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In recent years the great progress in knowledge on bone cell biology has allowed identification of molecular structures that can be targeted with pinpoint precision (druggable targets). Osteoclasts are regulated via the RANK-RANK-ligand (RANKL) signaling pathway and osteoblasts via the Wnt signaling pathway, both of which can be influenced for therapeutic measures. As a result the number of (functional) osteoclasts can be decreased or the genesis of osteoblasts can be increased and bone resorption is inhibited or bone formation is enhanced, respectively. Osteoclasts degrade collagen through cathepsin K and inactivation of this enzyme stabilizes the bone matrix; however, as osteoclasts are still able to maintain a stimulatory cross-talk with osteoblasts, formation of new bone will not be reduced. Parathyroid hormone-related protein plays a role in endochondral ossification and a synthetic analogue of this protein may have potent bone anabolic activity; however, the use of such new and highly efficient therapeutic principles comes with new questions and uncertainties on the sequence of therapies, duration of therapy, long-term side effects, undesired activation of metabolic pathways and effectiveness in comparison to other strategies of fracture prevention.

Previous studies revealed some comorbidity of Alzheimer's disease and osteoporosis not only for advanced disease, but also for the incipient conditions cognitive decline and decline of bone mineral density. To detect comorbidity with osteoporosis at a subclinical level, we studied concentrations of biochemical osteoporosis markers in blood plasma of subjects with mild cognitive impairment and mild Alzheimer's disease compared to subjects with primary osteoporosis and age-matched cognitively normal controls in an explorative approach. Regarding disease-spanning molecular pathology we also studied osteoprotegerin, a decoy receptor of RANKL and TRAIL. Equally increased C-terminal collagen fragments, marking bone catabolism, were seen in osteoporosis and Alzheimer's disease (+68%) versus controls. Osteocalcin, marking bone remodelling and anabolism, was concomitantly increased in osteoporosis (+63%), as a trend, and significantly in Alzheimer's disease (+76%). Osteoprotegerin was unchanged between patient groups and controls. 25 (OH) vitamin D plasma levels were low normal and of equal amount in all groups except for the osteoporosis group. These results point to increased bone catabolism and concomitant remodelling/anabolism unrelated to vitamin D state in mild Alzheimer's disease, but not in mild cognitive impairment. This corroborates previous findings of comorbidity of Alzheimer's disease with osteoporosis in the early disease course at the level of biochemical blood markers. Regarding osteoprotegerin, previously reported plasma level increases in Alzheimer's disease were not observed in this study, which does not rule out subtle changes to be detected in larger samples or the possibility that other components of osteoprotegerin pathways are affected in Alzheimer's disease.

Glucocorticoids interfere with bone metabolism at different levels. Therefore, glucocorticoid-induced osteoporosis (GIO) is the most frequent form of secondary osteoporosis and up to 50 percent of patients on chronic glucocorticoid therapy suffer fractures. This is also because GIO is still under-diagnosed and not adequately treated. Besides, the fracture risk is higher in GIO than in primary osteoporosis even in the presence of equal bone mass density. The risk of osteoporotic fractures increases with dose and duration of glucocorticoid therapy, although the loss of bone mass is more prominent within the first three to twelve months after initiation of treatment. Besides glucocorticoid treatment, other factors, such as e.g. the underlying disease, substantially influence the fracture risk. Therefore, a diagnostic screening is mandatory in each case and should include the patient's history, physical examination, laboratory studies, evaluation of the bone-mass density by dual X-ray absorptiometry and imaging of the spine. Education of the patients and pharmacological prevention are very important, antiresorptive therapy has to be started earlier than in primary osteoporosis and osteoanabolic agents have also been proven to be effective.

Recent in vitro and in vivo studies have shown a potent inhibition of cytochrome P450 CYP3A4 through human immune defi ciency virus (HIV) protease inhibitors (PIs). The PI ritonavir is described as the most potent compound within these CYP3A4 inhibitors. We present 2 cases who developed the sequelae of glucocorticoid excess following ritonavir therapy and inhalative glucocorticoid treatment: A 60-year-old HIV positive man developed the typical symptoms of Cushing's syndrome and a 52-year-old HIV positive man developed severe osteoporosis. [ABSTRACT FROM AUTHOR]