Search

Objective: Determine if LLP2A-Ale or PTH (1–34) affects the prevalence of glucocorticoid-induced osteonecrosis (ON) in a mouse model. Methods: Eight-week-old young adult male BALB/cJ mice were weight-randomized into Control (Con), glucocorticoid (GC)-only, or concurrent treatments with GC and LLP2A-Ale (250 μg/kg or 500 μg/kg, IV, Days 1, 14, 28) or parathyroid hormone hPTH (1–34) (40 μg/kg, 5×/week). Mice were necropsied after 45 days for qualitative evaluation of prevalent ON and quantitative evaluation of vascularity in the distal femoral epiphysis (DFE); and quantitative evaluation of bone mass, microarchitecture, and strength in the distal femoral metaphysis and lumbar vertebral body. Results: The prevalence of ON was 14% in the Con group and 36% in the GC-only group (P = 0.07). The prevalence of ON did not differ among GC-only, GC + LLP2A-Ale, and GC + PTH groups. GC-only mice had significantly lower trabecular and cortical bone strength than Con, while GC + LLP2A-Ale (500 μg/kg) and GC + PTH (1–34) groups had significantly greater trabecular bone strength than the GC-only group. GC + LLP2A-Ale (250 μg/kg and 500 μg/kg) and GC + PTH had significantly higher trabecular bone volume than GC-only mice at the vertebrae, distal femoral epiphyses and distal femoral metaphyses. DFE vascularity was lower in GC-only mice than in all other groups. Conclusion: Neither LLP2A-Ale nor hPTH (1–34) reduced the prevalence of GC-induced ON, compared to GC-only mice. However, GC-treated mice given LLP2A-Ale or hPTH (1–34) had better bone mass, microarchitecture, and strength in trabecular-rich regions, and higher levels of vascularity than GC-only mice. Keywords: hPTH (1–34), LLP2A-Ale, Distal femoral epiphysis, Dexamethasone, Prevention

ABSTRACT Glucocorticoids increase bone fragility in patients in a manner that is underestimated by bone mass measurement. This study aimed to determine if the adult mouse could model this bone strength/bone mass discrepancy. Forty‐two 13‐week‐old BALB/cJ mice were randomized into vehicle and glucocorticoid groups, implanted with vehicle or 6‐methylprednisolone pellets, and necropsied after 60 and 120 days. Bone strength and bone mass/microarchitecture were assessed at the right central femur (CF; cortical‐bone–rich) and sixth lumbar vertebral body (LVB6; trabecular‐bone–rich). Bound water (BW) of the whole right femur was analyzed by proton‐nuclear magnetic resonance (1H‐NMR) relaxometry. Data were analyzed by two‐factor ANOVA with time (day 60 and day 120) and treatment (vehicle and glucocorticoid) as main effects for all data. Significant interactions were further analyzed with a Tukey's post hoc test. Most bone strength measures in the CF were lower in the glucocorticoid group, regardless of the duration of treatment, with no time × treatment interaction. However, bone mass measures in the CF showed a significant time × treatment interaction (p = 0.0001). Bone strength measures in LVB6 showed a time × treatment interaction (p

Though osteoporosis is a significant cause of disability worldwide, treatment with pharmacologic agents decreases risk of fragility fracture. Though these treatments act through the bone remodeling system to improve bone mass, it is unclear if they alter the response of bone to mechanical loading at the level of the osteocyte. This pre-clinical study determined the relationship between microstructural bone tissue properties and osteocyte lacunar size and density to strain around osteocytes with standard osteoporosis treatment or sequential therapies. Six-month-old female ovariectomized (OVX) Sprague-Dawley rats were cycled through various sequences of pharmacological treatments [alendronate (Aln), raloxifene (Ral) and human parathyroid hormone-1,34 (PTH)] for three month intervals, over nine months. Linear nanoindentation mapping was used to determine Young's modulus in perilacunar and bone matrix regions around cortical bone osteocyte lacunae. Measurements of lacunar diameter and density were completed. Treatment-related differences in Young's modulus in the perilacunar and bone matrix regions were not observed. We confirmed previous data that showed that the bone matrix region was stiffer than the perilacunar matrix region. Whole bone material properties were correlated to perilacunar matrix stiffness. Finite element models predicted a range of mechanical strain amplification factors estimated at the osteocyte across treatment groups. In summary, though the perilacunar matrix near cortical osteocyte lacuna is not as stiff as bone matrix further away, osteoporosis treatment agents do not affect the stiffness of bone tissue near osteocyte lacunae. Keywords: Lacuna, Nanoindentation, Finite element model, Sequential treatment, PTH(1-34), Alendronate, Raloxifene