Exploiting new targets for old bones

I never think of the future. It comes soon enough.

—Albert Einstein, 1933

After alendronate was approved for the treatment of postmenopausal osteoporosis, expectations rose that new therapies would be developed to cure this debilitating disease. Public and private collaborations pushed the envelope to discover “druggable” targets in the skeletal remodeling unit. Initially, those efforts focused on the bone-resorbing osteoclast and ultimately led to the approval of three bisphosphonates that differed not in their mode of action but rather in their frequency of administration. In contrast, the development and subsequent approval of teriparatide paved the way for anabolic therapies that “turned on” osteoblasts. In JBMR this month, proof of concept is illustrated for two novel targets in the skeletal milieu, a protease secreted by osteoclasts and a peptide product of the osteocyte. As Einstein noted, the future of osteoporosis medicine is coming soon enough.1, 2

Antiresorptive therapies aimed at the osteoclast have a long and relatively successful history. Estrogen was used to prevent bone loss more than a half a century ago. Remarkably, recent studies have confirmed both its antifracture efficacy and its capacity to prevent bone loss.3 Estrogens block bone resorption by inhibiting cytokine differentiation of osteoclasts through the RANKL pathway.4 However, nonskeletal side effects have limited estrogen's utility for the long-term treatment of osteoporosis. Calcitonin was approved for the treatment of osteoporosis in the 1980s. Although osteoclasts express a surface receptor for calcitonin, the antiresorptive effects of nasal or subcutaneous calcitonin were much less pronounced than those of estrogen. In 1995, alendronate was introduced, and the bisphosphonates rapidly became the drugs of choice for the treatment of osteoporosis in part because of their ease of administration and their relatively strong efficacy. This class of agents acts by diffusing into the osteoclast from the skeletal matrix and inhibiting key enzymes in the HMG CoA reductase pathway. Bisphosphonates also can induce osteoclast apoptosis. Very recently, reports of subtrochanteric fractures and the rare occurrence of osteonecrosis of the jaw have spurred investigators to consider other targets in the osteoclast.5

Odanacatib is a cathepsin K inhibitor currently in phase III trials. Its mode of action is through inhibition of the enzyme cathepsin K (CatK), an abundant cysteine protease produced by osteoclasts and critical for collagenolytic activity. Because CatK is relatively specific for bone, it makes an ideal target for therapeutic intervention. Interestingly, unlike other antiresorptive drugs, odanacatib (ODN) inhibits matrix dissolution but does not affect acid secretion nor the viability of the osteoclast. Whether this may prove advantageous for its eventual safety profile still needs to be determined. Early trials with the prototypical CatK inhibitors suffered from high expectations. Some investigators felt that the CatK inhibitors were both antiresorptive and anabolic. Unfortunately, there were significant side effects from these agents, particularly in the skin.

In the current article, Bone and colleagues confirm earlier work suggesting that the CatK enzyme may be a good target to prevent bone loss and that ODN has a relatively strong safety profile.1 Their results arise from a straightforward phase IIb dosing trial in postmenopausal women with modestly low bone mineral density (BMD) but without fractures. The principal endpoint was change in bone mass at the lumbar spine, with secondary outcomes that included changes in hip and radial BMD as well as bone turnover markers. ODN successfully met both primary and secondary outcomes with a dose dependent increase in BMD at several sites and a 40% to 60% suppression in bone-resorption markers. Furthermore, adverse event reporting suggested that there was no increase in skin rashes or serious infections from any of the ODN doses compared with placebo treatment.

But a closer look at this study reveals the limitations as well as the value of small randomized trials for surrogate endpoints. Virtually all phase II trials are illustrative but not definitive. These trials are principally designed to examine adverse events and to define the most effective dose. The number of subjects in these trials is traditionally small, and adverse event reporting is short term. Thus, although it is reassuring that no increase in skin lesions or infections were noted in phase II, the phase III trial will be the penultimate determinant of the drug's clinical utility. Notwithstanding, two aspects of this trial are worth noting. First, the histomorphometric data revealed no obvious skeletal toxicity, although the small number of subjects randomized to each dosage arm limits any definitive conclusion. Second, women on the lowest dose of ODN (3 mg) had radial bone loss greater than placebo with similar but nonsignificant decreases at the spine, total hip, and femoral neck compared with placebo. Surprisingly, bone resorption was enhanced in the lowest-dose cohort when measured by DpD/Cr. Similarly, P1NP and BSAP, markers of bone formation, were increased in that same dose group. And, by histomorphomety, the women in the 3-mg dose group showed increased activation frequency and bone-formation rates, albeit not statistically different from controls. Thus changes in these histomorphometric and biochemical parameters were the exact opposite of the higher-dose groups! So what does this mean? It is still too early to know, and the numbers are small, but it appears that the low dose of ODN acts less like placebo and more like a stimulator of bone turnover, suggesting a unique dose response for remodeling (ie, activator at low dose, suppressor at high dose) not observed in clinical trials with other antiosteoporosis drugs. Unfortunately, phase II studies are designed to select the appropriate dose through surrogate endpoints for eventual marketing. Clearly, the 3-mg dose will not be used in future trials, but studying the pharmacodynamics of the lowest dose of ODN may shed new light on how the remodeling unit functions in health and disease.

The flip side of anticatabolic treatment is anabolic therapy. Although teriparatide has been on the market for nearly 8 years, the quest for alternative anabolic targets has not abated. Sclerostin is the protein product of SOST and is expressed principally in the osteocyte. It is a negative regulator of the Wnt/β-catenin signaling pathway by binding to LRP5 and LRP6.6 Removal of an inhibitor to the canonical pathway for Wnt signaling would be expected to cause profound increases in bone formation. Indeed, a naturally occurring 52-kb deletion in the downstream enhancer of SOST results in an autosomal recessive disorder called Von Buchem's disease.7 It is associated with high bone mass, asymmetric enlargement of the jaw, deafness, optic atrophy, and nerve entrapment. Sclerosteosis, another genetic disorder associated with high bone mass, results from loss-of-function mutations in the SOST gene.8 This disease is also characterized by increased bone formation but impaired osteoclastic activity. Interestingly, intermittent parathyroid hormone (PTH) administration suppresses sclerostin expression, resulting in enhanced osteoblastic function and reduced apoptosis.9

The discovery of sclerostin rapidly led to experimental interventions to suppress its production. Early results with monoclonal antibodies to sclerostin in rodents were quite impressive, raising expectations about future animal and human trials. In the current article, Ominsky and colleagues do not disappoint. They demonstrated that two doses of a sclerostin monoclonal antibody administered once monthly for 2 months to mature cynomolgus monkeys enhanced BMD, increased osteoblast-mediated bone formation, and doubled skeletal strength.2 The changes in areal bone mass were remarkable (15% to 30%), but only changes in femoral and total body bone mineral content (BMC) were statistically significant owing to the small number of animals (n = 2 to 3) per dose and the short duration. On the other hand, histomorphometric parameters demonstrated markedly increased bone-formation and mineral-apposition rates with the highest dose of 30 mg/kg of monoclonal antibody. Not surprisingly, the authors demonstrated that bone-formation markers correlated closely with the increased rate of bone formation and that the new bone formed was structurally sound.

The Ominsky study raises some intriguing questions about the therapeutic manipulation of the bone remodeling unit. As the authors nicely demonstrate, two doses of 30 mg/kg of sclerostin monoclonal antibody markedly increased bone formation but did not affect bone resoption. These results are not totally surprising because sclerostin null mice have a similar phenotype and subjects with von Buchem's disease do not have increases in bone-resorption markers. But how is this possible if the bone remodeling unit is balanced, and activation of osteoblasts invariably leads to the release of RANKL and the subsequent differentiation of osteoclasts? One mechanism may be due to Wnt activation of bone formation on a quiescent skeletal surface rather than in resorption lacunae. A similar phenotype has been documented during early (ie, 1 month) treatment with PTH; however, this effect is transient, and active remodeling takes over relatively quickly.10 Only long-term studies will be able to address whether drug-induced modeling can persist in older humans during Wnt activation from sclerostin inhibition.

It is also conceivable that balanced remodeling is not as we might predict, an “all or none” phenomena, and that certain ligands and signaling pathways may be proformative without activating resorption. Such a concept was considered heretical a decade ago but has been demonstrated in some animal models. For example, recent work from the Karsenty group proved that when they inhibited serotonin synthesis in the gut of rodents by a Tph1 antagonist, they were able to stimulate bone formation to nearly the same degree as PTH without significantly activating osteoclasts.11 Other in vivo studies have shown that Wnt activation not only increases osteoblastic recruitment but also stimulates OPG synthesis in stromal cells, thereby neutralizing RANKL-induced increases in osteoclastogenesis. Taken together, data from the skeletal phenotypes of recessive SOST mutations with our newer insights about Wnt signaling and recent work from the Amgen group suggest that novel treatments acting only on the formation side are clinically possible. In sum, the contrast between the modes of action of two novel agents reported this month informs us not only about future therapies but also about the physiology of bone remodeling. These reports will continue to heighten expectations for an ideal therapy to treat a devastating disease.