional interventions
Exercise (aerobic and/or weight lifting) Weight loss (if overweight) Patient education Use of assistive devices (e.g., cane or walker) Use of shoe insoles/orthotics (help align knees) Cold or hot packs Use of fitted knee braces	Transcutaneous electrical nerve stimulation Pulsed electromagnetic fields Static magnets Acupuncture Spa therapy Yoga

Pharmacologic therapy is used in conjunction with non-pharmacologic therapy as an aid to pain and symptom relief.^33,34,39 Agents for OA may be administered by the oral, topical, or intra-articular route. The ACR recommendations for drug therapy depend on the affected joint(s), prior success/failure with analgesics, and comorbid conditions.^33,40 In general, the drug of choice for the treatment of OA is acetaminophen.^33,34,39 Nonsteroidal anti-inflammatory drugs are alternative first-line agents, specifically in patients in which acetaminophen is contraindicated, not effective, or if the pain associated with OA is due to an inflammatory process. Topical NSAIDs (knee) or oral NSAIDs taken "as needed" are recommended to decrease adverse effects. Gastrointestinal effects are most common; approximately 30% to 40% of patients experience GI toxicity. If a patient is at high-risk for GI effects, a GI protective agent, such as a proton pump inhibitor, should be added. Patients that are not at risk for cardiovascular events may benefit from a cyclooxygenase-2 (COX-2) inhibitor in place of an NSAID. It is recommended that NSAIDs be used in patients < 75 years of age. Intra-articular corticosteroids, alone or in combination with NSAIDs or tramadol, may be used in patients unresponsive to NSAIDs alone. Alternative second-line agents include opioid analgesics, duloxetine (knee only), or intra-articular hyaluronates. Surgery is reserved for patients with functional disability and/or severe pain. A summary of NSAIDs, and other agents used in the management of OA, is provided in Tables 10 and 11, respectively.^17,33  

Table 10. Some NSAIDs Used in the Treatment of Osteoarthritis17,33
Drug	Usual dosage	Comments/dosing adjustments
Aspirin – plain, buffered, or EC (Bayer, Ecotrin, Bufferin)	325 to 650 mg 4 times daily	Doses of 3600 mg daily are needed for anti-inflammatory effects
Celecoxib (Celebrex)	100 mg twice daily or 200 mg daily	COX-2 inhibitor
Diclofenac IR (Cataflam)	50 mg twice or 3 times daily
Diclofenac XR (Voltaren-XR)	100 mg daily
Diflunisal (Dolobid)	500 to 750 mg twice daily
Etodolac (Lodine)	400 to 500 mg twice daily
Fenoprofen (Nalfon)	400 to 600 mg 3 to 4 times daily
Flurbiprofen (Ansaid)	200 to 300 mg daily in 2 to 4 divided doses
Ibuprofen (Motrin, Advil)	1200 to 3200 mg daily in 3 to 4 divided doses	Available as prescription and OTC
Indomethacin (Indocin)	Initiate 25 mg 2 to 3 times daily; titrate dose by 25 to 50 mg daily until pain controlled	Maximum dose is 50 mg 3 times daily
Indomethacin SR (Indocin SR)	Initiate 75 mg daily; titrate to 75 mg twice daily if needed
Ketoprofen (Orudis)	50 to 75 mg 3 to 4 times daily
Meclofenamate (Meclomen)	50 to 100 mg 3 to 4 times daily
Mefenamic acid (Ponstel)	250 mg 4 times daily	FDA-approved for 1 week of therapy
Meloxicam (Mobic)	15 mg daily
Nabumetone (Relafen)	500 to 1000 mg 1 to 2 times daily
Naproxen (Naprosyn)	500 mg twice daily	Available as prescription and OTC
Naproxen sodium (Anaprox, Aleve)	220 to 550 mg twice daily
Naproxen sodium XR (Naprelan)	375 to 750 mg twice daily
Oxaprozin (Daypro)	600 to 1200 mg daily
Piroxicam (Feldene)	20 mg daily
Salsalate (Disalcid)	500 to 1000 mg 2 to 3 times daily
COX = cyclooxygenase; EC = enteric-coated; FDA = Food and Drug Administration; IR = immediate-release; NSAIDs = nonsteroidal anti-inflammatory drugs; OTC = over-the-counter; SR = sustained-release; XR = extended-release.

Table 11. Commonly Used Agents for the Treatment of Osteoarthritis.17,33
Drug	Usual dosage	Comments/dosing adjustments
Oral analgesics
Acetaminophen (Tylenol)	325 to 650 mg every 4 to 6 hours or 1 g 3 to 4 times daily	Avoid in patients with chronic alcohol intake or hepatic disease Contained in many OTC combination products Maximum daily dose is 4 g
Tramadol (Ultram)	50 to 100 mg 3 times daily*	Maximum dose in patients with CrCl < 30 mL/min is 200 mg/day
Tramadol ER (Ultram ER)	Titrate to 200 to 300 mg daily*	Avoid in patients with CrCl < 30 mL/min
Opiates (various)	Usual dose varies by opiate prescribed	Titrate dose slowly in elderly patients For combination products, the maximum dose is limited by the total daily dose of acetaminophen
Topical analgesics
Capsaicin (Capzasin-HP)	Apply to affected joint 3 to 4 times daily
Diclofenac 1% gel (Voltaren)	Apply 2 or 4 g per site as prescribed, 4 times daily
Diclofenac 1.3% patch (Flector)	Apply 1 patch twice daily to the affected joint
Diclofenac 1.5% solution	Apply 40 drops to the affected knee; apply by rubbing in 10 drops at 1 time and repeat for a total of 4 times
Intra-articular injections
Corticosteroids
Methylprednisolone acetate (Depo-Medrol)	20 to 80 mg per large joint (knee, hip, shoulder)	10 to 40 mg for medium joints (elbows, wrists)
Triamcinolone (Trivaris)	10 to 40 mg per large joint (knee, hip, shoulder)	The maximum dose given at 1 visit (administered into 1 joint or separated among multiple joints) is 80 mg Often administered concomitantly with a local anesthetic
Hyaluronic acid derivatives
Euflexxa	20 mg once weekly for 3 weeks
Gel-One	30 mg as a single injection	May inject a local anesthetic prior to administration
Hyalgan	20 mg once weekly for 5 weeks	Some patients benefit with 3 injections given at weekly intervals May inject a local anesthetic prior to administration
Orthovisc	30 mg once weekly for 3 to 4 weeks	Repeat courses may be administered if symptoms return
Supartz	25 mg once weekly for 5 weeks	Some patients benefit with 3 injections given at weekly intervals May inject a local anesthetic prior to administration
Synvisc	16 mg once weekly for 3 weeks
Synvisc-One	48 mg as a single injection
*taper dose upon discontinuation to prevent withdrawal symptoms. CrCl = creatinine clearance; ER = extended-release; OTC = over-the-counter.

Monitoring Parameters

Table 12 provides a summary of the adverse effects and monitoring parameters for the agents used in the treatment of OA.^17,33 Clinically meaningful drug interactions are minimal with acetaminophen; however, some patients require close monitoring.^17,33 The risk of hepatotoxicity is increased with the concurrent administration of isoniazid. Chronic administration of maximum acetaminophen doses (4 grams daily) may intensify the anticoagulant effect in patients taking warfarin. Acetaminophen should be avoided in chronic alcoholics or limited to no more than 2 grams daily. Potentially serious drug interactions may occur when NSAIDs are administered with lithium, warfarin, or other agents that increase bleeding risk. The anti-hypertensive effects of angiotensin-converting enzyme inhibitors (ACE-I) and beta-blockers may be decreased when administered with NSAIDs. An increased risk of nephrotoxicity can occur when NSAIDs are coadministered with ACE-I or tacrolimus. Celecoxib is metabolized by cytochrome P450 (CYP) 2C9. Therefore, use caution when administered with CYP2C9 enzyme inducers or inhibitors. Tramadol must be used cautiously with medications that lower the seizure threshold, such as tricyclic antidepressants, first-generation antipsychotics, and cyclobenzaprine. Concurrent administration of tramadol with serotonergic agents increases the risk of serotonin syndrome. Drug interactions with topical NSAIDs (diclofenac) are similar to that of systemic agents; however, the incidence is decreased due to the limited systemic absorption of topical NSAIDs.   

Table 12. Monitoring Parameters for Common Medications Used in the Treatment of Osteoarthritis17,33
Drug	Adverse drug reactions	Monitoring parameters	Comments
Oral analgesics
Acetaminophen	Hepatotoxicity	Total daily dose limits (4 g daily)
Tramadol	Nausea, vomiting, somnolence	No routine labs recommended
Opioids	Sedation, constipation, nausea, dry mouth		Boxed warning: risk of addiction, dependence, and drug diversion Scheduled controlled substances
NSAIDs	Dyspepsia, CV events, GI bleeding, renal impairment	BUN/creatinine, Hgb/Hct, blood pressure	Boxed warning: may cause an increased risk of serious CV thrombotic events, myocardial infarction, and stroke, which can be fatal Risks of adverse effects increase over 75 years of age
Topical analgesics
Capsaicin	Skin irritation and burning	Inspect all areas of application	Wash hands thoroughly after application
NSAIDs	Skin itching, rash, irritation, dyspepsia, CV events, GI bleeding, renal impairment	Inspect all areas of application As needed: BUN/creatinine, Hgb/Hct, blood pressure	See oral NSAIDs
Intra-articular injections
Corticosteroids	Hypertension, hyperglycemia	Glucose, blood pressure	Pregnancy category C or D-triamcinolone (depends on product) Monitor HPA axis suppression if used too frequently
Hyaluronates	Local joint swelling, stiffness Pain	No routine labs recommended	Less effective than intra-articular corticosteroids Expensive
CV = cardiovascular; GI = gastrointestinal; Hgb = hemoglobin; Hct = hematocrit; HPA = hypothalamic-pituitary-adrenal; NSAIDs = nonsteroidal anti-inflammatory drugs; OTC = over-the-counter.

GOUT

Overview

Gout is an inflammatory arthritis caused by monosodium urate crystal deposits in the bone and joints.^41-43 It is the most common inflammatory arthritis among men and older women. The incidence and prevalence of gout is increasing, especially in people > 65 years of age. It is estimated that 8.3 million people suffer from gout in the United States.⁴⁴ Uric acid results from the breakdown in purine metabolism.^43-45 Hyperuricemia, defined as a serum urate ≥ 6.8 mg/dL, is the result of urate overproduction, urate underexcretion, or both.^41,43,45 This causes the formation of crystal salt deposits in the joints and soft tissues.^41-43 There is a direct correlation between serum urate levels and gout; however, hyperuricemia does not have to be present during an acute gouty attack. Factors that can contribute to hyperuricemia include increasing age, obesity, gender, hypertension, renal insufficiency, and medications, including diuretics, salicylates, and ethanol.^43,44

The diagnosis of gout is based on symptoms; the majority of patients with hyperuricemia will be asymptomatic.^43,44 Clinically, gout presents as a rapid onset of joint pain, erythema, and swelling. The majority of patients typically complain of symptoms in the first metatarsophalangeal joint at the base of the big toe; however, any lower extremity joint can be affected. Monosodium urate crystals will be present in synovial fluid or a tophus.  The goals in the treatment of gout are to treat the acute attack, prevent future attacks, and lower serum urate levels (< 6 mg/dL), thereby preventing complications of chronic crystal deposits.^43,44,46

Treatment Recommendations

The ACR has developed guidelines for the non-pharmacologic and pharmacologic management of hyperuricemia and the prevention and treatment of acute gouty attacks.^47,48 Lifestyle recommendations outlined by the ACR are designed to promote health and minimize co-morbidities (e.g., type 2 diabetes, hypertension), which in turn will lower serum urate levels and will decrease the risk of acute gouty attacks.⁴⁷ The recommendations are summarized in Table 13.

Table 13. Nonpharmacologic Recommendations for Patients with Gout47

Intervention

Weight loss for obese patients Exercise Smoking cessation Stay well hydrated Avoid: Organ meats high in purine content (e.g., liver, kidney) High fructose corn syrup sweetened sodas, beverages, or foods Alcohol overuse (> 2 daily servings for men and > 1 daily serving for women) Any alcohol use during periods of attack or advanced gout under poor control Limit: Servings sizes of beef, pork, lamb, and seafood with high purine content (e.g., sardines, shellfish) Servings of naturally sweet fruit juices Table sugar and sweetened beverages and desserts Table salt Alcohol in all patients (particularly beer, but also wines and spirits) Encourage: Low-fat or non-fat dairy products Vegetables

Acute attacks can be successfully treated with anti-inflammatory agents, specifically, NSAIDs, colchicine, or corticosteroids.^44,46,48 There is no evidence suggesting that 1 NSAID is preferred over another. Combination therapy of these agents may be necessary in patients with severe pain, multiple joints affected, or those unresponsive to monotherapy. Acute treatment should last no longer than 24 hours. Although not FDA-approved for gout, the interleukin-1 inhibitors, canakinumab and anakinra, may be used in patients unable to take NSAIDs, colchicine, or corticosteroids.

Once the pain associated with an acute attack has resolved, the focus of therapy shifts to the prevention of flares.^44,46,47 Pharmacologic therapy, in addition to lifestyle modifications, is recommended for patients who experience ≥ 2 gout attacks per year.⁴⁸ All patients with ≥ 1 tophus, chronic kidney disease (stage 2 or worse), and a history of urolithiasis should receive pharmacologic therapy as well. The ACR guidelines provide a step-wise approach for the treatment of gout. Xanthine oxidase inhibitors (allopurinol or febuxostat) are recommended first-line agents; probenecid is considered an alternative agent if at least 1 xanthine oxidase inhibitor is contraindicated or not tolerated. In refractory cases, combination therapy of a xanthine oxidase inhibitor and an agent that increases the renal clearance of uric acid (e.g., probenecid, losartan, fenofibrate) can be tried.^46,47 Pegloticase, an intravenous pegylated urate oxidase enzyme, is considered a third-line agent for highly symptomatic patients that have not responded to combination therapy as stated above. Prophylaxis with colchicine or an NSAID may be used to prevent an acute gout attack during the initiation of urate-lowering therapy. Table 14 provides a summary of select agents used in the treatment of gout.

Table 14. Selected Agents Used in the Treatment of Gout17,44,46-48
Drug	Usual dosage	Comments/dosing adjustments
Anti-inflammatory drugs
Colchicine (Colcrys)	Acute: 1.2 mg orally, then 0.6 mg orally 1 hour later Prophylaxis*: 0.6 mg orally once or twice daily for 6 months	Adjust dose in patients with CrCl < 30 mL/min or in patients receiving dialysis
NSAIDs (various)	Dosing based on specific agent
Interleukin-1 inhibitors*
Anakinra (Kineret)	100 mg SC daily for 3 days
Canakinumab (Ilaris)	150 mg SC for 1 dose
Urate-lowering drugs
Xanthine oxidase inhibitors
Allopurinol (Zyloprim, generic)	100 to 800 mg daily to achieve serum urate < 6 mg/dL	Initiate dose at 50 mg daily for patients with mild to moderate renal impairment; titrate to a maintenance dose > 300 mg daily
Febuxostat (Uloric)	40 to 80 mg once daily	No dosage adjustment in mild to moderate renal impairment; insufficient data in patients with several renal impairment (CrCl < 30 mL/min)
Uricosurics
Probenecid (Probalan, generic)	500 to 2000 mg daily to achieve serum urate < 6 mg/dL	Not recommended if CrCl < 50 mL/min
Other
Pegloticase (Krystexxa)	8 mg IV every 2 weeks	Optimal treatment duration has not been established
*not FDA-approved. CrCl = creatinine clearance; FDA = Food and Drug Administration; IV = intravenous; SC = subcutaneous.

Monitoring Parameters

Table 15 provides a summary of the adverse effects as well as monitoring parameters for select agents used in the treatment of gout.^17,44 Refer to Table 12 for information regarding NSAIDs. Of the medications used in the management of gout, colchicine is associated with the most drug interactions. Table 16 summarizes clinically significant drug interactions. The combination of allopurinol with thiazide diuretics or ACE-I may increase the risk of hypersensitivity reactions. Concurrent use of febuxostat and didanosine is contraindicated due to the increased systemic exposure of didanosine. Salicylates are contraindicated in patients on probenecid because it antagonizes the uricosuric action of probenecid.

Table 15. Monitoring Parameters for Common Medications Used in the Treatment of Gout17,44
Drug	Adverse drug reactions	Monitoring parameters	Comments
Anti-inflammatory drugs
Colchicine	Dose-dependent GI effects (diarrhea, nausea, vomiting), rare myelosuppression, reversible neuromyopathy	Therapeutic: resolution of pain, avoidance of gout attacks when used for prophylaxis Toxic: GI symptoms, complete blood count
Interleukin-1 inhibitors
Anakinra, canakinumab	Injection site reactions, neutropenia, immune hypersensitivity reaction, infectious disease, malignancy	Therapeutic: resolution of pain, avoidance of gout attacks when used for prophylaxis Toxic: neutrophil count (prior to initiation, monthly for the first 3 months, then after 6, 9, and 12 months of therapy), temperature (periodically to detect infection)
Urate-lowering drugs
Xanthine oxidase inhibitors
Allopurinol	Rash, potential for fatal hypersensitivity syndrome	Therapeutic: serum urate level, reduced frequency of gout attacks Toxic: rash, renal function
Febuxostat	Liver enzyme elevation, nausea, arthralgias, rash	Therapeutic: serum urate level, reduced frequency of gout attacks Toxic: LFTs, renal function
Uricosurics
Probenecid	Urolithiasis	Therapeutic: serum urate level, reduced frequency of gout attacks Toxic: renal function	Useful in urate underexcretion Avoid in patients with a history of urolithiasis
Other
Pegloticase	Acute gout attack during treatment initiation, anaphylaxis, GI symptoms (constipation, nausea, vomiting), chest pain, nasopharyngitis	Therapeutic: serum urate level, reduced frequency of gout attacks Toxic: signs/symptoms of anaphylaxis following infusion	Boxed warning: anaphylaxis and infusion reactions have been reported to occur during and after administration REMS: to increase awareness of the risk for anaphylaxis, infusion reactions, and the contraindicated use in those with G6PD deficiency Reserved for patients with gout refractory to conventional therapies Can be used in both urate overproduction and underexcretion
G6PD = glucose-6-phosphate dehydrogenase; GI = gastrointestinal; LFT(s) = liver function test(s); REMS = Risk Evaluation Mitigation Strategy.

Table 16. Colchicine Drug interactions and Recommended Dosing Adjustments17,44
Drug	Treatment of acute gout flares	Prophylaxis of gout flares
Strong CYP3A4 inhibitors: Atazanavir Clarithromycin Darunavir/ritonavir Indinavir Itraconazole Ketoconazole Lopinavir/ritonavir Nefazodone Nelfinavir Ritonavir Saquinavir Telithromycin Tipranavir/ritonavir	Single 0.6 mg oral dose followed by 0.3 mg orally 1 hour later; dose to be repeated no earlier than 3 days	0.3 mg orally once every other day to 0.3 mg once daily
Moderate CYP3A4 inhibitors: Amprenavir Aprepitant Diltiazem Erythromycin Fluconazole Grapefruit juice Verapamil	Single 1.2 mg oral dose; dose to be repeated no earlier than 3 days	0.3 to 0.6 mg orally daily (0.6 mg dose may be given as 0.3 mg twice daily)
P-glycoprotein inhibitors: Cyclosporine Ranolazine	Single 0.6 mg oral dose; dose to be repeated no earlier than 3 days	0.3 mg orally once every other day to 0.3 mg orally once daily
CYP = cytochrome P450.

Focus points for Medication Therapy Management (MTM) in Bone Disorders

Osteoporosis

• Goals of treatment are to prevent loss of BMD and prevent fractures.
• All patients should maintain a bone-healthy lifestyle, including an adequate intake of calcium and vitamin D.
• Calcium should be administered preferably with food, 2 hours before or after other medications.
• Patients with low BMD will not experience symptoms of osteoporosis; therefore, they must be counseled on the importance of medication adherence.
• First-line agents recommended by the AACE include alendronate, risedronate, zoledronic acid, or denosumab.
• Due to the risk of GI effects, oral bisphosphonates should not be administered with food or medications. Dosing instructions state that bisphosphonates should be administered first thing in the morning on an empty stomach with 6 to 8 oz of plain (not mineral) water. After administration, the patient may not eat or drink (except water) and remain upright for at least 30 minutes (60 minutes with ibandronate).
• Calcitonin nasal spray should be refrigerated prior to opening and primed prior to first use.
• The optimal duration of therapy for osteoporosis agents has not been established.

Rheumatoid Arthritis

• The initial goal of therapy is to reduce pain and improve quality of life; ideally treatment should prevent disease progression.
• Lifestyle modifications, including rest, occupational/physical therapy, and weight loss can help to alleviate joint pain.
• Corticosteroids and NSAIDs are used only for symptomatic relief.
• Combination therapy with DMARDs and biologic agents may be warranted early in the disease.
• Patients taking TNF-α inhibitors are at increased risk for developing serious infections; practice good hand hygiene to prevent infections.
• All patients should be vaccinated against influenza, pneumococcal, hepatitis B, and herpes zoster.

Osteoarthritis

• Goals of therapy are to decrease pain and stiffness, improve or maintain joint function, reduce disability, and increase quality of life.
• Lifestyle modifications are crucial to delay disease progression and improve joint function.
• The agent of choice for OA is acetaminophen.
• Patients should be counseled that acetaminophen is found in many OTC combination products; the maximum dose is 4 grams daily.
• Patients taking NSAIDs should be counseled on GI toxicities. The addition of an acid suppression agent may be necessary in some patients.

Gout

• Goals of therapy are to treat the pain of an acute attack, prevent future attacks, and lower serum urate levels to < 6 mg/dL.
• Lifestyle and diet modifications to prevent comorbidities will decrease the risk of acute gouty attacks.
• Anti-inflammatory agents, specifically, NSAIDs, colchicine, or corticosteroids, are the recommended agents for the treatment of an acute gouty attack.
• Preventative pharmacologic therapy is indicated in patients that experience ≥ 2 acute gouty attacks per year.
• Xanthine oxidase inhibitors (allopurinol or febuxostat) are recommended first-line agents for the prevention of acute gouty attacks.
• Patients with hyperuricemia do not require treatment to lower serum urate levels, as the majority of patients will never experience a gout attack.
• Colchicine is associated with numerous drug-drug interactions.

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