Enhancement of the inhibitory action of APD on the transformation of osteoclast precursors into resorbing cells after dimethylation of the amino group.

The amino-bisphosphonate APD is distinct from the bisphosphonates EHDP and Cl2MDP by a greater molar potency in vivo as inhibitor of osteoclastic bone resorption and in vitro by a pronounced inhibitory effect on the accession of osteoclast precursors to mineralized matrix. Dimethylation of the aminogroup, which increases the basic properties of this residue but precludes others, like the liability to glucuronidation or acetylation, increased the in vivo potency of this amino bisphosphonate, as well as its in vitro specificity for osteoclast-precursor accession, but decreased its cellular toxicity. The in vitro actions of dimethyl-APD were reversible with administration of PTH. It is concluded that the introduction of a basic residue in bisphosphonates may increase affinity for the specific sites on the mineralized matrix that are involved in directing the accession of precursors and their transformation into actively resorbing osteoclasts.