Corradini, Constantino

Privitera, Gaetano

Vegni, Ferdinando E

English

F. E. Vegni

G. Previtera

C. Corradini

AIR Universita degli studi di Milano

Effects of parathyroid hormone and alendronate alone or in combination in osteoporosis

LSHTM Research Online

Vegni, FE; Corradini, C; Privitera, G (2004) Effects of parathyroidhormone and alendronate alone or in combination in osteoporosis.The New England journal of medicine, 350 (2). 189-92; author reply189-92. ISSN 0028-4793Downloaded from: http://researchonline.lshtm.ac.uk/4740/Usage GuidelinesPlease refer to usage guidelines at http://researchonline.lshtm.ac.uk/policies.html or alterna-tively contact researchonline@lshtm.ac.uk.Available under license: Copyright the publishers n engl j med  350;2 www.nejm.org january  8, 2004 The  new england journal  of  medicine 189 correspondence Effects of Parathyroid Hormone and Alendronate Alone or in Combination in Osteoporosis to the editor:  Both Black et al. 1  and Finkelstein etal. 2  (Sept. 25 issue) measured markers of bone turn-over, but neither group took osteoprotegerin intoconsideration as a possibly relevant player in boneremodeling. Osteoprotegerin, a secreted member ofthe family of tumor necrosis factor receptors, is apotent inhibitor of osteoclast activation and differ-entiation. 3,4  In patients with osteoporosis, osteo-protegerin has been found to correlate strongly withmarkers of bone turnover 5  — a finding that maypoint toward a higher level of osteoprotegerin ex-pression in patients with a higher level of thesemarkers.In limited experimental settings, the serum os-teoprotegerin level has been found to be increased inPaget’s disease and to be decreased after treatmentwith tiludronate, a common bisphosphonate. 6  Os-teoprotegerin and receptor activator of nuclear fac-tor- k B (RANK) have been identified as importantdeterminants of increased bone resorption inducedby estrogen deficiency. 7  Taking these relevant find-ings into consideration, we suspect that there is apotential interaction among bone mineral density,changes in the serum alkaline phosphate level, oth-er possible markers of bone turnover, and the serumlevel of osteoprotegerin — an interaction that per-haps should be considered in further studies on thisissue. Ferdinando E. Vegni, M.D., Ph.D. University of Pisa56127 Pisa, Italyferdinando.vegni@lshtm.ac.uk Constantino Corradini, M.D. University of Milan20122 Milan, Italy Gaetano Privitera, M.D., Ph.D. University of Pisa56127 Pisa, Italy 1. Black DM, Greenspan SL, Ensrud KE, et al. The effects of para-thyroid hormone and alendronate alone or in combination in post-menopausal osteoporosis. N Engl J Med 2003;349:1207-15. 2. Finkelstein JS, Hayes A, Hunzelman JL, Wyland JJ, Lee H, NeerRM. The effects of parathyroid hormone, alendronate, or both inmen with osteoporosis. N Engl J Med 2003;349:1216-26. 3. Hofbauer LC, Schoppet M. Osteoprotegerin: a link between os-teoporosis and arterial calcification? Lancet 2001;358:257-9. 4. Aubin JE, Bonnelye E. Osteoprotegerin and its ligand: a newparadigm for regulation of osteoclastogenesis and bone resorption.Osteoporos Int 2000;11:905-13. 5. Fahrleitner-Pammer A, Dobnig H, Piswanger-Soelkner C, et al.Osteoprotegerin serum levels in women: correlation with age, bonemass, bone turnover and fracture status. Wein Klin Wochenschr2003;115:291-7. 6. Alvarez L, Peris P, Guanabens N, et al. Serum osteoprotegerinand its ligand in Paget’s disease of bone: relationship to disease ac-tivity and effect of treatment with bisphosphonates. ArthritisRheum 2003;48:824-8. 7. Eghbali-Fatourechi G, Khosla S, Sanyal A, Boyle WJ, Lacey DL,Riggs BL. Role of RANK ligand in mediating increased bone resorp-tion in early postmenopausal women. J Clin Invest 2003;111:1221-30. to the editor:  Bone resorption and bone forma-tion are coupled, and alendronate, which decreasesbone turnover, impairs the anabolic effect of para- THIS   WEEK ’ S   LETTERS 189 Effects of Parathyroid Hormone and Alendronate in Osteoporosis 192 d -Dimer in Venous Thromboembolism 194 HHV-8 in Pulmonary Hypertension 195 Delayed Onset of Malaria 197 Melanosis Coli? 197 Fondaparinux for Symptomatic Pulmonary Embolism 198 Validation of the Harvard Six Cities Study of Particulate Air Pollution and MortalityThe New England Journal of Medicine Downloaded from nejm.org at LONDON SCH HYGIENE & TROPICAL MED on February 19, 2014. For personal use only. No other uses without permission.  Copyright © 2004 Massachusetts Medical Society. All rights reserved.  The  new england journal  of  medicine 190 n engl j med  350;2 www.nejm.org january  8, 2004 thyroid hormone, which increases bone turnover. 1-3 Thus, combination therapy with the use of a drugthat does not affect bone turnover might be a goodchoice. The serum vitamin K level decreases as aperson gets older, and undercarboxylated osteocal-cin is a marker of skeletal fragility in elderly persons.Vitamin K has been approved for the treatment ofosteoporosis in Japan and has been reported to re-duce the risk of vertebral and hip fracture withoutchanging bone turnover or increasing bone mineraldensity. Although the mechanisms remain unclear,this vitamin might improve bone material proper-ties by promoting the incorporation of osteocalcininto bone 4  or might induce increases in bone size byincreasing periosteal bone formation. 5  Because ofthe limited efficacy of drugs and their potential tox-icity, combination therapy with drugs that have dif-ferent mechanisms of action is considered to reducethe risk of fracture. Vitamin K has a very wide safetyrange, and we propose combination therapy withthe use of vitamin K as an essential supplement forthe management of osteoporosis. Toshihiro Sugiyama, M.D., Ph.D.Hiroshi Tanaka, M.D., Ph.D.Shinya Kawai, M.D., Ph.D. Yamaguchi University School of MedicineYamaguchi 755-8505, Japantoshihiro.sugiyama@chive.ocn.ne.jp 1. Black DM, Greenspan SL, Ensrud KE, et al. The effects of para-thyroid hormone and alendronate alone or in combination in post-menopausal osteoporosis. N Engl J Med 2003;349:1207-15. 2. Finkelstein JS, Hayes A, Hunzelman JL, Wyland JJ, Lee H, NeerRM. The effects of parathyroid hormone, alendronate, or both inmen with osteoporosis. N Engl J Med 2003;349:1216-26. 3. Khosla S. Parathyroid hormone plus alendronate — a combina-tion that does not add up. N Engl J Med 2003;349:1277-9. 4. Sugiyama T, Taguchi T, Kawai S. Adaptation of bone to mechan-ical loads. Lancet 2002;359:1160. 5. Sugiyama T, Tanaka H, Kawai S. Vitamin K plus vitamin D treat-ment of bone problems in a child with skeletal unloading. J BoneMiner Res 1999;14:1466-7. to the editor:  Black et al. and Finkelstein et al.,as well as Khosla, in an accompanying editorial, 1 suggest that combining parathyroid hormone withbisphosphonates is a bad idea. I believe that thissuggestion is premature. Neither Black et al. norFinkelstein et al. tested the currently approved re-combinant human parathyroid hormone (1–34),and neither present any fracture or biopsy data. Spi-nal bone mineral density increased to a similar ex-tent with parathyroid hormone and combinationtherapy in the study by Black et al. and increasedan impressive 14.8 percent (at the posteroanteriorspine) with combination therapy in the study byFinkelstein et al. The total-hip bone mineral densi-ty, as measured by dual-energy x-ray absorptiometry,increased to a similar or greater extent with combi-nation therapy. The meaning of data obtained fromquantitative computed tomography (CT) with re-gard to reduction of the risk of fracture is unclear.Parathyroid hormone–mediated decreases in fore-arm bone mineral density are due to increases inbone area. 2 Bisphosphonates reduce the risk of hip frac-tures. It is unknown whether parathyroid hormonereduces the risk of hip fractures. The clinical mean-ing of the inhibition of parathyroid hormone–mediated increases in bone-formation markers byalendronate is also unknown. Markers of bone for-mation reflect osteoblast activity, not necessarilybone formation. 3  Additional evidence that we donot understand the meaning of the biomarkerchanges is the observation made by Finkelstein etal. that after 12 months of parathyroid hormoneadministration, levels of bone-formation markersdecline, yet bone mineral density continues to im-prove. It is too soon to make judgments about para-thyroid hormone–bisphosphonate combinationsfrom the available data. Paul D. Miller, M.D. Colorado Center for Bone ResearchLakewood, CO 80227millerccbr@aol.com 1. Khosla S. Parathyroid hormone plus alendronate — a combina-tion that does not add up. N Engl J Med 2003;349:1277-9. 2. Miller PD, Bilezikian JP. Bone densitometry in asymptomaticprimary hyperparathyroidism. J Bone Miner Res 2002;17:Suppl 2:N98-N102. 3. Manolagas S. Birth and death of bone cells: basic regulatorymechanisms and implications for the pathogenesis and treatmentof osteoporosis. Endocr Rev 2000;21:115-37. to the editor:  Since osteoporosis is correlatedwith serum 25-hydroxyvitamin D status, analyses oftreatments must take this measurement into ac-count, both at base line and throughout a study.Black et al. mention only that their subjects took adaily multivitamin containing 400 IU of vitamin D.The subjects in the study by Finkelstein et al. alsotook a multivitamin, and 25-hydroxyvitamin D wasmeasured at base line. Although other values weremeasured at six-month intervals, the serum level of25-hydroxyvitamin D was not. Given that the serum25-hydroxyvitamin D level is the best measurementof a person’s vitamin D status, and given the im-portance of adequate levels of vitamin D to boneThe New England Journal of Medicine Downloaded from nejm.org at LONDON SCH HYGIENE & TROPICAL MED on February 19, 2014. For personal use only. No other uses without permission.  Copyright © 2004 Massachusetts Medical Society. All rights reserved.  n engl j med  350;2 www.nejm.org january  8, 2004 correspondence 191 health, 1  it would be appropriate for all studies ofbone metabolism to include measurements of se-rum 25-hydroxyvitamin D at base line, during thestudy, and at its conclusion. Attempting to deter-mine the efficacy of treatment options related toosteoporosis without also taking into account con-current serum 25-hydroxyvitamin D status is prob-lematic. Kathleen E. Fuller, Ph.D. AnthroHealthPhoenix, AZ 85032kfuller@anthrohealth.net 1. Vieth R. Vitamin D nutrition and its potential health benefits forbone, cancer and other conditions. J Nutr Environ Med 2001;11:275-91. dr. black and colleagues reply:  Dr. Miller makessome interesting points regarding our study of para-thyroid hormone and alendronate, although we cer-tainly do not suggest in our article that combinationtherapy with parathyroid hormone and bisphospho-nate is a bad idea. In fact, we discuss virtually all thelimitations mentioned by Dr. Miller. As he states,combination therapy does increase bone mineraldensity, and this increase was more evident in thetwo-year study by Finkelstein et al. than in our one-year study. However, we hypothesized that the com-bination would have an additive or synergistic effect,and in neither study was there evidence that thecombination was superior to the better of the twoagents given alone. There is obviously a great needfor more data with regard both to recombinanthuman parathyroid hormone (1–34) (teriparatide),which was used by Finkelstein et al., and to the full-length molecule, recombinant human parathyroidhormone (1–84), which we used. However, the re-sults of these two studies, along with data present-ed at the September 2003 meeting of the AmericanSociety for Bone and Mineral Research, suggest thatparathyroid hormone (1–84) and parathyroid hor-mone (1–34) interact with alendronate in similarways. As we discuss in our article, the results withalendronate cannot necessarily be generalized tocombination therapy with other bisphosphonatesor other antiresorptive drugs. The implications ofquantitative CT and biochemical-marker end pointswith respect to bone strength and the risk of frac-ture are not entirely clear, and final judgment awaitsmore definitive trials. However, with that caveat,we believe that the data that are currently availablesupport the notion that responses to parathyroidhormone therapy are maximized when bone turn-over is not being suppressed during the course oftreatment.In response to Dr. Sugiyama and colleagues: Al-though our study did not provide evidence of a syn-ergistic effect of parathyroid hormone and alendro-nate, it is entirely possible that other combinationsof anabolic and antiresorptive agents would haveother results. In addition, other combinations, in-cluding combinations with vitamin K, might be use-ful to study.In response to Dr. Vegni and colleagues: Osteo-protegerin is a potentially useful surrogate markerthat might provide distinct information. We agreethat it should be included in future studies.In response to Dr. Fuller: Our patients had suffi-cient vitamin D levels, according to measurementsmade at base line. Because their dietary intake of vi-tamin D was supplemented with 400 IU daily (as rec-ommended by the Food and Drug Administration),it is highly unlikely that our patients became vitaminD–deficient during the study. We agree that this nu-trient is important in therapeutic regimens for os-teoporosis. We look forward to seeing analyses(from our own study and others) of the effect ofbase-line vitamin D levels on the effect of parathy-roid hormone. Dennis M. Black, Ph.D. University of California, San Francisco San Francisco, CA 94109dblack@psg.ucsf.edu John Bilezikian, M.D. Columbia UniversityNew York, NY 10032 Clifford J. Rosen, M.D. Maine Center for Osteoporosis Research and EducationBangor, ME 04401 for the PaTH (Parathyroid Hormone and Alendronate) Study Investigators dr. finkelstein and colleagues reply:  Dr. Vegniand colleagues note the importance of osteoprote-gerin as an inhibitor of osteoclastic bone resorption.Although the meaning of circulating osteoproteger-in levels is still unclear, we are measuring serum os-teoprotegerin levels in stored samples from our pa-tients and will analyze these data.Dr. Sugiyama and colleagues suggest that com-bining vitamin K with parathyroid hormone mightbe useful in the treatment of osteoporosis. Random-ized, controlled clinical trials are needed to test thisinteresting idea.The New England Journal of Medicine Downloaded from nejm.org at LONDON SCH HYGIENE & TROPICAL MED on February 19, 2014. For personal use only. No other uses without permission.  Copyright © 2004 Massachusetts Medical Society. All rights reserved.  The  new england journal  of  medicine 192 n engl j med  350;2 www.nejm.org january  8, 2004 Dr. Miller notes that we did not use the currentlyapproved formulation of recombinant human para-thyroid hormone (1–34). Our formulation of hu-man parathyroid hormone (1–34), made by solid-phase synthesis, is identical to the recombinantmolecule and produces results indistinguishablefrom those obtained with the recombinant moleculein animals and humans. Dr. Miller also notes thatwe did not report the incidence of fracture and can-not be certain how the observed changes in bonedensity and bone turnover will affect the risk of frac-ture. For that reason, we were careful to state in ourconclusions that “additional studies are needed be-fore combinations of antiresorptive agents andparathyroid hormone can be recommended for thetreatment of men with osteoporosis.” As Dr. Millernotes, combination therapy was associated with animpressive increase in spinal bone mineral density.Parathyroid hormone monotherapy was even better,however. In laboratory animals, there is a direct re-lationship between parathyroid hormone–inducedincreases in bone mineral density and resistance tofracture. Considerable evidence also demonstrates adirect relationship between increases in bone min-eral density and decreases in the risk of fracture inhumans. 1  Thus, until clinical trials compare the ef-fects of parathyroid hormone alone and those ofparathyroid hormone plus alendronate on the riskof fracture, it seems reasonable to treat patients withthe regimen that provides greater increases in bonedensity, particularly because parathyroid hormonemonotherapy is less expensive than combinationtherapy and exposes patients to a lower risk of sideeffects.Dr. Fuller is concerned that only base-line levelsof 25-hydroxyvitamin D are reported, and that theresults might have been altered if the subjects sub-sequently had vitamin D deficiency. Although we didnot report these data, we did measure serum 25-hydroxyvitamin D levels every six months. The mean( ± SD) levels ranged from a low of 23 ± 8 ng per mil-liliter to a high of 25 ± 9 ng per milliliter in the mentreated with alendronate alone, from 18 ± 5 to 27 ± 10ng per milliliter in the men treated with parathyroidhormone alone, and from 21 ± 7 to 28 ± 12 ng permilliliter in the men treated with both. These levelsdid not differ significantly among the groups. Joel S. Finkelstein, M.D.Robert M. Neer, M.D. Massachusetts General HospitalBoston, MA 02114jfinkelstein@partners.org 1. Wasnich RD, Miller PD. Antifracture efficacy of antiresorptiveagents are related to changes in bone density. J Clin EndocrinolMetab 2000;85:231-6.d -Dimer in Venous Thromboembolism to the editor:  Wells and colleagues (Sept. 25 is-sue) 1  report on the use of  d -dimer testing in patientswith suspected deep-vein thrombosis. Patients witha low pretest probability of deep-vein thrombosisand a negative result on the  d -dimer test did notundergo confirmatory testing. This is problematic.Current recommendations for the evaluation of newdiagnostic tests suggest an independent, blindedcomparison with a reference standard and applica-tion of that standard independently of the test beingevaluated. 2  The gold standard for deep-vein throm-bosis is either duplex ultrasonography or venogra-phy, neither of which was performed in this studygroup. The “gold standard” for these patients wasthe absence of a clinical event at three months. Afalse negative result would be identified if a patienthad a symptomatic recurrence. It is unclear whetherthere would be a significant number of such recur-rences in just three months. These limitations makeit likely that the study overestimates the sensitivityand clinical utility of  d -dimer testing. In addition,other studies have suggested that the SimpliREDassay has only 77 percent sensitivity for detectingpulmonary embolism. 3  Confirmation of the utilityof  d -dimer testing awaits trials that uniformly ap-ply diagnostic standards. Scott D. Stern, M.D. University of ChicagoChicago, IL 60637 1. Wells PS, Anderson DR, Rodger M, et al. Evaluation of  d -dimerin the diagnosis of suspected deep-vein thrombosis. N Engl J Med2003;349:1227-35. 2. Jaeschke R, Guyatt GH, Sackett DL. Users’ guides to the medicalliterature. III. How to use an article about a diagnostic test. B. Whatare the results and will they help me in caring for my patients. JAMA1994;271:703-7. 3. Wells PS, Anderson DR, Rodger M, et al. Excluding pulmonaryembolism at the bedside without diagnostic imaging: managementof patients with suspected pulmonary embolism presenting to theemergency department by using a simple clinical model and  d -dimer.Ann Intern Med 2001;135:98-107.The New England Journal of Medicine Downloaded from nejm.org at LONDON SCH HYGIENE & TROPICAL MED on February 19, 2014. For personal use only. No other uses without permission.  Copyright © 2004 Massachusetts Medical Society. All rights reserved. 

Effects of parathyroid hormone and alendronate alone or in combination in osteoporosis.

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Effects of parathyroid hormone and alendronate alone or in combination in osteoporosis.

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