Treatment of Paget disease of bone

INTRODUCTION — Paget disease of bone, also known as osteitis deformans, is a focal disorder of bone metabolism characterized by an accelerated rate of bone remodeling, resulting in overgrowth of bone at selected sites and impaired integrity of affected bone. The main clinical manifestations are pain and deformities in affected areas and a heightened risk of fracture, although many patients are asymptomatic. Osteoarthritis in nearby joints and neurologic disease are common complications, and the vascularity of pagetic bone may result in excessive bleeding during orthopedic surgery on affected areas.

Treatment with bisphosphonates, such as zoledronic acid, risedronate, and alendronate, can usually ease pain, slow bone turnover, and promote deposition of normal lamellar bone, which in turn results over time in the normalization of serum alkaline phosphatase and other markers of bone turnover and may lead to radiographic healing of lytic lesions [1-5]. However, alternative agents, such as calcitonin, are sometimes required in patients unable to use these bisphosphonates. Analgesic, rehabilitative, surgical, and other measures may also be of benefit.

The treatment of Paget disease of bone will be reviewed here. The pathogenesis, clinical manifestations, and diagnosis of this disorder are discussed separately. (See "Clinical manifestations and diagnosis of Paget disease of bone".)

TREATMENT APPROACH

Indications for treatment — Treatment is indicated in patients with symptomatic Paget disease and in selected asymptomatic patients with significant biochemical abnormalities or imaging changes indicating risk of complications from untreated disease. The goals of treatment are to ease pain and to reduce the rate of bone remodeling towards normal, which will enhance the deposition of normal lamellar bone, decrease the vascularity of bone, and slow disease progression. (See 'Symptomatic Paget disease' below and 'Asymptomatic Paget disease' below.)

Symptomatic Paget disease — Treatment is indicated in patients with symptoms caused by metabolically active Paget disease, which is usually associated with an elevated serum alkaline phosphatase of bone origin, although this might not be so in those with mono-ostotic disease. The most common symptom is bone pain at a pagetic site (eg, headache, limb, joint, or back pain) or radicular pain due to neural impingement by pagetic bone.

Symptoms and findings that may respond to pharmacologic treatment in patients with active disease include bone pain and symptomatic nerve compression, as well as radiographic findings of osteolytic bone lesions. However, patients with back or joint pain often have coexistent neuromuscular or joint disease, such as osteoarthritis, associated with nearby pagetic involvement [6-8]. The precise cause of pain in these patients may be difficult to determine; thus, a trial of bisphosphonate therapy is generally indicated, even if the serum alkaline phosphatase level is normal.

Fracture through a pagetic bone lesion is an additional manifestation of Paget disease in which treatment may be beneficial. Although formal recommendations from professional societies to guide therapy are lacking, we suggest antipagetic treatment in patients presenting with a pathologic fracture once the patient is stable, provided no contraindications to therapy exist.

Asymptomatic Paget disease — Treatment is indicated in some patients with asymptomatic Paget disease, which has typically been detected in the course of evaluation of an elevated serum alkaline phosphatase or noted incidentally on imaging studies performed for some other reason. Decisions regarding therapy in asymptomatic patients should take into account the location of the disease and the presence of comorbidities.

Treatment of patients with asymptomatic Paget disease is suggested when:

●The location of pagetic bone puts the patient at risk for future complications and there is evidence of active disease, either based upon elevated alkaline phosphatase or bone scintigraphy. Specific examples include lesions involving spine (risk of pathologic fracture or nerve impingement), weightbearing bones (risk of fracture), skull (risk of hearing loss), or bone abutting a joint (risk of secondary osteoarthritis).

●Surgery is planned at an active pagetic site. In patients with active disease in planned operative sites we initiate antipagetic therapy prior to surgery, preferably beginning three months before elective procedures.

●Hypercalcemia develops in the setting of immobilization. Hypercalcemia has been noted in some immobilized patients with polyostotic disease [9]. By contrast, hypercalcemia in an ambulatory patient suggests the presence of a second disorder, such as primary hyperparathyroidism, and would not itself be sufficient to indicate a need for antipagetic therapy. (See 'Preoperative antipagetic therapy' below and "Clinical manifestations and diagnosis of Paget disease of bone".)

Our approach to asymptomatic disease is consistent with the 2014 Endocrine Society clinical practice guideline [10]. It is important to note that while bisphosphonate treatment is clearly effective at reducing metabolic activity [11], strong evidence demonstrating that treatment prevents complications of disease is lacking. Indeed, the 2019 guidelines developed by the Paget's Association (United Kingdom)-led Guidelines Development Group state only that bisphosphonate therapy "may be considered" in asymptomatic patients with evidence of pagetic disease activity [12]. Thus, when treatment for asymptomatic patients is considered for the reasons noted above, we provide patient education with respect to guidelines, existing clinical evidence, and risks of treatment, thereby facilitating the incorporation of patient preference in treatment decisions. It is important to note that while data supporting the long-term benefit of treating asymptomatic Paget disease are sparse or lacking, many experts have expressed that the potential for benefit outweighs the risk.

Choice of initial antipagetic agent — Several antiresorptive agents are effective in treating Paget disease. These drugs target the osteoclast, which is the primary cell that mediates the high bone turnover characteristic of Paget disease. There are three classes of antiresorptive agents: the bisphosphonates, calcitonin, and denosumab. Of these drugs, bisphosphonates and calcitonin are used for the treatment of Paget disease. These drugs suppress bone resorption within days to weeks, followed by suppression of bone formation in weeks to months, with a reduction in the serum fraction of alkaline phosphatase that comes from bone [10]. Denosumab is not routinely used for Paget disease. (See 'Antipagetic agents' below.)

Zoledronic acid is the first-choice treatment for Paget disease because of its efficacy and ease of administration. The choice of zoledronic acid as the initial agent for most patients with active Paget disease is consistent with both the 2014 clinical practice guidelines of the Endocrine Society and the 2019 Paget's Association guidelines [10,12].

Zoledronic acid is highly potent, has the advantage of being infused over 15 to 20 minutes, and produces the most sustained response among the available bisphosphonates. In osteoporotic women, zoledronic acid reduced bone turnover markers for up to 3 years after administration [13]. In Paget disease, biochemical remission was induced in 96 percent of patients after a single dose [14]. Remission is maintained in the majority of patients out to 5 to 6 years [15] and as long as 10 years, with only 14 percent of patients having a biochemical relapse by 9 years [16]. In addition, zoledronic acid is effective in patients previously treated with other bisphosphonates [17] (see 'Zoledronic acid (zoledronate)' below). Pamidronate is an alternative intravenous agent, but it is less potent than zoledronic acid and takes longer to infuse. Also, some patients develop drug resistance to pamidronate. (See 'Pamidronate' below and 'Retreatment: Indications and approach' below.)

In patients wishing to avoid intravenous therapy, or if zoledronic acid is not available, a defined course of daily oral therapy with risedronate or alendronate is a reasonable alternative. The suggested regimens for risedronate and alendronate, respectively, are described below (see 'Risedronate' below and 'Alendronate' below).

Alternatively, simple bisphosphonates, such as etidronate or tiludronate, may be considered in patients who are unable to tolerate nitrogen-containing bisphosphonates. Although these drugs are not universally available, older studies demonstrated efficacy when administered according to the recommended doses and duration, and they may be tolerated in patients with side effects from nitrogen-containing bisphosphonates. (See 'Simple bisphosphonates' below.)

Patients intolerant of or unable to take bisphosphonates — In the rare patient intolerant of both parenteral and oral bisphosphonates, we suggest treatment with calcitonin. (See 'Calcitonin' below.)

Calcitonin is also preferred in patients who are unable to take bisphosphonates due to marginal renal function and is a reasonable choice in those for whom the goal of therapy is rapid easing of pain, without the need to achieve disease remission.

Preoperative antipagetic therapy

●Planned surgery – Reported complications of total hip arthroplasty in patients with Paget disease of the hip include excessive blood loss [18,19], surgical challenges due to bony deformities and sclerotic bone [20], and increased aseptic loosening and revision [20,21]. For planned surgery at an active pagetic site, preoperative medical treatment with a nitrogen-containing bisphosphonate (eg, zoledronic acid, risedronate, or alendronate), beginning three months prior to surgery, has been recommended to both reduce blood loss and decrease risk for revision [22]. This recommendation is expert opinion but is supported by a case series showing that loosening of hip implants was more common in patients with higher levels of serum alkaline phosphatase [23].

Calcitonin is an alternative in untreated patients unable to take a bisphosphonate or who require surgery prior to the time needed for a bisphosphonate to have sufficient benefit. Calcitonin can decrease vascularity of pagetic bone and has a rapid onset of action, with decreased skeletal blood flow observed within one week of starting treatment [24]. (See 'Calcitonin' below.)

●Following fracture at a pagetic site – In patients presenting with fracture through pagetic bone, clinical trials and formal recommendations to guide therapy are lacking. Bisphosphonates may be used once the patient is stable and after calcium, phosphorus, and vitamin D have been measured and appropriate treatment begun to prevent hypocalcemia [25-27]. (See 'Pretreatment testing and related interventions' below.)

Adjunctive therapies — The secondary consequences of Paget disease, such as hearing loss, osteoarthritis, and skeletal deformities, need to be treated with modalities other than bisphosphonates or calcitonin once the excessive bone turnover has been addressed. Additional interventions may include rehabilitative measures, such as physical therapy, bracing, and walking aids, including canes; analgesics and other interventions for osteoarthritis; and surgery. In addition, attention must be paid to psychosocial issues [9,28-30]. (See "Overview of the management of osteoarthritis" and 'Role of surgery' below and 'Prognosis' below.)

ANTIPAGETIC AGENTS

Nitrogen-containing bisphosphonates — The nitrogen-containing bisphosphonates (eg, zoledronic acid, risedronate, and alendronate) are effective, relatively safe, and have advantages for the treatment of Paget disease compared with the simple bisphosphonates (eg, etidronate, tiludronate) or calcitonin. The nitrogen-containing bisphosphonates have different mechanisms of action than the simple bisphosphonates, resulting in sustained suppression of bone turnover at doses that do not impair mineralization (table 1) [31-33]. The mechanisms of action and pharmacokinetics of the bisphosphonates are discussed separately. (See "Pharmacology of bisphosphonates" and "Bone physiology and biochemical markers of bone turnover".)

The nitrogen-containing bisphosphonates are the most often used and best studied agents for the initial treatment of Paget disease [5,9,10,12]. For Paget disease, zoledronic acid (zoledronate) is given intravenously as a single dose of 5 mg, while risedronate and alendronate are given orally as 30 mg/day for 60 days or 40 mg/day for 6 months, respectively. Another bisphosphonate given intravenously, pamidronate, has been studied for the treatment of Paget disease and was used in the past, but is now used infrequently because of the availability of more effective and more easily administered agents. Ibandronate, also given intravenously, and neridronate, given intravenously or by intramuscular injection (not available in the United States), are also sometimes utilized.

Prior to initiating therapy, selected laboratory studies are required, and patients using an oral agent should receive instructions for safe and effective use of the drug. (See 'Pretreatment testing and related interventions' below and 'Instructions for oral bisphosphonate administration' below.)

Pretreatment testing and related interventions

●Calcium, phosphorus, and vitamin D testing and supplementation – Normal serum levels of calcium and phosphorus and sufficient 25-hydroxyvitamin D (calcidiol) should be present when initiating bisphosphonate therapy and throughout the ensuing year.

While approaches to vitamin D supplementation may vary, our practice is to administer supplemental vitamin D if the vitamin D level is below 30 ng/mL. In patients whose 25-hydroxyvitamin D level is 20 ng/mL (50 nmol/L) or less, we prescribe vitamin D supplementation (50,000 international units weekly) for up to eight weeks, with monitoring of the 25-hydroxyvitamin D level to ensure an adequate level is achieved prior to initiation of intravenous bisphosphonate therapy (see "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Vitamin D replacement'). Patients should also be given supplemental calcium as needed depending on dietary intake, with the goal of achieving 1200 mg of elemental calcium/day to avoid hypocalcemia. (See "Calcium and vitamin D supplementation in osteoporosis".)

●Hypercalcemia and parathyroid hormone testing – Measurement of serum parathyroid hormone (PTH) is warranted in patients who are hypercalcemic. The serum PTH concentration in patients with Paget disease is low in patients with hypercalcemia associated with immobilization but increased in patients with coexistent primary hyperparathyroidism, which can occur in patients with Paget disease. (See "Clinical manifestations and diagnosis of Paget disease of bone", section on 'Additional diagnostic considerations'.)

●Prophylactic dental care – In patients requiring extensive dental work, such as dental extractions, such treatment should be performed at least three to six months prior to instituting bisphosphonates, whenever possible, to reduce risk for osteonecrosis of the jaw (ONJ). (See 'Side effects of bisphosphonates' below.)

Dental extractions convey a significant risk for ONJ in patients on bisphosphonates, although the risk appears to be lower than in patients being treated for Paget disease with shorter courses than those used for either osteoporosis or in patients with malignancy (see 'Side effects of bisphosphonates' below). There is a lack of sufficient data to guide decisions regarding the risk from dental implants, although cases of successful implants have been reported in patients with Paget disease receiving bisphosphonate therapy [34,35]. Evidence of benefit from suspending treatment with bisphosphonates for several months prior to dental care is also lacking. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Osteonecrosis of the jaw'.)

Instructions for oral bisphosphonate administration — All bisphosphonates are poorly absorbed when taken orally. Nitrogen-containing bisphosphonates (eg, risedronate, alendronate) must be taken with plain water, not other beverages, first thing in the morning and at least 30 minutes before the first food, other beverage, or other oral medications. Patients should not lie down during this period to prevent gastroesophageal reflux and possible esophageal irritation (see 'Risedronate' below and 'Alendronate' below). Etidronate and tiludronate should be taken with water midway through a four-hour fast (ie, two hours after food and at least two hours before the next food). (See 'Simple bisphosphonates' below.)

Side effects of bisphosphonates — The bisphosphonates in common use are generally well tolerated. However, several side effects occur more commonly or are of particular concern even though they are infrequent. Adverse effects that can occur with the dosing regimens used in Paget disease are briefly reviewed here. Bisphosphonate dosing in Paget disease is different from that in other disorders in which these drugs are used, such as osteoporosis and malignancy. Adverse effects with these treatment regimens are discussed separately. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy" and "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Risks specific to oral bisphosphonates'.)

Adverse effects include:

●Influenza-like symptoms – Any of the nitrogen-containing bisphosphonates, particularly the intravenous agents (zoledronic acid and pamidronate), can cause an influenza-like syndrome. This is a typical acute phase response, characterized by fever, chills, bone pain, myalgias, and arthralgias. Symptoms are usually self-limited, resolving after several days, and may be treated with acetaminophen or nonsteroidal antiinflammatory drugs (NSAIDs). Prior oral bisphosphonate exposure appears to decrease the risk for this reaction [36].

Influenza-like symptoms were reported in approximately 30 to 40 percent of patients in osteoporosis trials [37,38]. The rates appear similar in Paget disease patients, with 48 percent of bisphosphonate-naïve patients and 18 percent of those with prior bisphosphonate exposure experiencing an acute phase response [39]. Treatment with acetaminophen 650 mg starting 45 minutes prior to infusion and continuing with four times daily dosing for three days significantly reduced the incidence of acute phase reactions [40]. In Paget disease patients, a correlation of low 25-hydroxyvitamin D (25-OH vitamin D) levels and risk of acute phase reaction was observed, and vitamin D supplementation decreased incidence of acute phase reaction compared with observational cohort [39]. Achieving adequate vitamin D levels prior to treatment with intravenous bisphosphonates is already strongly recommended to decrease the small risk of hypocalcemia.

●Musculoskeletal pain – In a syndrome distinct from the acute phase response, severe and sometimes incapacitating bone, joint, or muscle pain can very infrequently occur within days, months, or years after starting a bisphosphonate and does not always resolve completely with discontinuation of therapy [41,42]. This syndrome has been the subject of an alert by the US Food and Drug Administration (FDA), as it may be overlooked by clinicians [43]. The alert advises that clinicians prescribing bisphosphonates should discuss this syndrome with their patients and advise them to promptly contact their doctor if they develop severe bone, joint, or muscle pain while taking a bisphosphonate.

●Osteonecrosis of the jaw – ONJ is a potentially serious complication of bisphosphonate use. It has primarily been described in patients with malignancy, particularly those treated with monthly intravenous therapy using high-potency bisphosphonates. In comparison, the risk is very low with the limited bisphosphonate therapy that is prescribed in Paget disease and in postmenopausal women with osteoporosis. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Osteonecrosis of the jaw' and "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Osteonecrosis of the jaw'.)

The degree of risk of ONJ in Paget disease is uncertain but appears to be low. There were no cases in the randomized trials that compared zoledronic acid with risedronate in 357 patients [14,44]. An observational study primarily using a postal survey of Australian oral and maxillofacial surgeons identified 158 patients with bisphosphonate-associated ONJ, eight of whom had Paget disease [45]. State and national prescription databases were used to calculate frequency estimates (minimum to maximum) in Paget disease of 0.26 to 1.8 percent; the frequency estimate was higher if tooth extractions were performed (2.1 to 13.5 percent).

●Other – In clinical trials comparing intravenous with oral bisphosphonates, gastrointestinal side effects were more common with oral agents [14,44,46]. Symptomatic hypocalcemia was rarely noted, but patients who did not take supplemental calcium and vitamin D may have been at higher risk [14].

A possible link between bisphosphonate therapy and atrial fibrillation has been proposed. However, this association has not been proven. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Atrial fibrillation'.)

Specific agents

Zoledronic acid (zoledronate) — Zoledronic acid is highly effective in Paget disease and generally well tolerated; effective suppression of bone turnover, indicated by biochemical response measures, occurs in over 95 percent of patients, and is typically sustained for at least several years. Zoledronic acid is given in a dose of 5 mg intravenously over at least 15 minutes in 100 mL of saline or 5 percent dextrose in water or as a premixed solution. It should be infused in an intravenous line separately from other medications. Zoledronic acid is not recommended by the FDA for use in patients with a creatinine clearance <30 to 35 mL/minute. It can be administered intravenously in hospital or outpatient settings, and is the most potent bisphosphonate approved for Paget disease in the United States. Zoledronic acid is well tolerated, although some patients who are naïve to nitrogen-containing bisphosphonates experience "flu-like" symptoms for several days following initial drug administration. (See 'Side effects of bisphosphonates' above.)

Sustained biochemical remissions are achieved in most patients. In a cohort of patients treated at a mean age of 76, more patients died (>50 percent) due to an unrelated cause than experienced a biochemical relapse (14 percent) after 10 years of follow-up [16], suggesting that many patients will only require a single treatment. In patients who relapse, retreatment appears to be effective based on an open label study of 6 patients who had biochemical relapse a mean of 6.5 years after initial treatment [47]. (See 'Retreatment: Indications and approach' below.)

Several trials have compared the efficacy and safety of zoledronic acid with other agents:

●Zoledronic acid versus risedronate (see 'Risedronate' below) – Zoledronic acid (a single 5 mg infusion) was compared with oral risedronate (30 mg/day for 60 days) in a combination of two identical, randomized, six-month trials involving a total of 357 patients with Paget disease [14]. Both groups had improvement in bone pain and quality of life; clinically significant improvement in body pain was more frequent at six months in patients who received zoledronic acid (50 versus 37 percent). Zoledronic acid resulted in more frequent attainment of the primary endpoint, normalization of the serum alkaline phosphatase, or a 75 percent reduction in total alkaline phosphatase excess (the difference from the midpoint of the reference range [96 versus 74 percent]); and was associated with a shorter median time to therapeutic response (64 versus 89 days) and a much lower frequency of loss of response in post-trial follow-up for a median of 190 days (1 versus 27 percent).

Suppression of bone turnover markers was sustained in patients treated with zoledronic acid during an 18-month extension of the original 6-month trial [44]. Among the 296 responders from the original trial, those who received zoledronic acid maintained serum alkaline phosphatase levels in the middle of the reference range throughout the extension, while the patients treated with risedronate, in the aggregate, showed a slow, linear increase in serum alkaline phosphatase beginning six months after the cessation of therapy.

Aside from acute and transient mild to moderate flu-like symptoms in the first three days following treatment initiation, which were more common among patients receiving zoledronic acid (54 versus 25 percent), both drugs were comparably well tolerated over the course of the study [14,44]. (See 'Side effects of bisphosphonates' above.)

●Zoledronic acid versus pamidronate (see 'Pamidronate' below) – Another trial included 120 patients with active Paget disease who were randomly assigned to zoledronic acid (a single 4 mg infusion) or pamidronate (30 mg intravenously for two consecutive days every three months) [17]. The primary efficacy endpoint was a biochemical response at six months, which was defined as normalization of serum alkaline phosphatase or at least a 75 percent reduction in alkaline phosphatase excess. At six months, zoledronic acid was associated with higher rates of both the biochemical response (97 versus 45 percent) and normalization of serum alkaline phosphatase (93 versus 35 percent). The 33 nonresponders to pamidronate were crossed over to zoledronic acid or neridronate (100 mg intravenously for two consecutive days). Both drugs produced a similar response rate (94 and 93 percent).

Pamidronate — Pamidronate is a nitrogen-containing bisphosphonate used for Paget disease that is administered intravenously. It is generally well tolerated other than the "flu-like" symptoms that may be seen with initial drug administration in patients naïve to nitrogen-containing bisphosphonates (see 'Side effects of bisphosphonates' above); however, it is now used less often with the availability for Paget disease of other more effective and more easily administered agents, such as zoledronic acid. (See 'Zoledronic acid (zoledronate)' above.)

Pamidronate can be administered in hospital or outpatient settings in a dose of 30 mg intravenously in 500 mL of one-half isotonic saline, isotonic saline, or 5 percent dextrose in water over four hours, daily for three consecutive days, according to the dosing regimen approved by the FDA. Other regimens that have been used may be more convenient than the FDA regimen, including intravenous administration of pamidronate 60 mg every three months until biochemical remission [46]; or as a 60 to 90 mg infusion in 250 to 300 mL over two to four hours on two or more nonconsecutive days [9].

The use of pamidronate should be avoided in patients with an estimated creatinine clearance <30 to 35 mL/minute. The manufacturer recommends that clinical judgment be used in patients with renal insufficiency to determine if benefits outweigh potential risks.

Pamidronate also may be associated with the development of drug resistance, reducing the efficacy of retreatment (see 'Retreatment: Indications and approach' below). The relative efficacy and safety of pamidronate have been compared with both zoledronic acid and alendronate in randomized trials. (See 'Zoledronic acid (zoledronate)' above and 'Alendronate' below.)

Risedronate — Risedronate is a nitrogen-containing bisphosphonate used for Paget disease that is taken orally and is usually well tolerated. It is given in a dose of 30 mg once daily for two months. The goal of therapy is normalization of the serum alkaline phosphatase, which results in a more sustained remission than in patients whose values do not decrease to this level. Thus, patients whose alkaline phosphatase levels do not reach normal levels within two months of therapy should be retreated. (See 'Retreatment: Indications and approach' below.)

Risedronate is not recommended by the FDA for use in patients with a creatinine clearance <30 mL/minute.

The efficacy and safety of risedronate and zoledronic acid have been compared directly (see 'Zoledronic acid (zoledronate)' above). The majority (75 to 80 percent) of patients responded to treatment with risedronate based on normalization of biochemical measures, such as the serum alkaline phosphatase. However, zoledronic acid was effective in 96 percent with a longer duration of action, with increases in serum alkaline phosphatase seen within six months of risedronate discontinuation. However, risedronate is substantially more effective than etidronate [32].

Alendronate — Alendronate is an orally administered nitrogen-containing bisphosphonate used in Paget disease at a dose of 40 mg/day [2,31,46]. The tablet form is given once daily for six months. It is usually well-tolerated and, like the other nitrogen bisphosphonates, is effective in normalizing the serum alkaline phosphatase, as shown by normalization of bone turnover markers in two trials in 63 and 86 percent of alendronate-treated patients [31,46]. Retreatment is indicated in patients who do not attain biochemical remission. (See 'Retreatment: Indications and approach' below.)

Alendronate is more effective than pamidronate in patients previously treated with a bisphosphonate and is more effective than etidronate [31,46]. However, alendronate and pamidronate are comparably effective in patients who are naïve to bisphosphonates. Retreatment is discussed below. (See 'Retreatment: Indications and approach' below.)

Alendronate is not recommended by the FDA for use in patients with a creatinine clearance <35 mL/minute.

The efficacy and safety of alendronate and pamidronate were evaluated in a two-year, randomized, open-label trial of 72 patients that compared pamidronate (60 mg intravenously once every three months) with alendronate (40 mg daily by mouth in three-month blocks); therapy was continued until biochemical remission was attained [46]. Randomization was stratified according to baseline serum alkaline phosphatase and according to whether or not the patient had received previous bisphosphonate therapy. Pamidronate nonresponders were crossed over to alendronate after one year. At one year, biochemical remission (defined as both the serum alkaline phosphatase and urine deoxypyridinoline/creatinine ratio being in the normal range) occurred more often in the alendronate group (86 versus 56 percent). However, the results were affected by whether or not the patients had previously been treated with pamidronate. In the 44 previously untreated patients, the rate of biochemical remission was similar in the two groups (91 versus 86 percent). By contrast, in the 28 patients previously treated with pamidronate, the rate of biochemical remission was higher with alendronate (79 versus 14 percent). These data suggested a high rate of acquired resistance to pamidronate and were consistent with prior observations of pamidronate resistance [48]. Both medications were well tolerated; the adverse effects of bisphosphonates are described separately. (See 'Side effects of bisphosphonates' above.)

Neridronate — Neridronate is a nitrogen-containing bisphosphonate that is efficacious in Paget disease but is only available in a small number of countries; it is not available in the United States [17,49,50]. It can be administered by either the intravenous or the intramuscular route [51]. Neridronate has exhibited comparable efficacy to zoledronic acid in a small randomized trial in patients who had had an inadequate response to pamidronate [17].

Simple bisphosphonates — The simple bisphosphonates, etidronate, tiludronate, and clodronate, are no longer employed as first-line therapy but may have a role in selected patients.

●Etidronate – Etidronate was the first bisphosphonate approved for the treatment of Paget disease in the United States; however, it is no longer being marketed in the United States, although it remains available in some other countries. The usual dose is 5 mg/kg (200 to 400 mg daily) taken orally for six months. Etidronate should be taken with water midway through a four-hour fast (ie, two hours after food and at least two hours before the next food). (See 'Instructions for oral bisphosphonate administration' above.)

Etidronate is a relatively weak bisphosphonate that normalizes the serum alkaline phosphatase in less than 20 percent of patients. In addition, etidronate worsens bone pain in many patients and can impair bone mineralization, resulting in osteomalacia and fractures. As a result, etidronate is contraindicated in patients with lytic lesions in weightbearing bones [52,53] and is used very little and only in patients with an intolerance to nitrogen-containing bisphosphonates.

When etidronate is given, care should be taken to administer only the prescribed doses, not exceeding six months per course. Patients can be retreated after at least a six-month interval off the drug, but this is not often done because of limited efficacy, the risk of impaired bone mineralization, and the possible development of drug resistance. (See 'Retreatment: Indications and approach' below.)

Specific guidelines are not available for use of etidronate in patients with decreased renal function. When the drug was available in the United States, the FDA recommended that etidronate be used cautiously, and dose reduction was advised in this setting.

●Tiludronate – The usual dose of tiludronate is 400 mg/day orally for three months. Tiludronate should be taken with water midway through a four-hour fast (ie, two hours after food and at least two hours before the next food) (see 'Instructions for oral bisphosphonate administration' above). Tiludronate is no longer available in the United States. Tiludronate was not recommended by the FDA for use in patients with a creatinine clearance <30 mL/minute.

Tiludronate is slightly more effective than etidronate and does not result in the impaired mineralization associated with etidronate. Evidence of efficacy is provided by both randomized trials and observational studies [54-58].

In a randomized, placebo-controlled trial of 149 patients, tiludronate at doses of 400 and 800 mg/day for three months significantly reduced serum and urine bone biomarkers and pain, although a significant frequency of complete resolution of pain was only seen at a dose of 800 mg/day [55]. Similar benefits were noted in another randomized trial of 112 patients, which noted that a 400 mg dose once daily appeared to offer the best balance of efficacy and tolerance [56]. In addition to reductions in bone biomarkers and pain, improvements are also seen on bone scintigraphy [57,58].

●Clodronate – Clodronate can be given both by mouth and intravenously for the treatment of Paget disease but is not approved for use in the United States, and evidence of efficacy comes from observational studies, not randomized trials [59-61]. In addition, acquired resistance has been described [62].

Calcitonin — Calcitonin is an antiresorptive agent that is less potent than the newer bisphosphonates and does not result in a sustained clinical remission. However, it is relatively safe and can be used in patients intolerant of bisphosphonates and in patients with a creatinine clearance below that considered safe for bisphosphonates use. (See 'Preoperative antipagetic therapy' above.)

Salmon calcitonin, given subcutaneously, is the only preparation approved in the United States for the treatment of patients with Paget disease who cannot tolerate bisphosphonates [63-65]. The usual initial dose is 50 to 100 units daily, as tolerated; the usual maintenance regimen is 50 units daily or 50 to 100 units every one to three days. Therapy is often continued indefinitely since cessation typically results in recurrent disease activity.

The efficacy of parenteral salmon calcitonin was evaluated in a report of 85 patients [65]. Markers of bone turnover, such as serum alkaline phosphatase or urine hydroxyproline excretions, were reduced by approximately 50 percent within two months. However, these parameters returned to pretreatment levels in 22 patients (26 percent) despite continuous therapy. Almost all of these patients developed high titer anti-calcitonin antibodies.

In addition to the reduction in markers of bone turnover, other clinical benefits that have been described with parenteral calcitonin therapy include relief of bone pain, improvement or stabilization of hearing loss and other neurologic deficits, and decreased bone vascularity [24,64].

Nausea, vomiting, or flushing are not uncommon but can be avoided or minimized in some patients by giving the drug at bedtime and slowly increasing the dose. The side effects of calcitonin are discussed in detail elsewhere. (See "Calcitonin in the prevention and treatment of osteoporosis".)

The intranasal formulation of calcitonin may be as effective as parenteral therapy in Paget disease, and the ease of administration makes it preferable to some patients [66-68]. However, the intranasal formulation is not approved in the United States for this indication.

Other agents and drugs not recommended — Denosumab is a fully human monoclonal antibody against receptor activator of nuclear factor kappa-B ligand (RANKL), a cytokine essential for osteoclast formation, and is a very potent antiresorptive that is used for the treatment of osteoporosis (see "Denosumab for osteoporosis"). The mechanism of action of denosumab suggests that it might be useful as an alternative treatment for Paget disease of bone in selected patients, such as those with renal insufficiency precluding bisphosphonate treatment; however, there are insufficient data and clinical experience to support its use in routine clinical practice in such patients, and its role in the treatment of Paget disease remains to be defined. Published evidence regarding denosumab in Paget disease has been limited to case reports [69], and severe hypocalcemia has been reported in patients with chronic kidney disease treated with denosumab [70,71].

More toxic agents, such as mithramycin or gallium nitrate, which have both been used historically for this condition, are not recommended.

MONITORING

Medically treated patients — In most patients who have elevated serum alkaline phosphatase levels at baseline, serial measurement of this marker can be useful for monitoring the response to therapy. In patients with normal bone turnover markers at baseline, such as many with very limited disease, the use of bone scintigraphy may be indicated. We take the following approach:

●Baseline elevation of serum alkaline phosphatase – Serum alkaline phosphatase should be measured at three to six months to assess the initial response to therapy; once the value plateaus, it can be measured once or twice a year as a marker of bone activity [57]. The more potent bisphosphonates suppress bone resorption within days to weeks, as shown by decreased urine n-telopeptides or serum C-telopeptide (beta-CTX), followed by suppression of bone formation in weeks to months, with a reduction in the serum fraction of alkaline phosphatase that comes from bone [10]. However, we do not routinely measure other markers of bone turnover, such as urinary pyridinium crosslink excretion, since there is no evidence that they are better measures of clinical response than serum alkaline phosphatase [72].

Normalization of serum alkaline phosphatase is associated with a sustained period of biochemical remission and histologic evidence of normal bone turnover; on the other hand, increases in serum alkaline phosphatase are consistent with increases in disease activity [1,2,14,31,73-75]. Thus, as a marker of bone turnover, serum alkaline phosphatase can be used as an appropriate outcome measure when monitoring the biochemical response to bisphosphonate therapy.

●Possible liver disease and elevated baseline alkaline phosphatase – A measurement of the gamma-glutamyl transpeptidase (GGT) level can help discriminate between liver and bone as the source of an elevated serum alkaline phosphatase; it is usually unnecessary to order more expensive bone markers to determine this, as the GGT is elevated in liver disease but is not in disorders of bone. For a patient with both Paget disease and liver disease, we use measurement of the serum procollagen type 1 propeptide (PINP) level as a marker to assess bone formation rate.

●Normal baseline alkaline phosphatase – In the subset of patients with monostotic disease and normal bone turnover markers at baseline, bone scintigraphy, which can detect active disease and determine its extent, may be helpful in monitoring the response to therapy after 6 to 12 months of treatment. However, while normalization of scintigraphy after therapy has been reported [76], the experience of many is that scintigraphic activity frequently persists, indicating that serial imaging studies, including bone scintigraphy, are not generally useful for routine monitoring of the treatment response.

Evaluation of nonresponders — Computed tomography (CT) or magnetic resonance imaging (MRI) should be used to further characterize bone lesions if bone pain does not respond as expected to medical therapy, raising concerns for a complication such as a secondary neoplasm. Advanced imaging is indicated in the evaluation of suspected complications of Paget disease of bone including fracture, spinal stenosis or nerve compression, basilar impression, or neoplasms that may arise within pagetic lesions, such as osteosarcoma, fibrosarcoma, chondrosarcoma, and giant cell tumor.

Patients not treated with antipagetic agents — In patients with a normal serum alkaline phosphatase in whom a pagetic lesion has been detected incidentally, but in whom treatment is not determined to be appropriate, we monitor the patient yearly for bone pain, functional impairment, and elevation of serum alkaline phosphatase. (See 'Indications for treatment' above.)

RETREATMENT: INDICATIONS AND APPROACH — Indications for retreatment with bisphosphonates generally depend upon evidence of increased or recurrent abnormal bone turnover, as determined by recurrent pain, periodic serial measurements of serum alkaline phosphatase, or radiographic progression of disease. Some clinicians retreat patients only for symptoms related to Paget disease, while others retreat whenever the serum alkaline phosphatase becomes elevated above normal or rises to a significant degree above the previous nadir [5,9]. New symptoms, which may respond to retreatment if due to Paget disease, should be distinguished from secondary or unrelated changes that are not caused by current disease activity.

Data from clinical trials do not address the issue of retreatment adequately, but available guidelines have been summarized [9]. In the Paget disease: randomized trial of intensive versus symptomatic management (PRISM) trial, which included an older adult population (mean age 74) with extant deformity and abnormal bone architecture, the findings suggested that an abnormal serum alkaline phosphatase was not by itself an indication for retreatment, as outcomes did not differ between the groups [77,78]. In an extension of this trial (PRISM-EZ), intensive treatment with zoledronate to maintain normal serum alkaline phosphatase over an additional three years conferred no clinical benefit compared with symptomatic treatment only [79]. However, the duration of follow-up in these studies was short and many experts believe that retreatment is beneficial.

We take the following approach, which is in accordance with the available evidence and expert opinion [9,10]:

●In patients with active Paget disease by biochemical markers or active lesions on bone scan, periodic retreatment is indicated in hopes of preventing progression of deformity of bone with aging. This can be done at intervals of 5 to 10 years in many, using zoledronic acid (zoledronate) (see 'Zoledronic acid (zoledronate)' above). More aggressive treatment on the basis of these disease markers alone is not indicated.

●We also retreat patients who are suffering due to pain from pagetic bone, experiencing progressive deformity or arthritis, or who are anticipating surgery. (See 'Preoperative antipagetic therapy' above.)

In those patients in whom retreatment is indicated, the dose and duration of therapy are the same as for initial treatment. We take the following approach in patients treated with the following agents initially:

●Zoledronic acid – We treat with zoledronic acid (a single 5 mg dose), consistent with the 2014 Endocrine Society guidelines [10]. Retreatment with zoledronic acid is indicated in those patients whose serum alkaline phosphatase does not normalize by 12 months or subsequently rises above normal. (See 'Nitrogen-containing bisphosphonates' above and 'Pretreatment testing and related interventions' above and 'Zoledronic acid (zoledronate)' above.)

●Pamidronate – Retreatment with pamidronate can be done when serum alkaline phosphatase values rise above normal or increase more than 25 percent above nadir levels if normal values were not reached with the prior course of treatment. However, an infusion of zoledronic acid may prove more efficacious in this setting and is preferred in patients who require retreatment. Pamidronate resistance has been reported in patients previously treated with pamidronate, but the mechanism is unclear. If resistance develops, a different nitrogen-containing bisphosphonate, such as alendronate, risedronate, zoledronic acid, or neridronate, is usually effective. (See 'Pamidronate' above and 'Antipagetic agents' above.)

●Risedronate – Retreatment with risedronate is warranted in patients whose serum alkaline phosphatase levels do not reach normal within two months of initial therapy or subsequently rise above normal. We suggest switching to zoledronic acid if two courses of risedronate do not result in normalization of the serum alkaline phosphatase. (See 'Risedronate' above and 'Zoledronic acid (zoledronate)' above.)

●Alendronate – Retreatment with alendronate can be given after a six-month post-treatment evaluation period if normal serum alkaline phosphatase values were attained and then rise above normal, or if normal values were not attained during the initial course. An alternative to retreatment is switching to zoledronic acid, which should be delayed until six months after the cessation of alendronate. (See 'Alendronate' above and 'Zoledronic acid (zoledronate)' above.)

●Etidronate – Retreatment with etidronate should be limited in duration and considered with caution because of its marginal benefit relative to risk. Tiludronate or clodronate may be preferred alternatives for patients who require retreatment with a simple bisphosphonate. Calcitonin is also an option. These drugs have less potential for adverse effects on bone and, unlike etidronate, may be used in patients with lytic lesions in weightbearing bones who are not candidates for a nitrogen-containing bisphosphonate. (See 'Simple bisphosphonates' above and 'Calcitonin' above.)

ROLE OF SURGERY — Orthopedic surgical options that may be considered in selected patients with Paget disease include corrective osteotomy for long bone deformity, fracture fixation, joint arthroplasty, spinal decompression, and resection of bone tumors [80]. Factors that may pose additional challenges for the surgeon include the abnormal quality and hypervascularity of bone, bowing deformity of the limbs, and/or distortion of the acetabulum. It has been reported that Paget disease increases risk for postoperative heterotopic bone formation [80,81]. However, a recent large retrospective case control study did not find an increased rate of heterotopic ossification after total hip arthroplasty in patients with Paget disease compared with controls [20]. By contrast, prior reports of high risk for implant loosening and revision arthroplasty were borne out by this study. (See "Clinical manifestations and diagnosis of Paget disease of bone".)

Patients with active disease in operative sites are at increased risk for blood loss, which may be decreased by preoperative antiresorptive treatment. We suggest that treatment with bisphosphonates be initiated three months prior to elective surgery. (See 'Preoperative antipagetic therapy' above.)

SPECIAL POPULATIONS

Advanced age — Life expectancy, which may be difficult to predict, should only be a limited consideration in decisions to treat. Age alone is generally not a factor, as the newer bisphosphonates are usually well tolerated. Further, in our view, when one weighs the consequence of this disease to an aging skeleton, and the increasing life expectancy of the population, treatment is also indicated in the younger population in hopes of preventing progression to deformity, easing pain, and restoring bone remodeling to more normal levels.

Kidney disease — In patients with chronic kidney disease and an estimated glomerular filtration rate less than 35 mL/minute/1.73 m², nitrogen-containing bisphosphonates at the usual doses and administration times are contraindicated according to the licensing information. In this case, calcitonin is the preferred agent. However, in patients in whom a bisphosphonate is warranted clinically, a reduced-dose bisphosphonate may still be considered in some patients in consultation with a nephrologist. (See "Osteoporosis in patients with chronic kidney disease: Diagnosis and evaluation" and "Osteoporosis in patients with chronic kidney disease: Management".)

Oral bisphosphonates for osteoporosis treatment have demonstrated efficacy in this population [82,83], but the safety and efficacy of Paget disease dosing is not known. If intravenous administration is preferred, clinical experience in patients with estimated glomerular filtration rate <35 mL/minute/1.73 m² suggests that risk of renal damage with zoledronate may be lower using a slower infusion rate (60 minutes) [84-86]. Lower doses of zoledronate (2 to 2.5 mg) are also often used in this setting, although data are lacking to support improved safety.

PROGNOSIS — With the nitrogen-containing bisphosphonates, particularly zoledronic acid (zoledronate), antipagetic interventions will usually be brief, be well tolerated, and offer pain relief and sustained clinical remission. At nine years after a single dose of zoledronic acid, fewer than 20 percent of patients experienced relapse as assessed by biochemical disease activity [16]. By contrast, progression of disease can occur in untreated patients, with extension of osteolytic lesions and progressive bony deformity [87]. Pain arising from pagetic bone usually responds rapidly to therapy, followed in weeks to months by gradual normalization of the serum alkaline phosphatase. However, most studies have not been designed to confirm the expectation that bisphosphonate therapy will prevent long-term complications [5,9,88].

In randomized trials of the bisphosphonates in patients with Paget disease, outcomes of effective treatment have included reduction in pain, reduction in serum alkaline phosphatase, normalization of other bone turnover markers, the replacement of abnormal bone with normal lamellar bone, radiographic healing, and some improvement in measures of quality of life [1,2,5,9,14,31,32,44,46,73-75]. (See 'Antipagetic agents' above.)

Some manifestations of Paget disease may not be reversible. As examples, antipagetic therapy will rarely restore hearing, although it may stabilize hearing loss; it will not reverse deformity of bone or, as noted, all radiographic evidence of Paget disease on plain radiography; and it will not diminish the pain and dysfunction caused by secondary osteoarthritic changes. There are also case reports of improvement in paraparesis or symptoms of spinal stenosis with bisphosphonate therapy [89,90]. (See 'Role of surgery' above.)

GUIDELINES OF MAJOR PROFESSIONAL SOCIETIES — Comprehensive clinical practice guidelines for the diagnosis and treatment of Paget disease of bone have been developed by the Endocrine Society and were co-sponsored by the European Society of Endocrinology [10]. Our approach to the evaluation and management of Paget disease is generally consistent with these guidelines.

The consensus treatment guidelines of the Endocrine Society clinical practice group, published in 2014, supported the use of bisphosphonate treatment as effective for preventing or slowing the progress of hearing loss and of osteoarthritis in joints adjacent to pagetic bone and noted that such therapy may reverse paraplegia associated with spinal Paget disease [10]. They also suggested treatment with a bisphosphonate before surgery on pagetic bone.

Largely similar guidelines have also been developed through a collaboration of the United Kingdom Paget's Association, the European Calcified Tissues Society, and the International Osteoporosis Foundation [12].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Paget disease of bone".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Paget disease of bone (The Basics)")

●Beyond the Basics topic (see "Patient education: Paget disease of bone (osteitis deformans) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●The goals of pharmacologic treatment for Paget disease are to ease pain and to normalize the rate of bone remodeling, which is pathologically increased in untreated patients. Success of treatment is generally assessed by periodic monitoring of the alkaline phosphatase. The secondary consequences of Paget disease need to be treated with other modalities. These include hearing aids, analgesics for arthritis pain, and, as adjuncts to antipagetic medications, physical therapy and walking aids. In addition, attention must be paid to psychosocial issues. (See 'Introduction' above and 'Prognosis' above.)

●Symptoms and findings that may respond to pharmacologic treatment in patients with active disease include bone pain, symptoms of nerve compression, and radiographic findings of osteolytic bone lesions. Although unproven, treatment with nitrogen-containing bisphosphonates is generally expected to prevent the long-term complications of disease, such as pathologic fractures, skeletal deformity, secondary osteoarthritis, and neurologic disorders including deafness. (See 'Antipagetic agents' above and 'Prognosis' above.)

●When treatment for Paget disease is indicated, we recommend zoledronic acid as first-line therapy (Grade 1A). (See 'Nitrogen-containing bisphosphonates' above.)

●In symptomatic patients:

•We recommend treatment if the alkaline phosphatase level is elevated (Grade 1A).

•We also suggest treatment in symptomatic patients if the alkaline phosphatase level is normal but there is evidence of active disease on bone scintigraphy (Grade 2B).

●In asymptomatic patients with active disease (as determined by bone scintigraphy or an increased alkaline phosphatase):

•We suggest treatment if disease is present at sites where complications could occur (eg, skull, spine, weightbearing bones, abutting joint lines) (Grade 2B).

•We suggest treatment if bone surgery is planned on sites with active disease or if the alkaline phosphatase is greater than twice the upper limit of normal (Grade 2C). (See 'Prognosis' above.)

●Potential side effects of bisphosphonates include an acute phase response lasting several days, which occurs most commonly but not exclusively with the intravenous medications on initial administration and which can be treated with acetaminophen or nonsteroidal antiinflammatory drugs (NSAIDs). (See 'Nitrogen-containing bisphosphonates' above and 'Choice of initial antipagetic agent' above and 'Side effects of bisphosphonates' above.)

●In the rare patient intolerant of both parenteral and oral bisphosphonates, we suggest treatment with calcitonin (Grade 2C). (See 'Choice of initial antipagetic agent' above.)

●In all patients who will be treated with bisphosphonates, normal serum levels of calcium and 25-hydroxyvitamin D (calcidiol) should be documented, and supplemental vitamin D and calcium supplements provided as needed. (See 'Nitrogen-containing bisphosphonates' above.)

●Because of a small but undetermined level of risk for osteonecrosis of the jaw (ONJ) in association with bisphosphonate use in Paget disease, planned invasive dental work, such as extractions or implants, should be performed at least three to six months prior to institution of bisphosphonate therapy whenever possible. (See 'Pretreatment testing and related interventions' above.)

●Indications for retreatment with bisphosphonates include evidence of increased or recurrent abnormal bone turnover as determined by periodic serial measurements of serum alkaline phosphatase, radiographic progression of disease, or recurrent pain. New symptoms, which may respond to retreatment if due to Paget disease, should be distinguished from secondary or unrelated changes that are not caused by current disease activity. (See 'Monitoring' above and 'Retreatment: Indications and approach' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Margaret Seton, MD, who contributed to an earlier version of this topic review.