Bisphosphonates for postmenopausal osteoporosis

doi:10.1016/j.bone.2011.02.011

Bone

Volume 49, Issue 1, July 2011, Pages 82-88

https://doi.org/10.1016/j.bone.2011.02.011 Get rights and content

Abstract

Bisphosphonates are effective in reducing bone turnover, increasing BMD and reducing fracture risk in postmenopausal women with osteoporosis. The licensed bisphosphonates exhibit some differences in potency and speed of onset and offset of action. These differences mean that different agents may be more advantageous in different situations.

Uncertainties still exist around the optimum duration of treatment and treatment holidays, how best to use bisphosphonates with anabolic treatments, and the benefits of treatment in patients who do not have a BMD T-score below − 2.5.

This article is part of a Special Issue entitled Bisphosphonates.

Research Highlights

► Bisphosphonates reverse the key pathophysiological changes of postmenopausal osteoporosis. ► The bisphosphonates that have been licensed in many countries for postmenopausal osteoporosis include alendronate, ibandronate, risedronate and zoledronic acid. ► These bisphosphonates all reduce the level of bone turnover and increase the bone mineral density in postmenopausal osteoporosis. ► The bisphosphonates differ in their potency in their effects on bone turnover and bone density. ► The licensed bisphosphonates have all been shown to reduce the risk of vertebral fractures; some of them have also been shown to reduce the risk of non-vertebral and hip fractures.

Introduction

The earliest reported use of bisphosphonate treatment for postmenopausal osteoporosis was in 1976 [1] when oral etidronate was administered to 10 women with osteoporosis and the authors noted a significant improvement in calcium balance. It was a further 15 years until oral etidronate (given at a much lower dose and in a cyclical regime) was licensed in countries including the UK (although it was never licensed for use in the USA).

Subsequently, a number of bisphosphonates have been evaluated in postmenopausal osteoporosis and investigated in large clinical trials with fracture as an end-point. This has resulted in the licensing of alendronate, risedronate, ibandronate and zoledronic acid for the treatment of postmenopausal osteoporosis (Table 1).

The purpose of this article is to consider the evidence that bisphosphonates reverse the key pathophysiological changes of postmenopausal osteoporosis, to compare the efficacy of each of the licensed bisphosphonates based on clinical trial data and address key questions that have arisen from these trials about the efficacy of different bisphosphonates. Drug safety and the use of bisphosphonates in other clinical settings will be covered in other articles in this issue. In general, the bisphosphonates are well tolerated. Patients may develop abdominal pain or dyspepsia that occurs within hours of taking the oral bisphosphonate and that is relieved by stopping the medication. Patients may develop an influenza-like illness within a few days of receiving an intravenous injection of an amino bisphosphonate (such as zoledronic acid) and this is usually worse after the first such injection rather than subsequent injections. These issues may limit the acceptance of the medication.

Section snippets

Pathogenesis

Bone loss occurs in postmenopausal osteoporosis as a result of an increase in the rate of bone remodeling and an imbalance between the activity of osteoclasts and osteoblasts [2]. Bone remodeling occurs at discrete sites within the skeleton and proceeds in an orderly fashion with bone resorption always being followed by bone formation, a phenomenon referred to as ‘coupling’. The sequence of bone remodeling is similar in both cortical and cancellous bone [3]. The quiescent bone surface is

Bone turnover markers

Bone turnover marker response to bisphosphonates has been studied. In general, there is an early decrease (2–4 weeks) in bone resorption markers and a later decrease (3–6 months) in bone formation markers. The effect of some bisphosphonates on bone resorption markers is earlier than others, for example, zoledronic acid has more rapid effects than alendronate [10] (Fig. 2). This quicker effect is likely to be due in part to the route of administration — intravenous for zoledronic acid and oral for

How long to treat — what happens when bisphosphonate therapy for osteoporosis is stopped?

One of the controversial topics in the treatment of osteoporosis is the duration of treatment. There is a concern that long-term suppression of remodeling could result in bone fragility, for example with atypical fractures of the femur [21]. There are one or two studies with sufficient length of follow-up to help address this question. In the FLEX study [22], patients with an average of 5 years previous alendronate treatment were continued for five more years on alendronate 5 mg or 10 mg/day or

Summary

Postmenopausal osteoporosis is a consequence of an increase in activation frequency and an imbalance between bone formation and resorption; bisphosphonate therapy acts by lowering the activation frequency and so slows the deterioration in bone architecture. Bisphosphonates are effective in reducing bone turnover, with an earlier decrease in bone resorption than bone formation; there are differences in the time course and magnitude of response, depending on the type and route of administration

Acknowledgments

RE has received consulting fees from Amgen, Astrazeneca, GlaxoSmithKline, Medtronics, Nastech, Nestle, Fonterra Brands, Novartis, Ono Pharma, Osteologix, Pfizer, Lilly, sanofi Aventis, Procter and Gamble, Tethys, Unilever, Unipath, Inverness Medical. RE has received grants from AstraZeneca, Unilever, Amgen, Procter and Gamble, Unipath, Pfizer, Lilly, Novartis, Osteologix, Medical Research Council, Arthritis Research UK, Crescent Diagnostics, Nittoboseki, Nestle, and sanofi avents. RE has

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^☆: Supported by the National Institute for Health Research National Institute for Health Research (NIHR) via its Biomedical Research Units Funding Scheme. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

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ReviewBisphosphonates for postmenopausal osteoporosis☆

Abstract

Research Highlights

Introduction

Section snippets

Pathogenesis

Bone turnover markers

How long to treat — what happens when bisphosphonate therapy for osteoporosis is stopped?

Summary

Acknowledgments

Lancet

Bone

Bone

Bone

Clin Ther

Am J Med

Lancet

Am J Med

Bone

Mayo Clin Proc

Maturitas

Lancet

Maturitas

Bone

Etidronate disordium in postmenopausal osteoporosis

Clin Pharmacol Ther

Pathogenesis of postmenopausal osteoporosis

A new model for the regulation of bone resorption, with particular reference to the effects of bisphosphonates

J Bone Miner Res

Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis

J Clin Invest

Effects of intravenous zoledronic acid once yearly on bone remodeling and bone structure

J Bone Miner Res

Comparative effects of teriparatide and strontium ranelate on bone biopsies and biochemical markers of bone turnover in postmenopausal women with osteoporosis

J Bone Miner Res

Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study

J Bone Miner Res

Treatment of postmenopausal osteoporosis

N Engl J Med

Once-monthly oral ibandronate compared with weekly oral alendronate in postmenopausal osteoporosis: results from the head-to-head MOTION study

Curr Med Res Opin

Reginster JY: risedronate reverses bone loss in postmenopausal women with low bone mass: results from a multinational, double-blind, placebo-controlled trial. BMD-MN Study Group

J Clin Endocrinol Metab

Intravenous zoledronic acid in postmenopausal women with low bone mineral density

N Engl J Med

Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group

N Engl J Med

Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial

JAMA

Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research

J Bone Miner Res

Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial

JAMA

Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the Fracture Intervention Trial long-term extension

J Bone Miner Res

Ten years' experience with alendronate for osteoporosis in postmenopausal women

N Engl J Med

Long-term use of bisphosphonates in osteoporosis

J Clin Endocrinol Metab

Bone safety of long-term bisphosphonate treatment

Curr Med Res Opin

Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial

J Bone Miner Res

Review
Bisphosphonates for postmenopausal osteoporosis☆