Somewhat paradoxically, fracture risk, which depends on applied loads and bone strength, is elevated in both anorexia nervosa and obesity at certain skeletal sites. Factor-of-risk (Φ), the ratio of applied load to bone strength, is a biomechanically-based method to estimate fracture risk; theoretically, higher Φ reflects increased fracture risk. We estimated vertebral strength [linear combination of integral volumetric BMD (Int.vBMD) and cross-sectional area from QCT], vertebral compressive loads, and Φ at L4 in 176 women (65 anorexia nervosa, 45 lean controls, 66 obese). Using biomechanical models, applied loads were estimated for: 1) standing; 2) arms flexed 90°, holding 5 kg in each hand (holding); 3) 45° trunk flexion, 5 kg in each hand (lifting); 4) 20° trunk right lateral bend, 10 kg in right hand (bending). We also investigated associations of Int.vBMD and vertebral strength with lean mass (from DXA) and visceral adipose tissue (VAT, from QCT). Women with anorexia nervosa had lower, whereas obese women had similar, Int.vBMD and estimated vertebral strength compared to controls. Vertebral loads were highest in obesity and lowest in anorexia nervosa for standing, holding, and lifting (p<0.0001), but were highest in anorexia nervosa for bending (p<0.02). Obese women had highest Φ for standing and lifting, whereas women with anorexia nervosa had highest Φ for bending (p<0.0001). Obese and anorexia nervosa subjects had higher Φ for holding than controls (p<0.03). Int.vBMD and estimated vertebral strength were associated positively with lean mass (R= 0.28–0.45, p≤0.0001) in all groups combined, and negatively with VAT (R= −[0.36–0.38], p<0.003) within obese group. Therefore, women with anorexia nervosa had higher estimated vertebral fracture risk (Φ) for holding and bending, due to inferior vertebral strength. Despite similar vertebral strength as controls, obese women had higher vertebral fracture risk for standing, holding, and lifting, due to higher applied loads from higher body weight. Examining the load-to-strength ratio helps explain increased fracture risk in both low-weight and obese women.

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Anorexia nervosa is complicated by low bone mineral density (BMD) and increased fracture risk associated with low bone formation and high bone resorption. The lumbar spine is most severely affected. Low bone formation is associated with relative insulin‐like growth factor 1 (IGF‐1) deficiency. Our objective was to determine whether bone anabolic therapy with recombinant human (rh) IGF‐1 used off‐label followed by antiresorptive therapy with risedronate would increase BMD more than risedronate or placebo in women with anorexia nervosa. We conducted a 12‐month, randomized, placebo‐controlled study of 90 ambulatory women with anorexia nervosa and low areal BMD (aBMD). Participants were randomized to three groups: 6 months of rhIGF‐1 followed by 6 months of risedronate (“rhIGF‐1/Risedronate”) (n = 33), 12 months of risedronate (“Risedronate”) (n = 33), or double placebo (“Placebo”) (n = 16). Outcome measures were lumbar spine (1° endpoint: postero‐anterior [PA] spine), hip, and radius aBMD by dual‐energy X‐ray absorptiometry (DXA), and vertebral, tibial, and radial volumetric BMD (vBMD) and estimated strength by high‐resolution peripheral quantitative computed tomography (HR‐pCT) (for extremity measurements) and multi‐detector computed tomography (for vertebral measurements). At baseline, mean age, body mass index (BMI), aBMD, and vBMD were similar among groups. At 12 months, mean PA lumbar spine aBMD was higher in the rhIGF‐1/Risedronate (p = 0.03) group and trended toward being higher in the Risedronate group than Placebo. Mean lateral lumbar spine aBMD was higher, in the rhIGF‐1/Risedronate than the Risedronate or Placebo groups (p < 0.05). Vertebral vBMD was higher, and estimated strength trended toward being higher, in the rhIGF‐1/Risedronate than Placebo group (p < 0.05). Neither hip or radial aBMD or vBMD, nor radial or tibial estimated strength, differed among groups. rhIGF‐1 was well tolerated. Therefore, sequential therapy with rhIGF‐1 followed by risedronate increased lateral lumbar spine aBMD more than risedronate or placebo. Strategies that are anabolic and antiresorptive to bone may be effective at increasing BMD in women with anorexia nervosa. © 2021 American Society for Bone and Mineral Research (ASBMR).