ANABOLIC AGENTS: ARE THEY THE FUTURE AND WHAT TO EXPECT

Abstract

Abstract: Osteoporosis is defined as a systemic skeletal disease characterized by an unbalanced bone–remodeling activity leading to a low BMD, microarchitectural deterioration of the bone, and fractures mainly at lumbar spine, femoral neck and distal radius. Osteoporosis is a major worldwide public health concern because spine and hip fractures are associated with an increase in morbidity and mortality. The lifetime risk of any osteoporotic fracture has been estimated to be 50 % in all women after 50 y and 25 % in men (1). The aim of osteoporosis therapy is the prevention and/or treatment of vertebral and nonvertebral fractures. The agents currently available for osteoporosis therapy act by inhibiting bone resorption and/or by stimulating bone formation. Both kinds of drugs are effective in lowering the risk of vertebral fractures but there is a relative lack of efficacy of antiresorptive drugs on nonvertebral fractures. This can be explained, at least in part, by differences in bone composition and microarchitecture. Vertebral fractures are mostly related to trabecular bone density and architecture and nonvertebral fractures are mostly dependent on cortical thickness and porosity. Cortical bone is more susceptible to modeling than remodeling activity mainly along the periostal surface. Antiresorptive drugs have their effects restricted to remodeling activities justifying its unsatisfactory effect on nonvertebral fractures. Anabolic therapies increase bone formation by bone modeling and remodeling and this can be measured by biochemical markers. The development of this kind of drugs may improve the prevention and treatment of nonvertebral fractures. Anabolic Agents: Actions of the anabolic drugs depends on increases of the bone turnover (activation frequency) favoring bone formation and/or on directly stimulating bone formation through activation of bone modeling. Bone formation can be measured by histomorphometry and biochemical markers procollagen type 1 amino-terminal propeptide (P1NP), bonespecific alkaline phosphatase and osteocalcin. Parathyroid Hormone (PTH) – Intermittent action: PTH is a hormone secreted by the parathyroid glands in response to a lowering in the serum calcium concentration. Increased serum levels of PTH induces the normalization of calcium levels by enhancing the calcium reabsorption in the kidneys, its uptake in the intestine and its release from bone by stimulating bone turnover. PTH binds to the PTH receptor (PTH1R) expressed on osteoblasts but not on osteoclasts. High levels of PTH lead to a marked increase in activation frequency and bone resorption but also in the number of osteoblasts showed in bone biopsies of patients with primary hyperparathyroidism. Osteoblasts exposed to PTH showed an increase in proliferation, differentiation and secretion of RANKL (2). It is well known that RANKL binding to RANK receptor in osteoclasts induce osteoclastogenesis and bone resorption. These observations lead to the conclusion that the PTH action starts with an increase in bone formation (anabolic response) followed by an interaction between osteoblasts and osteoclasts resulting in an increase in bone resorption (catabolic response). Studies in animals showed that this dual effect could be dissociated by short exposures to recombinant human PTH (rhPTH) enhancing the positive anabolic effect as opposed to sustained levels of the hormone inducing the negative catabolic response. Those experiments led to the development of the bioactive N-terminal 34-amino acid fragment rhPTH 1-34 for the treatment of osteoporosis. After the administration of the injectable form of the rhPTH, it rapidly reaches peak concentrations and is degraded in about 1 h. rhPTH increases cortical porosity secondary to enhanced endocortical remodeling but also increases bone formation along the periosteum (modeling surface) contributing to improve the trabecular and cortical architecture. rhPTH increases bone formation by modeling and remodeling actions but its anabolic function is more dependent on increasing the activation frequency, narrowing its therapeutic window. The introduction of the rhPTH in clinical practice was based on clinical trials including more than 2800 osteoporosis patients. The pivotal clinical trial took 19 months to be completed and showed a 65 % lowering in the risk of vertebral fractures and a 40 % reduced risk of nonvertebral fractures compared with placebo. New formulations, other than subcutaneous administration, are in development, including transdermal application and oral/inhaled delivery (3). PTH related protein (PTHrp) is homologous to PTH in its first 36 amino acids with the capacity of binding and activating the receptor PTH1R. In a recent study including 41 healthy postmenopausal women, PTHrp appeared to act as a pure anabolic agent without enhancing bone resorption (4) A one year phase 2 study showed that subcutaneous injection of the PTHrp analog BAO58 increased bone mineral density faster than rhPTH. Phase 3 studies are ongoing to determine the efficacy and safety of this new drug. Calcilytics: Cells of the parathyroid glands express on their surfaces the calcium-sensing receptor (CaSR), which inhibits PTH secretion when calcium is bound. When the calcium serum levels are low, the activity of the CaSR decreases and the parathyroid glands secrete PTH. The subsequent rise in serum calcium activates the CaSR terminating the secretion of PTH. Calcimimetics are drugs used to treat hypercalcemia and secondary hyperparathyroidism. Calcilytics mimic hypocalcemia and may induce PTH secretion independently of the serum calcium levels. The idea behind its use in osteoporosis treatment was that short-acting calcilytics with a rapid onset of action, high clearance and low volume of distribution, by inducing a transient burst of endogenous PTH, could have the same effect of an intermittent use of rhPTH. A randomized trial reporting the use of a calcilytic drug named ronacaleret included 569 postmenopausal women with low bone mass for one year compared to rhPTH and alendronate. The gain in lumbar spine with ronacaleret was significantly below the increase seen with alendronate or rhPTH. There was also a decrease in hip bone mineral density in the ronacaleret patients compared with the two other drugs (5). The unsatisfactory results have led to the interruption of the clinical development of this drug. The results published at this point have not been convincing that calcilytic drugs may induce bone anabolism for osteoporosis treatment. Wnt-Signaling Pathway: The discovery of human mutations in the low-density lipoprotein receptor-related protein 5 (Lrp5) linked to high bone mass called the attention to the Wnt pathway as an important regulator of bone density in humans. A single point mutation in the Lrp5, inducing high bone mass, was shown to decrease the affinity of this protein for its inhibitors sclerostin and dickkopf1 (DKK1). When Wnt links to Lrp5, the protein β-catenin accumulates in the cytosol and translocates in to the nucleus stimulating several osteoblast marker genes and osteoprotegerin genes thus activating bone formation and decreasing bone resorption. Sclerostin and proteins of the Dkk family can inhibit this anabolic process by binding itself to Lrp5/6 and thus interfering with the Wnt binding. A phase 1 randomized, double-blind study, with AMG 785, a humanized monoclonal sclerostin antibody, in healthy men and postmenopausal women, showed increase in bone formation markers within 1 month after a single dose of 10 mg/kg of this compound, a result comparable to daily injections of rhPTH for 6 months. The analysis of bone mineral density in lumbar spine and total hip showed gain comparable to the results of rhPTH treatment (6). In a 12 months phase 2 study, AMG 785 significantly increased bone mineral density in the lumbar spine compared to placebo and teriparatide (not published yet, see www.amgen.com). These results are encouraging towards the use of sclerostin antibodies for the treatment of osteoporosis. Antibodies to Dkk1 are also being developed but mainly for the treatment of multiple myeloma. Initial studies are ongoing for low bone mass diseases and depending on the results of safety and efficacy, probably they may have a more general indication in bone diseases. Strontium Ranelate: Strontium ranelate (SR) is composed of an organic moiety and two atoms of strontium (Sr²+). Studies in vitro have been shown that SR enhances osteoblast functions and induces osteoclast apoptosis. SR stimulates proliferation of pre-osteoblasts and induces osteoblast differentiation to a mature, mineralizing phenotype. The effect of SR on osteoblasts and osteoclasts remains a matter discussion but activation of the CaSR, also present in osteoblasts and osteoclasts, is cited as a hypothesis. SR also enhances the osteoprotegerin expression while downregulating RANKL expression in osteoblasts indicating that the antiresorptive effect of the SR may be mediated by these actions. Two dose-ranging studies were performed using oral doses of 2 g/day in postmenopausal osteoporosis women. One protocol designed to study the effect of SR on the risk of vertebral fractures (SOTI) and the other designed to study the effect of SR on the risk of nonvertebral fractures (TROPOS). Both of them showed efficacy in reducing the targeted fractures (7,8). Extension of these studies showed that SR reduced the risk of vertebral fractures over 4 years and risk of nonvertebral fractures over 5 years (9) SR is relatively safe and has been licensed for the treatment of osteoporosis in the Europe and Latin America. Conclusions: The development of new agents with anabolic properties has been a priority in the field of osteoporosis treatment especially regarding patients with severe bone loss and those in higher risk of nonvertebral fractures where the antiresorptives have limited efficacy. The elucidation of the PTH action given in intermittent doses and the development of the rhPTH opened the way to increase bone formation and consequently increase bone density in patients severely affected by the disease although the rhPTH ability to reduce nonvertebral fractures had been modest. This is due mainly to its action be based predominantly on bone remodeling. In this regard the discovery of the anabolic way of the Wnt signaling opens new possibilities taking into account that this osteo-anabolic pathway exerts its effects through a modeling-based mechanism. Many trials are ongoing with new drugs and also combination of them. Even some new antiresorptive drugs (odanacatib) may avoid the antianabolic actions seen with bisphosphonates opening the possibility of improving the fracture outcomes.