High prevalence of lipoatrophy in pre-pubertal South African children on antiretroviral therapy: a cross-sectional study.

BACKGROUND: Despite changes in WHO guidelines, stavudine is still used extensively for treatment of pediatric HIV in the developing world. Lipoatrophy in sub-Saharan African children can be stigmatizing and have far-reaching consequences. The severity and extent of lipoatrophy in pre-pubertal children living in sub-Saharan Africa is unknown. METHODS: In this cross-sectional study, children who were 3-12 years old, on antiretroviral therapy and pre-pubertal were recruited from a Family HIV Clinic in South Africa. Lipoatrophy was identified and graded by consensus between two HIV pediatricians using a standardized grading scale. A professional dietician performed formal dietary assessment and anthropometric measurements of trunk and limb fat. Previous antiretroviral exposures were recorded. In a Dual-Energy X-ray Absorbtiometry (DXA) substudy body composition was determined in 42 participants. RESULTS: Among 100 recruits, the prevalence of visually obvious lipoatrophy was 36% (95% CI: 27%-45%). Anthropometry and DXA measurements corroborated the clinical diagnosis of lipoatrophy: Both confirmed significant, substantial extremity fat loss in children with visually obvious lipoatrophy, when adjusted for age and sex. Adjusted odds ratio for developing lipoatrophy was 1.9 (95% CI: 1.3 - 2.9) for each additional year of accumulated exposure to standard dose stavudine. Cumulative time on standard dose stavudine was significantly associated with reductions in biceps and triceps skin-fold thickness (p=0.008). CONCLUSIONS: The prevalence of visually obvious lipoatrophy in pre-pubertal South African children on antiretroviral therapy is high. The amount of stavudine that children are exposed to needs review. Resources are needed to enable low-and-middle-income countries to provide suitable pediatric-formulated alternatives to stavudine-based pediatric regimens. The standard stavudine dose for children may need to be reduced. Diagnosis of lipoatrophy at an early stage is important to allow timeous antiretroviral switching to arrest progression and avoid stigmatization. Diagnosis using visual grading requires training and experience, and DXA and comprehensive anthropometry are not commonly available. A simple objective screening tool is needed to identify early lipoatrophy in resource-limited settings where specialized skills and equipment are not available.

MKP-1 knockout does not prevent glucocorticoid-induced bone disease in mice.

Glucocorticoid-induced osteoporosis (GCOP) is predominantly caused by inhibition of bone formation, resulting from a decrease in osteoblast numbers. Employing mouse (MBA-15.4) and human (MG-63) osteoblast cell lines, we previously found that the glucocorticoid (GC) dexamethasone (Dex) inhibits cellular proliferation as well as activation of the MAPK/ERK signaling pathway, essential for mitogenesis in these cells, and that both these effects could be reversed by the protein tyrosine phosphatase (PTP) inhibitor vanadate. In a rat model of GCOP, the GC-induced changes in bone formation, mass, and strength could be prevented by vanadate cotreatment, suggesting that the GC effects on bone were mediated by one or more PTPs. Employing phosphatase inhibitors, qRT-PCR, Western blotting, and overexpression/knockdown experiments, we concluded that MKP-1 was upregulated by Dex, that this correlated with the dephosphorylation of ERK, and that it largely mediated the in vitro effects of GCs on bone. To confirm the pivotal role of MKP-1 in vivo, we investigated the effects of the GC methylprednisolone on the quantitative bone histology of wild-type (WT) and MKP-1 homozygous knockout (MKP-1(-/-)) mice. In WT mice, static bone histology revealed that GC administration for 28 days decreased osteoid surfaces, volumes, and osteoblast numbers. Dynamic histology, following time-spaced tetracycline labeling, confirmed a significant GC-induced reduction in osteoblast appositional rate and bone formation rate. However, identical results were obtained in MKP-1 knockout mice, suggesting that in these animals upregulation of MKP-1 by GCs cannot be regarded as the sole mediator of the GC effects on bone.

Prevalence of Sarcopenia in Older South African Patients Following Surgery for Fragility Fractures of the Hip.

INTRODUCTION: Geriatric patients with a fragility fracture of the hip (FFH) are especially prone to sarcopenia with poor functional outcomes and quality of life. We assessed the prevalence of sarcopenia in older South African patients with FFH. Risk factors for sarcopenia were also investigated. MATERIALS AND METHODS: From August 1 to November 30, 2018, all older patients with FFH were invited to participate. Sarcopenia was diagnosed based on the revised criteria of the European Working Group on Sarcopenia in Older People (EWGSOP2). Handgrip strength (HGS) and muscle strength were assessed. Muscle quantity was determined by dual-energy X-ray absorptiometry. Demographic information was collected, and 25-hydroxyvitamin D (25[OH]D) status was determined. RESULTS: Of the 100 hip fracture cases, 65 were enrolled, and 52% (34/65) were sarcopenic (women: 62%; men: 38%). HGS accurately identified sarcopenia (sensitivity and specificity: 100%). Patients >80 years of age had a prevalence of sarcopenia twice (18/21 [83%]) that of younger patients (18/44 [36%]). Women with sarcopenia were smaller than those without (weight: p < 0.001; height: p < 0.001; body mass index: p = 0.018). Low 25(OH)D was almost universally present, with median 25(OH)D levels significantly lower in the patients with sarcopenia (27 nmol/L [interquartile range {IQR}: 20-39] vs. 40 nmol/L [IQR: 29-53]). Several risk factors, including advanced age; female sex; a smaller body size, especially among women; limited physical activity; and low 25(OH)D levels, were identified. DISCUSSION: The accuracy of HGS testing in this cohort underscores EWGSOP2's recommendation that muscle strength is key to sarcopenia. Further study and follow-up are required to determine the clinical relevance of sarcopenia among FFH patients. CONCLUSION: The prevalence of sarcopenia in our FFH population is high. Sarcopenia is associated with poor patient outcomes following surgical intervention. Orthopaedic surgeons should therefore be cognizant of the presentation and associated risk of sarcopenia as our patient populations age.

CYP19A1 rs10046 Pharmacogenetics in Postmenopausal Breast Cancer Patients Treated with Aromatase Inhibitors: One-year Follow-up.

BACKGROUND: Significant individual variation in bone loss associated with aromatase inhibitors (AIs) emphasizes the importance of identifying postmenopausal breast cancer patients at high risk for this adverse effect. The study explores the clinical relevance of genetic variation in the Cytochrome P450 19A1 (CYP19A1) gene in a subset of South African patients during the first year of taking AIs for estrogen receptor (ER)-positive breast cancer. METHODS: The study population consisted of ER-positive breast cancer patients on AIs, followed in real-life clinical practice. Body mass index was measured and bone mineral density (BMD) was determined at baseline and at month 12. CYP19A1 genotyping was performed using real-time polymerase chain reaction analysis of rs10046, extended to Sanger sequencing and whole exome sequencing in 10 patients with more than 5% bone loss at month 12 at the lumbar spine. RESULTS: After 12 months of AI treatment, 72 patients had completed BMD and were successfully genotyped. Ten patients (14%) experienced more than 5% bone loss at the lumbar spine over the study period. Genotyping for CYP19A1 rs10046 revealed that patients with two copies of the A-allele were 10.79 times more likely to have an ordinal category change of having an increased percentage of bone loss or no increase at the lumbar spine, compared to patients with the GA or GG genotypes (CI of 1.771- 65.830, p=0.01). None of the 34 patients without lumbar spine bone loss at month 12 were homozygous for the functional CYP19A1 polymorphism. At the total hip region, patients with the AA genotype were 7. 37 times more likely to have an ordinal category change of having an increased percentage of bone loss or no increase (CI of 1.101- 49.336, p=0.04). CONCLUSION: Homozygosity for the CYP19A1 rs10046 A-allele may provide information, in addition to clinical and biochemical factors that may be considered in risk stratification to optimize bone health in postmenopausal breast cancer women on AIs. Further investigation is required to place the clinical effect observed for a single CYP19A1 gene variant in a genomic context.

Effect of rapamycin on hepatic osteodystrophy in rats with portasystemic shunting.

AIM: To study if T-cell activation related to portasystemic shunting causes osteoclast-mediated bone loss through RANKL-dependent pathways. We also investigated if T-cell inhibition using rapamycin would protect against bone loss in rats. METHODS: Portasystemic shunting was performed in male Sprague-Dawley rats and rapamycin 0.1 mg/kg was administered for 15 wk by gavage. Rats received powderized chow and supplemental feeds to prevent the effects of malnutrition on bone composition. Weight gain and growth was restored after surgery in shunted animals. At termination, biochemical parameters of bone turnover and quantitative bone histology were assessed. Markers of T-cell activation, inflammatory cytokine production, and RANKL-dependent pathways were measured. In addition, the roles of IGF-1 and hypogonadism were investigated. RESULTS: Portasystemic shunting caused low turnover osteoporosis that was RANKL independent. Bone resorbing cytokine levels, including IL-1, IL-6 and TNFalpha, were not increased in serum and TNFalpha and RANKL expression were not upregulated in PBMC. Portasystemic shunting increased the circulating CD8+ T-cell population. Rapamycin decreased the circulating CD8+ T-cell population, increased CD8+ CD25+ T-regulatory cell population and improved all parameters of bone turnover. CONCLUSION: Osteoporosis caused by portasystemic shunting may be partially ameliorated by rapamycin in the rat model of hepatic osteodystrophy.

Vertebral fracture prevalence in black and white South African women.

UNLABELLED: Black women are generally regarded as being less prone to the development of osteoporosis. This study reports a similar prevalence of morphometric vertebral fractures in black (9.1 %) and white (5.0 %) South African women. Clinical risk factors and bone strength parameters contributed differently to fracture risk in the two ethnic cohorts. PURPOSE: Vertebral fracture represents one of the most common osteoporotic fractures and is a significant cause of morbidity and mortality. Little is known regarding the prevalence of vertebral fractures on the African continent. We therefore prospectively examined the prevalence of vertebral fracture on radiographs of the thoraco-lumbar spine in otherwise healthy community-dwelling older black and white South African women. METHODS: Radiographs of the spine (T4-L5) were obtained randomly in 189 women (47 % black), aged 40 years or older, for the analysis of vertebral fracture. Radiographs were evaluated by a single radiologist, blinded to clinical data, using Genant's semi-quantitative method. Clinical risk factors for osteoporosis, risk factors for falls (fall history, quadriceps strength, lateral sway and reaction time), areal and volumetric bone mineral density of the spine and hip, calcaneal ultrasonography (QUS) and vertebral macro-geometry were assessed in the two ethnic groups and the association with prevalent vertebral fractures examined. RESULTS: Vertebral fracture prevalence in older South African black and white women was similar (9.1 % in black and 5.0 % in white women). In black women, lower body weight and lower areal and volumetric bone mineral density (BMD) at all sites could serve as markers of increased fracture risk. Older age, physical inactivity, lower muscle strength and lower femoral BMD were associated with vertebral fracture risk in whites. CONCLUSION: Our findings are noteworthy and the first attempt to compare vertebral fracture risk in women of different ethnicities on the African continent. A similar vertebral fracture risk between black and white women in South Africa must be considered at present to ensure appropriate evaluation in all subjects who present with clinical risk factors for osteoporosis, regardless of ethnicity.

Bone density in black and white South African women: contribution of ethnicity, body weight and lifestyle.

UNLABELLED: Ethnic differences in bone mineral density (BMD) between healthy adult black and white South African women were studied. Higher BMD was only noted at the femoral sites in black women. Body weight significantly impacted these findings. A lower fracture risk at all skeletal sites cannot be assumed in black South African (SA) women. PURPOSE: Bone mineral density (BMD) varies amongst women of different ethnicities. African-Americans have higher BMD at all skeletal sites compared with whites. On the African continent, bone density studies suggest site-specific ethnic differences in BMD. To examine the contribution of body weight and lifestyle characteristics to ethnic differences in BMD between adult black and white South African women, we assessed lumbar spine (SBMD), femoral neck (FNBMD) and total femoral BMD (FTBMD) by dual-energy X-ray absorptiometry (DXA) in 184 black and 143 white women aged between 23 and 82 years. METHODS: BMDs were compared amongst pre- and postmenopausal blacks and whites before and after adjustment for covariates with significant univariate association with BMD. Volumetric bone mineral apparent density (BMAD) of the spine and femoral neck was also calculated to account for ethnic differences in bone size. RESULTS: Before adjustment, SBMD was lower (p < 0.05), FTBMD similar and FNBMD (p < 0.01) higher in premenopausal black women. Similar SBMD, but significantly higher BMD at the femoral sites (p < 0.01), was noted in postmenopausal blacks compared with whites. Amongst anthropometric measures and lifestyle factors, only adjustment for weight significantly altered these observed ethnic differences in bone density. After adjustment for weight, SBMD remained lower in premenopausal blacks and became lower in young postmenopausal blacks. Weight adjustment eliminated all ethnic differences in proximal femoral BMD measurements, with the exception of FNBMD that remained higher in younger postmenopausal blacks. Before adjustment, calculated SBMAD was similar and FNBMAD consistently higher in blacks in all the menstrual groups. Adjustment for weight did not alter these findings. CONCLUSION: Most of the observed ethnic difference in BMD was explained by differences in body weight between black and white SA women. The higher femoral BMD in older blacks may explain, the lower hip fracture prevalence in black South African women. The lower SBMD in pre- and postmenopausal black women in this study suggests that factors other than BMD should be considered to explain a lower vertebral fracture prevalence in blacks, if a lower fracture prevalence does indeed exist.