Current and investigational approaches for reversing established osteoporosis

Osteoporosis is a disease of elderly women marked by low bone mass and increased risk of fracture. Though its prevalence can be reduced by timely estrogen replacement at menopause, many persons present with fragility fractures long after much bone has been lost. Osteoporotic subjects have low bone mass and poor structure but few or no metabolic abnormalities, such as ongoing bone loss, for treatment to normalize. The problem is to increase their bone mass and improve their bone structure. Today's major therapeutic approaches are summarized in Table 2. Ironically, they aim at stopping bone loss. Although preventing the skeleton of an osteoporotic person from growing weaker by stopping bone loss is better than allowing the process to continue, raising her to a significantly higher level of bone mass would be a better aim. Existing agents that stop bone loss by reducing turnover also increase bone mass mildly by filling the remodeling space. The result is a rise in bone mass during the first year or two of treatment to a new steady state 2% to 5% higher than baseline that persists throughout treatment. Fluoride increases spinal bone mass markedly. It decreases vertebral, but not hip fractures, but is associated with side effects and a nonresponse rate that makes pursuing other therapies attractive. Agents that upregulate bone mass through regulatory means have been tested in preclinical and a few clinical trials. PGE2 has been thoroughly tested preclinically. By studying PGE2, the field has learned that marked bone mass increases in the estrogen-deplete osteopenic skeleton are possible. The lack of bone specificity for PGE2 will probably limit its use to that of preclinical demonstration agent but leave open the possibility that less potent members of the prostaglandin family with better bone specificity might have promise as osteoporosis treatments. PTH or one of its analogues shows good promise for osteoporosis treatment. The wide availability of cheap PTH or proprietary analogues with similar activity will do much to speed its development. It increases bone formation and cancellous bone mass markedly. If PTH increases bone mass consistently in either large animal or human trials while causing only mild transient cortical bone mass declines, it can be a successful osteoporosis treatment agent. Bone growth factors appear to have much untapped potential for furthering the understanding of local control of bone processes and possibly for treating osteoporosis. Another possibility is biphasic therapy.(ABSTRACT TRUNCATED AT 400 WORDS)