Recurrence of bilateral atypical femoral fractures associated with the sequential use of teriparatide and denosumab: a case report.

We report that a postmenopausal woman with osteoporosis developed bilateral incomplete atypical femoral fractures (AFFs) after seven years of bisphosphonate therapy. Cessation of the bisphosphonate and treatment with teriparatide was associated with near complete radiological resolution of the AFFs. After 12 months without treatment, denosumab was commenced to prevent structural deterioration. Six months later she developed recurrent bilateral AFFs. This case highlights the management dilemma in patients with ongoing bone loss but prone to stress fractures associated with antiresorptive therapy. Stopping the antiresorptive is recommended but structural decay will recur predisposing to fragility fractures. If the antiresorptive is continued, bone material composition will be further compromised predisposing to atypical fractures. Teriparatide may assist healing of stress fractures and improvement in bone matrix composition. Later antiresosrptive therapy to preserve bone microstructure may compromise material composition.

Proteinase-activated receptor-2 is required for normal osteoblast and osteoclast differentiation during skeletal growth and repair.

Proteinase-activated receptor-2 (PAR(2)) is a G-protein coupled receptor expressed by osteoblasts and monocytes. PAR(2) is activated by a number of proteinases including coagulation factors and proteinases released by inflammatory cells. The aim of the current study was to investigate the role of PAR(2) in skeletal growth and repair using wild type (WT) and PAR(2) knockout (KO) mice. Micro computed tomography and histomorphometry were used to examine the structure of tibias isolated from uninjured mice at 50 and 90 days of age, and from 98-day-old mice in a bone repair model in which a hole had been drilled through the tibias. Bone marrow was cultured and investigated for the presence of osteoblast precursors (alkaline phosphatase-positive fibroblastic colonies), and osteoclasts were counted in cultures treated with M-CSF and RANKL. Polymerase chain reaction (PCR) was used to determine which proteinases that activate PAR(2) are expressed in bone marrow. Regulation of PAR(2) expression in primary calvarial osteoblasts from WT mice was investigated by quantitative PCR. Cortical and trabecular bone volumes were significantly greater in the tibias of PAR(2) KO mice than in those of WT mice at 50 days of age. In trabecular bone, osteoclast surface, osteoblast surface and osteoid volume were significantly lower in KO than in WT mice. Bone marrow cultures from KO mice showed significantly fewer alkaline phosphatase-positive colony-forming units and osteoclasts compared to cultures from WT mice. Significantly less new bone and significantly fewer osteoclasts were observed in the drill sites of PAR(2) KO mice compared to WT mice 7 days post-surgery. A number of activators of PAR(2), including matriptase and kallikrein 4, were found to be expressed by normal bone marrow. Parathyroid hormone, 1,25 dihydroxyvitamin D(3), or interleukin-6 in combination with its soluble receptor down-regulated PAR(2) mRNA expression, and fibroblast growth factor-2 or thrombin stimulated PAR(2) expression. These results suggest that PAR(2) activation contributes to determination of cells of both osteoblast and osteoclast lineages within bone marrow, and thereby participates in the regulation of skeletal growth and bone repair.

The spinal curvature irregularity index independently identifies vertebral fractures.

INTRODUCTION AND HYPOTHESIS: The spinal curvature irregularity index (SCII) is a quantitative measure of the irregularity of the spinal curvature. We evaluated the predictive ability of SCII to identify subjects with vertebral fractures (VF). METHODS: Vertebral heights were measured by quantitative vertebral morphometry in 461 Lebanese women 20-89 years of age and VFs were ascertained by the grade 1 Eastell method. SCII scores were log-transformed and expressed as Z-SCII, the number of standard deviations above or below the mean ln(SCII) of young patients without VF. Univariate and multivariate binary logistic regression models were used to identify clinical predictors of VF. RESULTS: Women with a higher SCII were more likely to have prevalent VF. A higher SCII was associated with a greater prevalence of VF within each category of femoral neck BMD (normal, osteopenia, osteoporosis). In univariate analysis, predictors of VF included Z-SCII (odds ratio, OR: 2.21, 95% CI: 1.80-2.71) and femoral neck T-score (OR: 1.35, 95% CI: 1.12-1.63). In multivariate analysis, predictors of VF were: Z-SCII (OR: 1.54, 95% CI: 1.02-2.32), femoral neck T-score (OR: 1.41, 95% CI: 1.11-1.78) and age(3) (OR: 1.40, 95% CI 1.10-1.82). At a cutoff SCII of 9.5%, the sensitivity and specificity of SCII for VF were 71 and 64% respectively, and higher SCII cutoffs identified VFs with greater specificity. CONCLUSION: The SCII is a robust, simple and independent indicator of the presence of VFs.

Calcitriol does not prevent bone loss in patients with asthma receiving corticosteroid therapy: a double-blind placebo-controlled trial.

INTRODUCTION: Oral glucocorticoid therapy reduces bone mineral density (BMD) and increases fracture risk. It is uncertain whether inhaled glucocorticoids, the most commonly used long-term therapy for asthma, have a similar effect. If bone loss does occur, it is unclear whether this is preventable by calcitriol. Patients with asthma receiving inhalational plus intermittent oral glucocorticoids lose bone, and treatment with 0.5 microg/day of calcitriol will prevent bone loss. METHODS: A 2-year randomized double-blind placebo-controlled trial. One hundred eight patients with asthma were stratified by gender, age, and inhaled glucocorticoid dose and treated with calcitriol (n=55) or placebo (n=53). There were 41 men (mean age 53.2+/-1.7 years) and 67 women (mean age 49.1+/-1 years) with moderate to severe asthma (requiring >/=800 microg/day of beclomethasone dipropionate or equivalent maintenance therapy). BMD values at the lumbar spine (LS) and femoral neck (FN) were measured at baseline and at 6, 12, and 24 months using dual x-ray absorptiometry. RESULTS: Changes in LS and FN BMD. Bone loss occurred in both groups at the FN (both p<0.03) and at the LS in the calcitriol (p<0.001), but not the control, group. Bone loss was not less in the calcitriol group at either site. CONCLUSION: Patients with asthma receiving inhalational plus intermittent short courses of oral glucocorticoids lose bone. Calcitriol is unlikely to be appropriate therapy against this bone loss.