US Pharm. 2012;37(10):29-34.
ABSTRACT: Paget’s disease (osteitis deformans), a localized
disorder of the skeletal system, is characterized by increased bone
turnover. The clinical presentation of Paget’s disease ranges from no
symptoms to bone pain, painful skeletal deformities, or fractures. It
often is discovered because of an elevated serum alkaline phosphatase
(ALK-P) of unknown origin or upon radiography. The goals of treatment
are to alleviate symptoms and to reduce bone turnover to prevent
complications. Both calcitonin and bisphosphonates inhibit osteoclastic
bone resorption and may be used to treat Paget’s disease; however,
bisphosphonates are the medication of choice. Although most comparison
trials of bisphosphonates report surrogate outcomes (normalization of
serum ALK-P), zoledronic acid—a more potent bisphosphonate that has
demonstrated efficacy and has the convenience of being administered as a
single infusion—is often the preferred bisphosphonate for Paget’s
Paget’s disease of bone, also known as osteitis deformans, is a
localized disorder of the skeletal system that is characterized by
increased bone turnover. It may involve a single bone (monostotic) or
multiple bones (polyostotic).1 Approximately 34% of patients diagnosed with Paget’s disease have a monostotic lesion.2
While any skeletal site has the potential to be affected by Paget’s
disease, some sites are more frequently involved, particularly the
pelvis, vertebrae, femur, tibia, and skull.1 Enlarged but
structurally weaker bones develop over time. Many patients have active
disease for many years before presentation, since the disorder
progresses at a rate of 1 cm per year in long bones.3 Over time, untreated Paget’s disease has the potential to become debilitating.
Increased osteoclastic bone resorption, greater vascularity, marrow
fibrosis, and disorganized bone formation occur in Paget’s disease.4
Osteoclasts, which predominate in the early course of disease, contain
more nuclei and are larger and more numerous in pagetic lesions of the
bone.3,4 As the pagetic lesion matures, osteoblasts
predominate and the pagetic bone is disorganized because of the faster
rate of bone turnover.3,4 This leads to a reduction in mechanical strength and potentially to deformities and fractures.
Genetic factors play a role in the development of Paget’s disease.
The disorder occurs more frequently in individuals of European descent
aged 55 years and older.1,4 Individuals of Scandinavian,
Eastern European, or Asian descent rarely develop Paget’s disease. For
first-degree relatives of patients with Paget’s disease, the risk of
developing the disorder is seven to 10 times that for the general
population.1 Environmental factors, such as low calcium
intake or childhood vitamin D deficiency, zoonotic infections, exposure
to toxins, and viral infections, have been suggested as potential
triggers for Paget’s disease.4 However, only the relationship between viral infections and the disease has been studied, and the results are conflicting.1
The clinical presentation of Paget’s disease ranges from no symptoms to bone pain, painful skeletal deformities, or fractures.1
Signs and symptoms are more common with polyostotic involvement of the
skeleton. Bone pain is characteristically present at rest, at night, and
with use of the affected bone.4 Deformities that occur in the skull, facial bones, and extremities are more easily identifiable.1
Incomplete fissure fractures and complete fractures, which are
typically transverse breaks, can be a major complication of Paget’s
disease.2 Degenerative arthritis of the hips is associated
with Paget’s disease occurring in the pelvis and can significantly
impair mobility. This complication may result in the need for a hip
Headaches and hearing loss may be associated with Paget’s disease
occurring in the skull. Hearing loss can be sensorineural, mixed, or
conductive. Dental complications may result in loss of teeth if the
disease occurs in the maxilla or mandibula. Neurologic complications,
such as spinal cord compression, occur in up to 76% of patients and can
produce considerable morbidity.1,2 Joint pain may be present when pagetic lesions affect bone segments adjacent to large joints.1
Cardiovascular complications, such as arterial calcification, are not
unusual in patients diagnosed with Paget’s disease, and the increased
vascularity of pagetic lesions may lead to increased cardiac output.
Sarcomas complicate Paget’s disease in fewer than 1% of patients.2 Finally, hypercalcemia may develop in patients who are immobilized by severe Paget’s disease.5
Since Paget’s disease often is asymptomatic, it frequently is
discovered accidentally because of an elevated serum alkaline
phosphatase (ALK-P) of unknown origin or upon radiography performed to
evaluate abdominal symptoms or bone, pelvic, or hip pain.1,2
Ninety-five percent of untreated patients with Paget’s disease have an
elevated serum ALK-P level; however, a normal concentration does not
exclude the diagnosis.4 Serum ALK-P may be normal in patients
with monostotic or metabolically inactive disease. Serum ALK-P
elevations are reflective of an increased number of osteoblasts in the
lesions.2 The level is indicative of both disease extent and disease activity.6
Serum total ALK-P levels are appropriate for following the disease, but
the bone-specific isoform should be used in patients with coexisting
hepatobiliary disease. Urinary deoxypyridinoline and cross-linked
N-telopeptide of type I collagen, other markers of bone resorption, have
not been found to confer additional benefit on serum ALK-P, and they
are more costly.6
To confirm the diagnosis and determine the location and extension of
Paget’s disease, radiographs and total bone scintigraphy are performed.
Bone scintigraphy is more sensitive for identifying pagetic lesions;
however, it has low specificity, as there are other diseases that cause
bone remodeling.1 If malignancy is suspected, CT, MRI, and biopsy may be performed.
Treatment for Paget’s disease focuses on alleviating symptoms and
reducing bone turnover, with a long-term goal of inducing remission to
prevent progression and complications.5 Both calcitonin and
bisphosphonates inhibit osteoclastic bone resorption and may be used to
treat Paget’s disease. Analgesics and nonsteroidal anti-inflammatory
drugs also may be employed to manage the associated symptoms.
Bisphosphonates: The treatment of choice for management
of Paget’s disease is a bisphosphonate. Bisphosphonates improve bone
formation by slowing bone turnover and inhibiting osteoclast activity.
Randomized, controlled trials have demonstrated that bisphosphonate
therapy can improve bone pain, promote healing of osteolytic lesions,
decrease ALK-P levels, and restore normal bone histology.4,5
Bisphosphonates localize to hydroxyapatite in the bone. They have a long
elimination from the skeleton, since they are embedded in the bone and
are released during subsequent resorption through a multiple-phase
process.7 Etidronate, tiludronate, pamidronate, risedronate,
alendronate, and zoledronic acid are FDA approved for the treatment of
Paget’s disease (TABLE 1). Although other bisphosphonates are
available, this article focuses on those with an FDA-approved indication
for Paget’s disease.
Bisphosphonates vary in their binding affinity to hydroxyapatite,
with higher-affinity agents possibly leading to improved disease
management.2,4 For example, zoledronic acid is about 10,000
times more potent than etidronate with regard to inhibiting osteoclastic
A limited number of comparative studies of Paget’s disease have been
conducted. One study compared the percentage of change in serum ALK-P
between oral alendronate 40 mg daily and oral etidronate 400 mg daily
for 6 months.5 At 6 months, there was a significant difference in serum ALK-P reduction between alendronate and etidronate (79% vs. 44%; P <.001). Another study compared oral risedronate 30 mg daily for 2 months with oral etidronate 400 mg daily for 6 months.8
Serum ALK-P concentrations at month 12 had normalized in 73% of
risedronate-treated patients versus 15% of etidronate-treated patients (P
<.001). In addition, statistically significant pain reduction was
seen in the risedronate group. A single infusion of IV zoledronic acid 5
mg was compared with oral risedronate 30 mg daily for 2 months.5
Once again, normal serum ALK-P concentrations were more common with the
higher-potency bisphosphonate. Approximately 89% of zoledronic
acid–treated patients achieved a normal serum ALK-P level, versus 58% of
risedronate-treated patients (P <.001).9 Normalization of serum ALK-P levels continued in 98% of zoledronic acid–treated patients for 2 years.5 Zoledronic acid also demonstrated a slight improvement in pain control compared with risedronate (P <.05).9
Bisphosphonates are given either IV or orally. Absorption rates of
oral bisphosphonates are low (0.7%-2.5%), and absorption occurs
throughout the entire gastrointestinal (GI) tract.7 All
bisphosphonates have a low oral bioavailability, and bioavailability
declines in the presence of food, calcium, magnesium or aluminum;
therefore, oral bisphosphonates should be taken on an empty stomach with
plain (nonmineral) water. Bisphosphonates are excreted unchanged in the
urine through glomerular filtration. A strong correlation exists
between renal excretion and renal function, so dosage adjustments can be
based on creatinine clearance (CrCl).7 Bisphosphonates should not be used in patients with a CrCl under 30 to 35 mL per minute.
Pamidronate, risedronate, alendronate, and zoledronic acid are
nitrogen-containing bisphosphonates; etidronate and tiludronate, the
older bisphosphonates, do not contain nitrogen. Dyspepsia, esophagitis,
esophageal reflux, gastritis, nausea, and other manifestations of GI
pain or discomfort are the most common adverse effects (AEs) associated
with oral nitrogen-containing bisphosphonates.10 Diarrhea is the most common AE associated with older, nonnitrogen-containing bisphosphonates.10
To reduce GI AEs, the patient should be instructed to refrain from
lying down for 30 minutes after administration of an oral
bisphosphonate. Other AEs have been tied to bisphosphonate therapy, but
at a much lower incidence rate. Bisphosphonates disrupt the process of
bone remodeling that repairs microdamage by reducing bone turnover;
therefore, atypical femoral fractures could result.10
Osteonecrosis of the jaw (ONJ) is characterized by an area of exposed
bone that will not heal, typically after dental surgery. It is a rare
AE of bisphosphonates, particularly with long-term, high-dose use.4
The risk of ONJ remains extremely low with oral bisphosphonate therapy
or 5 mg IV zoledronic acid once a year, the recommended dosage for the
treatment of Paget’s disease.10 Ocular inflammation, mainly uveitis and scleritis, has been associated with nitrogen-containing bisphosphonates.11 Discontinuation of the bisphosphonate and a short course of corticosteroids resolve the inflammation.10
Musculoskeletal pain from bisphosphonate use has been suggested, but
temporary or permanent discontinuation of the drug has provided relief.10
To avoid hypocalcemia, dietary calcium and vitamin D deficiencies must be corrected prior to bisphosphonate administration.4
In addition, patients should obtain 1,000 to 1,500 mg of calcium and
400 to 800 IU of vitamin D daily through diet or supplementation, as new
bone formation occurs during the process of repairing pagetic bone.5 Calcium and vitamin D supplementation is especially important in patients receiving zoledronic acid.
Calcitonin: Calcitonin has a shorter duration of
action and weaker antiresorptive effects than bisphosphonates;
therefore, it is less frequently used in the treatment of Paget’s
disease.4 If bisphosphonate therapy is contraindicated,
salmon calcitonin is an approved alternative. Salmon calcitonin rapidly
inhibits osteoclast activity and reduces levels of biochemical markers
of bone turnover by up to 50% over 3 to 6 months. Lesions have been
shown to resolve upon radiologic examination in the case of therapy
administered for more than 1 year.2 Nausea and flushing are considered the most common AEs.
Surgical procedures such as joint replacement, fracture fixation, and
correction of bone deformity or spinal stenosis may be necessary to
manage complications related to Paget’s disease.4 If joint pain is unresponsive to medical therapy, total joint arthroplasty is an option for pain relief.6 The hip is the most common site for joint arthroplasty. Pain may be diminished with tibial osteotomy to realign the knee.6 A neurosurgery consultation may be necessary for patients with spinal stenosis.
Patients diagnosed with Paget’s disease who have bone pain, articular
or neurogenic pain, hypercalcemia due to immobilization, or hearing
loss (in the case of cranial involvement) should receive
pharmacotherapy.12 To prevent excessive hemorrhage in
patients with Paget’s disease who are undergoing elective orthopedic
surgery involving a pagetic bone, drug therapy should be given for 2 to 3
months prior to surgery to reduce the bone’s vascularity. Treatment
should be considered to prevent the progression of skeletal deformities,
especially in patients with a long life expectancy.2 Early
treatment may be considered in asymptomatic Paget’s disease patients to
reverse osteolytic lesions and reduce skeletal deformity, arthritis, and
neurologic complications; however, evidence is lacking regarding the
ability of pharmacotherapy to prevent complications.2,4
Follow-up for Paget’s disease includes radiographs of the lesions at 1
year and serum ALK-P activity every 3 months during the first year.2
If drug treatment is used, serum ALK-P activity should be measured
every 3 to 12 months, depending upon which agent is used. These levels
typically decrease within a few months of therapy.6 If serum ALK-P activity rises at least 25% and/or bone pain recurs, retreatment should be considered.2
Counseling points regarding bisphosphonates are highly specific (TABLE 1).
Good oral hygiene is important throughout bisphosphonate treatment, and
patients should be reminded to inform their dentist that they are
taking a bisphosphonate, especially prior to a procedure. Prevention of
falls also should be discussed with patients to reduce their risk of
fractures. Weight control may reduce weight-bearing pain in the
extremities.6 Hypercalcemia can occur with complete immobilization, so a tolerable amount of activity should be encouraged.6
Adherence may be affected by the strict administration guidelines for
oral bisphosphonates, so the patient’s active participation in care and
the encouragement of adherence by multiple providers are important.
Although their mortality rates do not differ from those in the
general population, individuals with Paget’s disease may experience many
complications, which can greatly impact their quality of life.5
The increased bone remodeling resulting from osteoclast-mediated bone
resorption followed by disorganized osteoblast-mediated bone deposition
can cause pain, fractures, and skeletal deformities.13
Bisphosphonates improve bone pain, improve bone formation, and reduce
serum ALK-P; therefore, they are the preferred treatment modality.
Although most comparison trials of bisphosphonates report surrogate
outcomes (normalization of serum ALK-P), no trials have effectively
evaluated endpoints such as prevention of joint replacements or
deafness.3 Therefore, zoledronic acid, with its demonstrated
efficacy and convenient single-infusion administration, is often the
bisphosphonate of choice. This intervention shows promise of a sustained
improvement in quality of life for patients with Paget’s disease.
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