Good, good, good… good vibrations: the best option for better bones?

COMMENTARY

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vasculature of the normal human and alopecia areata (AA) hair follicle: an immunohistochemical, laser scanning confocal microscope study. In: Van Neste D, Randall VA, eds. Hair research for the next millenium. Amsterdam: Elsevier, 1996; 197–202. Rossi R, Del Bianco E, Isolani D, Baccari MC, Cappugi P. Possible involvement of neuropeptidergic sensory nerves in alopecia areata. Neuroreport 1997; 8: 1135–38. Paus R, Heinzelmann T, Schultz K-D, Furkert J, Fechner K, Czarnetski BM. Hair growth induction by substance P. Lab Invest 1994; 71: 134–40. Hordinsky M, Ericson M, Snow D, Boeck C, Klee WS. Peribulbar innovation and substance P expression following non-permanent injury to the human scalp hair follicle. J Invest Dermatol Symp Proc 1999; 4: 316–19. Olerud JE, Usui ML, Seekin D, et al. Neutral endopeptidase expression and distribution in human skin and wounds. J Invest Dermatol 1999; 112: 873–81. Daly TJ. Alopecia areata has low plasma levels of the vasodilater/ immunomodulator calcitonin gene-related peptide. Arch Dermatol 1998; 134: 1164–65. Peters EMJ, Botchkarev VA, Botchkarev NV, Tobin DJ, Paus R. Haircycle-associated remodeling of the peptidergic innervation of murine skin, and hair growth modulation by neuropeptides. J Invest Dermatol 2001; 116: 236–45. Hosoi J, Murphy GF, Egan CL, et al. Regulation of Langerhans cell function by nerves containing calcitonin gene-related peptide. Nature 1993; 363: 159–63. Duvic M, Nelson A, de Andrade M. The genetics of alopecia areata. Clin Dermatol 2001: 19: 135–39. Colombe BW, Lou CD, Price VH. The genetic basis of alopecia areata: HLA associations with patchy alopecia areata versus alopecia totalis and alopecia universalis. J Invest Dermatol Symp Proc 1999: 4: 216–19. Tobin DJ, Orentreich N, Fenton DA, Bystryn J-C. Antibodies to hair follicles in alopecia areata. J Invest Dermatol 1994; 102: 721–24. Christoph T, Müller-Röver S, Audring H, et al. The human hair follicle immune system: cellular composition and immune privilege. Br J Dermatol 2000; 142: 862–73. Gilhar A, Shalaginov R, Assay B, Serafimovich S, Kalish RS. Alopecia areata is a T-lymphocyte mediated autoimmune disease: lesional human T-lymphocytes transfer alopecia areata to human skin grafts on SCID mice. J Invest Dermatol 1999; 4: 207–10. McElwee KJ, Spiers EM, Oliver RF. In vivo depletion of CD8+T cells restores hair growth in the DEBR model for alopecia areata. Br J Dermatol 1996; 135: 211–17. Freyschmidt-Paul P, Seiter S, Zoller M, et al. Treatment with an antiCD44v10–specific antibody inhibits the onset of alopecia areata in C3H/HeJ mice. J Invest Dermatol 2000; 115: 653–57. Philpott MP. The roles of growth factors in hair follicles: investigations using cultured hair follicles. In: Camacho FM, Randall VA, Price VH. eds. Hair and its disorders; biology, pathology and management. London: Martin Dunitz, 2000; 103–13.

Good, good, good . . . good vibrations: the best option for better bones? There are many reports about the effects of exercise on bone but, overall, the data are not very encouraging. Some of the poor results may be attributed to difficulties with compliance. However, even among studies with positive results, the size of the effect, generally an increase of 1–2% in bone density, is disappointing. Not surprisingly, several meta-analyses have found the effect of impact or lowimpact exercise on proximal femoral and forearm sites to be minimal or absent.1-5 None of the studies on exercise has had enough power to assess fracture risk. In a recent brief communication, Clinton Rubin and colleagues6 reported that having adult ewes stand on a platform with high-frequency vibration for 20 min each day for 5 days a week over 1 year increased femoral trabecular bone density by 32%. Bone trabeculae were also shown to have closer spacing, which is consistent with stronger bone. Histomorphometric studies of bone turnover suggest that this effect may be due to the increased (more than two-fold, but not statistically significant) bone formation and mineralisation. However, there were no changes in cortical bone. One remarkable feature is that the load applied to 1924

bone from this vibration is about 5 microstrain, which is considerably less than the load sustained during roaming of the pasture, which the animals (treated and controls) did the rest of the time. This study follows a shorter-term study in mature female rats, in which a similar high-frequency, very-low-amplitude vibrations (0·25 g equivalent to <10 microstrain at 90 Hz vibration for 10 min, 5 days per week) was able to completely block the adverse effects on hindlimb bone density induced by tail suspension, whereas a similar period of normal load bearing did not.7 These data suggest a specific effect of the high frequency of these remarkably small loads. Could these animal studies be relevant to osteoporosis in human beings? At the recent meeting of the American Society for Bone and Mineral Research, Ward and colleagues8 reported results of a small randomised, placebo-controlled study among 20 children with cerebral palsy who used a similar, commercially available vibrating platform for 10 min per day, 5 days per week for 6 months. They observed a significant increase in tibial, but not lumbar-spine bone density in the treated group. Despite the simplicity and short duration of the “vibration” and the young age of the children, compliance was low—less than 50% completed the study. Such poor compliance is particularly disappointing if use of the vibration platform is seen as an alternative to “exercise”, which is generally not widely taken up. However, sex-hormone status may be another factor that could partly account for the difference in results between Ward and colleagues study and those from Rubin and colleagues. The animals in Rubin and colleagues’ studies were mature eugonadal animals. Extrapolated to human beings, perhaps vibration on a platform might be useful only in eugonadal individuals—ie, postpubertal, premenopausal, or on hormone-replacement therapy. Current preventive approaches to osteoporosis include lifestyle recommendations, including exercise and appropriate intake of calcium and vitamin D, the use of hormone replacement or similar therapy to reduce bone loss and, in later stages, antiresorptive agents, such as selective oestrogen-receptor modulators and biphosphonates. These antiresorptive agents are generally used after a fracture; they may reduce fracture risk by about 50% but do not return it to prefracture values. All these existing therapies have modest effects on measured bone density, of the order of a 5–10% increase over several years. Only parathyroid hormone (given subcutaneously) seems to have a true “anabolic” effect and has been reported to increase bone density to the extent seen in Rubin and colleagues’ study.9 Thus, the striking effects of a non-invasive “good vibrations” approach, if shown to be generally applicable and comparably effective in human beings, would be of considerable potential benefit. In human beings, bone density, the best predictor of fracture risk, is strongly associated with bodyweight. Bodyweight is the strongest and often only “environmental” determinant of bone density in crosssectional studies. Various investigators have suggested that this relation is due to the increased fat mass (and thus to humoral factors derived from it) or increased muscle mass (and thus to the muscular pull exerted on the skeleton). The studies from Rubin and colleagues suggest that the load associated with normal activities amplified by bodyweight may have a role in maintaining the integrity of bone structure. Could it be that the rapid corrections of muscle pulls during normal activities are amplified by the extra instability associated with moving a larger body bulk and may induce rapid high-frequency oscillations? Could this effect relate to neuromuscular function and neural or even paracrine effects on the adjacent bone? These findings

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COMMENTARY

are also consistent with the suggestion that horizontal forces during normal walking are needed for optimum skeletal loading.10 Similarly it is recognised that the anabolic response of bone to skeletal loading, both of animals and human beings, is most effective when the rates are rapid but of short duration and “unusual” in direction.11–13 There is however, a potentially narrow gap between benefits and adverse effects of load bearing. Spinal density has been shown to decrease in young women who exercise too heavily14 and application of a static load to rat ulna for 10 min per day slowed growth and decreased bone apposition, whereas a similar but dynamic strain (2 Hz, about 3500 microstrain) increased bone apposition.15 Another aspect of physical loading studies is that there seems to be important interindividual and interstrain differences in load responses,16–18 and there have been differences in effects by site (lower leg vs lumbar spine) and type of bone (trabecular vs cortical). Since bone strength is due to a composite of trabecular and cortical bone as well as complex aspects of bone geometry, it is not clear that the changes observed would necessarily translate into clinically relevant or sustained effects on overall bone strength.19 Thus, despite some uncertainties, the work of Rubin and his colleagues indicates the clinically relevant potential of non-invasive, short-duration, mechanical stimulation that could have an impact on osteoporosis risk. These studies of high-frequency vibrations on bone have raised many questions that can be answered only by careful randomised appropriately blinded, long-term studies. As with all other valid osteoporosis research, surrogate markers such as bone density and changes in bone turnover may identify the optimum dose for the important phase III studies that have clinically relevant endpoints, such as fracture risk. John A Eisman Bone and Mineral Research Program, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia (e-mail: [email protected]) 1

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Wallace BA, Cumming RG. Systematic review of randomized trials of the effect of exercise on bone mass in pre- and postmenopausal women. Calcif Tissue Int 2000; 67: 10–18. Kelley GA. Exercise and regional bone mineral density in postmenopausal women: a meta-analytic review of randomized trials. Am J Phys Med Rehabil 1998; 77: 76–87. Berard A, Bravo G, Gauthier P. Meta-analysis of the effectiveness of physical activity for the prevention of bone loss in postmenopausal women. Osteoporos Int 1997; 7: 331–37. Gregg EW, Pereira MA, Caspersen CJ. Physical activity, falls, and fractures among older adults: a review of the epidemiologic evidence. J Am Geriatr Soc 2000; 48: 883–93. Wolff I, van Croonenborg JJ, Kemper HC, Kostense PJ, Twisk JW. The effect of exercise training programs on bone mass: a meta-analysis of published controlled trials in pre- and postmenopausal women. Osteoporos Int 1999; 9: 1–12. Rubin C, Turner AS, Bain S, Mallinckrodt C, McLeod K. Anabolism. Low mechanical signals strengthen long bones. Nature 2001; 412: 603–04. Rubin C, Xu G, Judex S. The anabolic activity of bone tissue, suppressed by disuse, is normalized by brief exposure to extremely lowmagnitude mechanical stimuli. FASEB J 2001; 15: 2225–29. Ward KA, Alsop CW, Brown S, Caulton J, Adams JE, Mughal Z. (2001) A randomized, placebo controlled, pilot trial of low magnitude, high frequency loading treatment of low bone mineral density in children with disabling conditions. J Bone Miner Res 2001; 16: S173. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001; 344: 1434–41. Chang YH, Hamerski CM, Kram R. Applied horizontal force increases impact loading in reduced-gravity running. J Biomech 2001; 34: 679–85. Lanyon LE. Control of bone architecture by functional load bearing. J Bone Miner Res 1992; 7: S369–75. Muehleman C, Bareither D, Manion BL. A densitometric analysis of the human first metatarsal bone. J Anat 1999; 195: 191–97. Turner CH, Pavalko FM. Mechanotransduction and functional

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response of the skeleton to physical stress: the mechanisms and mechanics of bone adaptation. J Orthop Sci 1998; 3: 346–55. Rockwell JC, Sorensen AM, Baker S, et al. Weight training decreases vertebral bone density in premenopausal women: a prospective study. J Clin Endocrinol Metab 1990: 71: 988–93. Robling AG, Duijvelaar KM, Geevers JV, Ohashi N, Turner CH. Modulation of an appositional and longitudinal bone growth in the rat ulna by applied static and dynamic forces. Bone 2001; 29: 105–13. Lorentzon R, Lorentzon M. The human genome, exercise and bone mass prevention of osteoporosis and fragility fractures by exercise? A great challenge for sports medicine. Scand J Med Sci Sports 2001; 11: 131–33. Akhter MP, Iwaniec UT, Covey MA, Cullen DM, Kimmel DB, Recker RR. Genetic variations in bone density, histomorphometry, and strength in mice. Calcif Tissue Int 2000; 67: 337–44. Eisman JA. Pharmacogenetics of the vitamin D receptor and osteoporosis. Drug Metab Dispos 2001; 29: 505–12. Van der Meulen MCH, Jepsen KJ, Mikic, B. Understanding bone strength: size isn’t everything. Bone 2001; 29: 101–04.

SEN and sensibility: interactions between newly discovered and other hepatitis viruses? See page 1961 A Research letter is this issue of The Lancet by Basil Rigas and colleagues suggests that co-infection with the hepatitis C virus (HCV) and SEN viruses D and H may adversely affect the outcome of antiviral therapy with interferon and ribavirin. This preliminary observation, of course, needs to be independently confirmed in larger numbers of patients. Moreover, it is not clear how these particular 31 patients were selected for study and the sensitivity and specificity of the assays used to detect SEN virus DNA are not reported. Nonetheless, the findings are interesting. Several other questions must be addressed in further studies of this issue. Among the 12 patients with both HCV and a SEN virus, why was SEN virus DNA found in some patients (four with SEN D; three with SEN H) only during therapy? It is unlikely that these patients became infected with SEN during the course of treatment. It is more likely that SEN was present at very low concentrations before therapy and that treatment with interferon and ribavirin somehow allowed it to emerge. If HCV interferes with SEN replication, which would be in keeping with Rigas and colleagues’ observation that patients with known SEN infection had lower concentrations of HCV RNA, then interferon could perhaps allow this emergence by suppressing the concentration of HCV RNA. On the other hand, by modulating immune function,1 ribavirin might allow a viral infection that is kept in check by humoral immunity to emerge when immunity is altered. How might SEN infection interfere with the antiviral effects of interferon and ribavirin? It might alter the disease characteristics of hepatitis C, but data from this study suggest that liver disease was no more severe in those with than in those without SEN infection. It would be interesting to know if this was perhaps a cohort effect and patients with SEN infection had HCV for a longer time before therapy than those without SEN infection. An alternative explanation is that the two viruses directly interfere with each other. Again this idea is in keeping with the observed lower concentration of HCV RNA in SENpositive patients. If anything, though, SEN-positive patients would be expected to have a better therapeutic response since low serum concentrations of HCV RNA are a marker of a favourable treatment outcome. Interactions between other viral hepatitis infections are well known: perhaps the best example is that of hepatitis D virus infection, which not only requires hepatitis B virus (HBV) infection to replicate but also makes the liver injury 1925

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