Persistent bone and joint disease despite current treatments for mucopolysaccharidosis types I, II, and VI: Data from a 10-year prospective study.

The mucopolysaccharidosis (MPS) disorders have many potential new therapies on the horizon. Thus, historic control data on disease progression and variability are urgently needed. We conducted a 10-year prospective observational study of 55 children with MPS IH (N = 23), MPS IA (N = 10), non-neuronopathic MPS II (N = 13), and MPS VI (N = 9) to systematically evaluate bone and joint disease. Annual measurements included height, weight, and goniometry. Mixed effects modeling was used to evaluate changes over time. All participants had been treated with hematopoietic cell transplantation and/or enzyme replacement therapy. Height z-score decreased over time in MPS IH, MPS II, and MPS VI, but not MPS IA. Adult heights were 136 ± 10 cm in MPS IH, 161 ± 11 cm in MPS IA, 161 ± 14 cm in MPS II, and 128 ± 15 cm in MPS VI. Adult average BMI percentiles were high: 75 ± 30%ile in MPS IH, 71 ± 37%ile in MPS IA, 71 ± 25%ile in MPS II, and 60 ± 42%ile in MPS VI. Every participant had joint contractures of the shoulders, elbows, hips, and/or knees. Joint contractures remained stable over time. In conclusion, despite current treatments for MPS I, II, and VI, short stature and joint contractures persist. The elevation in average BMI may be related, in part, to physical inactivity due to the ongoing bone and joint disease. Data from this longitudinal historical control study may be used to expedite testing of experimental bone and joint directed therapies and to highlight the need for weight management as part of routine clinical care for patients with MPS.

Nutrition in Thalassemia: A Systematic Review of Deficiency, Relations to Morbidity, and Supplementation Recommendations.

BACKGROUND: Reports of nutritional deficiencies in patients with thalassemia (Thal) are common. Despite its importance, however, nutritionally focused research in Thal has been limited by inadequate sample size, inconsistent methodology, a lack of control comparisons, and few interventional trials. Due to these limitations, clinicians lack evidence-based nutrition recommendations to support clinical decision-making. This systematic review summarizes observed relationships between nutrition and morbidity in Thal published in the last 3 decades. METHODS: PubMed, Web of Science, and Embase were screened for articles pertaining to nutrition in Thal using comprehensive search terms. Studies performed in humans, written in English, and published between 1990 and 2020 were included. Over 2100 manuscripts were identified, from which 97 were included. RESULTS: Patients with Thal were most often deficient in vitamins A, C, D, selenium, and zinc. Prevalence of nutritional deficiency was positively correlated with age and iron overload. Evidence to support the role of vitamin D and zinc for bone health was observed; zinc was also found to improve glucose metabolism. CONCLUSIONS: Due to the risk for multinutrient deficiency, nutritional status should be assessed annually in patients with Thal with prompt nutrient replacement when deficiency is detected. Routine supplementation with vitamin D and zinc is recommended.

Zinc deficiency and its association with treatment-related toxicity in children with cancer.

BACKGROUND: Nutritional deficiencies in children with cancer at time of diagnosis and during treatment may negatively affect disease outcome and increase treatment-related toxicity. Yet zinc, an essential nutrient important for supporting immune function and known for reducing diarrheal episodes, is rarely assessed in these children. PROCEDURES: Fifty children (1 month to 18 years) with recently diagnosed cancer were enrolled in this study. An age and gender matched control group (n = 50) was also recruited. Plasma and urinary zinc, plasma copper, and C-reactive protein (CRP) levels were measured at baseline, 3, and 6 months following diagnosis. A retrospective review of the toxicity profile was performed in the cohort of children with cancer for the first 4 years after initial diagnosis. RESULTS: CRP and plasma copper (both acute-phase reactants) were elevated in patients with cancer compared to controls at baseline, both p < .03. Plasma zinc levels were not significantly different from controls at baseline, but decreased by 11% in the cancer group over 6 months of treatment, 83.2 ± 15.6 to 74.3 ± 14.8 µg/dl, p = .01. Plasma zinc dropped to deficient levels in 35% of cases over the initial 6 months. Zinc deficiency at 6 months was related to an increased incidence of severe diarrhea during 4 years of follow-up, p < .001. CONCLUSIONS: Zinc deficiency is an underrecognized problem among patients undergoing treatment for cancer and is associated with severe diarrhea. Further studies are needed to evaluate causes for zinc deficiency, related effects, and a possible role for zinc supplementation.

Urinary cross-linked carboxyterminal telopeptide, a bone resorption marker, decreases after vaso-occlusive crises in adults with sickle cell disease.

People with sickle cell disease often report severe bone pain with repeated bouts of vaso-occlusive crises, but the extent of skeletal injury incurred during these painful episodes remain unclear. We sought to quantify bone degradation by comparing urinary concentrations of carboxyterminal cross-linked telopeptide of type I collagen (CTX-1), a well-described marker of bone resorption, in a prospective cohort of 52 adults with sickle cell disease enrolled in the Sickle Cell Pain Markers Study. We also questioned if changes in urinary CTX-1 concentrations correlated with changes in hemolysis and inflammatory markers measured both during and after resolution of a painful vaso-occlusive episode. Thirty-one of the 52 adults enrolled in the study had paired urine samples for CTX-1 analysis. Urinary CTX-1, corrected for urine creatinine, significantly decreased from a mean of 3.45 µg/mmol during vaso-occlusive crises to 2.62 µg/mmol at recovery (p = 0.01). Thus, increased bone loss appears to correlate with acute vaso-occlusive crises in sickle cell disease. Our finding that urinary CTX-1 can be used to probe bone degradation in sickle cell disease provides an important new tool for diagnosing and monitoring response to therapy for people with sickle cell-related bone loss.

Precision of the Hologic DXA in the Assessment of Visceral Adipose Tissue.

INTRODUCTION: Visceral fat, also known as visceral adipose tissue (VAT), has been the focus of intensive research over the past several yr, as ground breaking studies have investigated its possible role in predicting long-term cardiac dysfunction, hypertension, and diabetes. Historically, magnetic resonance imaging and computed tomography were the instruments of choice for visceral fat quantification. However, with the introduction of visceral fat assessment software for Dual-energy X-ray Absorptiometry (DXA) scanners, DXA's use for VAT assessment has become increasingly common. To effectively utilize DXA in future VAT research studies, information about their precision and accuracy must be known. This study provides novel information regarding the precision of the Hologic Horizon DXA scanner in the assessment of VAT. METHODS: Sixty individuals (32.7 ± 17.1 yr, 51% male, 40% with body mass index (BMI) > 25 kg/m2) above the age of 16 years were recruited to participate in this study. Subjects found to be pregnant, have a lumbar vertebral compression fracture, nonremovable metal implants in the abdomen, or scoliosis/lordosis/kyphosis were excluded from the study. All subjects underwent 3 consecutive whole body scans on a Hologic Horizon A DXA scanner. RESULTS: VAT mass ranged from 102 g to 1454 g. VAT precision improved with increasing BMI (p = 0.025): coefficient of variation (%CV) was 15.2% for underweight subjects (n = 2), 7.1% for healthy subjects (n = 34), 6.4% for overweight subjects (n = 18), and 4.7% for obese subjects (n = 6). CONCLUSIONS: VAT measurement by Hologic DXA displays a satisfactory level of precision in individuals with a BMI of >18.5 kg/m2. Precision was found to be higher in those with the greatest risk of cardio-metabolic dysfunction (individuals with high VAT). Due to its low cost, brief examination time, noninvasiveness, and limited radiation exposure, DXA may be considered the tool of choice for VAT determination in future studies.

Vertebral Bone Density Measurements by DXA are Influenced by Hepatic Iron Overload in Patients with Hemoglobinopathies.

Interference from metal hardware (piercings; buttons on clothing; and ingested material, e.g. barium) is well documented in bone health assessments by dual-energy X-ray absorptiometry (DXA). It is unknown if iron in hepatic tissue of highly iron-loaded patients could be mistakenly assessed by DXA as bone, and if this would lead to increased areal bone mineral density (aBMD) lumbar spine Z-scores derived by DXA. Our hypothesis is that iron in the liver of heavily loaded patients will artificially raise aBMD in the spine, and thereby lead to an error in the DXA scan. This study consisted of a retrospective chart review and re-analysis of DXA scans from patients with sickle cell disease and thalassemia combined with prospective DXA and liver iron concentration (LIC) measurements from healthy controls. Patients who previously had both a DXA and LIC measurement were compared with controls. aBMD of individual vertebrae were analyzed and grouped by those that may be covered by the liver (L1 or L1/2) with those typically not (L3/4). Subjects were grouped by diagnosis and LIC severity. Phantoms were created to mimic the geometry of iron loaded liver tissue, and analyzed by DXA. A significant effect was observed in the difference of BMD Z-score of L1 and L 3/4 when patients with LIC < 1000 were compared to those with >5000 µg Fe/g wet tissue (p = 0.043). A significant relationship was also observed in the difference in aBMD Z-score of L1 and 3/4 when controls were compared to the high iron group (p = 0.037). These findings were supported by phantom experiments. These results suggest that there is a relationship between hepatic iron and increased L1 aBMD Z-scores in highly iron-loaded patients. Given patients with hemoglobinopathies are at increased risk for osteoporosis, clinicians should maintain a higher index of suspicion when diagnosing low bone mass.

The Answer is Vitamin D! From Pediatrics to Geriatrics in Orthopaedics.

Vitamin D is necessary for the regulation of calcium and phosphate in the human body. Decreased vitamin D levels can alter the bone mineralization process. The prevalence of vitamin D deficiency in the general population is high, and low vitamin D levels are associated with disorders such as rickets and osteoporosis. As knowledge about vitamin D metabolism increases, physicians of all specialties are becoming more attentive to the vitamin D status of their patients. Similarly, orthopaedic surgeons, through various initiatives such as "Own the Bone," are making greater efforts to medically manage skeletal disorders. Unfortunately, universal guidelines for the optimization of vitamin D levels have not been adopted by orthopaedic surgeons, and, despite substantial efforts, vitamin D is not an integral part of most orthopaedic residency training programs. Although this may be partially attributed to attitudes among orthopaedic surgeons, the large number of vitamin D recommendations in the literature may be confusing and require substantial effort to synthesize into a viable approach for a given patient. Despite this confusion, orthopaedic surgeons should understand how to diagnose and manage disorders related to vitamin D and calcium deficiency.

Dietary nonheme iron is equally bioavailable from ferritin or ferrous sulfate in thalassemia intermedia.

Transfusion-independent patients with thalassemia intermedia (TI) develop fatal iron overload from excessive iron absorption triggered by ineffective erythropoiesis. More information about iron pharmacokinetics and nonheme, dietary iron absorption in such patients is needed to optimize management. To obtain more information, different forms of supplemental nonheme iron sources (ferritin and ferrous sulfate) were compared in 4 TI (hemoglobin <9 g/dL) and 6 control (hemoglobin 12-16 g/dL) patients. Serial serum iron concentrations were measured during the 24 hours following consumption of 1 mg/kg of elemental iron as ferritin or ferrous sulfate. Serum iron concentrations were also measured for one TI patient and one control patient 2 hours after the ingestion of 2 mg/kg of dietary iron in ferritin or ferrous sulfate. Maximum serum iron concentrations were observed 4 hours after the consumption of either dietary iron source. However, the serum iron values were unchanged for either dietary iron source, even at the higher doses of consumed iron. Thus, the bioavailability of dietary iron, either as ferritin or ferrous sulfate, was equivalent in both groups of patients. The pilot data support ferritin as an alternative dietary iron supplement to ferrous sulfate. ABBREVIATIONS: CRP C-reactive protein; Hb hemoglobin; IDA iron-deficient anemia; ICP inductively coupled plasma; IE ineffective erythropoiesis; SCD sickle cell disease; sTf transferrin saturation; TI thalassemia intermedia; TIBC total iron binding capacity; TM thalassemia major; Tf transferrin.

Effects of early vitamin D deficiency rickets on bone and dental health, growth and immunity.

Vitamin D deficiency is associated with adverse health outcomes, including impaired bone growth, gingival inflammation and increased risk for autoimmune disease, but the relationship between vitamin D deficiency rickets in childhood and long-term health has not been studied. In this study, we assessed the effect of early vitamin D deficiency on growth, bone density, dental health and immune function in later childhood to determine if children previously diagnosed with rickets were at greater risk of adverse health outcomes compared with healthy children. We measured serum 25-hydroxyvitamin D, calcium, parathyroid hormone, bone mineral density, anthropometric measures, dietary habits, dental health, general health history, and markers of inflammation in 14 previously diagnosed rickets case children at Children's Hospital Oakland Research Center. We compared the findings in the rickets cases with 11 healthy children selected from the population of CHO staff families. Fourteen mothers of the rickets cases, five siblings of the rickets cases, and seven mothers of healthy children also participated. Children diagnosed with vitamin D deficiency rickets had a greater risk of fracture, greater prevalence of asthma, and more dental enamel defects compared with healthy children. Given the widespread actions of vitamin D, it is likely that early-life vitamin D deficiency may increase the risk of disease later in childhood. Further assessment of the long-term health effects of early deficiency is necessary to make appropriate dietary recommendations for infants at risk of deficiency.

Guidelines for the Standard Monitoring of Patients With Thalassemia: Report of the Thalassemia Longitudinal Cohort.

Chronic transfusion therapy has played a central role in extending life expectancy for patients with hemoglobinopathies such as thalassemia. However, this life-saving therapy is associated with numerous complications that now comprise the bulk of management considerations for patients with thalassemia. This review reports on the experience of the Thalassemia Longitudinal Cohort and reviews available literature to establish guidelines for the management of patients with thalassemia.

Relationships among Physical Activity, Pain, and Bone Health in Youth and Adults with Thalassemia: An Observational Study.

Patients with thalassemia (Thal) engage in less physical activity than non-Thal populations, which may contribute to pain and osteoporosis. The purpose of this study was to assess relationships between physical activity, pain, and low bone mass in a contemporary sample of patients with Thal. Seventy-one patients with Thal (50 adults ≥18 years, 61% male, 82% transfusion-dependent) completed the Brief Pain Inventory Short Form and validated physical activity questionnaires for youth and adults. Nearly half of the patients reported daily somatic pain. Using multiple regression, after controlling for age and gender, sedentary behavior was positively associated with pain severity (p = 0.017, r 2 = 0.28). Only 37% of adult participants met CDC recommendations for physical activity. Spine BMD Z-score was higher (-2.1 ± 0.7) in those who met activity guidelines compared to those who did not (-2.8 ± 1.2, p = 0.048). A positive relationship was observed between self-reported physical activity (hours/week) and hip BMD Z-score in adults with Thal after controlling for transfusion status and sedentary activity time (p = 0.009, r 2 = 0.25). These results suggest that decreased physical activity and increased sedentary behavior contribute to low bone mass, which may be related to pain severity in some patients with Thal. Studies focused on increasing physical activity may contribute to improved bone health and reduced pain in patients with Thal.

Rapid remineralization of the distal radius after forearm fracture in children.

BACKGROUND: Bone mineral content (BMC) and density (BMD) have been shown to diminish after fracture and immobilization in adults. Distal radius fractures are common in children, and unlike adults, there is a low incidence of refracture. The primary aim of this study was to assess the change in radial BMC and BMD after upper extremity fracture and casting in healthy pediatric patients. METHODS: Patients were recruited at the time of distal radius fractures casting. The nonfractured (non-Fx) distal radius was initially scanned by dual energy x-ray absorptiometry (baseline), and then both arms were scanned at the time of cast removal (CastOff), and 4, 8, 12, 24, and 52 weeks post CastOff. RESULTS: Twenty-one patients were enrolled (13 male, 13 Caucasian; 10.4±2.5 y) with an average length of casting of 38±11 days. Eighteen patients (86%) completed all protocol requirements. At CastOff, there was no significant difference in total BMC or BMD between the Fx and non-Fx arms. From CastOff to 24 weeks, the overall change in BMC and BMD for the non-Fx arm was +4.2% and +0.2%, respectively, whereas for the Fx arm, the change was +8.3% and +3.4%, respectively. By 24 weeks, the difference in the overall change in BMD between the Fx and non-Fx arms was statistically significant (greater than instrumental error; P<0.05). However, by 52 weeks, these differences were no longer significant. The increased mineralization was unrelated to age, sex, arm dominance, or calcium intake. CONCLUSIONS: These data show that there is rapid remineralization after a simple forearm fracture in children, with a transient elevation in BMD in the Fx arm after casting. This novel finding suggests that bone may be stronger around the site of fracture and could significantly change how we counsel young patients recovering from forearm fracture. Future research should focus on children immobilized for varying lengths of time and those with repeat fractures, using volumetric techniques of bone geometry and strength assessment. CASE SERIES: Therapeutic Studies-investigating the results of treatment, Level IV.

Success of Distance Learning During 2020 COVID-19 Restrictions: A Report from Five STEM Training Programs for Underrepresented High School and Undergraduate Learners.

In 2020, STEM training programs across the country were challenged to provide support to students during a nation-wide shutdown of research institutions in response to the COVID-19 pandemic. Five U.S. high school science internship programs funded by the Doris Duke Charitable Foundation, with a history of collaboration, developed innovative strategies for distance-learning (DL) opportunities during the pandemic. Forty under-represented high school and undergraduate students were paired with scientific mentors at one of the programs for a DL scientific internship. Summer training combined synchronous and asynchronous programming with research projects adapted for DL success. Ninety-five percent of students who participated were satisfied with the training experience, nearly identical to exit survey responses from 2019 when our programs were held in-person. More students were interested in pursuing a career in research at the end of the program and credited the DL experience with increasing interest in research careers. Some DL elements were ideal for underrepresented youth, including a more flexible schedule and elimination of cost and time for travel. While the lack of in-person instruction challenged our ability to create a strong student community, we found that preparation, communication, and flexibility were key elements to these successful DL programs. The increased emphasis on interpretation and analysis of data, rather than data collection, enhanced student learning. This manuscript highlights the changes made to our curricula, elements which were most successful, and recommends strategies for future distance-learning programming.

Biomarkers for prediction of skeletal disease progression in mucopolysaccharidosis type I.

BACKGROUND: Orthopedic disease progresses in mucopolysaccharidosis type I (MPS I), even with approved therapies and remains a major factor in persistent suffering and disability. Novel therapies and accurate predictors of response are needed. The primary objective of this study was to identify surrogate biomarkers of future change in orthopedic disease. METHODS: As part of a 9-year observational study of MPS I, range-of-motion (ROM), height, pelvic radiographs were measured annually. Biomarkers in year 1 were compared to healthy controls. Linear regression tested for associations of change in biomarkers over the first year with change in long-term outcomes. RESULTS: MPS I participants (N = 19) were age 5 to 16 years and on average 6.9 ± 2.9 years post treatment initiation. Healthy controls (N = 51) were age 9 to 17 years. Plasma IL-1ß, TNF-α, osteocalcin, pyridinolines, and deoxypyridinolines were higher in MPS than controls. Within MPS, progression of hip dysplasia was present in 46% to 77%. A 1 pg/mL increase in IL-6 was associated with -22°/year change in ROM (-28 to -15; P < .001), a 20 nmol/mmol creatinine/year increase in urine PYD was associated with a -0.024 Z-score/year change in height Z-score (-0.043 to -0.005; P = .016), and a 20 nmol/mmol creatinine/year increase in urine PYD was associated with a -2.0%/year change in hip dysplasia measured by Reimers migration index (-3.8 to -0.1; P = .037). CONCLUSIONS: Inflammatory cytokines are high in MPS I. IL-6 and PYD were associated with progression in joint contracture, short stature, and hip dysplasia over time. Once validated, these biomarkers may prove useful for predicting response to treatment of skeletal disease in MPS I.

Relationship between chronic transfusion therapy and body composition in subjects with thalassemia.

OBJECTIVE: To measure body composition in patients with thalassemia and explore its relationship to abnormal growth and bone mass. STUDY DESIGN: We conducted a cross-sectional, multicenter study. Fat, lean, and bone mineral density (BMD) were assessed with dual-energy x-ray absorptiometry. Medical history, food frequency, and physical activity questionnaires were conducted in 257 transfused patients with thalassemia (age, 23.7+/-11 years [mean+/-SD]; 51% male) compared with 113 non-transfused patients (21.3+/-13 years; 44% male). RESULTS: Subjects with thalassemia were leaner compared with healthy American subjects from National Health and Nutrition Examination Survey III data. Transfused subjects had a higher percentage of body fat compared with non-transfused subjects after controlling for age, sex, and ethnicity; 11.8% of non-transfused pediatric subjects were considered underweight, significantly lower than National Health and Nutrition Examination Survey data (P=.03). Hemoglobin level was positively related to lean mass (P=.008). Body fat and lean mass were positive predictors for both height and BMD z-scores after adjustment for transfusion status, age, sex, ethnicity, calcium intake, and physical activity (all P<.001). CONCLUSION: Although most adult patients with thalassemia had healthy body composition with rare obesity, young non-transfused patients appear at risk for being underweight. Optimizing physical activity and appropriate use of transfusion therapy may improve growth and bone health in these patients who are at-risk for being underweight.

Dual-energy X-ray absorptiometry with serum ferritin predicts liver iron concentration and changes in concentration better than ferritin alone.

Accurate assessment of liver iron concentration (LIC) is critical for optimal monitoring of iron toxicity in multitransfused patients. Serum ferritin is the most widely used although its association to LIC is only modest. We studied if a liver-specific measure using dual-energy X-ray absorptiometry (DXA) systems could improve LIC estimates over ferritin alone in Thalassemia (Thal) patients. Thirty-seven patients with Thal (19.2 ± 9.0 yr, 20 male) were studied and 10 had multiple visits. Height, weight, ferritin, whole-body DXA, and hepatic superconducting quantum interference device (SQUID) were measured within 5 wk. DXA hepatic density was measured using right rib, whole liver, and multiple subliver regions. The best agreement to SQUID LIC was found using a combination of ferritin, weight, DXA subliver region 3 bone mineral content (BMC), and right rib BMC. DXA with ferritin improved the ferritin alone correlation from R(2)=0.35 to R(2)=0.62. Serial LIC changes using DXA were associated with serial SQUID changes (r=0.73, p=0.02). Changes in ferritin alone were not significant (p=0.06). We conclude that the addition of whole-body DXA measures and body weight substantially increased the accuracy of LIC and change in LIC estimates over the use of ferritin alone and could be useful when magnetic resonance imaging or SQUID is not available.

Differences in the prevalence of growth, endocrine and vitamin D abnormalities among the various thalassaemia syndromes in North America.

This study aimed to determine differences in the rates of growth, endocrine- and calcium-related abnormalities in the various thalassemia syndromes in North America treated with current therapies. Medical history, physical examinations and blood and urine collections were obtained from patients with all thalassemia syndromes age 6 years and older in the Thalassemia Clinical Research Network. 361 subjects, 49% male, mean age 23.2 years (range 6.1-75 years) were studied. Approximately 25% of children and adults, regardless of the thalassemia syndrome, had short stature. Overall growth in children was mildly affected. Final height was close to midparental height (z = -0.73 +/- 1.24). Patients with beta thalassemia major (TM) had higher rates of hypogonadism, multiple endocrinopathies, worse hyperglycaemia, subclinical hypoparathyroidism and hypercalciuria. Hypogonadism remained the most frequent endocrinopathy and was frequently under-treated. 12.8% of the subjects had 25 vitamin D concentrations less than 27 nmol/l and 82% less than 75 nmol/l, regardless of the thalassemia syndrome. Adolescents had lower 25 vitamin D levels than children and adults. Compared to patients with other thalassemia syndromes, those with beta TM suffered from higher rates of multiple endocrinopathies, abnormal calcium metabolism and hypercalciuria. Vitamin D abnormalities were high among adolescents.

Effect of prenatal calcium supplementation on bone during pregnancy and 1 y postpartum.

Background: Low calcium intake during pregnancy may cause maternal skeletal calcium mobilization to meet fetal needs. The Recommended Dietary Allowance (RDA) for calcium in nonpregnant, pregnant, or lactating women aged 19-50 y is 1000 mg/d; most women in the United States report consuming 60-80% of the calcium RDA. An insufficient calcium intake could increase maternal bone loss during pregnancy and reduce bone recovery postpartum. Objectives: The aim of this study was to determine the effect of maternal calcium supplementation on peripheral cortical and trabecular bone loss during pregnancy and bone gain postpartum. Methods: A total of 64 women were enrolled in the study at 16 wk of gestation and randomly assigned to receive 1000 mg Ca/d or placebo for the remainder of the pregnancy. Measurements were performed at 16, 26, and 36 wk of pregnancy and at 4 and 12 mo postpartum for serum 25-hydroxyvitamin D and markers of bone turnover. Trabecular and cortical bone mineral density (BMD) and content were assessed at the tibia and radius by peripheral quantitative computed tomography. Results: Mean ± SD daily calcium intake at baseline was 733 ± 350 mg; only 25% of the women met the RDA. Thirty women (47% of those enrolled) remained in the study at 12 mo postpartum. After controlling for baseline bone value, serum 25-hydroxyvitamin D concentrations, length of breastfeeding, and body mass index, the calcium group had significantly greater increases in radial total BMD (P = 0.02) and tibial cortical BMD (P = 0.03) at 12 mo postpartum than the placebo group. Trabecular and total BMD at the tibia trended toward higher values (P < 0.06) in the calcium group than in the placebo group in the same models. Conclusions: These data show that supplemental calcium provided during pregnancy may improve bone recovery postpartum in women consuming a typical US diet. A larger study is warranted to solidify the conclusions. This trial was registered at clinicaltrials.gov as NCT01145573.