Module 11 Pharmacotherapy For Musculoskeletal Disorders

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Copyright 2011 American Society of Consultant Pharmacists
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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-
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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 skeletons 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 skeletons 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 individuals 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 doesnt 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.: Cushings 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 Cushings 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 patients 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 (Fosamax / Fosamax Plus D)
Risedronate (Actonel)
Ibandronate (Boniva)
Calcitonin (Calcimar, Miacalcin, Cibacalcin) for treatment only
Selective Estrogen Receptor Modulator (SERM) for prevention and treatment
Raloxifene (Evista)
Parathyroid hormone (PTH) treatment for high risk patients
Teriparatide (Forteo)
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:
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
Back pain
Bronchitis
Dyspepsia
Upper respiratory tract infection
Monitoring:
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 Pagets 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
dailypreferably in the thigh or abdomenand 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;109:267276.
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;12:112.
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;42:23092318.
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;280:20772082.
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;337:16411647.
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:10631070.
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;43:7577.
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):113126.
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;166:480485.
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):436442.
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):333340.
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;285:785795.
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;76:3843.
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;11:8391.
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
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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)
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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
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 (Mercks 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, Sjogrens
syndrome, interstitial lung disease, pericardial disease, systemic
vasculitis, and Feltys 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
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
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 ! 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 leflunomides 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:
TNF" 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
TNF"
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.
ODell 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
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 patients 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 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
Compression of posterior tibial nerve in flexor
retinaculum tunnel caused by fracture of the
tarsal tunnel or severe pronation
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):
Repetitive microtrauma at the metatarsal
phalangeal joint, leading to degeneration and proliferation of dorsal bone
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
Excessive plantar forces leading to repetitive
microtrauma under the forefoot
Mortons 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.
Mortons 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
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
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
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 Penlacs 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)
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 Parkinsons
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: 544559.
Bennett SP, Griffiths GD, Schor AM, Leese GP, Schor SL.Growth factors in the treatment of diabetic foot ulcers.Br J
Surg 2003;90:133146.
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;138:811816.
Jeffcoate WJ, Harding KG.Diabetic foot ulcers. Lancet 2003;361:15451541.
Gupta AK.Ciclopirox nail lacquer: a brush with onychomycosis.Cutis 2001;68(suppl 2):1316.
Vander Straten MR, Hossain MA, Ghannoum MA.Cutaneous infections: dermatophytosis, onychomycosis, and tinea
versicolor. Infect Dis Clin North Am 2003;17(1):87112.
Watkins PJ.The diabetic foot.BMJ 2003;326:977979.
Footcare Direct:
Foot Care: American Diabetes Association
Ingrown Toenail:
Information on foot dystonia

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