Surface-specific bone formation effects of osteoporosis pharmacological treatments

Current anti-osteoporotic pharmacological treatments reduce fracture risk in part by altering bone remodeling/modeling. These effects can manifest on any or all of the bone envelopes—periosteal, intracortical, and trabecular/endocortical—each of which has unique effects on the biomechanical properties of bone. The purpose of this review is to provide an overview of how the most common FDA-approved anti-osteoporosis agents [bisphosphonates, estrogen/hormone replacement therapy, selective estrogen receptor modulators (SERMs), and parathyroid hormone (PTH)] affect tissue-level remodeling/modeling on each of the bone surfaces. Iliac crest biopsy data, the only means of assessing surface-specific bone formation in humans, exist for all of these agents although they predominately focus on trabecular/endocortical surfaces. Data from pre-clinical animal models provide an essential complement to human studies, particuarily for changes on periosteal surfaces and within the intracortical envelope. Although all of the anti-catabolic agents (estrogen replacement therapy, SERMs, bisphosphonates) exert positive effects on the various bone surfaces, the bisphosphonates produce the unique biomechanical combination of allowing normal periosteal expansion while limiting remodeling-induced bone loss on intracortical and trabecular/endocortical surfaces. PTH, the only FDA-approved anabolic agent, exerts biomechanically favorable alterations though enhanced trabecular/endocortical surface activity while also stimulating periosteal expansion. Through understanding how current and future anti-osteoporotic agents influence surface-specific bone activity we will move one step closer to developing agents that could potentially target a particular bone surface

Preclinical Models for Skeletal Research: How Commonly Used Species Mimic (or Don’t) Aspects of Human Bone

Preclinical studies play an indispensable role in exploring the biological regulation of the musculoskeletal system. They are required in all drug development pipelines where both small and large animal models are needed to understand efficacy and side effects. This brief review highlights 4 aspects of human bone, longitudinal bone growth, intracortical remodeling, collagen/mineral interface, and age-related changes, and discusses how various animal models recapitulate (or don’t) these aspects of human skeletal physiology

Recent Advances in Understanding Bisphosphonate Effects on Bone Mechanical Properties

Purpose of the Review Bisphosphonates have well-established effects on suppressing bone resorption and slowing bone loss, yet the effects on bone mechanical properties are less clear. We review recent data from pre-clinical and clinical experiments that assessed mechanical properties of bisphosphonate-treated specimens. Recent Findings Pre-clinical work has utilized new techniques to show reduced fatigue life and transfer of stress from the mineral to collagen. Several notable studies have examined mechanical properties of tissue from patients treated with bisphosphonates with mixed results. Pre-clinical data suggest effects on mechanics may be independent of remodeling suppression. Summary The direct effect of bisphosphonates on bone mechanics remains unclear but recent work has set a solid foundation for the coming years

Mandibular necrosis in beagle dogs treated with bisphosphonates

Objectives –  To test the effect of bisphosphonate (BP) treatment for up to 3 years on bone necrosis and osteocyte death in the mandible using a canine model. Materials and Methods –  Dogs were treated with clinical doses of oral alendronate (ALN, 0.2 or 1.0 mg/kg/day) for 1 or 3 years. In a separate study, dogs were treated with i.v. zoledronate (ZOL) at 0.06 mg/kg/day for 6 months. En bloc staining was used to identify necrotic areas in the mandible; viable osteocytes were identified using lactate dehydrogenase. Results –  None of the treatments was associated with exposed bone, but 17–25% of dogs treated for 1 year and 25–33% of dogs treated for 3 years with ALN showed pockets of dead bone. Necrotic areas had no viable osteocytes and were void of patent canaliculi. No control animals demonstrated necrotic bone. ZOL treatment for 6 months was associated with osteocyte death greater than that seen in animals treated with ALN or saline. It is not clear whether osteocyte death occurs because of direct toxic effects of BPs, or because suppressed remodelling fails to renew areas that naturally undergo cell death. Necrotic areas are also associated with bone other than the mandible, e.g. the rib, which normally undergo high rates of remodelling. Conclusions –  Reduced remodelling rate using BPs may contribute to the pathogenesis of bone matrix necrosis. The development of an animal model that mimics important aspects of BP-related osteonecrosis of the jaw is important to understanding the pathogenesis of osteonecrosis

The pathogenesis of bisphosphonate-related osteonecrosis of the jaw: so many hypotheses, so few data.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) has generated great interest in the medical and research communities yet remains an enigma, given its unknown pathogenesis. The goal of this review is to summarize the various proposed hypotheses underlying BRONJ. Although a role of the oral mucosa has been proposed, the bone is likely the primary tissue of interest for BRONJ. The most popular BRONJ hypothesis-manifestation of necrotic bone resulting from bisphosphonate--induced remodeling suppression--is supported mostly by indirect evidence, although recent data have shown that bisphosphonates significantly reduce remodeling in the jaw. Remodeling suppression would be expected, and has been shown, to allow accumulation of nonviable osteocytes, whereas a more direct cytotoxic effect of bisphosphonates on osteocytes has also been proposed. Bisphosphonates have antiangiogenic effects, leading to speculation that this could contribute to the BRONJ pathogenesis. Compromised angiogenesis would most likely be involved in post-intervention healing, although other aspects of the vasculature (eg, blood flow) could contribute to BRONJ. Despite infection being present in many BRONJ patients, there is no clear evidence as to whether infection is a primary or secondary event in the pathophysiology. In addition to these main factors proposed in the pathogenesis, numerous cofactors associated with BRONJ (eg, diabetes, smoking, dental extraction, concurrent medications) could interact with bisphosphonates and affect remodeling, angiogenesis/blood flow, and/or infection. Because our lack of knowledge concerning BRONJ pathogenesis results from a lack of data, it is only through the initiation of hypothesis-driven studies that significant progress will be made to understand this serious and debilitating condition

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

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

Skeletal Microdamage: Less About Biomechanics and More About Remodeling

The mechanical consequences of skeletal microdamage have been clearly documented using various experimental methods, yet recent experiments suggest that physiological levels of microdamage accumulation are not sufficient to compromise the bones’ biomechanical properties. While great advances have been made in our understanding of the biomechanical implications of microdamage, less is known concerning the physiological role of microdamage in bone remodeling. Microdamage has been shown to act as a signal for bone remodeling, likely through a disruption of the osteocyte-canalicular network. Interestingly, age-related increases in microdamage are not accompanied by increases in bone remodeling suggesting that the physiological mechanisms which link microdamage and remodeling are compromised with aging

Short-courses of dexamethasone abolish bisphosphonate-induced reductions in bone toughness.

Bone Biology Laboratory http://www.iupui.edu/~bonelab/ Department of Anatomy and Cell Biology Indiana University School of MedicineAtypical femoral fractures, which display characteristics of brittle material failure, have been associated with potent remodeling suppression drugs. Given the millions of individuals treated with this class of drugs it is likely that other factors play a role in these fractures. Some evidence suggests concomitant use of corticosteroids may contribute to the pathogenesis although data in this area is lacking. The goal of this study was to assess the combined role of bisphosphonates and examethasone on bone mechanical properties. Skeletally mature beagle dogs were either untreated controls, or treated with zoledronic acid (ZOL), dexamethasone (DEX), or ZOL + DEX. Zoledronic acid (0.06 mg/kg) was given monthly via IV infusion for 9 months. DEX (5 mg) was administered daily for one week during each of the last three months of the 9 month experiment. Ribs were harvested and assessed for bone geometry, mechanical properties, and remodeling rate (n=3-6 specimens per group). DEX significantly suppressed intracortical remodeling compared to vehicle controls while both ZOL and the combination of DEX+ZOL nearly abolished intracortical remodeling. ZOL treatment resulted in significantly lower bone toughness, determined from 3-point bending tests, compared to all other treatment groups while the toughness in ZOL+DEX animals was identical to those of untreated controls. These findings suggest not only that short-courses of dexamethasone do not adversely affect toughness in the setting of bisphosphonates, they actually reverse the adverse effects of its treatment. Understanding the mechanism for this tissue-level effect could lead to novels approaches for reducing the risk of atypical femoral fractures.We would like to thank Carrie Pell and her staff for assistance with animal care, Keith Condon for his assistance with histological processing. This work was supported by a grant from the NIH (DE019686 – MRA)

Three years of alendronate treatment results in similar levels of vertebral microdamage as after one year of treatment

Three years of daily alendronate treatment increases microdamage in vertebral bone but does not significantly increase it beyond levels of microdamage found after 1 yr of treatment. This suggests microdamage accumulation peaks during the early period of bisphosphonate treatment and does not continue to accumulate with longer periods of treatment. INTRODUCTION: Clinically relevant doses of alendronate increase vertebral microdamage by 4- to 5-fold in skeletally mature beagles after 1 yr of treatment. The goal of this study was to determine whether microdamage would continue to accumulate with 3 yr of alendronate treatment in an intact beagle dog model. MATERIALS AND METHODS: One-year-old female beagles were treated with daily oral doses of vehicle (VEH, 1 ml/kg/d) or alendronate (ALN, 0.2 or 1.0 mg/kg/d) for 3 yr. These ALN doses were chosen to approximate, on a milligram per kilogram basis, those used to treat osteoporosis (ALN0.2) and Paget's disease (ALN1.0). Microdamage accumulation, static and dynamic histomorphometry, densitometry, and mechanical properties of lumbar vertebrae were assessed. Comparisons were made among the three groups treated for 3 yr and also within each treatment group to animals treated under the same conditions for 1 yr. RESULTS: Overall microdamage accumulation (crack surface density) was not significantly higher in animals treated for 3 yr with either dose of ALN, whereas crack density increased significantly (100%; p < 0.05) with the higher dose of ALN compared with VEH. Both ALN doses significantly suppressed the rate of bone turnover (-60% versus VEH). There was no difference among groups for any of the structural biomechanical properties-ultimate load, stiffness, or energy absorption. However, when adjusted for areal BMD, ALN-treated animals had significantly lower energy absorption (-20%) compared with VEH. Toughness, the energy absorption capacity of the bone tissue, was significantly lower than VEH for both ALN0.2 (-27%) and ALN1.0 (-33%). Compared with animals treated for 1 yr, there was no significant difference in microdamage accumulation for either ALN dose. VEH-treated animals had significantly lower bone turnover (-58%) and significantly higher levels of microdamage (+300%) compared with values in 1-yr animals. Toughness was significantly lower in animals treated for 3 yr with ALN1.0 (-18%) compared with animals treated for 1 yr, whereas there was no difference in toughness between the two treatment durations for either VEH or ALN0.2. CONCLUSIONS: Although 3 yr of ALN treatment resulted in higher microcrack density in vertebral trabecular bone compared with control dogs, the amount of microdamage was not significantly higher than animals treated for 1 yr with similar doses. This suggests that bisphosphonate-associated increases in microdamage occur early in treatment. Because toughness continued to decline significantly over 3 yr of treatment at the higher ALN dose, decreases in toughness are probably not dependent on damage accumulation.The authors thank Keith Condon, Diana Jacob, and Lauren Waugh for histological preparation and Andrew Koivuniemi and Mark Koivuniemi for assistance with densitometry and mechanical testing. This work was supported by NIH Grants AR047838 and AR007581 and utilized an animal facility constructed with support from Research Facilities Improvement Program Grant Number C06 RR10601-01 from the National Center for Research Resources, National Institutes of Health