Investigational anabolic therapies for osteoporosis.
BACKGROUND
Anabolic therapy, or stimulating the function of bone-forming osteoblasts, is the preferred pharmacological intervention for osteoporosis.


METHODS
We reviewed bone anabolic agents currently under active investigation. The bone anabolic potential of IGF-I and parathyroid hormone-related protein is discussed in the light of animal data and human studies. We also discuss the use of antagonists of the calcium-sensing receptor (calcilytics) as orally administered small molecules capable of transiently elevating serum parathyroid hormone (PTH). Further, we reviewed novel anabolic agents targeting members of the wingless tail (Wnt) signaling family that regulate bone formation including DKK-1, sclerostin, Thp1, and glycogen synthase kinase 3beta. We have also followed up on the promise shown by beta-blockers in modulating the activity of sympathetic nervous system, thus affecting bone anabolism. We give critical consideration to neutralizing the activity of activin A, a negative regulator of bone mass by soluble activin receptor IIA, as a strategy to promote bone formation.


RESULTS
Update on various strategies to promote osteoblast function currently under evaluation.


CONCLUSIONS
In spite of favorable results in experimental models, none of these strategies has yet achieved the ultimate goal of providing an alternative to injectable PTH, the sole anabolic therapy in clinical use.
Trivedi
Ritu
R
Central Drug Research Institute (Council of Scientific and Industrial Research), Division of Endocrinology, Lucknow, India. ritu_trivedi@cdri.res.in
Goswami
Ravinder
R
Chattopadhyay
Naibedya
N
D029404:Activin Receptors / Q000737:chemistry / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D045930:Anabolic Agents / Q000627:therapeutic use*; D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D015507:Drugs, Investigational; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D010024:Osteoporosis / Q000188:drug therapy* / Q000503:physiopathology; D044162:Parathyroid Hormone-Related Protein / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051155:Wnt1 Protein / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D045930:Anabolic Agents; D015507:Drugs, Investigational; D044162:Parathyroid Hormone-Related Protein; D044169:Receptors, Calcium-Sensing; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D007334:Insulin-Like Growth Factor I; D029404:Activin Receptors