Bisphosphonate-Induced Osteopetrosis: Novel Bone Modeling Defects, Metaphyseal Osteopenia, and Osteosclerosis Fractures After Drug Exposure Ceases

Authors

  • Michael P Whyte,

    Corresponding author
    1. Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children, St Louis, Missouri, USA
    2. Division of Bone and Mineral Diseases, Washington University School of Medicine at Barnes-Jewish Hospital, St Louis, Missouri, USA
    • Address reprint requests to: Michael P Whyte, MD, Shriners Hospitals for Children, 2001 South Lindbergh Boulevard, St Louis, MO 63131-3597, USA
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  • William H McAlister,

    1. Mallinckrodt Institute of Radiology, Washington University School of Medicine at St Louis Children's Hospital, St Louis, Missouri, USA
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  • Deborah V Novack,

    1. Division of Bone and Mineral Diseases, Washington University School of Medicine at Barnes-Jewish Hospital, St Louis, Missouri, USA
    2. Department of Pathology, Washington University School of Medicine at Barnes-Jewish Hospital, St Louis, Missouri, USA
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  • Karen L Clements,

    1. Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children, St Louis, Missouri, USA
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  • Perry L Schoenecker,

    1. Departments of Orthopedic Surgery, Shriners Hospitals for Children and Washington University School of Medicine at Barnes-Jewish Hospital, St Louis, Missouri, USA
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  • Deborah Wenkert

    1. Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children, St Louis, Missouri, USA
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  • Presented in part at the American Society for Bone and Mineral Research meeting “Targeting Bone Remodeling for the Treatment of Osteoporosis,” December 6–7, 2007, Washington, DC, USA.

    The authors state that they have no conflicts of interest.

Abstract

In 2003, we reported on a 12-yr-old boy who had developed osteopetrosis (OPT) while receiving pamidronate (PMD) for idiopathic bone pain and enigmatic elevation in circulating bone alkaline phosphatase. Now 17 yr of age, he was re-evaluated 6.5 yr after PMD exposure stopped. Our patient described less bone pain but further limb fractures. His growth plates were fused, yet hyperphosphatasemia persisted. Radiographs documented interval fractures of a metacarpal, an osteosclerotic distal radius, and a dense diaphyseal segment of an ulna where a “chalkstick” break remained incompletely healed after 2 yr. There was new L4 spondylolysis, and previous L5 spondylolysis had caused spondylolisthesis. Modeling disturbances of OPT persisted, but partial recovery was shown by metaphyseal surfaces with a unique concave shape. Metaphyseal osteosclerosis had remodeled imperfectly to become focal areas of dense, diaphyseal bone. Newer metaphyseal bone was unexpectedly osteopenic, especially in his distal femurs where cortices were thin and a paucity of trabeculae was documented by CT. Femoral necks had become short and wide with an abnormal contour. A “bone-within-bone” configuration was now present throughout his skeleton. In vertebrae, endplates were thin, and trabecular osteopenia was present central and peripheral to the bands of osteosclerosis. BMD Z-scores assessed by DXA had decreased into the normal range in his spine, hip, and whole body. Iliac crest biopsy showed active bone formation, with much less accumulated primary spongiosa than during the PMD infusions. Osteoclasts that had been dysmorphic, round cells without polarization and off of bone surfaces were now unremarkable in number, location, and appearance. In conclusion, bisphosphonate toxicity during childhood can impair skeletal modeling and remodeling with structural changes that evolve and carry into adult life.

INTRODUCTION

In 2003, the first skeletal complication of aminobisphosphonate exposure was documented by our report of a boy with pamidronate (PMD)-induced osteopetrosis (OPT).math image More than 20 yr earlier, rickets and osteomalacia were known to follow excesses of etidronate, a first-generation bisphosphonate (BP).math image In 2004, osteonecrosis of the jaw,math image and in 2005, suppressed bone turnover,math image emerged as concerns for adults receiving amino-BPs.

We studied our patient in 2002 at 12 yr of age, 1.5 yr after cessation of intravenous doses of PMD.math image PMD had been administered by others for his unexplained episodic bone pains, claims of appendicular fractures during minor trauma, elevation of bone alkaline phosphatase (ALP) in serum, and “osteopenia” on DXA (spine Z-score, −1.0).math image However, our review of his extensive medical records indicated that OPT had developed in a previously normal skeleton. PMD had been infused in escalating doses and frequency probably because his bone pain seemed to respond,math image in keeping with early reports regarding osteogenesis imperfecta (OI),math image and his idiopathic hyperphosphatasemia improved, yet neither problem was corrected. While he received ∼2.8 g of PMD over 2.75 yr,math image bone modeling became suppressed, causing club-shaped deformities of his femurs and tibias, primary spongiosa (calcified cartilage) accumulated during endochondral bone formation, and spondylolysis appeared at L5math image—together signifying OPT.math image Two years after the BP was stopped, he fractured an osteosclerotic distal radius, suggesting a lingering toxic effect of the PMD.math image

Here, we report our re-evaluation of this patient 5 yr later and 6.5 yr after PMD exposure ended.

MATERIALS AND METHODS

Patient

Interval medical history:

Now 17 yr of age, our patient was again accompanied on admission to Shriners Hospital for Children–St Louis by his mother, a nurse. He had declined earlier re-evaluation.

Episodic bone pain of the same intensity (6–7 on a 10-point pain scalemath image), but diminished in frequency (∼bimonthly) and of shorter duration (∼1 h), still recurred in his knees and legs. Naproxen and rofecoxib had not been necessary for several years. Soaking in hot water was helpful, but he had not identified precipitating or exacerbating factors.

He claimed that fractures had occurred approximately three times yearly from minor trauma. Although some precautions had been taken to avoid trauma, he had not protected his back. He played basketball, tackle football in the snow, and baseball. His mother said the breaks tended to involve growth plates of fingers and sclerotic areas of forearms. As published,math image one was a Salter II fracture of his osteosclerotic distal right radius that occurred when he caught a light ball 2 yr after cessation of PMD (Aredia; Novartis Pharma, Basel, Switzerland). A left ulna diaphyseal fracture occurred at age 15 yr when he twisted his wrist. He broke his right fifth metacarpal falling onto a basketball court and reported a chip fracture from stubbing his right great toe 1 yr earlier.

His fractures were said to mend slowly. Orthopedic records indicated that the radius break was casted for 1 mo, but then splinted for a few additional weeks. The ulna fracture was casted for 1 mo, followed by a soft splint for several weeks because of delayed union. The metacarpal fracture healed after 1 mo in a hard cast. For the broken toe, he reportedly used crutches for 2 wk and wore an orthopedic boot for a further 2 wk. He noticed a “bump” on the medial aspect of both proximal tibias (see radiologic findings). Pain near his left sacroilium (5 using the 10-point pain scalemath image) ended participation in baseball. It was aggravated by physical activity. MRI, 4 yr after PMD exposure stopped, showed persistent spondylolysis at L5. His orthopedist advised against a rodding procedure because of concerns about bone integrity. Dental implants for “missing” 12-yr molars seemed risky because his jaw might be brittle.

Medications, prescribed at a pain clinic, included valdecoxib and tramadol, which were rarely used because of lethargy. He took no supplements. Our research dietitian estimated from a 7-day food record that he consumed ∼1580 mg of calcium daily (recommended daily allowance = 1300 mg).

Pressure or throbbing frontal headaches occurred two or three times monthly, but without nausea or vomiting, and were not precipitated by coughing, sneezing, etc.

Family medical history was unchanged and without migraine headaches, but included deafness and common variable immune deficiency affecting his sister.

Physical findings:

Vital signs were normal. Weight was 61 kg (134 lbs; 35th percentile), height was 179 cm (5 ft 10 in; 70th percentile), arm span was significantly less than height at 170 cm (5 ft 7 in; 24th percentile),math image sitting height was 97 cm (∼75th percentile),math image and head circumference was 57 cm (∼75th percentile).math image He was well-appearing, masculinized, and in no distress. There was palpable widening of his proximal tibias, equal hip and shoulder heights, and a negative Gaenslen's test for sacroiliac derived pain.

Methods

After informed written consent approved by the Human Research Protection Office, Washington University School of Medicine, St Louis, MO, USA, our patient took two, 3-day courses of tetracycline hydrochloride (250 mg, orally, four times a day) separated by 13 days, with 2.5 days lapsing after the final dose before iliac crest biopsy.

Biochemical studies:

Biochemical studies were performed while he consumed a diet matched for his customary calcium intake. The same analytical techniques and instruments were used,math image unless otherwise stated. Age-appropriate reference ranges established in our laboratory were available for most of the parameters. Findings from both admissions were contrasted (Table 1).

Table Table 1.. Biochemical Findings At Diagnosismath image And Follow-Up
original image

Radiologic studies:

Skeletal radiographs and DXA (QDR 4500-A; Hologic, Waltham, MA, USA) were repeated, and interval radiologic images (lacking only the foot radiographs) were reviewed. All available DXA BMD Z-scores were recalculated using the 2007 method and data of Kalkwarf et al.math image and contrasted (Table 2).

Table Table 2.. BMD Z-Scores*
original image

Additionally, high-resolution CT of the expanded metaphyseal bone at his knees was performed at St Louis Children's Hospital, St Louis, MO, USA using 0.75-mm slice thickness, followed by coronal and sagittal reconstructions. Comparisons were made with scans from 10 age-matched, healthy boys with contralateral symptoms.

Also, we conducted an image search for radiographs of children receiving BPs using Google (http://images.google.com) and Yahoo (http://www.yahoo.com/).

Iliac crest biopsy:

An area at the left iliac apophysis (previous wedge biopsy on the right) was exposed through a 2- to 3-cm skin incision. To evaluate the depth of any unresorbed primary spongiosa, two transapophyseal specimens containing trabecular and cortical bone were obtained using a 3.4-mm-ID Trap-Lok needle (Medical Device Technologies, Gainesville, FL, USA) hammered gently and perpendicularly down into the top of the iliac crest. Also, a transiliac core was removed nearby using a 5-mm-ID Bordier trephine after subperiosteal dissection on either side of the ilium.

Similar transapophyseal specimens had been taken with permission and processed the same way after the traumatic deaths of healthy 13- and 16-yr-old boys.

Specimens were fixed in 70% ethanol and 30% water, embedded nondecalcified in methylmethacrylate, sectioned to 10 μm, and stained using the Goldner's trichrome and toluidine blue methods. Unstained sections were used for fluorescence microscopy to identify tetracycline labels.

RESULTS

Biochemical findings

On average, 1450 mg calcium was consumed each day. Serum total and bone-specific ALP had decreased over the 5-yr interval, consistent with a maturing skeleton, but both values remained proportionately elevated (Table 1). Once again, unremarkable levels were found for urine collagen cross-linked N-telopeptide (NTX) and deoxypyridinoline. Serum osteocalcin was no longer slightly increased (Table 1). Two serum markers for OPT were now normal: the brain isoenzyme of creatine kinase (BB-CK)math image and TRACP.math image Serum lactate dehydrogenase was again unremarkable at 132 U/liter (reference range, 117–217 U/liter), in contrast to increased levels sometimes observed with heritable OPTs.math image

Erythrocyte sedimentation rate was 1 mm/h (reference, <15 mm/h), and carbohydrate-reactive protein was <0.5 mg/dl (reference, <0.9 mg/dl). His idiopathic thrombocytopenia, documented since early childhood, was unchanged at 85 k/μl (reference range, 140–350 k/μl). Urine free cortisol was 27 μg/d (reference range, 3–55 μg/d).

Radiological findings

Radiographs:

In 2007, growth plates were fused, showing that his skeleton was essentially mature. Between 2002 and 2007, widened, osteosclerotic, metaphyseal bone formed during PMD exposure (and persisting for at least 2 yr afterward)math image improved its shape as he grew 9 in. Some concavity returned at the surfaces (Figs. 1 and 2). Nevertheless, metaphyses remained wide in 2007, especially in the distal femurs and proximal tibias. Remarkably, these metaphyses were now osteopenic, including areas of thin cortex (Figs. 1 and 2).

Figure FIG. 1..

Modeling and remodeling abnormalities in the lower limbs in 2007 (A) include novel shaping changes and osteopenia, especially apparent in the distal femurs and proximal tibias, that developed between 2002 (B) and 2007 (C). At the right knee, metaphyseal osteosclerosis and expansion (B) has been replaced by osteopenia and modeling failure (C) (follow matching arrows). Some of the original osteosclerotic metaphyseal bone persists as dense metadiaphyseal bone. Newer metaphyseal bone (C) once again has a concave surface.

Figure FIG. 2..

Posteroanterior radiographs of the left hand and wrist document modeling and remodeling abnormalities that change from age 12 yr in 2002 (A) to skeletal maturity at age 17 yr in 2007 (B). In 2002 (A), metaphyseal osteosclerosis in the radius and ulna lies within an OPT modeling defect featuring widening and loss of concave surfaces (brackets). By 2007 (B), the osteosclerosis has “migrated” proximally (brackets) and remodeled to become an expanded dense area within the diaphyseal shaft. In 2007, the distal radial metaphysis remains somewhat wide, but a concave surface there and in the distal ulna indicates recovery of modeling. However, the metaphyseal bone formed in the radius and ulna in this 5-yr interval has become osteopenic. Similarly, sclerotic metaphyses (e.g., arrow) in the tubular bones of the hand in 2002 (A) have become dense diaphyseal bone in 2007 (B) (arrow). A “bone-within-bone” appearance has developed in the carpal bones (B).

Metaphyseal osteosclerosis, especially of major long bones, had become diaphyseal, undertubulated, sclerotic areas consisting of thick, coalescent trabeculae (Fig. 3). The 2005 pathologic fracture of the left ulna was a “chalkstick” break in this dense bone (Fig. 3A). Two years later, a faint fracture line persisted despite solid periosteal bone over the break (Fig. 3B). In 2007, both the Salter II fracture through the osteosclerotic distal right radius and ulna styloid,math image as well as the right fifth metacarpal fracture, were healed (data not shown).

Figure FIG. 3..

In 2005 at age 15 yr (A), a pathologic “chalkstick” fracture (arrow) traverses the area of widened and dense diaphyseal bone in the left ulna. In 2007 (B), a faint fracture line persists but is surrounded by solid, bridging callus (solid arrow). In the radius, there is a persisting lucent line (dotted arrow) in the area of diaphyseal sclerosis. This is a peculiar site consisting of few trabeculae, also noted in the patient's distal femurs and proximal tibias (Figs. 1B and 1C).

Lumbar radiographs spanning 1998–2007 (ages 8–17 yr) showed a succession of abnormalities during and after PMD. In 2001, the vertebral endplates were dense, and there was a faint pars defect at L5. In 2002, the pars break was obvious, with a 4-mm separation (Fig. 4A). Four years later, there was healing, but in 2007 the gap had widened and was less well defined, and a grade I spondylolisthesis had developed (Fig. 4B). A faint pars fracture had also occurred in L4. Osteosclerosis in the spine, and more faintly in the ribs, evolved to a “bone-within-bone” appearance. The vertebral endplates in 2007 had become thin (Fig. 4B), but without compression fractures.

Figure FIG. 4..

Lateral radiograph of the lumbar spine in 2002 (A) at diagnosis of BP-induced OPT shows “window framing” of the vertebrae by endplate osteosclerosis. Subsequently, this evolved with skeletal growth to form a “bone-within-bone” configuration (B). In 2007, the vertebral endplates appear less dense than appropriate for a boy his age (B). Spondylolysis of L5 (solid arrows) in 2002 (A) persists over the 5-yr interval (B), and a grade I spondylolisthesis has developed by 2007 (B). Also, a new pars defect has occurred in L4 by 2007 (B), identified by a lucent line (not apparent here) and an area of osteosclerosis (dotted arrow).

In 2007, the femoral necks had become wide and short with a bulge distal to the closed physeal line consistent with that seen in femoroacetabular impingement syndromes (Fig. 5). The carpal and tarsal bones, epiphyses, and pelvis (Fig. 5) also showed a “bone-within-bone” appearance. In some areas (e.g., pelvis), the osteosclerosis appeared layered. Metaphyseal expansion and talar tilting were present at the ankles (Fig. 1). Panorex dental radiographs in 2006 showed missing second and third mandibular molars on the left. Other interval radiographs documented no additional fractures.

Figure FIG. 5..

In 2007, anteroposterior view of the left hemipelvis (where the follow-up iliac crest biopsies were performed) and proximal femur shows “bone-within-bone” (white and black dotted arrows). Notably, the femoral neck has become short and wide with an acquired bulge (white solid arrow) distal to the closed physeal line, which resembles the cause of “acetabulofemoral impingement syndrome.”

DXA:

Each sequential DXA Z-score was re-evaluated using data reported in 2007math image (Table 2). The first DXA, performed elsewhere in 1997 at age 7 yr (before PMD) and showing a L1–L4 BMD Z-score of −1.0 using Hologic reference values, showed a recalculated Z-score of +0.24. In 2002 and 2007, the spine Z-scores were +3.10 and +1.83, respectively.math image Notably, his spine at follow-up was radiographically osteopenic, except for the “bone-within-bone” bands of osteosclerosis (Fig. 4B). Thus, the areas of spinal osteopenia were not shown by DXA. Total hip BMD Z-scores decreased between ages 12 and 17 yr from +2.32 to +1.35, respectively. In the left proximal one-third radius (without radiographic osteosclerosis or widening), BMD Z-scores had progressively increased, but stayed within the normal range. Whole body BMD Z-score was unremarkable before PMD, elevated in 2002, and normal in 2007 (Table 2).

CT:

CT showed focal areas of sclerosis in the ascending ramus of the mandible. High-resolution CT of the knees in 2007 documented a striking paucity of trabecular bone within the expanded metaphyses, as well as areas of cortical thinning (Fig. 6).

Figure FIG. 6..

(A) CT of the patient's knees in 2007 (top) shows that the distal femurs have widened metaphyses compared with a healthy boy of similar age (bottom). The patient's metaphyses are expanded and contain a large central area (arrows) with a paucity of trabecular bone. (B) Coronal section of the patient's left knee shows the modeling defects and metaphyseal osteopenia with vertical trabeculae (solid white arrows) probably caused by dropout of horizontal trabeculae. The articular epiphyseal bone is inexplicably dense (white dotted arrows).

Histopathologic findings

The iliac crest proved quite hard. The Trap-Lok needle was hammered to obtain the two cores of bone. The Bordier trephine cut manually.

Transapophyseal sections showed cortex and subjacent trabecular bone to a depth of at least 1 cm. Growth plate tissue was absent. Toluidine staining showed calcified cartilage remnants within trabecular bone at least 5–7 mm away from the cortex (Fig. 7A). In contrast, no cartilage was present as far as 10 mm from the cortex in the two control boys (Fig. 7B). Nevertheless, the amount of encased cartilage in the patient was much less compared with during PMD exposure.math image

Figure FIG. 7..

(A and B) Toluidine blue staining of a nondecalcified section of the patient's iliac crest from 2007 at age 17 yr (A) shows retained cartilage (stained purple, arrows) within trabecular bone. This is not seen in an age-matched control (B) (scale bar, 200 μm). (C and D) Golder's trichrome stain of the iliac crest during PMD exposure at age 10 yr (C) shows lack of new bone formation (osteoid). At follow-up in 2007 (D), there is abundant osteoid (red, arrows) (scale bar, 200 μm). (E and F) Osteoclasts during PMD toxicity (E, arrow) are rounded and not polarized toward bone, whereas those at follow-up (F, arrow) have a normal flat and polarized morphology (scale bar, 50 μm).

During the PMD infusions, little osteoblast activity was apparent, with no osteoid shown by Goldner's trichrome stain (Fig. 7C).math image In 2007, there were normal amounts of osteoid along trabecular bone surfaces (Fig. 7D) and abundant double labels from tetracycline (data not shown).

During PMD, osteoclasts had abnormal, rounded morphology, lack of polarization, and were off of the bone surface (Fig. 7E). At follow-up, normal appearing osteoclasts were juxtaposed to bone (Fig. 7F).

DISCUSSION

There is considerable controversy whether amino-BPs can cause oversuppression of bone remodeling in adults.math image In 2002, our patient showed that severe disruption of skeletal remodeling and modeling is possible from PMD in children.math image He acquired clinical, biochemical, radiographic, and histopathological features of OPT caused by cessation of osteoclast activity during exposure to this amino-BP.math image Accumulation of primary spongiosa and dysmorphic osteoclasts off bone surfaces documented and explained the resorption failuremath image while he received a total dose of PMD approximately four timesmath image the amount emerging in the late 1990s as treatment for severe OI.math image Before the PMD infusions stopped at 10.5 yr of age, the dose had escalated to 100 mg once monthly. Accordingly, we recommended in 2003,math image as had been our practice,math image that bone modeling be monitored radiographically for children exposed to prolonged courses of BPs.

Amino-BPs have now been administered for many pediatric conditions.math image Nevertheless, optimum doses and durations for the skeletal disorders remain unclear,math image and withdrawal of treatment after several years followed by observation is becoming commonplace.math image The skeletal effects of BPs are known to linger,math image and PMD excretion in urine has been shown to continue up to 8 yr in children.math image

Now, our 2007 findings with this patient suggest that novel skeletal aberrations might develop in children when potent BP therapy ceases, especially if there has been significant impairment of bone modeling. As reviewed below, experience elsewhere may be emerging to support this concern.

The first publication regarding PMD for OI, the paradigm of pediatric osteoporosis, appeared in 1987.math image Radiographs of a girl given courses of PMD orally for 1 yr showed dense, parallel, metaphyseal bands.

In 1992, Van Persijn van Meerten et al.math image reported subtle metaphyseal undertubulation during amino-BP treatment for children with various disorders and “bone-within-bone” osteosclerosis after therapy. It was said that metaphyseal osteosclerosis resolved after treatment, with formation of new bone of normal density and original width.math image Of interest, the published radiograph of a knee of a boy with polyostotic fibrous dysplasia shows an expanded distal femoral metaphysis with a thin cortex during treatment,math image remarkably like what we encountered in our patient.math image

In 1996, Adami and Zamberlanmath image cautioned that excessive BPs might impair bone modeling and remodeling and induce OPT-like changes in children, because this effect had been recognized a decade earlier in growing rats.math image

In 2002, Rauch et al.math image reported calcified cartilage accumulation and large osteoclasts in the iliac crests of children with OI treated with PMD, but no indication that this decreased remodeling caused clinical problems, although they stated that the possibility required close monitoring. Two years later, they examined the histology of PMD-induced, osteosclerotic bands in the iliac crest of a child with OI and concluded that this nascent bone containing primary spongiosa remodeled into bands of trabecular bone with less calcified cartilage.math image

Up to 2005, skeletal modeling defects within the long bones of OI patients receiving PMD were otherwisemath image not encountered,math image or were sometimes illustrated without comment.math image Then, Ward et al.math image used radiographs in 2005 to evaluate metaphyseal modeling in children said to be receiving appropriate doses of PMD for localized bone diseases (e.g., osteonecrosis) and devised a “metaphyseal index” to quantitate physiologic “inwasting” in the distal femur. Their preliminary data indicated correct bone shaping. Nevertheless, it was recommended that metaphyseal modeling be evaluated in safety protocols.math image Also in 2005, Letocha et al.math image described improved vertebral geometry and spine BMD (by DXA and QCT) for a small number of OI children given PMD for 1 yr.

In 2006, Land et al.math image reported partial reconstitution of vertebral shaping during 2–4 yr of PMD therapy for moderate-severe pediatric OI. They concluded that the transverse metaphyseal bands from PMD persist ∼4 yr on average (range, 2–8 yr),math image consistent with normal bone remodeling.math image They noted that the femoral metaphyseal index was increased on average 26% after treatment.math image Whether there were clinical consequences of the bone expansion was judged unclear, with no evidence of adverse implications, and perhaps some benefit.

Also in 2006, Vallo et al.math image showed that PMD therapy for pediatric OI led to “size-adjusted” spine BMD increments that stabilized or sometimes waned after 2 yr of treatment. They questioned whether repeated cycles of PMD were necessary or would courses without intermediate therapy be of identical benefit.

With the exception of the 1992 paper by Van Persijn van Meerten et al.,math image no mention is made in these publicationsmath image of metaphyseal mineral content or shaping after BP withdrawal, because treatment was continuing or finishing.

Then, in 2006, Rauch et al.math image described spine BMD Z-scores in children and adolescents with moderate-severe OI 2 yr after 3–4 yr of cyclical PMD therapy. Bone resorption activity, judged by urine NTX levels, accelerated, but not to pretreatment values.math image The Z-scores decreased, although not nearly to pretreatment values, and fracture rates did not increase. Rates of change in BMD toward baseline were greatest in patients who continued to grow. Newly acquired bone appeared less dense radiographically compared with during treatment, both in vertebrae and in wrist metaphyses.math image Knees and post-treatment metaphyseal modeling changes were not commented on.math image

In 2007, Rauch et al.math image used CT to evaluate the distal radius of 23 OI children on average 1.9 yr after at least 3 yr (average, 5.8 yr) of PMD therapy. Z-scores for BMC decreased more in the metaphysis than diaphysis. The metaphyseal Z-score changes suggested that the osseous tissue added by growth after the last PMD infusion was probably as fragile as before treatment.math image Hence, BP therapy might be necessary until growth ceases, although they cautioned that the risk/benefit ratio was not yet clear. The junction of the old, dense bone and new, less dense bone might be the site of future fracture.math image

In 2007, Waterhouse et al.math image examined 17 children with various disorders on average 26 mo after a mean of 22 mo of treatment either with PMD or zolendronate. Knees were said not to show OPT modeling changes. They observed no adverse effects, including on lumbar spine radiographs.

Notably, however, Ward et al.,math image in 2007, reported a girl with OI who showed a marked decrease to below baseline in volumetric BMD Z-scores in the lumbar spine and distal radius within 2 yr after stopping 4.5 yr of PMD therapy. They questioned whether BP treatment should be discontinued before completion of linear growth. Our inspection of their published radiographs showed metaphyseal widening.math image

Our patient still seems predisposed to fracture 6.5 yr after cessation of PMD. In 2005, Grissom et al.math image offered three mechanisms whereby fracturing could continue in children with OI despite PMD therapy: (1) BMD remains below fracture threshold, (2) bone fragility persists despite increased or even normal density, and (3) increased physical activity by the patient.math image Despite our patient's recurrent bone pain and enigmatic hyperphosphatasemia, we cannot say that a skeletal disease predating his PMD exposure is now causing some of his current findings. He does not have OI, and bone fragility seems to have occurred from BP-induced suppression of bone remodeling. We believe that toxic doses of PMD led to spondylolysis and forearm fractures in areas of dense bone. He may now be additionally prone to fractures because of metaphyseal expansion with osteopenia.

Skeletal modeling is increasingly understood to influence bone strength.math image Treatment of pediatric patients with BPs can disturb modeling because osteoclast-mediated resorption must continue for proper shaping of growing bones. Despite the improvement in remodeling shown by our patient's follow-up iliac crest histology, he acquired two modeling aberrations, documented best at his knees, that will now likely persist lifelong: metaphyseal expansion and regions of cortical thinning. Additionally, there are now metadiaphyseal notches in his distal femurs and proximal tibias, as well as aberrant shaping of his femoral necks. Why he has diminished cortical thickness in metaphyseal areas at his knees is unknown, but perhaps these reflect the increased bone circumference.

There is also evidence that abnormal bone remodeling persists in our patient. Some excess of calcified cartilage remains in his iliac crest, radiographically dense cortical bone is seen in diaphyses, and osteosclerotic periarticular bone is present in his knees. In fact, our patient sustained a pathologic fracture across an ulna at radiographically dense and widened diaphyseal bone, showing it to be weaker than the adjacent osteopenic, expanded, metaphyseal bone. This “chalkstick” fracture remains incompletely healed after 2 yr, perhaps reflecting some persisting PMD effect. Failure of skeletal resorption in OPT compromises bone quality because calcified cartilage accumulates and remodeling-mediated interconnection of osteons is impaired.math image Accordingly, we worry that he will continue to fracture through this dense, but poor-quality, diaphyseal bone. Recently, Weinstein et al.,math image in a preliminary report, encountered the osteoclast dysmorphology seen in our patient's iliac crestmath image in women who had received several years of alendronate orally. Return of our patient's osteoclast morphology to normal currently is somewhat reassuring. Clearly, our patient did not have a congenital OPT, but instead reversible osteoclast suppression. Improved remodeling might eventually restore normal BMD and quality at the osteosclerotic sites, but it seems unlikely the modeling defects will ever correct. Our patient warns that metaphyseal osteopenia may occur if antiresorptive therapy widens metaphyses and then stops as growth continues. In fact, this may be what Ward et al. (discussed above) described in 2007.math image Hence, CT or MRI should be especially important to investigate this concern in other BP-treated children and is being used to study some of our patients.

Before PMD exposure,math image the height, density, and endplate width of our patient's vertebrae did not appear diminished on radiographs, and his spine BMD Z-score was normal. When diagnosed with BP-induced OPT in 2002, he had developed end-plate thickening and an unhealed L5 spondylolysis, although bone scintigraphy showed no evidence of vertebral fractures.math image In 2007, after further linear growth without PMD exposure, there was a “bone-within-bone” (endobone) configuration in his vertebrae and throughout his skeleton. This finding occurs in genetic OPTmath image and was reported after amino-BP withdrawal in children by van Persijn van Meerten et al. in 1992.math image However, our patient's vertebral endplates are now thin, trabecular bone peripheral and central to the osteosclerotic bands appears osteopenic, and the vertebral bodies have become somewhat rectangular. Spondylolysis (leading to spondylolisthesis) seems more prevalent in OPTmath image and occurred during and several years after his PMD exposure. Notably, Aström et al.math image in 2007 reported an increased prevalence of spondylolysis and L5 spondylolisthesis after PMD treatment in infants with severe OI.

Our patient illustrates a pitfall in BMD interpretation when there is heterogeneous bone density. DXA assesses relatively large areas and can, therefore, be misleading. His spine, radius, and whole body BMD increased during PMD at an accelerated rate compared with age-matched controls and decreased to normal by age 17 yr despite areas of spinal and metaphyseal osteopenia and sclerotic “bone-within-bone” bands shown radiographically. “Neo-osseous osteoporosis” in widened metaphyses would likely go undetected by DXA that provides an “areal” (g/cm2) assessment of BMD.

Clinicians hope that biochemical markers of skeletal turnover will help prevent excessive suppression of bone remodeling when they use antiresorptive pharmaceuticals.math image For our patient, markers other than ALP gave no hint of skeletal disease 1.5 yr subsequent to PMD exposure. Despite his enigmatic hyperphosphatasemia, only serum osteocalcin was slightly increased in 2002. Urine NTX and free deoxypyridinoline (also hydroxyproline) were unremarkable then and again in 2007. In 2002, these markers emanated from elevated skeletal mass (total body BMD Z-score ∼ +2.3), perhaps explaining why low bone turnover would go undetectable. Of interest, however, serum BB-CK and TRACP activities in 2002 were consistent with OPTmath image and are now unremarkable. This supports our impression that assaying both enzymes can help to monitor for ongoing BP toxicity.math image

In conclusion, follow-up of the first reported case of drug-induced OPT calls for continued study of long-term BP exposure in pediatric patients to know whether remodeling and modeling disturbances, including metaphyseal “neo-osseous osteoporosis,” will complicate cessation of therapy. This may occur if bone modeling has been suppressed and tubular bones are expanded. In these patients, both cortical bone thickness and trabecular bone porosity in metaphyses require evaluation. Currently, it is not clear if some level of BP treatment should continue for children until growth plates fuse.

Acknowledgements

Our report was made possible by the skill and dedication of the nursing, laboratory, and dietary staff at the Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children–St Louis, St Louis, MO, USA. Angelia English provided expert secretarial help. Vivienne Lim and Dawn Russell helped to illustrate the manuscript. Steven L Teitelbaum, MD, reviewed the histopathology. This work was supported by Shriners Hospitals for Children, The Clark and Mildred Cox Inherited Metabolic Bone Disease Research Fund, and The Barnes-Jewish Hospital Foundation.

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