Randomised controlled trial location and funding

Four RCTs were multicentre RCTs undertaken in the USA^55,61,64,67 and six RCTs were international multicentre RCTs.^{76,83,84,91,94,98} One multicentre RCT was undertaken in Italy⁵³ and one in Canada.⁷³ Single-centre RCTs were undertaken in Italy,⁶⁰ Turkey⁶⁵ and Jordan.⁹³ The countries and number of participating centres was unclear for one RCT⁵⁷ and the number of participating centres was unclear for one RCT undertaken in China.⁷¹ RCT sponsor details were not reported for four RCTs.^53,60,65,93 The total numbers of participants randomised ranged from 63⁹³ to 4432.⁶⁴ Where reported, RCTs typically excluded patients with underlying conditions or receiving medications that affect bone metabolism, and patients either with upper GI tract disorders or receiving medication for the condition.

Populations recruited and treatment dosage

Fourteen RCTs recruited postmenopausal women and evaluated 10 mg per day of alendronic acid.^{53,55,57,60,61,64,65,67,68,71,76,84,91,93} Two of these RCTs also included an evaluation of other doses of alendronic acid not currently licensed.^76,91,98 Two of the RCTs in postmenopausal women reported that participants were switched from a 5 mg daily dose of oral alendronic acid to 10 mg per day after 24 months, spending the remaining 12 months of the RCT on 10 mg per day.^55,64 One RCT evaluated a daily dose of 10 mg of oral alendronic acid in men with osteoporosis,⁸³ one RCT evaluated a daily 10 mg dose of oral alendronic acid in men and women (51% male) with airways disease⁹⁴ and one RCT evaluated 70 mg per week of oral alendronic acid in men with ADT bone loss in non-metastatic prostate cancer.⁷³ One RCT, in men and women (37.4% male) with underlying diseases requiring long-term oral glucocorticoid therapy, evaluated 5 mg or 10 mg per day of oral alendronic acid (two active treatment groups) and reported fracture outcomes for both groups combined (data not used in the analysis for this assessment report).⁹¹

Adjuvant therapy

Adjuvant treatment in the form of calcium alone or in combination with vitamin D was reported for all RCTs. The doses varied across the RCTs (see Table 3).

Bone mineral density of recruited participants

Inclusion criteria varied across the RCTs in terms of baseline BMD and T-scores (skeletal site and cut-off). Seven RCTs^{53,57,60,71,76,84,93} reported inclusion criteria that would identify women with osteoporosis according to the current WHO definition.¹ Two RCTs recruited women aged 55–81 years with a femoral neck BMD of ≤ 2 SDs below that of a normal young adult,^55,64 an additional inclusion criterion for one of these RCTs being the presence of at least one vertebral fracture.⁵⁵ One RCT recruited women aged 42–75 years with lumbar spine BMD approximately 2 SDs below the young normal value,⁶¹ and another RCT recruited women with BMD ≥ 2 SDs below young adult mean at either lumbar spine or femoral neck.⁶⁵ One RCT recruited ambulatory women aged 65 years in long-term care with a lumbar spine or total hip BMD T-score of ≤ –2.0 SDs.⁶⁷ One RCT recruited community-dwelling women aged 65 years.⁶⁷ Femoral neck BMD above mean peak was an exclusion criterion for one RCT.⁶⁸ One RCT recruited men and women with underlying diseases requiring long-term oral glucocorticoid therapy, irrespective of baseline BMD.⁹¹ One RCT recruited men with femoral neck and lumbar T-scores of < 2 SDs and < 1 SD below the normal for young men, or femoral neck BMD of ≤ 1 SD below the normal for young men plus vertebral deformity or fracture.⁸³ The RCT in men and women with airways disease included only participants with a T-score of < –2.5 SDs or z-score of < –1.0 at hip or lumbar spine.⁹⁴ The RCT in men with ADT bone loss reported that 38% of all participants had osteopenia and 7% had osteoporosis.⁷³

Age, race, years post menopause, body mass index and smoking status

The mean age of participants was in the sixth decade (between 51 and 60 years) in two RCTs.^53,91 One RCT did not report mean age, but recruited women aged 44–73 years.⁶⁰ Another RCT not reporting mean age included participants 61–69 years.⁹⁴ In one RCT, the mean age of all included participants was 73.6 years⁷³ and in all others the mean age of included participants was between 61 and 70 years. Seven RCTs in women reported on the number of years since menopause.^{53,57,61,65,70,84,93} The mean number of years since menopause ranged from 10 to 15 years with the exception of one RCT recruiting women after hysterectomy, in which the mean number of years since menopause was 22.⁵⁷ BMI was available for 12 RCTs.^{53,55,61,64,65,68,71,76,83,84,91,93} Across these RCTs, all mean BMI values were > 18.5 kg/m². In one RCT,⁹³ the mean BMI was > 30 kg/m². Race of included participants was reported by eight RCTs.^{55,57,61,64,67,71,84,91} One of these studies recruited 100% East Asian women.⁷¹ Across the other RCTs the proportion of Caucasian participants was ≥ 90%.^{55,57,61,64,67,84,91} Smoking status was reported by five trials,^{53,55,64,73,94} with four reporting that ≥ 10% of included participants were current smokers.^53,55,64,94 Mean smoking duration of 26.2 years and mean quantity of 0.98 packs per day were reported by one RCT.⁷³

Fractures at baseline

The presence of fractures or fracture history at baseline was reported by nine RCTs.^{53,55,64,67,68,71,73,76,83} One reported that 5% of all participants had vertebral fractures,⁵³ one that 37% had vertebral fractures⁷¹ and one that 41.9% had vertebral fractures.⁸³ One RCT reported that 64% of participants had at least one vertebral fracture and that 14% had three or more vertebral fractures.⁵⁵ One study reported that 21% of participants had vertebral fractures and 5% had non-vertebral fractures at baseline.⁷⁶ Fifty-five per cent of participants in one RCT had a history of fracture.⁶⁷ One RCT reported that, of the 47% who reported prior fracture, 1% had a history of hip or vertebral fracture.⁷³ One RCT reported that 36% had experienced fractures since age 50 years⁶⁸ and another RCT reported that 35% had experienced fractures since age 45 years.⁶⁴

Assessment of treatment compliance

Compliance with treatment in the form of a pill count was assessed by three RCTs.^53,55,64

Follow-up and participants completing randomised controlled trials

Final follow-up was 12 months in six RCTs,^{65,71,73,84,93,94} 24 months in five RCTs,^{53,57,61,67,83} 30 months in one RCT,⁶⁰ 36 months in three RCTs^55,68,76 and 48 months in one RCT.⁶⁴ One RCT reported an initial follow-up of 12 months,⁹¹ with an extension to 24 months.⁹⁸

The number of participants completing was not reported for two RCTs^60,67 (Table 5). Overall completion rates of ≥ 90% were reported by seven RCTs^{53,55,64,68,71,73} (see Table 5). The highest rate of participant withdrawal was reported by Shilbayeh et al. 2004,⁹³ with 40% of participants withdrawing overall (see Table 5).

TABLE 5

Outcome data reported by included RCTs

Post-treatment fracture assessment

Fractures were not assessed as an outcome in four RCTs.^53,61,71,93 Across the RCTs assessing fractures, classification of the fracture and the method of assessment was diverse (see Table 3). Five RCTs recorded fractures as AEs,^{57,67,68,73,84} four of which did not report details of the assessment method.^57,67,68,73 Vertebral fractures were assessed by seven RCTs.^{55,60,64,65,76,83,91} All seven RCTs reported that vertebral fractures were assessed radiographically. One of the RCTs also assessed clinical fractures (non-spine clinical fractures, hip fractures, wrist fractures and clinical vertebral fractures, and other clinical fractures) reported by participants and confirmed by radiography⁵⁵ and one reported that clinical fractures (clinical vertebral, hip or wrist) were assessed by participant self-reports and confirmed by radiograph.⁶⁴ One RCT reported that non-vertebral fractures were assessed from patient reporting and confirmed by radiography.⁸³

Post-treatment femoral neck bone mineral density assessment

Femoral neck BMD assessment was reported by all but one of the RCTs.⁶⁰ Where assessed, BMD assessment was by DXA. With the exception of one RCT that did not report on DXA manufacturer⁶⁵ all studies assessed BMD using DXA Hologic or Luner machines.

Randomised controlled trial location and funding

All five RCTs were multicentre RCTs: one was undertaken in the UK,⁷⁴ one in the USA,⁸⁰ one in Europe and the USA,⁴⁵ one in the USA, Canada, Mexico, Europe, Australia and South Africa,⁴⁹ and one in the USA, Canada, Europe, Australia, South Africa, Mexico and Brazil.⁴⁷ The RCT sponsor details were reported for all five RCTs. The total numbers of participants randomised ranged from 50⁷⁴ to 2946.⁴⁵

Populations recruited and treatment dosage

All of the RCTs recruited postmenopausal women; one recruited postmenopausal women with a histologically confirmed diagnosis of oestrogen receptor-positive breast cancer.⁷⁴

Adjuvant therapy

Daily adjuvant treatment in the form of 500 mg of calcium and 400 IU (international unit) of vitamin D was prescribed across all five RCTs.

Bone mineral density of recruited participants

Four of the RCTs^45,47,49,80 reported inclusion criteria that would identify women with osteoporosis according to the current WHO definition.¹ The RCT in women with breast cancer recruited women classified as osteopenic (T-scores of > –2.5 SDs and < –1.0 SD at either the lumbar spine or total hip).⁷⁴

Age, race, years post menopause and body mass index

Four RCTs recruited participants with a mean age between 61 and 70 years.^45,47,49,74 Mean age in the other RCT was 53.6 years.⁸⁰ The mean number of years since menopause, in one RCT recruiting early postmenopausal women, was 4.2 years.⁸⁰ Mean years since menopause was 20.8 in one trial,⁴⁵ 18.7 in one RCT⁴⁹ and 18.6 in another RCT.⁴⁷ One RCT did not report on years since menopause.⁷⁴ Mean BMI values were > 18.5 kg/m² in all RCTs. One RCT reported a median BMI of < 30 kg/m² in both placebo and ibandronic acid participants.⁷⁴ Race of included participants was not reported by any RCT.

Fractures at baseline

The presence of fractures at baseline was reported by three RCTs:^45,47,49 one in which 93% of participants had at least one vertebral fracture at baseline and 43% had two,⁴⁵ one in which 42.1% had fractures at baseline⁴⁹ and one in which 4.9% had fractures at baseline.⁴⁷

Assessment of treatment compliance

Compliance with treatment in the form of a pill count was assessed by one RCT.⁷⁴

Follow-up and participants completing RCTs

Final follow-up was 12 months in two RCTs,^47,80 24 months in two RCTs^49,74 and 36 months in one RCT.⁴⁵ None of the RCTs reported a completion rate of ≥ 90% (see Table 5).

The highest rate of participant withdrawal was reported by the BONE trial,⁴⁵ with 34% participants withdrawing overall (see Table 5).

Post-treatment fracture assessment

Fractures were recorded as AEs, but the assessment method was not reported in two RCTs.^47,74 Two RCTs also assessed fractures as AEs confirmed by radiography.^49,80 The number of vertebral fractures confirmed by radiography was the primary outcome in one RCT.⁴⁵

Post-treatment femoral neck bone mineral density assessment

Femoral neck BMD assessment was reported by all of the RCTs. BMD assessment was by DXA using Hologic or Lunar machines.

Bone mineral density and antifracture efficacy of ibandronic acid pivotal randomised controlled trials

One of the three placebo-controlled RCTs in ibandronic acid was the pivotal 3-year BONE study, in which the antifracture efficacy of daily oral ibandronic acid 2.5 mg and intermittent oral ibandronic acid 20 mg every other day for 12 doses every 3 months (unlicensed dose) was assessed over 36 months.⁴⁵ The BONE RCT reported comparable vertebral antifracture efficacy of daily and intermittent administration, suggesting that ibandronic acid could be administered at intervals longer than daily or weekly. A further non-inferiority RCT, the MOBILE trial,⁴⁷ evaluated a monthly dose of 100 mg of ibandronic acid administered as two single 50-mg doses on consecutive days; a single monthly 100-mg dose; a single monthly 150-mg dose; and a daily 2.5-mg dose (four ibandronic acid study groups). The 150-mg dose (licensed dose) produced the greatest gains in BMD compared with a daily 2.5-mg dose of ibandronic acid at 2 years (lumbar spine BMD: 6.6% vs. 5.0%, respectively; p < 0.001).⁴⁷ The DIVA study then compared the efficacy of two regimens of intermittent i.v. injections of ibandronic acid [2 mg every 2 months (unlicensed dose) and 3 mg quarterly (licensed dose)] with a daily 2.5-mg dose of oral ibandronic acid. The regimen of daily 2.5 mg oral ibandronic acid has proven antifracture efficacy.⁴⁹ At 2 years, the 2- and 3-monthly i.v. regimens produced improvements in spinal BMD (6.4% and 6.3%, respectively) that were superior to oral ibandronic acid (4.8%; p < 0.001). The MOBILE and the DIVA studies confirmed a sustained efficacy of monthly oral and quarterly i.v. regimens, respectively, over 5 years.^108,109

Randomised controlled trial location and funding

Three RCTs were multicentre RCTs undertaken in the USA.^63,70,78 One multicentre RCT was undertaken in Australia,⁷² one was undertaken in China⁷⁵ and one was undertaken in the UK.⁸⁶ Three RCTs were international multicentre RCTs.^58,66,85 One single-centre RCT was undertaken in Germany.⁸⁹ The number of participating centres was unclear for one RCT undertaken in Canada⁶² and one RCT undertaken in the USA.⁹⁵ With the exception of one RCT (two publications),^89,101 sponsor details were reported for all included studies. The total numbers of participants randomised ranged from 40⁹⁵ to 9331.⁷⁸

Populations recruited and treatment dosage

Six RCTs recruited postmenopausal women and evaluated 5 mg per day of risedronic acid.^{66,70,72,75,78,85} Two of these RCTs also included an evaluation of other doses of risedronic acid not currently licensed.^66,78 Both of these RCTs reported fracture outcomes for participants in the 2.5-mg and 5-mg groups combined (data not used in the analysis for this assessment report). One RCT evaluated oral risedronic acid at a dosage of 35 mg per week in men with osteoporosis⁵⁸ and one RCT evaluated oral risedronic acid at 5 mg per day in men with osteoporosis.⁸⁹ Two RCTs evaluated 35 mg of oral risedronic acid per week in men with non-metastatic prostate cancer receiving ADT.^62,95 Two RCTs in men and women^63,86 (32.5% male⁶³ and 38% male,⁸⁶ respectively) receiving glucocorticoids evaluated oral risedronic acid at a dosage of 5 mg per day. Where reported, RCTs typically excluded patients with underlying conditions or receiving medications that affect bone metabolism, and patients with upper GI tract disorders or receiving medication for these conditions.

Adjuvant therapy

Adjuvant treatment in the form of calcium alone or in combination with vitamin D was reported for all RCTs. The dosages varied across the RCTs (see Table 3).

Bone mineral density of recruited participants

Inclusion criteria varied across the RCTs in terms of baseline BMD and T-scores (skeletal site and cut off). Six RCTs^{58,66,72,75,78,89} reported inclusion criteria that would identify men and women with osteoporosis according to the current WHO definition.¹ One RCT recruited women aged ≤ 85 years with at least one vertebral fracture at baseline⁷⁰ and another RCT recruited women aged ≤ 85 years with at least two radiographically confirmed vertebral fractures.⁸⁵ Baseline BMD was not an inclusion criterion for either of the two RCTs in men and women receiving glucocorticoids^63,86 or the two RCTs in men with prostate cancer receiving ADT.^62,95

Age, race, years post menopause and body mass index

The mean age of participants was between 51 and 60 years in three RCTs.^72,86,89 One RCT categorised women by age into two groups: those aged 70–79 years and those aged ≥ 80 years.⁷⁸ In two RCTs, the mean age of all included participants was 71 years.^85,95 In all other RCTs the mean age of included participants was between 61 and 70 years. Five RCTs in women reported on the number of years since menopause.^{66,70,72,75,85} The mean number of years since menopause was 15 years in one RCT,⁷⁵ 17 years in another RCT⁶⁶ and ranged from 24 to 25 years in two RCTs.^70,85 The mean number of years since menopause was < 5 years in one RCT.⁷² In the RCT categorising women by age into two groups (those aged 70–79 years and those ≥ 80 years), the mean number of years since menopause was 28 years and 37 years, respectively.⁷⁸ The mean years since menopause in one RCT recruiting early postmenopausal women was 3.7 years.⁷² BMI was available for five RCTs.^{58,66,70,75,89} Across these RCTs, all mean BMI values were > 18.5 kg/m². Race of included participants was reported by only one of the RCTs in which proportion of Caucasian participants was 95%.⁵⁸

Fractures at baseline

The presence of fractures or fracture history at baseline was reported by eight RCTs,^{63,66,70,72,78,85,86,89} with 20% of women in one RCT having vertebral fractures at baseline.⁷² In two RCTs approximately 31% of all participants had baseline vertebral fractures,^63,66 and in one RCT 35% had vertebral fractures.⁸⁶ One RCT reported that 42% had vertebral fractures at baseline⁷⁸ and one that 52% had vertebral fractures.⁸⁹ In one trial, 80% of all participants had vertebral fractures at baseline.⁷⁰ One RCT reported the median number of vertebral fractures at baseline, which was three in the placebo group and four in the risedronic acid group.⁸⁵

Assessment of treatment compliance

Compliance with treatment in the form of a pill count was assessed by two RCTs.^58,95

Follow-up and participants completing randomised controlled trials

Final follow-up was 12 months in three RCTs^63,75,86 and 24 months in four RCTs.^58,62,66,72 One RCT reported a final follow-up of 6 months⁹⁵ and another reported a follow-up of 36 months.⁷⁸ One RCT reported an initial follow-up of 12 months,⁸⁹ with an extension to 24 months.¹⁰¹ Two RCTs reported an initial follow-up of 36 months,^70,85 with an extension to 60 months.^99,100

The number of participants completing the trial was not reported by three RCTs^62,75,95 (see Table 5). Only one RCT reported a completion rate of ≥ 90%⁸⁹ (see Table 5). The highest rate of participant withdrawal was reported by McClung et al.,⁷⁸ with 40% participants withdrawing overall (see Table 5).

Post-treatment fracture assessment

Fractures were not assessed as an outcome in four RCTs.^62,75,86,95 Across the RCTs assessing fractures, classification of the fracture and the method of assessment were diverse (see Table 3). One recorded clinical fractures (non-vertebral and vertebral fractures) confirmed by radiography as AEs.⁹⁹ This was an extension to a RCT in which vertebral fractures were the primary outcome and were assessed radiographically.⁷⁰ One RCT recorded non-vertebral fractures (not described) and vertebral fractures as AEs, with vertebral fractures assessed radiographically.⁶⁶ Vertebral fractures were assessed by six other RCTs.^{58,63,72,85,86,89} All six RCTs reported that vertebral fractures where assessed radiographically. One of these RCTs also assessed clinical vertebral and non-vertebral fractures reported as AEs; vertebral fractures reported as AEs included symptomatic and asymptomatic radiographically confirmed fractures.⁵⁸ One RCT assessed radiographically confirmed hip fractures and non-vertebral osteoporotic fractures; non-vertebral osteoporotic fractures were defined as all radiographically confirmed fractures of the wrist, leg, humerus, hip, pelvis or clavicle.⁷⁸

Post-treatment femoral neck bone mass density assessment

Femoral neck BMD assessment was reported by all of the RCTs. BMD assessment was by DXA using Hologic or Lunar machines.

Randomised controlled trial location and funding

All four RCTs were international multicentre RCTs. Sponsor details were reported for all trials and it was the same sponsor across the RCTs. The total number of participants randomised ranged from 400⁷⁹ to 7765.⁵⁶

Populations recruited, bone mass density of participants and treatment dosage

Two RCTs recruited postmenopausal women with osteoporosis^56,79 and one recruited men with osteoporosis.⁵⁹ Across these RCTs, baseline BMD and T-scores would identify men and women with osteoporosis according to the current WHO definition.¹ One RCT recruited ambulatory men (24.5%) and women who had undergone repair of a hip fracture.⁷⁷ Baseline BMD was not an inclusion criterion for this RCT. All RCTs evaluated 5 mg per year of i.v. zoledronic acid.

Adjuvant therapy

Adjuvant treatment in the form of calcium in combination with vitamin D was reported for all RCTs. The dosages varied across the RCTs (see Table 3).

Age, race, years post menopause and body mass index

The mean age of participants in the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly (HORIZON) RCTs was between 61 and 70 years.^56,77 The mean age of all participants was 66 years in one trial⁵⁹ and 60 years in another trial.⁷⁹ The mean number of years since menopause was reported for only one RCT and was 11.4.⁷⁹ BMI was available for three RCTs,^56,77,79 and across these RCTs, all mean BMI values were > 18.5 kg/m². The race of included participants was reported by all four RCTs, and > 90% of the participants were Caucasian.

Fractures at baseline

The presence of fractures at baseline was reported by three of the RCTs,^56,59,77 one of which reported all patients who were enrolled in the RCT had undergone repair of a hip fracture.⁷⁷ One RCT reported that 28% of participants had one vertebral fracture at baseline and 35% had more than two.⁵⁶ One RCT reported that 22.1% of participants had one vertebral fracture at baseline and 10.8% had more than two.⁵⁹

Assessment of treatment compliance

An assessment method of compliance was not reported by any RCT evaluating zoledronic acid with placebo.

Follow-up and participants completing randomised controlled trials

Final follow-up was 24 months in two RCTs^59,79 and 36 months in the other two RCTs.^56,77 The proportion of participants completing each of the RCTs was 83.9%,⁵⁶ 71.1%,⁷⁷ 89.2%⁵⁹ and 89.3%.⁷⁹ (see Table 5).

Post-treatment fracture assessment

Fractures were assessed as an outcome in three RCTs.^56,59,77 One RCT assessed vertebral fractures from radiographs.⁵⁶ In this RCT, clinical fracture reports were also obtained from patients at each visit and non-vertebral fracture reports required central confirmation. Fractures of the toe, facial bone, finger and those caused by excessive trauma were excluded. In another RCT, non-vertebral fractures (not a vertebral, facial, digital or skull fracture) were confirmed when a radiograph, a radiographic report or a medical record documented a new fracture.⁷⁷ In this RCT, a new clinical vertebral fracture was defined as new or worsening back pain with a reduction in vertebral body height. The third RCT assessed vertebral fractures from radiographs.⁵⁹ In this RCT, clinical fractures (vertebral and non-vertebral) were reported by participants at each visit and were verified centrally by means of a radiographic report or surgical notes.

Post-treatment femoral neck bone mineral density assessment

Femoral neck BMD assessment by DXA was reported by all of the RCTs. Only one RCT reported the DXA model (Hologic or Lunar machines).⁷⁹

Alendronic acid versus ibandronic acid

One RCT compared alendronic acid with monthly oral ibandronic acid (at a dose of 150 mg) in postmenopausal women;⁸¹ there was no placebo arm in this trial. This was a multicentre non-inferiority RCT conducted in North America, Latin America, Europe and South Africa, with sponsor details reported. In total, 1760 women were randomised. Mean age was 65.6 years, mean years since menopause was 18.3 years, mean BMI was 25.9 kg/m² and race of participants was reported as 82% Caucasian. BMD inclusion criteria were based on lumbar spine [lumbar vertebrae 2–4 (L2–L4)] BMD T-score of < –2.5 and ≥ –5.0 SDs. Previous fractures (not described) were experienced by 38.2% of the alendronic acid group and 39% of the ibandronic acid group. Patients with either upper GI tract disorders or diseases affecting bone metabolism were excluded. The alendronic acid dosage was 70 mg per week and the ibandronic acid dosage was 150 mg per month. Both groups also received 500 mg of calcium and 400 IU of vitamin D per day. For compliance assessment, returned study tablets were counted. Fractures were recorded as AEs and follow-up was 12 months. Overall, 90% of participants completed the 12-month follow-up (see Table 5).

Alendronic acid vs. risedronic acid

Five RCTs across seven publications compared alendronic acid with risedronic acid in postmenopausal women.^{54,82,87,90,92,104,105} There was no placebo arm in any of these RCTs.

Three RCTs evaluated 10 mg per day of alendronic acid and 5 mg per day of risedronic acid.^54,82,92 Two of these RCTs were undertaken in Turkey^54,92 and the other in Italy.⁸² The number of participating centres and RCT sponsor details were not reported for any of the RCTs. One trial randomised 28 participants (14 in each group)⁵⁴ and one randomised 50 participants (25 in each group).⁹² The third trial randomised 2000 participants to treatment groups also including clodronic acid and raloxifene. In total, 1000 participants were randomised to risedronic acid and 100 to alendronic acid⁸² (10 : 1 randomisation ratio). All three RCTs reported osteoporosis to be an inclusion criterion, but only one reported a BMD T-score inclusion criterion.⁵⁴ Mean ages were 66 years,⁵⁴ 70.5 years⁸² and 58.8 years.⁹² One RCT reported on mean years since menopause, which was 15.6 years,⁵⁴ and one RCT⁹² reported on mean BMI, which was 27.3 kg/m². Race was not reported by any of the three RCTs. All three RCTs prescribed a daily adjuvant of calcium and vitamin D. Fractures at baseline were not reported by two of the RCTs;^54,82 however, in the other trial, approximately 10% of participants in both groups had vertebral fractures at baseline.⁹² Two of the RCTs reported fracture as an outcome^82,92 and one reported fracture as an AE;⁹² however, details of the assessment method were not reported by either RCT. Final follow-up was at 12 months in two RCTs^54,92 and 24 months in the third.⁸² Two of the RCTs reported 12-month femoral neck BMD assessment by DXA, using either a Hologic⁵⁴ or Lunar machine.⁹² None of the three RCTs reported on numbers withdrawing, but all reported that 100% of participants randomised were included in the analysis (see Table 5). Where reported, conditions or medications affecting bone metabolism were exclusion criteria, with one RCT also considering upper GI conditions as an exclusion criterion.⁹²

Two further RCTs undertaken by the same study group compared 70 mg per week of alendronic acid with 35 mg per week of risedronic acid in postmenopausal women.^87,90 One was undertaken as a 12-month multicentre RCT in the USA,⁹⁰ with a 12-month extension to 24 months,¹⁰⁴ and the other was a 12-month multicentre RCT across 75 centres in 27 countries in Europe, the Americas and the Asia-Pacific region,⁸⁷ with a 12-month extension to 24 months.¹⁰⁵ Sponsor details were the same across these RCTs. The number randomised was 1053 in the US study⁹⁰ and 936 in the multinational study.⁸⁷ Both RCTs recruited postmenopausal women with osteoporosis according to the current WHO definition.¹ Mean age, years since menopause and BMI was 64.5 years, 18.5 years and 25.3 kg/m², respectively, in the US study⁹⁰ and 64.1 years, 16.9 years and 25.3 kg/m², respectively, in the international study.⁸⁷ The last RCT reported that participants with conditions or medications affecting bone metabolism were excluded. Both RCTs reported that > 90% of participants were Caucasian and both RCTs prescribed a daily adjuvant of 1000 mg of calcium and 400 IU of vitamin D.

The study undertaken in the USA reported that 12% of participants had a history of hip, spine or wrist fracture after the age of 45 years.⁹⁰ The multinational study reported that 33.7% of participants had a history of fractures (not described), and that 41% had a family history of osteoporosis.⁸⁷ Across both RCTs, clinical fractures that occurred during the trial, regardless of association with trauma or skeletal site, were reported by investigators as clinical AEs. Femoral neck BMD was assessed in both RCTs using DXA (Hologic). Both RCTs reported a completion rate of > 90% at the 12-month follow-up^87,90 (see Table 5).

Zoledronic acid versus alendronic acid

One RCT evaluated 5 mg once per year of i.v. zoledronic acid with 70 mg per week of alendronic acid.⁶⁹ There was no placebo arm in this trial and the sponsor was reported. In total, 604 postmenopausal women aged 55–90 years with a BMD T-score of ≤ –2.0 SDs at total hip or lumbar spine were randomised. Both groups were prescribed a daily adjuvant of 1200 mg of calcium and 800 IU of vitamin D. The mean age of participants was 67.8 years and mean BMI was 26.2 kg/m². Of all the participants, 33% had fractures (not described) at baseline and the proportion of participants who were current or previous smokers was 22.9%. Participants with conditions affecting bone metabolism were excluded. Fractures and femoral neck BMD were not outcomes for this RCT. Quality of life was assessed using a visual analogue scale (VAS) and compliance was assessed by investigator or study personnel at each visit.¹⁰⁶ The triallists reported that > 90% of participants completed the 12-month follow-up (see Table 5).

Zoledronic acid versus risedronic acid

One RCT reported as the HORIZON study [i.e. not the HORIZON – Pivotal Fracture Trial (HORIZON-PFT) or HORZON – Recurrent Fracture Trial (HORIZON-RFT), which compared zoledronic acid vs. placebo] recruited men and women aged 18–85 years receiving at least 7.5 mg of oral prednisolone daily (or equivalent) and who were expected to receive glucocorticoids for at least another 12 months.⁸⁸ There was no placebo arm in this trial. The RCT, which was an international multicentre RCT, categorised 416 participants receiving steroids for > 3 months as a ‘treatment’ subgroup and 417 participants receiving steroids for ≤ 3 months as a ‘prevention’ subgroup; both subgroups were randomised to receive 5 mg of i.v. zoledronic acid once annually or 5 mg per day of risedronic acid. The RCT sponsor was reported. All treatment groups were prescribed a daily adjuvant of 1200 mg of calcium and 800 IU of vitamin D. Across treatment groups, 31% were male, the mean age of all participants was 54.4 years and race was not reported. Participants with conditions or previous treatments affecting bone metabolism were excluded. Follow-up was at 12 months. Vertebral fractures were assessed by radiography and femoral neck BMD by DXA (Hologic or Lunar). EuroQol (EQ-5D) HRQoL was assessed.¹¹⁰ The triallists reported that > 90% of participants completed the 12-month follow-up (see Table 5).

Alendronic acid.

Five RCTs reported any AE associated with 10 mg of alendronic acid and placebo in postmenopausal women treated for periods ranging from 12 to 36 months.^{55,57,67,84,91} Across these RCTs there were 3535 AEs; among participants on alendronic acid the incidence of AEs was 73.3% (1749/2384), compared with 76.5% (1786/2336) among those treated with placebo (pooled RR 0.98, 95% CI 0.90 to 1.06; p = 0.63). The difference between treatments was not statistically significant (Figure 11).

FIGURE 11

Any AE in the alendronic acid group compared with placebo. M–H, Mantel–Haenszel.

Three RCTs reported the proportion of AEs that were considered serious in postmenopausal women.^57,84,91 One reported events at 48 weeks,⁹¹ one at 12 months⁸⁴ and one at 24 months.⁵⁷ One RCT in osteoporotic men reported events at 24 months.⁸³ Across the three RCTs in women, 205 serious AEs were observed: 103 (out of 1199 participants) in the alendronic acid groups (8.6%) and 102 (out of 1167 participants) in the placebo groups (8.7%) (pooled RR 0.96, 95% CI 0.74 to 1.25; p = 0.70). The difference between treatments was not statistically significant (Figure 12). In osteoporotic men, the number of AEs was not significantly different in different treatment groups (RR 0.80, 95% CI 0.48 to 1.32; p = 0.38).⁸³

FIGURE 12

Any serious AE in the alendronic acid group compared with placebo. M–H, Mantel–Haenszel.

Seven RCTs reported on withdrawals as a result of AEs.^{55,57,64,76,83,84,91} Across all RCTs the difference between treatments was not statistically significant. There were 807 withdrawals in total, and the incidence was 7.8% (376/4777) in the alendronic acid groups, compared with 8.8% (431/4882) in the placebo groups (pooled RR 0.86, 95% CI 0.73 to 1.07; p = 0.07). There was no statistically significant between-group difference across six RCTs in postmenopausal women^{55,57,64,84,91} ranging in duration from 48 weeks⁹¹ to 48 months.⁶⁴ There were 793 withdrawals in total and the incidence was 8.0% (372/4631) in the alendronic acid groups, compared with 8.8% (421/4787) in placebo groups (pooled RR 0.90, 95% CI 0.79 to 1.03; p = 0.13). However, in osteoporotic men, placebo treatment was associated with a significantly higher rate of withdrawals at 24 months (10/95, 10.5%) than alendronic acid (4/146, 2.7%) (RR 0.26, 95% CI 0.08 to 0.81; p = 0.02).⁸³ However, a statistically significant difference between treatments was not evident when RCTs were pooled by RCT duration (p = 0.68) (Figure 13).

FIGURE 13

Withdrawals as a result of an AE in the alendronic acid group compared with placebo. M–H, Mantel–Haenszel.

Ibandronic acid

Both Chesnut et al.⁴⁵ and McClung et al.⁸⁰ reported on the number of AEs of any type in an ibandronic acid group (unlicensed 2.5 mg daily oral dose⁴⁵ and licensed monthly 150 mg oral dose⁸⁰) and a placebo group. Both recruited postmenopausal women and follow-up duration was 36 months and 12 months, respectively. The proportion of participants who experienced any AE did not differ by treatment group. A total of 1870 participants experienced AEs, 939 (out of 1054 participants; 89.9%) in the ibandronic acid groups and 931 (out of 1058 participants; 88.0%) in the placebo groups (pooled RR 1.01, 95% CI 0.98 to 1.04; p = 0.45), and this did not vary by dosage of ibandronic acid (p = 0.99) (Figure 14).

FIGURE 14

Any AE in the ibandronic acid group compared with placebo. M–H, Mantel–Haenszel.

The same RCTs^45,80 also reported the number of AEs that were considered serious. The difference between treatments across these trials was not statistically significant. A total of 449 participants experienced serious AEs: 237 (out of 1054 participants; 22.5%) in the ibandronic acid groups and 212 (out of 1058 participants; 20.0%) in the placebo groups (pooled RR 1.11, 95% CI 0.95 to 1.31; p = 0.20). The difference between treatments by dosage was also not statistically significant (Figure 15).

FIGURE 15

Any serious AE in the ibandronic acid group compared with the placebo group. M–H, Mantel–Haenszel.

The same RCTs also reported the number of withdrawals as a result of AEs.^45,80 Overall, the proportion of withdrawals was similar among participants who were on ibandronic acid [17.8% (188/1054)] and those on placebo [17.6% (186/1058)] (374 AEs in total; pooled RR 1.24, 95% CI 0.56 to 2.75; p = 0.59). The difference between treatments across these RCTs was not statistically significant and results did not vary by ibandronic acid dosage (p = 0.17) (Figure 16).

FIGURE 16

Withdrawals as a result of an AE in the ibandronic acid group compared with the placebo group. M–H, Mantel–Haenszel.

Risedronic acid

Six RCTs compared AEs in a risedronic acid-treated group and a placebo group.^{58,66,70,72,78,85} Five of these were in postmenopausal women, with treatment duration ranging from 12 to 24 months,^{66,70,72,78,85} and one was in osteoporotic men with a follow-up at 24 months.⁵⁸ Pooled data across all six RCTs (8674 AEs) showed that the proportion of participants experiencing an AE was the same in the risedronic acid group [90.6% (4370/4821)] and the placebo group [90.5% (4304/4754)] (pooled RR 0.95, 95% CI 0.84 to 1.08; p = 0.44). The difference between treatments was not statistically significant and the results did not vary by age, sex, drug dosage (p = 0.67) or duration of follow-up (p = 0.64) (Figure 17).

FIGURE 17

Any AE in the risedronic acid group compared with the placebo group. BMD-NA, Bone Mineral Density – North America trial; M–H, Mantel–Haenszel.

Pooled data from the same RCTs revealed that the proportions of participants experiencing serious AEs was also similar in both treatment groups; of the total of 2789 serious AEs reported, 1398 occurred in the risedronic acid group (of 4821 participants; 29.0%) and 1391 (of 4754 participants; 29.3%) in the placebo group (pooled RR 1.01, 95% CI 0.93 to 1.11; p = 0.76). The difference between treatments was not statistically significant. There were no statistically significant differences between treatments evident by age, sex or dosage (p = 0.27) or treatment duration (p = 0.18) (Figure 18).

FIGURE 18

Any serious AE in the risedronic acid group compared with the placebo group. BMD-NA, Bone Mineral Density – North America trial; M–H, Mantel–Haenszel.

Pooled data from these six RCTs^{58,66,70,72,78,85} also showed that there were no statistically significant differences between treatments in withdrawals as a result of AEs [1596 withdrawals: 784 (of 4820 participants; 16.3%) in the risedronic acid group and 812 (of 4754 participants; 17.1%) in the placebo group (pooled RR 0.94, 95% CI 0.81 to 1.10; p = 0.45). However, the difference between treatments for the one RCT in osteoporotic men with follow-up at 24 months⁵⁸ was statistically significant (p = 0.05) (Figure 19).

FIGURE 19

Withdrawals as a result of an AE in the risedronic acid group compared with placebo. BMD-NA, Bone Mineral Density – North America trial; M–H, Mantel–Haenszel.

Zoledronic acid

Four RCTs reported AEs for zoledronic acid compared with placebo.^56,59,77,79 Two RCTs evaluated postmenopausal women who were followed up for 36⁵⁶ and 24 months,⁷⁹ one evaluated men and women with hip fracture who were followed up for 36 months⁷⁷ and one RCT evaluated osteoporotic men who were followed up for 36 months.⁵⁹

Pooled data across the two RCTs in postmenopausal women^56,79 showed that zoledronic acid was associated with a statistically significant increase in the incidence of AEs (total 7663 AEs): the incidence was 94.5% (3861/4043) in the zoledronic acid group and 93.8% (3802/4054) in the placebo group (pooled RR 1.02, 95% CI 1.01 to 1.03; p = 0.0007). In one RCT in osteoporotic men,⁵⁹ in which a total of 1000 AEs were reported, the incidence of AEs was 19% higher in the zoledronic acid group [90.8% (534 AEs in 588 participants)] than in the placebo group [76.3% (466 AEs in 611 participants) (RR 1.19, 95% CI 1.13 to 1.25; p < 0.00001]; the difference between treatments was statistically significant. Another RCT in men and women found no statistically significant difference between treatments.⁷⁷ A total of 1719 AEs effects were reported, 867 (in 1054 participants; 82.3%) in the zoledronic acid group and 852 (in 1057 participants; 80.6%) in the placebo group (RR 1.02, 95% CI 0.98 to 1.02; p = 0.33). Pooled data across all four RCTs indicated that the incidence of AEs did not differ significantly by treatment group. The total number of AEs was 10,382, and 92.5% of study participants (5262/5685) treated with zoledronic acid group experienced an AE, compared with 89.5% of placebo-treated participants (5120/5722) (pooled RR 1.06, 95% CI 1.00 to 1.13; p = 0.06) (Figure 20).

FIGURE 20

Any AE in the zoledronic acid group compared with placebo. M–H, Mantel–Haenszel.

The number of serious AEs was reported by four RCTs.^56,59,77,88 Across these RCTs the difference between treatments was not statistically significant. There were a total of 3427 serious AEs: 1679/5504 (30.5%) in the zoledronic acid groups and 1748/5520 (32.2%) in the placebo groups (pooled RR 0.96, 95% CI 0.91 to 1.02; p = 0.16). The incidence of serious AEs did not differ by sex (p = 0.86) or by RCT duration (p = 0.68) (Figure 21).

FIGURE 21

Any serious AE in the zoledronic acid group compared with placebo. M–H, Mantel–Haenszel.

Two RCTs reported data on withdrawals as a result of AEs.^56,77 Pooled data across these RCTs showed that the rates of withdrawal were similar in the two treatment groups. There were a total of 189 withdrawals: 101/4961 (2.0%) in the 5 mg per year of zoledronic acid group and 88/4909 (1.8%) in the placebo groups (pooled RR 1.15, 95% CI 0.86 to 1.52; p = 0.35). The difference between treatments was not statistically significant. The number of withdrawals was the same for both sexes (p = 0.12) (Figure 22).

FIGURE 22

Withdrawals as a result of an AE in the zoledronic acid group compared with placebo. M–H, Mantel–Haenszel.

Head to head: alendronic acid versus ibandronic acid

The MOTION trial⁸¹ compared 70 mg per week of alendronic acid with 150 mg per month of oral ibandronic acid in postmenopausal women for 12 months. The total number of AEs was 1291 and the proportion of participants experiencing an AE was higher in the alendronic acid group than in the ibandronic acid group [75.4% (659/859) versus 73.6% (632/874); RR 1.06, 95% CI 1.0 to 1.12; p = 0.04]; the difference between treatments was statistically significant (Figure 23).

FIGURE 23

Head-to-head comparison of alendronic acid with ibandronic acid and any AE. M–H, Mantel–Haenszel.

Head to head: alendronic acid versus risedronic acid

Two RCTs compared 70 mg per week of alendronic acid with 35 mg per week of risedronic acid in postmenopausal women treated for 12 months.^87,90 Pooled data across these RCTs indicate that the risk of AEs was similar in both groups. The total number of AEs was 1413 and the proportion of participants experiencing an AE was 71.2% (700/983) in the alendronic acid group and 71.7% (713/995) in the risedronic acid group (pooled RR 1.0, 95% CI 0.94 to 1.05; p = 0.93); the difference between treatments was not statistically significant (Figure 24).

FIGURE 24

Head-to-head comparison of alendronic acid with risedronic acid and any AE. M–H, Mantel–Haenszel.

Head to head: alendronic acid versus zoledronic acid

The Rapid Onset and Sustained Efficacy (ROSE) trial⁶⁹ compared 70 mg per week of alendronic acid with 5 mg per year of zoledronic acid. The total number of AEs was 465 and the risk of AEs was similar in the two treatment groups [74.7% (145/194) in the alendronic acid group, compared with 78.4% (320/408) in the zoledronic acid group; RR 0.95, 95% CI 0.87 to 1.05; p = 0.33]; the difference between treatments was not statistically significant (Figure 25).

FIGURE 25

Head-to-head comparison of alendronic acid with zoledronic acid and any AE. M–H, Mantel–Haenszel.

Head to head: zoledronic acid versus risedronic acid

The HORIZON trial⁸⁸ compared 5 mg per year of zoledronic acid with 5 mg per day of risedronic acid in both men and women receiving steroids; the participants were divided into treatment and prevention subgroups for 12 months. The difference between treatments in any AE in the treatment subgroup was a RR of 1.14 (95% CI 1.06 to 1.26; p = 0.01) and the difference between treatments in the prevention subgroup was a RR of 1.19 (95% CI 1.03 to 1.26; p = 0.01), with more AEs in the zoledronic acid groups in both cases. The differences between treatments were statistically significant. No forest plot is presented for these data.

Head to head: alendronic acid versus ibandronic acid

The MOTION trial⁸¹ also reported the number of AEs experienced by participants receiving weekly alendronic acid (n = 859) or monthly oral ibandronic acid (150 mg/month) (n = 874). There were 94 serious AEs and the risk of experiencing a serious AE was similar in the two groups [4.5% (39/859) in the alendronic acid group and 6.4% (55/874) in the ibandronic acid group; RR 0.72, 95% CI 0.48 to 1.08; p = 0.11]. The difference between treatments was not statistically significant (Figure 26).

FIGURE 26

Head-to-head comparison of alendronic acid with ibandronic acid and any serious AE. M–H, Mantel–Haenszel.

Head to head: alendronic acid versus risedronic acid

Pooled data across two RCTs^87,90 indicate no statistically significant difference in the incidence of serious AEs between the two treatments [157 serious AEs; 7.0% (69/983) in the alendronic acid group and 8.8% (88/995) in the risedronic acid group; RR 0.76, 95% CI 0.35 to 1.66; p = 0.50] (Figure 27).

FIGURE 27

Head-to-head comparison of alendronic acid with risedronic acid and any serious AE. M–H, Mantel–Haenszel.

Head to head: alendronic acid versus zoledronic acid

In the ROSE trial,⁶⁹ the proportion of participants experiencing a serious AE was not significantly different between the group receiving 70 mg per week of alendronic acid and the group receiving 5 mg per year of zoledronic acid [64 serious AEs: 21/194 (10.8%) in the alendronic acid group and 43/403 (10.5%) in the zoledronic acid group; RR 1.03, 95% CI 0.63 to 1.68, p = 0.92] (Figure 28).

FIGURE 28

Head-to-head comparison of alendronic acid with zoledronic acid and any serious AE. M–H, Mantel–Haenszel.

Head to head: zoledronic acid versus risedronic acid

In the HORIZON trial,⁸⁸ in which men and women receiving steroids were divided into treatment and prevention subgroups for 12 months, the difference between treatments in serious AEs in the treatment subgroup was a RR of 0.93 (95% CI 0.66 to 1.31; p = 0.68) and the difference between treatments in the prevention subgroup was a RR of 1.13 (95% CI 0.68 to 1.88; p = 0.64). The differences between treatments were not statistically significant. No forest plot is presented for these data.

Head to head: alendronic acid versus risedronic acid

Two RCTs reported withdrawals as a result of AEs.^87,90 Pooled data across these RCTs indicate no statistically significant difference between treatments [114 withdrawals: 53/983 (5.4%) in the alendronic acid group and 61/995 (6.1%) in the risedronic acid group; pooled RR 0.88, 95% CI 0.62 to 1.26; p = 0.50] (Figure 29).

FIGURE 29

Head-to-head comparison of alendronic acid with risedronic acid and withdrawals as a result of AEs. M–H, Mantel–Haenszel.

Head to head: alendronic acid versus zoledronic acid

The difference between treatments in withdrawals as a result of AEs was statistically significant for one trial⁶⁹ comparing 70 mg per week of alendronic acid with 5 mg per year of zoledronic acid [21 withdrawals: 19/194 (9.8%) in the alendronic acid group and (2/408 (0.5%) in the zoledronic acid group; RR 19.98, 95% CI 4.70 to 84.92; p < 0.0001] (Figure 30).

FIGURE 30

Head-to-head comparison of alendronic acid with zoledronic acid and withdrawals as a result of AEs. M–H, Mantel–Haenszel.

Head to head: zoledronic acid versus risedronic acid

In the HORIZON trial,⁸⁸ in which men and women receiving steroids were divided into treatment and prevention subgroups for 12 months, the difference between treatments in the number of withdrawals as a result of AEs was a RR of 1.00 (95% CI 0.20 to 4.93; p = 1.00) in the treatment subgroup and a RR of 2.00 (95% CI 0.51 to 7.84; p = 0.32) in the prevention subgroup; the differences between treatments were not statistically significant. No forest plot is presented for these data.

Alendronic acid

Six RCTs reporting upper GI AEs evaluated 10 mg per day of alendronic acid in postmenopausal women^{55,57,64,67,84,91} and one investigated 10 mg per day of alendronic acid in men with osteoporosis.⁸³

Pooled data across all seven RCTs indicated no statistically significant difference between treatments in the incidence of upper GI AEs. There were a similar incidence of upper GI events reported in patients receiving alendronic acid (38.6%) and placebo (37.6%) when pooling data across trials (pooled RR 1.03, 95% CI 0.98 to 1.08; p = 0.30) (Figure 31). There was also no statistically significant difference between treatments according to sex (see Figure 31) or RCT duration (p = 0.83).

FIGURE 31

Any upper GI AEs in the alendronic acid group compared with placebo. M–H, Mantel–Haenszel; UGI, upper GI.

Ibandronic acid

Only one trial⁸⁰ using ibandronic acid reported upper GI events. The difference between treatments was not statistically significant [44 upper GI events: 24/77 (31.2%) in the ibandronic acid (monthly oral dose) group and 20/83 (24.1%) in the placebo group; RR 1.29 95% CI 0.78 to 2.15; p = 0.32] (Figure 32).

FIGURE 32

Any upper GI AEs in the ibandronic acid group compared with placebo. M–H, Mantel–Haenszel; UGI, upper GI.

Risedronic acid

Five RCTs evaluated 5 mg per day of risedronic acid in postmenopausal women^{66,70,72,78,85} and one evaluated 35 mg per week of risedronic acid in osteoporotic men.⁵⁸ Pooled data across the five RCTs in postmenopausal women showed that the overall risk of upper GI AEs was similar in the two treatment groups [2150 upper GI events: 1076/4630 (23.2%) in the risedronic acid group and 1074/4661 (23.0%) in the placebo group; pooled RR 1.04, 95% CI 0.97 to 1.13; p = 0.75]. The difference between treatments was not statistically significant. Pooled results across all the six RCTs showed that there was no statistically significant difference between treatments in upper GI events in the risedronic acid treatment group or placebo [2183 upper GI events; 1092/4821 (22.7%) in the risedronic acid group and 1091/4754 (22.9%) in the placebo group; RR 0.99, 95% CI 0.87 to 1.14; p = 0.93] and this did not vary with RCT duration (p = 0.45). However, in the RCT in osteoporotic men,⁵⁸ in which 33 upper GI events were reported, the risk was significantly higher (16/191, 8.4%) in the risedronic acid group than in the placebo group (19/93, 20.4%) (RR 0.46, 95% CI 0.24 to 0.87; p = 0.02) (Figure 33).

FIGURE 33

Any upper GI AEs in the risedronic acid group compared with placebo. M–H, Mantel–Haenszel; UGI, upper GI.

Alendronic acid versus risedronic acid

Pooled data across two RCTs^87,90 revealed no statistically significant difference in the number of upper GI events between the alendronic acid treatment group and the risedronic acid treatment group [411 upper GI events: 211/983 (21.5%) in the alendronic acid group and 00/995 (20.1%) in the risedronic acid group; pooled RR 1.07, 95% CI 0.90 to 1.27; p = 0.45] (Figure 34).

FIGURE 34

Any upper GI AEs in the alendronic acid group compared with the risedronic acid group. M–H, Mantel–Haenszel; UGI, upper GI.

Alendronic acid versus zoledronic acid

One RCT reporting upper GI events as an outcome⁶⁹ found a significantly higher incidence of upper GI events in the 70 mg per week alendronic acid treatment group than in the 5 mg per year zoledronic acid group [132 upper GI events: 57/194 (29.4%) in the alendronic acid group, compared with 75/408 (18.4%) in the zoledronic acid group; RR 1.60, 95% CI 1.19 to 2.16; p = 0.002] (Figure 35).

FIGURE 35

Any upper GI AEs in the alendronic acid group compared with the zoledronic acid group.

Head to head: zoledronic acid versus risedronic acid

The HORIZON trial⁸⁸ compared 5 mg per year of zoledronic acid with 5 mg per day of risedronic acid in both men and women receiving steroids and divided the participants into treatment and prevention subgroups for 12 months. The p-values for the differences between treatments in upper GI AEs reported between the treatment subgroup were as follows: upper abdominal pain, p = 0.158; abdominal pain, p = 0.16; dyspepsia, p = 0.70; nausea, p = 0.19; vomiting, p = 0.04; gastritis, p = 0.68; and gastro-oesophageal reflux, p = 0.37. The p-values for the differences between treatments reported between the prevention subgroup were as follows: upper abdominal pain, p = 1.00; abdominal pain, p = 1.00; dyspepsia, p = 0.57; nausea, p = 0.52; vomiting, p = 1.00; gastritis, p = 1.00; and gastro-oesophageal reflux, p = 0.44.

Zoledronic acid

In HORIZON-PFT¹⁰² the proportion of participants experiencing any GI event (abdominal pain, anorexia, diarrhoea, nausea, vomiting) in the first 3 days following i.v. administration was significantly higher in the zoledronic acid group than in the placebo group [380 GI events: 300/3862 (7.8%) in the zoledronic acid group and 80/3852 (2.1%) in the placebo group; RR 3.74, 95% CI 2.93 to 4.77; p < 0.00001] (Figure 36).

FIGURE 36

Any GI AEs in the zoledronic acid group compared with placebo. M–H, Mantel–Haenszel; UGI, upper GI.

Alendronic acid

One RCT⁸³ reported the incidence of influenza-like symptoms in osteoporotic men: 146 treated with alendronic acid and 95 treated with placebo.⁸³ Overall, 113 participants experienced influenza-like symptoms [66/146 (45.2%) in the alendronic acid group and 47/95 (49.5%) in the placebo group; RR 0.91, 95% CI 0.70 to 1.20; p = 0.51]. The difference between treatments was not statistically significant.

Ibandronic acid

In the RCT by McClung et al.,⁸⁰ 4.8% (4/83) of participants receiving 150 mg per month of oral ibandronic acid developed influenza-like symptoms, whereas none of the 83 (0%) participants receiving placebo developed symptoms. The difference between treatments was not statistically significant (p = 0.12).

Risedronic acid

Boonen et al.⁵⁸ reported the number of participants treated with 35 mg per week of risedronic acid or placebo who developed influenza and nasopharyngitis. The differences between treatment groups were not statistically significant. There were 15 influenza cases: 11 (among 191 participants, 5.8%) in the risedronic acid group and five (among 93 participants, 5.4%) in the placebo group (RR 1.07, 95% CI 0.38 to 2.99; p = 0.90). There were also 15 cases of nasopharyngitis: 11/191 (5.8%) in the risedronic acid group and 5/93 (5.4%) in the placebo group (RR 1.07, 95% CI 0.38 to 2.99; p = 0.90).

Zoledronic acid

Five of the included RCTs using zoledronic acid reported on influenza-like symptoms.^{56,59,77,79,88} Across these RCTs, zoledronic acid was associated with a significantly higher incidence of pyrexia, headache and chills than placebo. There were 1048 reports of pyrexia: 907 (in 5957 participants, 15.2%) in the zoledronic acid group and 141 (among 5866 participants, 2.4%) in the placebo group (pooled RR 4.36, 95% CI 1.91 to 9.98; p < 0.0005) (Figure 37). There were 554 cases of headache: 405 (among 4903 participants, 8.3%) in the zoledronic acid group and 149 (among 4809 participants, 3.1%) in the placebo group (pooled RR 2.14, 95% CI 1.36 to 3.39; p = 0.001) (Figure 38). There were 53 reports of chills: 44/453 (9.7%) in the zoledronic acid group and 9/346 (2.6%) in the placebo group (pooled RR 3.81, 95% CI 1.25 to 11.60, p < 0.02) (Figure 39). The incidence of pyrexia and headache significantly differed by sex (p < 0.00001 and p = 0.004, respectively).

FIGURE 37

Pyrexia: zoledronic acid compared with placebo. M–H, Mantel–Haenszel.

FIGURE 38

Headache: zoledronic acid compared with placebo. M–H, Mantel–Haenszel.

FIGURE 39

Chills: zoledronic acid compared with placebo. M–H, Mantel–Haenszel.

Alendronic acid versus ibandronic acid

In the MOTION trial,⁸¹ the incidence of neither influenza nor nasopharyngitis differed significantly between treatment groups [influenza (85 events): 36 (among 859 participants, 4.2%) in the alendronic acid group and 49 (among 874 participants, 5.6%) in the ibandronic acid group (monthly oral dose, 150 mg) (RR 0.75, 95% CI 0.49 to 1.14; p = 0.17); nasopharyngitis (92 events): 41 among 859 participants, 4.8%) in the alendronic acid group and (51 among 874 participants, 5.8%) in the ibandronic acid group (RR 0.82, 95% CI 0.55 to 1.22; p = 0.33)].

Alendronic acid versus zoledronic acid

The ROSE trial⁶⁹ found that 5 mg per year of zoledronic acid was associated with significantly more influenza-like symptoms than 70 mg per week of alendronic acid [137 cases: 5/194 (2.6%) in the alendronic acid group and 132/408 (32.4%) in the zoledronic acid group; RR 1.44, 95% CI 1.34 to 1.55; p < 0.00001]. It was also associated with a slight increase in pyrexia [23 cases: 2/194 (1.0%) in the alendronic acid group and 21/408 (5.2%) in the zoledronic acid group; RR 1.04, 95% CI 1.02 to 1.07; p = 0.002] and an increase in chills [26 cases: 3/194 (1.5%) in the alendronic acid group and 13/408 (3.2%) in the zoledronic acid group; RR 1.02, 95% CI 0.99 to 1.04; p = 0.19] (Figure 40).

FIGURE 40

Influenza-like symptoms: 70 mg per week of alendronic acid compared with 5 mg per year of zoledronic acid.

Head to head: zoledronic acid compared with risedronic acid

The HORIZON trial⁸⁸ compared 5 mg per year of zoledronic acid with 5 mg per day of risedronic acid in both men and women receiving steroids, and divided the participants into treatment and prevention subgroups for 12 months. The difference between treatments in influenza-like symptoms in the treatment subgroup was a RR of 5.02 (95% CI 1.47 to 17.14; p = 0.01) and the difference between treatments in the prevention subgroup was a RR of 10.00 (95% CI 1.30 to 77.09; p = 0.03); the differences between treatments were statistically significant (more events with zoledronic acid). No forest plot is presented for these data.

Alendronic acid

Three RCTs in postmenopausal women reported on hospitalisation.^55,64,68 A total of 1850 participants were hospitalised during 36 months^55,68 or 48 months of follow-up.⁶⁴ Across these RCTs there was no statistically significant difference in the risk of hospitalisation between participants receiving alendronic acid (27.9%, 928/3329) than those on placebo (27.8%, 922/3316) (pooled RR 1.01, 95% CI 0.79 to 1.28; p = 0.96) (Figure 41).

FIGURE 41

Forest plot for hospitalisation in postmenopausal women on 10 mg per day of alendronic acid compared with placebo.

Head to head: zoledronic acid compared with risedronic acid

The HORIZON trial⁸⁸ compared 5 mg per year of zoledronic acid with 5 mg per day of risedronic acid in both men and women receiving steroids, and divided the participants into treatment and prevention subgroups for 12 months. The difference between treatments in bone pain in the treatment subgroup was a RR of 2.61 (95% CI 0.94 to 7.22; p = 0.06). The difference between treatments was not statistically significant. There were zero events in both arms of the prevention subgroup. No forest plot is presented for these data.

Head to head: alendronic acid compared with zoledronic acid

The ROSE RCT⁶⁹ compared 70 mg per week of alendronic acid with 5 mg per year of zoledronic acid. The difference between treatments in bone pain was a RR of 6.91 (95% CI 3.02 to 15.83; p < 0.00001). The difference between treatments was statistically significant (more events with zoledronic acid). No forest plot is presented for these data. There were zero events in both arms of the prevention subgroup.

Zoledronic acid

The HORIZON-PFT¹⁰² reported on eye inflammation as an AE in the first 3 days following administration of 5 mg per year of zoledronic acid or placebo in osteoporotic women. The difference between treatments in eye inflammation was a RR of 6.98 (95% CI 1.59 to 30.70; p = 0.01). The difference between treatments was statistically significant (more events with zoledronic acid). No forest plot is presented for these data.

Zoledronic acid

The HORIZON-RFT⁷⁷ reported on stroke as an AE in men and women with history of hip fracture receiving 5 mg per year of zoledronic acid or placebo over 5 years. The difference between treatments in stroke was a RR of 1.21 (95% CI 0.80 to 1.85; p = 0.37); the difference between treatments was not statistically significant. No forest plot is presented for these data.

Zoledronic acid

Four placebo-controlled RCTs evaluated zoledronic acid,^56,59,77,79 one compared zoledronic acid with risedronic acid⁸⁸ and one compared zoledronic acid with alendronic acid;⁶⁹ all studies reported that no cases of spontaneous osteonecrosis were observed during the course of the RCT. The HORIZON-PFT⁵⁶ reported that cases of osteonecrosis in both the zoledronic acid and placebo groups following dental surgery (one case in each group) resolved with antibiotic therapy.

Any AE/upper gastrointestinal events

The review by Bobba et al.¹¹² evaluated the evidence from 14 studies of alendronic acid, eight studies of risedronic acid, 10 studies of ibandronic acid and nine studies in zoledronic acid. RCTs and observational studies were included. Summarising the evidence base, the reviewers reported that the rates of GI toxicity associated with alendronic acid, risedronic acid and oral ibandronic acid are similar to those associated with placebo. In addition, no significant difference in renal toxicity was evident for i.v. ibandronic acid compared with placebo; however, a decrease in renal function was evident with zoledronic acid. Osteonecrosis of the jaw was rarely described in participants receiving oral bisphosphonates, but it was more commonly reported in participants with malignancy receiving zoledronic acid. The authors concluded that the AEs associated with alendronic acid, risedronic acid and oral ibandronic acid are minimal; however, zoledronic acid may be compromised by renal toxicity. Myalgias and arthralgias were evident in the acute phase following i.v. administration.

In a review of clinical efficacy of risedronic acid for postmenopausal osteoporosis, Paget’s disease, breast cancer and participants taking glucocorticoids, Crandall¹¹³ evaluated the evidence across nine RCTs and seven clinical trials. Safety data from six RCTs of risedronic acid for any condition indicated that the safety of risedronic acid is similar to that of placebo; none of the trials found a notable rate of upper GI AEs.

In a comparative review of pivotal trials of alendronic acid and risedronic acid including a meta-analysis, Kherani et al.¹¹⁴ concluded that both alendronic acid and risedronic acid result in similar rates of AEs as placebo.

In a review of clinical studies and review articles concerning the use of risedronic acid, Umland and Boyce¹¹⁵ observed that, although post-marketing surveillance studies reported an increase in serious or severe upper GI side effects with alendronic acid, similar findings were not evident for risedronic acid. The reviewers concluded that risedronic acid has been associated with a lower incidence of gastric ulcers than alendronic acid; however, the number of AEs associated with risedronic acid is generally similar to those observed with placebo in most clinical trials.

As part of a NICE report on adverse effects and persistence with oral bisphosphonates, Lloyd-Jones and Wilkinson¹¹⁶ reported that across UK prescription event monitoring studies, treatment with daily alendronic acid or risedronic acid is associated with a high level of reporting of a number of conditions in the first month of therapy, particularly those affecting the upper GI tract. There were around 30 reports of dyspepsia, the most commonly reported condition, per 1000 patient-months of exposure. However, RCTs of tolerability found no increased incidence of AEs in patients randomised to alendronic acid.

The Actavis consultee submission for this assessment reported that the patients who switched from risedronic acid to alendronic acid experienced a significant increase in the risk of GI side effects. In a retrospective cohort study evaluating anonymous medical records from 390 general practices in the UK, Ralston et al.¹²⁶ reported that the risk of developing a GI AE was higher in patients who switched to alendronic acid than in those who remained on risedronic acid (HR 1.85, 95% CI 1.26 to 2.72). The authors also reported that the risk was even greater in the subgroup of patients with a history of upper GI events (HR 3.18, 95% CI 2.79 to 3.63), but was also observed in patients with no history of GI events (HR 1.76, 95% CI 1.15 to 2.69). The authors concluded that switching patients who are stabilised on risedronic acid to alendronic acid is associated with an increased risk of GI AEs.

Osteonecrosis of the jaw

In a review specifically of bisphosphonate-induced osteonecrosis of the jaw, Krueger et al.¹¹⁷ reviewed the evidence from 11 case reports and 26 case series studies reporting actual cases linking osteonecrosis of the jaw with bisphosphonate use, the majority of which reported on zoledronic acid. The available literature showed that i.v. bisphosphonates, especially zoledronic acid, are more likely to predispose patients to osteonecrosis of the jaw. However, in addition to bisphosphonate use, there appears to be several other factors involved in the development of osteonecrosis of the jaw. Other risk factors noted from the included studies were dental extraction or trauma to the jaw exposing part of the bone.

Van den Wyngaert et al.¹¹⁸ also reviewed the evidence of an asssociation between bisphosphonates and osteonecrosis of the jaw across 22 studies based on retrospective chart reviews without a control, of which three included patients with osteoporosis. Zoledronic acid and pamidronic acid (Aredia^®, Novartis Pharmaceuticals Ltd) were the main bisphosphonates covered. Of the patients included in the studies, 69.3% had undergone a dental extraction prior to the development of osteonecrosis, confirming the importance of trauma in the initiation of the disease. However, not enough evidence is available to prove a causal link.

Woo et al.¹¹⁹ reviewed the evidence of a link between bisphosphonates and osteonecrosis of the jaw across 29 case reports. Zoledronic acid, aledronic acid and pamidronic acid were the main bisphosphonates covered and 94% of patients were treated with zoledronic acid or pamidronic acid or both; 85% of affected patients had multiple myeloma or metastatic breast cancer and 4% had osteoporosis. The authors concluded that the prevalence of osteonecrosis in patients with cancer is 6–10% and the prevalence in those taking alendronic acid for osteoporosis is unknown. The authors also concluded that more than half of all cases (60%) occur after dentoalveolar surgery (such as tooth extraction) to treat infections, and the remaining 40% are probably related to infection, denture trauma or other physical trauma.

Recently, Lee et al.¹²⁰ undertook a meta-analysis of 12 cohort and case–control studies evaluating oral and i.v.-administered bishphosphonates. An inclusion criterion was that the studies were carried out in non-cancer patients. The pooled effect estimate indicated that the use of bisphosphonates was associated with a significantly increased risk of jaw osteonecrosis (OR 2.32, 95% CI 1.38 to 3.91). The reviewers concluded that the use of bisphosphonates in non-cancer patients is associated with a substantial risk of jaw osteonecrosis and that patients receiving i.v. bisphosphonates are at highest risk.

Atypical fracture

Giusti et al.¹²¹ reviewed the evidence from 39 publications reporting on women treated with a bisphosphonate in a regimen used for the prevention or treatment of osteoporosis. Twenty-seven of the publications were case series or case reports (one abstract), four were retrospective studies and one was a prospective article including three new cases. In most cases, the bisphosphonate was alendronic acid, prescribed for prevention or treatment of osteoporosis. Across the included studies, there were 58 femoral shaft fractures and 41 subtrochanteric fractures; the precise fracture site was not specified in 42 cases. Nineteen fractures were diagnosed at presentation as insufficiency fractures, with 12 of these progressing to a complete fracture. Overall, 53 (44.2%) of the 120 patients for whom data were available had a contralateral fracture (32 of which were insufficiency fractures), either concurrently with or subsequent to the initial fracture, of which 34 (64.2%) occurred in the same anatomical location as the first fracture. The authors concluded that the analysis allowed the clinical identification of patients at risk of developing atypical fractures; however, the reviewers also concluded that long-term bisphosphonate therapy is not a prerequisite for development of atypical fractures. Moreover, the use of glucocorticoids and proton pump inhibitors is an important risk factor for atypical fracture.

Recently, Gedmintas et al.¹²² undertook a meta-analysis of atypical fractures reported in five case–control studies and six cohort studies. The studies were mainly carried out in women and evaluated mainly alendronic acid but also ibandronic acid, risedronic acid, zoledronic acid and other bisphosphonates. The overall pooled estimate for atypical fractures associated with bisphosphonates using data from the five case–control and six cohort studies was a RR of 1.70 (95% CI 1.22 to 2.37). Gedmintas et al.¹²² concluded that there is an increased risk of atypical fracture among bisphosphonate users but that atypical fractures are rare events, even in bisphosphonate users.

Oesophageal cancer

Andrici et al.¹²³ undertook a meta-analysis of seven cohort or case–control studies investigating oral bisphosphonates and the risk of oesophageal cancer. Participants were anyone who had filed a prescription for any antiresorptive drug. The authors found a positive relationship between exposure to bisphosphonates and oesophageal cancer, with an OR of 1.74 (95% CI 1.19 to 2.55). An increased risk of oesophageal cancer was also found in the group exposed to bisphosphonates for a longer period of time. According to the authors, the results suggest a possible association between oral bisphosphonates and oesophageal cancer, and this risk is increased with a longer exposure period. An increased risk was observed for etidronic acid, but not alendronic acid.

Recently, Sun et al.¹²⁴ undertook a a meta-analysis of observational studies. Seven epidemiological studies, four cohort studies and three case–control studies, were included and, where reported, alendronic acid was the main bisphosphonate. The underlying conditions for which patients were being treated with a bisphosphonate were not reported. In the primary analysis, bisphosphonate treatment was not associated with a risk of oesophageal cancer in either the cohort studies (pooled RR 1.23, 95% CI 0.79 to 1.92) or the case–control studies (pooled OR 1.24, 95% CI 0.98 to 1.57). The authors also observed no significant increased risk of oesophageal cancer in users of alendronic acid alone across cohort studies (RR 1.08, 95% CI 0.67 to 1.75) or across case–control studies (OR 1.16, 95% CI 0.82 to 1.63). They concluded that bisphosphonate treatment is not significantly associated with an excess risk of oesophageal cancer.

Atrial fibrillation

Loke et al.¹²⁵ evaluated the risk of atrial fibrillation associated with biphosphonate use in patients with osteoporosis or fractures. RCTs of any biphosphonate compared with placebo and case–control and prospective or retrospective cohort studies in patients with osteoporosis that reported on the association between biphosphonate exposure and atrial fibrillation were eligible for inclusion. Interventions in the included RCTs included alendronic acid, risedronic acid and zoledronic acid. Interventions in the included case–control studies were mostly alendronic acid or etidronic acid. Across nine RCTs, biphosphonates significantly increased the risk of atrial fibrillation compared with placebo (OR 1.47, 95% CI 1.01 to 2.14). Biphosphonates did not significantly increase the risk of stroke or cardiovascular mortality (three RCTs). One case–control study found that patients with atrial fibrillation were more likely than control patients to have used biphosphonates (OR 1.86, 95% CI 1.09 to 3.15), but the second case–control study found no association. Neither study found a greater likelihood of current use of bisphosphonates among patients with atrial fibrillation. The authors concluded that bisphosphonates were associated with atrial fibrillation, but heterogeneity of the existing evidence and a paucity of information on some agents precluded any definitive conclusions with respect to risk.

Mortality

Only one review reported on mortality.¹¹⁶ The authors did not report an overall conclusion on this outcome, but did say that one cohort study found no difference in all-cause mortality, cancer mortality or mortality from cancer of the lung or GI tract between patients treated with risedronic acid and those treated with placebo. A non-statistically significant reduction in deaths from cardiovascular causes in the risedronic acid group was largely caused by a statistically significant reduction in stroke mortality in the combined risedronic acid groups (p = 0.015); and from one prescription event monitoring study that serious upper GI events included gastric, duodenal and peptic ulceration, gastritis, and duodenitis. However, only 9 of the 502 reported deaths for which the cause of death was established were attributed to GI causes.

Summary of reviews of adverse events

The 14 reviews were published from 2001 to 2014.^112–125 One review considered any antresorptive therapy,¹²³ 10 considered any bisphosphonate therapy^{112,114,117–122,124,125} and three reported on AEs associated with specific bisphosphonates (two in risedronic acid^113,115 and one in alendronic acid or risedronic acid¹¹⁶). Four reviews included evidence from both observational studies and RCTs^{112,116,117,125} and seven included only observational studies.^118–124 Five reviews reported on any AE,^112–115 whereas nine reported on specific AEs (four in jaw osteonecrosis,^117–120 two in atypical fracture,^121,122 two in oesophogeal cancer^123,124 and one in atrial fibrillation¹²⁵). Four reviews pooled data across studies in a meta-analysis.^{120,122–124}

Evidence from these reviews indicates that rates of GI toxicity are similar following treatment with alendronic acid, risedronic acid, oral ibandronic acid and placebo. However, observational data suggest a high level of reporting of a number of conditions in the first month of therapy with alendronic acid or risedronic acid, particularly those affecting the upper GI tract. Zoledronic acid may be compromised by renal toxicity, and myalgia and arthralgia are evident in the acute phase following i.v. administration of the drug. Intravenous bisphosphonates, especially zoledronic acid, are more likely to predispose patients to osteonecrosis of the jaw, although absolute risk is very low. In addition to bisphosphonate use, there appears to be several other factors involved in the development of osteonecrosis of the jaw. There is an increased risk of atypical fracture among bisphosphonate users; however, events are rare and long-term bisphosphonate therapy is not a prerequisite for development of atypical fractures. Moreover, the use of glucocorticoids and proton pump inhibitors are important risk factors. Bisphosphonates are associated with serious atrial fibrillation, but heterogeneity of the existing evidence and a paucity of information on some agents preclude any definitive conclusions with respect to risk. The review evidence for the use of bisphosphonates and oesophogeal cancer is equivoval; no overlaps in this evidence either across the included reviews or with the RCT evidence base included in this assessment report were identified.

Summary of reviews of continuance and concordance

Seven reviews were identified, published between 2006 and 2014.^{116,127–132} These are summarised in Appendix 6, Table 49. The majority of these reviews reported on aledronic acid and risedronic acid. One review also included studies in ibandronic acid¹³² and two included zoledronic acid.^130,132 The majority of reviews evaluated compliance as a MPR and persistence measured as the number of days of possession. Data were pooled across studies by three reviews.^128–130

Evidence across these reviews indicates that although patients using weekly bisphosphonate medication follow their prescribed regimens better than those using daily therapy, overall compliance and persistence rates are suboptimal for postmenopausal women receiving bisphosphonate therapy for the treatment of osteoporosis. Furthermore, one-third to one-half of patients, including men being treated with bisphosphonates for osteoporosis, did not take their medication as directed. No overlaps in this evidence either across the included reviews or with the RCT evidence base included in this assessment report were identified.

Sensitivity analysis 1: vertebral outcomes – class-effects model

A NMA was used to compare the effects of alendronic acid, risedronic acid, zoledronic acid, 150 mg per month of oral ibandronic acid and 2.5 mg per day of oral ibandronic acid relative to placebo on the occurrence of vertebral fractures. Data were available from 19 RCTs comparing two treatments.^{45,56,58–60,63,65,66,70,72,76,77,81–83,85,86,88,89} The network of evidence is the same as that presented in Figure 42, except for the exclusion of the two alendronic acid RCTs,^55,64 so that the modified network contains only four direct estimates between placebo and alendronic acid rather than six. Figure 60 presents the effects of each treatment relative to placebo. The model fitted the data well, with a total residual deviance of 36.78 (compared with the total number of data points included in the analysis of 38). The between-study SD was estimated to be 0.23 (95% CrI 0.02 to 0.59) and the between-treatment SD was estimated to be 0.20 (95% CrI 0.01 to 0.96). On exclusion of the two RCTs,^55,64 a treatment effect of 0.45 (95% CrI 0.28 to 0.68) was estimated for alendronic acid. The estimated treatment effect was the same as before, but with an increase in uncertainty.

FIGURE 60

Sensitivity 1: vertebral outcomes – class-effects model (HRs and 95% CrIs). Note that the mean effect estimates are plotted in black; predictive effects in a new study are plotted in green beneath. Points to the right of the line favour the reference (more...)

Sensitivity analysis 1: non-vertebral outcomes

An NMA was used to compare the effects of alendronic acid, risedronic acid, zoledronic acid, 150 mg per month of oral ibandronic acid and 2.5 mg per day of oral ibandronic acid relative to placebo on the occurrence of non-vertebral fractures. Data were available from 12 RCTs comparing two treatments.^{45,56,57,66,70,72,77,81,83–85,89} The network of evidence is the same as that presented in Figure 46, except for the exclusion of the two alendronic acid RCTs,^55,64 so that the modified network contains only three direct estimates between placebo and alendronic acid rather than five. Figure 61 presents the effects of each treatment relative to placebo. The model fitted the data well, with a total residual deviance of 18.02 (compared with the total number of data points included in the analysis of 24). The between-study SD was estimated to be 0.10 (95% CrI 0.00 to 0.38) and the between-treatment SD was estimated to be 0.23 (95% CrI 0.01 to 1.00). On exclusion of the two RCTs,^55,64 a more pronounced treatment effect of 0.68 (95% CrI 0.45 to 0.94) is observed for alendronic acid, compared with a value of 0.80 (95% CrI 0.65 to 0.94) estimated in the main analyses, Non-vertebral fractures: class-effects model, and there is an increase in uncertainty.

FIGURE 61

Sensitivity 1: non-vertebral outcomes – class-effects model (HRs and 95% CrIs). Note that the mean effect estimates are plotted in black; predictive effects in a new study are plotted in green beneath. Points to the right of the line favour the (more...)