How can bone turnover modify bone strength independent of bone mass?

Hernandez, Christopher J.

doi:10.1016/j.bone.2008.02.001

Cited by 73 publications

(67 citation statements)

References 62 publications

(80 reference statements)

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“…The magnitude and rate of BMD or BTM offset may be of clinical significance because, even in treated patients, bone density and bone remodeling may be determinants of bone strength and thus, fracture risk. (1) Although fracture risk reduction remains the gold standard for the assessment of efficacy of pharmacological interventions, robust fracture data beyond 3 years of treatment are not available for most antiresorptives, and the few discontinuation studies have been underpowered to demonstrate the consequence of cessation of therapy on fracture risk. Thus, the effects of long-term continuation of treatment and its offset can generally only be assessed using BMD and BTM changes as surrogates for fracture risk.…”

Section: Introductionmentioning

confidence: 99%

“…Elevated levels of biochemical BTMs in untreated patients have been reported to predict fracture (1,(10)(11)(12)(13) independent of BMD, (12,(14)(15)(16) in part because they reflect stress risers in cancellous bone. A significant association between treatmentinduced changes in BTMs at 3 to 6 months and subsequent fracture risk reduction has also been demonstrated, (17) suggesting that changes in bone turnover per se affect bone strength and fracture risk.…”

Section: Introductionmentioning

confidence: 99%

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Postmenopausal osteoporosis treatment with antiresorptives: Effects of discontinuation or long-term continuation on bone turnover and fracture risk—a perspective

Boonen¹,

Ferrari²,

Miller³

et al. 2012

Journal of Bone and Mineral Research

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Osteoporosis may be a lifelong condition. Robust data regarding the efficacy and safety of both long-term osteoporosis therapy and therapy discontinuation are therefore important. A paucity of clinical trial data regarding the long-term antifracture efficacy of osteoporosis therapies necessitates the use of surrogate endpoints in discussions surrounding long-term use and/or discontinuation. Long-term treatment (beyond 3-4 years) may produce further increases in bone mineral density (BMD) or BMD stability, depending on the specific treatment and the skeletal site. Bisphosphonates, when discontinued, are associated with a prolonged reduction in bone turnover markers (BTMs), with a very gradual increase to pretreatment levels within 3 to 60 months of treatment cessation, depending on the bisphosphonate used and the prior duration of therapy. In contrast, with nonbisphosphonate antiresorptive agents, such as estrogen and denosumab, BTMs rebound to above pretreatment values within months of discontinuation. The pattern of BTM change is generally mirrored by a more or less rapid decrease in BMD. Although the prolonged effect of some bisphosphonates on BTMs and BMD may contribute to residual benefit on bone strength, it may also raise safety concerns. Adequately powered postdiscontinuation fracture studies and conclusive evidence on maintenance or loss of fracture benefit is lacking for bisphosphonates. Similarly, the effects of rapid reversal of bone turnover upon discontinuation of denosumab on fracture risk remain unknown. Ideally, studies evaluating the effects of long-term treatment and treatment discontinuation should be designed to provide head-to-head ''offset'' data between bisphosphonates and nonbisphosphonate antiresorptive agents. In the absence of this, a clinical recommendation for physicians may be to periodically assess the benefits/risks of continuation versus discontinuation versus alternative management strategies. ß

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Postmenopausal osteoporosis treatment with antiresorptives: Effects of discontinuation or long-term continuation on bone turnover and fracture risk—a perspective

Boonen¹,

Ferrari²,

Miller³

et al. 2012

Journal of Bone and Mineral Research

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“…The mechanical properties of bone can be significantly influenced by the number, size, and location of resorption cavities [16]. Their effect can be related to the initial porosity [16,17] and to the strain distribution.…”

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confidence: 99%

The complex relationship between bone remodeling and the physical and material properties of bone

Burr

2014

Osteoporos Int

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“…(22,(27)(28)(29) Biochemical markers of bone turnover (BTM) that also reflect the pharmacological response(s) to osteoporosis therapies to reduce fracture risk, at least in groups of patients, are certainly in the orchestra and may take an increasingly important role in monitoring: perhaps, now, the third fiddle. (30)(31)(32)(33) For individual patient management, there must be improvements in the BTM assay standardization, harmonization, and reference population databases before they become a trusted third fiddle. (34)(35)(36) In this issue of the JBMR, Jacques and colleagues (37) report that, once again, there appears to be a robust relationship between the increase in total hip BMD as measured by DXA and the reduction in fracture risk with annual (5 mg) IV zoledronic acid.…”

mentioning

confidence: 99%

“…Both of these FDA-registered agents seem to have the greatest effect on reducing bone remodeling (turnover), and there is evidence that fracture risk reduction with antiresorptive agents is independently associated with reduction in bone turnover-an effect seen even after adjusting for the component of fracture risk reduction due to increases in BMD. (19,22,(30)(31)35) Bone microarchitectural data suggests that bone strength is impaired by the effect of higher bone turnover on remodeling space (''stress-risers'' and/or geometry of the trabecular plates or cortical porosity) which may influence bone strength beyond bone density. (39)(40)(41)(42)(43) What can we take away from these important data?…”

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confidence: 99%

Bone strength and surrogate markers: The first, second, and third fiddle

Miller

2012

Journal of Bone and Mineral Research

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Ever since the publication of the United States fluoride clinical trial data showing that the studied dose of fluoride therapy in postmenopausal osteoporosis (PMO) induced a linear increase in spinal bone mineral density (BMD) but without a reduction in fracture risk, (1) registration for all subsequent therapies for the treatment of PMO required evidence for fracture risk reduction as the primary endpoint-the first fiddle.(2) The previous preemptive role that this surrogate marker (pharmacologically-induced increase in BMD) had held as the indicator for improvement in bone strength now became the second fiddle. In a symphony orchestra the second fiddle plays a less robust role to the first fiddle-changes in BMD became the less robust endpoint for risk reduction and it now became the second fiddle for registration of therapies for the treatment of PMO. Nevertheless, despite fracture reduction required for primary registration, the subsequent registration of the intermittent dosing formulations of bisphosphonate therapies for the treatment of PMO, with the exception of annual intravenous (IV) zoledronic acid, were approved, not on the basis of any fracture data, but on the demonstration that the weekly or monthly oral, or quarterly IV bisphosphonates showed a noninferior increase in lumbar spine BMD as the fracture-proven daily formulation.(3-5) For these studies, the second fiddle regained the first fiddle's chair. Annual zoledronic acid registration for PMO still required fracture data for primary registration, because there had not been a previous dosing formulation studied with a placebo group in a fracture trial with this bisphosphonate.In the years 2000 and 2002 there appeared two meta-analyses from similar datasets, examining the relationship between osteoporosis drug-induced increases in spine BMD and fracture risk reduction that came to dissimilar conclusions: the first, that the relationship between increases in BMD and risk reduction was linear; the second, that it was not. (7,8) Since these meta-analyses were published, there have been analyses examining either the validity or the magnitude of this relationship, (9,10) and others comparing osteoporosis therapies that increase BMD between bisphosphonates but without fracture data. (11,12) Some of the differences among published conclusions may be related to real differences between or among agents, differences in compliance, or differences in study design or study analysis. (13)(14)(15)(16)(17)(18)(19)(20)(21)(22) The uncertainty between the importance of the first fiddle versus the second fiddle, understandably, has led the U.S. Food and Drug Administration (FDA) to still require evidence for fracture risk reduction over 3 years as compared to placebo for registration of treatments for PMO-a prohibitively expensive, and perhaps unethical, place for patients, clinical investigators, and industry research and development to be put at this time. The search for the replacement of the first fiddle and an accurate surrogate marker of bone strength has been...

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How can bone turnover modify bone strength independent of bone mass?

Cited by 73 publications

References 62 publications

Postmenopausal osteoporosis treatment with antiresorptives: Effects of discontinuation or long-term continuation on bone turnover and fracture risk—a perspective

Postmenopausal osteoporosis treatment with antiresorptives: Effects of discontinuation or long-term continuation on bone turnover and fracture risk—a perspective

The complex relationship between bone remodeling and the physical and material properties of bone

Bone strength and surrogate markers: The first, second, and third fiddle

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