Original Full Length ArticleBisphosphonate-osteoclasts: Changes in osteoclast morphology and function induced by antiresorptive nitrogen-containing bisphosphonate treatment in osteoporosis patients
Introduction
Bisphosphonates (BP) as a treatment for osteoporosis have been in clinical use for over two decades and proven to be effective in fracture prevention [1], [2], [3]. Following early laboratory experiments by Fleisch et al. in the late 1960s [4], several bone markers and histomorphometry studies have shown the antiresorptive action of BP. Based on their effects on osteoclasts' (Oc) function, BP were reported to cause a general reduction in bone turnover, the degree of which can be perceived as a surrogate parameter for treatment efficacy [5], [6], [7], [8], [9], [10], [11]. BPs are incorporated into bone for an extended period of time and continue to affect bone metabolism long after cessation of intake [11], [12]. The substance is relatively safe, however, possible osteonecrosis of the jaw in oncology patients under high-dose BP administration and atypical femoral fractures are nowadays believed to be caused by oversuppression of bone remodeling — although this is still a matter of debate [11], [13], [14], [15], [16], [17], [18], [19].
BP molecules have a strong affinity to the bone surface [20] where nitrogen-containing BPs (N-BP) once assimilated by osteoclasts inhibit the mevalonate pathway enzyme farnesyldiphosphate (FPP) synthase and disrupt the cytoskeleton which affects the ruffled border and results in a loss of function [21]. Given that the osteoclasts/osteoblasts ratio in histological sections is approximately 1:6 [22] and since osteoclasts display a three- to four-fold shorter lifespan than osteoblasts, the cells capable of bone resorption are rare in histological sections [23], [24]. The short time span of Oc apoptosis makes this brief stage a rarely observed event in histological sections which makes it difficult to acquire large subgroups of this cell type with special findings. Despite extensive research on both the therapeutic benefits and side effects of BP, the true nature of their effects on osteoclast morphology, vitality, life-span and fate remains inconclusive.
Following earlier histological studies that described treatment-induced changes in the Oc phenotype, Weinstein et al. reported data on “giant osteoclast formation after long-term oral BP therapy” [25]. Weinstein's study in a clinical setting frequently showed morphological changes and apoptosis of osteoclasts, as well as an increase in Oc number following BP treatment. Similar morphological cell changes have also been observed by others and ourselves [26], [27], [28], [29]. However, so far a number of questions regarding the affected osteoclasts remain unanswered, such as i) how the bisphosphonates affect Oc function as reflected in erosion surface and resorption depth in osteoporotic patients, and ii) whether there is discordance between osteoclast number and anti-resorptive effects. In addition, the effect of BP in a male cohort without the influence of hormonal changes, the role of intravenous BP administration, as well as the influence of different BP classes all require proper attention [30], [31].
To directly explore the effects of N-BP treatment on osteoclasts' morphology and function in each individual, we conducted a histomorphometric paired-biopsy study in osteoporosis patients before and after the anti-resorptive bisphosphonate treatment.
Section snippets
Material and methods
Bone biopsies from the dorsal iliac crest were acquired by an experienced physician performing the Jamshidi technique from 37 patients at one institution, as described previously [32]. Patients had osteoporosis as defined by the WHO and confirmed by dual X-ray absorptiometry. For each patient, a baseline biopsy and a follow-up biopsy were available. In the treatment group, 23 patients (18 males, 5 females; age: 52.6 ± 11.5 yrs) underwent bone biopsy at two time points: at baseline (before starting
Osteoclast morphology and resorption patterns
Unusual osteoclast morphology or hypernucleation (> 3–4 nuclei) was not observed in the two control groups or at baseline in the treatment group. However, in 39.1% of patients in the N-BP treatment group, there was an obvious increase in osteoclast cell size and shape, as well as in the number of nuclei (> 10 nuclei/Oc) in follow-up biopsies (Fig. 2A). Six out of nine patients who developed bisphosphonate osteoclasts had received oral alendronate treatment, while the remaining three received
Discussion
Osteoclasts play a pivotal role in bone remodeling and are key factors in many bone disorders such as osteoporosis, which is of major interest to the health care community. In this paired-biopsy study of osteoporosis patients, we focused on osteoclast morphology under the influence of antiresorptive treatment with nitrogen-containing bisphosphonates and expand knowledge about Oc vitality, life cycle and implications. Osteoclastogenesis, which includes the development, differentiation and
Conclusion
In paired biopsies from a cohort of osteoporosis patients, we assessed changes in osteoclast morphology induced by nitrogen-containing bisphosphonate treatment. Characteristic large osteoclasts as described here, are uniquely found in patients under bisphosphonate-treatment and were termed ‘Bisphosphonate-Osteoclasts’ to clearly distinguish them from giant osteoclasts in other bone disorders, such as Paget's disease, secondary hyperparathyroidism or osteopetrosis [71], [72], [73]. Our study
Conflict of interest
All authors state that they have no conflicts of interest.
Acknowledgments
Dr. Petar Milovanovic is a fellow of the DAAD (Deutscher Akademischer Austauschdienst — German Academic Exchange Service; A/11/83161), Serbian Ministry of Education and Science (III45005), and acknowledges the support from the European Federation for Experimental Morphology (EFEM Travel Grant 2013). Dr. Björn Busse is a fellow of the DFG — Emmy Noether program (Deutsche Forschungsgemeinschaft — German Research Foundation; BU 2562/2-1). This study was supported by grants from the
References (73)
- et al.
The effect of risedronate on bone mineralization as measured by micro-computed tomography with synchrotron radiation: correlation to histomorphometric indices of turnover
Bone
(2005) - et al.
Effects of long-term risedronate on bone quality and bone turnover in women with postmenopausal osteoporosis
Bone
(2002) - et al.
Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday
Am J Med
(2013) - et al.
Atypical femoral fractures are a separate entity, characterized by highly specific radiographic features. A comparison of 59 cases and 218 controls
Bone
(2013) - et al.
Apoptosis and osteoporosis
Am J Med
(2000) - et al.
Quantitative bone histology: a new method
Pathology
(1980) - et al.
Effects of strontium ranelate administration on bisphosphonate-altered hydroxyapatite: matrix incorporation of strontium is accompanied by changes in mineralization and microstructure
Acta Biomater
(2010) - et al.
Osteoclast enlargement in endstage renal disease
Kidney Int
(1985) - et al.
Effects of ethane-1-hydroxy-1, 1-diphosphonate on cell-differentiation, and proteoglycan and calcium-metabolism, in the proximal tibia of young-rats
Bone
(1991) - et al.
Histomorphometry of how ships lacunae formed invivo and invitro — depths and volumes measured by scanning electron and confocal microscopy
Bone
(1993)
RNA-synthesis in isolated rat osteoclasts — inhibitory effect of calcitonin
Bone
Ultrastructural and cytochemical studies on cell death of osteoclasts induced by bisphosphonate treatment
Bone
High bone turnover is associated with low bone mass in both pre- and postmenopausal women
Bone
Biochemical markers for prediction of 4-year response in bone mass during bisphosphonate treatment for prevention of postmenopausal osteoporosis
Bone
Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial
Bone
Calcitonin induces podosome disassembly and detachment of osteoclasts by modulating Pyk2 and Src activities
Bone
Malignant osteopetrosis — a disease of abnormal osteoclast proliferation
Metab Bone Dis Relat Res
Effects of continuing or stopping alendronate after 5 years of treatment — the Fracture Intervention Trial long-term extension (FLEX): a randomized trial
JAMA
Ten years' experience with alendronate for osteoporosis in postmenopausal women
N Engl J Med
Efficacy and safety of a once-yearly intravenous zoledronic acid 5 mg for fracture prevention in elderly postmenopausal women with osteoporosis aged 75 and older
J Am Geriatr Soc
Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo
Science
Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial
J Bone Miner Res
Dose–response relationships for alendronate treatment in osteoporotic elderly women
J Clin Endocrinol Metabol
Effect of monitoring bone turnover markers on persistence with risedronate treatment of postmenopausal osteoporosis
J Clin Endocrinol Metabol
Markers of bone turnover predict postmenopausal forearm bone loss over 4 years: the OFELY study
J Bone Miner Res
Fracture risk remains reduced one year after discontinuation of risedronate
Osteoporos Int
Atypical femur fractures: 81 individual personal histories
J Clin Endocrinol Metabol
Bisphosphonate use and atypical fractures of the femoral shaft
N Eng J Med
Disease-specific risk for an osteonecrosis of the jaw under bisphosphonate therapy
J Cancer Res Clin Oncol
Severely suppressed bone turnover: a potential complication of alendronate therapy
J Clin Endocrinol Metabol
Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research
J Bone Miner Res
Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research
J Bone Miner Res
Bisphosphonates — history and experimental basis
Bone
In vivo effects of bisphosphonates on the osteoclast mevalonate pathway
Endocrinology
Osteoblast and osteoclast cell number and cell-activity in postmenopausal osteoporosis
Miner Electrolyte Metab
Diminished rates of bone-formation in normal black adults
N Eng J Med
Cited by (102)
Development of an injectable chitosan-based hydrogel containing nano-hydroxy-apatite and alendronate for MSC-based therapy
2024, International Journal of Biological MacromoleculesThe multi-faceted nature of age-associated osteoporosis
2024, Bone ReportsDisruption of FDPS/Rac1 axis radiosensitizes pancreatic ductal adenocarcinoma by attenuating DNA damage response and immunosuppressive signalling
2022, eBioMedicineCitation Excerpt :In preclinical 3D tumouroid models, treatment with Zol attenuated tumouroid growth.8 Due to its inhibitory effects on osteoclasts, Zol has been primarily investigated as a palliative treatment for cancers that are related to bone (e.g., osteosarcomas), associated with bone metastasis (e.g., breast, prostate, and lung), and causing bone turnover (multiple myeloma).12–14 In multiple myeloma, Zol was shown to reduce the risk associated with mortality by 25%, along with a reduction of skeletal-related events by 25%, compared with pamidronate, another bisphosphonate approved for multiple myeloma treatment.15
Impact of preoperative treatment of osteoporosis on re-operations, complications and health care utilization in patients undergoing thoraco-lumbar spine fusions. A 5-year national database analysis
2021, Journal of Clinical NeuroscienceCitation Excerpt :Among these medications, bisphosphonates are commonly used medications in routine clinical practice, in our study 81% of patients received pre-operative bisphosphonates. Bisphosphonates act by inhibiting osteoclastic activity; therefore, reducing bone resorption and stabilizing bone mass [39]. Given the anti-resorptive mechanism of bisphosphonates, there was concern regarding imbalance between osteoblastic and osteoclastic activity which may result in poor integration of graft and subsequent fusion [40].