Bone alterations associated with HIV.

HIV infection and initiation of antiretroviral therapy (ART) have been consistently associated with decreased bone mineral density (BMD), with growing evidence linking HIV to an increased risk of fracture. This is especially concerning with the expanding number of older persons living with HIV. Interestingly, recent data suggest that HIV-infected children and youth fail to achieve peak BMD, possibly increasing their lifetime risk of fracture. Elucidating the causes of the bone changes in HIV-positive persons is challenging because of the multifactorial nature of bone disease in HIV, including contribution of the virus, immunosuppression, ART toxicity, and traditional osteoporosis risk factors, such as age, lower weight, tobacco, and alcohol use. Thus, practitioners must recognize the risk of low BMD and fractures and appropriately screen patients for osteoporosis if risk factors exist. If fractures do occur or elevated fracture risk is detected through screening, treatment with bisphosphonate medications appears safe and effective in the HIV+population.

Molecular mechanism of thiazolidinedione-mediated inhibitory effects on osteoclastogenesis.

Thiazolidinediones are synthetic peroxisome proliferator-activated receptor γ agonists used to treat type 2 diabetes mellitus. Clinical evidence indicates that thiazolidinediones increase fracture risks in type 2 diabetes mellitus patients, but the mechanism by which thiazolidinediones augment fracture risks is not fully understood. Several groups recently demonstrated that thiazolidinediones stimulate osteoclast formation, thus proposing that thiazolidinediones induce bone loss in part by prompting osteoclastogenesis. However, numerous other studies showed that thiazolidinediones inhibit osteoclast formation. Moreover, the molecular mechanism by which thiazolidinediones modulate osteoclastogenesis is not fully understood. Here we independently address the role of thiazolidinediones in osteoclastogenesis in vitro and furthermore investigate the molecular mechanism underlying the in vitro effects of thiazolidinediones on osteoclastogenesis. Our in vitro data indicate that thiazolidinediones dose-dependently inhibit osteoclastogenesis from bone marrow macrophages, but the inhibitory effect is considerably reduced when bone marrow macrophages are pretreated with RANKL. In vitro mechanistic studies reveal that thiazolidinediones inhibit osteoclastogenesis not by impairing RANKL-induced activation of the NF-κB, JNK, p38 and ERK pathways in bone marrow macrophages. Nonetheless, thiazolidinediones inhibit osteoclastogenesis by suppressing RANKL-induced expression of NFATc1 and c-Fos, two key transcriptional regulators of osteoclastogenesis, in bone marrow macrophages. In addition, thiazolidinediones inhibit the RANKL-induced expression of osteoclast genes encoding matrix metalloproteinase 9, cathepsin K, tartrate-resistant acid phosphatase and carbonic anhydrase II in bone marrow macrophages. However, the ability of thiazolidinediones to inhibit the expression of NFATc1, c-Fos and the four osteoclast genes is notably weakened in RANKL-pretreated bone marrow macrophages. These in vitro studies have not only independently demonstrated that thiazolidinediones exert inhibitory effects on osteoclastogenesis but have also revealed crucial new insights into the molecular mechanism by which thiazolidinediones inhibit osteoclastogenesis.

Effect of self-referral on bone mineral density testing and osteoporosis treatment.

BACKGROUND: Despite national guidelines recommending bone mineral density screening with dual-energy x-ray absorptiometry (DXA) in women aged 65 years and older, many women do not receive initial screening. OBJECTIVE: To determine the effectiveness of health system and patient-level interventions designed to increase appropriate DXA testing and osteoporosis treatment through (1) an invitation to self-refer for DXA (self-referral); (2) self-referral plus patient educational materials; and (3) usual care (UC, physician referral). RESEARCH DESIGN: Parallel, group-randomized, controlled trials performed at Kaiser Permanente Northwest (KPNW) and Kaiser Permanente Georgia (KPG). SUBJECTS: Women aged 65 years and older without a DXA in past 5 years. MEASURES: DXA completion rates 90 days after intervention mailing and osteoporosis medication receipt 180 days after initial intervention mailing. RESULTS: From >12,000 eligible women, those randomized to self-referral were significantly more likely to receive a DXA than UC (13.0%-24.1% self-referral vs. 4.9%-5.9% UC, P<0.05). DXA rates did not significantly increase with patient educational materials. Osteoporosis was detected in a greater proportion of self-referral women compared with UC (P<0.001). The number needed to receive an invitation to result in a DXA in KPNW and KPG regions was approximately 5 and 12, respectively. New osteoporosis prescription rates were low (0.8%-3.4%) but significantly greater among self-referral versus UC in KPNW. CONCLUSIONS: DXA rates significantly improved with a mailed invitation to schedule a scan without physician referral. Providing women the opportunity to self-refer may be an effective, low-cost strategy to increase access for recommended osteoporosis screening.

Osteoporosis diagnosis and medical treatment.

Osteoporosis, the presence of either low bone mineral density or a history of a fragility fracture, is known to be associated with an increased risk of future fracture. Fracture prevention is possible through use of both nonpharmacologic and prescription treatments. Despite recent controversy regarding the safety of calcium supplementation and the appropriate dosing of calcium and vitamin D, calcium and vitamin D remain an important part of bone health. However, prescription osteoporosis treatments should be considered for those at higher risk for fracture, and there are currently several treatment options available.

A randomized trial of a mailed intervention and self-scheduling to improve osteoporosis screening in postmenopausal women.

Guidelines recommend bone density screening with dual-energy X-ray absorptiometry (DXA) in women 65 years or older, but <30% of eligible women undergo DXA testing. There is a need to identify a systematic, effective, and generalizable way to improve osteoporosis screening. A group randomized, controlled trial of women ≥65 years old with no DXA in the past 4 years, randomized to receive intervention materials (patient osteoporosis brochure and a letter explaining how to self-schedule a DXA scan) versus usual care (control) was undertaken. Outcome of interest was DXA completion. Of 2997 women meeting inclusion criteria, 977 were randomized to the intervention group. A total of 17.3% of women in the intervention group completed a DXA, compared to 5.2% in the control group (12.1% difference, p < 0.0001). When including only those medically appropriate, we found a difference of 19% between the two groups (p < 0.0001). DXA receipt was greater in main clinic patients compared to satellite clinic patients (20.9% main clinic versus 10.1% satellite clinic). The cost to print and mail the intervention was $0.79 per patient, per mailing. The number of women to whom intervention needed to be mailed to yield one extra DXA performed was 9, at a cost of $7.11. DXA scan completion was significantly improved through use of a mailed osteoporosis brochure and the availability for patients to self-schedule. This simple approach may be an effective component of a multifaceted quality improvement program to increase rates of osteoporosis screening.