The diabetes-fracture association in women with type 1 and type 2 diabetes is partially mediated by falls: a 15-year longitudinal study.

This study evaluated mediators of fracture risk in postmenopausal women with type 1 (T1D) and type 2 diabetes (T2D), over a 15-year follow-up period. This study provides evidence that the increased fracture risk in women with T1D or T2D is partially explained by falls. Furthermore, a shorter reproductive lifespan in women with T1D contributes modestly to fracture risk in this cohort. PURPOSE: Skeletal fragility is associated with diabetes mellitus, while limited estrogen exposure during the reproductive years also predisposes to lower bone mass and higher fracture risk. We aimed to determine osteoporosis diagnosis, fall and fracture rates in women with type 1 (T1D) and type 2 (T2D) diabetes mellitus, and explore mediators of the diabetes-fracture relationship. METHODS: Prospective observational data drawn from the Australian Longitudinal Study in Women's Health (ALSWH) from 1996 to 2010. Women were randomly selected from the national health insurance database. Standardized data collection occurred at six survey time points, with main outcome measures being self-reported osteoporosis, incident fracture, falls, and reproductive lifespan. Mediation analyses were performed to elucidate relevant intermediaries in the diabetes-fracture relationship. RESULTS: Exactly 11,313 women were included at baseline (T1D, n = 107; T2D, n = 333; controls, n = 10,873). A total of 885 new cases of osteoporosis and 1099 incident fractures were reported over 15 years. Women with T1D or T2D reported more falls and fall-related injuries; additionally, women with T1D had a shorter reproductive lifespan. While fracture risk was increased in women with diabetes (T1D: OR 2.28, 95% CI 1.53-3.40; T2D: OR 2.40, 95% CI 1.90-3.03), compared with controls, adjustment for falls attenuated the risk of fracture by 10% and 6% in T1D and T2D, respectively. In women with T1D, reproductive lifespan modestly attenuated fracture risk by 4%. CONCLUSION: Women with T1D and T2D have an increased risk of fracture, which may be partially explained by increased falls, and to a lesser extent by shorter reproductive lifespan, in T1D.

New insights into the diagnosis and management of bone health in premature ovarian insufficiency.

Premature ovarian insufficiency (POI), defined as a loss of ovarian function before the age of 40 years, is a life-changing diagnosis that has numerous long-term consequences. Musculoskeletal complications, including osteoporosis and fractures, are a key concern for women with POI. The risk of bone loss is influenced by the underlying etiology of POI, and the degree and duration of estrogen deficiency. A decline in muscle mass as a result of estrogen and androgen deficiency may contribute to skeletal fragility, but has not been examined in women with POI. This article aims to review musculoskeletal health in POI; summarize the traditional and novel modalities available to screen for skeletal fragility and muscle dysfunction; and provide updated evidence for available management strategies.

Fractures in spina bifida from childhood to young adulthood.

This study assessed the prevalence and types of fractures in spina bifida and examined risk factors for fracture. Fracture prevalence was highest in childhood and reduced in adolescence and young adulthood. The importance of maintaining mobility is highlighted by the increased risk of fracture in those who are non-ambulatory. INTRODUCTION: The aims of this study are to study the prevalence and types of fractures according to age group in spina bifida and examine risk factors associated with fracture. METHODS: This is a retrospective cohort study of 146 individuals with spina bifida aged 2 years or older who attended the paediatric or adult spina bifida multidisciplinary clinic at a single tertiary hospital. RESULTS: Median age at which first fracture occurred was 7 years (interquartile range 4-13 years). Fracture rates in children (ages 2-10), adolescents (ages 11-18) and adults (age > 18) were 10.9/1000 (95 % confidence interval 5.9-18.3), 5.4/1000 (95 % CI 1.5-13.8) and 2.9/1000 (95 % CI 0.6-8.1) patient years respectively. Childhood fractures predominantly involved the distal femur and femoral shaft; these fractures were rarely seen in adulthood. Non-ambulatory status was associated with a 9.8 times higher risk of fracture compared with ambulatory patients (odds ratio 9.8, p = 0.016, 95 % CI 1.5-63.0). Relative risk of re-fracture was 3.1 (95 % CI 1.4-6.8). Urological intervention with intestinal segments was associated with renal calculi (p = 0.037) but neither was associated with fracture. CONCLUSIONS: The risk of fracture is lower in adults compared with children with spina bifida. The predominant childhood fracture affects the distal femur, and immobility is the most significant risk factor for fracture. Clinical factors contributing to fracture risk need to be elucidated to enable selection of patients who require investigation and treatment of osteoporosis.

Delay in estrogen commencement is associated with lower bone mineral density in Turner syndrome.

OBJECTIVE: Turner syndrome (TS) is associated with hypogonadism, osteoporosis and fractures. We investigated the prevalence and risk factors for low bone density and fractures in a TS cohort. METHODS: We included 76 TS patients (median age 28.5 years) attending a tertiary hospital between 1998 and 2015 who underwent dual-energy X-ray absorptiometry. Spine and femoral neck (FN) areal bone mineral density (aBMD) were compared with those of a control group. To adjust for smaller bone size, bone mineral apparent density (BMAD) was calculated. RESULTS: Primary amenorrhea was common (83%) in the TS cohort; the median age of pubertal induction was 15 years (range 11-30 years), and non-continuous estrogen therapy (ET) recorded in 40%. Almost one-third of TS patients reported fractures. TS patients had lower median spinal aBMD (1.026 g/cm2 vs. 1.221 g/cm2) and BMAD (0.156 g/cm3 vs. 0.161 g/cm3) than controls, and lower median FN aBMD (0.850 g/cm2 vs. 1.026 g/cm2) (all p < 0.01). More women with TS had spinal Z-score < -2.0 compared to controls (26.0% vs. 3.6%, p = 0.001). Spine and FN aBMD, BMAD and Z-scores were inversely associated with age commencing ET or years of estrogen deficiency. CONCLUSIONS: Delay in ET commencement was an independent risk factor for the lower bone density observed in women with TS. Early pubertal induction and ET compliance are important targets to optimize aBMD.

Management of bone disease in women after breast cancer.

Breast cancer and osteoporosis are common conditions affecting women, particularly following menopause. With increasing breast cancer incidence, effects of therapies and decreasing mortality, issues relating to the preservation of bone health with breast cancer therapy have become a priority. Contributing factors to bone loss and fractures in women with breast cancer include tumor effects, estrogen deprivation secondary to breast cancer therapies (chemotherapy, ovarian ablation or aromatase inhibitors), natural menopause and secondary causes of bone loss, typically from concurrently prescribed medications. Management of osteoporosis and other survivorship care is complex, and a multi-disciplinary approach is recommended with assessment of risk factors for bone loss, optimization of bone health through lifestyle approaches and pharmacological interventions based on evidence-based algorithms. This review examines the pathophysiology of bone loss and gives guidelines for the management of bone disease in women with breast cancer.

The effect of gonadal status on body composition and bone mineral density in transfusion-dependent thalassemia.

UNLABELLED: Patients with transfusion-dependent thalassemia have abnormal growth, hormonal deficits, and increased bone loss. We investigated the relationship between skeletal muscle mass, fat mass, and bone mineral density in adult subjects with transfusion-dependent thalassemia based on their gonadal status. Our findings show that hypogonadism attenuates the strength of the muscle-bone relationship in males but strengthens the positive correlation of skeletal muscle mass and fat mass in female subjects. INTRODUCTION: Transfusion-dependent thalassemia is associated with a high prevalence of fractures. Multiple hormonal complications, in particular hypogonadism, can lead to changes in body composition and bone mineral density (BMD). We investigated for the first time the relationship between skeletal muscle mass (SMM), fat mass, and BMD in adult subjects with transfusion-dependent thalassemia based on their gonadal status. METHODS: A retrospective cohort study of 186 adults with transfusion-dependent thalassemia was analyzed. Body composition and BMD were measured using dual energy X-ray absorptiometry. The association between skeletal muscle, fat, and BMD was investigated through uni-, multi-, and stepwise regression analyses after adjusting for multicollinearity. SMM was derived using the formula, SMM = 1.19 × ALST-1.65, where ALST is equivalent to the sum of both arm and leg lean tissue mass. RESULTS: There were 186 subjects, males (43.5 %) and females (56.5 %), with a median age of 36.5. Hypogonadism was reported in 44.4 % of males and 44.7 % of females. SMM and BMD were positively correlated and strongest in eugonadal males (0.36 ≤ R (2) ≤ 0.59), but the association was attenuated in hypogonadal males. SMM (0.27 ≤ R (2) ≤ 0.69) and total fat mass (0.26 ≤ R (2) ≤ 0.55) were positively correlated with BMD in hypogonadal females, but the correlation was less pronounced in eugonadal females. Leg lean tissue mass and arm lean tissue mass in males and females, respectively, were most highly correlated to BMD in the stepwise regression analysis. CONCLUSION: Hypogonadism attenuates the strength of the muscle-bone relationship in males but strengthens the positive correlation of skeletal muscle mass and fat mass in female subjects. This study supports the notion that exercise is important for maintaining BMD and the need to optimize treatment of hypogonadism in patients with transfusion-dependent thalassemia.

Thalassemia bone disease: the association between nephrolithiasis, bone mineral density and fractures.

UNLABELLED: Thalassemia bone disease is well described, but the prevalence of nephrolithiasis has not been characterized. The association between nephrolithiasis, reduced bone density, and increased fractures has been demonstrated through this retrospective study of 166 participants with transfusion-dependent thalassemia. The findings support the need for increased vigilance of kidney and bone disease in this cohort. INTRODUCTION: Previous studies have revealed that thalassemia is associated with reduced bone mineral density (BMD) and fractures. Many causes are implicated including hypogonadism, growth hormone deficiency, marrow expansion, and iron overload. Nephrolithiasis is associated with reduced BMD and increased fractures in the general population. However, the prevalence of nephrolithiasis and its association with bone density and fractures have not been characterized in thalassemia. METHODS: We have addressed this question by performing a retrospective cohort study of 166 participants with transfusion-dependent thalassemia who had undergone dual-energy X-ray absorptiometry between 2009 and 2011. Logistic regression modeling was used to adjust for potential confounders. RESULTS: We found a high prevalence of kidney stones (18.1 %) which was greater in males compared to females (28.7 vs 9.7 %, respectively). Renal stones were associated with reduced femoral neck Z-score and fractures in men after adjusting for potential confounders. These results indicate that nephrolithiasis is highly prevalent in patients with transfusion-dependent thalassemia and is significantly associated with reduced BMD and increased fractures. CONCLUSIONS: The findings from this study strongly support the need for ongoing surveillance of BMD, fractures, and nephrolithiasis in the management of transfusion-dependent thalassemia.

Trabecular bone score in adults with cerebral palsy.

CONTEXT: Bone fragility in cerebral palsy (CP) is secondary to a complex interplay of functional, hormonal, and nutritional factors that affect bone remodelling. A greater understanding of bone microarchitectural changes seen in CP should assist therapeutic decision making. OBJECTIVE: To examine the relationship between trabecular bone score (TBS), BMD and fractures in adults with CP; the influence of clinical factors and body composition on bone microarchitecture were explored. DESIGN: Retrospective cross-sectional study. SETTING AND PARTICIPANTS: 43 adults (25 male) with CP of median age 25 years (interquartile range 21.4-33.9) who had evaluable dual-energy X-ray absorptiometry imaging of the lumbar spine from a single tertiary hospital between 2005-March 2018. RESULTS: 24/43 (55.8%) of patients had TBS values indicating intermediate or high risk of fracture (<1.31). TBS correlated with areal BMD at the lumbar spine, femoral neck and total body. TBS was significantly associated with arm and leg lean mass, with adjustment for age, gender and height (adjusted R2 = 0.18, p = 0.042 for arm lean mass; adjusted R2 = 0.19, p = 0.036 for leg lean mass). There was no difference in TBS when patients were grouped by fracture status, anticonvulsant use, gonadal status or use of PEG feeding. TBS was lower in non-ambulatory patients compared with ambulatory patients (1.28 vs 1.37, p = 0.019). CONCLUSIONS: Abnormal bone microarchitecture, as measured by TBS, was seen in >50% of young adults with CP. TBS correlated with both areal BMD and appendicular lean mass. Maintaining muscle function is likely to be important for bone health in young adults with CP and needs to be confirmed in further studies.

Musculoskeletal and Endocrine Health in Adults With Cerebral Palsy: New Opportunities for Intervention.

CONTEXT: Cerebral palsy (CP) increases fracture risk through diminished ambulation, nutritional deficiencies, and anticonvulsant medication use. Studies examining bone mineral density (BMD) in adults with CP are limited. OBJECTIVE: To examine the relationship between body composition, BMD, and fractures in adults with CP. The effect of functional, nutritional, and endocrine factors on BMD and body composition is also explored. DESIGN: Retrospective cross-sectional study. SETTING AND PARTICIPANTS: Forty-five adults with CP (mean age, 28.3 ± 11.0 years) who had dual-energy x-ray absorptiometry imaging at a single tertiary hospital between 2005 and 2015. RESULTS: Seventeen (38%) had a past history of fragility fracture; 43% had a Z-score of ≤ -2.0 at the lumbar spine (LS) and 41% at the femoral neck (FN). In nonambulatory patients, every one unit decrease in FN Z-score increased the risk of fracture 3.2-fold (95% confidence interval, 1.07-9.70; P = .044). Stepwise linear regression revealed that the Gross Motor Function Classification System was the best predictor of LS Z-score (R(2) = 0.550; ß = -0.582; P = .002) and FN Z-score (R(2) = 0.428; ß = -0.494; P = .004); 35.7% of the variance in BMD was accounted for by lean tissue mass. Hypogonadism, present in 20% of patients, was associated with reduced lean tissue mass and reduced LS BMD. Lean tissue mass positively correlated with BMD in eugonadal patients, but not in hypogonadal patients. CONCLUSIONS: Low BMD and fractures are common in adults with CP. This is the first study to document hypogonadism in adults with CP with detrimental changes in body composition and BMD.

Management of hypoparathyroidism in pregnancy and lactation - A report of 10 cases.

INTRODUCTION: Hypoparathyroidism in pregnancy is rare, but important, as it is associated with maternal morbidity and foetal loss. There are limited case reports and no established management guidelines. Optimal maintenance of calcium levels during pregnancy is required to minimise the risk of related complications. This study aims to identify causes and examine outcomes of hypoparathyroidism in pregnancy in a cohort of women delivering at a large referral centre. DESIGN AND METHOD: The Monash Health maternity service database captures pregnancy and birthing outcomes in over 9000 women each year. We audited this database between 2000 and 2014 to examine the clinical course, treatment and outcomes of pregnant women with hypoparathyroidism. RESULTS: We identified 10 pregnancies from 6 women with pre-existing hypoparathyroidism secondary to idiopathic hypoparathyroidism (n = 3), autosomal dominant branchial arch disorder with hypoparathyroidism (n = 3) and autosomal dominant hypocalcaemia (n = 1), surgery for thyroid cancer (n = 2) and Graves' disease (n = 1). Maternal calcium levels were monitored through pregnancy and management adjusted to maintain normocalcaemia. One woman was delivered by caesarean section at 34 weeks' gestation because of intrauterine growth restriction, and oligohydramnios complicated two other pregnancies. The postpartum period was complicated by severe hypercalcaemia in one woman and by symptomatic, labile serum calcium levels during lactation in another woman, requiring close monitoring over a 6 month period. CONCLUSION: Although rare, hypoparathyroidism in pregnancy poses a management challenge for clinicians, and co-ordinated care is required by obstetricians and endocrinologists to ensure optimal outcomes for both mother and baby. Continued monitoring of maternal calcium levels during lactation and weaning is essential to avoid the potential complications of either hypercalcaemia or hypocalcaemia.

Prolonged hypocalcemia following denosumab therapy in metastatic hormone refractory prostate cancer.

Prostate cancer is a leading cause of cancer death, frequently associated with widespread bone metastases. We report two cases of hypocalcemia following the first dose of denosumab in metastatic hormone refractory prostate cancer, the first case requiring 26 days of intravenous calcium therapy. This is the first report of prolonged hypocalcemia following denosumab in a patient with normal renal function.

Vascular dysfunction and autonomic neuropathy in Type 2 diabetes.

AIMS: To test the hypothesis that arterial dysfunction in Type 2 diabetes is related to autonomic neuropathy. METHODS: Arterial function and autonomic neuropathy were assessed over two consecutive days in 45 Type 2 diabetic and control subjects. Systemic arterial compliance (SAC), arterial stiffness (pulse-wave velocity, PWV) and carotid intima thickness (IMT) were assessed; these markers reflect early vascular disease and predict clinical vascular events. Autonomic neuropathy was assessed using heart rate variability with continuous ECG recording during various breathing and postural manoeuvres and an overall autonomic score was generated. Fasting metabolic parameters including glucose, insulin, HbA(1c) and lipid profile were measured. RESULTS: Autonomic neuropathy tests were all repeatable in diabetic subjects. Compared with controls, diabetic subjects had arterial dysfunction with increased PWV (P = 0.009), IMT (P < 0.001) and reduced SAC (P = 0.053). After adjustment for age, central PWV correlated with fasting insulin (r(2) = 0.45, P < 0.05) and autonomic score (r(2) = 0.44, P < 0.05), peripheral PWV correlated with autonomic score (r(2) = 0.51, P < 0.005) and IMT correlated with fasting insulin (r(2) = 0.5, P < 0.005). The presence of autonomic neuropathy correlated with fasting insulin (P = 0.015), but not age, duration diabetes, lipids or blood pressure. CONCLUSION: Using repeatable measures of autonomic neuropathy and vascular function in Type 2 diabetic subjects, we have demonstrated associations between autonomic neuropathy, vascular dysfunction and hyperinsulinaemia. This may help to explain the excess cardiovascular mortality seen in diabetic subjects with autonomic neuropathy.