Long-Term Sequelae of Bisphosphonate-Induced Osteopetrosis: Metaphyseal Osteopenia, Osteosclerosis Fragility, and Novel Bone Modeling Defects After Drug Administration Ceases Deborah Wenkert1, William H. McAlister2, Deborah V. Novack2, Karen L. Clements1, Perry L. Schoenecker1, Michael P. Whyte1 1Shriners Hospitals for Children, St. Louis, MO; 2Washington University School of Medicine, St. Louis, MO.

Iliac Crest Biopsy DISCUSSION (continued) The iliac apophysis was exposed through a 2 - 3 cm skin incision. To evaluate the depth of unresorbed primary spongiosa, In 1996, Adami and Zamberlan(3) cautioned that excessive inhibition of osteoclasts by BPs in children might impair bone Persign van Meerten et al. in 1992.(46) Also, our patient’s vertebral endplates are now thin, and the vertebral bodies have 1A B modeling and remodeling and induce OPT-like changes. Such findings had been recognized a decade earlier in growing become somewhat rectangular. Despite the osteosclerosis acquired during PMD exposure, our patient fractures the ABSTRACT two specimens sampling trabecular as well as cortical bone were obtained using a 3.4 mm internal diameter Trap-Lok™ 4A B Alteration Of Skeletal Modeling And Remodeling After Bisphosphonate Withdrawal needle (Medical Device Technologies, Inc., Gainesville, FL) hammered gently and perpendicularly down into the top of his rats given amino-BPs.(47) posterior elements of his vertebrae. Spondylolysis (leading to spondylolisthesis) seems more prevalent in OPT,(7) and this left iliac crest. Then, after subperiosteal dissection on either side of the ilium, a core was removed from the patient using a5 In 1985, Hoekman et al.(44) reported PMD treatment for a boy with juvenile osteoporosis. The first In 2002, Rauch et al.(22) reported increased amounts of calcified cartilage and large osteoclasts in the iliac crest of problem appeared in our patient during, and recurred years after, his PMD exposure. Notably, Aström et al.(66) in 2007 publication concerning PMD for OI, the paradigm of pediatric osteoporoses, appeared in 1987(45) in reported an increased prevalence of spondylolysis and L5 spondylolisthesis after PMD treatment in infants with severe The first reported individual with drug‐induced osteopetrosis (NEJM 349: 455, '03) agreed to mm internal diameter Bordier trephine. Identical, transapophyseal, needle specimens, processed the same way, had been children with OI treated with PMD, and concluded “there is no indication at present that the decreased remodeling activity taken at harvest, following traumatic death, from healthy 13 and 16 year-old boys. which radiographs of a girl given oral courses of PMD for one year showed dense, parallel, and the increased amount of calcified cartilage cause clinical problems. Nevertheless, this possibility must be closely OI. re‐evaluation 5 years after diagnosis (6 years after pamidronate (PMD) exposure ceased). At metaphyseal bands. Specimens were fixed in 70% ethanol and 30% water for subsequent nondecalcified embedding in methylmethacrylate, monitored”. Now for our patient, with revelation of neo-osseous osteoporosis, bone modeling defects that will probably persist in adult age 17 years, biochemical, radiological, and histopathologic parameters of skeletal In 1992, van Persign van Meerten, et al.(46) reported “subtle” metaphyseal undertubulation occurring life, and fracture twice through osteosclerotic forearm long bones despite cessation of PMD exposure, we again counseled homeostasis were reassessed. Idiopathic bone pain and hyperphosphatasemia of skeletal sectioning, and staining using the Goldner’s trichrome and toluidine blue methods. Unstained sections were used for In 2004, Rauch et al.(48) examined histologically the PMD-induced, osteosclerotic bands in the iliac crest of a child with OI, fluorescence microscopy to identify tetracycline labels. during amino-BP treatment, and “bone-within-bone” involving osteosclerosis after therapy, in children and concluded that this nascent trabecular bone containing primary spongiosa remodeled into bands of trabecular bone him to do no heavy lifting (hoping to avoid vertebral collapses), and to guard against falls to protect especially major long origin [that had led others to administer PMD] were still present, but serum alkaline with various disorders. The osteosclerosis was said to resolve following amino-BP exposure, with having less calcified cartilage. We are struck by the paucity of trabeculae illustrated between these bands. bones. phosphatase was lower in keeping with his now mature skeleton. Radiographs showed formation of new metaphyseal bone of normal density. However, the published radiograph of a knee of DXA and Osteosclerosis persistent modeling defects of osteopetrosis, especially in metaphyses of long bones, but one of these children,(46) a boy with polyostotic fibrous dysplasia, shows a considerably expanded In 2004, Munns et al.,(49) revealed greater likelihood of delayed healing of osteotomy sites created for intramedullary with some unique features. Metaphyseal osteosclerosis had remodeled to become diaphyseal distal femoral metaphysis with a thin cortex during treatment, remarkably like what we had illustrated for rodding in children with OI treated with PMD. Our patient illustrates difficulties inherent in BMD interpretation when there are areas of osteosclerosis. DXA gives a BMD RESULTS our patient.(1) It was said (46) that “in all patients with metaphyseal undertubulation, the newly formed Over the previous two decades, assessments for OI children treated with PMD were otherwise positive as fracture estimation for a relatively large skeletal area and can, therefore, be misleading when bone density is heterogeneous. Our osteosclerosis. Newer metaphyseal bone was not osteosclerotic, but unexpectedly patient’s spine and radius BMD increased during PMD at an accelerated rate between ages 7 and 12 years compared to osteopenic with thin cortices (Figure) and with cystic areas in trabecular bone shown by Biochemical Findings bone regained its original width after termination of nitrogen-containing bisphosphonate administration”. frequency was said to decrease,(20,21) with increases in mobility,(50) Z-scores for especially spine BMD,(20) cortical width of long bones,(22) and cancellous bone volume.(22) After our report in 2003,(1) age-matched controls, and then decelerated to normal Z-score values by age 17 years despite sclerotic bands seen on computed tomography. Metaphyses remained widened, yet their surfaces were no longer During reassessment, he consumed on average 1450 mg calcium each day. The biochemical findings from the two radiographs. BMD in his total hip followed the same pattern. It is not known whether this diminution in density is from hospitalizations are compared in Table 1. skeletal modeling defects in OI patients receiving PMD were at first not mentioned,(51,52) or abnormally straight or convex, but once again concave. A “bone‐in‐bone” appearance was were sometimes illustrated without comment.(53-56) increased bone circumference with decreased need for cortical thickness and trabecular bone mass for protection against now present in both the axial and appendicular skeleton (Figure). Although DXA recorded Serum total and bone-specific ALP activity had decreased over the 5-year interval consistent with a maturing skeleton, but A fractures. Understandably, these areas of “neo-osseous osteoporosis” in widened metaphyses were not identified by DXA normal spine BMD, radiographs suggested vertebral osteopenia surrounding the bands of both values remained distinctly and proportionately elevated: 485 IU/L (30 - 114 normal) and 243 U/L (3 - 38 normal), Then, in 2005, Ward et al.(57) used radiographs to evaluate metaphyseal modeling in in our patient. 7 children receiving PMD for localized bone diseases (e.g.; osteonecrosis), and devised a respectively. Once again, unremarkable levels were found for urine collagen cross-linked N-telopeptide (NTX) and osteosclerosis, but no collapses. L5 spondylolysis persisted, and spondylolisthesis had “metaphyseal index” to quantitate physiologic “inwasting” in the distal femur. Their Markers of Skeletal Remodeling developed. Spondylolysis of L4 developed. Claims of interval fractures included a Salter II deoxypyridinoline. Serum osteocalcin was no longer slightly increased (Table 1). Two serum biochemical markers for OPT preliminary data from patients given “appropriate dosing regimens” indicated undisturbed Clinicians hope that biochemical markers of skeletal turnover will help them prevent excessive suppression of bone break of an osteosclerotic distal radius, and subsequently a contralateral “chalkstick” fracture were now normal: activity of the brain isoenzyme of creatine kinase(13) and tartrate resistant acid phosphatase.(1) Serum lactate dehydrogenase activity was once again unremarkable at 132 U/L (117 - 217 normal), and not increased as bone shaping. Nevertheless, it was agreed that metaphyseal modeling should be evaluated remodeling.(6,22,38) For our patient, these parameters gave no hint of suppressed skeletal turnover either in 2002 or 2007. across an osteosclerotic ulnar diaphysis that was incompletely healed 2 years later. Repeat observed in some individuals with heritable OPT.(14) in safety protocols.(57) In addition to his persistent, enigmatic hyperphosphatasemia with elevated bone ALP, serum osteocalcin was slightly iliac crest biopsy showed that nascent endochondral bone contained an excess of unresorbed Also in 2005, Letocha et al.(58) described better vertebral geometry as well as improved increased in 2002. Urine NTX and free deoxypyridinoline were unremarkable in 2002 (also hydroxyproline) and again in primary spongiosa ("cartilage bars"), but much less so than during PMD exposure. Osteoclasts Erythrocyte sedimentation rate was 1 mm/hr (< 15 normal), and carbohydrate-reactive protein (CRP) was < 0.5 mg/dl (< 2007. In 2002, these markers emanated from a skeletal mass that was increased, as indicated by spine and hip BMD,. This 0.9 normal). His unexplained thrombocytopenia, documented since early childhood, was unchanged at 85 k/µL (140 - 350 spine BMD (by DXA and QCT) for a small number of OI children given PMD for one year. ‐‐ abnormal during PMD administration (round cells without polarized nuclei, off of bone In 2006, Land et al. reported partial reconstitution of vertebral shaping(59) during 2 - 4 years suggest that perhaps when his bone remodeling was maximally suppressed during PMD exposure 1-1/2 years before normal). Urine free cortisol was 27 µg/day (3 - 55 normal). referral, low bone turnover may not have been detectable biochemically. Of interest, however, serum BB-CK and TRAP surfaces) ‐‐ were normal in number, location, and appearance. BP toxicity during childhood of PMD therapy for moderate-severe OI. Also, they concluded for 50 such children and can cause aberrations of skeletal modeling and remodeling that evolve years after drug adolescents that the transverse metaphyseal bands from PMD persist approximately 4 years activities were consistent with OPT diagnosis in 2002,(1) and are now unremarkable, supporting our impression they could withdrawal and carry into adult life. Radiologic Findings on average (range 2 - 8 years),(60) consistent with normal bone remodeling.(48) However, help monitor for BP toxicity.(1,13) To date, excessive BP suppression of bone turnover has been viewed a hypothetical concern.(67) However, in a mouse model for OI, metaphyses retained primary spongiosa after high-dose exposure to Radiographs the metaphyseal index in the distal femur was 26 % greater on average after this duration of treatment.(60) Any clinical consequences of these findings were judged unclear, with no alendronate.(68) Follow-up experience with our patient supports our concern that children who receive BPs could develop compromised bone quality despite increases in BMD. Skeletal radiographs, spanning 2002 at diagnosis of OPT to 2007 at reevaluation, showed that poorly modeled (widened), evidence of clinical implications, and perhaps some benefit.(60) osteosclerotic, metaphyseal bone formed during PMD administration (and persisting for at least two years after infusions stopped)(1) was followed as he grew by bone shaping that seemed improved with a return of some surface concavity In 2006, Weber et al.(61) evaluated the material properties of iliac bone from children with OI INTRODUCTION (rather than abnormal linearity or convexity) (Figures 1, 2). However, metaphyses were still widened in 2007 (especially in and concluded that the only significant effect of PMD was an increase in bone mass, mainly the distal femurs and proximal tibias), and there was now osteopenic metaphyseal bone, including areas of thin cortex in the cortex, in agreement with previous studies.(22,62) Reduced fracture incidence would, CONCLUSIONS (Figures 1, 2). Growth plate fusion indicated that his skeleton was now essentially mature, and that the shaping FIGURE 1: Posteroanterior radiographs of the left hand and wrist document modeling and remodeling abnormalities that FIGURE 4: Lateral radiograph of the lumbar spine in 2002 (A) shows how “window framing” of vertebrae with therefore, probably be due to increased amounts of cortical bone in combination with the In 2003, the first skeletal complication of aminobisphosphonate exposure was documented by our report of a boy with growth of the patients, while the intrinsic material properties of bone tissue, including deformities would persist. change from diagnosis of BP-induced OPT at age 12 years in 2002 (A) to follow-up at age 17 years in 2007 (B), 6-1/2 years endplate sclerosis at diagnosis of BP-induced OPT (1-1/2 years after PMD exposure ceased) evolved with Follow-up of the first reported patient with drug-induced OPT calls for studies which will document whether “neo-osseous pamidronate (PMD)-induced osteopetrosis (OPT).(1) More than 20 years earlier,(2) rickets and osteomalacia were after cessation of PMD exposure. During this 5-year interval, bone growth continued until closure of physes at skeletal skeletal growth to form a “bone-within-bone” configuration (B). In 2007, the vertebral endplates should appear stiffness and hardness, remained unaffected.(61) known to follow excesses of etidronate, a first-generation bisphosphonate (BP).(3,4) In 2004, “osteonecrosis of the Metaphyseal osteosclerosis (initiated at the old provisional zone of calcification) had become undertubulated, sclerotic, 6 osteoporosis” will commonly follow cessation of BP exposure in pediatric populations if metaphyses have widened, and diaphyseal areas especially in his major long bones. These areas appeared to be thick, coalescent trabeculae (Figure 3). maturation (B). more dense for a boy his age (B). Also in 2006, Vallo et al.(63) showed that PMD given for pediatric OI led to “size-adjusted” whether there will be clinical sequellae. Assessment of both cortical bone thickness and trabecular bone porosity in such jaw”,(5) and in 2005, “suppressed bone turnover”(6) emerged as concerns for adults receiving amino-BPs. spine BMD improvements that stabilized or sometimes decreased after two years of therapy. In 2005, radiographs showed a pathologic “chalkstick” break across his left ulna in this dense bone; not through the more In 2002 (A), metaphyseal osteosclerosis in the radius and ulna (brackets) accompanies a modeling defect featuring Spondylolysis of L5(arrow) in 2002(A) still persists after 5 years (2007). Also, a new pars defect has occurred metaphyses requires investigation. It may be that this complication of BP toxicity during childhood is unique to our patient Our patient had been referred in 2002 at 12 years-of-age, 1-½ years after cessation of escalating intravenous doses of recently formed, osteopenic, metaphyseal bone (Figure 3A). Two years later, a faint fracture line persisted despite solid They questioned whether repeated cycles of PMD were necessary, or would courses (with from his especially great exposure to PMD, but this does not seem likely, and we are monitoring children receiving lesser PMD.(1) PMD had been given by others apparently for his unexplained episodic bone pains and elevation in serum widening and loss of concave surfaces. By 2007 (B), this osteosclerosis has “moved” proximally (brackets) and remodeled in L4 in 2007(B). no intermediate therapy) be of identical benefit. periosteal bone around the break (Figure 3B). We previously illustrated the Salter II fracture that occurred through his to become a wide area of osteosclerosis within the diaphyseal shaft. In 2007, the metaphysis of the distal radius remains doses of BP for metaphyseal shaping and structure. We find that it might be necessary to treat growing children and bone alkaline phosphatase (ALP) activity, “osteopenia” on dual energy x-ray absorptiometry (spine Z-score -1.0), and osteosclerotic, distal right radius two years after PMD exposure ceased.(1) Hand and forearm radiographs in 2007 showed With the exception of the 1992 paper by van Persign van Meerten et al.,(46) no mention is adolescents with some dose of antiresorptive therapy until growth plates fuse. Perhaps this would help achieve peak worry he was having appendicular fractures from little trauma.(1) Our review of his extensive medical record (including somewhat wide, yet concave surfaces there and in the distal ulna indicate recovery of modeling. However, the metaphyseal that this break, and an interval right 5th metacarpal fracture, had healed (not shown). bone formed in the radius and ulna in this 5-year interval is osteopenic. made in these previous publications(51,55,57,60,63) concerning metaphyseal mineral metaphyseal BMD, especially if the metaphyses are widened. biochemical and radiological tests) prior to BP administration indicated that OPT had developed in a normal skeleton.(1) content after BP exposure stopped, because treatment was being continued or finishing when While he received approximately 2.8 gm PMD over 2-¾ years, he acquired bone modeling disturbances including club- Lumbar radiographs spanning 1998 to 2007 (ages 8 - 17 years) showed a normal spine that became abnormal during PMD. In 2001, the vertebral endplates were dense, and there was a faint pars defect at L5 seen on a lateral radiograph (uncertain Similarly, sclerotic metaphyses (e.g., arrow) in the long bones of the hand in 2002 (A) have become dense diaphyseal bone 5 6B the data were acquired. shaped deformities of his distal femurs and proximal tibias, primary spongiosa (calcified cartilage) persisted within his in 2007 (B) (arrow). A “bone-within-bone” appearance has developed in the carpal bones (B). iliac crest,(1) and spondylolysis developed in keeping with OPT.(7) Furthermore, two years after the PMD stopped, he if unilateral or bilateral). In 2002, the pars defect was obvious with a 4 mm separation (Figure 4A). Four years later, the Then, in 2006, Rauch et al. (38) described Z-scores for spine BMD in children and fractured an osteosclerotic distal radius, suggesting a lingering toxic effect.(1) spondylolysis was healing (less well defined with increased sclerosis), but in 2007 the gap had widened and was less well adolescents with moderate-severe OI two years after cyclical PMD therapy (given for at least ACKNOWLEDGEMENTS defined, and a grade I spondylolisthesis had developed (Figure 4B). Furthermore, a faint pars fracture line had emerged in three or four years) ceased. The Z-scores decreased, although not nearly to pretreatment Here, we report 5-year reevaluation of this patient, now 17-years-old, whose PMD exposure ended 6-½ years ago. L4. Both pars defects remain unhealed. Osteosclerosis in the spine, and more faintly in the ribs, evolved to a “bone-within- values, but reportedly fracture rates did not increase. Bone resorption activity, judged by bone” appearance. The vertebral endplates now appeared thin (Figure 4B), but there were no compression fractures. urine NTX levels, accelerated, but not to pretreatment values.(38) Rates of change toward Our report was made possible by the skill and dedication of the nursing, laboratory, and dietary staff at the Center for 2A B Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children; St. Louis, MO, U.S.A. Angelia English The femoral necks had become wide and short (Figure 5). baseline were greatest in those patients who continued to grow. New bone appeared less dense radiographically compared to during treatment, both in vertebrae and in wrist provided expert secretarial help. Vivienne Lim and Dawn Russell helped to illustrate the manuscript. Steven L. Teitelbaum, We did not have interval radiographs of his feet. The other interval radiographs documented no other fractures. metaphyses,(38) but there was no mention whether density could be worse compared to M.D. kindly reviewed the histopathology. The carpal and tarsal bones, epiphyses, and pelvis (Figure 5) also showed the “bone-within-bone” appearance. In some before treatment.(38,39) Knees were not commented upon, and no mention was made PATIENT AND METHODS areas, such as the pelvis, the lines of osteosclerosis were layered. At the ankles, in addition to metaphyseal expansion, concerning post-treatment metaphyseal modeling changes.(38) REFERENCES there was talar tilting from lateral to medial, greater on the right (not shown). In 2007, Rauch et al.(39) used peripheral quantitative CT to evaluate the metaphysis and Panorex dental radiographs, the most recent in 2006, showed missing 2nd and 3rd molars in the left mandible. diaphysis of a distal radius of 23 OI children on average 1.9 years after at least 3 years 1. Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm S 2003 Bisphosphonate-induced osteopetrosis. N Engl J Med 349:457-463. Following informed written consent approved by the Human Research Protection Office, Washington University School (average 5.8 years) of PMD exposure. Z-scores for bone mineral content (BMC) decreased 2. Weinstein RS 1982 Focal mineralization defect during disodium etidronate treatment of calcinosis. Calcif Tissue Int more in the metaphysis than diaphysis. They concluded “previous PMD administration has 34:224-228. of Medicine, St. Louis, MO, our patient prepared for readmission to Shriners Hospital for Children, St. Louis, MO and DXA 3. Adami S, Zamberlan N 1996 Adverse effects of bisphosphonates. A comparative review. Drug Saf 14:158-170. iliac crest biopsy by taking two, 3-day courses of tetracycline hydrochloride (250 mg p.o. q.i.d.) separated by 13 days, little effect on bone tissue that is created after the last infusion of the drug”.(39) Also, “the low 4. Labinson P, Taxel D 2007 Multiple fractures in a woman receiving 24 years of etidronate treatment for Paget’s disease. Conn Med 71:269-273. The first DXA evaluation, performed elsewhere at age 7 years (prior to PMD), showed a L1 - L4 BMD Z-score metaphyseal bone mass after PMD discontinuation suggests that the bone tissue added by 5. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL 2004 Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 62:527- with 2-½ days lapsing after the final dose before the procedure. Now 17 years-of-age, he was again accompanied by 534. his mother, a nurse, to our facility. of - 1.0 using Hologic reference values and was therefore considered “osteopenia”. Reevaluation using data reported in growth after the last PMD infusion probably is as fragile as the ‘older’ parts of the skeleton 6. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY 2005 Severely suppressed bone turnover: A potential complication of alendronate therapy. J Clin Endocrinol Metab 2007(12) (293 non-black boys ages 7 and 8 years) showed a Z-score of + 0.24 (Table 2). At diagnosis of BP-induced were before the start of the PMD treatment”.(39) Although they cautioned that the risk/benefit 90:1294-1301. 7. Martin RP, Deane RH, Collett V 1997 Spondy-lolysis in children who have osteopetrosis. J Bone Joint Surg Am OPT, the spine Z-score was + 3.10, and + 1.83 at follow-up.(12) However, his spine at follow-up was radiographically ratio is not yet clear, BP therapy might be necessary until growth ceases. They illustrated 79:1685-1689. Interval Medical History osteopenic, except where there was “bone-within-bone” bands of osteosclerosis (Figure 4B). DXA had scanned both the that the junction of the old, dense bone and new, less dense bone might be the site of future 8. Williamson A, Hoggart B 2005 Pain: A review of three commonly used pain rating scales. J Clin Nurs 14:798-804. osteosclerotic and the osteopenic bone. Thus, the osteopenia (now apparent throughout much of his spine, as well as in FIGURE 7: A,B) Toluidine blue staining of non-decalcified sections of the patient’s iliac crest cores from 2007 (A) fracture.(39) 9. Kuczmarski RJ, Ogden CL, Grummer-Strawn LM 2000 CDC growth charts: United States. Advance data from vital and health statistics (#314). National Center for Health Statistics, Since evaluated 5 years previously, episodic bone pain of the same intensity (“6” or “7” on a 10-point pain scale(8)) still demonstrates retained cartilage (stained purple, arrows) within trabecular bone not seen in an age-matched control (B). Hyattsville, Maryland. recurred in his knees and legs, but was now less frequent (~ once every two months) and of shorter duration, typically major long bone metaphyses) was not revealed by the BMD Z-score. In 2007, Waterhouse et al.(40) examined BP cessation for an average of 26 months in 17 10.Tanner JM 1978 Physical growth and development. In: Forfar JO, Arneil GC (eds.) Textbook of Pediatrics. Churchill Livingstone, Edinburgh, UK, pp. 253-303. lasting about one hour. He did not identify precipitating or exacerbating factors. There was no history to suggest knee Total hip BMD Z-scores decreased between ages 12 and 17 years from + 2.32 to + 1.35, respectively.(12) (Scale bar 200 µm). C,D) Golder’s trichrome stain of iliac crest during PMD exposure (C) shows lack of new bone children treated an average of 22 months either with PMD or zolendronate for various 11.Roche AF, Mukherjee D, Guo SM, Moore WM 1987 Head circumference reference data: Birth to 18 years. Pediatrics formation (osteoid). At followup in 2007 (D), there is abundant osteoid (red, arrows) (Scale bar 200 µm). conditions and observed no adverse effects, including evaluation of lumbar spine 79:706-712. instability. For relief, he soaked in hot water. Naproxen and rofecoxib had not been necessary for several years. He In the left proximal 1/3 radius (without radiographic osteosclerosis or bone widening from PMD), Z-scores had progressively E,F) Osteoclasts during PMD toxicity (E, arrow) were rounded and not polarized toward bone, whereas those at 12.Kalkwarf HJ, Zemel BS, Gilsanz V, Lappe JM, Horlick M, Oberfield S, Mahboubi S, Fan B, Frederick MM, Winer K, Shepherd JA 2007 The bone mineral density in childhood study: Bone recognized a “bump” on the medial aspect of his tibias proximally. radiographs. Radiographs of the knees were said not to show OPT modeling changes. mineral content and density according to age, sex, and race. J Clin Endocrinol Metab 92:2087-2099. increased (-0.6, -0.26, -0.21, respectively), and all values were normal (Table 2).(12) followup (F, arrow) have a normal flat and polarized morphology (Scale bar 50 µm). 13.Whyte MP, Chines A, Silva DP Jr, Landt Y, Ladenson JH 1996 Creatine kinase brain isoen-zyme (BB-CK) presence in serum distinguishes osteopetroses among the sclerosing bone He claimed to have fractured approximately three times yearly. Although some precautions had been taken, such as not Notably, however, Ward et al.(41) in 2007 reported in a young child with OI marked decrease disorders. J Bone Miner Res 11:1438-1443. skateboarding, he had not protected his back despite the spondylolysis.(1) He played basketball, tackle football in the FIGURE 5: Anteroposterior view of the left (1) in volumetric BMD Z-scores to below baseline in the lumbar spine and distal radius occurring 14.Whyte MP, Wenkert D 2006 Lactate dehydrogenase (LDH) isoenzyme elevation in human osteopetrosis. J Bone Miner Res 21:S431. High-Resolution CT Of The Knees TABLE 1: BIOCHEMICAL FINDINGS AT DIAGNOSIS AND FOLLOW‐UP 15.Ott SM 2006 Long-term safety of bisphosphonates. J Clin Endocrinol Metab 90:1897-1899. snow, and baseball recalling that he probably slid into bases and dived for a ball or two. Reportedly, the interval hemipelvis, including proximal femur, within two years after stopping 4-½ years of PMD therapy. They questioned whether BP 16.Armamento-Villareal R, Napoli N, Panwar V, Novack D 2006 Suppressed bone turnover during alendronate therapy for fractures clustered within a few months each year and occurred from minor trauma. His mother said these fractures CT of his knees in 2007 (Figure 6) documented striking paucity of trabecular bone in the expanded metaphyses as demonstrates especially well the acquired “bone- treatment could be discontinued before completion of linear growth.(41) Inspection of their high-turnover osteoporosis. N Engl J Med 355:2048-2050. tended to involve growth plates of fingers and sclerotic areas of forearms. As published,(1) one was a Salter II fracture well as areas of cortical thinning. within-bone” configuration (dark blue arrow). (2002) (2007) published radiographs reveals metaphyseal widening.(41) 17.Chapurlat RD, Arlot M, Burt-Pichat B, Chavassieux P, Roux JP, Portero-Muzy N, Delmas PD 2007 Microcrack frequency and bone remodeling in postmenopausal osteoporotic women PARAMETER REFERENCE REFERENCE on long-term bisphosphonates: A bone biopsy study. J Bone Miner Res 22:1502-1509. of his osteosclerotic distal right radius that occurred while catching a light basketball two years after cessation of PMD Notably, the femoral neck has become short and PATIENT’S PATIENT’S 18.Whyte MP 2002 Osteopetrosis. In: Royce PM, Steinmann B (eds.) Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects, 2nd ed. Wiley-Liss, New (Aredia®; Novartis Pharma AG, Basle, Switzerland). A left ulna diaphyseal fracture occurred at age 15 years while wide, and there is an acquired bulge (light blue VALUES RANGES * VALUES RANGES * York, pp. 789-807. “inner tubing” when a tow rope twisted his wrist (see below). He broke his right 5th metacarpal falling onto a basketball Histopathology Findings Perspective From Our Patient’s Follow-Up 19.Whyte MP, Wenkert D, McAlister WH 2003 Bisphosphonates in children with bone diseases (reply letter). N Engl J Med 349:2069-2071. arrow) distal to the closed physeal line, similar to SERUM (Fasting) 20.Glorieux FH, Bishop NJ, Plotkin H, Chabot G, Lanoue G, Travers R 1998 Cyclic admin-istration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 339:947- court. He reported stubbing his right great toe one year earlier causing a chip fracture, but the foot radiographs The iliac crest proved quite hard. The Trap-Lok® needle was hammered to obtain the two cores. The Bordier trephine cut what causes “acetabulofemoral impingement”. We worry that 6-1/2 years after cessation of PMD exposure our patient still seems 952. were not available for review. with manual rotation. The procedure was tolerated well. Calcium (mg/dl) 9.1 9.4 – 10.6 9.5 9.1 – 10.3 predisposed to fracture. In 2005, Grissom et al.(51) offered three mechanisms whereby 21.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. fracturing could continue in children with OI despite PMD therapy: J Clin Endocrinol Metab 85:1846-1850. His fractures were said to mend slowly. Orthopedic records indicated the right radius fracture was casted for one Non-decalcified staining of methylmethacrylate-embedded, 10 µm sections from the Trap-Lok® needle showed cortex and 4.9 – 5.4 4.8 – 5.4 22.Rauch F, Travers R, Plotkin H, Glorieux FH 2002 The effects of intravenous pamidronate on the bone tissue of children and adolescents with osteogenesis imperfecta. J Clin Invest Ionized Calcium (mg/dl) 4.9 4.8 i) bone density remains below fracture threshold, 110:1293-1299. month, but then perhaps splinted for a few additional weeks. The left ulna fracture was treated with a hard cast for one subjacent trabecular bone to a depth of at least 1 cm, but growth plate was absent. Toluidine staining demonstrated Patient 23.Klein GL, Bachrach LK, Holm IA 2007 Effects of pharmacologic agents on bone in childhood: An editorial overview. Pediatrics 119:S125-S130. month, followed by a soft splint for several weeks ― reportedly because some instability was delaying the union. The calcified cartilage remnants at least 5 - 7 mm away from the cortex (Figure 7A). In contrast, no cartilage was present up to 6A Phosphate (mg/dl) 4.4 4.3 – 5.7 4.9 2.5 – 4.4 ii) bone fragility persists despite increased or even normal density, and 24.Brumsen C, Hamdy NA, Papapoulos SE 1997 Long-term effects of bisphosphonates on the growing skeleton. Studies of young patients with severe osteoporosis. Medicine (Baltimore) metacarpal fracture healed after one month in a hard cast. For the broken toe, he reportedly used crutches for a 76:266-283. 10 mm from the cortex in the two control boys (Figure 7B). However, the amount of cartilage encased within the patient’s Intact PTH (pg/ml) 92 7–53 24 10 – 69 iii)increased physical activity by the patient.(51) 25.Shoemaker LR 1999 Expanding role of bis-phosphonate therapy in children. J Pediatr 134:264-267. fortnight, and then wore an orthopedic boot for another two weeks. trabecular bone was now greatly decreased compared to during PMD exposure.(1) 26.Srivastava T, Alon US 1999 Bisphosphonates: From grandparents to grandchildren. Clin Pediatr (Phila) 38:687-702. Pain near his left sacroilium and iliac crest (“5” using the 10-point pain scale(8)) ended further participation in baseball. Alkaline Phosphatase (U/liter) 1493 133 – 347 485 30 – 114 For our patient, bone fragility seems largely from BP-induced deceleration of bone 27.Hickey J, Lemons D, Waber P, Seikaly MG 2006 Bisphosphonate use in children with bone disease. J Am Acad Orthop Surg 14:638-644. During PMD, little osteoblast activity was apparent, with absence of osteoid revealed by Goldner’s trichrome stain remodeling. Additionally, fracture susceptibility could now occur because of permanent 28.Plotkin H, Coughlin S, Kreikemeier R, Heldt K, Bruzoni M, Lerner G 2006 Low doses of pamidronate to treat osteopenia in children with severe cerebral palsy: A pilot study. Dev Med Although this discomfort improved with rest, physical activity made it worse. Magnetic resonance imaging (MRI) of his (Figure 7C)(1). In contrast, follow-up showed normal amounts of osteoid along trabecular bone surfaces (Figure 7D), and Bone-specific Alkaline Phosphatase †(U/liter) 47 – 181 3–38 Child Neurol 48:709-712. spine four years after PMD exposure stopped showed persistent spondylolysis. His orthopedist reportedly told him that 746 243 disturbances in modeling with osteopenia. 29.Isaia GC, Lala R, Defilippi C, Matarazzo P, Andreo M, Roggia C, Priolo G, de Sanctis C 2002 Bone turnover in children and adolescents with McCune-Albright syndrome treated with abundant double labels from the tetracycline (not shown). pamidronate for bone fibrous dysplasia. Calcif Tissue Int his spondylolysis could be treated by a rodding procedure, but this seemed inadvisable with concerns about bone Osteocalcin ** (ng/ml) 124 15 – 103 53 14 – 67 Bone modeling is increasingly understood to influence skeletal quality and strength.(64) 71:121-128. integrity. During PMD, osteoclasts had abnormal rounded morphology, lack of polarization, and were off of the bone surface Treatment of infants, children, and adolescents with BPs can have skeletal modeling effects 30.Atabek ME, Pirgon O, Sert A 2006 Oral alendronate therapy for severe vitamin D intoxication of the infant with nephrocalcinosis. J Pediatr Endocrinol Metab 19:169-172. (Figure 7E). The follow-up specimens demonstrated normal appearing osteoclasts juxtaposed to bone (Figure 7F). Acid Phosphatase (U/liter) 25 < 6 ‡ *** 10.2 6.3 – 26.7**** because their growth plates (physes) are open, and osteoclast-mediated bone resorption 31.Brown JJ, Zacharin MR 2005 Attempted randomized controlled trial of pamidronate versus calcium and calcitriol supplements for management of steroid-induced osteoporosis in children He said that dental implants for “missing” 12-year molars had been discussed with his dentist, but seemed risky and adolescents. J Paediatr Child Health 41:580-582. Accordingly, both osteoblast and osteoclast activity had improved at follow-up, but some primary spongiosa persisted. must continue for proper shaping of bones. Experience with our patient indicates that because his jaw might be brittle. He had worn dental braces, however it was unclear if osteoclasts were activated FIGURE 2: Compared to the hands and wrists (Fig. 1), the similar (but more severe) modeling and remodeling abnormalities 32.Ambler GR, Chaitow J, Rogers M, McDonald DW, Ouvrier RA 2005 Rapid improvement of calcinosis in juvenile dermatomyositis with alendronate therapy. J Rheumatol 32:1837-1839. so that his teeth could move properly. metaphyseal osteopenia can occur if antiresorptive therapy widens metaphyses and is then 33.Cagle AP, Waguespack SG, Buckingham BA, Shankar RR, DiMeglio LA 2004 Severe infantile hypercalcemia associated with Williams syndrome successfully treated with intravenously in the distal femurs and proximal tibias developed novel changes between 2002 (A) and 2007 (B). stopped as growth continues. The mechanism for this osteopenia is not clear, but this administered pamidronate. Pediatrics 114:1091-1095. Pressure or throbbing frontal headaches had occurred approximately two or three times monthly, and at any time of day, URINE (24‐Hour) 34.Kerrison C, Davidson JE, Cleary AG, Beresford MW 2004 Pamidronate in the treatment of childhood SAPHO syndrome. Rheumatology(Oxford). 43:1246-1251. Here, at the right knee, metaphyseal osteosclerosis, documented to be unchanged radiographically in the wrist up to 2 years scenario is described in the case report (discussed above) by Ward et al. in 2007.(41) 35.Carpenter PA, Hoffmeister P, Chesnut CH 3rd, Storer B, Charuhas PM, Woolfrey AE, Sanders JE 2007 Bisphosphonate therapy for reduced bone mineral density in children with chronic but without nausea or vomiting and were not precipitated by coughing, sneezing, etc. Computed tomography (CT) of his DISCUSSION Collagen cross-linked N- graft-versus-host disease. Biol Blood Marrow Transplant 13:683-690. following cessation of PMD exposure,(1) has become unexpectedly osteopenic after the 5-year interval (B). Areas of Our patient has three disturbances, possibly four, in his metaphyses. First, the distal femoral head in 2003 was said to show “banding of bone”, representing a “possible concern for the future”. Review of systems telopeptide 197 91 + 1115 76 5 – 87 36. Yamazaki Y, Satoh C, Ishikawa M, Notani K, Nomura K, Kitagawa Y 2007 Remarkable response of juvenile diffuse sclerosing osteomyelitis of mandible to pamidronate. Oral Surg Oral was otherwise unremarkable. osteosclerotic metaphyseal bone 1-1/2 years after PMD infusions ceased (A), have remodeled to become dense diaphyseal metaphyseal index of 0.034 (normal 0.7) is remarkably low, and metaphyseal expansion will Med Oral Pathol Oral Radiol Endod 104:67-71. bone (follow matching arrows) (B). (nmol of bone collagen equivalents/nmol of crt) likely persist lifelong in his mature skeleton. Second, radiographs showed areas of thin 37. Andiran N, Alikasifoğlu A, Küpeli S, Yetgin S 2006 Use of bisphosphonates for resistant hypercalcemia in children with acute lymphoblastic leukemia: Report of two cases and review of His interval medications from a pain clinic included tramadol, which he rarely used because of lethargy, and valdecoxib. Bisphosphonate-Induced Osteopetrosis In Our Patient the literature. Turk J Pediatr 48:248-252. Free Deoxypyridinoline (nmol/mmol cortex. Third, there was a paucity of cancellous bone and narrow, longitudinal trabeculae in 38. Rauch F, Munns C, Land C, Glorieux FH 2006 Pamidronate in children and adolescents with osteogenesis imperfecta: Effect of treatment discontinuation. J Clin Endocrinol Metab Lifelong, he had taken three methylprednisolone “dose packs” for “asthma”. He received no other pharmaceuticals or There is considerable controversy whether amino-BPs can cause oversuppression of bone remodeling in adults.(6,15-17) 17 2–58 5.1 1.1 – 26 the distal femur and proximal tibia metaphysis at his knees. Fourth, follow-up histology of his 91:1268-1274. supplements. Our research dietician estimated from a 7-day food record that he consumed ~ 1,580 mg of calcium each Our patient demonstrates, unequivocally, that oversuppression from PMD is possible for both skeletal modeling and crt) iliac crest showed significant recovery of remodeling, but some excess primary spongiosa 39. Rauch F, Cornibert S, Cheung M, Glorieux FH 2007 Long-bone changes after pamidronate discontinuation in children and adolescents with osteogenesis imperfecta. Bone 40:821-827. day (Recommended Daily Allowance = 1300 mg). remodeling in children.(1) 40. Waterhouse KM, Auron A, Srivastava T, Haney C, Alon US 2007 Sustained beneficial effect of intravenous bisphosphonates after their discontinuation in children. Pediatr Nephrol 3A B remains. It seems likely this retention of calcified cartilage also affects his metaphyses, 22:282-287 His family’s medical history was unchanged and without migraine headaches, but included deafness and common In 2003, we published a description of our patient’s acquired bone disorder;(1) the first report of drug-induced OPT.(18) although one was not biopsied. We worry that this he is at risk lifelong for fracture through 41. Ward KA, Adams JE, Freemont TJ, Mughal MZ 2007 Can bisphosphonate treatment be stopped in a growing child with skeletal fragility? Osteoporos Int 18:1137-1140. * Unless otherwise stated, normal ranges for 42. Marini JC 2003 Do bisphosphonates make children’s bones better or brittle? N Engl J Med 349:423-426. variable immune deficiency affecting his sister. Elsewhere, over 2-¾ years, he had been dispensed a cumulative dose of PMD that was approximately four times(19) the Control ** Diagnostic Products Corp (Los Angeles, CA) his deformed and osteopenic metaphyseal bone. CT or MRI might be especially helpful to 43. Papapoulos SE, Cremer SCLM 2007 Prolonged bisphosphonate release after treatment in children. N Engl J Med 356:10. amount emerging during the 1990s as a treatment for children and adolescents with severe osteogenesis imperfecta (OI). fasting blood and 24‐hour urine collections investigate this concern in other patients, as we are doing for some of our BP-treated 44. Hoekman K, Papapoulos SE, Peters ACB, Bijvoet OLM 2007 Characteristics and bisphosphonate treatment of a patient with juvenile osteoporosis. J Clin Endocrinol Metab 61:952-956. (20-22) Concerns that initiated his BP exposure seemed to be: are the mean (±2 SD). Pediatric reference *** Quest Diagnostics children. 45. Devogelaer JP, Malghem J, Maldague B, Nagant de Deuxchaisnes C 1987 Radiological manifestations of bisphosphonate treatment with APD in a child suffering from osteogenesis Physical Findings values for blood represent 20 healthy imperfecta. Skeletal Radiol 16:360-363. i) a perception that he was fracturing during minor trauma, children (ages 4.6 to 12.9 years) and for **** Quidel Kit (Metra TRAP5B; San Diego, CA) Furthermore, our patient sustained, with seemingly mild trauma, a pathologic fracture across 46. Van Persijn van Meerten EL, Kroon HM, Papapoulos SE 1992 Epi- and metaphyseal changes in children caused by administra-tion of bisphosphonates.Radiology 184:249-254. Physical examination at age 17 years showed normal vital signs with weight 61 kg or 134 lbs (35%), height 179 cm or 5 urine represent 33 healthy children (ages an ulna at radiographically dense and widened diaphyseal bone. It seems that this area of 47. Schenk R, Eggli P, Flesich H, Rosini S 1986 Quantitative morphometric evaluation of the inhibitory activity of new aminobisphosphonates on bone resorption in the rat. Calcif Tissue Int ii) “osteopenia” according to a DXA spine BMD Z-score of - 1.0, 38:342-349. ft 10 in (70%), arm span significantly less than height at 170 cm or 5 ft 7 in (24%),(9) sitting height 97 cm (~ 75%),(10) 0.5 to 14.5 years), respectively, receiving ad † Metra Biosystems assay skeletal weakness formed as dense trabecular bone within the metaphysis remodeled into 48. Rauch F, Travers R, Munns C, Glorieux FH 2004 Sclerotic metaphyseal lines in a child treated with pamidronate: Histomorphometric analysis. J Bone Miner Res 19:1191-1193. and head circumference 57 cm (~ 75%).(11) He was well-appearing, well-masculinized, and in no distress. There was iii) unexplained episodic bone pain, and iv) idipathic hyperphosphatasemia of skeletal origin. libitum diets in St. Louis, MO. Adult sclerotic diaphyseal bone. Despite its increased radiographic density, this bone containing a 49. Munns CF, Rauch F, Zeitlin F, Fassier F, Glorieux FH 2004 Delayed osteotomy but not fracture healing in pediatric osteogenesis imperfecta patients receiving pamidronate. J Bone subtle widening of his proximal tibias, but equal hip and shoulder heights and a negative Gaenslen’s test for sacroiliac PMD infusions were probably continued because, in keeping with early reports regarding OI, (20,21) his bone pain reference values for fasting blood represent pathologic “chalkstick fracture” proved structurally weaker than the adjacent osteopenic (but Miner Res 19:1779-1786. 31 healthy men and women ‡ Adult reference range 50. Land C, Rauch F, Montpetit K, Ruck-Gibis J, Glorieux FH 2006 Effect of intravenous pamidronate therapy on functional abilities and level of ambulation in children with osteogenesis derived pain. seemed to respond.(1) Also, PMD decreased, but did not correct, his hyperphosphatasemia.(1) expanded) metaphyseal bone, perhaps reflecting some PMD effect lingering 6-1/2 years after imperfecta. J Pediatr 148:456-460. Nevertheless, our review of his extensive medical record did not indicate (from radiological or other biochemical studies) exposure stopped. In fact, this fracture remains incompletely healed after 2 years, despite 51. Grissom LE, Kecskemethy HH, Bachrach SJ, McKay C, Harcke HT 2005 Bone densitometry in pediatric patients treated with pamidronate. Pediatr Radiol 35:511-517. bridging periosteal bone. Absence of skeletal resorption in all forms of OPT compromises 52. Adiyaman P, Ocal G, Berberoğlu M, Evliyaoğlu O, Aycan Z, Cetinkaya E 2004 The clinical and radiological assessment of cyclic intravenous pamidronate administration in children with Biochemical Studies skeletal disease prior to the BP exposure.(1) Subsequently, however, radiographic and histopathologic findings between TABLE 2: BONE MINERAL DENSITY Z‐SCORES* osteogenesis imperfecta. Turk J Pediatr 46:322-328. 7-¾ and 10-½ years-of-age, together with biochemical and radiological disturbances 1-½ years after PMD stopped, were bone quality because primary spongiosa containing calcified cartilage persists, and because 53. Glorieux FH, Rauch F, Shapiro JR 2003 Bisphosphonates in children with bone diseases. (reply letter) N Engl J Med 349:2068-2069. Follow-up biochemical studies were once again performed while he was an in-patient and consumed a diet matched to interconnection of osteons is impaired.(18) Accordingly, we remain concerned for fracture 54. Falk MJ, Heeger S, Lynch KA, DeCaro KR, Bohach D, Gibson KS, Warman ML 2003 Intravenous bisphosphonate therapy in children with osteogenesis imperfecta. Pediatrics those of OPT.(18) OPT was confirmed by its characteristic histopathologic aberration showing osteoclast failure,(18) i.e., 7 111:573-578. through similar areas of dense, poor quality, diaphyseal bone; especially in his femurs or his daily intake of calcium. The same analytic techniques and instruments were used,(1) unless noted otherwise. The accumulation of primary spongiosa (calcified cartilage), in his iliac crest. Additionally, there were dysmorphic osteoclasts Age (years) 7 12 17 55. Bin-Abbas BS, Al-Ashwal AA, Al-Zayed ZS, Sakati NA 2004 Radiological features of bisphosphonate therapy in children with osteogenesis imperfecta. Saudi Med J11:1772-1773. findings were contrasted to values from his initial evaluation, at both times using age-appropriate reference ranges off of bone surfaces.(1) In keeping with OPT,(18) he had developed elevated skeletal mass and seemed clearly tibias. Remodeling should eventually restore bone of normal density and quality at these 56. Srinivasan R 2005 Pamidronate lines. Indian Pediatr 42:959-960. established in our laboratory for most parameters (Table 1).(1) susceptible to fracture within the acquired, osteosclerotic bone.(1) Two years after PMD exposure ceased, metaphyseal sites, but this will probably take at least several additional years, and it seems unlikely that 57. Ward K, Cowell CT, Little DG 2005 Quantification of metaphyseal modeling in children treated with bisphosphonates. Bone 36:999-1002. Spine (L ‐L ) + 0.24 + 3.10 + 1.83 modeling will ever become normal. Recently, Weinstein et al.,(65) in a preliminary report, 58. Letocha AD, Cintas HL, Troendle JF, Reynolds JC, Cann CE, Chernoff EJ, Hill SC, Gerber LH, Marini JC 2005 Controlled trial of pamidronate in children with types III and IV bone remained just as radiographically dense, consistent with a lingering pharmacologic effect.(1) Our search for gene 1 4 osteogenesis imperfecta confirms vertebral gains but not short-term functional improvement. J Bone Miner Res 20:977-986. mutations that might explain his problems was unrevealing.(1) Accordingly, as had been our practice,(23) we described the same type of osteoclast dysmorphology seen in our patient(1) in women who 58A.Rauch F, Glorieux FH 2005 Bisphosphonate treatment in osteogenesis imperfecta: Which drug, for whom, for how long? had received conventional doses of alendronate for osteoporosis. Return of our patient’s Ann Med 37:295-302. recommended that bone modeling be assessed periodically with radiographs of metaphyses of wrists and knees of Total hip ND + 2.32 + 1.35 59. Land C, Rauch F, Munns CF, Sahebjam S, Glorieux FH 2006 Vertebral morphometry in children and adolescents with osteogenesis imperfecta: Effect of intravenous pamidronate Radiologic Studies children exposed to prolonged courses of BPs to monitor the suppression of skeletal resorption.(1,19) Our patient osteoclast morphology to normal is somewhat reassuring. Clearly, he did not have a treatment. Bone 39:901-906 Skeletal radiographs and dual energy x-ray absorptiometry (DXA, Hologic QDR 4500-A, Waltham, MA) were repeated, declined reevaluation by us until after five years had passed. congenital or permanent OPT, but instead reversible suppression of osteoclast action from 60. Land C, Rauch F, Glorieux FH 2006 Cyclical intravenous pamidronate treatment affects metaphyseal modeling in growing patients with osteogenesis imperfecta. J Bone Miner Res Radius (proximal 1/3) BP-induced OPT. 21:374-379. and all interval radiologic images (excluding the foot radiographs) were reviewed, including the MRI and CT of his spine ‐ 0.6 ‐ 0.26 ‐ 0.21 61. Weber M, Roschger P, Fratzl-Zelman N, Schöberl T, Rauch F, Glorieux FH, Fratzl P, Klaushofer K 2006 Pamidronate does not adversely affect bone intrinsic material properties in and head, respectively. DXA results from both admissions included bone mineral density (BMD) assessments of total Prior to PMD exposure,(1) our patient’s vertebral heights and bone mass, including endplate children with osteogenesis imperfecta. Bone 39:616-622. 62. Rauch F, Travers R, Glorieux FH 2006 Pamidronate in children with osteogenesis imperfecta: Histomorphometric effects of long-term therapy. J Clin Endocrinol Metab 91:511-516. body, L1 - L4 spine, total hip, and radius. Z-scores were calculated using the method and data of Kalkwarf et al. Bisphosphonate Treatment For Children ND width, did not appear diminished on radiographs. This fit with his concomitant, unremarkable, Whole body ‐ 0.53 (porta cath in place) + 0.55 63. Vallo A, Rodriguez-Leyva F, Rodriguez Soriano J 2006 Osteogenesis imperfecta: Anthropometric, skeletal and mineral metabolic effects of long-term intravenous pamidronate therapy. published in 2007.(12) Amino-BPs have now been administered for many pediatric conditions.(24--37) However, optimum doses and durations FIGURE 6: A) Computed tomography of the patient’s knees in 2007, here showing the distal femur (Top), spine BMD Z-score. When diagnosed with BP-induced OPT in 2002, delayed whole body Acta Paediatr 95:332-339. bone scintigraphy showed no evidence of fractures, although he had developed vertebral 64. Seeman E 2003 Periosteal bone formation — a neglected determinant of bone strength. N Engl J Med 349:320-323. Additionally, high-resolution CT of the expanded metaphyseal bone at our patient’s knees was performed at St. Louis of BP exposure for the skeletal disorders remain uncertain,(58A) and withdrawal of treatment after several years (followed revealed widened metaphyses with thin cortices and a paucity of trabecular bone (arrow), compared to healthy † † † 65. Weinstein RS, Chambers TM, Hogan RS, Webb EE, Wicker CA, Manolagas SC 2007 Giant osteoclast formation after Children’s Hospital, St. Louis, MO using 0.75 mm slice thickness, followed by coronal and sagittal reconstructions. by observation) is becoming commonplace.(38-41,58) It is widely recognized that BP effects on the skeleton may persist FIGURE 3: In 2005 (A), a pathologic “chalkstick” fracture (arrow) spans an area of widened and dense diaphyseal bone in the boys of similar age (Bottom). In both distal femoral metaphyses there is expanded bone with a remarkable, Spine (L1‐L4) ‐ 1.0 + 2.2 + 2.2 end-plate thickening and an unhealed L5 spondylolysis.(1) At follow-up in 2007, after linear long-term oral amino bisphosphonate therapy for postmenopausal osteoporosis. J Bone Miner Res 22(Suppl 1):S17. Comparisons were made using scans from ten age-matched, healthy boys with contralateral symptoms. for years.(42) In fact, PMD excretion in the urine of children (24) has been shown to last up to 8 years.(43) As discussed left ulna. In 2007 (B), a faint fracture line persists, but is surrounded by solid, bridging callus (solid arrow). large, central area (arrow) featuring a paucity of trabecular bone. growth and no further exposure to PMD, there was an osteosclerosis “bone-within-bone” 66. Ǻström E, Håkan J, Söderhäll S 2007 Intravenous pamidronate treatment of infants with severe osteogenesis imperfecta. Arch Dis Child 92:332-338. All values calculated from the references ranges of Kalkwarf et al.(12) (endobone) configuration in his vertebrae and throughout his skeleton, as occurs in 67. Imai K, Yamamoto S, Anamizu Y, Horiuchi T 2007 Pelvic insufficiency fracture associated with severe suppression of bone turnover by alendronate therapy. J Bone Miner Metab Also, we conducted an image search for radiographs of children receiving BP using Google (http://images.google.com) below, experience with our patient indicates that novel skeletal aberrations(41) may emerge in children when potent BPs * 25:333–336. are stopped, especially if there has been significant impairment of bone modeling. In the radius, there is a persisting lucent line in an area of diaphyseal sclerosis ― a peculiar site of fewer trabeculae (dotted B) Coronal sectioning of the CT shows the modeling defects and metaphyseal osteopenia and a vertical pattern unless designated † which are from Hologic software. ND = Not Done. OPT(1,18) In fact, this finding after amino-BP withdrawal had been reported in children by van 68. Camacho NP, Raggio CL, Doty SB, Root L, Zraick V, Ilg WA, Toledano TR, Boskey AL 2001 A controlled study of the effects of alendronate in a growing mouse model ofosteo-genesis and Yahoo (http://images.yahoo.com/). arrow) also noted in the patient’s distal femurs and proximal tibias. of trabeculae. The subarticular epiphyseal bone is inexplicably dense (arrow). imperfecta. Calcif Tissue Int 69:94-101.