Elsevier

Bone

Volume 44, Issue 5, May 2009, Pages 744-751
Bone

Review
Efficacy and safety of pharmacological agents in managing osteoporosis in the old old: Review of the evidence

https://doi.org/10.1016/j.bone.2008.12.003Get rights and content

Abstract

Introduction

Osteoporosis and fracture risk increase exponentially in postmenopausal females. This places a significant burden in terms of morbidity, mortality and costs that are likely to increase with an ageing population. Despite this there is very limited data on pharmacological management of osteoporosis in this high risk group.

Objectives of this review

To review the published literature on the clinical efficacy and safety of specific anti osteoporosis treatments in the reduction in fracture risk in females ≥ 75 years of age. The following major endpoints were used in this review:

  • 1.

    Vertebral fracture reduction at 1 year and 3 years.

  • 2.

    Non-vertebral fracture and hip fracture reduction at 1 year and 3 years.

  • 3.

    Safety data in this group.

Search methods for identification of studies

We performed an electronic search of Medline (1970 to June 2007) and the Cochrane Library (1996 to June 2007). Our search strategy included MeSH terms for osteoporosis and treatments. We reviewed the reference list of identified articles for additional relevant published trials.

Results

Two hundred and fifty-two potentially relevant abstracts were identified. Only six publications were deemed to meet full eligibility criteria and one met most criteria. There is evidence for significant vertebral fracture relative risk reduction(RR) at 1 year for Risedronate (RR 81%; p < 0.001), Teriparatide (RR 65%; p < 0.05) and Strontium Ranelate (RR 59%; p = 0.002) and 3 years for Risedronate (RR 44%; p = 0.003), Alendronate (RR 38%; p < 0.05) and Strontium Ranelate (RR 32%; p = 0.013). There is evidence for significant non-vertebral fracture relative risk reduction at 1 year for Strontium Ranelate (RR 41%; p = 0.027) but not Teriparatide (p = 0.66) and 3 years for Strontium Ranelate (RR 31%; p = 0.011) but not Risedronate (p = 0.66). The only study to report a reduction in hip fracture at 3 years is the TROPOS study with Strontium Ranelate (RR 36%; p = 0.046).

Discussion

This review reinforces the irony that the least evidence is available for fragility fracture reduction in the group at greatest risk; the old old and those with non vertebral and hip fracture. Although there is good evidence for the benefit of the bisphosphonates (Alendronate and Risedronate), Teriparatide and Strontium Ranelate in vertebral fracture reduction, there are very limited data for non vertebral and hip fracture reduction. Strontium Ranelate is the only agent to date that has demonstrated a reduction in non vertebral and hip fracture events in this high risk elderly female population. Perhaps we need to adopt different strategies in managing older patients with osteoporosis as their fracture risks and treatment strategies may be quite different from younger populations.

Introduction

Osteoporosis increases in prevalence with age such that it is common in the elderly [1], [2], [3]. For any bone mineral density (BMD) measurement, fracture risk is much higher in the elderly than in the young [4]. Age is one of the most important components of the fracture index derived by Black et al. [5]; and older age groups experience the greatest growth rate of osteoporosis risk in the population [6], [7]. So although BMD is a strong risk factor for fragility fracture, its relative importance diminishes if there are other strong risk factors for fracture: advanced age, prior fragility fracture or family history of fragility fracture [4], [8].

Older patients are at higher risk of falls [9] due to muscle weakness [10] and more than 90% of fractures occur after a fall [11], [12], [13]. Falls result in any fracture in 5% and specifically hip fracture in 1–2% of events [11]. Hence, in an ageing, osteoporotic population, fracture prevention through the optimisation of bone health as well as reducing falls risk should be important goals.

Epidemiological data worldwide have consistently demonstrated that the annual incidence of fragility fracture increases with age [14], [15], [16], [17], [18], [19]. Above average fracture rates were described in Australian females residing in Dubbo [20] and Geelong [3] with an exponential increase in risk in the population groups over 74 years of age. The burden of fracture is expected to increase with an ageing population as the oldest old i.e. women ≥ 80 years of age comprise approximately 8% of the post-menopausal population but contribute > 30% of all fragility fractures and 60% of hip fractures because of the high prevalence of osteoporosis and falls in this age group [21], [22]. After age 75, hip fracture is the commonest fracture [23], [24], [25] with 1/3 of women and 1/6 of men estimated to sustain a hip fracture by the 9th decade [26] and is associated with significant morbidity and mortality [27], [28], [29] and financial burden [22], [30], [31], [32], [33].

Despite the high risk of osteoporotic fracture in older individuals, there is little data regarding treatment of this group. Studies have either included limited numbers or excluded older individuals due to strict entry criteria based on age and related factors. However, economic evaluations have suggested that if current anti osteoporosis agents are as effective in older patients as in younger trial patients, the cost benefit ratios are more favourable given the higher absolute risk in older patients [34], [35], [36].

Section snippets

Objectives of this review

To review the published literature on the clinical efficacy and safety of specific anti osteoporosis treatments in the reduction in fracture risk in females ≥ 75 years of age. The following major endpoints were used:

  • 1.

    Vertebral fracture reduction at 1 year and 3 years.

  • 2.

    Non-vertebral fracture and hip fracture reduction at 1 year and 3 years.

  • 3.

    Safety data in this group.

Eligibility criteria for inclusion in review

Studies were randomised placebo or active comparator control trials or age comparison trials of at least 1 year duration and included post-menopausal females. Pooled analysis and published sub-group analysis, specifying the sub-groups ≥ 75 years were included.

Analysis

The following outcome and efficacy measures were predetermined:

  • 1.

    The primary efficacy outcome was the proportion of women with incident vertebral fractures at 1 year and 3 years.

  • 2.

    The secondary endpoint was non-vertebral and hip fractures at 1 and 3 years.

  • 3.

    Vertebral fractures and non-vertebral fractures were required to be radiographically proven.

  • 4.

    Safety measures included the following:

  • a)

    The proportion with any adverse event reported.

  • b)

    The proportion that withdrew due to adverse events.

  • c)

    The proportion

Search methods for identification of studies

An electronic search of Medline (1970 to June 2007) and the Cochrane Library (1996 to June 2007) using MeSH terms for osteoporosis and treatments was performed. We reviewed the reference list of identified articles for additional relevant published trials. We excluded studies specifically investigating hormone replacement therapy, calcium and vitamin D as a primary treatment measure in this review.

Abstracts of all possibly relevant articles were reviewed independently (AF and ML) for potential

Descriptions of studies

Two hundred and fifty-two potentially relevant abstracts were identified. After excluding studies that did not meet eligibility criteria, 104 studies were fully reviewed for potential inclusion. The number of studies with each anti osteoporosis agent reviewed was as follows:

  • 1.

    Alendronate 31

  • 2.

    Clodronate 4

  • 3.

    Etidronate 7

  • 4.

    Ibandronate 10

  • 5.

    Pamidronate 1

  • 6.

    Parathyroid hormone (PTH 1–34 [Teriparatide]/PTH 1–84) 19

  • 7.

    Raloxifene 12

  • 8.

    Risedronate 11

  • 9.

    Strontium Ranelate 6

  • 10.

    Zoledronic acid 3

Only six publications were deemed to

Strontium Ranelate study

The Strontium Ranelate study [37] was a pooled analysis of patients from the SOTI [44] and TROPOS [43] studies. The SOTI study assessed the anti vertebral fracture efficacy in 1649 white post menopausal women with osteoporosis and at least one prevalent vertebral fracture and the TROPOS study (5091 patients) assessed the anti non-vertebral fracture efficacy in 1977 white post menopausal women ≥ 74 years of age with osteoporosis and femoral neck BMD  cm per cm2 (measured by Hologic). Subjects were

Vertebral fracture risk reduction in patients 75 years of age or older

The results are summarised in Table 2. There are limited published data on vertebral fracture risk reduction in this age group. There are published data at 1 year and 3 years for Risedronate and Strontium Ranelate, 1 year for Teriparatide and 3 years for Alendronate. There are no published data for Clodronate. There is evidence for significant vertebral fracture relative risk reduction at 1 year for Risedronate (RR 81%; p < 0.001), Teriparatide (RR 65%; p < 0.05)) and Strontium Ranelate (RR 59%; p = 

Non-vertebral fracture risk reduction in patients 75 years of age and older

The results are summarised in Table 2. There are 1 year data for Strontium Ranelate (≥ 80 years) and Teriparatide (≥ 75 years) and 3 year data in the over 80 age group for Strontium Ranelate and Risedronate. Risedronate was demonstrated to reduce non vertebral fracture in a combined analysis of subjects in the HIP study (70–79 years and 80 years and over groups); relative risk 0.8 (95% CI = 0.7–1.0; p = 0.03); no benefit was demonstrated in the older cohort selected primarily on the basis of

Hip fracture risk reduction in patients 75 years of age and older

The results are summarised in Table 2. There are only 2 studies specifically designed to look at hip fracture as the primary outcome — the HIP study (Risedronate) and the Clodronate Study. A third study, TROPOS (Strontium Ranelate) reported hip fracture outcome as a secondary outcome in the subgroup ≥ 74 years, with more severe osteoporosis. The 80+ subgroup from the latter was also included in the pooled analysis by Seeman et al. [37] which reported hip fracture outcome as a secondary endpoint

Zoledronic acid

A double-blind, placebo controlled study by Black et al. [49] randomised 3889 postmenopausal, osteoporotic women, mean age 73 ± 5 (range 65–89) years, to either an annual infusion of zoledronic acid 5 mg or placebo at baseline with 12, 24 and 36 months of follow up. In this study 1452 (37.6%) of the placebo group and 1497 (38.6%) of the zoledronic acid group were > 75 years of age. However, there are no published data on this subgroup to date and permission for access was declined by the authors

Adverse events reported in patients 75 years of age or older

There are limited published data on adverse outcomes in older patient subgroups. The most comprehensive data is published for Risedronate [38] and Strontium Ranelate [37] in the over 80 age group pooled analyses. Table 3 summarises the published adverse events. Neither Risedronate nor Strontium Ranelate resulted in more adverse events than placebo for the following categories: any adverse event, withdrawal due to adverse events, serious adverse events or deaths.

Strontium Ranelate pooled

The current evidence

There is a significant paucity of evidence-based literature on randomised controlled trials in older patients with only some studies including patients over 75 years but the numbers are often small and infrequently analysed as subgroups. Hence, reliance on pooled analysis is required. There are published safety data for Strontium Ranelate, Risedronate and Teriparatide which demonstrate relative safety in the older age groups.

There is acceptable evidence to recommend the bisphosphonates

Conclusions

Teriparatide, Risedronate, Alendronate and Strontium Ranelate demonstrate significant benefit in vertebral fracture reduction but Strontium Ranelate is the only agent to date that demonstrates reduction in non-vertebral and hip fracture events in a high risk elderly female population.

This review reinforces the irony that the least evidence is available for fragility fracture reduction in the group at greatest risk, who are likely to sustain the greatest potential harm in terms of disability and

Acknowledgments

The authors wish to acknowledge the following:

1. Servier Australia for the provision of an unconditional education grant for this review.

2. Eli Lilly, Merck Sharp and Dohme, Novartis, Sanofi Aventis, Servier and Roche/GSK for the provision of additional information and references.

3. Professor Ego Seeman, Dr Denise Glennon and Dr Kate Ingram and Ms Kate Poland for their review, comments and suggestions.

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