Enzyme replacement therapy (ERT) for murine hypophosphatasia

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Abstracts / Bone 44 (2009) S18–S55

goal of reducing pain and improving quality of life. We performed a randomized trial to assess its efficacy and safety. Methods: Patients with up to 3 acute vertebral fractures were randomly assigned to kyphoplasty (N = 149) or nonsurgical care (N = 151). The intervention was not blinded. The primary outcome was the difference in the SF-36 physical component summary at 1 month. Quality of life measurements and spine radiographs were assessed through 12 months. Results: Subjects randomized to kyphoplasty had greater improvement than controls in the SF-36 physical component summary (difference 5.2 points on a 0–100 scale; 95% confidence interval [CI], 2.9–7.4; p < 0.001) at 1 month; the difference was 1.5 (95% CI, −0.8– 3.8; p = 0.2) at 12 months. Kyphoplasty improved quality of life by the 1-point EuroQol questionnaire at one (0.18 point; 95% CI, 0.08– 0.28; p < 0.001) and twelve (0.12; 95% CI, 0.01–0.22; p = 0.025) months and back function by the 24-point Roland–Morris scale at one (4.0 points; 95% CI, 2.6–5.5; p < 0.001) and twelve (2.6; 95% CI, 1.0– 4.1; p = 0.001) months. Kyphoplasty patients reported fewer days with limited activity, less back pain, and less use of analgesics or walking aids. Two serious adverse events, a soft tissue hematoma and a post-operative urinary tract infection, were attributed to kyphoplasty. The frequency of new vertebral fractures did not differ significantly between kyphoplasty (33.0%) and nonsurgical (25.3%) groups (7.7% difference; 95% CI −4.5–20.0; p = 0.22). Two-year data will be available prior to the meeting and will be presented. Conclusion: Among patients with acute vertebral fractures, balloon kyphoplasty improved quality of life, reduced back pain and disability and decreased pain medication and walking aid usage. Most of these improvements last at least 1 year without increasing adverse events or new vertebral fractures. doi:10.1016/j.bone.2009.01.136

099 Enzyme replacement therapy (ERT) for murine hypophosphatasia J.L. Millana, I. Lemireb, S. Narisawaa, T.P. Loiselb, G. Boileauc, P. Leonardb, M.D. McKeed, P. Crineb, M.P. Whytee Sanford Children's Health Research Center, Burnham Institute, La Jolla, California, United States Enobia Pharma, Inc, Montreal, Quebec, Canada University of Montreal, Montreal, Quebec, Canada McGill University, Montreal, Quebec, Canada Shriners Hospitals for Children and Washington University, St. Louis, Missouri, United States Hypophosphatasia (HPP) is the inborn-error-of-metabolism that features rickets or osteomalacia due to loss-of-function mutation(s) within the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNALP). Consequently, natural substrates for this ectoenzyme accumulate extracellulary including inorganic pyrophosphate (PPi), an inhibitor of mineralization, and pyridoxal 5′-phosphate (PLP), a cofactor form of vitamin B6. Babies with the infantile form of HPP often die with severe rickets and sometimes hypercalcemia and vitamin B6-responsive seizures. There is no established medical treatment. We bio-engineered human TNALP with a C-terminus extended by the Fc region of human IgG for onestep purification, and a deca-aspartate sequence (D10) for targeting to mineralizing tissue (sALP-FcD10). TNALP null mice (Akp2−/−), an excellent model for infantile HPP, were treated from birth using sALP-FcD10. Short-term and long-term efficacy studies consisted of once daily s.c. injections of 1, 2, or 8.2 mg/kg sALP-FcD10 for 15, 19, and 15 or 52 days, respectively. We evaluated survival and growth rates, circulating levels of sALP-FcD10 activity, calcium, PPi, and pyridoxal, as well as skeletal and dental manifestations using

radiography, μCT, and histomorphometry. Akp2−/− mice receiving high-dose sALP-FcD10 grew normally and appeared well without skeletal or dental disease or epilepsy. Plasma calcium, PPi, and pyridoxal concentrations remained in their normal ranges. We found no evidence of significant skeletal or dental disease and concluded that ERT with this bone-targeted form of TNALP prevents all the manifestations of infantile HPP (Millán et al., JBMR 23: 777– 787, 2008). Subsequent dose response studies yielded a positive correlation between administered dose and 75% survival and mineralization improvement in the hind limbs. Longer dosing intervals with bone-targeted TNALP can be used to prevent the appearance of the mineralization defects and improve survival in the Akp2−/− mouse model of HPP. We also assessed rescuing overt disease by starting treatments at day 12 or 15 of life when the clinical manifestations of HPP were evident. ERT could also rescue Akp2−/− mice with advanced disease. Dosing less frequently than daily could also increase survival. Clinical trials administering bonetargeted TNALP to infants with HPP are now underway. doi:10.1016/j.bone.2009.01.137

100 Association between hyperglycemia and fracture risk in non-diabetic middle-aged and older Australians: A national, population based prospective study (AusDiab) C. Gagnona, D.J. Maglianob, P.R. Ebelinga, D.W. Dunstanb, P.Z. Zimmetb, J.E. Shawb, R.M. Dalya Department of Medicine, The University of Melbourne, Western Hospital, Melbourne, VIC, Australia Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia Purpose: The relationship between type 2 diabetes mellitus (DM) and fracture risk is controversial; even less is known about the relationship between impaired glucose tolerance and fracture risk. The primary aim of this study was to examine the association between plasma glucose (PG) and insulin levels, and fracture risk in non-diabetic middle-aged and older Australians. The secondary aim was to assess whether fracture risk was increased in people with prediabetes [impaired glucose tolerance (IGT) or impaired fasting glucose (IFG)]. Methods: This national, population-based prospective study undertaken in 1999/2000 (AusDiab) with a follow-up of 5 years included 6255 men and women aged ≥40 years (mean ± SD; 56.2 ± 11.0) with normal glycemia (NGT, n = 4855) and pre-diabetes (IFG and IGT, n = 1400) determined from an OGTT (1999 WHO criteria) at baseline. People with diagnosed type 2 DM were excluded. Non-traumatic clinical fractures (e.g. fall from a standing height) were self reported at follow-up and used to calculate incident fracture data. Results: Overall, 318 (5.1%) of the participants suffered at least one non-traumatic fracture (women 7.4%; men 2.2%). After adjusting for age, BMI and smoking, having a 2-h PG ≥ 8.29 mmol/L (highest quartile) were significantly associated with a decreased risk of fracture in women [OR 0.62 (95% CI 0.42, 0.92)], but not men (see Figure). These results remained unchanged after adjusting for fasting insulin, physical activity, or previous history of low trauma fracture. Similar results were observed when the analyses were repeated with 2-h PG as a continuous variable. However, no significant associations were found for fracture risk and quartiles of fasting PG or insulin. Logistic regression analysis also revealed that compared with women with NGT, there was a trend for those with pre-diabetes to have a reduced fracture risk after adjusting for age, BMI and smoking [OR 0.72 (95% CI 0.51, 1.01)]. Conclusion: Increased 2-h PG levels and pre-diabetes appeared to be protective against non-traumatic clinical fractures in non-diabetic