JOURNAL OF BONE AND MINERAL RESEARCH
`Volume 18, Number 1, 2003
`© 2003 American Society for Bone and Mineral Research
`
`Intravenous Neridronate in Adults With Osteogenesis Imperfecta
`
`S ADAMI,1 D GATTI,1 F COLAPIETRO,1 E FRACASSI,1 V BRAGA,1 M ROSSINI,1 and L TATO` 2
`
`ABSTRACT
`
`Osteogenesis imperfecta (OI) is a heritable disease of connective tissue, characterized by increased bone
`fragility. Bisphosphonates currently seems to be the most promising therapy, at least in children. We tested
`IV neridronate, an amino-bisphosphonate structurally similar to alendronate and pamidronate in adults with
`OI. Twenty-three men and 23 premenopausal women with OI were randomized to either iv neridronate (100
`mg infused intravenously for 30 minutes every 3 months) or no treatment with a ratio of 2 to 1. Control
`patients were given the same bisphosphonate therapy at the end of the first year. Clinical evaluation included
`bone densitometry measurements using dual energy X-ray absorptiometry (DXA), fasting serum and urinary
`biochemistry every 6 months, and radiographs of the spine taken at baseline and after 12 and 24 months of
`follow-up. Spine and hip bone mineral density rose by 3.0 ⴞ 4.6% (SD) and by 4.3 ⴞ 3.9%, respectively, within
`the first 12 months of treatment, whereas small insignificant changes were observed in the control group.
`During the second year of follow-up, additional 3.91% and 1.49% increases were observed at the spine and
`hip, respectively. Markers of skeletal turnover significantly fell during neridronate treatment. Fracture
`incidence during neridronate treatment was significantly lower than before therapy and compared with
`controls. Neridronate iv infusions, administered quarterly, significantly increase bone mineral density and
`lowered the risk of clinical fracture in adults with OI. Bisphosphonate therapy seems to provide clinical
`benefits, not only to children with OI, but also to adult patients. (J Bone Miner Res 2003;18:126 –130)
`
`INTRODUCTION
`
`OSTEOGENESIS IMPERFECTA (OI) is a heritable disease of
`
`connective tissue caused by heterologous mutations in
`the genes encoding for type I collagen and characterized by
`increased bone fragility.(1) Four types are commonly distin-
`guished based on clinical and genetic features, although
`overlap forms are often observed. In its mildest form (type
`I), fractures tend to occur mostly before puberty and again
`after menopause. Type II OI leads to perinatal death. Type
`III OI causes fractures that are very frequent, resulting in
`short stature, severe deformities, and shortened life expect-
`ancy. These fractures are also typical of type IV but are less
`severe.(2)
`Several therapies have been proposed for the treatment of
`OI, including fluoride, calcitonin,(3) growth hormone,(4) and
`bone marrow transplantation.(5) To date, bisphosphonates
`seems to be the most promising therapy, at least for children
`with OI. Beneficial effect were reported in a number of early
`relatively small studies,(6 –11) which have been recently sup-
`ported in a larger cohort of children treated for up to 5 years
`
`The authors have no conflict of interest.
`
`with cyclical iv pamidronate.(12) This treatment resulted in
`significant increases in bone mineral density (BMD) by dual
`energy X-ray absorptiometry (DXA) at any investigated
`skeletal site, leading to a partial catch-up toward normal
`values. These BMD changes were reported with increased
`physical activity and lower fracture risk compared with
`retrospective events.(12,13)
`However, all these studies were carried out in children
`with severe OI and understandably encourage bisphospho-
`nate therapy for adults with type I OI.
`In 1995, in collaboration with the Istituto Superiore di
`Sanita` (part of the Ministry of Health) and of the Italian
`Association of patients with OI [AsItOI]), we initiated a
`large randomized, controlled therapeutical trial of iv neridr-
`onate in all patients with OI. Here, we report the preliminary
`results obtained in men and in premenopausal women.
`Neridronate is an amino-bisphosphonate structurally similar
`to alendronate and pamidronate, differing only in the num-
`ber of methyl groups of the side-chain: five for neridronate,
`three for alendronate, and two for pamidronate.(14) It has
`been investigated for the treatment of Paget’s disease of
`bone(15–18) and recently registered in Italy for the treatment
`
`1Rheumatologic Rehabilitation, University of Verona, Verona, Italy.
`2Clinica Pediatrica, University of Verona, Verona, Italy.
`
`126
`
`Grun. Exh. 1014
`PGR for U.S. Patent No. 9,707,245
`
`

`

`BISPHOSPHONATES IN ADULTS WITH OSTEOGENEIS IMPERFECTA
`
`127
`
`Patients
`
`All
`
`Active group
`
`Control group
`
`N
`
`46
`
`31
`
`15
`
`TABLE 1. PRINCIPAL CLINICAL AND ANAGRAPHIC CHARACTERISTICS OF STUDY POPULATION
`
`Type of OI
`(I—III—IV)
`
`Sex
`(male—female)
`
`Age
`[mean ⫾ SD (range)]
`
`Weight
`[mean ⫾ SD (range)]
`
`Height
`[mean ⫾ SD (range)]
`
`38—2—6
`
`26—2—3
`
`23—23
`
`15—16
`
`12—0—3
`
`8—7
`
`34.9 ⫾ 7.9
`(21–50)
`35.1 ⫾ 7.1
`(22–48)
`34.7 ⫾ 9.3
`(21–50)
`
`57.8 ⫾ 13.6
`(22–87)
`57.7 ⫾ 11.7
`(31–77)
`57.9 ⫾ 16.9
`(22–87)
`
`150.9 ⫾ 20.7
`(90–180)
`151.3 ⫾ 17.9
`(111–180)
`150.4 ⫾ 25.7
`(90–180)
`
`TABLE 2. BASELINE BONE DENSITOMETRY AND BONE MARKERS (SERUM BONE ALKALINE PHOSPHATASE [BAP], SERUM CROSS-LAPS [SCTX],
`AND URINARY FREE-IDROSSY PYRIDINOLINE [UFDPD]) VALUES OF STUDY POPULATION
`
`N
`
`46
`
`31
`
`15
`
`All
`
`Active group
`
`Control group
`
`Normal range
`
`Spine BMD
`[mg/cm2 (T score)]
`
`Hip BMD
`[mg/cm2 (T score)]
`
`BAP (U/I)
`
`sCTX
`(pmol/liter)
`
`ufDPD
`(nmol/mmol creatinine)
`
`727 ⫾ 103
`(⫺3.4 ⫾ 1.0)
`712 ⫾ 105
`(⫺3.5 ⫾ 1.0)
`766 ⫾ 98
`(⫺3.0 ⫾ 0.9)
`
`727 ⫾ 103
`(⫺2.5 ⫾ 1.5)
`721 ⫾ 152
`(⫺2.6 ⫾ 1.4)
`762 ⫾ 190
`(⫺2.3 ⫾ 1.6)
`
`20.1 ⫾ 9.1
`
`2366 ⫾ 1706
`
`19.0 ⫾ 8.7
`
`2295 ⫾ 1718
`
`20.6 ⫾ 9.4
`
`2468 ⫾ 1844
`
`10.4 ⫾ 13.3
`
`10.9 ⫾ 13.2
`
`10.0 ⫾ 13.7
`
`11.5–25.1
`
`1111–2559
`
`2.3–7.8
`
`of OI based on clinical trial, the results of which are, in part,
`reported here.
`
`MATERIALS AND METHODS
`
`Patients
`
`All subjects affected by any type of OI and registered
`with the AsItOI were informed by the association newslet-
`ter, either directly or through their parents, regarding the
`possibility to participate in a clinical trial of a new bisphos-
`phonate. Several others contacted our center after a public
`appeal on national radio. After excluding the patients who
`had already received bisphosphonates or were younger than
`3 years, an informed written consent was obtained from 209
`patients. Seventy-eight of these were adults, and 46 con-
`cluded after the first 2 years of study follow-up. These latter
`patients provide the data for this per-protocol, pre-planned,
`interim analysis. The principal characteristics of the 46
`patients are listed in Tables 1 and 2. The history of prior
`clinical fracture during 4 years preceding recruitment was
`carefully collected from all patients.
`
`Treatment
`
`The patients were randomized according to OI type (type
`I or type III and IV) to either iv neridronate or no treatment
`with a ratio of 2 to 1. One hundred milligrams neridronate
`diluted in 250 ml of saline solution was infused intrave-
`nously in 30 minutes every 3 months. The dose used was the
`lowest effective dose in lowering biochemical evidence of
`Paget’s disease activity by 50% after a single infusion.(15–18)
`All patients had their dietary calcium intake regularly
`evaluated and maintained above 1000 mg daily, through
`diet or supplementation. Vitamin D2 supplements (50,000 U
`
`monthly) were given if the serum 25OH-vitamin D levels
`fell below 20 ng/ml. Calcium and/or vitamin D2 supple-
`ments were necessary throughout the study in five of the
`patients. It is worth noting that all patients but one had
`adequate calcium and vitamin D intake for years, because of
`the continuous educational program from AsItOI.
`The control patients commenced the neridronate treat-
`ment after 12 months of follow-up with continued con-
`trolled calcium and vitamin D intake.
`Study protocol was approved and constantly monitored
`by the local ethical committee and the Istututo Superiore
`della Sanita` (part of the Italian Ministry of Health).
`Measurements
`
`All patients were seen at 3-month intervals, but full
`clinical evaluation including bone densitometry measure-
`ments by DXA and fasting serum and urinary (second
`morning voiding) biochemistry was obtained per-protocol
`every 6 months. Radiographs of the spine (anteroposterior
`and lateral views) were obtained at baseline and after 12 and
`24 months. Prevalent vertebral fractures were identified and
`graded blindly by a semiquantitative scale.(19) A new ver-
`tebral fracture was defined as a decrease in anterior, mid-, or
`posterior vertebral height of at least 4 mm. Additional
`X-rays were obtained at any skeletal site whenever symp-
`toms of fractures occurred. All patients were assessed for
`clinical fractures that had occurred during the 4 years pre-
`ceding recruitment. An interim analysis of fracture rate was
`a safety end-point specifically required by the ethical com-
`mittee.
`Changes in the BMD at the lumbar spine and total hip
`were measured by DXA (QDR 4000; Hologic, Waltham,
`MA, USA). The precision error for BMD at different skel-
`
`

`

`128
`
`ADAMI ET AL.
`
`etal sites ranges from 0.9% to 2.1% in subjects with a wide
`range of bone mass values.
`Serum cross-laps (sCTX; Osteometer Biotech, Herler, Den-
`mark), urinary free-deoxy pyridinoline (ufDPD, Pyrilinks-D;
`Metra Biosystems, Mountain View, CA, USA), and serum
`bone alkaline phosphatase (BAP, Alkphase–B; Metra Bio-
`systems) were measured by enzyme-linked immunoabsor-
`bent assay. The inter- and intra-assay variations ranged from
`7% to 12%.
`
`Statistical analysis
`
`The within-subject changes in BMD and in biochemical
`markers were tested by two-sided paired t-test, and the
`between group differences were tested by analysis of vari-
`ance (ANOVA) and then by Student t-test. Intention-to-treat
`analysis was planned, but it was not applied because all
`patients completed the treatment follow-up.
`
`RESULTS
`
`Before treatment, all subjects had normal serum calcium,
`phosphate, 25 OH-vitamin D (⬎12 ng/ml), and parathyroid
`hormone (PTH) levels (Allegro intact PTH, normal val-
`ues ⬍ 60 pg/ml), and there was no evidence of other
`relevant diseases. The two groups of patients were compa-
`rable with for age, weight, height, and female-male ratio,
`and nonstatistically different for bone markers and baseline
`BMD values (Tables 1 and 2), which was below the World
`Health Organization (WHO) definition of osteoporosis(20) in
`81% of the patients at the spine. The distribution of the type
`of OI was also similar.
`The mean changes in BMD in the two groups are shown
`in Fig. 1. Spine and hip BMD rose by 3.0 ⫾ 4.6% and by
`4.3 ⫾ 3.9%, respectively, after the first 12 months of treat-
`ment, whereas small insignificant changes were observed in
`the control group. During the second year, additional 3.9%
`and 1.5% increases were observed at the spine and hip,
`respectively, in the treatment group. The densitometric re-
`sponse to treatment during the second year in the patients
`who served as controls during the first year was very similar
`to the changes obtained during the first year by the first
`group.
`In Table 3, the pooled BMD changes during administra-
`tion of neridronate are listed according to gender and sep-
`arately for the patients with type I OI. There were no
`differences in the BMD increments between men and
`women. All patients with type III and IV OI had BMD
`increases (data not shown) at the end of the 1 year treatment
`that were greater than 3% as the lowest detectable change
`(CV% ⫻ 2公2) in individual subjects for our instrument.
`Markers of skeletal
`turnover significantly fell during
`neridronate treatment. The mean decrease was 20% for BAP
`and 25% for sCTX. ufDPD also decreased by 20%, but the
`changes were less consistent throughout the treatment
`(Fig. 2).
`Some deformities (N1 to 3) of thoracic and lumbar ver-
`tebrae, mostly of grade 1, were visible at baseline in all
`patients. Overt morphometric fracture (grade ⱖ 2) were
`found in 21 of the patients. One clinical-morphometric
`vertebral fracture and one limb fracture occurred in the
`
`FIG. 1. Bone mineral density changes during treatment with iv
`neridronate (solid line) and control period (dashed line): *p ⬍ 0.05
`between groups; †p ⬍ 0.05 from baseline; ‡p ⬍ 0.001 from baseline.
`
`control group during the first year of observation. One limb
`fracture was recorded in the treatment patients, but no
`fractures occurred in the control group while on treatment
`during the second year of follow-up. Overall, 18 clinical
`fractures during 4 years prior recruitment were reported by
`16 patients. The most recent clinical fracture occurred 5
`months prior recruitment. The difference in fracture inci-
`dence during treatment (1/77 patient-years) and during
`pooled pre-recruitment and control time (18/199 patient-
`years) was at the limit of significance (p ⫽ 0.03; Fisher’s
`exact t-test; relative risk [RR], 0.14; 95% CI, 0.02 to 1.09).
`Thirteen of the patients complained of flu-like symptoms,
`resembling a typical acute phase reaction,(21) 24 –36 h after
`the first iv infusion, lasting less than 36 h. An attenuated
`reaction was also noted by four patients after the second
`infusion. None of the patients complained of symptomatic
`hypocalcemia or other side effects associated with iv ami-
`nobisphosphonate administration.(22)
`
`DISCUSSION
`
`This the first “per-protocol” controlled clinical trial car-
`ried out
`in patients with OI, although in some studies
`attempts were made to have control data.(12,13) This is also
`the first report on the effects of bisphosphonate therapy in
`adults.
`Bone fragility in OI results from quantitative and quali-
`tative alterations in type I collagen that are not expected to
`benefit directly from a treatment with antiresorbing agents,
`
`

`

`BISPHOSPHONATES IN ADULTS WITH OSTEOGENEIS IMPERFECTA
`
`129
`
`TABLE 3. PERCENT CHANGES OF SPINE AND OF HIP BONE MINERAL DENSITY (BMD) IN TYPE I OI PATIENTS (POOLING ACTIVE GROUP AND
`THE FIRST YEAR OF TREATMENT OF THE CONTROL GROUP) AFTER NERIDRONATE THERAPY ACCORDING TO GENDER
`(NUMBER OF OBSERVATIONS IN BRACKETS)
`
`Time intervals (months)
`
`All patients
`
`Males
`
`Females
`
`Type I patients
`
`Spine BMD
`0–6
`0–12
`0–18
`0–24
`Hip BMD
`0–6
`0–12
`0–18
`0–24
`
`* p ⬍ 0.02 from baseline.
`
`3.0 ⫾ 6.4 (46)*
`3.6 ⫾ 5.4 (46)*
`4.6 ⫾ 6.0 (31)*
`6.9 ⫾ 3.5 (31)*
`
`1.2 ⫾ 3.5 (29)
`3.5 ⫾ 3.9 (29)*
`5.5 ⫾ 5.1 (19)*
`7.6 ⫾ 6.3 (19)*
`
`1.8 ⫾ 7.2 (23)
`2.5 ⫾ 5.5 (23)
`4.2 ⫾ 6.9 (17)*
`6.4 ⫾ 3.6 (17)*
`
`1.2 ⫾ 2.2 (15)
`4.2 ⫾ 2.7 (15)*
`5.7 ⫾ 3.1 (10)*
`5.5 ⫾ 2.1 (10)*
`
`4.4 ⫾ 5.2 (23)*
`4.8 ⫾ 5.3 (23)*
`5.1 ⫾ 5.0 (14)*
`7.5 ⫾ 3.3 (14)*
`
`1.1 ⫾ 4.6 (14)
`2.7 ⫾ 4.8 (14)*
`5.4 ⫾ 6.7 (9)*
`9.8 ⫾ 8.5 (9)*
`
`2.9 ⫾ 6.4 (38)*
`3.2 ⫾ 5.3 (38)*
`4.3 ⫾ 6.2 (26)*
`6.7 ⫾ 3.3 (26)*
`
`0.9 ⫾ 3.4 (26)
`3.6 ⫾ 3.7 (26)*
`5.7 ⫾ 4.9 (18)*
`6.7 ⫾ 5.7 (18)*
`
`such as bisphosphonates. However, there is histomorpho-
`metric and biochemical evidence of
`increased bone
`resorption.(23–25) This was also somewhat apparent in the
`patients described here and in the entire cohort of our
`patients. The high bone turnover might be caused by recur-
`rent fracture or be directly related to the abnormal bone
`structure, but it might contribute to the pathogenesis of OI.
`In fact, beneficial effects of antiresorptive agents were
`shown in children with OI, in whom intermittent iv pam-
`idronate resulted in large and sustained increases in
`BMD.(12) The substantial effect on bone mass observed in
`that study might has been related to the young age of the
`patients (very high bone turnover); however, a control group
`was not reported.
`In our study, we show that intermittent iv neridronate
`results in significant increases in BMD in adult OI patients.
`The magnitude of the observed changes in bone mass
`should be considered clinically relevant based on the rela-
`tionship found in postmenopausal osteoporosis between
`BMD changes and fracture risk reduction during bisphos-
`phonate therapy.(26) In fact, a trend for a reduction in frac-
`ture rate, which was significant by pooling retrospective and
`prospective events, was observed, although the study was
`not powered for such an endpoint(s). On the other hand, in
`comparing retrospective to prospective events, the effect of
`improved education associated with the participation “per
`se” to a clinical trial, on reducing risks of trauma (falling,
`lifting heavy objects, etc.), cannot be excluded.
`The increases in BMD observed during neridronate therapy
`are likely caused by suppression of bone resorption and sec-
`ondary lowering of bone remodeling space.(27) In children with
`OI treated with pamidronate, an improvement in the balance
`between bone formation and bone resorption has been sug-
`gested based on the relative changes in urinary N-telopeptide
`of type I collagen and alkaline phosphatase markers of bone
`resorption and bone formation, respectively.(12) In our adult
`patients, the pattern of changes in bone markers did not
`support this hypothesis, with an apparent equivalent sup-
`pression for both. The magnitude of changes in bone mark-
`ers was less than observed in children with OI given iv
`pamidronate(12) or in postmenopausal women after oral 10
`mg alendronate or 5 mg risedronate.(28,29) This does not
`
`FIG. 2. Changes in bone alkaline phosphatase (BAP), serum CTX
`(sCTX), and urinary free DPD/creatinine ratio (ufDPD) during treat-
`ment with iv neridronate (solid line) and control period (dashed line):
`*p ⬍ 0.05 between groups; †p ⬍ 0.05 from baseline; ‡p ⬍ 0.01 from
`baseline.
`
`

`

`130
`
`ADAMI ET AL.
`
`imply that neridronate was underdosed. In fact, in prior
`studies, baseline bone turnover was considerably greater
`than documented in our male or premenopausal adult pa-
`tients with OI. It should also be recalled that sCTX was
`measured 3 months after the last infusion of neridronate and
`immediately before the next one when bone resorption had
`possibly resumed. Our results cannot be easily compared
`with others because bisphosphonates have been rarely eval-
`uated in premenopausal women or in young men without
`focal bone diseases.
`In conclusion, iv infusions of neridronate given quarterly
`increase bone density in adults with OI, and this is associ-
`ated with a lower risk for clinical fracture. Until now, data
`indicating some clinical benefit of bisphosphonate therapy
`were available only for growing individuals with the most
`severe form of the disease. The densitometric results and the
`effects on fracture rate we observed support the efficacy of
`bisphosphonate treatment for adults with type I OI, in whom
`fracture risk can be at least as large as that observed in
`postmenopausal women in whom a T score ⬍ ⫺2.5 SD
`represents a widely accepted threshold for pharmacologic
`intervention. An additional benefit of bisphosphonates ther-
`apy in adults with OI may be the preservation of better bone
`mass for later age or after menopause.
`
`REFERENCES
`
`1. Smith R 1986 Osteogenesis imperfecta. Clin Rheum Dis 12:655–
`689.
`2. Sillence DO, Senn A, Danks DM 1979 Genetic heterogeneity in
`osteogenesis imperfecta. J Med Genet 16:101–116.
`3. Castells S 1973 New approaches to treatment of osteogenesis
`imperfecta. Clin Orthop 93:239 –249.
`4. Marini JC, Bordenick S, Heavner G, Rose S, Hintz R, Rosenfeld R,
`Chrousos GP 1993 The growth hormone and somatomedian axis in
`short children with osteogenesis imperfecta. J Clin Endocrinol
`Metab 76:251–256.
`5. Horewitz EM, Prockop DJ, Gordon PL, Koo WW, Fitzpatrick LA,
`Neel MD, McCarville ME, Orchard PJ, Pyeritz RE, Brenner MK
`2001 Clinical responses to bone marrow transplantation in children
`with severe osteogenesis imperfecta. Blood 97:1227–1231.
`6. Devogelaer JP, Malghem J, Maldague B, Nagant de Deuxchaisnes
`C 1987 Radiological manifestations of bisphosphonate treatment
`with APD in a child suffering from osteogenesis imperfecta. Skel-
`etal Radiol 16:360 –363.
`7. Huaux JP, Lokietek W 1988 Is APD a promising drug in the
`treatment of severe osteogenesis imperfecta? J Pediatr Orthop
`8:71–72.
`8. Brumsen C, Hamdy NAT, Papapoulos SE 1997 Long-term effects of
`bisphosphonates on the growing skeleton: Studies of young patients
`with severe osteoporosis. Medicine (Baltimore) 76:266–283.
`9. Bembi B, Parma A, Bottega M, Ceschel S, Zanatta M, Martini C,
`Ciana G 1997 Intravenous pamidronate treatment in osteogenesis
`imperfecta. J Pediatr 131:622– 625.
`10. Åstro¨m E, So¨derha¨ll S 1998 Beneficial effect of bisphosphonate
`during five years of treatment of severe osteogenesis imperfecta.
`Acta Pediatr 87:64 – 68.
`11. Gonzalez E, Pavia C, Ros J, Villaronga M, Valls C, Escola J 2001
`Efficacy of low dose schedule pamidronate infusion in children with
`osteogenesis imperfecta. J Pediatr Endocrinol Metab 14:529–533.
`12. Glorieux FH, Bishop NJ, Plotkin H, Chabot G, Lanoue G, Travers
`R 1998 Cyclic administration of pamidronate in children with
`severe osteogenesis imperfecta. N Engl J Med 339:947–952.
`13. Plotkin H, Rauch F, Bishop NJ, Montpetit K, Ruck-Gibis J,
`Travers R, Glorieux FH 2000 Pamidronate treatment of severe
`
`osteogenesis imperfecta in children under 3 years of age. J Clin
`Endocrinol Metab 85:1846 –1850.
`14. Fleisch H 2000 Bisphosphonates: Mechanism of action. Endocri-
`nol Rev 19:80 –100.
`15. McCloskey EV, Yates AJ, Beneton MN, Galloway J, Harris S, Kanis
`JA 1987 Comparative effects of intravenous diphosphonates on cal-
`cium and skeletal metabolism in man. Bone 8(Suppl 1):S35–S41.
`16. Delmas PD, Chapuy MC, Edouard C, Meunier PJ 1987 Beneficial
`effects of aminohexane diphosphonate in patients with Paget’s disease
`of bone resistant to sodium etidronate. Am J Med 83:276–282.
`17. Atkins RM, Yates AJ, Gray RE, Urwin GH, Hamdy NA, Beneton
`MN, Rosini S, Kanis JA 1987 Aminohexane diphosphonate in the
`treatment of Paget, s disease of bone. J Bone Miner Res 2:273–9.
`18. Adami S, Bevilacqua M, Broggini M, Filipponi P, Ortolani S,
`Palummeri E, Ulivieri F, Nannipieri F, Braga V 2002 Short-term
`intravenous therapy with neridronate in Paget’s disease. Clin Exper
`Rheumatol 220:55–58.
`19. Genant HK, Jergas M, Palermo L, Nevitt M, Valentin RS, Black D,
`Cummings SR for the Study of Osteoporotic Fractures Research
`Group 1996 Comparison of semiquantitative visual and quantita-
`tive morphometric assessment of prevalent and incident vertebral
`fractures in osteoporosis. J Bone Miner Res 11:984 –996.
`20. WHO 1994 Assessment of fracture risk and its application to
`screening for postmenopausal osteoporosis. WHO Technical report
`series, 843, World Health Organization, Geneva, Switzerland.
`21. Adami S, Bhalla AK, Dorizzi R, Montesanti F, Rosini S, Salvagno
`G, LoCascio V 1987 The acute-phase response after bisphospho-
`nate administration. Calcif Tissue Int 41:326 –331.
`22. Adami S, Zamberlan N 1996 Adverse effects of bisphosphonates:
`A comparative review. Drug Safety 14:158 –170.
`23. Baron R, Gertner JM, Lang R, Vignery A 1983 Increased bone
`turnover with decreased bone formation by osteoblasts in children
`with osteogenesis imperfecta tarda. Pediatr Res 17:204 –207.
`24. Brenner RE, Vetter U, Bollen Am, Mo¨rike M, Eyre DR 1994 Bone
`resorption assessed by immunoassay of urinary cross linked col-
`lagen peptides in patients with osteogenesis imperfecta. J Bone
`Miner Res 9:993–997.
`25. Glorieux FH, Travers R, Chabot G, Lanoue G 1994 Bone histo-
`morphometric analysis in osteogenesis imperfecta. J Bone Miner
`Res 9(Suppl 1):S226.
`26. Hockberg MA, Greenspan S, Wasnich RD, Miller P, Thompson
`DE, Ross PD 2002 Changes in bone density and turnover explain
`the reductions in incidence of nonvertebral fractures that occur
`during treatment with antiresorptive agents. J Clin Endocrinol
`Metab 87:1586 –1592.
`27. Adami S, Kanis JA 1995 Assessment of involutional bone loss:
`Methodological and conceptual problems. J Bone Miner Res 10:
`511–517.
`28. Chesnut CH, McClung MR, Ensrud KE, Bell NH, Genant HK,
`Harris ST, Singer SR, Stock JL, Yood RA, Delmas PD, Pryor-
`Tillotson S, Santora AC 1995 Alendronate treatment of the post-
`menopausal osteoporotic woman: Effect of multiple dosages on
`bone mass and bone remodeling. Am J Med 99:144 –152.
`29. Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T,
`Keller M, Chesnut CH, Brown J, Eriksen EF, Hoseyni MS, Axel-
`rod DW, Miller PD 1999 Effects of risedronate treatment on
`vertebral and non-vertebral fractures in women with postmeno-
`pausal osteoporosis. A randomized controlled trial. JAMA 282:
`1344 –1352.
`
`Address reprint requests to:
`Silvano Adami, MD
`Ospedale
`37067 Valeggio
`Verona, Italy
`
`Received in original form June 4, 2002; in revised form July 24,
`2002; accepted August 1, 2002.
`
`