Current therapy and drugs in development

Table 2 provides a list of current therapies and those likely to become available in the near future. Current therapies (Eastell 1998) are based on drugs that are inhibitors of bone resorption and remodelling rather than stimulators of bone

TABLE 2 Some of the genes that may contribute to osteoporosis by influencing bone mass and rates of bone loss (Ralston 1997)

• Vitamin D receptor

• Oestrogen receptor

• Sp1 site in a1 chain of Type I collagen

• Parathyroid hormone receptor

• Interleukin 1 receptor antagonist

• Other loci identified in mice formation. The major current therapies include vitamin D and Ca2+ supplements, oestrogens and related compounds, and the bisphosphonates (Fig. 5).

Oestrogens and SERMs

Recent advances in the uses of oestrogens include the development of novel delivery systems, particularly by the transdermal route. Future developments may include additional novel routes of administration, e.g. pulmonary

FIG. 5. Chemical structures of drugs relevant to osteoporosis. The SERMs raloxifene, tamoxifen, and lasofoxiphene are shown alongside the natural oestrogen, oestradiol. The two bisphosphonates shown here are risedronate and ibandronate.

inhalation. One of the more interesting recent achievements has been the development of more tissue-selective oestrogens or SERMs (selective oestrogen receptor modulators). The ideal compound of this type would possess all the good properties of oestrogens but none of the bad (MacGregor & Jordan 1998). Such an agent would therefore be effective in osteoporosis, ischaemic heart disease and Alzheimer's disease, without adverse effects on the breast or uterus in terms of increasing cancer risk, and with no risk of inducing venous thromboembolism. The first compound in this class is raloxifene. Although raloxifene does not yet fulfil all these criteria, it is effective in reducing bone loss and vertebral fracture, and also the incidence of newly diagnosed breast cancers. Other SERMs may follow relatively soon.

It is encouraging that the opportunities for chemical innovation in this area are enormous. The biological basis for tissue selectivity is beginning to be understood. Although there are now known to be at least two functional oestrogen receptors, a and fl isoforms, the differential tissue distribution of these receptors does not account for the differences in action among the known SERMs. It is likely that the differential tissue effects are related to altered conformations of the oestrogen receptors to which they bind, followed by different associations with other transcriptional regulatory proteins in individual cell types. In theory it may be possible to develop drugs with the ideal properties if the basic biology allows it.


Bisphosphonates (BPs) are now well established as successful anti-resorptive agents for the prevention and treatment of osteoporosis (Bijvoet et al 1995, Russell 1999). In particular, etidronate, alendronate and, more recently, risedronate, are approved therapies in many countries and both can increase bone mass and reduce fracture rates at the spine, hip and other sites by up to 50% in post menopausal women.

The use of BPs in osteoporosis is relatively recent compared with the many years ofexperience in other diseases such as Paget's disease ofbone, and bone metastases, for which compounds such as pamidronate and clodronate have been used extensively. The clinical pharmacology of BPs is characterized by low intestinal absorption, but highly selective localization and retention in bone.

In osteoporosis, the effects of BPs on bone mass may account for some of their action to reduce fractures, but it is likely that their ability to reduce activation frequency, and possibly to enhance osteon mineralization, may also be related to the reduction in fractures.

Current issues with BPs include the use of intermittent rather than continuous dosing, intravenous versus oral therapy, the optimal duration of therapy, the combination with other drugs such as oestrogens, and their extended use in

FIG. 6. Mechanism of action of nitrogen-containing bisphosphonates as inhibitors of the mevalonate pathway.

related indications, e.g. glucocorticosteroid-associated osteoporosis, male osteoporosis, childhood osteopenic disorders and arthritis. There is therefore much that needs to be done to improve the way in which existing drugs can be used as well as introducing new ones.

BPs inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of osteoclasts. It is likely that bisphosphonates are internalised by osteoclasts and interfere with specific biochemical processes. Recent mechanistic studies show that BPs can be classified into at least two groups with different modes of action. Those that most closely resemble inorganic pyrophosphate (PPi), e.g. clodronate and probably etidronate, can be incorporated into toxic ATP analogues. In contrast, more potent nitrogen-containing BPs, such as alendronate and risedronate, interfere with other reactions, e.g. those in the mevalonate pathway (Fig. 6). These may affect cellular activity such as apoptosis by interfering with protein prenylation (Fig. 7), and therefore disrupt the intracellular trafficking of key regulatory proteins (Fisher et al 1999, van Beek et al 1999). There may therefore be subtle differences between compounds in terms of their clinical effects.


Despite many years of use in some countries, there is still controversy about whether calcitonin reduces fractures in osteoporosis, although recent studies

FIG. 7. Mechanism of action of bisphosphonates within cells as inhibitors of protein prenylation (Rogers 2000).

suggest that this may be the case for selected doses of salmon calcitonin. With more powerful and less expensive options available for inhibiting bone resorption, the impetus behind developing new therapies based on calcitonins or its peptide analogues has diminished, although there is still some interest in improving drug delivery, e.g. by the oral route.

Other anti-resorptive compounds

Other compounds currently under study include ipriflavone, a synthetic isoflavenoid derived from soya beans that has some oestrogen-like properties. The potential place for other phyto-oestrogens in the management of osteoporosis remains unclear, although differences in the dietary intake of such compounds may contribute to the geographical variations observed in the prevalence of osteoporosis.

The needfor anabolic agents: parathyroid hormone, high-dose oestrogens, strontium salts and other options

It would be a significant advance if anabolic agents could be developed that would enhance the formation of new bone and therefore produce bigger changes in bone mass and strength than can be achieved with current drugs, such as the

Decrease production & activity of bone-resorbing cells {osteoclasts)

Increase production & activity of bone-forming cells (osteoblasts)




Calcitonins & synthetic analogues

Oestrogens & analogues

SERMs ( Post Raloxifene, e.g. Lasomeloxifene)

Other agents: testosterone, vitamin D and analogues, ipriflavone

IL-1ra, TNF & IL-1 receptor constructs)


Proton (H+) pump inhibitors

Calcium receptor modulators

Nitric oxide modulators

Enzymo inhibitors, e.g. metailoproteinases, cat hep sin K, etc.

Adhesion molecule inhibitors (RGO peptides) Intracellular signalling targets, e.g. c-src, TRAFs, NF-kB.

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