Bisphosphonate effects on bone turnover, microdamage, and mechanical properties: What we think we know and what we know that we don't know

doi:10.1016/j.bone.2010.10.159

Bone

Volume 49, Issue 1, July 2011, Pages 56-65

https://doi.org/10.1016/j.bone.2010.10.159 Get rights and content

Abstract

The bisphosphonates (BPs) have been useful tools in our understanding of the role that bone remodeling plays in skeletal health. The purpose of this paper is to outline what we know, and what is still unknown, about the role that BPs play in modulating bone turnover, how this affects microdamage accumulation, and ultimately what the effects of these changes elicited by BPs are to the structural and the material biomechanical properties of the skeleton. We know that BPs suppress remodeling site-specifically, probably do not have a direct effect on formation, and that the individual BPs vary with respect to speed of onset, duration of effect and magnitude of suppression. However, we do not know if these differences are meaningful in a clinical sense, how much remodeling is sufficient, the optimal duration of treatment, or how long it takes to restore remodeling to pre-treatment levels following withdrawal. We also know that suppression is intimately tied to microdamage accumulation, which is also site-specific, that BPs impair targeted repair of damage, and that they can reduce the energy absorption capacity of bone at the tissue level. However, the BPs are clearly effective at preventing fracture, and generally increase bone mineral density and whole bone strength, so we do not know whether these changes in damage accumulation and repair, or the mechanical effects at the tissue level, are clinically meaningful. The mechanical effects of BPs on the fatigue life of bone, or BP effects on bone subject to an impact, are entirely unknown. This paper reviews the literature on these topics, and identifies gaps in knowledge that can be addressed with further research.

This article is part of a Special Issue entitled Bisphosphonates.

Introduction

The effect of bisphosphonates (BPs) to reduce bone remodeling has been appreciated since the early days of their discovery. Implicitly, reducing bone loss should result in reduced fracture risk. But suppression of remodeling alters material properties of bone and allows microdamage accumulation, changes that interact in complex ways to affect biomechanical integrity of the skeleton. Over the past 40 years, a number of reviews have detailed the effects of BPs on various tissue-level aspects of bone. The goal of this review is not to regurgitate what already can be found in these works but rather to briefly highlight key points regarding what is known about how BPs affect bone turnover, microdamage accumulation, and mechanical properties and then discuss where gaps in knowledge exist in each of these areas. We hope outlining some of these knowledge gaps will continue to stimulate work on BPs with the goal of optimizing BP treatment, and skeletal health in general, in the years to come.

Section snippets

BPs and bone turnover — what we know (Table 1)

In the adult skeleton, the majority of osteoblast and osteoclast activity involves coupled remodeling in which the process of bone resorption and formation are linked in space and time. The negative bone balance associated with each remodeling unit (more bone is resorbed than is formed) combined with the accelerated number of remodeling units both contribute to bone loss in postmenopausal osteoporosis. To a lesser extent the adult skeleton also undergoes modeling — where either formation or

BPs and bone turnover — what we don't know (Table 1)

With the goal of reducing fracture risk to the greatest degree, the push within the field has generally been to reduce bone turnover to the greatest degree possible. Yet it remains unclear whether the basic premise of more turnover suppression equals greater fracture risk reduction is correct. In fact, it seems rather clear that it is not. Raloxifene, a selective estrogen receptor modulator, suppresses bone remodeling by only 20–40%, yet achieves nearly the same fracture risk reduction in the

BPs and microdamage — what we know (Table 2)

It is now well established in animal models that the suppression of remodeling allows microdamage accumulation [36], [50], [51], [52], and that this is not necessarily a BP-specific effect [53]. Any suppression of remodeling will prevent the repair of naturally occurring damage to bone, and will allow it to accumulate. Even a 40% suppression of remodeling with a half-dose of risedronate caused a 3-fold increase in microdamage accumulation [54], and a 20% suppression with a non-BP, raloxifene,

BPs and microdamage — what we don't know (Table 2)

It is still an unresolved question whether microdamage accumulates in postmenopausal women who have taken BPs. Stepan et al. [67], using human transilial biopsies, showed in a subsample that microcrack accumulation occurs in women treated for an average of 5 years with alendronate, but the study is inconclusive because the analysis of biopsies from the two different research centers associated with the study differed. However, Stepan et al. were able to show definitively that microcrack

BPs and biomechanical properties — what we know (Table 4)

The efficacy of BPs on reducing fracture risk is clear and relatively consistent [1], [77]. New vertebral fractures are significantly reduced over three years with alendronate, risedronate, ibandronate, and zoledronate relative to placebo-treated controls. Non-vertebral fracture risk reduction is also significantly lower with all four BPs over the first three years. When hip fractures are assessed independent of other non-vertebral sites, only alendronate, risedronate, and zoledronate show

BPs and biomechanical properties — what we don't know (Table 4)

In life, bone is loaded cyclically and not quasi-statically, and the properties of the bone in cyclic loading, and its residual fatigue life with additional cycles of loading, may not be estimated very accurately from quasi-static tests of structural or material biomechanical properties. Cyclic fatigue tests of bone treated with BPs have not been performed to determine whether the reduced toughness measured quasi-statically translates into reduced residual strength and shorter fatigue life of

Summary

The BPs have been extremely successful in reducing fracture risk and improving patients' quality of life. Still, given how much attention has been paid to these agents, there is still much to learn. Much of this has less to do with the drugs themselves, than with the role that remodeling suppression plays in bone physiology and maintenance. For example, while we know that suppressing bone turnover is important to prevent fractures in postmenopausal women, we don't know how suppression is

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ReviewBisphosphonate effects on bone turnover, microdamage, and mechanical properties: What we think we know and what we know that we don't know

Abstract

Introduction

Section snippets

BPs and bone turnover — what we know (Table 1)

BPs and bone turnover — what we don't know (Table 1)

BPs and microdamage — what we know (Table 2)

BPs and microdamage — what we don't know (Table 2)

BPs and biomechanical properties — what we know (Table 4)

BPs and biomechanical properties — what we don't know (Table 4)

Summary

Bone

Bone

Bone

Bone

J Oral Maxillofac Surg

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J Biomech

Bone

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J Theor Biol

J Biomech

Bone

Bone

J Orthop Res

Bone

Bone

J Biomech

Bone

Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy

Osteoporos Int

Bisphosphonates: mechanisms of action

J Clin Investig

Morphological assessment of basic multicellular unit resorption parameters in dogs shows additional mechanisms of bisphosphonate effects on bone

Calcif Tissue Int

Structure–activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates

J Pharmacol Exp Ther

Structure–activity relationships among the nitrogen containing bisphosphonates in clinical use and other analogues: time-dependent inhibition of human farnesyl pyrophosphate synthase

J Med Chem

Comparison of weekly treatment of postmenopausal osteoporosis with alendronate versus risedronate over two years

J Clin Endocrinol Metab

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

Comparison of a single infusion of zoledronic acid with risedronate for Paget's disease

N Engl J Med

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

J Clin Investig

Histomorphometric evaluation of daily and intermittent oral ibandronate in women with postmenopausal osteoporosis: results from the BONE study

Osteoporos Int

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

J Bone Miner Res

Cancer treatment dosing regimens of zoledronic acid result in near-complete suppression of mandible intracortical bone remodeling in beagle dogs

J Bone Miner Res

Antiremodeling agents influence osteoblast activity differently in modeling and remodeling sites of canine rib

Calcif Tissue Int

Alendronate reduces bone toughness of ribs without significantly increasing microdamage accumulation in dogs following 3 years of daily treatment

Calcif Tissue Int

Effectiveness of bisphosphonates on nonvertebral and hip fractures in the first year of therapy: the risedronate and alendronate (REAL) cohort study

Osteoporos Int

Short-term effect of alendronate on bone mass and bone remodeling in postmenopausal women

Osteoporos Int

Long-term effects of a treatment course with oral alendronate of postmenopausal osteoporosis

J Bone Miner Res

Review
Bisphosphonate effects on bone turnover, microdamage, and mechanical properties: What we think we know and what we know that we don't know