Bisphosphonates for Paget's disease of bone in adults

Review question

We wanted to find out if using bisphosphonate treatment was better or worse than dummy treatment (placebo) to relieve bone pain in people with Paget's disease of bone and determine if treatment could prevent complications. We also wanted to discover which bisphosphonates were better.

What is Paget's disease of bone and what are bisphosphonates?

Paget's disease of bone is a chronic problem which usually affects one or a few bones. Paget's disease causes bone renewal and repair to become abnormal; bones become weak enlarged and misshapen, leading to pain, fractures and arthritis in joints close to affected bones.

Bisphosphonates are medications that slow down the bone remodelling process.

Search date

March 2017.

Study characteristics

We included 20 studies that involved 3168 people. Of these, 10 studies (801 people) compared bisphosphonates with placebo. Studies included elderly people; slightly more participants were men; and nearly all had raised blood serum markers of bone turnover. Fourteen studies recruited participants from hospitals, outpatient and general practitioner clinics. Studies were performed in USA, Canada, UK, Europe; Australia, New Zealand and Argentina.

What are the effects of bisphosphonates in people with Paget's disease of bone?

Bisphosphonates probably help to relieve bone pain. We are uncertain which bisphosphonate is better. Results were similar across studies.

We are uncertain if bisphosphonates can prevent bone fractures.

Effects on quality of life, need for orthopaedic surgery and hearing loss prevention were not reported in studies that compared bisphosphonates with placebo.

What are the side effects of bisphosphonates in people with Paget's disease of bone?

Most studies did not report details about drug-related side effects and complications. Bisphosphonates may make little or no difference in side effects except for temporary fever or tiredness with intravenous treatments and mild gastrointestinal side effects with oral medications. Severe side effects causing treatment discontinuation were rare.

What happens to people with Paget's disease of bone treated with bisphosphonates?


We found that of 100 adults with Paget's disease of bone, 31 would experience complete pain relief if they took bisphosphonates for six months compared with 9 people not taking bisphosphonates.

Side effects

We found that of 100 adults with Paget's disease of bone, 64 would experience side effects if they took bisphosphonates for six months compared with 48 not taking bisphosphonates.

The number of people who stopped treatment due to side effects was the same for the bisphosphonate and placebo groups (4 out of 100).

Quality of evidence

Pain relief data provided moderate-quality evidence, but data on fractures was assessed as providing very low-quality evidence. Data on side effects provided low-quality evidence; treatment discontinuation data provided moderate-quality evidence. Evidence was downgraded mainly due to limited data and concerns about study design.

Study funding sources

Eleven studies were funded by drug manufacturers. Four studies were funded by government agencies or charities. Data on funding sources were not provided or unclear in five studies.

Authors' conclusions: 

We found moderate-quality evidence that bisphosphonates improved pain in people with Paget's disease of bone when compared with placebo. We are uncertain about the results of head-to-head studies investigating bisphosphonates. We found insufficient evidence of benefit in terms of pain or quality of life from intensive treatment. Information about adverse effects was limited, but serious side effects were rare, and rate of withdrawals due to side effects was low.

Read the full abstract...

Bisphosphonates are considered to be the treatment of choice for people with Paget's disease of bone. However, the effects of bisphosphonates on patient-centred outcomes have not been extensively studied. There are insufficient data to determine whether reducing and maintaining biochemical markers of bone turnover to within the normal range improves quality of life and reduces the risk of complications.


To assess the benefits and harms of bisphosphonates for adult patients with Paget's disease of bone.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ISI Web of Knowledge and trials registers up to March 2017. We searched regulatory agency published information for rare adverse events.

Selection criteria: 

Randomised controlled trials (RCTs) of bisphosphonates as treatment for Paget's disease in adults.

Data collection and analysis: 

Two review authors independently screened search results, extracted data and assessed studies for risk of bias. We used standard methodological procedures expected by The Cochrane Collaboration.

Main results: 

We included 20 trials (25 reports, 3168 participants). Of these, 10 trials (801 participants) compared bisphosphonates (etidronate, tiludronate, ibandronate, pamidronate, olpadronate, alendronate, risedronate, zoledronate) versus placebo, seven compared two bisphosphonates (992 participants), one trial compared a bisphosphonates with a bisphosphonate plus calcitonin (44 participants), and two studies, the largest trial (1331 participants) and its interventional extension study (502 participants), compared symptomatic treatment and intensive treatment where the goal was to normalise alkaline phosphatase.

Most studies were assessed at low or unclear risk of bias. Six of 10 studies comparing bisphosphonates versus placebo were assessed at high risk of bias, mainly around incomplete outcome data and selective outcome reporting.

Participant populations were reasonably homogeneous in terms of age (mean age 66 to 74 years) and sex (51% to 74% male). Most studies included participants who had elevated alkaline phosphatase levels whether or not bone pain was present. Mean follow-up was six months.

Bisphosphonates versus placebo

Bisphosphonates tripled the proportion (31% versus 9%) of participants whose bone pain disappeared (RR 3.42, 95% confidence interval (CI) 1.31 to 8.90; 2 studies, 205 participants; NNT 5, 95% CI 1 to 31; moderate-quality evidence). This result is clinically important. Data were consistent when pain change was measured as any reduction (RR 1.97, 95% CI 1.29 to 3.01; 7 studies, 481 participants).

There was uncertainty about differences in incident fractures: 1.4% fractures occurred in the bisphosphonates group and none in the placebo group (RR 0.89, 95% CI 0.18 to 4.31; 4 studies, 356 participants; very low-quality evidence).

None of the studies reported data on orthopaedic surgery, quality of life or hearing thresholds.

Results regarding adverse effects and treatment discontinuation were uncertain. There was a 64% risk of mild gastrointestinal adverse events in intervention group participants and 48% in the control group (RR 1.32, 95% CI 0.91 to 1.92; 6 studies, 376 participants; low-quality evidence). The likelihood of study participants discontinuing due to adverse effects was slightly higher in intervention group participants (4.4%) than the control group (4.1%) (RR 1.01, 95% CI 0.41 to 2.52; 6 studies, 517 participants; low-quality evidence). Zoledronate was associated with an increased risk of transient fever or fatigue (RR 2.57, 95% CI 1.21 to 5.44; 1 study, 176 participants; moderate-quality evidence).

Bisphosphonates versus active comparator

More participants reported pain relief with zoledronate than pamidronate (RR 1.30, 95% CI 1.10 to 1.53; 1 study, 89 participants; NNT 5, 95% CI 3 to 11) or risedronate (RR 1.36, 95% CI 1.06 to 1.74; 1 study, 347 participants; NNT 7, 95% CI 4 to 24; very low quality evidence). This result is clinically important.

There was insufficient evidence to confirm or exclude differences in adverse effects of bisphosphonates (RR 1.05, 95% CI 0.95 to 1.76; 2 studies, 437 participants; low-quality evidence) and treatment discontinuation (2 studies, 437 participants) (RR 2.04, 95% CI 0.43 to 9.59; 2 studies, 437 participants; very low-quality evidence).

Intensive versus symptomatic treatment

There was no consistent evidence of difference to response in bone pain, bodily pain or quality of life in participants who received intensive versus symptomatic treatment.

Inconclusive results were observed regarding fractures and orthopaedic procedures for intensive versus symptomatic treatment (intensive treatment for fracture: RR 1.84, 95% CI 0.76 to 4.44; absolute risk 8.1% versus 5.2%; orthopaedic procedures: RR 1.58, 95% CI 0.80 to 3.11; absolute risk 5.6% versus 3.0%; 1 study, 502 participants; low-quality evidence).

There was insufficient evidence to confirm or exclude an important difference in adverse effects between intensive and symptomatic treatment (RR 1.05, 95% CI 0.79 to 1.41; low-quality evidence).

There was insufficient evidence to confirm or exclude an important difference of risk of rare adverse events (including osteonecrosis of the jaw) from the regulatory agencies databases.

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