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The following common bone diseases are discussed within this module:

• Osteoporosis
• Rheumatoid arthritis
• Osteoarthritis
• Gout

OSTEOPOROSIS

Overview

Epidemiologic studies have estimated that 8 million women and 2 million men in the United States have osteoporosis, making it the most common bone disorder in this country.^1,2 Osteoporosis is defined as a reduction in bone strength that leads to increased fracture risk. Considered a “silent disease,” patients with osteoporosis are often asymptomatic until a fracture occurs.³ If signs and symptoms do occur, they are often fracture-related and 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.⁴

Osteoporosis results from an imbalance in bone remodeling; osteoclast activity (bone resorption) exceeds osteoblast activity (bone formation) causing decreased bone mineral density (BMD).^2,5 This imbalance in bone remodeling is a normal age-related process that begins around age 30 and, for women, this imbalance becomes more apparent after menopause.² Physical activity and adequate vitamin D and calcium intake are important for developing and maintaining adequate BMD. Other factors that can contribute to low BMD or osteoporotic fractures include low body weight, premature menopause, chronic disease, smoking, alcohol use (3 or more drinks/d), and medications (eg, corticosteroids).⁴

Clinically, osteoporosis can be diagnosed by the presence of a fracture without major trauma (also known as a fragility fracture).^3,4 Osteoporosis may also be diagnosed based on BMD with a dual-energy x-ray absorptiometry (DXA) scan, which measures bone density at the hip and spine. The DXA report includes the actual bone density, a T-score, and a Z-score.⁴ The T-score is used for diagnosis and compares the patient’s bone density to the peak bone density of a healthy 20- to 29-year-old adult. The T-score is the number of standard deviations from the mean reference population. 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. Z-scores help diagnose osteoporosis in men younger than 50 years old, children, or premenopausal women.

The World Health Organization (WHO) has defined bone density levels which are summarized in Table 1.^3,6 Additionally, the Fracture Risk Assessment Tool (FRAX), developed by the WHO, calculates the estimated risk of fracture based on BMD and individual patient factors.^3,7

The incidence of osteoporosis can be reduced by optimizing skeletal development and peak bone mass early in life.⁴ Prevention of age-related and secondary causes of bone loss is also important. Once osteoporosis develops, the goal is to prevent fractures, 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.^3,8,9 Additional guidelines from the Endocrine Society, the American Society for Bone and Mineral Research, (ASBMR) and the American College of Physicians (ACP) focus on the pharmacologic treatment of osteoporosis.^10-12 Maintenance of a bone-healthy lifestyle can reduce the risk of fractures. Specific lifestyle modifications are summarized in Table 2.

Adequate calcium intake is essential for the development of bone mass during childhood and for maintenance of bone mass throughout life.³ The primary source of calcium should be obtained through a patient’s diet. Supplementation with calcium is recommended when dietary intake is inadequate. Calcium intake recommendations are based on the amount of elemental calcium in each product. 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.

Pharmacologic treatment is recommended for postmenopausal women or men who are at least 50 years of age with T-scores less than 2.5 in the femoral neck, total hip, or lumbar spine; those with a hip or vertebral fracture; or those with a T-score between -1 and -2.5 and a 10-year fracture probability of at least 20% for major osteoporotic fracture or at least 3% for hip fracture based on the FRAX tool.^4,10,13

The choice of pharmacologic therapy is based on antifracture benefits demonstrated in clinical studies.^3,9,10 The various agents approved by the US 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.³ They recommend use of oral agents for patients at low or moderate risk of fractures. Injectable medications are preferred as initial therapy in those with a very high fracture risk, those with gastrointestinal (GI) concerns, and those who have difficulty remembering or adhering to a medication schedule. The 2019 guidelines from the Endocrine Society recommend bisphosphonates as first-line therapy in postmenopausal women at high risk of fractures.¹⁰ They do note that ibandronate is not recommended to reduce nonvertebral or hip fractures. Denosumab is recommended as an alternative initial treatment, and the parathyroid hormone analogs (teriparatide and abaloparatide) are reserved for postmenopausal women at very high risk of fracture. The selective estrogen receptor modulators (raloxifene and bazedoxifene) reduce the risk of vertebral fractures and can be used in patients who have a low risk of thromboembolism when bisphosphonates or denosumab are inappropriate. Calcitonin is the last-line agent recommended only in patients who do not tolerate any other therapy. The role of romosozumab has not yet been addressed in clinical practice guidelines.^3,10

Osteoporosis is one of the most significant adverse effects of glucocorticoid therapy. The ACR published guidelines in 2017 for the prevention and treatment of osteoporosis in patients who are treated with glucocorticoids.⁸ They recommend all patients practice a bone-healthy lifestyle and optimize calcium and vitamin D intake. Specific pharmacologic agents are recommended based on age and risk factors. An oral bisphosphonate is recommended for patients who are at least 40 years of age with a moderate or high risk of fracture.

Safety and 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.^4,14,15 An important consideration with bisphosphonate therapy is the duration of therapy to maximize benefits while minimizing adverse events. Recent guidelines from the Endocrine Society and ASBMR have focused on appropriate duration of these agents.^10,12 Generally, patients at high risk of fracture are recommended to continue oral therapy for up to 10 years or up to 6 years with IV therapy. However, those at lower risk may consider a drug holiday for 2 or 3 years after an initial 3 to 5 years of therapy.

Oral bisphosphonates should not be administered at the same time as food or other medications.^4,14,15 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 GI effects. 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. There are no known drug interactions with abaloparatide or romosozumab.¹⁵

Patient Case #1:

Chief Complaint
“I am worried I am going to get osteoporosis.”

MB is a 53-year-old female who presents to her gynecologist to discuss preventive measures for osteoporosis. She started having irregular periods about 6 months ago with mild hot flashes at night.

Personal medical history:
None

Family history:
Strong history of breast cancer

Social history:
Former cigarette smoker (until age 30); drinks 1 to 2 glasses of wine per month

Allergies:
None

Medications:
Calcium carbonate 1000 mg daily
Acetaminophen – as needed for headaches

Physical examination is normal.

Vital signs: BP 112/70, P 80, RR 14, T 37; Wt 108 pounds, Ht 5′2″

All labs WNL

DXA scan of spine: T-score is –2
What preventive measures would help decrease MB’s risk for developing osteoporosis?

• Starting an aerobic and weight-bearing exercise program
• Ensuring an adequate intake of calcium and vitamin D (recommendation is 1200 mg elemental calcium and 800-1000 IU vitamin D daily)

What are the goals of pharmacotherapy for MB?

• Prevent additional loss of BMD
• Prevent fractures

What recommendations should be made regarding therapy for MB?

• Initiate preventative therapy with alendronate 35 mg weekly
• Counsel to administer first thing in the morning on an empty stomach with 6 to 8 oz of plain (not mineral) water. After administration, she may not eat or drink (except water) and remain upright for at least 30 minutes.

RHEUMATOID ARTHRITIS

Overview

Rheumatoid arthritis (RA) is a common chronic inflammatory disorder.^16-18 The prevalence is estimated to be 0.5% to 1% worldwide. The disease is more common in women. Rheumatoid arthritis has the highest incidence in patients between 25 and 55 years of age, and incidence declines after 75 years of age.¹⁸ The cause of RA is complex and multifactorial.^16-18 Genetic predisposition, environmental factors (eg, cigarette smoking), 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 joint deformity and destruction of cartilage, bone, tendons, ligaments, and joints.^17,19 Antibodies that may indicate a poorer prognosis with RA include rheumatoid factors and anticitrullinated protein antibody (ACPA).¹⁷

Individuals with RA initially present with pain, stiffness, and swelling of multiple joints for > 6 weeks.^17,19,20 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.”^19,21

The diagnosis of RA cannot be made by 1 physical finding or laboratory result.^20,22 The ACR/European League Against Rheumatism (EULAR) provides specific criteria for the diagnosis of RA.^20,22,23 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).

The primary goal in the treatment of RA is to improve quality of life by reducing pain and maintaining or improving functional abilities.¹⁷ Ideally, the goal of therapy is disease remission or low disease activity.^21,24 Additional goals include slowing destructive joint damage and delaying disability.¹⁷ Treatment of RA includes both nonpharmacologic and pharmacologic therapies. An emphasis is placed on aggressive treatment in early RA.^17,24,25

Treatment Recommendations

A nonpharmacologic treatment plan includes rest, occupational or physical therapy, weight loss, and/or surgery.¹⁷ 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), Janus kinase (JAK) inhibitors and biologic DMARDs, which include tumor necrosis factor (TNF)-α inhibitors, interleukin-6 inhibitors and other non-TNF agents.^17,24-26 Table 6 provides a summary of agents used in the treatment of RA, with a focus on synthetic and biologic DMARDs.^17,18,24 Corticosteroids and NSAIDs are used for symptomatic relief but have no effect on disease progression.¹⁷ The ACR guidelines provide pharmacologic recommendations based on disease activity, stage of RA (early vs established), and degrees of prognosis.^24,25 Generally, in patients with early RA (< 6 mo), 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 mo). 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).²⁶

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.^14,15,17,26 Of the medications used in the treatment of RA, methotrexate is associated with the most drug interactions.^14,15 Drugs that interfere with folate metabolism, such as trimethoprim/sulfamethoxazole, may increase bone marrow suppression caused by methotrexate.¹⁵ A decrease in the renal clearance of methotrexate, which may increase toxicity, is the result of concomitant therapy with probenecid and NSAIDs; however, clinically methotrexate and NSAIDs have been used together without adverse effects. A 20% 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. Iron supplements may reduce the absorption of sulfasalazine.¹⁷ Additionally, sulfasalazine may potentiate the effect of warfarin or cause warfarin resistance.^14,15,17 Drug-herbal interactions have been reported for some of the agents. Echinacea increases the therapeutic effects of immunosuppressants and the combination should be avoided.¹⁴ Tocilizumab and sarilumab may reduce concentrations of cytochrome (CYP) 3A4 substrates (eg, combined oral hormonal contraceptives).^14,15,17 Additionally, monitor patients taking tocilizumab and sarilumab with drugs with a narrow therapeutic index (eg,warfarin).

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 after starting biologic agents.¹⁷ Such vaccines include herpes zoster (Zostavax), MMR (measles, mumps, rubella), varicella, and intranasal influenza.²⁷ If live-attenuated vaccines are necessary in patients with RA, it is recommended that they are given at least 3 months after immunosuppressants.¹⁴

Patient Case #2:

Chief complaint:
“I ache all over, I feel exhausted, and I am having a hard time getting going in the morning.”

SP is a 33-year-old female who presents to her rheumatologist with generalized arthralgias, fatigue, and morning stiffness. She presented with similar symptoms 3 months ago, at which time she was started on a regimen of methotrexate and prednisone. She reports slight improvement in her symptoms relative to her visit 3 months ago.

Personal medical history:
Rheumatoid arthritis x 3 months

Family history:
Father is alive and is being treated for hypertension and hypercholesterolemia. Mother is alive and suffers with severe RA and osteoporosis. Two siblings with no health issues.

Social history:
Executive secretary. Married for 3 years; wants to start a family within the next year. Denies tobacco use. Drinks 1 to 2 glasses of wine per week.

Allergies:
None

Medications:
Prednisone 5 mg orally daily
Methotrexate 15 mg orally once weekly (2.5 mg x 6 tablets)
Folic acid 1 mg orally daily

Review of systems:
Eighteen tender joints and 16 swollen joints bilaterally; decreased range of motion, in hands and wrists; morning stiffness every day for about 2 hours; fatigue experienced daily during afternoon hours; swelling in hands, knees, and feet; denies HA, chest pain, SOB, bleeding episodes, or syncopal attacks; denies nausea, vomiting, diarrhea, loss of appetite, or weight loss.

Physical examination:
Caucasian woman in moderate distress because of pain, swelling, and fatigue related to arthritis

VS: BP 118/76, P 82, RR 14, T 37; Wt 65 kg, Ht 5′6″

Assessment:

A 33-year-old woman in moderate distress with RA not adequately controlled with current therapy. Disease Activity Score exhibits high disease activity although patient reports slight improvement in symptoms over 3 months ago. Patient is adherent with current medication regimen. Patient expresses desire to start a family within the next year.

List SP’s drug therapy problems.

• Prednisone is not helping to treat SP’s symptoms
• The dose of methotrexate may be increased up to 25 mg weekly
• Methotrexate is contraindicated in pregnancy and should not be used in women of child bearing age
• Methotrexate may be contributing to SP’s fatigue

What are the goals of pharmacotherapy for SP?

The goals of therapy for SP are:

• Reduce pain
• Maintain or improve functional abilities
• Improve quality of life
• Lower disease activity and induce disease remission

What nonpharmacologic modalities may be beneficial for SP?

• SP may benefit from physical/occupational therapy

What recommendations should be made regarding therapy for SP?

• SP has a poor response to therapy with methotrexate. Additionally, this is not an appropriate agent, as it is contraindicated in pregnancy. Prednisone is not helping to relieve the pain.

The following should be recommended:

• Discontinue prednisone and methotrexate
• Initiate sulfasalazine 0.5 to 1 gram daily; increase the dose weekly to a maintenance dose of 1 gram twice daily
• Initiate a TNF-α inhibitor (adalimumab, certolizumab, etanercept, or golimumab). Choice of agent should be based on cost
• Discontinue folic acid and initiate a prenatal vitamin once daily
• Ensure adequate intake of elemental calcium and vitamin D

OSTEOARTHRITIS

Overview

Osteoarthritis (OA) is the most common type of arthritis in the United States and a leading cause of disability in the elderly.^28-30

OA is estimated to affect over 30 million people in the United States.³¹ The incidence is on the rise due to increasing rates of obesity and longer life expectancy.³⁰ The prevalence of OA increases with age (> 60 years), is higher in females, and prevalence varies by race and ethnicity.^28-31 The causes of OA are complex and multifactorial.²⁸ Age, gender, joint trauma, previous joint injury or surgery, occupation, obesity, genetic predisposition, and muscle weakness are common risk factors.^28,30 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 present with pain in the affected joint.³⁰ Patients may also experience stiffness that is prevalent in the morning and after periods of rest. Additional symptoms of pain are described as:²⁸

• Deep and aching
• Joint pain increases with activity (eg, 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 (eg, holding, gripping, or writing with a pen)

The diagnosis of OA is primarily based on symptoms and physical examination, but may also include laboratory blood tests and screening autoantibodies (to rule out other arthritis causes), and radiographic imaging.^29,30 The ACR has established criteria for classification of OA of the hand, knee, and hip (Table 8).^28,32

As previously mentioned, OA is a leading cause of disability in the elderly.²⁸ The prognosis of OA depends on the joint(s) affected; it is the leading cause of hip and knee replacements in the United States.^28,33 Goals of therapy are to: decrease pain and stiffness, improve or maintain joint function, reduce disability, and increase quality of life.^28,30,33

Treatment Recommendations

The treatment of OA relies heavily on nonpharmacologic therapy as it is simple and effective.^28-30,33 It is the only treatment that delays disease progression and improves joint function.²⁸ It is recommended that patients avoid painful activities.^29,30 Additional interventions are summarized in Table 9.

Pharmacologic therapy is used in conjunction with nonpharmacologic therapy as an aid to pain and symptom relief.^28-30 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.^28,34 In general, the drug of choice for the initial treatment of OA is acetaminophen.^28-30,35 However, acetaminophen often is not adequate for complete symptom control and so most patients require additional agents. NSAIDs are alternative first-line agents, specifically in patients in which acetaminophen is contraindicated or not effective. Topical NSAIDs (knee) or oral NSAIDs taken “as needed” are recommended to decrease adverse effects. GI effects are most common; approximately 30% to 40% of patients experience GI toxicity.^29,35 If a patient is at high-risk for GI effects, a GI protective agent, such as a proton pump inhibitor, should be added.^28-30,35 Patients may also benefit from a cyclooxygenase-2 (COX-2) inhibitor in place of an NSAID; however, COX-2 inhibitors should be prescribed with caution in patients at risk for cardiovascular events. Topical rather than oral NSAIDs are recommended in patients ≥ 75 years of age.^28,34 Intra-articular corticosteroids, alone or in combination with NSAIDs or tramadol, may be used in patients unresponsive to NSAIDs alone. Alternative agents include opioid analgesics as needed, duloxetine, or intra-articular hyaluronates.^28,29,35 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,

Monitoring Parameters

Table 12 provides a summary of the adverse effects and monitoring parameters for the agents used in the treatment of OA.^14,28 Clinically meaningful drug interactions are minimal with acetaminophen; however, some patients require close monitoring. The risk of hepatotoxicity is increased with the concurrent administration of isoniazid. Chronic administration of maximum acetaminophen doses (4 g daily) may intensify the anticoagulant effect in patients taking warfarin. Acetaminophen should be avoided in the setting of chronic alcoholic intake. Potentially serious drug interactions may occur when NSAIDs are administered with lithium, warfarin, or other agents that increase bleeding risk. The antihypertensive 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 CYP2C9. 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 likely decreased due to the limited systemic absorption of topical NSAIDs. Additive central nervous system depression is potentiated when opioids are used concurrently with other central nervous system depressants.

GOUT

Overview

Gout is an inflammatory arthritis caused by monosodium urate crystal deposits in the bone and joints as a result of excess uric acid in the blood.^36,37 It is the most common inflammatory arthritis among men.³⁸ The incidence and prevalence of gout are increasing. It is estimated that 8.3 million people suffer from gout in the United States.³⁶

Uric acid in the body results from purine metabolism.^36,39 Excess uric acid or hyperuricemia is the result of urate overproduction, urate underexcretion, or both. Some causes of uric acid overproduction include alcohol, purine-rich diet, or obesity while decreased uric acid excretion can occur with hypertension, renal insufficiency, or drugs such as salicylates, diuretics, or alcohol.^37,40 The majority of patients with hyperuricemia will be asymptomatic, but patients with gout typically present with an acute episode of arthritis resulting from the formation of crystal salt deposits in the joints and soft tissues. There is a direct correlation between serum urate levels and gout; however, hyperuricemia does not have to be present during an acute gouty attack.

The diagnosis of gout is based on symptoms.^36,39 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.^36,39,41,42

Treatment Recommendations

Both the ACR and ACP have developed guidelines for the nonpharmacologic and pharmacologic management of hyperuricemia and the prevention and treatment of acute gouty attacks.^37,41,42 Lifestyle recommendations outlined by the ACR are designed to promote health and minimize comorbidities (eg, type 2 diabetes, hypertension), which in turn will lower serum urate levels and decrease the risk of acute gouty attacks.⁴¹ The recommendations are summarized in Table 13.

Acute attacks can be successfully treated with anti-inflammatory agents, specifically, NSAIDs, colchicine, or corticosteroids.^37,42 There is no evidence suggesting that 1 NSAID is preferred over another.³⁷ Combination therapy of these agents may be necessary in patients with severe pain, multiple joints affected, or those unresponsive to monotherapy.^36,42 Acute treatment should begin within 24 hours of the attack and continue for the duration of the attack. 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.⁴²

Once the pain associated with an acute attack has resolved, the focus of therapy shifts to the prevention of flares.^36,39 Pharmacologic therapy, in addition to lifestyle modifications, is recommended for patients who experience ≥ 2 gout attacks per year.^36,41,42 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.⁴¹ 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 (eg, probenecid, losartan, fenofibrate) can be tried. 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.

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.^14,15,36 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 allopurinol or febuxostat with 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. Do not use pegloticase with other medications for gout due to enhanced toxic effects of pegloticase.

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. The Endocrine Society guidelines recommend bisphosphonates as first-line therapy
• 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 min with ibandronate)
• 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 biologic therapies 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 g 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
• 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

References

1. Osteoporosis. North American Spine Society website. https://www.spine.org/KnowYourBack/Conditions/Degenerative-Conditions/Osteoporosis. Accessed May 17, 2019.
2. Lindsay R, Cosman F. Osteoporosis. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 20^th ed. New York, NY: McGraw-Hill; 2018. http://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=19253067. Accessed May 13, 2019.
3. Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for the diagnosis and treatment of postmenopausal osteoporosis – 2016. Endocr Pract. 2016;22(Suppl 4):1-42.
4. O’Connell M, Borchert JS. Osteoporosis and osteomalacia. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L, eds. Pharmacotherapy: A Pathophysiologic Approach. 10th ed. New York, NY: McGraw-Hill; 2017. http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=146068952. Accessed May 13, 2019.
5. Raisz LG. Physiology and pathophysiology of bone remodeling. Clin Chem. 1999;45(8 Pt 2):1353-1358.
6. Bone mass measurement: what the numbers mean. National Institute of Health website. https://www.bones.nih.gov/health-info/bone/bone-health/bone-mass-measure#c. Accessed May 13, 2019.
7. Calculation tool. FRAX: Fracture Risk Assessment Tool website. https://www.sheffield.ac.uk/FRAX/tool.aspx?country=9. Accessed May 15, 2019.
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