Hearing loss in individuals with osteogenesis imperfecta in North America: Results from a multicenter study.

Hearing loss (HL) is an extra-skeletal manifestation of the connective tissue disorder osteogenesis imperfecta (OI). Systematic evaluation of the prevalence and characteristics of HL in COL1A1/COL1A2-related OI will contribute to a better clinical management of individuals with OI. We collected and analyzed pure-tone audiometry data from 312 individuals with OI who were enrolled in the Linked Clinical Research Centers and the Brittle Bone Disorders Consortium. The prevalence, type, and severity of HL in COL1A1/COL1A2-related OI are reported. We show that the prevalence of HL in OI is 28% and increased with age in Type I OI but not in Types III and IV. Individuals with OI Types III and IV are at a higher risk to develop HL in the first decade of life when compared to OI Type I. We also show that the prevalence of SNHL is higher in females with OI compared to males. This study reveals new insights regarding prevalence of HL in OI including a lower general prevalence of HL in COL1A1/COL1A2-related OI than previously reported (28.3 vs. 65%) and high prevalence of SNHL in females. Our data support the need in early routine hearing evaluation in all types of OI that can be adjusted to the severity of the skeletal disease.

A Multicenter Observational Cohort Study to Evaluate the Effects of Bisphosphonate Exposure on Bone Mineral Density and Other Health Outcomes in Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is characterized by low bone mass and bone fragility. Using data from a large cohort of individuals with OI from the Osteogenesis Imperfecta Foundation's linked clinical research centers, we examined the association between exposure to bisphosphonate (BPN) treatment (past or present) and lumbar spine (LS) areal bone mineral density (aBMD), fractures, scoliosis, and mobility. From 466 individuals, we obtained 1394 participant-age LS aBMD data points. Though all OI subtypes were examined, primary analyses were restricted to type I OI (OI-1). Using linear regression, we constructed expected OI-1 LS aBMD-for-age curves from the data from individuals who had never received BPN. LS aBMD in those who had been exposed to BPN was then compared with the computed expected aBMD. BPN exposure in preadolescent years (age <14 years) was associated with a LS aBMD that was 9% more than the expected computed values in BPN-naïve individuals (p < 0.01); however, such association was not observed across all ages. Exposure to i.v. BPN and treatment duration >2 years correlated with LS aBMD in preadolescent individuals. BPN exposure also had a significant association with non-aBMD clinical outcome variables. Logistic regression modeling predicted that with BPN exposure, a 1-year increase in age would be associated with an 8.2% decrease in fracture probability for preadolescent individuals with OI-1, compared with no decrease in individuals who had never received any BPN (p < 0.05). In preadolescent individuals with OI-1, a 0.1 g/cm2 increase in LS aBMD was associated with a 10.6% decrease in scoliosis probability, compared with a 46.8% increase in the BPN-naïve group (p < 0.01). For the same changes in age and LS aBMD in preadolescent individuals, BPN exposure was also associated with higher mobility scores (p < 0.01), demonstrating that BPN treatment may be associated with daily function. © 2018 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Mobility in osteogenesis imperfecta: a multicenter North American study.

PURPOSE: Osteogenesis imperfecta (OI) is a genetic connective tissue disorder that causes bone fragility. Phenotypic severity influences ability to walk, however, little is known about ambulatory characteristics of individuals with OI, especially in more severe forms. The purpose of this work was to characterize mobility in OI using standard clinical assessment tools and determine if patient characteristics could be used to predict mobility outcomes. METHODS: We collected mobility data at five clinical sites to analyze the largest cohort of individuals with OI (n = 491) to date. Linear mixed models were developed to explore relationships among subject demographics and mobility metrics. RESULTS: Results showed minor limitations in the mild group while the more severe types showed more significant limitations in all mobility metrics analyzed. Height and weight were shown to be the most significant predictors of mobility. Relationships with mobility and bisphosphonates varied with OI type and type used (oral/IV). CONCLUSION: These results are significant to understanding mobility limitations of specific types of OI and beneficial when developing rehabilitation protocols for this population. It is important for physicians, patients, and caregivers to gain insight into severity and classification of the disease and the influence of disease-related characteristics on prognosis for mobility.

ADULT OSTEOPOROSIS WITH A HISTORY OF CHILDHOOD-ONSET FRACTURE DUE TO AN LRP5 RECEPTOR VARIANT MUTATION.

OBJECTIVE: This case highlights the value of genetic screening for idiopathic osteoporosis with recurrent fractures. METHODS: Case report and review of the literature. RESULTS: A 52-year-old Caucasian female with idiopathic osteoporosis with recurrent fractures was identified with a heterozygous low-density lipoprotein receptor related protein 5 (LRP5) mutation. CONCLUSION: This case highlights the variability in clinical expression of LRP5 polymorphisms and suggests that standard treatment in cases of recurrent fracture may be ineffective.

Growth characteristics in individuals with osteogenesis imperfecta in North America: results from a multicenter study.

PURPOSE: Osteogenesis imperfecta (OI) predisposes people to recurrent fractures, bone deformities, and short stature. There is a lack of large-scale systematic studies that have investigated growth parameters in OI. METHODS: Using data from the Linked Clinical Research Centers, we compared height, growth velocity, weight, and body mass index (BMI) in 552 individuals with OI. Height, weight, and BMI were plotted on Centers for Disease Control and Prevention normative curves. RESULTS: In children, the median z-scores for height in OI types I, III, and IV were -0.66, -6.91, and -2.79, respectively. Growth velocity was diminished in OI types III and IV. The median z-score for weight in children with OI type III was -4.55. The median z-scores for BMI in children with OI types I, III, and IV were 0.10, 0.91, and 0.67, respectively. Generalized linear model analyses demonstrated that the height z-score was positively correlated with the severity of the OI subtype (P < 0.001), age, bisphosphonate use, and rodding (P < 0.05). CONCLUSION: From the largest cohort of individuals with OI, we provide median values for height, weight, and BMI z-scores that can aid the evaluation of overall growth in the clinic setting. This study is an important first step in the generation of OI-specific growth curves.

A multicenter study to evaluate pulmonary function in osteogenesis imperfecta.

Pulmonary complications are a significant cause for morbidity and mortality in osteogenesis imperfecta (OI). However, to date, there have been few studies that have systematically evaluated pulmonary function in individuals with OI. We analyzed spirometry measurements, including forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1 ), in a large cohort of individuals with OI (n = 217) enrolled in a multicenter, observational study. We show that individuals with the more severe form of the disease, OI type III, have significantly reduced FVC and FEV1 which do not follow the expected trends of the normal population. We also show that "normalization" of FVC and FEV1 using general population data to generate percent predicted values underestimates the pulmonary involvement in OI. Within each subtype of OI, we used linear mixed models to find potential correlations between FEV1 and FVC with the clinical variables including mobility, bisphosphonate use, and scoliosis. Our results are an important step in understanding the extent of pulmonary involvement in individuals with OI and for developing pulmonary endpoints for use in the routine patient care as well as in the investigation of new therapies.

Hypophosphatasia in Adults: Clinical Assessment and Treatment Considerations.

Hypophosphatasia (HPP) is a rare inherited disorder of bone affecting approximately 500 to 600 known individuals in the United States. HPP is the result of mutations involving the gene for tissue nonspecific alkaline phosphatase. Five clinical types of HPP are recognized. The clinical presentation of HPP varies from devastating prenatal intrauterine disease to mild manifestations in adulthood. In adults, main clinical involvement includes early loss of primary or secondary teeth, osteoporosis, bone pain, chondrocalcinosis, and fractures. Treatment for HPP is limited. Asfotase alfa is a subcutaneously administered synthetic human alkaline phosphatase that is approved for treatment of patients, including adults, with perinatal/infantile- and juvenile-onset HPP. However, guidelines for the treatment of adults with HPP are not available. This discussion addresses diagnostic and treatment considerations for adults with HPP. © 2017 American Society for Bone and Mineral Research.

Zoledronic acid improves bone histomorphometry in a murine model of Rett syndrome.

Rett syndrome (RTT) is a neurodevelopmental disorder predominately affecting young females, caused by deficiency of the global transcriptional protein methyl CpG binding protein 2 (MeCP2). Osteoblasts express MeCP2 and girls with RTT experience early onset osteoporosis, decreased bone mass and an increased fracture risk. There is no defined treatment for osteoporosis associated with RTT. The present study evaluated the effects of zoledronic acid (ZA), a third generation nitrogen-containing bisphosphonate with primarily anti-osteoclastic activity, in a mouse model of MeCP2 deficiency. Mice received weekly injections of 20µg/kg ZA for six weeks. Due to the shortened lifespan of hemizygous male (Mecp2-null) mice, treatment began at 3weeks of age for this group and corresponding wildtype (WT) male mice. Treatment for heterozygous (HET) and WT female mice began at 8weeks of age. Micro-computed tomography (micro-CT) and dynamic analyses of bone turnover were performed. ZA treatment led to significant increases in bone volume fraction, number, connectivity density and apparent density of trabecular bone in all genotypes of mice. In contrast, cortical bone generally was unaffected by ZA injections. Parameters of bone turnover, including mineral apposition rate, labeled bone surface and bone formation rate decreased after treatment with ZA. Mecp2-null mice had reduced labeled bone surface and bone formation rate compared to WT male mice. The results indicate that ZA treatment significantly improved trabecular bone mass in a murine model of RTT with little effect on cortical bone.

Health outcomes of neonates with osteogenesis imperfecta: a cross-sectional study.

OBJECTIVE: To assess at-birth health outcomes of neonates with osteogenesis imperfecta (OI). STUDY DESIGN: A total of 53 women who self-reported having had at least one child with OI completed the survey. We evaluated pregnancy length, neonatal intensive care unit (NICU) usage, at-birth complications, and the child's clinical information including OI type, height and weight. RESULTS: Information was gathered on a total of 77 children (60 type I, 4 type III and 13 type IV). Health conditions reported at birth included breech presentation (24%), prematurity (27%), fracture (18%), bone deformity (18%) and respiratory problems (22%). Approximately 31% (n = 24) received NICU care. There was a significant association between younger maternal age, preterm delivery and NICU admission. CONCLUSION: Our findings suggest that newborns with OI appear to be at high risk of skeletal disorders, preterm delivery and breech presentation. Younger maternal age and preterm delivery seem to be strong predictors of the need for NICU care. Our data suggest that pregnant women with OI younger than 20 years of age may benefit from added clinical supervision in anticipation of adverse effects on their child.

Clinical Guidelines for Management of Bone Health in Rett Syndrome Based on Expert Consensus and Available Evidence.

OBJECTIVES: We developed clinical guidelines for the management of bone health in Rett syndrome through evidence review and the consensus of an expert panel of clinicians. METHODS: An initial guidelines draft was created which included statements based upon literature review and 11 open-ended questions where literature was lacking. The international expert panel reviewed the draft online using a 2-stage Delphi process to reach consensus agreement. Items describe the clinical assessment of bone health, bone mineral density assessment and technique, and pharmacological and non-pharmacological interventions. RESULTS: Agreement was reached on 39 statements which were formulated from 41 statements and 11 questions. When assessing bone health in Rett syndrome a comprehensive assessment of fracture history, mutation type, prescribed medication, pubertal development, mobility level, dietary intake and biochemical bone markers is recommended. A baseline densitometry assessment should be performed with accommodations made for size, with the frequency of surveillance determined according to individual risk. Lateral spine x-rays are also suggested. Increasing physical activity and initiating calcium and vitamin D supplementation when low are the first approaches to optimizing bone health in Rett syndrome. If individuals with Rett syndrome meet the ISCD criterion for osteoporosis in children, the use of bisphosphonates is recommended. CONCLUSION: A clinically significant history of fracture in combination with low bone densitometry findings is necessary for a diagnosis of osteoporosis. These evidence and consensus-based guidelines have the potential to improve bone health in those with Rett syndrome, reduce the frequency of fractures, and stimulate further research that aims to ameliorate the impacts of this serious comorbidity.

Cross-sectional and longitudinal growth patterns in osteogenesis imperfecta: implications for clinical care.

BACKGROUND: There is strikingly limited information on linear growth and weight in the different types of osteogenesis imperfecta (OI). Here, we define growth patterns further with the intent of implementing appropriate adaptations proactively. METHODS: We report cross-sectional anthropometric data for 343 subjects with different OI types (144 children, 199 adults). Longitudinal height data for 36 children (18 girls, 18 boys) with OI type I and 10 children (8 girls, 2 boys) with OI type III were obtained. RESULTS: In all cases, the height Z-scores were negatively impacted, and final height Z-scores were impacted the most. In type I, the growth velocities taper near puberty, and there is a blunted pubertal growth spurt. The growth velocities of children with type III decelerate before age 5 y; poor growth continues without an obvious pubertal growth spurt. Obesity is a concern for all patients with OI, with type III patients being the most affected. CONCLUSION: The linear growth patterns, in addition to the marked increase in weight over time, indicate a need for lifestyle modifications early in childhood, especially a need for weight control. Further definition of the anthropometric measures in OI enables patients to begin modifications as early as possible.

Osteoblast function and bone histomorphometry in a murine model of Rett syndrome.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder due to mutations affecting the neural transcription factor MeCP2. Approximately 50% of affected females have decreased bone mass. We studied osteoblast function using a murine model of RTT. Female heterozygote (HET) and male Mecp2-null mice were compared to wild type (WT) mice. Micro-CT of tibia from 5 week-old Mecp2-null mice showed significant alterations in trabecular bone including reductions in bone volume fraction (-29%), number (-19%), thickness (-9%) and connectivity density (-32%), and increases in trabecular separation (+28%) compared to WT. We also found significant reductions in cortical bone thickness (-18%) and in polar moment of inertia (-45%). In contrast, cortical and trabecular bone from 8 week-old WT and HET female mice were not significantly different. However, mineral apposition rate, mineralizing surface and bone formation rate/bone surface were each decreased in HET and Mecp2-null mice compared to WT mice. Histomorphometric analysis of femurs showed decreased numbers of osteoblasts but similar numbers of osteoclasts compared to WT, altered osteoblast morphology and decreased tissue synthesis of alkaline phosphatase in Mecp2-null and HET mice. Osteoblasts cultured from Mecp2-null mice, which unlike WT osteoblasts did not express MeCP2, had increased growth rates, but reductions in mRNA expression of type I collagen, Runx2 and Osterix compared to WT osteoblasts. These results indicate that MeCP2 deficiency leads to altered bone growth. Osteoblast dysfunction was more marked in Mecp2-null male than in HET female mice, suggesting that expression of MeCP2 plays a critical role in bone development.

Sandwich allografts for long-bone nonunions in patients with osteogenesis imperfecta: a retrospective study.

BACKGROUND: Patients with osteogenesis imperfecta often develop nonunions, as internal fixation has limited applicability in this condition. We report the outcomes of a modified "sandwich technique" in the treatment of long-bone nonunions in patients with osteogenesis imperfecta; this technique brings circumferential stabilization and normal collagen to the nonunion site. METHODS: From May 2003 through February 2012, twelve patients (eight females, four males; median age, 39.0 years; range, eleven to seventy-eight years) who had osteogenesis imperfecta (Sillence type I [three], type III [eight], and type IV [one]) and a combined total of thirteen nonunions (two humeral, two radial, three femoral, four tibial, and two ulnar; median duration, 15.0 months; range, six to 204 months) were treated at our institution with compressed sandwich allograft cortical struts. The struts were fashioned to be wide enough to allow for increased osteoconductive surface area and to approximate a hemicylindrical shape. Treatment history and demographics data were acquired through retrospective chart review. Follow-up radiographs were analyzed by two attending orthopaedic surgeons to determine radiographic findings. The median follow-up time was 4.6 years (range, 2.1 to 10.3 years). RESULTS: All thirteen nonunions, including one requiring a second graft procedure, healed with abundant, smooth allograft incorporation, resulting in an initial healing rate of 92% because of a refracture in one patient. This patient's nonunion ultimately healed with additional allograft struts and a new intramedullary rod. One patient required removal of prominent screws. The final follow-up examinations revealed no pain or refracture at the original nonunion site. All patients regained their prefracture level of function. CONCLUSIONS: Sandwich allograft struts constitute a durable, safe method for the stabilization and healing of persistent long-bone nonunions in patients with osteogenesis imperfecta. All patients showed incorporation of the allograft to the native diaphysis.

Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.

Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel gene KCNJ5 that result in cell depolarization and Ca(2+) influx cause ∼40% of these tumors. We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5. The altered residues lie in the S6 segments that line the channel pore. Both alterations result in channel activation at less depolarized potentials; Gly403 alterations also impair channel inactivation. These effects are inferred to cause increased Ca(2+) influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa. We also identified de novo germline mutations at identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain-of-function Ca(2+) channel mutations in APAs and primary aldosteronism.

Increased fracture risk and low bone mineral density in patients with loeys-dietz syndrome.

Loeys-Dietz syndrome is a recently recognized connective tissue disorder with widespread systemic involvement. Little is known about its skeletal phenotype. Our goal was to investigate the risk of fracture and incidence of low bone mineral density in patients with Loeys-Dietz syndrome. We performed a cross-sectional, descriptive, survey-based study with subsequent chart review from July 2011 to April 2012. Fifty-seven patients (26 men, 31 women) with Loeys-Dietz syndrome confirmed by genetic testing completed the survey (average age, 25.3 years; range, 0.9-79.6 years). There were a total of 51 fractures (33 patients): 35 fractures in the upper extremities, 14 in the lower extremities, and two in the spine. Fourteen patients (24.6%) reported two or more fractures. There was a 50% risk of fracture by age 14 years. The incidence of any fracture in this cohort was 3.86 per 100 person-years. Seventeen patients had dual-energy X-ray absorptiometry scans available for review, 11 (64.7%) of whom had at least one fracture. Thirteen included lumbar spine absorptiometry reports; eight (61.5%) indicated low or very low bone mineral density. In the left hip, ten of 14 participants (71.4%) had low or very low bone mineral density. In the left femoral neck, nine of 13 participants (69.2%) had low or very low bone mineral density. The lowest Z- and T-scores were not associated with an increased number of fractures. Patients with Loeys-Dietz syndrome have a high risk of fracture and a high incidence of low bone mineral density.

Phenotypic variability of osteogenesis imperfecta type V caused by an IFITM5 mutation.

In a large cohort of osteogenesis imperfecta type V (OI type V) patients (17 individuals from 12 families), we identified the same mutation in the 5' untranslated region (5'UTR) of the interferon-induced transmembrane protein 5 (IFITM5) gene by whole exome and Sanger sequencing (IFITM5 c.-14C > T) and provide a detailed description of their phenotype. This mutation leads to the creation of a novel start codon adding five residues to IFITM5 and was recently reported in several other OI type V families. The variability of the phenotype was quite large even within families. Whereas some patients presented with the typical calcification of the forearm interosseous membrane, radial head dislocation and hyperplastic callus (HPC) formation following fractures, others had only some of the typical OI type V findings. Thirteen had calcification of interosseous membranes, 14 had radial head dislocations, 10 had HPC, 9 had long bone bowing, 11 could ambulate without assistance, and 1 had mild unilateral mixed hearing loss. The bone mineral density varied greatly, even within families. Our study thus highlights the phenotypic variability of OI type V caused by the IFITM5 mutation.

Bone mass in Rett syndrome: association with clinical parameters and MECP2 mutations.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the MECP2 gene. In 49 female RTT children, aged 1.9-17 y, bone mass was assessed and correlated with clinical parameters and mutations involving the MECP2 gene. We also studied five adult females, aged 20-33 y, and one male child, aged 6 y. Lumbar spine bone mineral content (BMC) and bone mineral density (BMD) were correlated with weight, height, BMI, clinical severity, degree of scoliosis, use of anticonvulsants, and ambulatory status. L1-L4 BMD and BMC showed that 48.9% of them had BMD values >2 SD below age-related norms. BMD values were in the osteoporotic range in the five adult females with RTT. Eleven percent of the children and adults with RTT experienced fractures. Low bone mass was correlated with marginal significance to clinical severity and ambulation but not to scoliosis or anticonvulsant use. Lowest bone mass occurred in patients with T158M or R270X mutations but without statistical significance. Studies in a murine model of RTT confirmed low bone mass as an inherent component of this syndrome. MECP2 mutations and clinical parameters impact bone mass in RTT, but an association with a specific mutation was not demonstrable.

Bone mineral density and fracture rate in response to intravenous and oral bisphosphonates in adult osteogenesis imperfecta.

The effect of bisphosphonate treatment on bone mineral density (BMD) and fracture rates was assessed in adults with osteogenesis imperfecta (OI). This observational nonrandomized study included 90 OI adults treated with intravenous pamidronate (n = 28), oral alendronate (n = 10), or oral residronate (n = 17) or not treated (n = 35). There were 63 type I, 15 type III, and 12 type IV OI patients. BMD results were observed for up to 161 months and an average of 52 months of treatment. For type I and grouped type III/IV patients, treatment with pamidronate showed an increasing rate in L1-L4 BMD from baseline (0.006 [P = 0.03] and 0.016 [P < 0.001] gm/cm(2)/year, respectively); oral bisphosphonate treatment showed a significant increasing rate in L1-L4 BMD (0.004 gm/cm(2)/year [P = 0.047]) for type I patients. Pamidronate-treated type III/IV and oral bisphosphonate-treated type I patients showed significant increases in total-hip BMD (0.006 [P = 0.003] and 0.011 [P = 0.046] gm/cm(2)/year, respectively). Bisphosphonate effect on fracture rate was assessed for 5-year periods before and after treatment in 51 treated and 22 nontreated individuals matched for age at which bisphosphonate was first administered to the treated group. Bisphosphonate treatment did not decrease fracture rate in type I OI patients. Fracture rate decreased in type III/IV patients following pamidronate but not following oral bisphosphonate treatment. These results underscore a need to consider whether bisphosphonate treatment is appropriate for all adults with OI.

Osteogenesis imperfecta: questions and answers.

PURPOSE OF REVIEW: Considerable attention has recently been focused on the pathogenesis, diagnosis and treatment of osteogenesis imperfecta. Two new genes have been defined in patients with recessive severe or lethal osteogenesis imperfecta types. Diagnostic concerns involve testing procedures, either skin biopsies or DNA analysis. Bisphosphonates have been accepted as 'standard of care' for children with osteogenesis imperfecta. However, questions remain as to the selection of patients for treatment, effectiveness in fracture prevention, which bisphosphonates should be used and the duration of treatment. Orthopedic intervention occurs on several levels: including the immediate treatment of fractures, the treatment of scoliosis and the use of intramedullary rods. RECENT FINDINGS: The discovery of mutations involving CRTAP and LEPRE1 genes in severe/lethal and recessively inherited osteogenesis imperfecta has provided partial answers to questions about 'other' osteogenesis imperfecta genes in patients with an osteogenesis imperfecta phenotype but no COL1A1 and COL1A2 mutations. Current experience suggests that DNA analysis is a better test for diagnosis as compared with dermal biopsy. There are no standardized guidelines for initiating bisphosphonate treatment in children. Recent data suggest either intravenous or oral bisphosphonates are effective, but differences exist between different bisphosphonates. Two recent reports document the paucity of evidence-based data regarding the effectiveness of bisphosphonate treatment in fracture prevention. SUMMARY: This report will update the medical and orthopedic approaches to care for children with osteogenesis imperfecta.

Osteogenesis imperfecta:epidemiology and pathophysiology.

Osteogenesis imperfecta (OI) is the most common of the inherited connective tissue disorders that primarily affect bone. However, it is a systemic disorder, as evidenced by the occurrence of ocular complications, dentinogenesis imperfecta, hearing loss, joint laxity, restrictive pulmonary disease, and short stature. The OI classification initially included four phenotypes (I-IV) involving COL1A1 and COL1A2 mutations. Three new phenotypes have been added, of which one, type VII, is the result of mutations of the cartilage-associated protein (CRTAP) gene. Investigation of recessive forms of OI particularly reported among South African blacks have revealed mutations involving both the CRTAP gene and the leucine proline-enriched proteoglycan 1 (LEPRE1) gene, each involved in collagen proline-3 hydroxylation. Issues related to the treatment of OI with bisphosphonates involve patient selection, evaluation of the results of treatment, and the duration of treatment. Also, questions exist regarding the difference in treatment response between children and adults with OI. Other treatment options, such as recombinant human parathyroid hormone (1-34), Rank ligand inhibitors, and stem cell technology, are being evaluated or are of future investigative interest.