Rachel I Gafni

National Institutes of Health, Bethesda, MD, United States

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Publications (26)133.37 Total impact

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    ABSTRACT: Context: Leptin alters bone and mineral metabolism in rodents, but this has not been verified in humans. Patients with congenital generalized lipodystrophy (CGL) have low leptin due to deficient adipose mass and serve as models of leptin deficiency and replacement. Objective: To study the effects of recombinant human methionyl leptin (metreleptin) on bone mineral content (BMC) and mineral metabolism. Design and Setting: An open-label nonrandomized study at the National Institutes of Health. Patients: Thirty-one patients with CGL (ages 4.3 to 46.7 y). Intervention: Metreleptin (0.06 to 0.24 mg/kg/d) for 6 months to 11 years. Outcome Measures: BMC was assessed by dual-energy x-ray absorptiometry. SD scores (SDS) for BMC were calculated based on height, race, sex, and age using population normative data. Calcium, phosphorus, PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were measured at baseline and follow-up. Results: At baseline, patients demonstrated significantly increased total body less head BMC (mean SDS, 1.8 ± 0.7), height (mean SDS, 1.3 ± 1.3), and lean mass index, defined as lean body mass per height squared (mean SDS, 1.5 ± 0.83), vs population normative data. No change in total body less head BMC was observed after metreleptin. Lean mass index decreased with metreleptin. Serum calcium decreased with metreleptin, but remained within normal limits. No changes were seen in phosphorus, PTH, or vitamin D. Conclusions: In contrast to rodent models, CGL patients have increased BMC in the leptin-deficient state, which does not change with leptin replacement. The high BMC in these patients is partially explained by high lean mass and tall stature.
    The Journal of clinical endocrinology and metabolism. 07/2014;
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    ABSTRACT: Context: Denosumab is a humanized monoclonal antibody to RANKL used primarily for post-menopausal osteoporosis and skeletal-related events from metastatic cancer. Its safety in children has not been established. Objective: To investigate the effects of denosumab treatment on skeletal growth and histology. Design: Observational case report with radiologic and histopathological analyses. Setting: Clinical Research Center Patients: A 9-year-old boy with fibrous dysplasia treated with a 7-month course of denosumab. Intervention: Histologic analyses were performed and compared on growth plates from limbs that had been amputated before and 17 months after denosumab treatment. Main Outcome Measures: Skeletal radiographs and bone histopathology from before and after treatment. Results: After initiating denosumab sclerotic metaphyseal bands appeared on radiographs. Post-treatment radiographs revealed migration of the bands away from the growth plates, consistent with continued linear growth. Histologically, the bands were composed of horizontally-arranged trabeculae containing calcified cartilage. This cartilage appeared to derive from unresorbed primary spongiosa as a result of osteoclast inhibition by denosumab, similar to what has been observed with bisphosphonates. By 17 months post-treatment active bone resorption and formation had returned, as evidenced by the presence of active osteoclasts in resorption pits and osteoid surfaces. Conclusions: Further studies are needed to determine the safety of denosumab on the growing skeleton. However in this child there was continued epiphyseal activity both during and after treatment, and reversal of bone turnover suppression after treatment discontinuation, suggesting that denosumab did not have significant adverse effects on growth.
    The Journal of Clinical Endocrinology and Metabolism 01/2014; · 6.31 Impact Factor
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    ABSTRACT: Generalized arterial calcification of infancy (GACI) is an autosomal recessive disorder characterized by congenital calcification of large and medium sized arteries, associated with early myocardial infarction, heart failure, and stroke, and premature death. Most cases of GACI are caused by mutations in the ENPP1 gene. We first studied two siblings with GACI from a non-consanguineous family without mutations in the ENPP1 gene. To search for disease-causing mutations, we identified genomic regions shared between the two affected siblings but not their unaffected parents or brother. The ABCC6 gene, which is mutated in pseudoxanthoma elasticum (PXE), resided within a small region of homozygosity shared by the affected siblings. Sequence analysis of ABCC6 revealed that the two affected siblings were homozygous for the missense mutation p.R1314W. Subsequently, ABCC6 mutations were identified in five additional GACI families with normal ENPP1 sequences. Genetic mutations in ABCC6 in patients with PXE are associated with ectopic tissue mineralization in the skin and arterial blood vessels. Thus, our findings provide additional evidence that the ABCC6 gene product inhibits calcification under physiologic conditions and confirm a second locus for GACI. In addition, our study emphasizes the potential utility of shared homozygosity mapping to identify genetic causes of inherited disorders.Journal of Investigative Dermatology accepted article preview online, 5 September 2013. doi:10.1038/jid.2013.370.
    Journal of Investigative Dermatology 09/2013; · 6.19 Impact Factor
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    ABSTRACT: Pathologically elevated serum levels of FGF23, a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain, and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia, and osteomalacia are associated with pathologic Ras activation, and may provide insight in the heretofore limited understanding of the regulation of FGF23.
    Human Molecular Genetics 09/2013; · 7.69 Impact Factor
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    ABSTRACT: Tumor-induced osteomalacia (TIO) is a rare disorder of phosphate wasting due to fibroblast growth factor-23 (FGF23)-secreting tumors that are often difficult to locate. We present a systematic approach to tumor localization and post-operative biochemical changes in 31 subjects with TIO. All had failed either initial, or re-localization (in case of recurrence or metastases at outside institutions). Functional imaging with (111) Indium- octreotide with single photon emission computed tomography (octreo-SPECT or SPECT/CT), and (18) fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) were performed, followed by anatomic imaging (CT,MRI). Selective venous sampling (VS) was performed when multiple suspicious lesions were identified or high surgical risk was a concern. Tumors were localized in 20/31 subjects (64.5%). Nineteen of 20 subjects underwent octreo-SPECT imaging, and 16/20 FDG-PET/CT imaging. Eighteen of 19 (95%) were positive on octreo-SPECT, and 14/16 (88%) on FDG-PET/CT. Twelve of 20 subjects underwent VS; 10/12 (83%) were positive. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were: sensitivity=0.95, specificity=0.64, PPV=0.82 and NPV=0.88 for octreo-SPECT; sensitivity=0.88, specificity=0.36, PPV=0.62 and NPV=0.50 for FDG-PET/CT. Fifteen subjects had their tumor resected at our institution, and were disease-free at last follow-up. Serum phosphorus returned to normal in all subjects within 1-5 days. In 10 subjects who were followed for at least 7 days postoperatively, intact FGF23 (iFGF23) decreased to near undetectable within hours and returned to the normal range within 5 days. C-terminal FGF23 (cFGF23) decreased immediately but remained elevated, yielding a markedly elevated cFGF23/iFGF23 ratio. Serum 1,25-dihydroxyvitamin D(3) (1,25D) rose and exceeded the normal range. In this systematic approach to TIO tumor localization Octreo-SPECT was more sensitive and specific, but in many cases FDG-PET/CT was complementary. VS can discriminate between multiple suspicious lesions and increase certainty prior to surgery. Sustained elevations in cFGF23 and 1,25D were observed, suggesting novel regulation of FGF23 processing and 1,25D generation. © 2013 American Society for Bone and Mineral Research.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 01/2013; · 6.04 Impact Factor
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    ABSTRACT: Context:Nephrocalcinosis is a complication of hypoparathyroidism and other metabolic disorders. Imaging modalities include ultrasonography (US) and computed tomography (CT). Few studies have compared these modalities, and standard clinical practice is not defined.Objective:The objective of the study was to determine the preferred method for assessing nephrocalcinosis.Design:The design of the study was a retrospective, blinded analysis.Setting:The study was conducted at a clinical research center.Patients:Twenty-two hypoparathyroid subjects and 7 controls participated in the study.Interventions:Contemporaneous renal US and CT images were reviewed in triplicate by 4 blinded radiologists. Nephrocalcinosis was classified using a 0-3 scale with 0 meaning no nephrocalcinosis and 3 meaning severe nephrocalcinosis.Main Outcome Measures:Intraobserver, interobserver, and interdevice agreements were measured.Results:Intraobserver agreement was high, with an overall weighted kappa of 0.83 for CT and 0.89 for US. Interobserver agreement was similar between modalities, with kappas of 0.74 for US and 0.70 for CT. Only moderate agreement was found between US and CT scores, with an intermodality kappa of 0.47 and 60% concordance. Of discordant pairs, 81% had higher US scores and only 19% had higher CT scores. Of nephrocalcinosis seen on US and not CT, 45%, 46%, and 9% were grades 1, 2, and 3, respectively. Overall, US scores were higher than CT with a cumulative odds ratio (95% confidence interval) of 5.97 (2.60, 13.75) (P < .01). In controls, 100% of US ratings were 0, and 95% of CT ratings were 0.Conclusions:US is superior to CT for assessment of mild to moderate nephrocalcinosis in patients with hypoparathyroidism. This finding, in combination with its low cost, lack of radiation, and portability, defines US as the preferred modality for assessment of nephrocalcinosis.
    The Journal of Clinical Endocrinology and Metabolism 01/2013; · 6.31 Impact Factor
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    ABSTRACT: Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates and is regulated by blood levels of phosphate and active vitamin D. Post-translational glycosylation by the enzyme GALNT3 and subsequent processing by furin have been demonstrated to be a regulated process that plays a role in regulating FGF23 levels. In physiologic states, FGF23 signaling is mediated by an FGF receptor and the coreceptor, Klotho. Recent work identifying a role for iron/hypoxia pathways in FGF23 physiology and their implications are discussed. Beyond its importance in primary disorders of mineral metabolism, recent work implicates FGF23 in renal disease-associated morbidity, as well as possible roles in cardiovascular disease and skeletal fragility.
    Trends in Endocrinology and Metabolism 08/2012; · 8.90 Impact Factor
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    ABSTRACT: Parathyroid hormone (PTH) has variable actions on bone. Chronically increased PTH is catabolic and leads to osteoporosis; yet intermittent administration is anabolic and increases bone mass. PTH deficiency is associated with decreased bone remodeling and increased bone mass. However, the effects of PTH replacement therapy on bone in hypoparathyroidism are not well known. We discontinued calcitriol therapy and treated 5 hypoparathyroid subjects (2 adults and 3 adolescents) with synthetic human PTH 1-34 (hPTH 1-34), injected two to three times daily for 18 months, with doses individualized to maintain serum calcium at 1.9 to 2.25 mmol/L. Biochemical markers and bone mineral density (BMD) were assessed every 6 months; iliac-crest biopsies were performed before and after 1 year of treatment. hPTH 1-34 therapy significantly increased bone markers to supranormal levels. Histomorphometry revealed that treatment dramatically increased cancellous bone volume and trabecular number and decreased trabecular separation. Changes in trabecular width were variable, suggesting that the increase in trabecular number was due to the observed intratrabecular tunneling. Cortical width remained unchanged; however, hPTH 1-34 treatment increased cortical porosity. Cancellous bone remodeling was also stimulated, inducing significant changes in osteoid, mineralizing surface, and bone formation rate. Similar changes were seen in endocortical and intracortical remodeling. BMD Z-scores were unchanged at the spine and femoral neck. Total hip Z-scores increased; however, total body BMD Z-scores decreased during the first 6 months of treatment and then stabilized, remaining significantly decreased compared to baseline. Radial Z-scores also decreased with treatment; this was most pronounced in the growing adolescent. Daily hPTH 1-34 therapy for hypoparathyroidism stimulated bone turnover, increased bone volume, and altered bone structure in the iliac crest. These findings suggest that treatment with hPTH 1-34 in hypoparathyroid adults and adolescents has varying effects in the different skeletal compartments, leading to an increase in trabecular bone and an apparent trabecularization of cortical bone.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 04/2012; 27(8):1811-20. · 6.04 Impact Factor
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    ABSTRACT: Fibrous dysplasia (FD) is a skeletal disease caused by somatic activating mutations of the cyclic adenosine monophosphate (cAMP)-regulating protein, α-subunit of the Gs stimulatory protein (G(s) α). These mutations lead to replacement of normal bone by proliferative osteogenic precursors, resulting in deformity, fracture, and pain. Medical treatment has been ineffective in altering the disease course. Receptor activator of NF-κB ligand (RANKL) is a cell-surface protein involved in many cellular processes, including osteoclastogenesis, and is reported to be overexpressed in FD-like bone cells. Denosumab is a humanized monoclonal antibody to RANKL approved for treatment of osteoporosis and prevention of skeletal-related events from bone metastases. We present the case of a 9-year-old boy with severe FD who was treated with denosumab for a rapidly expanding femoral lesion. Immunohistochemical staining on a pretreatment bone biopsy specimen revealed marked RANKL expression. He was started on monthly denosumab, with an initial starting dose of 1 mg/kg and planned 0.25 mg/kg dose escalations every 3 months. Over 7 months of treatment he showed marked reduction in pain, bone turnover markers (BTMs), and tumor growth rate. Denosumab did not appear to impair healing of a femoral fracture that occurred while on treatment. With initiation of treatment he developed hypophosphatemia and secondary hyperparathyroidism, necessitating supplementation with phosphorus, calcium, and calcitriol. BTMs showed rapid and sustained suppression. With discontinuation there was rapid and dramatic rebound of BTMs with cross-linked C-telopeptide (reflecting osteoclast activity) exceeding pretreatment levels, accompanied by severe hypercalcemia. In this child, denosumab lead to dramatic reduction of FD expansion and FD-related bone pain. Denosumab was associated with clinically significant disturbances of mineral metabolism both while on treatment and after discontinuation. Denosumab treatment of FD warrants further study to confirm efficacy and determine potential morbidity, as well as to determine the mechanism of RANKL in the pathogenesis of FD and related bone marrow stromal cell diseases.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 03/2012; 27(7):1462-70. · 6.04 Impact Factor
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    ABSTRACT: Fibroblast growth factor-23 (FGF23) is a phosphate- and vitamin D-regulating hormone derived from osteoblasts/osteocytes that circulates in both active (intact, iFGF23) and inactive (C-terminal, cFGF23) forms. O-glycosylation by O-glycosyl transferase N-acetylgalactosaminyltransferase 3 (ppGalNAcT3) and differential cleavage by furin have been shown to be involved in regulating the ratio of active to inactive FGF23. Elevated iFGF23 levels are observed in a number of hypophosphatemic disorders, such as X-linked, autosomal recessive, and autosomal dominant hypophosphatemic rickets, whereas low iFGF23 levels are found in the hyperphosphatemic disorder familial tumoral calcinosis/hyperphosphatemic hyperostosis syndrome. Fibrous dysplasia of bone (FD) is associated with increased total FGF23 levels (cFGF23 + iFGF23); however, classic hypophosphatemic rickets is uncommon. Our results suggest that it can be explained by increased FGF23 cleavage leading to an increase in inactive cFGF23 relative to active iFGF23. Given the fact that FD is caused by activating mutations in the small G-protein G(s) α that results in increased cyclic adenosine monophosphate (cAMP) levels, we postulated that there may be altered FGF23 cleavage in FD and that the mechanism may involve alterations in cAMP levels and ppGalNacT3 and furin activities. Analysis of blood specimens from patients with FD confirmed that the elevated total FGF23 levels are the result of proportionally increased cFGF23 levels, consistent with less glycosylation and enhanced cleavage by furin. Analysis of primary cell lines of normal and mutation-harboring bone marrow stromal cells (BMSCs) from patients with FD demonstrated that BMSCs harboring the causative G(s) α mutation had higher cAMP levels, lower ppGalNAcT3, and higher furin activity. These data support the model wherein glycosylation by ppGalNAcT3 inhibits FGF23 cleavage by furin and suggest that FGF23 processing is a regulated process that controls overall FGF23 activity in FD patients.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 01/2012; 27(5):1132-41. · 6.04 Impact Factor
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    ABSTRACT: Recent advances in understanding the epidemiology, genetics, diagnosis, clinical presentations, skeletal involvement, and therapeutic approaches to hypoparathyroidism led to the First International Workshop on Hypoparathyroidism that was held in 2009. At this conference, a group of experts convened to discuss these issues with a view towards a future research agenda for this disease. This review, which focuses primarily on hypoparathyroidism in the adult, provides a comprehensive summary of the latest information on this disease. © 2011 American Society for Bone and Mineral Research
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 09/2011; 26(10):2317 - 2337. · 6.04 Impact Factor
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    Alison M Boyce, Rachel I Gafni
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    ABSTRACT: Evaluation of the child with fractures is challenging, as no clear guidelines exist to distinguish traumatic from pathological fractures. Although most fractures in childhood are benign, recurrent fractures may be associated with a wide variety of primary skeletal diseases as well as secondary causes, necessitating a careful history and physical exam to guide the evaluation. There is no "gold standard" for the evaluation and treatment of children with fractures and low bone mineral density (BMD); therefore, the diagnosis of osteoporosis in a pediatric patient should be made using a combination of clinical and radiographic features. Interpretation of bone densitometry in growing patients presents a unique set of challenges because areal BMD measured by dual-energy x-ray absorptiometry depends on multiple dynamic variables. Interpretation of pediatric dual-energy x-ray absorptiometry should be based on Z-scores (sd scores compared to age, sex, and ethnicity-matched controls), using normative databases specific to the brand of densitometer and the patient population. Given the skeleton's ability to recover from low BMD through modeling and remodeling, optimizing management of underlying conditions leading to bone fragility is the initial step. Conservative measures including calcium and vitamin D supplementation and weight-bearing physical activity are important interventions that should not be overlooked. The use of bisphosphonates in children and adolescents is controversial due to lack of long-term efficacy and safety data and should be limited to clinical trials and compassionate therapy in children with significantly compromised quality of life. Close monitoring is required, and further study is necessary to assess their long-term safety and efficacy in children.
    The Journal of Clinical Endocrinology and Metabolism 07/2011; 96(7):1943-52. · 6.31 Impact Factor
  • Rachel I. Gafni, Jeffrey Baron
    Bone 01/2009; 45. · 4.46 Impact Factor
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    ABSTRACT: 5 of 6 children infected with human immunodeficiency virus (HIV) receiving Tenofovir disoproxil fumarate (TDF) experienced absolute decreases in bone mineral density (BMD). 2 pre-pubertal subjects experienced >6% BMD decreases. 1 subject was the smallest child and experienced a 27% decrease, necessitating withdrawal of TDF. Subsequently, her BMD recovered. Monitoring of children infected with HIV who require treatment with TDF is warranted.
    The Journal of pediatrics 04/2008; 152(4):582-4. · 4.02 Impact Factor
  • Rachel I Gafni, Jeffrey Baron
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    ABSTRACT: During childhood and adolescence, bone mass acquisition occurs primarily through skeletal growth. It is widely assumed that bone mass acquisition throughout childhood is an important determinant of the risk of osteoporosis in late adulthood; bone mass is thought to resemble a bank account in which deposits persist indefinitely. However, several well-controlled clinical studies suggest that increasing bone mass acquisition during childhood will have only transient effects. A likely explanation is that bone mass is governed by a homeostatic system that tends to return to a set point after any perturbation and, therefore, bone mass depends primarily on recent conditions, not those in the distant past. Indeed, in an animal model, we have shown evidence that bone mass acquisition in early life has no effect on bone mass in adulthood, in part because many areas of the juvenile skeleton are replaced in toto through skeletal growth. Therefore, it should not be assumed that alterations in childhood bone mass acquisition will affect bone mass many decades later in late adulthood. This issue remains open and the solution may depend on the type of childhood condition (for example calcium intake versus exercise) and its magnitude, timing, and duration. To date, both animal studies and clinical studies suggest that much of the effect of early bone mass acquisition does not persist.
    PEDIATRICS 04/2007; 119 Suppl 2:S131-6. · 4.47 Impact Factor
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    ABSTRACT: Hypoparathyroidism is characterized clinically by the presence of hypocalcemia and hyperphosphatemia due to inadequate supply or effectiveness of circulating parathyroid hormone (PTH). It may be present either as an isolated finding or as a component of a more complex developmental, metabolic, or endocrinologic syndrome. While the most common cause of hypoparathyroidism continues to be surgical destruction1, several genetic etiologies have been identified that help define the molecular basis for less common causes. These genetic disorders can result in impaired embryologic development of the parathyroids, disordered synthesis or secretion of PTH, autoimmune destruction of the parathyroid gland, or inappropriate end-organ response to PTH (Table 1).
    02/2007: pages 159-178;
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    ABSTRACT: Tenofovir disoproxil fumarate, a nucleotide analog HIV reverse transcriptase inhibitor with demonstrated activity against nucleoside-resistant HIV, is approved for use in adults but not children. Metabolic bone abnormalities have been seen in young animals given high-dose tenofovir and HIV-infected adults that were treated with oral tenofovir disoproxil fumarate. However, tenofovir disoproxil fumarate is being used in children despite a lack of bone safety data. We hypothesized that, given the higher rate of bone turnover that is associated with normal skeletal growth, the potential for TDF-related bone toxicity may be greater in children than in adults. Fifteen highly antiretroviral-experienced HIV-infected children who were 8 to 16 years of age (mean +/- SD: 12 +/- 2) and required a change in therapy received tenofovir disoproxil fumarate 175 to 300 mg/m2 per day (adult dose equivalent) as part of highly active antiretroviral therapy for up to 96 weeks. Bone mineral density of the lumbar spine, femoral neck, and total hip by dual-energy x-ray absorptiometry and blood and urine markers of bone metabolism were measured at 0, 24, 48, 72, and 96 weeks. Median z score (SD score compared with age, gender, and ethnicity-matched control subjects) of the lumbar spine, femoral neck, and total hip were decreased from baseline at 24 weeks and 48 weeks and then stabilized. Lumbar spine bone mineral apparent density (which estimates volumetric bone mineral density independent of bone size) z scores also decreased at 24 weeks. Absolute decreases in bone mineral density were observed in 6 children; the mean age of these children was significantly younger than the bone mineral density stable group (10.2 +/- 1.1 vs 13.2 +/- 1.8 years). The change in lumbar spine bone mineral density correlated with decreases in HIV plasma RNA during treatment. Metabolic markers of bone formation and resorption were variable. Two children in whom tenofovir disoproxil fumarate was discontinued because of bone loss that exceeded protocol allowances demonstrated partial or complete recovery of bone mineral density by 96 weeks. Tenofovir disoproxil fumarate use in children seems to be associated with decreases in bone mineral density that, in some children, stabilize after 24 weeks. Increases in bone markers and calcium excretion suggest that tenofovir disoproxil fumarate may stimulate bone resorption. Bone turnover is higher in children than in older adolescents and adults because of skeletal growth, potentially explaining the greater effect seen in young children. Decreases in bone mineral density correlate with decreases in viral load and young age, suggesting that young responders may be at greater risk for bone toxicity.
    PEDIATRICS 10/2006; 118(3):e711-8. · 4.47 Impact Factor
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    ABSTRACT: Highly active antiretroviral therapy has altered the course of HIV infection among children, but new antiretroviral agents are needed for treatment-experienced children with drug-resistant virus. Tenofovir disoproxil fumarate (DF) is a promising agent for use in pediatric salvage therapy, because of its tolerability, efficacy, and resistance profile. We designed this study to provide preliminary pediatric safety and dosing information on tenofovir DF, while also providing potentially efficacious salvage therapy for heavily treatment-experienced, HIV-infected children. Tenofovir DF, alone and in combination with optimized background antiretroviral regimens, was studied among 18 HIV-infected children (age range: 8.3-16.2 years) who had progressive disease with > or = 2 prior antiretroviral regimens, in a single-center, open-label trial. Tenofovir DF monotherapy for 6 days was followed by the addition of individualized antiretroviral regimens. Subjects were monitored with HIV RNA reverse transcription-polymerase chain reaction, flow cytometry, and routine laboratory studies; monitoring for bone toxicity included measurement of lumbar spine bone mineral density (BMD) with dual-energy x-ray absorptiometry. Subjects were monitored through 48 weeks. Two subjects developed grade 3 elevated hepatic transaminase levels during monotherapy and were removed from the study. The remaining 16 subjects had a median of 4 antiretroviral agents (range: 3-5 agents) added to tenofovir DF. HIV plasma RNA levels decreased from a median pretreatment level of 5.4 log10 copies per mL (range: 4.1-5.9 log10 copies per mL) to 4.21 log10 copies per mL at week 48 (n = 15), with 6 subjects having < 400 copies per mL, including 4 with < 50 copies per mL. The overall median increases in CD4+ T cell counts were 58 cells per mm3 (range: -64 to 589 cells per mm3) at week 24 and 0 cells per mm3 (range: -274 to 768 cells per mm3) at week 48. The CD4+ cell responses among the virologic responders were high and sustained. The major toxicity attributed to tenofovir DF was a >6% decrease in BMD for 5 of 15 subjects evaluated at week 48, necessitating the discontinuation of tenofovir DF therapy for 2; all 5 subjects experienced >2 log10 copies per mL decreases in HIV plasma RNA levels. Tenofovir DF-containing, individualized, highly active antiretroviral therapy regimens were well tolerated and effective among heavily treatment-experienced, HIV-infected children. Loss of BMD may limit tenofovir DF use among prepubertal patients.
    PEDIATRICS 12/2005; 116(6):e846-54. · 4.47 Impact Factor
  • Rachel I Gafni, Jeffrey Baron
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    ABSTRACT: Dual-energy x-ray absorptiometry (DEXA) is increasingly used to evaluate children for osteoporosis. However, the interpretation of pediatric DEXA is complicated by growth and development. Because most DEXA scans are performed on adults, we hypothesized that physicians who interpret DEXA may not be aware of these pediatric issues, potentially leading to misdiagnosis. Children (n=34, aged 4-17 years) diagnosed with low bone mineral density (BMD) based on a DEXA scan were referred for possible inclusion in a childhood osteoporosis protocol. The referral DEXA scans were analyzed for accuracy. Thirty (88%) of the scans had at least one error in interpretation. The most frequent error (62%) was use of T-score (SD score compared with young adults) to diagnose osteoporosis, which is inappropriate for children. Other errors included use of a reference database that does not consider gender or ethnic differences (21%), incorrect bone map (21%), inattention to short stature (15%), and other measurement or statistical error (12%). After correcting for these errors, 53% had normal BMD, whereas only 26% retained the diagnosis of low BMD. The remaining 21% could not be given a definitive diagnosis. In children, the diagnosis of osteoporosis is often due to misinterpretation of a DEXA scan.
    Journal of Pediatrics 03/2004; 144(2):253-7. · 4.04 Impact Factor
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    ABSTRACT: The purpose of the present study was to determine whether longitudinal growth of the cortex occurs through intramembranous bone formation involving the periosteum or through endochondral bone formation involving the growth plate and to explore the cellular and biochemical mechanisms responsible for this process. Cortical bone formation was studied in the metaphyses of growing New Zealand White rabbits by means of (1) oxytetracycline labeling and fluorescence microscopy, (2) computer-assisted histomorphometry, (3) osteoblast culture and [(3) H]-thymidine incorporation in the presence of periosteum or periosteum-conditioned medium, and (4) surgical insertion of membranes between the periosteum and the underlying spongiosa. Within the metaphyseal cortex, oxytetracycline labeling produced fluorescent closed curves outlining enlarging trabeculae derived from coalescing endochondral trabecular bone. In this region of coalescing trabeculae close to the periosteum, osteoblast surface was increased compared with trabeculae farther from the periosteum (p < 0.001). The osteoclast surface did not differ. In vitro, osteoblast proliferation was increased in the presence of periosteum (p < 0.001) or periosteum-conditioned medium (p < 0.001). Surgical insertion of permeable or impermeable membranes between the periosteum and the spongiosa did not prevent cortex formation. These observations demonstrate that metaphyseal cortical bone is formed by coalescence of endochondral trabecular bone. This coalescence is associated with increased osteoblast surface in the peripheral spongiosa. The increased osteoblast surface could be due to inductive effects of periosteum; in the present study, periosteum stimulated osteoblast proliferation in vitro but was not required for metaphyseal cortical bone formation in vivo. Clinical Relevance: Understanding metaphyseal cortical growth may help to elucidate the pathophysiology of osseous growth disorders in children.
    The Journal of Bone and Joint Surgery 09/2003; 85-A(9):1739-48. · 3.23 Impact Factor

Publication Stats

755 Citations
133.37 Total Impact Points

Institutions

  • 2001–2013
    • National Institutes of Health
      • • Branch of Craniofacial and Skeletal Diseases
      • • Section on Growth and Development
      • • Branch of HIV and AIDS Malignancy
      Bethesda, MD, United States
  • 2011
    • Eunice Kennedy Shriver National Institute of Child Health and Human Development
      Maryland, United States
  • 2007
    • University of Maryland, Baltimore
      Baltimore, Maryland, United States
  • 2001–2002
    • National Institute of Child Health and Human Development
      Maryland, United States