Correspondence
Giant Osteoclast Formation and Long-Term Oral Bisphosphonate Therapy
N Engl J Med 2009; 360:1676-1678April 16, 2009
- Article
To the Editor:
Weinstein et al. (Jan. 1 issue)1 report on giant osteoclast formation in women receiving long-term oral bisphosphonate therapy. In accordance with the results of their study, our findings from a study of paired biopsy specimens, reported in 2006,2 showed giant osteoclast formation after 38 months in 9 of 23 men who received bisphosphonate therapy (39%). In addition to their presence in men who received alendronate, giant osteoclasts were observed when other nitrogen-containing bisphosphonates, such as risedronate and pamidronate, were administered. All these agents appeared to be associated with cytoskeletal disruption. A prolonged effect of bisphosphonates on the morphologic features of osteoclasts, as detected in biopsy specimens obtained from the group of patients who received 20 mg of alendronate in the study by Weinstein et al., was also seen in biopsy specimens obtained after teriparatide treatment in patients who had previously received bisphosphonates.3
In the editorial accompanying the report by Weinstein et al., Glowacki4 notes that the spatial resolution of intracytoplasmic details in osteoclasts is too poor with the use of conventional microscopy and staining to investigate resorptive capability (Figure 1Figure 1
Biopsy Specimens Obtained from a Patient Who Received Bisphosphonate Therapy for 38 Months.). Instead, the authors could have used histomorphometric resorption indexes as indirect measurements.Considering the small groups and heterogeneity of remodeling sites at the iliac crest, the finding of a dose-dependent increase in the number of osteoclasts in the study reported by Weinstein et al. may be limited by the fact that a baseline comparison was not possible and the initial histologic bone-turnover status (high or low) in the individual patient was not investigated.5
5 ReferencesBjörn Jobke, M.D.
HELIOS Klinikum Berlin-Buch, 13125 Berlin, Germany
bjobke@yahoo.de 1
Weinstein RS ,Roberson PK ,Manolagas SC . Giant osteoclast formation and long-term oral bisphosphonate therapy. N Engl J Med 2009;360:53-62
Full Text | Web of Science | Medline2
Jobke B ,Kulle B ,Semler J ,Delling G . Bisphosphonates improve bone microarchitecture in middle-aged males with osteoporosis by reducing bone turnover: a paired biopsy micro-CT analysis over 38 months. J Bone Miner Res 2006;21:S87-S87
Web of Science3
Jobke B ,Pfeifer M ,Minne HW . Teriparatide following bisphosphonates: initial and long-term effects on microarchitecture and bone remodeling at the human iliac crest. Connect Tissue Res 2009;50:46-54
CrossRef | Web of Science | Medline4
Glowacki J . The deceiving appearances of osteoclasts. N Engl J Med 2009;360:80-82
Full Text | Web of Science | Medline5
Eriksen EF ,Melsen F ,Sod E ,Barton I ,Chines A . Effects of long-term risedronate on bone quality and bone turnover in women with postmenopausal osteoporosis. Bone 2002;31:620-625
CrossRef | Web of Science | Medline
To the Editor:
Weinstein et al. found that alendronate treatment results in the formation of giant hypernucleated osteoclasts, and the authors suggest that these cells form by fusion of existing osteoclast cells. However, there is evidence to suggest endoploidy, or nuclear replication without cytokinesis, as an alternative explanation. First, there was an increase, by a factor of 2.5, in the total number of osteoclasts in patients who received treatment; a reduction would have been expected if there had been widespread fusion. Second, osteoclasts are mononuclear in origin, and such cells are particularly prone to polyploidy. Multinucleated Gaucher's cells, for instance, which are also derived from monocytes, probably form because of glycosylsphingosine-mediated inhibition of cytokinesis.1 Third, Weinstein et al. state that bisphosphonates cause cytoskeletal disruption. We and others2 have shown that treatment with jasplakinolide — a compound derived from a Japanese sea sponge that acts directly on actin to stabilize its filamentous form (and thereby also disrupts the cytoskeleton) — results in failed cytokinesis and the formation of multinucleated cells. Finally, bisphosphonates act synergistically with paclitaxel and with tamoxifen3; such antiproliferative properties would suggest a failure of cell division rather than cell–cell fusion. Further experiments will be needed to determine how these giant osteoclasts form.
3 ReferencesJonathan C. Roos, M.A.
Timothy M. Cox, M.D.
University of Cambridge, Cambridge CB2 2QQ, United Kingdom1
Kanazawa T ,Nakamura S ,Momoi M , et al. Inhibition of cytokinesis by a lipid metabolite, psychosine. J Cell Biol 2000;149:943-950
CrossRef | Web of Science | Medline2
Moulding DA ,Blundell MP ,Spiller DG , et al. Unregulated actin polymerization by WASp causes defects of mitosis and cytokinesis in X-linked neutropenia. J Exp Med 2007;204:2213-2224
CrossRef | Web of Science | Medline3
Green JR . Skeletal complications of prostate cancer: pathophysiology and therapeutic potential of bisphosphonates. Acta Oncol 2005;44:282-292
CrossRef | Web of Science | Medline
Author/Editor Response
We welcome Jobke's confirmation of our findings on the association of long-term bisphosphonate treatment with an increase in giant, hypernucleated, detached osteoclasts. We did not attempt to estimate the erosion depth or other indirect measurements of bone resorption in our study because a previous effort was not successful in showing a difference between the alendronate and placebo groups.1 Osteoclast activity or, more precisely, osteoclast resorptive vigor, cannot be inferred from a static examination of bone after treatment with nitrogen-containing bisphosphonates. Our data indicate that although the number of normal-appearing osteoclasts is significantly increased in patients receiving bisphosphonate therapy, as compared with those receiving placebo, the decrease in biochemical markers and increase in bone density suggest that even normal-appearing osteoclasts may resorb bone poorly. Jobke's micrograph of an osteoclast in a shallow resorption lacuna could represent a cell that has just begun to erode or one that has no current resorptive capability at all. Only in diseases involving very high rates of bone turnover can the rate of resorption be revealed by means of dynamic histomorphometry. For example, in Paget's disease, direct measurement of the rate of bone erosion in individual osteoclasts is possible when pagetic osteoclasts bore through the double-tetracycline-labeled cancellous perimeter while excavating a cavity. From the mean depth of the erosion cavity, dates of tetracycline administration, and time of the biopsy procedure, the minimum initial rate of bone erosion can be calculated in micrometers per day just as precisely as the mineral appositional rate.2 Such an opportunity did not arise in our study.
We believe that Roos and Cox have misunderstood our statements about the production of multinuclear osteoclasts by the fusion of mononuclear precursors to form polykaryons. We did not suggest that this fusion occurred between existing multinuclear osteoclasts. Considerable evidence indicates that osteoclasts are formed by fusion of mononuclear precursors. These findings are from studies that use quail–chick chimeras with some osteoclasts containing nuclei with morphologic features of both quail and chicks,3 as well as from experiments using 3H-thymidine and autoradiography to show that osteoclasts form by the fusion of mononuclear precursors,4,5 not by nuclear replication. The fate of all cells that originate in the hematopoietic environment is to leave, do their work, and die. Finally, it is highly unlikely that the apoptotic nuclei in the giant osteoclasts that we described could divide.
5 ReferencesRobert S. Weinstein, M.D.
Paula K. Roberson, Ph.D.
Stavros C. Manolagas, M.D., Ph.D.
University of Arkansas for Medical Sciences
weinsteinroberts@uams.edu 1
Chavassieux PM ,Arlot ME ,Reda C ,Wei L ,Yates AJ ,Meunier PJ . Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis. J Clin Invest 1997;100:1475-1480
CrossRef | Web of Science | Medline2
Reid IR ,Nicholson GC ,Weinstein RS , et al. Biochemical and radiologic improvement in Paget's disease of bone treated with alendronate: a randomized, placebo-controlled trial. Am J Med 1996;101:341-348[Erratum, Am J Med 1997;102:322.]
CrossRef | Web of Science | Medline3
Kahn AJ ,Simmons DJ . Investigation of cell lineage in bone using a chimera of chick and quail embryonic tissue. Nature 1975;258:325-327
CrossRef | Web of Science | Medline4
Mundy GR. Bone remodeling and its disorders. London: Martin Dunitz, 1995:18-9.
5
Jilka RL, Bellido T, Almeida M, et al. Apoptosis in bone cells. In: Bilezikian JP, Raisz LG, Martin TJ, eds. Principles of bone biology. 3rd ed. Vol. 1. San Diego, CA: Academic Press, 2008:235-59.
