Bone Quality and Fractures in Women With Osteoporosis Treated With Bisphosphonates for 1 to 14 Years

Malluche, Hartmut H.; Chen, Jin; Lima, Florence; Liu, Lucas J.; Monier‐Faugere, Marie‐Claude; Pienkowski, David

doi:10.1002/jbm4.10549

Cited by 6 publications

(7 citation statements)

References 38 publications

(65 reference statements)

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“…This motivates a comprehensive study of all bone quality parameters to provide clinically relevant information regarding bisphosphonate therapy. Our prior work contributes toward this goal because it presents individual mathematical models relating changes in bone structure and modulus to bisphosphonate treatment duration 12,13,42 . The present study contributes additional mathematical models relating changes in bone microdamage to bisphosphonate treatment duration.…”

Section: Discussionmentioning

confidence: 97%

Trabecular bone microcrack accumulation in patients treated with bisphosphonates for durations up to 16 years

Pienkowski

Wood

Malluche

2022

Journal Orthopaedic Research

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This study quantified the length, number, and density of microcracks in bone from patients treated with bisphosphonates as a function of duration. Anterior iliac crest bone samples from 51 osteoporotic Caucasian females continuously treated with oral bisphosphonates for 1-16 years were obtained by bone biopsy. Samples were histologically processed and analyzed for bone area, microcrack number, and microcrack length. The analyses used statistical modeling and considered patient age, bone mineral density, bone volume/total volume, trabecular thickness, and bone turnover as potential covariates. Microcrack density (number of microcracks/total examined bone area) was linearly related (p = 0.018) to bisphosphonate treatment duration. None of the analyzed covariates contributed significantly to the observed relationship between microcrack density and bisphosphonate treatment duration. Observed increases in microcrack density with increasing bisphosphonate treatment duration is important because increasing levels of microcracks may not only affect bone remodeling but also reduce elastic modulus and are suspected to adversely affect other mechanical properties that may influence fracture risk. The present findings add to our prior results showing changes in bone material properties and modulus with bisphosphonate treatment duration and thereby provide a more comprehensive assessment of the relationship between bisphosphonate treatment duration and bone quality. Statement of Clinical Significance: The present findings provide information guiding clinical use of oral bisphosphonates for post-menopausal osteoporosis therapy.

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Section: Discussionmentioning

confidence: 97%

Trabecular bone microcrack accumulation in patients treated with bisphosphonates for durations up to 16 years

Pienkowski

Wood

Malluche

2022

Journal Orthopaedic Research

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“…Using machine‐learning models, 8 years was the “sweet spot” in which oral BP users optimized their bone quality while avoiding abnormalities in mineralization that would predispose to AFF beyond this time period. ( 20 ) Drug holidays are effective in neutralizing the risk of AFF with a 48% reduction at 3 to 15 months and further risk reduction up to 79% in the subsequent years following BP discontinuation. ( 25 ) The notion of “resetting” the risk of AFF by embarking on a drug holiday in at‐risk individuals should however be weighed up against the progressive risk of fragility fracture with a lengthy holiday.…”

Section: Discussionmentioning

confidence: 99%

“…(18) Due to the inhibition of osteoclastic activity and long residence time in bone, there have been concerns that prolonged treatment with BPs can lead to critical suppression of bone remodeling, microfracture accumulation, and the development of insufficiency fractures. (7,19,20) In recent years there is emerging evidence of a duration-dependent association between BP use and atypical femur fractures (AFFs), with the risk increasing substantially beyond 5 to 8 years of treatment and returning to baseline postcessation. (21)(22)(23)(24)(25) AFF frequency increases with increased duration of BP treatment, rising from 2.5 AFFs per 10,000 person-years at ≤5 years of BP use up to 13.1 per 10,000 person-years at ≥8 years.…”

Section: Introductionmentioning

confidence: 99%

Bisphosphonate Drug Holidays: Evidence From Clinical Trials and Real‐World Studies

Wang

Girgis

2022

JBMR Plus

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Bisphosphonates (BPs) are commonly used in the treatment of osteoporosis and are effective in the prevention of fragility fracture. Long‐term use has been associated with the development of atypical femur fractures (AFFs) and osteonecrosis of the jaw (ONJ). Drug holidays seek to reduce the risk of insufficiency fractures (AFFs) while maintaining durable effects of long‐term treatment in the prevention of fragility fracture. Guidelines suggest that BP drug holidays be considered after 3 to 5 years. However individual factors impacting this decision and outcomes are unclear. This review examines key factors in the planning of a safe BP drug holiday and surrogate markers of fracture risk in patients discontinuing treatment. Fifteen randomized control trials and 19 real‐world studies were included, including nationwide prospective studies from several countries. Increases in bone turnover markers (BTMs) and reductions in bone mineral density (BMD) were generally observed during BP drug holidays. Resurgent bone turnover was problematic in high‐risk patients in whom fractures recurred as early as 12 months following a drug holiday. Risk factors for holiday‐related fractures included older age, low hip BMD, underweight, low medication adherence, and prevalent/incident fractures. Zoledronic acid conferred the most durable reduction in fractures, particularly after six annual infusions. Five years of alendronate was insufficient in preventing vertebral fractures in high‐risk patients embarking on a drug holiday. Relatively faster offset of antiresorptive effect was seen in risedronate users with more frequent fractures than alendronate during a drug holiday. Studies directly counterbalancing effects of long‐term treatment on AFF risk versus drug holiday outcomes in the same population were lacking. In the absence of persistently high fracture risk and following a specific treatment duration dependent on the BP used, drug holidays are safe and mitigate the risk of AFF. However, anti‐resorptive effects diminish over time; ongoing monitoring and careful planning of BP resumption is necessary. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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“…The mineral-to-matrix ratio is a key parameter of bone composition which is related to bone stiffness and energy-to-fracture; high values are associated with reduced fracture toughness (fracture resistance) 57 , increased microdamage 58 , and fractures. 59,60 Further details on FTIR parameters and measurements of bone quality are described in Malluche et al, Nature Reviews, 2013. 44 The trabecular bone score (TBS) is a non-invasive tool to assess bone microarchitecture.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

“… 6 FTIR is a very sensitive method of assessing material properties that have recently been used to study bone quality in patients with osteoporosis. 9 , 10 , 11 We use it here for the first time in patients with CKD.…”

mentioning

confidence: 99%

Bone Quality and Fractures in Women With Osteoporosis Treated With Bisphosphonates for 1 to 14 Years

Abstract: This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as

Cited by 6 publications

References 38 publications

Trabecular bone microcrack accumulation in patients treated with bisphosphonates for durations up to 16 years

Trabecular bone microcrack accumulation in patients treated with bisphosphonates for durations up to 16 years

Bisphosphonate Drug Holidays: Evidence From Clinical Trials and Real‐World Studies

Low Turnover Renal Osteodystrophy With Abnormal Bone Quality and Vascular Calcification in Patients With Mild-to-Moderate CKD

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