Complications and Revisions After Spine Surgery in Patients With Skeletal Dysplasia: Have We Improved?

STUDY DESIGN: Retrospective case series. OBJECTIVE: To report contemporary rates of complications and subsequent surgery after spinal surgery in patients with skeletal dysplasia. METHODS: A case series of 25 consecutive patients who underwent spinal surgery between 2007 and 2017 were identified from a single institution's skeletal dysplasia registry. Patient demographics, medical history, surgical indication, complications, and subsequent surgeries (revisions, extension to adjacent levels, or for pathology at a non-contiguous level) were collected. Charlson comorbidity indices were calculated as a composite measure of overall health. RESULTS: Achondroplasia was the most common skeletal dysplasia (76%) followed by spondyloepiphyseal dysplasia (20%); 1 patient had diastrophic dysplasia (4%). Average patient age was 53.2 ± 14.7 years and most patients were in excellent cardiovascular health (88% Charlson Comorbidity Index 0-4). Mean follow up after the index procedure was 57.4 ± 39.2 months (range). Indications for surgery were mostly for neurologic symptoms. The most commonly performed surgery was a multilevel thoracolumbar decompression without fusion (57%). Complications included durotomy (36%), neurologic complication (12%), and infection requiring irrigation and debridement (8%). Nine patients (36%) underwent a subsequent surgery. Three patients (12%) underwent a procedure at a non-contiguous anatomic zone, 3 (12%) underwent a revision of the previous surgery, and another 3 (12%) required extension of their previous decompression or fusion. CONCLUSIONS: Surgical complication rates remain high after spine surgery in patients with skeletal dysplasia, likely attributable to inherent characteristics of the disease. Patients should be counseled on their risk for complication and subsequent surgery.

Patient-reported prevalence of gastrointestinal issues in the adult skeletal dysplasia population with a concentration on osteogenesis imperfecta.

Patient-reported concerns indicate that gastrointestinal (GI) manifestations affect the skeletal dysplasia population, but quantitative information regarding prevalence and severity of GI issues is limited. We examined the frequency and characteristics of GI symptoms in adults with skeletal dysplasias by reviewing 101 responses to the Gastrointestinal Symptom Rating Scale (GSRS). Participant demographics, medication history, and ambulatory status were collected from medical records. Compared to published GSRS reference data, our cohort scored higher on reflux, diarrhea, and total scores, and lower on abdominal pain and indigestion scores; none of these differences were statistically significant. Although osteogenesis imperfecta respondents had more severe symptoms across all domains, only reflux reached significance (p = 0.009). Scores in patients with achondroplasia were higher for indigestion, constipation, diarrhea, and total scores and lower on abdominal pain and reflux scores than the general population; only the diarrhea score was significant (p = 0.034). There were no statistically significant differences in any of the domain or total GSRS scores across ambulatory status groups. Increased height correlated with worse abdominal pain domain score (p = 0.033). The number of medications positively correlated with total GSRS score (p = 0.013). Future studies should include larger numbers of individuals to allow a more in-depth analysis of patient-reported symptoms and signs within this population.

Orthopedic considerations and surgical outcomes in Ehlers-Danlos syndromes.

The Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of connective tissue disorders with varying physical manifestations. There are no clear guidelines for addressing orthopedic concerns or reporting surgical outcomes in this population. This article reviews the literature, reports on a new study, and offers considerations prior to surgical intervention. The new study seeks to determine the effectiveness of surgical intervention in individuals with EDS. It is a retrospective chart review of 154 individuals clinically diagnosed with EDS who had orthopedic surgery >2 years ago at Hospital for Special Surgery. A total of 120 individuals were included in the study. One hundred eleven females and 9 males underwent a total of 320 orthopedic surgeries, of which 204 surgeries had available post-operative follow-up. The average age at surgery was 38.2 years (range: 7.6-83.3). Multiple post-operative complications (290) were reported in 91% of cases. Common complications were persistent pain/discomfort (45), continued subluxation/dislocation (20), instability (19), pain/discomfort from hardware (17), and infection (16). Our results suggest that surgical outcomes are worse for individuals with EDS compared to the general population, a finding which is similar to other studies. Complications occurred more frequently in the EDS population than the average population, suggesting that surgery should be undertaken by a multidisciplinary team of clinicians with careful pre-operative planning and full knowledge of the risks and benefits. Guidelines for the care of this unique population must be established.

Quality of life in adults with achondroplasia in the United States.

Studies examining quality of life (QoL) in adults with achondroplasia are limited. We report on QoL and psychiatric illness diagnoses in a modern cohort of adults with achondroplasia. SF-36 Health Survey scores from adults with achondroplasia were compared to general population scores. Demographics, physical measurements, and psychiatric illness diagnoses were recorded from medical records. The achondroplasia population had lower scores than the general population in all categories. Most people with achondroplasia (56%) had a diagnosed psychiatric illness. Those with a diagnosed psychiatric illness had lower scores in physical functioning, role limitations due to physical and emotional health, and mental health. Pain, energy/fatigue, and general health scale scores were roughly equivalent (<2 points difference). Social functioning was >15 points higher in individuals with psychiatric illness diagnoses. Adults with achondroplasia report significantly lower physical and mental well-being and had nearly 3× the rate of psychiatric illness diagnosis than the general population, highlighting the importance of total care for this population. Healthcare providers must understand the physical and mental comorbidities of achondroplasia, beyond short stature and orthopedic issues, so they can proactively improve QoL across the lifespan for patients and families.

Joint Replacements in Individuals With Skeletal Dysplasias: One Institution's Experience and Response to Operative Complications.

BACKGROUND: Skeletal dysplasias are a heterogeneous group of >400 genetic disorders characterized by abnormal bone growth. Many individuals experience joint pain and limitation, coming to require joint replacement much earlier than the average-statured population. In addition, prosthesis survival rate is less in the dysplastic population. The purpose of this study is to identify risk factors for surgery and provide recommendations to improve surgical outcomes. METHODS: This a retrospective review of 29 individuals with a skeletal dysplasia who had 64 joint replacements between April 1985 and January 2019 at a single institution. We collected demographics, physical examination, medical history, imaging studies, surgical indication, and complications. RESULTS: Spondyloepiphyseal dysplasia was the most common skeletal dysplasia (7), followed by pseudoachondroplasia (4) and multiple epiphyseal dysplasia (4). Average age of the cohort was 40.6 years (range 14-64). Hip arthroplasty (34) was the most commonly performed surgery. The majority of arthroplasties (75%) required custom components. Complication rate was 37.3%, most commonly pulmonary embolism (3) and pneumonia (3). Most complications (81.8%) occurred in individuals with either a pre-existing cardiopulmonary comorbidity or lumbar/sacral deformity. Body mass index did not correlate with complication severity (R = -0.042, P = .752) or rate (R = 0.006, P = .963). CONCLUSION: Surgical complications are highest in patients with pre-existing cardiopulmonary conditions. Body mass index does not predict complications in this cohort. Preoperative evaluations for individuals with skeletal dysplasias should include comprehensive work-up of spine issues and extraskeletal systems that present an operative risk. Intraoperative protocol should include special consideration for placement on the table, airway maintenance, and spinal cord monitoring in select cases.

Blood pressure in adults with short stature skeletal dysplasias.

Hypertension, compounded by obesity, contributes to cardiovascular disease and mortality. Data describing hypertension prevalence in adults with short stature skeletal dysplasias are lacking, perhaps due to poor fit of typical adult blood pressure cuffs on rhizomelic or contracted upper extremities. Through health screening research, blood pressure was measured in short stature adults attending support group meetings and skeletal dysplasia clinics. Blood pressure was measured with a commercially available, narrower adult cuff on the upper and/or lower segment of the arm. Height, weight, age, gender, diagnosis, exercise, and medications were collected. Subjects were classified as normotensive, prehypertensive, or hypertensive for group analysis; no individual clinical diagnoses were made. In 403 short stature adults, 42% were hypertensive (systolic >140, diastolic >90 OR taking antihypertensive medications). For every BMI unit and 1 kg weight increase in males, there was a 9% and an 8% increase, respectively, in the odds of hypertension versus normotension. In females, the increase was 10% and 6%, respectively. In those with achondroplasia, the most common short stature dysplasia, males (n = 106) had 10% greater odds of hypertension versus normotension for every BMI unit and kilogram increase. In females with achondroplasia (n = 128), the odds of hypertension versus normotension was 8% greater for each BMI unit and 7% for each additional kilogram. These data suggest a high population prevalence of hypertension among short stature adults. Blood pressure must be monitored as part of routine medical care, and measuring at the forearm may be the only viable clinical option in rhizomelic short stature adults with elbow contractures.

Autosomal dominant frontometaphyseal dysplasia: Delineation of the clinical phenotype.

Frontometaphyseal dysplasia (FMD) is caused by gain-of-function mutations in the X-linked gene FLNA in approximately 50% of patients. Recently we characterized an autosomal dominant form of FMD (AD-FMD) caused by mutations in MAP3K7, which accounts for the condition in the majority of patients who lack a FLNA mutation. We previously also described a patient with a de novo variant in TAB2, which we hypothesized was causative of another form of AD-FMD. In this study, a cohort of 20 individuals with AD-FMD is clinically evaluated. This cohort consists of 15 individuals with the recently described, recurrent mutation (c.1454C>T) in MAP3K7, as well as three individuals with missense mutations that result in substitutions in the N-terminal kinase domain of TGFß-activated kinase 1 (TAK1), encoded by MAP3K7. Additionally, two individuals have missense variants in the gene TAB2, which encodes a protein with a close functional relationship to TAK1, TAK1-associated binding protein 2 (TAB2). Although the X-linked and autosomal dominant forms of FMD are very similar, there are distinctions to be made between the two conditions. Individuals with AD-FMD have characteristic facial features, and are more likely to be deaf, have scoliosis and cervical fusions, and have a cleft palate. Furthermore, there are features only found in AD-FMD in our review of the literature including valgus deformity of the feet and predisposition to keloid scarring. Finally, intellectual disability is present in a small number of subjects with AD-FMD but has not been described in association with X-linked FMD.

Bone robusticity in two distinct skeletal dysplasias diverges from established patterns.

Achondroplasia (ACH) is a heritable disorder of endochondral bone formation characterized by disproportionate short stature. Osteogenesis imperfecta (OI) is a heritable bone and connective tissue disorder characterized by bone fragility. To investigate bone morphology of these groups, we retrospectively reviewed 169 de-identified bone age films from 20 individuals with ACH, 39 individuals with OI and 37 age- and sex-matched controls (matched to historical measurements from the Bolton-Brush Collection). We calculated robustness (Tt.Ar/Le) and relative cortical area (Ct.Ar/Tt.Ar) from measurements of the second metacarpal, which reflect overall bone health. Relative cortical area (RCA) is a significant predictor of fracture risk and correlates with robustness at other sites. Individuals with OI had RCH values above and robustness values below that of the control population. Bisphosphonate treatment did not significantly impact either robustness or RCA. In contrast to that reported in the unaffected population, there was no sexual dimorphism found in OI robustness or relative cortical area. We suggest that the underlying collagen abnormalities in OI override sex-specific effects. Individuals with ACH had robustness values above and RCA values below that of the control population. Sexual dimorphism was found in ACH robustness and RCH values. CLINICAL SIGNIFICANCE: Identifies morphologic trends in two distinct skeletal dysplasia populations (OI and ACH) to better understand development of bone robusticity and slenderness in humans. Understanding these patterns of bone morphology is important to predict how individuals will respond to treatment and to increase treatment effect. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2392-2396, 2017.

Non-Lethal Type VIII Osteogenesis Imperfecta Has Elevated Bone Matrix Mineralization.

CONTEXT: Type VIII osteogenesis imperfecta (OI; OMIM 601915) is a recessive form of lethal or severe OI caused by null mutations in P3H1, which encodes prolyl 3-hydroxylase 1. OBJECTIVES: Clinical and bone material description of non-lethal type VIII OI. DESIGN: Natural history study of type VIII OI. SETTING: Pediatric academic research centers. PATIENTS: Five patients with non-lethal type VIII OI, and one patient with lethal type VIII OI. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Clinical examinations included bone mineral density, radiographs, and serum and urinary metabolites. Bone biopsy samples were analyzed for histomorphometry and bone mineral density distribution by quantitative backscattered electron imaging microscopy. Collagen biochemistry was examined by mass spectrometry, and collagen fibrils were examined by transmission electron microscopy. RESULTS: Type VIII OI patients have extreme growth deficiency, an L1-L4 areal bone mineral density Z-score of -5 to -6, and normal bone formation markers. Collagen from bone and skin tissue and cultured osteoblasts and fibroblasts have nearly absent 3-hydroxylation (1-4%). Collagen fibrils showed abnormal diameters and irregular borders. Bone histomorphometry revealed decreased cortical width and very thin trabeculae with patches of increased osteoid, although the overall osteoid surface was normal. Quantitative backscattered electron imaging showed increased matrix mineralization of cortical and trabecular bone, typical of other OI types. However, the proportion of bone with low mineralization was increased in type VIII OI bone, compared to type VII OI. CONCLUSIONS: P3H1 is the unique enzyme responsible for collagen 3-hydroxylation in skin and bone. Bone from non-lethal type VIII OI children is similar to type VII, especially bone matrix hypermineralization, but it has distinctive features including extremely thin trabeculae, focal osteoid accumulation, and an increased proportion of low mineralized bone.

Multiparametric Classification of Skin from Osteogenesis Imperfecta Patients and Controls by Quantitative Magnetic Resonance Microimaging.

The purpose of this study is to evaluate the ability of quantitative magnetic resonance imaging (MRI) to discriminate between skin biopsies from individuals with osteogenesis imperfecta (OI) and skin biopsies from individuals without OI. Skin biopsies from nine controls (unaffected) and nine OI patients were imaged to generate maps of five separate MR parameters, T1, T2, km, MTR and ADC. Parameter values were calculated over the dermal region and used for univariate and multiparametric classification analysis. A substantial degree of overlap of individual MR parameters was observed between control and OI groups, which limited the sensitivity and specificity of univariate classification. Classification accuracies ranging between 39% and 67% were found depending on the variable of investigation, with T2 yielding the best accuracy of 67%. When several MR parameters were considered simultaneously in a multivariate analysis, the classification accuracies improved up to 89% for specific combinations, including the combination of T2 and km. These results indicate that multiparametric classification by quantitative MRI is able to detect differences between the skin of OI patients and of unaffected individuals, which motivates further study of quantitative MRI for the clinical diagnosis of OI.

Mutations in MAP3K7 that Alter the Activity of the TAK1 Signaling Complex Cause Frontometaphyseal Dysplasia.

Frontometaphyseal dysplasia (FMD) is a progressive sclerosing skeletal dysplasia affecting the long bones and skull. The cause of FMD in some individuals is gain-of-function mutations in FLNA, although how these mutations result in a hyperostotic phenotype remains unknown. Approximately one half of individuals with FMD have no identified mutation in FLNA and are phenotypically very similar to individuals with FLNA mutations, except for an increased tendency to form keloid scars. Using whole-exome sequencing and targeted Sanger sequencing in 19 FMD-affected individuals with no identifiable FLNA mutation, we identified mutations in two genes-MAP3K7, encoding transforming growth factor ß (TGF-ß)-activated kinase (TAK1), and TAB2, encoding TAK1-associated binding protein 2 (TAB2). Four mutations were found in MAP3K7, including one highly recurrent (n = 15) de novo mutation (c.1454C>T [ p.Pro485Leu]) proximal to the coiled-coil domain of TAK1 and three missense mutations affecting the kinase domain (c.208G>C [p.Glu70Gln], c.299T>A [p.Val100Glu], and c.502G>C [p.Gly168Arg]). Notably, the subjects with the latter three mutations had a milder FMD phenotype. An additional de novo mutation was found in TAB2 (c.1705G>A, p.Glu569Lys). The recurrent mutation does not destabilize TAK1, or impair its ability to homodimerize or bind TAB2, but it does increase TAK1 autophosphorylation and alter the activity of more than one signaling pathway regulated by the TAK1 kinase complex. These findings show that dysregulation of the TAK1 complex produces a close phenocopy of FMD caused by FLNA mutations. Furthermore, they suggest that the pathogenesis of some of the filaminopathies caused by FLNA mutations might be mediated by misregulation of signaling coordinated through the TAK1 signaling complex.

Nylon 6,6 Nonwoven Fabric Separates Oil Contaminates from Oil-in-Water Emulsions.

Industrial oil spills into aquatic environments can have catastrophic environmental effects. First responders to oil spills along the coast of the Gulf of Mexico in the southern United States have used spunbond nylon fabric bags and fences to separate spilled oil and oil waste from contaminated water. Low area mass density spunbond nylon is capable of sorbing more than 16 times its mass in low viscosity crude oil and more than 26 times its mass in higher viscosity gear lube oil. Nylon bags separated more than 95% of gear lube oil contaminate from a 4.5% oil-in-water emulsion. Field testing of spunbond nylon fences by oil spill first responders has demonstrated the ability of this material to contain the oily contaminate while allowing water to flow through. We hypothesize that the effectiveness of nylon as an oil filter is due to the fact that it is both more oleophilic and more hydrophilic than other commonly used oil separation materials. The nylon traps oil droplets within the fabric or on the surface, while water droplets are free to flow through the fabric to the water on the opposite side of the fabric.

Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish.

Paclitaxel is a microtubule-stabilizing chemotherapeutic agent that is widely used in cancer treatment and in a number of curative and palliative regimens. Despite its beneficial effects on cancer, paclitaxel also damages healthy tissues, most prominently the peripheral sensory nervous system. The mechanisms leading to paclitaxel-induced peripheral neuropathy remain elusive, and therapies that prevent or alleviate this condition are not available. We established a zebrafish in vivo model to study the underlying mechanisms and to identify pharmacological agents that may be developed into therapeutics. Both adult and larval zebrafish displayed signs of paclitaxel neurotoxicity, including sensory axon degeneration and the loss of touch response in the distal caudal fin. Intriguingly, studies in zebrafish larvae showed that paclitaxel rapidly promotes epithelial damage and decreased mechanical stress resistance of the skin before induction of axon degeneration. Moreover, injured paclitaxel-treated zebrafish skin and scratch-wounded human keratinocytes (HEK001) display reduced healing capacity. Epithelial damage correlated with rapid accumulation of fluorescein-conjugated paclitaxel in epidermal basal keratinocytes, but not axons, and up-regulation of matrix-metalloproteinase 13 (MMP-13, collagenase 3) in the skin. Pharmacological inhibition of MMP-13, in contrast, largely rescued paclitaxel-induced epithelial damage and neurotoxicity, whereas MMP-13 overexpression in zebrafish embryos rendered the skin vulnerable to injury under mechanical stress conditions. Thus, our studies provide evidence that the epidermis plays a critical role in this condition, and we provide a previously unidentified candidate for therapeutic interventions.

Frontometaphyseal dysplasia and keloid formation without FLNA mutations.

Frontometaphyseal dysplasia (FMD) is a distinctive sclerosing skeletal dysplasia associated with a number of non-skeletal manifestations including hearing loss, cardiac malformations, and stenosis, particularly of the upper airway and urinary tract. Some, but not all, patients have mutations in FLNA causing the condition. Consonant with the X chromosomal location of FLNA males are generally more severely affected than females. FLNA mutations can be detected in 82% of affected males. We describe seven patients (one male, six females) all of whom have the major clinical and radiological features of FMD, but without detectable mutations in FLNA. The females in our cohort are affected to a similar degree as is usually found in males. In addition, all patients have marked keloid formation at various body sites, including the eye, from an early age. Other features that may indicate a different etiology in these patients are the increased frequency of cleft palate, Robin sequence, tracheal stenosis, and mild intellectual disability, which all occur in three of more patients in the present group. All patients are isolated. We hypothesize that the presently reported patients represent further evidence that phenotypes strongly resembling FMD exist that are not accounted for by mutations in FLNA. Since the frequency of several of the manifestations, their sporadic presentations, and the presence of keloid formation differ from the X-linked form of this condition we propose de novo autosomal dominant acting mutations in a gene functionally related to FLNA, underpin this disorder.

Prolonged spontaneous normocalcaemia in pseudohypoparathyroidism from resorption of soft tissue calcium deposits: a cautionary tale.

A 42-year-old man diagnosed with pseudohypoparathyroidism and Albright's hereditary osteodystrophy as an infant was lost to follow-up and remained, unmonitored, on calcitriol and calcium for over 20 years. He presented after having an ST-elevation myocardial infarction. In addition to coronary artery calcifications, he was found to have diffuse subcutaneous and joint calcifications. His calcium, phosphate and parathyroid hormone (PTH) levels were normal, and given the lack of prior documentation in the diagnosis he was instructed to discontinue calcitriol and calcium until further investigations were completed. Despite stopping the medication, his serum calcium remained normal for over 1 year. It was not until 18 months later, when his soft tissue calcium stores were depleted, that he finally developed symptomatic hypocalcaemia and an elevated PTH. This case not only emphasises the importance of long-term follow-up for patients with pseudohypoparathyroidism, but also highlights the potential complications of long-term, unmonitored, calcitriol use.

Adenosine A2A receptor contributes to ischemic brain damage in newborn piglet.

Pharmacologic inactivation or genetic deletion of adenosine A2A receptors protects ischemic neurons in adult animals, but studies in neonatal hypoxia-ischemia (H-I) are inconclusive. The present study in neonatal piglets examined the hypothesis that A2A receptor signaling after reoxygenation from global H-I contributes to injury in highly vulnerable striatal neurons where A2A receptors are enriched. A2A receptor immunoreactivity was detected in striatopallidal neurons. In nonischemic piglets, direct infusion of the selective A2A receptor agonist CGS 21680 through microdialysis probes into putamen increased phosphorylation of N-methyl-D-aspartic acid (NMDA) receptor NR1 subunit and Na(+),K(+)-ATPase selectively at protein kinase A (PKA)-sensitive sites. In ischemic piglets, posttreatment with SCH 58261, a selective A2A receptor antagonist, improved early neurologic recovery and preferentially protected striatopallidal neurons. SCH 58261 selectively inhibited the ischemia-induced phosphorylation of NR1, Na(+),K(+)-ATPase, and cAMP-regulated phosphoprotein 32 KDa (DARPP32) at PKA-sensitive sites at 3 hours of recovery and improved Na(+),K(+)-ATPase activity. SCH 58261 also suppressed ischemia-induced protein nitration and oxidation. Thus, A2A receptor activation during reoxygenation contributes to the loss of a subpopulation of neonatal putamen neurons after H-I. Its toxic signaling may be related to DARPP32-dependent phosphorylation of PKA-sensitive sites on NR1 and Na(+),K(+)-ATPase, thereby augmenting excitotoxicity-induced oxidative stress after reoxygenation.

Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population.

Rare variation in protein coding sequence is poorly captured by GWAS arrays and has been hypothesized to contribute to disease heritability. Using the Illumina HumanExome SNP array, we successfully genotyped 191,032 common and rare non-synonymous, splice site, or nonsense variants in a multiethnic sample of 2,984 breast cancer cases, 4,376 prostate cancer cases, and 7,545 controls. In breast cancer, the strongest associations included either SNPs in or gene burden scores for genes LDLRAD1, SLC19A1, FGFBP3, CASP5, MMAB, SLC16A6, and INS-IGF2. In prostate cancer, one of the most associated SNPs was in the gene GPRC6A (rs2274911, Pro91Ser, OR = 0.88, P = 1.3 × 10(-5)) near to a known risk locus for prostate cancer; other suggestive associations were noted in genes such as F13A1, ANXA4, MANSC1, and GP6. For both breast and prostate cancer, several of the most significant associations involving SNPs or gene burden scores (sum of minor alleles) were noted in genes previously reported to be associated with a cancer-related phenotype. However, only one of the associations (rs145889899 in LDLRAD1, p = 2.5 × 10(-7) only seen in African Americans) for overall breast or prostate cancer risk was statistically significant after correcting for multiple comparisons. In addition to breast and prostate cancer, other cancer-related traits were examined (body mass index, PSA level, and alcohol drinking) with a number of known and potentially novel associations described. In general, these findings do not support there being many protein coding variants of moderate to high risk for breast and prostate cancer with odds ratios over a range that is probably required for protein coding variation to play a truly outstanding role in risk heritability. Very large sample sizes will be required to better define the role of rare and less penetrant coding variation in prostate and breast cancer disease genetics.

High- and low-dose OPG-Fc cause osteopetrosis-like changes in infant mice.

BACKGROUND: Receptor activator of nuclear factor-κB ligand (RANKL) inhibitors are being considered for use in children with osteogenesis imperfecta (OI). We sought to assess efficacy of two doses of a RANKL inhibitor, osteoprotegerin-immunoglobulin Fc segment complex (OPG-Fc), in a growing animal model of OI, the col1α2-deficient mouse (oim/oim) and its wild-type controls (+/+). METHODS: Treated mice showed runting and radiographic evidence of osteopetrosis with either high- (20 mg/kg twice weekly) or low-dose (1 mg/kg/week) OPG-Fc. Because of this adverse event, OPG-Fc treatment was halted, and the mice were killed or monitored for recovery with monthly radiographs and assessment of serum osteoclast activity (tartrate-resistant acid phosphatase 5b, TRACP-5b) until 25 wk of age. RESULTS: Twelve weeks of OPG-Fc treatment resulted in radiographic and histologic osteopetrosis with no evidence of bone modeling and negative tartrate-resistant acid phosphatase staining, root dentin abnormalities, and TRACP-5b activity suppression. Signs of recovery appeared 4-8 wk post-treatment. CONCLUSION: Both high- and low-dose OPG-Fc treatment resulted in osteopetrotic changes in infant mice, an outcome that was not seen in studies with the RANKL inhibitor RANK-immunoglobulin Fc segment complex (RANK-Fc) or in studies with older animals. Further investigations of RANKL inhibitors are necessary before their consideration for use in children.