Severe osteopenia in a young boy with Kostmann's congenital neutropenia treated with granulocyte colony-stimulating factor: suggested therapeutic approach.

Kostmann's syndrome is a congenital disorder that causes an impairment of myeloid differentiation in the bone marrow characterized by severe neutropenia, which can be treated with recombinant human granulocyte colony-stimulating factor (G-CSF). We present the case of a 13-year-old boy with Kostmann's syndrome who was treated with recombinant human G-CSF from age 3.5 years. His growth and development was normal, although complicated by intermittent infections. Bone mineral density (BMD) measurement revealed severe osteopenia at the spine and hips (lumbar spine BMD 0.486 g/cm(2); Z score -3.6), and he was referred to the Endocrine Service. Relevant laboratory evaluation showed a pretreatment ionized calcium level at the upper limit of normal (1.28 mmol/L; range: 1.13-1.32 mmol/L), suppressed intact parathyroid hormone (iPTH) level (12 pg/mL; range: 10-65 pg/mL), and a low 1,25-dihydroxy vitamin D level (21 pg/mL; range: 24-65 pg/mL). He had evidence of increased bone turnover evidenced by elevated urinary deoxypyridinoline (DPD) cross-links (46.9 nmol/mmol creatinine; range: 2-34 nmol/mmol creatinine) and a simultaneous increase in markers of bone formation with elevated osteocalcin level (200 ng/mL; normal: 20-80 ng/mL) and alkaline phosphatase level (236 IU/mL; normal: 38-126 IU/mL). Because of clinical concern for his skeletal health, bisphosphonate therapy with intravenous pamidronate was initiated. One month after treatment, the iPTH and DPD cross-links were in the normal range (54 pg/mL and 17.7 nmol/mmol creatinine, respectively) and the 1,25-dihydroxy vitamin D level was elevated (111 pg/mL). Four months after treatment, there was a striking increase in BMD at the lumbar spine (+30.86%), femoral necks (left, +20.02%; right, +17.98%), and total hips (left, +18.40%; right, +15.94%). Seven months after bisphosphonate therapy, his biochemical parameters showed a return toward pretreatment levels with increasing urinary DPD cross-links (28.7 nmol/mmol creatinine) and decreasing iPTH (26 pg/mL). However, the BMD continued to increase (8 months posttreatment), but the magnitude of the increment was attenuated (lumbar-spine, +4.8%; left total hip, +1.2% and right total hip +2.4%), relative to BMD at 4 months. Eight months after the initial treatment, his iPTH was suppressed at 14 pg/mL and he again received pamidronate (at a lower dose); 3 months later, he had an additional increase in BMD (lumbar spine +7.4%, left total hip +3.9%, right total hip +2.7%), relative to the previous study. We hypothesize that prolonged administration of G-CSF as treatment for Kostmann's syndrome is associated with increased bone resorption, mediated by osteoclast activation and leading to bone loss. In children, the resulting osteopenia can be successfully managed with antisreorptive bisphosphonate therapy with significant improvement in bone density. Measurements of biochemical parameters of bone turnover can be used to monitor the magnitude and duration of the therapeutic response and the need for BMD reassessment and, perhaps, retreatment.

Interplay of pregnancy, lactation, and hyperthyroidism leading to severe osteoporosis in a young woman.

OBJECTIVE: To describe the case of a young woman who had severe osteoporosis due to the compounding effects of pregnancy, lactation, and hyperthyroidism and who had a presumed metastatic lesion in the lumbar spine. METHODS: We present the clinical, pathologic, radiologic, and laboratory findings and describe the clinical course of our patient. RESULTS: A 31-year-old Arabic woman was referred to the M. D. Anderson Cancer Center because of a lytic lesion in her lumbar spine, presumed to be metastatic deposits. She had a history of two consecutive pregnancies and intermittently treated hyperthyroidism. Our initial evaluation revealed that the patient had clinical and biochemical thyrotoxicosis, and we treated her with thionamides, corticosteroids, and radioiodine ablation. Radiologic studies disclosed a complex renal cyst that had increased uptake on a bone scan, which was highly suggestive of a primary malignant lesion. Ultimately, however, it proved benign on pathologic analysis after a left nephrectomy. Bone mineral density measurements identified severe osteoporosis (T-scores: lumbar spine, -3.3; right hip, -2.2; and left hip, -2.0), which had led to vertebral collapse and was misinterpreted as malignant metastatic disease. The bone mineral densities improved (+5 to +11% at the various sites) within 4 months after definitive treatment and cure of the hyperthyroidism. CONCLUSION: The effect of pregnancies and prolonged lactation, in the milieu of other risk factors for bone depletion such as hyperthyroidism, may cause severe osteoporosis in a young patient. The resulting osteoporosis may manifest as a lesion suggestive of malignant metastatic involvement.

Diet induced thermogenesis with oral & intravenous feeding in chronically undernourished human subjects.

The parasympathetic nervous system (PNS) has been shown to be important in the mediation of diet induced thermogenesis (DIT). Chronically energy deficient (CED) subjects have a high resting parasympathetic tone, which could lead to a greater than expected DIT. DIT was studied in chronically energy deficient adult men and healthy age-matched volunteers (6 controls, 7 CED subjects) with an isocaloric (600 kcal) meal given by the oral and intravenous (i.v.) routes on two consecutive days, on a crossover basis. The resting metabolic rate (RMR) and the DIT were measured over 6 h, along with cardiovascular, biochemical and anthropometric parameters. Anthropometrically (height, weight, fat free mass, body mass index, mid upper arm circumference and sum of skinfolds), the CED group differed significantly from the well-nourished control group. There were no significant differences between the two groups in the basal state for metabolic (RMR, oxygen consumption, respiratory quotient), cardiovascular [blood pressure (BP), heart rate, cardiac output], and biochemical (plasma glucose, insulin and norepinephrine) parameters. The CED group had a significantly higher DIT response for both meal types when compared to the controls, when expressed as an absolute value and as a percentage response. However, the response was not significant when corrected for the meal size and body weight. There were also no significant differences between the two meal types in each group for the metabolic, cardiovascular and biochemical parameters during the DIT period, although, in general, the oral meal gave a larger DIT response compared to the i.v. meal. Both groups predominantly oxidised fat during the fasted stage and switched to carbohydrate oxidation when fed. It appears that, the previously demonstrated higher tone in the PNS, does not make a significant contribution to the thermic response of a meal in these subjects.

Relationship between rate of administration of electroconvulsive shocks and rate of learning in rats: implications for the practice of ECT.

Number of electroconvulsive therapy (ECT) treatments administered and severity of psychopathology confound the interpretation of clinical studies that address the relationship between the rate of administration of ECT and cognitive morbidity occasioned by the treatment. A preclinical study was therefore conducted to address the issue. Three groups (n = 8/group) of adult male Sprague-Dawley rats received six electroconvulsive shocks (ECS) in daily ECS, 3 ECS/week, and 2 ECS/week schedules; a fourth group (control; n = 8) received only sham ECS. From days 2 to 7 after the conclusion of the ECS/sham ECS course, the rats were monitored for learning on the Hebb-Williams complex maze. The control, 2 ECS/week, and 3 ECS/week groups showed significant learning by days 3, 5, and 7, respectively, while the daily ECS group showed no significant learning during the assessment period. This indicates that even when the cumulative effect of ECS on learning is controlled for, more frequent ECS is associated with slower learning. Extrapolating to clinical settings, it is suggested that wider spacing of ECT may lessen ECT-induced cognitive morbidity.