Further complicating matters is that although
Further complicating matters is that although menopause can increase serum BTMs, other normal physiological conditions, certain disease states, and drugs are also associated with elevated BTM concentrations [81–83]. Low body-mass index (BMI) is a risk factor for low bone density  and evidence has shown that women with low BMIs have higher BTM levels consistent with elevated bone resorption under these conditions . Alcoholism and smoking are also associated with elevated BTMs [81,82]. There is a diurnal variation in bone turnover too, with peak rates of turnover in the early morning with subsequent elevated serum BTMs at these times .
Conclusion Overall, despite extensive pre-clinical and clinical rationale for the benefits of adjuvant bone-targeted therapies, the results of the adjuvant trials have not met expectations. Indeed, the multiple deficiencies of the animal models used in this setting have led authors to question their validity as pre-clinical models for patient studies . Given the thousands of patients enrolled on these studies this is clearly disappointing and the results from studies prospectively designed and powered to show adjuvant benefit on the whole have been resoundingly negative. Similar to the situation with any targeted agent such as endocrine therapy or trastuzumab-based studies, it is important to identify whether or not a population of patients exists within the main study population that might derive greater benefit from the treatment. Although the data presented to date suggest enhanced benefit in post-menopausal patients or those with a so called “low gaba receptor environment”, definitive studies supporting this are lacking. Linking bone, adjuvant BPs and the estrogen environment could lead to the development of a unifying hypothesis to explain the results of different trials and to help us target appropriate patients in the future. Unfortunately, no randomized control studies in this population are currently planned, and anticipated results from the remaining studies SWOG 0307, D-CARE study and NATAN trial will not be able to formally answer the question of the role of estrogen in response to adjuvant bone-targeted therapy. While groups will likely continue to publish meta-analyses of the published data  we eagerly await the results of the Oxford overview analysis of individual patient data to see if we can tease out whether estrogen levels play a role in the efficacy of bone-targeted therapies in adjuvant breast cancer treatment.
Conflict of interest
Introduction Two comprehensive reviews have addressed total lung irradiation (TLI) in patients with metastases from osteo- and Ewing\'s sarcoma [1,2]; a technique that has been used for decades and presented in textbooks [3,4]. Such radiotherapy involves parallel opposing anteroposterior/posterioranterior fields encompassing the apices and distal costo-phrenic sinuses of both thoracic cavities. The two lungs may be treated simultaneously or sequentially. Several non-randomized studies have been reported [5–7]. Bilateral lung irradiation might, theoretically, combat micrometastases within the lungs and subsequently prevent overt metastases to develop. We have not identified studies adequately addressing whether TLI might benefit patients with macroscopic metastases. Radiation pneumonitis was first described in 1922 by Groover et al. . To our knowledge, the literature lacks information about lethal toxicity following such treatment. The tolerance of the lungs to radiation depends on the volume treated, total dose and dose per fraction [9,10]. Lung tissues poorly tolerate high-dose irradiation . The fundamental problem with TLI is that pulmonary parenchymal tolerance to radiation is exceeded before sound tumoricidal doses are achieved . During treatment planning, the general recommendation is to not exceed a total dose of 18–20Gy in 1.5–2.0Gy daily fractions administered over 2 weeks in order to respect lung tolerance . For children and young adults under the age of 15 the standard total dose is 15Gy.