Lars Hyldstrup

BACKGROUND: Mortality is increased after a hip fracture, and strategies that improve outcomes are needed. METHODS: In this randomized, double-blind, placebo-controlled trial, 1065 patients were assigned to receive yearly intravenous zoledronic acid (at a dose of 5 mg), and 1062 patients were assigned to receive placebo. The infusions were first administered within 90 days after surgical repair of a hip fracture. All patients (mean age, 74.5 years) received supplemental vitamin D and calcium. The median follow-up was 1.9 years. The primary end point was a new clinical fracture. RESULTS: The rates of any new clinical fracture were 8.6% in the zoledronic acid group and 13.9% in the placebo group, a 35% risk reduction with zoledronic acid (P=0.001); the respective rates of a new clinical vertebral fracture were 1.7% and 3.8% (P=0.02), and the respective rates of new nonvertebral fractures were 7.6% and 10.7% (P=0.03). In the safety analysis, 101 of 1054 patients in the zoledronic acid group (9.6%) and 141 of 1057 patients in the placebo group (13.3%) died, a reduction of 28% in deaths from any cause in the zoledronic acid group (P=0.01). The most frequent adverse events in patients receiving zoledronic acid were pyrexia, myalgia, and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported, and no adverse effects on the healing of fractures were noted. The rates of renal and cardiovascular adverse events, including atrial fibrillation and stroke, were similar in the two groups. CONCLUSIONS: An annual infusion of zoledronic acid within 90 days after repair of a low-trauma hip fracture was associated with a reduction in the rate of new clinical fractures and with improved survival. (ClinicalTrials.gov number, NCT00046254 [ClinicalTrials.gov].).

A non-invasive evaluation of bone metabolism was performed in 44 morbidly obese patients before and after a mean weight loss of 22.4 kg (range 7.9–43.4 kg) after 2 months and a further weight loss of 7.3 kg after 8 months (0.8–20.0 kg). This weight reduction was obtained by a nutritionally adequate very-low-calorie diet. Before treatment the bone mineral content of the distal forearm was increased compared to normals (51.9 U vs 43.7 U, p<0.001). Bone formation was evaluated by serum alkaline phosphatase and serum osteocalcin. Serum alkaline phosphatase was increased (187.8 U/l vs 147.4 U/l, p<0.001) while serum osteocalcin was lower than in the controls (0.67 nmol/l vs 0.98 nmol/l, p<0.01). Bone resorption, as measured by the urinary hydroxyproline/creatinine ratio, was not increased in the obese patients (19.2 molar ratio × 10 −3 vs 16.7 molar ratio × 10 −3 , NS). After 2 months, the bone mineral content had declined by 3.3%. Serum alkaline phosphatase remained unchanged (187.8 U/l vs 186.9 U/l, NS) but serum osteocalcin demonstrated a significant rise (3.94 nmol/l vs 10.53 nmol/l, p<0.001), parallel to changes in the hydroxyproline/creatinine ratio (19.2 molar ratio × 10 −3 vs 25.2 molar ratio × 10 −3 , p<0.001). At 8 months, no further change in the bone mineral content was seen. The hydroxyproline/creatinine ratio did still increase (from 25.8 molar ratio × 10 −3 to 30.1 molar ratio × 10 −3 , p<0.05), while serum alkaline phosphatase and serum osteocalcin remained unchanged. In conclusion, the bone mineral content is increased in morbid obesity. During weight loss obtained by a very-low-calorie diet supplying the recommended amounts of vitamin D and minerals, bone resorption is increased rapidly and bone mass reduced. Owing to linkage of bone remodelling processes, bone formation increases with a longer observation period and the bone mineral content is stabilized.