module 11 - pharmacotherapy for musculoskeletal disorders

Geriatric Pharmacy Review

Module 11 Pharmacotherapy for Musculoskeletal Disorders

Copyright 2011 American Society of Consultant Pharmacists

Accreditation Information

ASCP is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

This home study web activity has been assigned 2 credit hours.

ACPE UPN: 0203-0000-10-094-H01-P

Release Date: 6/14/2010

Expiration Date: 6/14/2013

To receive continuing education credit for this course, participants must complete an on-line evaluation form and pass the on-line assessment with a score of 70% or better. If you do not receive a minimum score of 70% or better on the assessment, you are permitted 4 retakes. After passing the assessment, you can print and track your continuing education statements of credit online.

Geriatric Pharmacy Review courses have not yet been approved for Florida consultant pharmacy continuing education.


Content Experts

Current Content Experts:

Joshua Neumiller, PharmD Associate Professor Washington State University School of Pharmacy

Stephen M. Setter, PharmD, CDE, CGP, DVM Assistant Professor of Pharmacotherapy Washington State University Elder Services / Visiting Nurses Association

Travis E. Sonnett Geriatric Fellow/Clinical Research Associate College of Pharmacy Washington State University

Legacy Content Expert:

Donald R. Miller, PharmD, FASHP Professor and Chair of Pharmacy Practice College of Pharmacy North Dakota State University


Faculty Disclosures

Joshua Neumiller has no relevant financial relationships to disclose.

Stephen Setter discloses the following relationships: •  Speakers Bureau: Pfizer, Forest Labs, Teva

Travis E. Sonnett has no relevant financial relationships to disclose.

Donald R. Miller has no relevant financial relationships to disclose.


Osteoporosis

Learning Objectives:

By the end of this Review Concept you should be able to:

• Describe the epidemiology of osteoporosis.

• Describe goals of treatment for patients with osteoporosis.

• List risk factors for osteoporosis.

• Cite indications for bone mineral density testing.

• Describe common interventions for the prevention of osteoporosis.

• Describe the role of calcium supplementation and vitamin D therapy in the prevention and treatment of osteoporosis.

• List indications for the pharmacological treatment of osteoporosis.

• Describe agents, dosing, and adverse drug reactions associated with classes of drugs used to prevent and/or treat osteoporosis.


Review of Skeletal Tissue

Osteoporosis:

Defined as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.

Like every other system in the human body, the musculoskeletal system is susceptible to the effects of aging. To understand these effects, it is helpful to review the nature of skeletal tissue and bone metabolism. Bone is constantly being broken down (a process known as resorption) and rebuilt.

Osteoclasts are a type of bone cell that invades the surface of the bone and erodes it, dissolving both mineral and matrix. Osteoclasts create a cavity on the surface of the bone. Osteoblasts then fill in the cavity with new bone, which contains collagen and minerals. Osteoclast and osteoblast activity is physiologically coupled so that bone that is resorbed is replaced. Osteoporosis occurs when bone resorption outpaces the laying down of new bone.


Review of Skeletal Tissue

Recall that the human skeleton is composed of cortical bone, which is relatively dense and compact, and trabecular or cancellous bone, consists of a lattice network of trabeculae that is commonly called “spongy” bone. As mentioned, trabecular bone is also referred to as cancellous bone. Cortical bone is the type found in the skull and the shafts of long bones and accounts for eighty percent of the skeleton’s weight but only thirty percent of its surface area. Cortical bone turns over very slowly with only 3-5% being replaced per year.

Trabecular bone, on the other hand, accounts for twenty percent of the skeleton’s weight and seventy percent of its surface area. Trabecular bone is found in vertebrae, ribs, the pelvis, and the ends of long bones and is very metabolically active. Roughly 25% of all trabecular bone turns over annually. In essence, every five to ten years, a completely new skeleton is formed.


Age-Related Changes in Bone Metabolism

Normally, bone resorption is balanced with bone replacement. That is, the osteoclasts that resorb (or chew up) old bone matrix are in equilibrium with the osteoblasts that produce (or build) new bone matrix. Although this process of bone remodeling occurs throughout the individual’s lifetime, age-related changes in calcium and bone metabolism can cause bone resorption to outpace bone formation, causing a net loss of bone mass. Osteoporosis can be considered a pediatric disease that doesn’t manifest itself until older age. It is critical for individuals up to the age of 35 to maintain adequate dietary calcium intake as this is the period of time for maximal skeletal growth. After roughly age 35 the amount of new bone built no longer exceed bone resorption.

In cortical bones, this is seen as a progressive reduction in cortical density and increase in cortical porosity. In trabecular bone, this manifests as a thinning and eventual perforation or destruction of entire trabeculae. The strength of trabecular bone is dependent on the interjoining of the fine lattice structure that is present. When trabeculae thin and perforate, the bone is weakened, much like a bridge that has weakened or loosened joists or crossbars. Bare in mind that bone quality and its susceptibility to fracture is related to more than just bone mineral density. Bone quality is also related to the microarchitecture of the bone, the rapidity of bone turnover, degree of mineralization, and age.


Epidemiology of Osteoporosis

Incidence:

• 30 million affected per year • 8 million women and 2 million men • 20 million have low bone mass (formerly known as osteopenia)

• 250,000 hip fractures per year • 25-30% of all hip fractures occur in men

• 750,000 vertebral fractures/year • 15% of white females will fracture hip and another 15% will fracture forearm • 50% of women and 13% of men will sustain an osteoporosis related fracture during their lifetime • 50% of women between 80-84 have vertebral compression fractures • Incidence of all fractures increases with age

Costs:

• $10 billion per year • Year 2002 estimates:$13.8 billion per year


Epidemiology of Osteoporosis

Mobidity/Mortality:

* Chronic complications are common * 50% require assistance with activities of daily living (ADLs) post hip fracture * 15% to 25% must be institutionalized * 12% to 20% of women die within the first year after hip fracture * 50% of men die within the first year after hip fracture

The skeletal changes that result from the disequilibrium between bone resorption and replacement are part of a systemic disease known as osteoporosis. Osteoporosis or low bone mass (formerly identified as osteopenia) affects roughly 30 million people in the United States and costs more than ten billion dollars in health care expenditures. These expenditures are related primarily to injuries that occur as the bones become more fragile and fracture. As women age, they are especially susceptible to osteoporotic fractures. These fractures cannot only impair the activities of daily living, but they can also lead to chronic complications, institutionalization, and even death.

Bear in mind that by the year 2050 the number of people beyond age 65 years in the United States will increase to 69 million and more than 15 million people will exceed 85 years of age. Hip and spine fractures incidence increases with advancing age. Also bear in mind that the national health-care cost of osteoporosis was estimated to be $13.8 billion in 2002 and that this cost is expected to rise to $240 billion during the next 50 years.

The key points to remember regarding osteoporosis are first, osteoporosis is often asymptomatic until it is complicated by a fracture second, a diagnosis of osteoporosis does not require the presence of a fracture and third early diagnosis and intervention is essential to prevent a fracture.


Types of Osteoporosis Based on Pathophysiology

Postmenopausal (Type I) • Affects women aged 51 – 75 • Affects trabecular bone primarily • Bone resorption increases while bone formation is unchanged • Vertebral fractures most common

Senile (Type II) • Affects ages 75 – 90 • Women are affected twice as often as men • Affects trabecular and cortical bone • Common fracture sites include:hip, spine, pelvis, humerus

Secondary (Type III) • Affects all ages • Affects men and women equally • Affects trabecular and cortical bone • Can be caused by medications (e.g.: glucocorticoids), cancer (e.g.: multiple myeloma), endocrine disorders (e.g.: Cushing’s disease, hyperthyroidism or hyperparathyroidism), chronic renal and/or hepatic disease, malnutrition and/or malabsorption

Disorders related to osteoporosis can be classified in different ways. The classification shown here is based on characteristic pathophysiology. Type I or menopausal osteoporosis affects primarily trabecular bone, while senile and secondary osteoporosis affect both trabecular and cortical bone. Secondary osteoporosis can affect individuals of any age, and affects men and women equally. Medication-induced osteoporosis is a type of secondary osteoporosis. Medication-induced osteoporosis is very important to pharmacists as it is our responsibility to identify drugs that can cause low bone mass. Once drugs that can lead to osteoporosis are identified, pharmacists need to make appropriate recommendations to decrease damage to the bone caused by these drugs. For example, glucocorticoids as a class of medications are most often implicated in causing osteoporosis. In addition to medications, secondary osteoporosis can be due to cancer such as multiple myeloma, endocrine disorders such as Cushing’s disease, hyperthyroidism or hyperparathyroidism, chronic renal and/or hepatic disease, celiac disease, malnutrition and/or malabsorption.


Risk Factors for Osteoporosis

Race • Caucasian • Asian

Age • Elderly

Gender • Females > Males • Note: 25% of all osteoporosis occurs in males

Body type • Thin or petite builds • Weight < 127 pounds

Family history • Family history of fracture or of osteoporosis • Personal history of fracture after age 40

Miscellaneous • Loss of height (+ 4cm [1.5”] from peak height) • Low dietary calcium • Sedentary lifestyle • Cigarette smoking (probable) • Caffeine (?)

Individuals at highest risk for osteoporosis include those of Caucasian or Asian descent, the elderly, females, and individuals that have thin or petite builds. In general weighing less than 127 pounds places women at increased risk. Other risk factors for osteoporosis include: a positive family history of the disease or fracture, personal history of fracture, low dietary calcium intake, and sedentary lifestyle. Low levels of testosterones or estrogens are also risk factors. In older males, a history of fracture or clinical risk factors such as hypogonadism can place males at increased risk of osteoporosis. Keep in mind that although osteoporosis primarily affects women, 25% of all osteoporosis occurs in men. Women who are smokers have even lower levels of estrogen and thus have menopause significantly earlier than nonsmokers. Smokers, therefore, should be considered to be at increased risk for osteoporosis.

The role of caffeine is controversial. It has been argued that tea drinkers are less likely to have osteoporosis than coffee drinkers. Caffeine is a diuretic and causes hypercalciuria, and current evidence indicates that aging individuals are less able to compensate for the diuretic effect of caffeine by increasing serum concentrations of 1,25-dihydroxyvitamin D. It is estimated that for every cup of coffee, you lose 6 mg of additional calcium. Elderly persons who are heavy consumers of coffee may have a negative calcium balance, which in turn aggravates age-related bone loss.


Medications That Increase Osteoporosis Risk

• Glucocorticoids • Heparin (long term use) • Anticonvulsants • Phenytoin • Lithium • Immunosuppressants • Methotrexate, cyclosporine • Aromatase inhibitors (anastrazole, exemestane, letrozole) • Cytotoxic drugs • Excessive thyroxine • Gonadotropin releasing hormone agonists


Medications That Increase Osteoporosis Risk

Numerous medications are associated with an increased risk for developing osteoporosis. Glucocorticoids inhibit osteoblastic activity allowing for the uncoupling of bone formation and resorption and a secondary increase in parathyroid hormone. The result is a pronounced loss of bone as early as 6 months after starting oral corticosteroids in doses of 7.5 mg or greater per day. Even low doses, those less than 8 mg per day have an annualized rate of bone loss of 3% with doses greater than 20 mg/day resulting up to 30% annualized bone lose per year. The inhaled corticosteroids are also associated with bone loss and may not be recognized until 3 years or more of continued use in doses of greater than 800 mcg of becolomethasone diproprionate equivalent per day.

Heparin in doses of 20 – 30,000 Units/day for 3 – 6 months are risk factors for developing osteoporosis. Pregnant women suffering a DVT may receive extended doses of heparin as warfarin therapy is teratogenic. The occurrence of heparin-induced osteoporosis appeared to be strictly related to the length of treatment (longer than 4 or 5 months) and the dosage (15,000 U or more daily), but the pathogenesis is poorly understood. It has been suggested that heparin could cause an increase in bone resorption by increasing the number of differentiated osteoclasts and by enhancing the activity of individual osteoclasts.

Anticonvulsant agents increase the metabolism of Vit D resulting in reduced calcium absorption, hypophosphatemia, and a 10 – 30% reduction in bone mineral density over prolonged exposure.

Additionally, excessive use of aluminum-containing antacids, thyroxine, lithium and certain drugs used in cancer treatment can all cause osteoporosis. A newer class of drugs, the aromatse inhibitors which includes anastrazole (Arimidex), exemestane (Aromasin) and Letrozole (Femara) are approved for the treatment of breast cancer. However, the aromatase inhibitors can cause bone loss by lowering the levels of endogenous estrogen, which is in contrast to tamoxifen which acts as a weak estrogen to preserve bone mineral density and my in fact decrease risk of fractures.


Bone Loss Associated with Menopause


Bone Loss Associated with Menopause

The post-menopausal loss of estrogen and its direct effect on bone cells makes women in their late forties and early fifties especially susceptible to the consequences of osteoporosis. As many as twenty-five to thirty percent of these women suffer from rapid bone loss, which typically varies between one to five percent annually, following menopause. Decreases in bone mass and rapid turnover are the most accurate predictors of fractures in older women.


Indications for Bone Mineral Density (BMD) Testing

• Patient being considered for hormone replacement therapy (HRT) • Signs of vertebral fractures • Radiologic evidence of low bone mass (osteopenia) • Use of glucocorticoids longer than 2 months • Loss of 1.5” (4cm) of height • Family history or other risk factors • Age 60 with risk factors

• Treat if T score < - 2.0 • Age 65 or greater without risk factors

• Treat if T score < - 2.5

T-Score

• Difference in a patient’s BMD compared with peak bone mass in a young adult of the same gender • Expressed as number of standard deviations (sd) above or below average for normal young adults • BMD: surrogate marker for fracture risk

National Osteoporosis Foundation and World Health Organization Guidelines

T – Score Normal > - 1.0 Low Bone Mass (osteopenia) < - 1.0 to > - 2.5 Osteoporosis < - 2.5 **Note: Fracture risk doubles for every 1 standard deviation below the mean

• 1 standard deviation represents a 12% bone loss


Indications for Bone Mineral Density (BMD) Testing

Osteoporosis and its effect on bone mass are determined by testing bone mineral density, commonly referred to as BMD. BMD identifies accumulated bone mineralization, while bone turnover markers identify current remodeling activity or bone loss and bone growth. Indications for BMD testing are listed on this slide. Patients should be tested if they are being considered for hormone replacement therapy, if they present with vertebral fractures or radiologic evidence of low bone mass (osteopenia), or if they have been on glucocorticoid therapy for longer than 2 months. Early intervention to prevent the consequences of osteoporosis is important, since many patients can be expected to live twenty-five or more years after the onset of the disease.

The definite measurement of BMD is with a DEXA scan. This is a scan that is typically done of the vertebrae and hips and yields a T-score which is compared with peak bone mass in a young adult of the same gender. The T-score is expressed as number of standard deviations above or below average for normal young adults.

Each 10% decrease in spinal BMD is associated with a doubling in vertebral fracture risk. Each 15% decrease in BMD is associated with a 2.4-fold increase in hip fracture risk. Each 12% decrease in distal radius BMD is associated with a 2.7-fold increase in forearm fracture risk.

Treatment should be considered when: the T-score is < - 2.0 in a person with risk factors and whose age is 60 or greater. Treatment should also be considered in people aged 65 or greater, without risk factors if the T score is < - 2.5.


Treatment of Osteoporosis

Goals: • Increase bone mass • Decrease bone loss • Prevent fractures • Preserve remodeling

Indications for Pharmacotherapy: • Post-menopausal women with low bone mineral density

• At age 65 without risk factors with a BMD < - 2.5 • At age 60 with risk factors and BMD < -2.0

• Patients with secondary causes of osteoporosis (e.g., glucocorticoids)

Agents: • Vitamin D and Calcium – for prevention and treatment

• Essential co-therapy for the prevention and treatment of osteoporosis with other pharmacologic agents • Vitamin D is necessary for adequate absorption and utilization of calcium

• Estrogen – for prevention • Bisphosphonates – for prevention and treatment

• Alendronate (Fosamaxâ / Fosamax Plus D) • Risedronate (Actonelâ) • Ibandronate (Boniva)

• Calcitonin (Calcimarâ, Miacalcinâ, Cibacalcinâ) – for treatment only • Selective Estrogen Receptor Modulator (SERM) – for prevention and treatment

• Raloxifene (Evistaâ) • Parathyroid hormone (PTH) – treatment for high risk patients

• Teriparatide (Forteoâ)


Treatment of Osteoporosis

Treatment of osteoporosis focuses on: decreasing risk of fracture, decreasing bone loss, and preserving normal bone remodeling. Drug therapy for the prevention or treatment of osteoporosis should be considered in all post-menopausal women. Some agents, such as the bisphosphonates and raloxifene, are indicated for both prevention and treatment. Others, such as calcitonin, are used only for treatment of osteoporosis. Bone mineral density measurements may be useful in deciding when to begin therapy and which therapy to use. Adequate intake of vitamin D and calcium are essential co-therapies. A critical role for pharmacists is to ensure that their patients are receiving adequate vitamin D and calcium from their diets or in the form of supplements. Any patients with risk factors such as patients receiving glucocorticoid or aromatase inhibitor therapy are also good candidates for bone mineral density testing and drug therapy.


Treatment of Osteoporosis with Calcium Supplements

Calcium Salt Tablets per Day for 1 Gram of Elemental Calcium

Tablet Size in mg (mg elemental calcium per tablet)

Carbonate

Generic 4 600 (240)

Cal – Sup® 600 2 1500 (600)

Caltrate® 600 2 500 (600)

Os – Cal® 500 2 1250 (500)

Tums® 5 500 (200)

Viactiv® 2 chews 500

Citrate (generic) 4 1200 (250)

Gluconate (generic) 17 650 (58.5)

Lactate (generic) 12 650 (84.5)

Phosphate (generic) 9 500 (115)


Treatment of Osteoporosis with Calcium Supplements

Calcium

DOSING: • 1200 – 1500 mg per day in 2 – 4 divided doses • Intake of more than 2000 mg per day is not more beneficial • Separate by at least 4 hours from thyroid supplements, iron supplements, and antibiotics that are listed below

INTERACTIONS: • Thyroid supplements – can bind supplements and require a higher supplemental dose of the thyroid medicine • Iron supplements – can bind iron supplements and require a higher supplemental dose of the iron • Tetracyclines – chelates the antibiotic, making it inactive • Fluoroquinolones – chelates the antibiotic, making it inactive

SIDE EFFECTS: • GI upset – citrate salt is least upsetting; carbonate is most • Constipation – may need to consider a standard bowel regimen in order to maintain regular bowel movements

While insufficient as monotherapy for osteoporosis, an increase in dietary calcium can help to compensate for the loss of calcium associated with menopause and aging in general. In addition to recommending foods that have higher calcium content, clinicians may prescribe calcium supplements such as the ones listed on your screen. Keep in mind that diseases causing poor calcium absorption or excessive renal calcium loss are numerous. Sufficient vitamin D intake or supplementation needs to be ensured as well.


Treatment of Osteoporosis with Estrogen

Preparations and Dosing:

• CEE (Conjugated equine estrogens):0.625 mg • Esterified estrogens:0.3 – 1.25 mg • Micronized estradiol:0.5 – 1.0 mg • Transdermal estradiol:0.05 – 0.1 mg

Administration:

Oral or transdermal

Side Effects:

• Breast tenderness, bloating, and nausea • Coagulopathies, Deep Vein Thrombosis (DVT), Pulmonary Emboli (PE) • Migraine headaches • Cholecystitis

Estrogen replacement therapy is no longer considered first-line therapy for prevention or treatment of osteoporosis. Currently, estrogen is only indicated for the prevention of osteoporosis. Side effects of estrogen replacement therapy include those associated with menstrual cycles such as breast tenderness, bloating, and nausea. The use of estrogen has also been associated with an increase in cholecystitis. Estrogen is now labeled as a carcinogen associated with breast, endometrial and ovarian cancer and carries a black box warning. Estrogen should not be used to decrease risk of cardiovascular disease and may actually increase risk of cardiovascular events. Estrogen also increases the risk of venous thromboembolic events (known as VTEs). However, a 34% decrease in colorectal cancer has been shown in randomized controlled trials.


Risks and Contraindications Associated with Estrogen Replacement Therapy

Risks:

Endometrial hyperplasia – reduce risk by prescribing estrogen-progestin regimen and careful follow-up: Continuous: 0.625 mg conjugated estrogen + 2.5 mg medroxyprogesterone acetate (MPA) daily Cyclic: 0.625 mg conjugated estrogen + 5 mg MPA for 12 – 14 days per month

Breast cancer

Contraindications:

Known or suspected breast cancer Other suspected estrogen-dependent cancers Known or suspected pregnancy Undiagnosed abnormal genital bleeding Active thrombophlebitis or thromboembolic disease History of thromboembolic disease

Audio Transcript Despite its effectiveness in preventing osteoporosis, estrogen replacement therapy is not without risks. It is well appreciated that unopposed estrogen therapy increases the risk of endometrial cancer. Prescribing a combination estrogen-progestin regimen and monitoring the patient regularly can minimize this risk. Estrogen may also increase the risk of breast cancer. Estrogen replacement therapy is contraindicated in patients with known or suspected breast cancer or other estrogen-dependent cancers. Patients with abnormal genital bleeding or thromboembolic disease should also avoid such therapy.


Treatment of Osteoporosis with Bisphosphonates

1st Generation:

• Etidronate (Didronel®) – not approved for treatment of osteoporosis

2nd Generation:

• Alendronate (Fosamax®)

3rd Generation:

• Risedronate (Actonel®) • Ibandronate (Boniva): PO or IV • Zoledronic acid (Zometa®):Intravenous

Bisphosphonates bind to the surface of hydroxyapatite crystals, and disrupt osteoclastic activity and therefore decrease bone resorption. Alendronate and risedronate have been found to reduce vertebral and hip fractures significantly while ibandronate has been shown to significantly decrease vertebral fracture risk. Patients prescribed bisphosphonates must have adequate intake of vitamin D and calcium, and take the agents with plain water. Additionally, over-suppression of remodeling may occur with the bisphosphonates creating, a decrease in bone quality.


Treatment of Osteoporosis with Alendronate

Dosing:

• Prevention:5 mg/d or 35 mg/week • Treatment:10 mg/d or 70 mg/week

Adverse Drug Reactions:

• Abdominal pain • Constipation • Diarrhea • Flatulence • Musculoskeletal pain • Esophagitis, esophageal erosions, esophageal ulcers (rare)

Monitoring:

• Renal insufficiency (CLcr < 35 mL/min) • Upper GI problems (maybe greater with ASA or traditional NSAIDs) • Interactions with Ca2+, Mg2+, Fe2+, Zn2+

Contraindications:

• Achalasia • Esophageal abnormalities • Patients unable to sit upright for at least 30 minutes • Hypocalcemia • Hypersensitivity to agent


Treatment of Osteoporosis with Alendronate

When used for prevention of osteoporosis, alendronate is dosed at five milligrams per day, or 35 milligrams once weekly. Patients with existing disease should receive twice the previously stated amounts (10 mg daily or 70 mg once weekly). Alendronate is approved for the treatment of osteoporosis in men. Alendronate is also approved for the treatment of glucocorticoid-induced osteoporosis in men or women who are taking systemic glucocorticoids - oral prednisone of 7.5 mg or greater or prednisone equivalents.

Side effects of alendronate include: abdominal pain, constipation, diarrhea, and esophagitis. To minimize esophageal adverse effects, patients must sit or stand upright for thirty minutes after taking the drug. Patients should also be monitored for renal insufficiency and upper gastrointestinal problems. Interactions with calcium and other multivalent cations should be avoided. Precautions and contraindications for alendronate include patients with esophageal abnormalities, dysphagia, hypocalcemia, and hypersensitivity reactions to the agent.


Treatment of Osteoporosis with Risedronate (Actonel®)

Dosing:

For prevention or treatment, 5 mg/d; or 35 mg/week


• Abdominal pain • Constipation • Diarrhea • Flatulence • Musculoskeletal pain • Esophagitis (rare)

Monitoring:

• Renal insufficiency (CLcr < 30 mL/min) • Upper GI problems (maybe greater with ASA / traditional NSAIDs) • Interactions with Ca2+, Mg2+, Fe2+, Zn2+

Contraindications:

• Esophageal abnormalities • Patients unable to sit upright for at least 30 minutes • Hypocalcemia • Hypersensitivity to agent

When used for prevention or treatment of osteoporosis, risedronate is dosed at five milligrams per day or 35 milligrams per week. Risedronate is also approved for the treatment and prevention of corticosteroid-induced osteoporosis in men and women who are either initiating or continuing chronic systemic glucocorticoid therapy (7.5 mg or greater of oral prednisone therapy or equivalent).

Side effects of risedronate include abdominal pain, constipation or diarrhea, and arthralgia. To minimize the potential esophageal adverse effects, patients must sit or stand upright for thirty minutes after taking the drug.

Patients should be also monitored for renal insufficiency and upper gastrointestinal problems. Interactions with calcium and other multivalent cations should be avoided. Precautions and contraindications for risedronate are similar to those for alendronate, and include patients with esophageal abnormalities, hypocalcemia, and hypersensitivity reactions to the agent.


Treatment of Osteoporosis with Risedronate (Actonel®

Treatment with Ibandronate (Boniva®)

Dosing: • Prophylaxis or Treatment • 150 mg PO once monthly • Treatment: 3 mg IV once every 3 months • Infusion given over 15-30 seconds

Adverse Drug Reactions: • Back pain • Bronchitis • Dyspepsia • Upper respiratory tract infection

Monitoring: • Renal insufficiency (CLcr < 30 mL/min) • Upper GI problems • Drug interactions (e.g., Al, Mg, Fe)

Contraindications:

• Achalasia (PO formulation) • Esophageal stricture (PO formulation) • Renal failure • Uncorrected hypocalcemia • Inability to remain upright for 60 minutes (PO formulation)

Ibandronate can be given PO or IV. PO ibandronate is approved for the prevention and treatment of osteoporosis while IV ibandronate is approved for the treatment of postmenopausal osteoporosis. When given orally, 150 mg of ibandronate should be taken with a full glass of water 60 minutes prior to consumption of any other liquid or food. Additionally, the patient must remain upright for 60 minutes after swallowing ibandronate.


Treatment of Osteoporosis with Risedronate (Actonel®

Contraindications to oral ibandronate include achalasia, esophageal stricture, uncorrected hypocalcemia, renal failure and the inability to remain upright for 60 minutes. IV ibandronate has been specifically been tested in geriatric patients and no overall diffeneces in effectiveness or safety were noted between older and younger patients. Redness or swelling at the site of injection is less than 2% with most mild to moderate in severity. As with oral ibandronate it is essential that patients be normocalcemic prior to administration and that patients with a CLcr less than 30 ml/min not receive PO or IV ibandronate. If an IV dose of ibandronate is missed than it should be administered as soon as it can be rescheduled. Do not administer IV ibandronate more frequently than every 3 months.


Osteonecrosis of the Jaw

• Reported in patients receiving bisphosphonates •  Most were cancer patients with recent dental procedures •  Risk factors include

• CA diagnosis • Concomitant therapies such as chemotherapy, radiotherapy, • Corticosteroids

•  Majority of cases with IV bisphosphonates

Jaw osteonecrosis has been reported most often in patients with cancer receiving IV bisphosphonates (most commonly with zolendronic acid /Zometa and pamidronate/Aredia) and undergoing recent dental procedures. Osteonecrosis also has very rarely been reported with orally administered bisphosphonates including alendronate, risedronate and ibandronate.

Risk factors for osteonecrosis of the jaw in those receiving IV bisphosphonates include cancer, those receiving chemotherapy, radiotherapy or corticosteroids and those with serious co-morbid disorders such as infection, anemia or coagulopathies. Dental surgery appears to worsen the condition. Currently it is recommended that patients planning on receiving IV bisphosphonate therapy receive a dental examination prior to initiating therapy and that invasive dental procedures be avouded while receiving IV bisphosphonate therapy. For patients about to begin oral bisphosphonate therapy ist is recommended that a comprehenxive oral evaluation be carried out before initiation of therapy or as soon as possible after beginning treatment.


Treatment with Calcitonin

Agents and Dosing:

• Salmon • Injectable: Miacalcin®, Calcimar® • Initial doses 50 – 100 IU daily or every other day (rarely used) • Intransal: Miacalcin® • Dosing: 200 – 400 IU daily (may produce analgesic effect which can decrease bone pain due to vertebral fracture)

• Human (Cibacalcin®) • Injectable: 50 – 100 IU daily or every other day (rarely used)


• Injectable: flushing, dizziness, skin rash, nausea • Intranasal: rhinitis, epistaxis, back pain, arthralgias, headache

Calcitonin is often prescribed for patients with osteoporosis because it decreases osteoclastic bone resorption. Calcitonin is available in injectable salmon and human forms and as a nasal spray in salmon form only. With intranasal delivery of calcitonin, there is lower bioavailability; hence the higher dosage. Side effects include rhinitis, epistaxis, back pain, and arthralgias.

One disadvantage of salmon calcitonin is that it produces antibodies that eventually neutralize the effectiveness of the agent in up to two thirds of patients. Those that either do not respond to salmon calcitonin or develop a resistance to it should try the human form or be evaluated for other therapies. Dosages should be based on the extent of the disease. (Emphasize this following point) Keep in mind that in controlled clinical trials, vertebral fracture incidence is decreased; however, there is no evidence that calcitonin decreases the incidence of hip fracture.


Treatment of Osteoporosis with Vitamin D

Stimulates bone formation by:

• Stimulates calcium absorption • Inhibits parathyroid hormone (PTH) effects • Promotes mineralization

Some forms of vitamin D have shown promise in the treatment of osteoporosis because it is an indirect stimulator of bone formation. In addition to stimulating calcium absorption, it inhibits the effects of parathyroid hormone and promotes mineralization. The results of clinical trials with vitamin D; however, are conflicting at this time.

There is also mounting evidence that vitamin D may help decrease the risk of falls by about 20% among ambulatory or institutionalized older adults in stable health. All people should have adequate vitamin D intake, either through diet or supplementation. The required daily amount is 400 – 800 IU of vitamin D with the higher amounts required in the elderly.


Prevention and Treatment of Osteoporosis with Raloxifene HCL

Mechanism of Action:

• Modulates estrogen receptors • Positive Estrogen-like effects on bone tissue and lipids • Estrogen antagonist activity in uterine and breast tissue

Dosing:

60 mg / day


• Hot flashes • Breast pain • Vaginal bleeding • VTE (venous thromboembolic events)

• 28 per 100,000 patient years

One other agent that may provide therapeutic benefits for patients with osteoporosis is raloxifene hydrochloride, a selective estrogen receptor modulator also known as a SERM. Raloxifene has estrogen-like effects on bone tissue and lipids, and acts like an estrogen antagonist in uterine and breast tissues.

Recommended dosage is sixty milligrams per day. Raloxifene is indicated for the prevention and treatment of osteoporosis in postmenopausal women past their vasomotor symptoms.

Reduction in vertebral fractures of about 50% is seen with 3 – 4 years of therapy. Raloxifene inhibits osteoclasts in a manner similar to estrogen. While adverse effects such as breast pain and vaginal bleeding are much less severe than for standard estrogen replacement therapy, patients taking raloxifene hydrochloride have a higher risk of hot flashes. Published data suggests a reduction in breast cancer.


Treatment of Osteoporosis with Teriparatide (Forteo®)


• Binds to PTH receptor and has the same physiological actions as PTH on bone and kidney • Stimulates new bone formation on trabecular and cortical bone surfaces by stimulating osteoblastic activity over osteoclastic activity

Dosing:

• 20 mcg/day SQ (not recommended for more than 2 years of therapy) • Available as pre-filled pen

Black Box Warning:

In rats teriparatide caused an increase in the incidence of osteosarcoma that was dependent on dose and treatment duration


• Dizziness • Leg cramps • Nausea • Headache


Treatment of Osteoporosis with Teriparatide (Forteo®)

Teriparatide is manufactured using recombinant DNA technology and contains the first 34 amino acids of the naturally occurring parathyroid hormone peptide commonly known as P-T-H. Teriparatide is indicated for the treatment of postmenopausal women with osteoporosis who are at high risk of fracture and for men with primary or hypogonadal osteoporosis who are at high risk of fracture. Teriparatide is the only anabolic agent available to treat osteoporosis, and it acts to form new bone by stimulating osteoblastic activity over osteoclastic activity on both trabecular and cortical bone surfaces. The difference between anti-resorptive agents and anabolic agents is significant. Anti-resorptive agents reduce fracture rate by 30 – 50% due to their ability to decrease bone loss and promote repair of remodeling skeletal defects.

PTH as an anabolic agent promotes skeletal remodeling and trabecular connectivity, thereby increasing bone mineralization, bone size, bone strength and architecture. Fracture reductions of 50% have been noted.

Due to its propensity to induce osteosarcoma in rats, patients who are at increased risk of this type of bone tumor should not receive this drug. This also includes patients with Paget’s disease of bone, those with unexplained elevations of alkaline phosphatase, pediatric or young adults with open epiphyses, and patients that have received prior radiation therapy to their skeleton. Additionally, patients with bone metastases or with a history of skeletal malignancies or other metabolic bone diseases should not receive teriparatide. A black box warning exists due to this increase of osteosarcoma in rats. However, the data that exists in regard to osteosarcoma does not appear to be applicable to human or primate models.

Adverse effects include: dizziness, leg cramps, nausea, and headache. Teriparatide is injected subcutaneously once daily—preferably in the thigh or abdomen—and is available as a prefilled pen. This medication should not be used beyond 18 to 24 months. Keep in mind that teriparatide is the only agent that has been shown to positively affect osteoblastic activity and should be reserved for patients at high risk for fracture.


Resources

For additional information, see:

AACE Clinical Practice Guidelines for the Prevention and Treatment of Postmenopausal Osteoporosis: 2001 Edition, with selected updates for 2003. www.aace.com/pub/pdf/osteoporosis2001Revised.pdf

Berenson JR. “Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases.” Cancer 2001;91:1191-1200.

Bolognese M.“Effective pharmacotherapeutic interventions for the prevention of hip fractures.”The Endocrinologist.2002;12(1):29-37.

Chesnut CH, Silverman S, Andriano K, et al.“A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study.”Am J Med.2000;109:267–276.

Chnitzer T, Bone HG, Crepaldi G, et al.“Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Alendronate Once-Weekly Study Group.”Aging.2000;12:1–12.

Clement D and Spencer CM.“Raloxifene:a review of its use in postmenopausal osteoporosis.”Drugs.2000;60(2):379-411.

Cohen S, Levy RM, Keller M, et al.“Risedronate therapy prevents corticosteroid-induced bone loss:a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.”Arthritis Rheum.1999;42:2309–2318.

Cranney A. “Meta-analysis of therapies for postmenopausal osteoporosis. IX. Summary of meta-analyses of therapies for postmenopausal osteoporosis.” Endocr Rev 2002;23:570-578.


Resources

Cummings SR, Black DM, Thompson DE, et al.“Effect of alendronate on risk of fracture in women with low bone density but without vertebral fracture:results from the Fracture Intervention Trial.”JAMA.1998;280:2077–2082.

Delmas PD, Bjarnason NH, Mitlak BH et al.“Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women.”N Engl J Med.1997;337:1641–1647.

Dempster DW. “Effects of daily treatment with parathyroid hormone on bone microarchitecture and turnover in patients with osteoporosis.” J Bone Miner Res 2001;16:1846-1853.

EPOS.”Incidence of vertebral fracture in Europe: results from the European Prospective Osteoporosis Study (EPOS).” J Bone Miner Res 2002;17:716-724.

Foundation for Osteoporosis Research and Education: http://www.fore.org/

Freedman KB, Kaplan FS, Bilker WB et al.“Treatment of osteoporosis; are physicians missing an opportunity?”J Bone Joint Surg.2000;82-A:1063–1070.

Gardner MJ. Interventions to improve osteoporosis treatment following hip fracture. A prospective, randomized trail. J Bone Joint Surg Am 2005;87;3-7.

Grados R. “Prevalence of vertebral fractures in French women older than 75 years from the EPIDOS study.” Bone 2004;34:362-367.


Resources

Hodes RJ.“Osteoporosis:emerging research strategies aim at bone biology, risk factors, and interventions.” J Am Geriatr Soc.1995;43:75–77.

Hodgson SF. “American Association of Clinical Endocrinologists 2001 medical guidelines fro clinical practice for the prevention and management of postmenopausal osteoporosis.” Endocr Pract 2001;7:293-312.

Johansen A, Stone M, and Rawlinson F.“Bisphosphonates and the treatment of bone disease in the elderly.”Drugs Aging.1996;8(2):113–126.

Koot VC, Peeters PH, de Jong JR et al.“Functional results after treatment of hip fracture:a multicentre, prospective study in 215 patients.”Eur J Surg.2000;166:480–485.

Lips P.“Vitamin D deficiency and osteoporosis:the role of vitamin D deficiency and treatment with vitamin D and analogues in the prevention of osteoporosis-related fractures.”Euro J Clin Invest.1996;26(6):436–442.

McClung MR, Geusens P, Miller PD et al.“Effect of risedronate on the risk of hip fracture in elderly women.”N Engl J Med.2001;344(5):333–340.

National Osteoporosis Foundation. http://www.nof.org

Neuner JM. “Diagnosis and treatment of osteoporosis in patients with vertebral compression fractures.” J Am Geriatr Soc 2003;51:483-491.


Resources

Nevitt MC, Cummings SR, Stopne KL, et al. ”Risk factors fora first-incident radiographic vertebral fracture in women > or = 65 years of age: the study of osteoporotic fractures.” Bone Miner Res 2005;20:131-140.

NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy:Osteoporosis prevention, diagnosis, and therapy.JAMA.2001;285:785–795.

Osteoporosis and Bone Physiology. Susan Ott, MD www.courses.washington.edu/bonephys/

Palomba S, Sammartino A, Di Carlo C, et al.“Effects of raloxifene treatment on uterine leiomyomas in postmenopausal women.”Fertil Steril.2001;76:38–43.

Reginster J, Minne HW, Sorensen OH, et al.“Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis.Vertebral Efficacy with Risedronate Therapy (VERT) Study Group.”Osteoporosis Int.2000;11:83–91.

Rosen CJ. “Restoring aging bones” Sci Am 2003;288:70-77.

Rosen CJ. “Clinical practice. Postmenopausal osteoporosis.” N Engl J Med 2005;353:595-603.


Resources

Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. “Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases.” J Oral Maxillofac Surg 2004;62:527-534.

Tashjian AH and Chabner BA.“Commentary on clinical safety of recombinant human parathyroid hormone 1-34 in the treatment of osteoporosis in men and postmenopausal women.”Journal of Bone and Mineral Research.2002;17(7):1151–1161.

Van der Klift M. “The incidence of vertebral fractures in men and women: the Rotterdam Study.” J Bone Miner Res 2002;17:1051-1056.

Watts NB.“Understanding the bone mass measurement act.”Journal of Clinical Densitometry.1999;2:211–217.

Zanchetta JR, Bogado CE, Ferretti JL, et al.“Effects of teriparatide (recombinant human parathyroid hormone (1-34)) on cortical bone in postmenopausal women with osteoporosis.”Journal of Bone and Mineral Research.2003;18(3):539–543.

Zimmerman SI, Girman CJ, Buie VC, et al.“The prevalence of osteoporosis in nursing home residents.”Osteoporos Int.1999;9:151–157.


Osteoarthritis



• Describe the biochemical changes that compromise joint function as a person ages.

• Differentiate between osteoarthritis and rheumatoid arthritis.

• Describe the epidemiology of osteoarthritis.

• List risk factors for osteoarthritis.

• Describe the clinical presentation of osteoarthritis.

• List goals and pharmacological/nonpharmacological options for the treatment of osteoarthritis.

• Describe advantages, dosing, contraindications, adverse reactions, and monitoring guidelines for agents commonly used to treat osteoarthritis.


Effect of Aging on the Joints

• Biomechanical stresses favor cartilage remodeling • Matrix metalloproteinases break down cartilage • Increased stress on subchondral bone stimulates osteophyte (“bone spur”) formation

Osteoarthritis, commonly abbreviated OA, is a disease associated with aging that affects articular cartilage which is cartilage that lines diarthrodial (moveable) joints. Biomechanical stresses on cartilage begin to favor production of matrix metalloproteinases that break down cartilage faster than it can be repaired.

Changes in cartilage include a decrease in tensile strength due to the altered biochemical structure of proteoglycans and collagen in the matrix. The changes in cartilage mechanical properties lead to cracking and erosion or wearing away of cartilage and hypertrophy of subchondral bone.


Osteoarthritis (OA) vs. Rheumatoid Arthritis (RA)

Osteoarthri*s Rheumatoid Arthri*s

Onset Insidious Acute or subacute

Morning s3ffness < 30 min. > 30 min.

Systemic Illness Absent Present

Joints involved Weight-‐bearing, fingers Peripheral

Inflamma3on Usually absent Always present

Joint paJern Asymmetric Symmetric

Lab findings Normal Elevated ESR and/or (+) RF

Osteoarthritis differs from rheumatoid arthritis in several important respects. Unlike rheumatoid arthritis, there is generally no systemic illness associated with osteoarthritis. Joint involvement is asymmetric with morning stiffness typically lasting less than 30 minutes upon rising. Osteoarthritis primarily affects weight bearing joints. Inflammation of joints is not prominent and there are no specific lab findings. This is in direct contrast with rheumatoid arthritis where morning stiffness typically lasts greater than 30 minutes, systemic illness is often present and joints are variably inflamed. In addition, the erythrocyte sedimentation rate is often elevated and up to 80% of patients will be Rheumatoid factor positive.


Epidemiology of Osteoarthritis

• Most common form of joint disease • Major cause of disability and health expenditures • Affects 60-70% of elderly age 60-80 years

Osteoarthritis is the most common form of joint disease. In the elderly population, it is a major cause of disability and health care expenditures. X-ray changes of osteoarthritis of the knee or hip are evident in the majority of persons over 60. Exact prevalence depends on whether osteoarthritis is defined radiologically or by symptoms, since about half of persons with x-ray evidence have no symptoms and experience little if any pain.


Pathophysiology of Osteoarthritis

Osteoarthritis is the result of disruption in the normal balance of degradation and repair in articular cartilage. Loss of normal cushioning from cartilage upsets the dynamic interaction between synovium, cartilage, and bone. Excessive loading of subchondral bone leads to hypertrophy and formation of the characteristic osteophytes. With continued joint destruction and loss of articular cartilage subchondral bone becomes ivory-like, a process called eburnation.


Risk Factors for Osteoarthritis

• Age • Obesity • Joint trauma • Joint hypermobility and instability • Repetitive joint overuse

The onset of osteoarthritis is insidious and may be a primary condition or secondary to joint injury, congenital or developmental defects, or metabolic disturbances. Risk factors for osteoarthritis include increasing age, obesity, repetitive joint overuse and joint trauma. Genetic and environmental factors may also play a role.


Clinical Presentation of Osteoarthritis

Joints Commonly Involved:

• Hand –distal interphalangeal, proximal interphalangeal • Foot – first metatarsophalangeal • Knee • Hip • Spine – cervical and lower lumbar

Signs and Symptoms:

• Pain with use of joint (may be present at rest) • Joint stiffness, esp. in morning (< 30 min.) • Bony swelling around joint • Crepitus • Limited joint motion

In patients with osteoarthritis, joint involvement is usually asymmetric. The joints that are usually involved include those joints of the hand, foot, knee, hip and spine. In contrast to rheumatoid arthritis, osteoarthritis tends to be more axial while rheumatoid arthritis tends to affect more distal joints. Classic symptoms of osteoarthritis include pain on joint use and limitations of motion. Short-duration joint stiffness in the morning is also common. Physical examination typically reveals bony enlargement and crepitus. When used in reference to joints, crepitus refers to the grating sound as the joint is moved and is due to the loss of cartilage and bone rubbing on bone. Radiographic changes show loss of cartilage, osteophytosis, altered bony contour and soft tissue swelling. However, there is a poor correlation between radiographic findings and symptoms.


Treatment of Osteoarthritis

Goals:

• Controlling pain and other symptoms • Minimize disability • Maintain quality of life

Nonpharmacological Options:

• Patient/family education • Social support from health professionals • Weight loss • Physical and occupational therapy • Exercise programs • Surgery – e.g., total knee irrigation, arthroscopic

lavage, osteotomy, total joint arthroplasty

Pharmacological Options:

• Analgesics • Capsaicin • NSAIDs/COX-2 inhibitor • Intra-articular corticosteroids • Glucosamine • Chondroitin • Hyaluronans

Treatment of patients with osteoarthritis should focus on controlling pain and other symptoms in order to minimize disability and maintain quality of life. In addition to educating the patient and family, nonpharmacological interventions should include physical and occupational therapy, regular exercise, and weight loss, if needed. Surgical options for the treatment of osteoarthritis include total knee irrigation, arthroscopic lavage, osteotomy, and total joint arthroplasty. Pharmacological treatment of osteoarthritis relies on the use of analgesics and nonsteroidal anti-inflammatory drugs initially. Newer options include glucosamine, chondroitin, and intra-articular hyaluronans.


Treatment of Osteoarthritis with Acetaminophen (APAP) (Tylenol®)

Advantages:

• Nearly as effective as NSAIDs, • Lower side effect profile; does not cause GI toxicity • Inexpensive

Initial pharmacologic choice for OA treatment, especially in the elderly, due to the above reasons

Dosing:

• 325-1000 mg QID PRN or scheduled • Maximum dose = 4 g/day (consider APAP from all sources); maximum dose in patients with history of alcoholism or other liver disease = 2 g/day

Contraindications: patients with liver disease.

Warnings: Alcohol warning: increased toxicity in patients who drink > 3 drinks/day.

Monitoring: Hepatotoxicity


Treatment of Osteoarthritis with Acetaminophen (APAP) (Tylenol®)

Acetaminophen, commonly abbreviated APAP in the United States, is often used to treat osteoarthritis. It is slightly less effective than nonsteroidal anti-inflammatory drugs, but is less expensive and safer to use in elderly patients. Therefore, it should be tried first in all osteoarthritis patients unless specifically contraindicated. Patients may receive three hundred twenty-five to one thousand milligrams as needed for pain, up to four times daily. Clinically significant side effects are rare at recommended doses. Patients receiving chronic acetaminophen for osteoarthritis should have liver enzymes, transaminases such as ALT and AST, monitored for hepatotoxicity.


Treatment of Osteoarthritis with Capsaicin Cream (Zostrix®)

Advantages: Topical administration

Dosing: TID or QID

Adverse Drug Reactions: Burning sensation on initial use. Patients should be advised to wash hands after use and avoid contact with eyes, nose or mouth.

Monitoring: Clinical efficacy

Capsaicin cream may be effective for patients with osteoarthritis. Administration three to four times daily for two weeks is required to achieve maximal effect; therefore it should NOT be prescribed PRN. Patients using capsaicin cream may initially experience a burning sensation; however, this sensation dissipates with continued use. Some patients will also require additional systemic therapy for satisfactory pain relief.


Treatment of Osteoarthritis with Opioid Analgesics

Advantages: May help as adjunct therapy

Agents:

• Codeine/APAP (e.g. Tylenol #3®) • Hydrocodone/APAP (Lortab® / Vicodin®) • Oxycodone/APAP (Percocet®) • Oxycodone (Oxycontin®)

Adverse Drug Reactions: Constipation, nausea, CNS effects (sedation, cognitive impairment)

Other analgesics used to treat osteoarthritis include opioids such as codeine, hydrocodone and oxycodone. They must be used with particular caution in the elderly due to the high risk of constipation, nausea, and central nervous system side effects such as somnolence and confusion. Older patients using opioids should also be carefully observed for unsteady gait that can lead to falls. Despite these potential side effects, opioid analgesics used with or without acetaminophen may be an important option when pain is not relieved by other means.


Treatment of Osteoarthritis with Tramadol (Ultram®)

Mechanism: An analgesic that binds to mu-opioid receptors and inhibits serotonin and norepinephrine reuptake

Indications: An alternative to opioids in moderate to moderately-severe pain

Dosing:

• 50-100 mg every 4-6 hours not to exceed 400 mg/day • Patients > 75 years old: administer < 300 mg/day in divided doses as above • If creatinine clearance less than 30 ml/min , maximum dosage interval is q12 hours • In patients with cirrhosis, maximum dose is 50 mg q 12 hours • Avoid abrupt discontinuation to prevent withdrawal syndrome


• Side effect profile similar to opioids with lower incidence of respiratory depression • Potential for physical dependence may be slightly less than opioids but should still be avoided in patients with history of opioid abuse • Seizure risk especially in combination with certain other drugs (e.g. SSRIs, TCAs, MAO inhibitors, neuroleptics)

Tramadol is an analgesic used to treat moderate to moderately-severe pain and is available as a single agent or in combination with acetaminophen in a product called Ultracet®). Tramadol is now also available in an extended release formulation (Ultram ER®). Note that tramadol does not reduce inflammation. It is considered a safe alternative in patients with a past history of gastrointestinal problems who cannot tolerate NSAIDs and who have already tried acetaminophen for pain control. It may be tried before the opioid analgesics or after in opioid intolerant individuals.


Treatment of Osteoarthritis with NSAIDS

Advantages: Often effective at low doses

Agents: Many, including

• Aspirin • Salicylates (e.g. salsalate, Disalcid®) • Ibuprofen (Motrin®, Advil®) • Naproxen (Naprosyn®, Aleve®) • Naproxen sodium (Anaprox®) • Ketoprofen (Orudis®) • Nabumetone (Relafen®) • Oxaprozin (Daypro®) • Etoldolac (Lodine®)

Dosing: Start low (e.g., ibuprofen 400 mg TID-QID) and PRN

Contraindications: Patients with GI ulcers, renal dysfunction, circulating volume depletion (e.g., diuretic use, CHF, hypotension, cirrhosis, nephrotic syndrome)

Adverse Drug Reactions: GI and renal toxicity, CNS effects (e.g., drowsiness, dizziness, headache, depression, confusion),

Monitoring: GI toxicity, hepatotoxicity


Treatment of Osteoarthritis with NSAIDS

Nonsteroidal anti-inflammatory drugs can be reserved for osteoarthritic patients unresponsive to acetaminophen or topical analgesics. Agents such as ibuprofen may be administered in low doses as needed, since analgesia (not anti-inflammatory effects) is the main endpoint.

Nonacetylated salicylates such as salsalate may also be considered and may be safer in older adults. Because nonsteroidal anti-inflammatory drugs are known to cause serious gastrointestinal toxicity, patients with a history of peptic ulcer disease should consider a COX- selective drug or use of concurrent misoprostol or a proton pump inhibitor (PPI).

Elderly patients with pre-existing hypertension, CHF, renal dysfunction, or risk of renal insufficiency, should use these medications very cautiously. Other adverse drug reactions to watch for include central nervous system effects such as drowsiness, dizziness, and depression.


Treatment of Osteoarthritis with COX-2 selective NSAIDs

Indications: Relief of signs and symptoms of OA

Agents: Celecoxib (Celebrex®)

Dosing: Celecoxib: 200 mg/d administered as a single daily dose or 100 mg BID

Adverse Drug Reactions: • Similar to other NSAIDs, with reduction of GI events and no effects on platelet function. • Adverse effects in patients with renal dysfunction may occur, so use should be avoided in such cases.

Precautions: Patients allergic to sulfonamides should take celecoxib with caution.

The COX-2 specific inhibitor celecoxib is no more effective than older nonsteroidals for osteoarthritis. Celecoxib has adverse effects similar to older NSAIDs, but may be a safer alternative for the elderly at risk of GI bleeding. Unlike traditional NSAIDs, which inhibit both COX-1 and COX-2, celecoxib selectively inhibits the COX-2 inflammatory pathway. By not interfering with COX-1 prostaglandins that assist in platelet aggregation and stomach protection, COX-2 inhibitors reduce the occurrence of lower gastrointestinal events. Rofecoxib (Merck’s Vioxx®) was withdrawn from the market in October 2004 due to an approximate doubling in the risk of myocardial infarction and stroke, with valdecoxib (Bextra®) being removed from the market in April of 2005. At this time, the risk of cardiovascular events in the elderly with celecoxib remains unclear, although it is almost certainly lower than with rofecoxib. It is prudent to avoid COX selective drugs in patients at high risk of MI.


Treatment of Osteoarthritis with Intra-articular Corticosteroids

• e.g. triamcinolone (Aristocort®, Kenalog®) • Reserved for intra-articular treatment of knee osteoarthritis

Intra-articular corticosteroids such as triamcinolone hexacetonide may be useful in patients with osteoarthritis of the knee, especially when effusion is present. Pain relief may last from days to months. Intra-articular injections with corticosteroids should not be given more than 3-4 times a year into the same joint.


Treatment of Osteoarthritis with Glucosamine

Mechanism: May stimulate proteoglycan synthesis or inhibit degradation of existing cartilage.

Indications: Relief of OA symptoms; inhibit loss of cartilage.

Dosing: 500 mg TID or 1500 mg daily

Adverse Drug Reactions: GI upset

Contraindications: Allergy to shellfish

Monitoring: Blood sugar in patients with diabetes (decreased glucose tolerance in animals, but no problems in human studies)

Glucosamine is a “dietary supplement” that now has substantial support from clinical trials to support its use. A pair of three-year long studies confirmed that glucosamine not only relieves pain over a sustained period, but it slows the loss of cartilage. Therefore, glucosamine appears to be the first “disease-modifying” drug for osteoarthritis. Glucosamine is generally well tolerated. The most significant problem with recommending a glucosamine supplement is that strength and purity of U.S. supplements are not standardized. Relief of pain typically takes about four to eight weeks.


Treatment of Osteoarthritis with Chondroitin

Mechanism: May stimulate cartilage synthesis or inhibit enzymes that degrade cartilage.

Indications: Relief of OA symptoms; inhibit loss of cartilage.

Dosing: 400 mg TID

Adverse Drug Reactions: GI upset

Monitoring: May increase clotting times

Chondroitin is the most abundant glycosaminoglycan in cartilage. It is another dietary supplement often given with glucosamine. Although evidence for efficacy is not as strong as with glucosamine, there is preliminary evidence for both pain relief and disease-modifying activity.


Treatment of Osteoarthritis with Hyaluronans

1. Sodium hyaluronate: • 3 weekly intra-articular injections (Euflexxa®) • 3 to 4 weekly intra-articular injections (Orthovisc®) • 3 to 5 weekly intra-articular injections (Supartz®) • 5 weekly intra-articular injections (Hyalgan®)

2. Hylan G-F 20 • 3 weekly intra-articular injections (Synvisc®)

Indications: Treatment of knee OA in conjunction with oral therapies or in place of oral therapies when oral medications are inappropriate or contraindicated.

Hyaluronans are high molecular weight glycosaminoglycans found in cartilage and synovial fluid. It was initially thought that injections would increase viscosity within the joint fluid by replacing natural hyaluronans, but their actual mechanism is unclear. Pain relief in knee OA may last up to eight months, and injection courses may be repeated every six months. Note that parts of the Euflexxa® syringe contain natural rubber latex and therefore patients with latex allergy should not receive this product. Furthermore, patients with feather, bird, or egg allergy should discuss this prior to receiving Hyalgan® or Synvisc® as these products are made from rooster combs. Additionally Orthovisc® and Supartz® are not advised if the patient has a feather, bird or egg allergy.

Patients not candidates for intra-articular injections are those with broken skin over the injection site, those with a bacterial infection, those with cellulitis of the knee or patients taking blood thinners or those with a blood clotting disorder.


Resources and References


AGS Panel on Persistent Pain in Older Persons. The management of persistent pain in older persons. J Am Geriatr Soc 2002;50(6 suppl):s205-s224.

American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. Arthritis Rheum 2000;43:1905-15.

Boh, L. E. & Elliot, M.E..(2002).Osteoarthritis. In Dipiro, J. T., Talbert, R. L. Yee, G. C., Matzke, G. R.. Wells, B. G., & Posey, L. M. (Eds.). Pharmacotherapy:A Pathophysiologic Approach, 3rd ed.New York, NY, McGraw-Hill, 1639-1658.

Drug Facts and Comparisons.(Updated monthly). St. Louis: Facts and Comparisons.

Ernst E, Vassiliou VS, Pelletier JP, Clegg DO, Reda DJ. Glucosamine and chondroitin sulfate for knee osteoarthritis. N Engl J Med 2006;354:841-848.

Loeser, R.FA stepwise approach to the management of osteoarthritis. Bull Rheum Dis 2003;52(5):1-5.

Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli G, Rovati LC. Glucosamine sulfate use and delay of progression of osteoarthritis. Arch Intern Med 2002;162:2113-2123.

Raynaud JP, Buckland-Wright C, Ward R, Choquette D, Haraoui B, Martel-Pelletier J, et al. Safety and efficacy of long term intraarticular steroid injections in osteoarthritis of the knee. Arthritis Rheum 2003;48:370-377.

Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomized, placebo-controlled trial. Lancet 2001;357:251-256.



Roth SH, Fleischmann RM, Burch FX, Dietz F, Bockow B, Rapoport RJ, et al. Around-the-clock, controlled-release oxycodone therapy for osteoarthritis-related pain. Arch Intern Med 2000;160:853-860.

Schnitzer TJ, Posner M, Lawrence ID. High strength capsaicin cream for osteoarthritis pain. J Clin Rheumatol 1995;1:268-273. Van Baar ME, Assendelft WJ, Dekker J, Oostendorf RA, Bijlsma JW. Effectiveness of exercise therapy in patients with osteoarthritis of the hip or knee. Arthritis Rheum 1999; 42:1361-1369.

Weinstein, S. L., Jacobs, J. J., Goldberg, M. J., Koff, R. S., Dart, R. C., Felson, D. T. Osteoarthritis of the knee. N Engl J Med 2006;354:2508-2509.


Rheumatoid Arthritis



• Describe the defining characteristics and epidemiology of rheumatoid arthritis.

• Explain the pathophysiological changes that occur in the joints of patients with rheumatoid arthritis.

• Describe treatment goals for patients with rheumatoid arthritis.

• List pharmacological and nonpharmacological treatment options for patients with rheumatoid arthritis.

• Describe indications, onset, dosing, adverse reactions and toxicities related to the various types of drugs used to treat rheumatoid arthritis.


Characteristics of Rheumatoid Arthritis

Rheumatoid arthritis is an autoimmune disease with unknown etiology. It affects about 1% of the overall population, with women affected approximately twice as often as men.

The disease produces painful synovial inflammation that may cause irreversible damage to surrounding cartilage and bone, and can produce extraarticular inflammation involving other organs such as rheumatoid nodules, scleritis, Sjogren’s syndrome, interstitial lung disease, pericardial disease, systemic vasculitis, and Felty’s syndrome.


Pathophysiology of Rheumatoid Arthritis

The pathogenesis of rheumatoid arthritis is complex, involving a T lymphocyte response to an unknown antigen resulting in synovial cell proliferation and fibrosis, pannus formation, and cartilage and bone erosion. Lymphocytes, neutrophils, macrophages and proinflammatory cytokines, such as interleukin-1 and tumor necrosis factor-alpha, perpetuate an inflammatory process that may lead to joint destruction. It is now recognized that damage to joints is set in motion very early in the disease process. Patients also have a higher mortality than the general population, dying 5 to 10 years earlier on average with higher mortality correlated with greater disease activity.


Clinical Manifestation of Rheumatoid Arthritis

• polyarticular, peripheral, symmetrical involvement • morning stiffness (> 30 min.) • fatigue and malaise • arthralgia and myalgia • rheumatoid nodules • x-rays show erosions, periarticular osteopenia • lab tests may show increased erthrocyte sedimentation rate (ESR) and C-reactive protein, mild anemia, (+) rheumatoid factor.

Rheumatoid arthritis tends to involve spongy swelling of many joints, especially the hands and feet. Involvement tends to be symmetrical. Other common signs and symptoms of the disorder include prolonged morning stiffness, joint and/or muscle pain, fatigue and malaise. On physical examination, rheumatoid nodules may be seen, and radiographs may show erosions and evidence of periarticular osteopenia. Lab findings include elevated erythrocyte sedimentation rate and C-reactive protein, anemia, and positive rheumatoid factor.


Rheumatoid Arthritis in the Elderly

• Prevalence of 2% • May be more active at onset • Responds to therapy similarly to younger onset disease

The prevalence of rheumatoid arthritis in the elderly is about 2%. While rheumatoid arthritis may affect people of any age, it sometimes has a late age onset. The onset of rheumatoid arthritis may be more abrupt and more active in the elderly than in younger patients, but the clinical course and response to therapy appears to be similar in both groups.


Treatment of Rheumatoid Arthritis

Goals: • Decrease pain • Relieve symptoms of inflammation • Prevent joint destruction and deformity • Minimize disability and preserve quality of life

Nonpharmacological Options:

• Patient/family education • Physical and occupational therapy • Psychosocial support • Range of motion and strengthening exercises

Primary goals in the treatment of rheumatoid arthritis are to decrease pain, relieve symptoms, prevent joint destruction and deformity, and maintain function and quality of life. Aggressive and early pharmacological treatment is now recommended by the American College of Rheumatology. However, nonpharmacological strategies for meeting these goals must also be incorporated throughout treatment. Nonpharmacological treatment includes patient/family education, physical and occupational therapy, psychosocial support, and daily exercise routines to maximize and maintain joint range of motion and strength.


Pharmacological Options for Treating Rheumatoid Arthritis

NSAIDs

Cox-2 Inhibitors • celecoxib (Celebrex®)

Corticosteroids

Disease-Modifying Anti-rheumatic Drugs (DMARDs) • methotrexate (Rheumatrex®, Folex®) • sulfasalazine (Azulfadine®) • hydroxychloroquine (Plaquenil®) • gold compounds • azathioprine (Imuran®) • penicillamine (Cuprimine®) • cyclosporine • minocycline (Minocin®) • leflunomide (Arava®)

Biological Agents • etanercept (Enbrel®) • infliximab (Remicade®) • adalumimab (Humira®) • anakinra (Kineret®) • abatacept (Orencia®) • rituximab (Rituxan®)

Many options are now available for treating rheumatoid arthritis, Nonsteroidal anti-inflammatory drugs are often used as initial therapy to relieve joint pain and swelling; however, they have no effect on disease progression and must be used with caution in the elderly. Although disease modifying anti-rheumatic drugs such as methotrexate and leflunomide must be closely monitored for adverse drug effects, they should be started as early as possible in the disease course.

The American College of Rheumatology guidelines suggest beginning disease-modifying drugs within three months of diagnosis. Glucocorticoids are also used and can often provide effective symptomatic relief for many patients. Glucocorticoids are often used as bridge therapy and for the treatment of acute flares.

The newest class of medications, known as the biological agents, alters the disease process of rheumatoid arthritis by inhibiting the actions of proinflammatory cytokines or cells within the immune system responsible for the immune-mediated joint destruction that occurs with rheumatoid arthritis.


Treatment of Rheumatoid Arthritis with NSAIDS

• Analgesic • Anti-inflammatory in higher doses

Nonsteroidal anti-inflammatory drugs, or NSAIDs, are very useful in controlling pain and inflammation; however, they have no effect on disease progression. Therefore disease-modifying therapy must be initiated early in the disease. Once the disease process is under better control, nonsteroidal therapy can be tapered to the lowest effective dose to provide symptomatic relief.


Treatment of Rheumatoid Arthritis with COX-2 Inhibitors

Indications: Relief of signs and symptoms of rheumatoid arthritis (RA)

Agents: •  celecoxib (Celebrex®) 100-200 mg bid

Adverse Drug Reactions: • Similar to other NSAIDs, with reduction of side effects associated with COX-1 (GI events, platelet dysfunction). • Although associated with fewer adverse GI events than with traditional NSAIDs, ulcers can occur.

Contraindications: patients allergic to sulfonamides use celecoxib cautiously

Celecoxib, a COX-2 inhibitor, is not more effective than older nonsteroidals in the treatment of rheumatoid arthritis, and is much more expensive. By inhibiting COX-2 but not COX-1, celecoxib reduces the gastrointestinal side effects associated with traditional NSAIDs. While other adverse effects are similar to traditional NSAIDs, celecoxib may be a safer alternative for the elderly. However, because rofecoxib (Vioxx®) was withdrawn from the market due to increased risk of myocardial infarction and stroke, it may be prudent to avoid COX selective agents in patients at high risk for MI. Keep in mind that RA patients are at an increased risk of developing cardiovascular disease.


Treatment of Rheumatoid Arthritis with Corticosteroids

Indications: • Useful while waiting for slower-acting drugs to take effect (bridge therapy) • Occasional intra-articular administration may be helpful • High dose corticosteroids may be needed for some extra-articular complications

Dosing: •  Low doses (e.g., up to 10 mg/d prednisone) control joint symptoms and may slow the rate of joint damage

Adverse Drug Reactions: osteoporosis, hypertension, cataracts, skin and muscle atrophy, and metabolic disturbances such as hyperglycemia

Low doses of corticosteroids provide rapid relief of inflammation and may be used while waiting for slower-acting drugs to take effect. Intra-articular administration of corticosteroids may be useful in joints with severe inflammation. Systemic corticosteroids in high doses may need to be prescribed for some extra-articular complications such as vasculitis, pulmonary fibrosis or pericarditis. Elderly patients using corticosteroids for long periods may experience osteoporosis, fractures, cataracts, and skin and muscle atrophy as well as metabolic disturbances such as hyperglycemia. Although corticosteroids have been found to slow the rate of joint damage, they should not be used alone in place of disease-modifying drugs.


Treatment of Rheumatoid Arthritis with Methotrexate

Mechanism: Methotrexate is a structural analog of folic acid that inhibits DNA synthesis by competitively inhibiting the enzyme dihydrofolate reductase.

Indications: Disease-Modifying Anti-rheumatic Drug for the treatment of Rheumatoid Arthritis

Onset: 1-2 months

Dosing: Maintenance dose of 7.5-15 mg/wk (max. dose = 20 mg/week)

Adverse Drug Reactions: GI symptoms, stomatitis

Toxicities:

• Liver disease – age and duration of therapy are independent risk factors, monitor LFTs monthly for the first 6 months and every 4-8 weeks thereafter. The standard of therapy no longer requires liver biopsy during methotrexate therapy.

• Myelosuppression – renal function important; monitor every 4-8 wks; folic acid supplementation may diminish toxicity

• Pneumonitis – pre-existing lung disease a risk factor, obtaining a baseline chest radiograph is recommended prior to methotrexate initiation


Treatment of Rheumatoid Arthritis with Methotrexate

Methotrexate is the most commonly prescribed disease-modifying therapy for rheumatoid arthritis. It is usually well tolerated, and has good efficacy. There is recent evidence that use of methotrexate may reduce mortality in rheumatoid arthritis.

A normal maintenance dose of methotrexate is seven-point-five to fifteen milligrams per week. In addition to side effects such as nausea and stomatitis, methotrexate may cause some serious toxicities in elderly patients. For example, patients are at risk for liver disease and should be tested for elevated liver function tests every four to eight weeks. Renal function and complete blood count should also be monitored every four to eight weeks to check for drug-related myelosuppression. Folic acid supplements may help reduce these toxic effects, and every patient receiving methotrexate should be on at least 1 milligram of folic acid daily.


Treatment of Rheumatoid Arthritis with Sulfasalazine and Hydroxychloroquine

Sulfasalazine (Azulfadine®):

• Onset: 1-3 months • Dosing: maintenance dose 1 g bid-tid • ADRs: GI symptoms, rash, leucopenia

Hydroxychloroquine (Plaquenil®):

• Onset: 2-6 months • Dosing: maintenance dose 200 mg bid • ADRs: GI symptoms • Toxicity: Macular damage

Two other frequently used disease-modifying drugs are sulfasalazine and hydroxychloroquine. The maintenance dose for sulfasalazine is one gram two to three times a day, while the dose for hydroxychloroquine is two hundred milligrams twice daily. Both drugs produce gastrointestinal disturbances. Sulfasalazine cannot be taken by patients with a sulfa allergy. With hydroxychloroquine, there is a very small risk of macular toxicity in elderly patients and ophthalmologic exams are recommended every six to twelve months. Hydroxychloroquine, however, is considered the least toxic DMARD and is relatively well tolerated in the elderly.


Treatment of Rheumatoid Arthritis with Gold Compounds

Indications: Use is limited due to poor efficacy/toxicity ratio

Onset: 3-6 months

Dosing: • Maintenance dose IM (gold sodium thiomalate , Myochrysine®),25-50 mg every 2-4 weeks • Maintenance dose PO (auranofin,, Ridaura®) –3 mg bid to tid

Adverse Drug Reactions: mouth ulcers, metallic taste, diarrhea (with auranofin)

Toxicities: • Renal disturbances (e.g., proteinuria, membranous glomerulonephritis) • Hematologic disorders (e.g., thrombocytopenia, leucopenia, aplastic anemia) • Severe rashes

Gold compounds are another class of medications that were commonly used in the past but have fallen out of favor. Their toxicity limits their use in elderly patients. Although auranofin is less toxic than intramuscular gold compounds, it is also less effective. Intramuscular injections of gold sodium thiomalate may be prescribed; a normal maintenance dose is twenty-five to fifty milligrams every 2-4 weeks,after a loading dose period of fifty milligrams weekly for five months. The dose of oral auranofin is six to nine milligrams per day. In addition to side effects such as mouth ulcers and diarrhea, gold compounds may cause proteinuria, hematologic disorders, and severe skin rashes.


Treatment of Rheumatoid Arthritis with Azathioprine (Imuran®)

Indications: Use when alternatives have failed

Onset: 2-3 months

Dosing: • Maintenance dose 50-150 mg/d • Reduced for renal impairment

Adverse Drug Reactions: GI upset, mucosal ulcers, rash, alopecia, leukopenia, hepatotoxicity

Drug Interactions:

Allopurinol – reduce dose of azathioprine to ¼ usual dose

Azathioprine is prescribed for patients with rheumatoid arthritis only after most other pharmacological alternatives have failed. A normal maintenance dose is fifty to one hundred fifty milligrams per day, adjusted for renal impairment. Adverse effects include gastrointestinal upset, mucosal ulcers, leukopenia, and hepatotoxicity. If used with allopurinol for control of hyperuricemia, azathioprine should be reduced to one fourth of the usual dose. Monitoring for patients on azathioprine includes a complete blood count every 1-2 weeks with dosage changes, and every 1-3 months thereafter.


Treatment of Rheumatoid Arthritis with Leflunomide (Arava®)

Indications: • Treatment of active rheumatoid arthritis in adults to reduce signs and symptoms and slow joint damage • Not for use during pregnancy – category X

Onset: 4-12 weeks

Dosing: • Loading dose:100 mg/day orally x 3 days • Maintenance dose:20 mg/day (can be reduced to 10 mg/day if 20 mg/day dose not tolerated)

Adverse Drug Reactions: common side effects are diarrhea, rash, alopecia.

Monitoring: Transaminases should be monitored at baseline and monthly upon initiation. If stable, monitor periodically thereafter. Dosage reduction is required for elevated ALT.

Drug Interactions: • Cholestyramine decreases leflunomide absorption • Other hepatotoxic drugs should be avoided due to increased likelihood of hepatotoxicity • Rifampin increases serum concentrations of leflunomide’s active metabolite

Leflunomide is a Disease Modifying Antirheumatic Drug that is a pyrimidine synthesis inhibitor. It requires a loading dose for initiation of therapy and liver function test monitoring for safety. Leflunomide is a pregnancy category X, and should be used with caution in women of child bearing age. Usual adverse effects are diarrhea, rash, alopecia, and elevated transaminases. Leflunomide can be used with aspirin, NSAIDs, and low dose corticosteroids, but coadministration with methotrexate is generally discouraged due to an increased risk of hepatotoxicity.


Treatment of Rheumatoid Arthritis with Other Drugs

• Cyclosporine (Neoral®) 2.5 - 4 mg/kg/day in two divided doses • Minocycline (Minocin®) 100 mg bid

Other drugs that are sometimes used in the treatment of rheumatoid arthritis include cyclosporine and minocycline. Cyclosporine is approved for severe RA not responsive to methotrexate and is used alone or in combination with methotrexate. Minocycline is not FDA approved for rheumatoid arthritis, but several studies support its use as a mildly effective disease-modifying drug.


Treatment of Rheumatoid Arthritis with Anti-TNF Agents

Mechanism:

• TNFα is a key cytokine involved in inflammatory and immune responses • Anti-TNF agents bind to TNF to prevent it from binding to endogenous receptors thus blunting the cytokine-mediated inflammatory cascade

Indications:

• Moderately to severely active RA, usually in patients who have had an inadequate response to >1 DMARD • Can be used in combination with DMARDs

Agents:

• etanercept (Enbrel®) • infliximab (Remicade®) • adalimumab (Humira®)

Dosing:

• etanercept: 50 mg/week SC given once or split twice weekly • infliximab: 3 mg/Kg IV at baseline, 2 weeks, 6 weeks, and every 8 weeks thereafter • adalimumab: 40 mg SC every other week in combination with MTX, or 40 mg SC every week as monotherapy


Treatment of Rheumatoid Arthritis with Anti-TNF Agents

Adverse Drug Reactions: injection site reactions, headache, dizziness, abdominal pain, dyspepsia, and rash.

Monitoring: Patients should be monitored closely for severe infections, and drug should be discontinued if a serious infection develops.

Anti-Tumor Necrosis Factor agents bind in various ways to tumor necrosis factor alpha, thus preventing the action of the cytokine. These biological agents are also disease-modifying drugs, but are considered a special subset. Although very effective, they are also extremely costly. Therefore, their use is often reserved for failure of more than one disease-modifying drug, however, these agents are increasingly being used as monotherapy prior to disease-modifying drug failure. The anti-tumor necrosis factor agents are commonly used in combination with other Disease Modifying Antirheumatic drugs. In fact, infliximab is approved for use in RA in combination with methotrexate and not as monotherapy.


Treatment of Rheumatoid Arthritis with Interleukin-1 Antagonists

Agents: Anakinra (Kineret®)

Mechanism:

• Interleukin-1 is a key cytokine involved in the inflammatory and immune response associated with rheumatoid arthritis • Anakinra acts as an IL-1 antagonist by competitively binding IL-1 and preventing it from binding and activating endogenous IL-1 receptors

Indications:

• moderately to severely active RA, usually in patients who have had an inadequate response to 1 or more DMARDs • can be used in combination with DMARDs but not TNF antagonists

Dosing: 100 mg injected subcutaneously daily

Adverse Drug Reactions: injection site reactions, headache, nausea, increased risk of infection

Monitoring: Patients should be monitored closely for severe infections, and drug should be discontinued if a serious infection develops.

Anakinra is the only antagonist of interleukin-one currently available. It is a biologically engineered interleukin-one receptor antagonist. Its uses and adverse reactions are similar to the TNF antagonists. However, anakinra should not be used concurrently with TNF antagonists due to the increased risk of severe infection.


Treatment of Rheumatoid Arthritis with Abatacept

Agents: Abatacept (Orencia®)

Mechanism:

• Abatacept is a recombinant fusion protein that mimics endogenous cytotoxic T-lymphocyte associated antigen (CTLA4), which blocks costimulatory signals and activation of T cells • Abatacept prevents the activation of T cells in turn preventing the production of proinflammatory cytokines such as TNFα

Indications:

• moderate to severe RA, usually in patients who have had an inadequate response to 1 or more DMARDs • can be used alone or in combination with DMARDs such as methotrexate or TNF antagonists

Dosing: <60 kg: 500 mg IV every 2 weeks for two doses, then monthly 60-100 kg: 750 mg IV every 2 weeks for two doses, then monthly >100 kg: 1000 mg IV every 2 weeks for two doses, then monthly

Adverse Drug Reactions: Infusion site reactions, headache, dizziness, increased risk for infection, possible association with malignancy development

Monitoring: Patients should be monitored closely for severe infections, and the drug should be discontinued if a serious infection develops.


Treatment of Rheumatoid Arthritis with Abatacept

Abatacept is the only recombinant fusion protein currently available for the treatment of rheumatoid arthritis. Abatacept works by inhibiting the second costimulatory message required for the activation of T cells. By preventing T cell activation, abatacept decreases the secretion of pro-inflammatory cytokines, the proliferation of inflammatory cells, and the production of autoantibodies. Because T cells are important mediators for cellular immune responses, abatacept may adversely affect host defenses against infection and malignancy, thus careful monitoring for infection and cancer development is warranted.


Treatment of Rheumatoid Arthritis with Rituximab

Agents: Rituximab (Rituxan®)

Mechanism:

• Rituximab is a monoclonal antibody that binds the antigen CD20 on the surface of B cells • CD20 regulates an early step in the activation of B cells, and by binding CD20, rituximab prevents the activation of B cells leading to B cell lysis

Indications:

Moderately to severely active RA in combination with methotrexate who have had an inadequate response to one or more TNF antagonists

Dosing: 1000 mg IV on days 1 and 15

Adverse Drug Reactions: severe infusion reactions, severe rash, cardiac arrhythmia, increased risk of infection

Monitoring: Patients should be monitored closely for severe infections. In addition, monitoring should include complete blood counts, ECGs, and monitoring of renal function.

Rituximab is a monoclonal antibody that blocks the antigen CD20 on the surface of B cells, a molecule important in the activation of B cells. By blocking CD20, rituximab prevents the activation of B cells leading to B cell lysis. Rituximab is reserved for patients with moderately to severely active rheumatoid arthritis, and is used in combination with methotrexate in patients who have had an inadequate response to one or more tumor necrosis factor antagonists. Rituximab is associated with severe and sometimes life threatening infusion reactions. It is recommended that methylprednisolone 100mg IV is given 30 minutes prior to each infusion of rituximab. The efficacy and safety of more than one course of rituximab (two infusions) has not been established. Patients receiving rituximab should be monitored closely for signs of infection, rash, cardiac side effects, and changes in renal function.


Treatment of Rheumatoid Arthritis with Penicillamine, Cyclophosphamide, and Chlorambucil

Use is limited due to toxicity

Some older disease-modifying drugs are seldom used today because they have poor risk to benefit ratios. These include penicillamine, cyclophosphamide, gold and chlorambucil. Toxicities associated with penicillamine include skin reactions, hematologic and renal disorders, and rarely, drug-induced autoimmune disease. Cyclophosphamide is associated with hemorrhagic cystitis and risk of malignancy.


Treatment of Rheumatoid Arthritis with Combination Therapy

• Commonly used today • Used for aggressive disease control • Usually include methotrexate

Combinations of disease-modifying drugs, or disease-modifying drugs with biologicals, are often used. This is consistent with the strategy of aggressive disease control. Some of the more common combinations include methotrexate with sulfasalazine and hydroxychloroquine, methotrexate and cyclosporine, and methotrexate with a biological agent.


Resources


American College of Rheumatology. Guidelines for the management of rheumatoid arthritis:2002 update. Arthritis Rheum 2002;46:328-46.

Arthritis Foundation. www.arthritis.org

Bendtsen, P., Akerlind, I., & Hornquist, J. O.(1995). Pharmacological intervention in older patients with rheumatoid arthritis. Quality of life aspects. Drugs Aging: 7(5): 338-46.

Choi HK, et al. Methotrexate and mortality in patients with rheumatoid arthritis: A prospective study.Lancet 2002;359:1173-7.

Cohen, S.B.; Moreland, L.W.; Cush, J.J.; et al. A multicentre, double-blind, randomized, placebo-controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate. Ann. Rheum. Dis. 63:1062-8; 2004.

Drug Facts and Comparisons.(Updated monthly). St. Louis: Facts and Comparisons.

Jiang Y, Genant HK, Watt I, et al. A multicenter, double-blind , dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. Arthritis & Rheumatism 2000;43:1001-1009.

O’Dell JR. Treating rheumatoid arthritis early: a window of opportunity? Arthritis Rheum 2002;46:283-5.

Landewe RB, Boers M, Verhoeven AC, Westhoevens R, van de Laar MA, Markusse HM, et al. COBRA combination therapy in patients with early rheumatoid arthritis: long term structural benefits of a brief intervention. Arthritis Rheum 2002;46:347-356.


Resources

Louie SG, Park B, Yoon. Biological response modifiers in the management of rheumatoid arthritis. Am J Health-Syst Pharm 2003;60:346-355. Maini, R; St. Clair, E.W.; Breedveld, F.; et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) vs. placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomized phase III trial. ATTRACT Study Group. Lancet 354:1932-9; 1999.

Peltomaa R, Leirisalo-Repo M, Helve T, Paimela L. Effect of age on 3 year outcome in early rheumatoid arthritis. J Rheumatol 2000;27:638-43.

Rasch EK, Hirsch R, Paulose-Ram R, Hochberg MC. Prevalence of rheumatoid arthritis in persons 60 years of age and older in the United States. Arthritis Rheum 2003;48:917-926.

Setter SM, Baker DE, Gates B (1999). New Therapies for the Treatment of Rheumatoid Arthritis. Consultant Pharmacist; 14(7): 758-65. Van Schaardenburg, D.& Breedveld, F. C.(1994). Elderly-onset rheumatoid arthritis. Sem Arthritis Rheum; 23(6): 367-78.

Van de Putte LB. Key randomized trials of single agents in early rheumatoid arthritis. J Rheumatol 2002;29(suppl 66):13-19.


Gout



• Explain the pathophysiology of gout.Describe the epidemiology of gout.List the risk factors associated with gout.

• Describe the clinical presentation of gout.

• Outline goals and pharmacological/nonpharmacological options for the treatment of gout.

• Describe indications, dosing, administration, and precautions for agents commonly used to treat gout.


Gout

Gout is a syndrome resulting from monosodium urate crystal deposition in joints (gouty arthritis), soft tissue (tophi), the urinary tract (renal stones), and the kidney (gouty nephropathy). Ninety percent of patients with gout have trouble excreting uric acid, while ten percent are overproducers. Pseudogout (chondrocalcinosis) is a different condition caused by deposition of calcium pyrophosphate dihydrate crystals in the joints.


Epidemiology of Gout

• More frequent in males • Increases with age • 80% report a family history of hyperuricemia • Black males more likely to develop than white males • Image of uric acid crystals

Overall prevalence of gout is about 6 in 1000 in men and 1 in 1000 in women, but prevalence increases with age, especially in women. In males over 65 years, prevalence exceeds 5%. Overall, gout occurs twice as frequently in males than in females. Black males are more likely to have the syndrome than white males.


Risk Factors for Gout

Medical:

• Hyperuricemia • Hypertension • Renal insufficiency • Obesity

Drug-induced:

• Alcohol • Diuretics • Low-dose salicylates (i.e. ASA 81 mg) • Cyclosporine • Ethambutol • Pyrazinamide • Levodopa • Cytotoxic medications

The major risk factor for gout is hyperuricemia. However, patients with hyperuricemia may be asymptomatic, and hyperuricemia alone should not be treated. Other common risk factors for gout are obesity, hypertension, and renal insufficiency. Drugs that impair renal urate excretion that have been linked to gout include: alcohol, diuretics, and levodopa. Cytotoxic drugs may increase uric acid production by causing cell death and release of purines into circulation.


Clinical Presentation of Acute/Recurrent Gout

Typical Presentation:

• Acute arthritis attacks characterized by severe, acute pain, erythema, swelling

• Monoarticular • Most often in lower extremities (e.g., 50% of acute attacks

occur in the great toes) • Tophi rare at presentation

Atypical Presentation (common in elderly):

• Gradual onset • Any joint, polyarticular • Moderate (vs. severe) pain

The synovial inflammation characteristic of gout occurs when leukocytes engulf urate crystals and release cytokines. Patients typically experience acute attacks characterized by joint pain, erythema, and swelling, which develops over a period of hours. Although the lower extremities are usually affected, any joint may be involved. Over time, the period between acute attacks may shorten and attacks may be polyarticular. Elderly patients often have an atypical presentation of the disease, which includes gradual onset, polyarticular involvement, and moderate as opposed to severe pain. With chronic untreated gout of either type, patients may develop tophi and gouty nephropathy.


Treatment of Gout

Goals: • Alleviate the inflammation and pain of acute attacks • Prevent recurrent attacks (maintain serum uric acid < 5-6 mg/dL) • Prevent and/or treat tophi, joint destruction

Nonpharmacological Options: • Low purine diet (avoid meats such as beef, lamb, and pork) • Abstinence from alcohol • Weight loss

Pharmacological Options: • Colchicine • NSAIDs • Corticosteroids • Corticotropin • Uricosurics • Allopurinol

Initial treatment goals for patients with gout focus on alleviating the inflammation and pain associated with acute attacks. Therapies include colchicine, nonsteroidal anti-inflammatory drugs, and corticosteroids. Maintaining patient uric acid levels below five to six milligrams per deciliter, by using uricosuric drugs or allopurinol, may prevent recurrent attacks. Patients should be monitored and treated for complications such as tophi, joint destruction, and nephrolithiasis. Achievement of therapeutic goals may be partially met with a low purine diet, discontinuing potentially exacerbating medications, abstinence from alcohol, and weight loss.


Treatment of Gout with Colchicine

Indications:

• Management of acute attacks • Prevention of recurrent attacks (of questionable efficacy)


• Anti-mitotic drug interferes with leukocyte chemotaxis and phagocytosis • No effect on serum uric acid

Dosing:

• Acute Attacks: • 1 tablet (0.6 mg) every 1-2 hours until symptoms are relieved or gastrointestinal toxicity occurs; (not to exceed 6 mg/10 tablets). • Some clinicians recommend a maximum of 3 doses due to the potential for toxicity.

Maintenance Dose (prophylaxis): • 0.6 BID; initial and/or subsequent dosage should be decreased (i.e. 0.6 mg once daily) in patients at risk of toxicity or in those who are intolerant (including weakness, loose stools, or diarrhea) • Reduce maintenance/prophylactic dose by 50% in individuals > 70 years • If CrCl = 35-49 mL/minute: 0.6 mg once daily • If CrCl = 10-34 mL/mL/minute: 0.6 mg every 2-3 days • If CrCl < 10 mL/minute: Avoid chronic use of colchicine. Use in serious renal impairment is contraindicated by the manufacturer.



Maintenance Dose (prophylaxis):

• 0.6 BID; initial and/or subsequent dosage should be decreased (i.e. 0.6 mg once daily) in patients at risk of toxicity or in those who are intolerant (including weakness, loose stools, or diarrhea) • Reduce maintenance/prophylactic dose by 50% in individuals > 70 years • If CrCl = 35-49 mL/minute: 0.6 mg once daily • If CrCl = 10-34 mL/mL/minute: 0.6 mg every 2-3 days • If CrCl < 10 mL/minute: Avoid chronic use of colchicine. Use in serious renal impairment is contraindicated by the manufacturer.


• GI disturbances (e.g.:nausea, diarrhea, vomiting) • Alopecia • Anorexia

Toxicities with high doses or renal/hepatic insufficiency:

• Myopathy • Neuropathy • Bone marrow suppression



Colchicine is commonly used to manage patients suffering from acute gout attacks. Gastrointestinal side effects may be dose limiting. In addition to gastrointestinal intolerance, colchicine poses a serious toxicity risk in the elderly, especially in large doses. Patients with renal or hepatic insufficiency may experience toxic effects such as myopathy, neuropathy, and bone marrow suppression. Colchicine should be used carefully in patients with renal insufficiency, and doses should be reduced accordingly.

Although it has no effect on serum urate levels, one or two tablets of colchicine daily may be used to prevent recurrent inflammatory gouty arthritis. This therapy, while effective at treating the pain and inflammation associated with gouty arthritis, may mask the joint damaging effects of hyperuricemia. Monitoring of joints affected during a gouty attack is warranted in patient using colchicine long-term.


Treatment of Gout with NSAIDs

• Most useful for management of pain associated with acute gouty attacks • Most clinical experience with indomethacin; not all NSAIDs proven effective, regardless of dose. • More effective than colchicine if treatment has been delayed

Nonsteroidal anti-inflammatory drugs or NSAIDS, are often used as initial therapy to relieve the inflammation and joint pain associated with acute attacks of gout. Maximum anti-inflammatory doses, at least for the first few days, are usually recommended. Indomethacin has historically been commonly used. While other NSAIDs may be better tolerated at maximal doses, their efficacy is questionable in the treatment of gout. Experience with COX-2 selective NSAIDs in gout is limited to date. NSAIDs may be more effective than colchicine when treatment has been delayed. Side effects must be monitored as well, as Indomethacin can cause CNS effects such as decline in mental function, and GI effects such as upset stomach, abdominal pain, and increased bleeding/ulceration risk.


Treatment of Gout with Corticosteroids

• Intra-articular injections useful for acute attacks • Short course of oral prednisone

• Tapered over 7 – 10 days

Treatment of Gout with Corticotropin (ACTH®, Acthar®)

Dosing: 40 – 80 units x 1, OR every 8 hours for 2 – 3 days Administration: IM, SC, or IV

Corticosteroids, administered via oral, intra-muscular, or intra-articular route may also relieve the symptoms of acute gout attacks. They are especially useful in patients with renal insufficiency and contraindications to NSAIDs. A short course with oral prednisone, starting at 20 to 40 mg/day for 3 days, then tapering by 5 mg daily, is effective.

Corticotropin is also used to manage acute attacks of gout. Forty to eighty units can be given once, or repeated every eight hours for two to three days with the dose then tapered.


Prevention of Recurrent Gout with Uricosurics

Mechanism of Action • Interferes with tubular handling of organic acids • within the nephron

• Ineffective if CrCl < 50 mL/minute • Increase urinary excretion of uric acid • Contraindicated in patients with urate nephrolithiasis, hyperuricosuria • Several potential drug interactions • Should be started 6-8 weeks post-acute gouty attack • Colchicine use for 3-6 months during the beginning of uricosuric therapy is recommended • Compliance/patient adherence to regimen is most important

Dosing • Probenecid: 250 mg PO twice daily for the first week, then 500 mg PO twice daily to a maximum of 2-3 g per day • Increase to maximum dose by 500mg increments every 4 weeks

Adverse Drug Reactions • Headache • Nausea/Vomiting • Anorexia

Uricosuric agents are useful for preventing the recurrence of gout attacks. Probenecid is more commonly prescribed than sulfinpyrazone. These agents are generally effective only when the patient’s creatinine clearance is greater than fifty milliliters per minute. In addition to potential drug interactions, these agents can cause problems in patients with urate nephrolithiasis and hyperuricosuria. Patients must adhere to the prescribed regimen, as the risk of urate crystal deposition in the kidneys increases every time a uricosuric medication is stopped and restarted.


Prevention of Recurrent Gout with Allopurinol


Decreases the production of uric acid by inhibiting the action of xanthine oxidase

Indications:

• Preferred over uricosurics for elderly patients • Preferred in patients with tophaceous gout, renal dysfunction, or urate nephrolithiasis

Dosing:

• Initial dose: 100 mg/day, increased weekly in 100 mg/day increments • Maximum dose: 300 mg/day • CrCl 100-119 ml/min: maximum dose of 300 mg/day PO. • CrCl 80-99 ml/min: maximum dose of 250 mg/day PO. • CrCl 60-79 ml/min: maximum dose of 200 mg/day PO. • CrCl 40-59 ml/min: maximum dose of 150 mg/day PO. • CrCl 20-39 ml/min: maximum dose of 100 mg/day PO. • CrCl 10-19 ml/min: reduce dose to 100 mg PO every 2 days or 200 mg/day IV. • CrCl 0-9 ml/min: reduce dose to 100 mg PO every 3 days or 100 mg/dose IV, administered at extended intervals


Prevention of Recurrent Gout with Allopurinol


• GI disturbances • Skin rash • Hypersensitivity reactions (e.g.: rash, renal dysfunction, hepatocellular injury, eosinophilia)

Allopurinol is also useful in preventing recurrent attacks of gout. It is preferred over uricosuric agents for treating patients with renal dysfunction or urate nephrolithiasis. The dosage of allopurinol should be initially low and titrated slowly to reduce the risk of acute attack: one hundred milligrams a day increased weekly to a maximum dose of three hundred milligrams a day. This dosage may need to be adjusted in patients with renal insufficiency. The most common side effects of allopurinol include gastrointestinal upset, skin rash, and hypersensitivity reactions. Hypersensitivity syndrome is more common in patients who are older, have pre-existing renal insufficiency, or are taking concomitant thiazide diuretics.




Altman RD, Honig S, Levin S, Lightfoot RW.(1988).Ketoprofen versus indomethacin in patients with acute gouty arthritis: a multicenter, double-blind comparative study. J Rheumatol 15:1422-1426.

Axelrod D and Preston S.(1998).Comparison of parenteral adrenocorticotropic hormone with oral indomethacin in the treatment of gout. Arthritis Rheum 31:803-5.

Emmerson B (1996). The management of gout. N Engl J Med; 334:455-551.

Fam AG.(2002).Treating acute gouty arthritis with selective COX-2 inhibitors. BMJ 325:980-981.

George TM and Mandell B.(1996).Individualizing the treatment of gout. Clev Clin Med J; 63(3): 150-155.

Gonzalez EB, Miller SB, and Agudelo CA.(1994).Optimal management of gout in older patients. Drugs Aging; 4(2):128-134.

Lipsky PE (Ed.).(1997).Algorithms for the diagnosis and management of musculoskeletal complaints. Am J Med; 103(suppl 6A):1S-85S.

Monu JUV, Pope TL (2004). Gout: A clinical and radiologic review. Radiol Clin N Am; 42:169-184.

Nesher G and Moore TL.(1994). Clinical presentation and treatment of arthritis in the aged. Clin Geriatr Med; 10(4):659-675.


Disorders of the Foot



• List common foot problems that afflict the elderly.

• Describe the mechanism of injury, clinical presentation, and treatment of plantar fasciitis.

• Describe the mechanism of injury, clinical presentation, and treatment of tarsal tunnel syndrome.

• Compare and contrast the clinical features of hallux valgus, and hallux rigidus.

• Describe the mechanism of injury, clinical presentation, and treatment of metatarsalgia.

• Describe the mechanism of injury, clinical presentation, and treatment of onychomycosis.

• Describe the mechanism of injury, clinical presentation, and treatment of diabetic foot.


Foot Problems in the Elderly

• Plantar fasciitis (heel pain) • Tarsal tunnel syndrome • Hallux valgus • Hallux rigidus • Metatarsalgias • Tibial tendonitis • Onychomycosis • Diabetic foot • Ingrown toenail • Dystonia of the foot

Foot problems are a special concern in the elderly because they frequently impede physical activity and compromise the sense of well-being and independence that is so important to this population. Examples of such problems include: heel pain, due to overuse and chronic fatigue of the plantar fascia, tarsal tunnel syndrome, and toe deformities such as hallux valgus and hallux rigidus. Diabetic foot is a common complication of diabetes mellitus and must be treated promptly. Ingrown toenails and dystonia of the foot are other conditions that may require pharmacological and non-pharmacological treatment in order for older adults to maintain their quality of life.


Plantar Fasciitis

Mechanism of Injury: Inflammation, weakening, and re-tearing of fibers caused by fatigue and eventual failure of plantar fascia at the calcaneal insertion

Clinical Presentation: • Point tenderness over the medial calcaneal • Tightness of the Achilles tendon • Pronate foot posture (flat foot)

Treatment: • Heel cups or inlays • Rigorous exercise • NSAIDs to reduce inflammation • Surgery for recalcitrant cases

Overuse and chronic fatigue of the plantar fascia from the repetitive loading of a heel strike can lead to failure of the plantar fascia at the calcaneal insertion. Plantar fascia tension may also be caused by tightness of the Achilles tendon or insufficiency of the posterior tibial tendon. This condition is often seen in the older female who has experienced a recent weight gain or change in activity. In any case, the result is a cycle of inflammation, weakening, and re-tearing of the fascia. The patient will have point tenderness over the medial calcaneal tuberosity that worsens by the end of the day. The patient will also have a tight heel cord and flat foot.

Conservative treatment measures include heel cups or inlays and rigorous exercise. Responsible use of non-steroidal anti-inflammatory drugs (NSAIDs) may be helpful, but cortisone injections must be limited to prevent fat-pad atrophy, rupture of the plantar fascia, and depigmentation. Surgical treatment is reserved for recalcitrant cases.


Tarsal Tunnel Syndrome

Mechanism of Injury: • Compression of posterior tibial nerve in flexor • retinaculum tunnel caused by fracture of the • tarsal tunnel or severe pronation

Clinical Presentation: • Point tenderness over the medial calcaneal • Tight heel cord • Pronate foot posture (flat foot)

Treatment: • Hind foot orthosis • NSAIDs to reduce inflammation • Surgical release of tarsal tunnel for • recalcitrant cases

Although uncommon, tarsal tunnel syndrome is a condition that can result from fractures of the tarsal tunnel or severe pronation. Compression of the posterior tibial nerve in the flexor retinaculum tunnel, just posterior to the medial malleolus, produces a burning in the arch and numbness in the toes. The symptoms are aggravated by activity. Anti-inflammatory agents (such as NSAIDs) in combination with hind foot orthosis usually relieve symptoms. If not, surgical release of the entire tarsal tunnel may be necessary.


Hallux Valgus and Hallux Rigidus

Hallux Valgus (bunion):

Mechanism of Injury: • Repetitive microtrauma at the metatarsal • phalangeal joint, leading to degeneration and proliferation of dorsal bone

Clinical Presentation: • Pain with walking and limited range of • motion (ROM), (especially during dorsiflexion)

Treatment: • Rocker-bottom soled shoes, analgesics, • Surgery

Hallux valgus, more commonly known as a bunion, involves a lateral deviation of the great toe at the metatarsal phalangeal joint. As the deformity develops, the medial aspect of the first metatarsal head will be uncovered, and the secondary irritation will develop into a painful callous with underlying bursitis. Conservative treatment with shoe modification and bunion pads is often sufficient to alleviate the symptoms. If not, surgery may be needed.

Hallux rigidus is characterized by a painful and limited range of motion of the metatarsal phalangeal joint, predominantly in dorsiflexion. Pain in the joint with walking is common and is usually corrected with rocker-bottom soled shoes.


Metatarsalgia

Mechanism of Injury:

• Excessive plantar forces leading to repetitive • microtrauma under the forefoot

Clinical Presentation:

• Morton’s Neuroma - inflammation, burning pain • under forefoot • Second-toe or “transfer” metatarsalgia – diffuse • plantar callus, possible bunion • Intractable plantar keratosis – callus with • associated pain

Treatment:

• Metatarsal pads and custom inlays • Corticosteroid injections and oral NSAIDs to • reduce inflammation and pain • Surgery for recalcitrant cases


Metatarsalgia

The metatarsalgias are a constellation of foot problems that present with pain under the forefoot.

Morton’s neuroma is caused by repetitive microtrauma of the common digital nerves, leading to a cycle of inflammation, accumulation of perineural fibrosis, and enlargement of the neurolemma.

Second-toe metatarsalgia is often associated with hallux valgus and the classic “transfer metatarsalgia.”

Intractable plantar keratosis results from a callous arising from a pressure point on the plantar surface.

The inflammation and pain these disorders produce may be alleviated through the use of corticosteroid injections and oral anti-inflammatory agents (NSAIDs).


Posterior Tibial Tendonitis


• Chronic and recurrent teniosynovitis of the • posterior tibial tendon, with possible tendon • Rupture

Clinical Presentation:

• Pain and swelling over the medial aspect of • the ankle

Treatment:

• Shoe modification with arch support • Limiting activity • NSAIDs for inflammation and pain

Chronic and recurrent tenosynovitis (also called peritendonitis) of the posterior tibial tendon can lead to degeneration with age. Rupture of the tendon at the medial malleolus is not uncommon.

Symptoms include pain and swelling over the medial aspect of the ankle. Conservative treatment includes shoe modification with arch support. Anti-inflammatory medication and activity limitations are also helpful.


Onychomycosis

Mechanism of Injury: • Fungal or dermatophyte infection leads to • local irritation, chronic inflammation, and • accumulation of keratotic debris

Epidemiology: • May affect up to 28% of adults over 60 • More common in elderly, patients with • diabetes, and immunocompromised patients

Clinical Presentation: • Brownish-yellow discoloration • Thickening and cracking of toenail • Pain

Onychomycosis, or tinea unguium, is a fungal infection of the toenail or nail bed. It begins as an area of localized discoloration that begins at the tip and eventually enters through the nail plate itself. As the nail bed becomes chronically irritated from persistent local inflammation, the accumulation of keratitic debris leads to thickening, cracking, and brownish-yellow discoloration. It is common in the elderly. It may cause painful disfigurement of the nail.


Onychomycosis: Drug Treatment

Treatment Options:

Terbinafine (Lamisil ®) • 250 mg po daily for 12 weeks

• Most common side effects include abdominal pain, diarrhea, N/V, HA, dizziness and elevated hepatic enzymes as well as rash, urticaria and pruritus • Drug interactions are many as terbinafine is a significant CYP 2D6 inhibitor • Contraindicated in those with alcoholism, hepatic disease, hepatitis, jaundice

• Monitoring includes CBC w/ differential and LFTs prior to initiation and periodically thereafter if therapy lasts longer than 4-6 weeks

Itraconazole (Sporanox ®) • 200 mg po daily for 12 weeks

• Most common side effects include N/V, diarrhea, abdominal pain and anorexia. LFT abnormalities occur in up to 4% of patients • Drug interactions with itraconazole are many as it is a substrate of CYP 3A4 and a

significant inhibitor of CYP 3A4 • Contraindications include renal or heart failure • Monitoring includes periodic LFTs if therapy lasts longer than 4 weeks


Onychomycosis: Drug Treatment

Ciclopirox (Penlac®) nail lacquer 8% • Apply daily for 6 months

• Adverse effects equal to placebo however erythema/rash of the treatment area can occur • Laboratory monitoring not needed and no reported drug interactions • The only contraindications includes hypersensitivity to any of Penlac®’s components.

Because toenails grow so slowly, fungal remnants can persist for months after treatment is begun, and treatment must be prolonged. Several newer treatments have superseded griseofulvin and ketoconazole as the agents of choice for the treatment of onychomycosis.

A systematic review has found terbinafine to be the drug of choice. Topical treatments have limited efficacy due to poor penetration of the nail bed; however, ciclopirox nail lacquer can be used topically on mild to moderate early onychomycosis, or it may be used as an adjunct to oral therapy in severe infection.


Diabetic Foot


• Poor blood glucose control, leading to peripheral neuropathy** and ischemia • Impaired circulation to the extremities (Peripheral arterial disease)

Clinical Presentation: Feeling of numbness Prickling or tingling sensations Failure to sense pinprick or vibration, esp. against toe with 10g monofilament Cold, pulseless foot

Treatment: Treatment of underlying condition Self-examine feet DAILY for first signs of ulceration

**Note: A detailed discussion of diabetic neuropathy is beyond the scope of this module however treatment often includes use of antiepileptic agents (e.g., gabapentin, pregabalin), SNRI (serotonin norepinephrine reuptake inhibitor) antidepressants (e.g., duloxetine, venlafaxine, nortriptyline), opioids, and sometimes topical agents such as capsaicin or lidocaine patches.

Complications if untreated: Disabling pain, ulcers, permanent loss of sensation in feet


Diabetic Foot

Diabetic foot may develop after many years of diabetes and poor blood glucose control. A form of polyneuropathy, patients with diabetic foot may present with numbness and prickling sensations not unlike that experienced when you hit your “funny bone” which is actually your ulnar nerve.

Some patients feel pain in the toes or feet. During a neurological examination, patients may show a marked inability to feel a pinprick or a vibration, especially against the toe. While some of the symptoms of diabetic foot may go away after several months, others, such as loss of sensation in the feet, are irreversible.

Yearly medical exams should identify risk factors, while protective footwear and custom orthotics can reduce shear forces on the foot that lead to ulcers.


Diabetic Foot Ulcers

Epidemiolgy: The lifetime risk of a foot ulcer for a patient with diabetes is up to 15%

Ulcer management: General interventions are directed at treating infection, peripheral ischemia, and abnormal pressure loading due to neuropathy

Specific wound care: • Dress and keep ulcer clean • Remove necrotic material • Topical growth factors (becaplermin- • Regranex®)

Ulceration of the foot in diabetes is common and may lead to amputation. Healing is often difficult and ulcers frequently recur. Attention must be given to alleviating underlying causes, then managing the ulcer. Topical growth factors have given generally disappointing results at improving healing; however, topical platelet-derived growth factor, or becaplermin, should be considered in non-healing, well-perfused ulcers after failure of conventional wound care.


Ingrown Toenail

Ingrown toenails are common in older adults particularly in those who have improperly trimmed nails. It is not uncommon for ingrown nails to be painful, red and swollen. Treatment options vary and patients should be referred to a podiatrist. In general, prevention consists of proper footwear, proper trimming of nails that involve cutting the nail straight across the top, avoiding tapering of the corners.


Dystonia of the Foot

Dystonia of the foot may occur as a separate disorder or related to other movement disorders such as Parkinson’s disease. Foot dystonia involves involuntary contraction of the muscles of the foot and is often painful. Treatment can involve use of muscle relaxants, injections of botulinum toxin and/or surgery.


Resources


Beers MH and Berkow R.(2000).“Foot Disorders.”The Merck Manual of Geriatrics. 3nd edition Section 7, Musculoskeletal Disorders.Whitehouse Station, NJ:Merck Research Laboratories: 544–559.

Bennett SP, Griffiths GD, Schor AM, Leese GP, Schor SL.“Growth factors in the treatment of diabetic foot ulcers.”Br J Surg 2003;90:133–146.

Black JR, Bernard JM, and Williams LA.(1993).“Heel pain in the older patient.”Clin Podiatr Med Surg; 10(1):113 –119.

Crawford F, Young P, Godfrey C, Bell-Syer SE, Hart R, Brunt E, Russell I.“Oral treatments for toenail onychomycosis: a systematic review.”Arch Dermatol 2002;138:811–816.

Jeffcoate WJ, Harding KG.“Diabetic foot ulcers.” Lancet 2003;361:1545–1541.

Gupta AK.“Ciclopirox nail lacquer: a brush with onychomycosis.”Cutis 2001;68(suppl 2):13–16.

Vander Straten MR, Hossain MA, Ghannoum MA.“Cutaneous infections: dermatophytosis, onychomycosis, and tinea versicolor.” Infect Dis Clin North Am 2003;17(1):87–112.

Watkins PJ.“The diabetic foot.”BMJ 2003;326:977–979.

Footcare Direct: Foot Care: American Diabetes Association Ingrown Toenail: Information on foot dystonia

module 11 - pharmacotherapy for musculoskeletal disorders

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