YEAR IN REVIEW ANABOLIC BONE THERAPIES IN 2014
New bone-forming treatments for osteoporosis Socrates E. Papapoulos
In 2014, two phase II clinical studies reported rapid, impressive increases in BMD in women with low bone mass who were treated with sclerostin inhibitors for 1 year. The antifracture efficacy and tolerability of these new, bone-building therapies are currently being investigated in phase III clinical trials. Papapoulos, S. E. Nat. Rev. Endocrinol. advance online publication 9 December 2014; doi:10.1038/nrendo.2014.214
Osteoporosis is characterized by low bone mass and structural decay of bone tissue, which lead to increased bone fragility and fractures. Pharmacological interventions for osteoporosis aim to decrease the risk of fractures and the associated clinical consequences (such as deterioration in quality of life and risk of new fractures and mortality) by correcting the imbalance between bone resorption and bone formation that constitutes the pathophysiological basis of the disease. Most currently available pharmacological agents inhibit bone resorption and bone turnover to varying degrees and decrease the risk of fractures; however, these agents do not stimulate the formation of new bone that is essential for the management of patients with severe disease. For these patients, agents capable of stimulating new bone formation are required. Teriparatide (a recombinant form of parathyroid hormone, PTH1–34, that is the most extensively studied bone-forming treatment) stimulates not only bone formation but also bone resorption, and acts mainly at sites in the bone that are undergoing active remodel ling rather than at quiescent bone surfaces, a property which, in my view, differentiates a bone-forming therapy from an anabolic therapy. A key question is whether concurrent inhibition of bone resorption might improve the effect of teriparatide on bone mass, particularly at cortical sites. Previously, it was reported that postmeno pausal women with osteoporosis who were treated with both teriparatide and denosumab (a bone resorption inhibitor) for 1 year had considerably increased BMD at the spine and at the hip compared with
women who received either monotherapy alone.1 The greater increase in BMD was probably due to inhibition by denosumab of the production of RANKL, which is stimulated by PTH. In 2014, Leder and colleagues reported the results of the second year of this study.2 For 24 months, 94 women with osteo porosis received teriparatide (20 μg per day), denosumab (60 mg every 6 months) or both agents. Although BMD increased further with all treatments, the increase in BMD did not differ between the groups, which led the authors to suggest that the most cost-effective way to achieve greater increases in BMD might be to use the combination therapy for 1 year followed by an antiresorptive agent in the second year. An early rapid increase in bone mass is particularly relevant for patients with severe disease and a recent fracture, as these patients are at the highest risk of a new fracture in the following 1–2 years. In addition to illustrating the feasibility of an efficacious combination therapy for patients with osteoporosis, the results of this study 2 strongly suggest that for an optimal effect on bone mass in cancellous bone and
cortical bone, stimulation of bone formation should be accompanied by a decrease in bone resorption. Treatments to achieve this aim are currently being investigated following the identification of new targets in bone. One such target is sclerostin, a natural inhibitor of the Wnt signalling pathway that is produced in the skeleton exclusively by osteocytes and inhibits bone formation.3 The restricted expression of sclerostin in the skeleton, the markedly increased bone mass and bone strength in patients and mice with sclerostin deficiency, and the lack of extraskeletal complications has made sclerostin an attractive therapeutic target in osteoporosis.4 Inhibitors of sclerostin increase bone formation at all skeletal envelopes and considerably improve bone strength without affecting or even decreasing bone resorption in appropriate animal models.5,6 The latter action of sclero stin inhibitors was confirmed in a phase I clinical study by measuring the levels of biochemical markers of bone turnover.7 In 2014, two phase II studies of different sclerostin inhibitors (the humanized antibodies romosozumab and blosozumab) and with different study designs were reported.8,9 Recker et al. reported the results of a dosefinding study of blosozumab given sub cutaneously for 1 year to 120 postmenopausal women aged 45–85 years with BMD T‑scores between –2.0 and –3.5.8 All women received calcium and vitamin D supplements and were randomly assigned to receive placebo or blosozumab (180 mg every 4 weeks; 180 mg every 2 weeks or 270 mg every 2 weeks). Blosoz umab treatment induced dose- dependent increases in spine BMD of 8.4%, 14.9% and 17.0%, respectively, in total hip BMD of 2.1%, 4.5% and 6.3%, respectively, in femoral neck BMD of 2.7%, 3.9% and 6.3%, respectively, and in total body bone mineral
Key advances ■■ Teriparatide, a bone-forming agent, stimulates not only bone formation but also bone resorption2 ■■ During a 1 year extension of the combination study of teriparatide and denosumab, further increases in BMD were observed at the spine and at the hip for a second year2 ■■ Antibodies to sclerostin rapidly stimulate bone formation, decrease bone resorption and impressively increase BMD at the spine and at the hip after 1 year 8,9 ■■ Treatment with the sclerostin antibody romosozumab resulted in considerably greater increases in BMD than those observed with either teriparatide or alendronate treatment9 ■■ The increase in bone mass with sclerostin antibodies is mainly due to the stimulation of bone formation at quiescent bone surfaces,10 establishing these agents as new bone-building therapies for osteoporosis
NATURE REVIEWS | ENDOCRINOLOGY
ADVANCE ONLINE PUBLICATION | 1 © 2014 Macmillan Publishers Limited. All rights reserved
YEAR IN REVIEW
Changes of markers of bone turnover (%)
content of 1.7%, 4.2% and 7.3%, respectively, after 1 year; blosozumab treatment had no effect on BMD at the distal radius. Mild injection site reactions were more frequently observed with blosozumab than with placebo and neutralizing antibodies developed in one patient, which affected her response to treatment. Although the frequency of adverse events was similar among all groups, four women (all Japanese) were diagnosed with breast cancer in the period between 3 months of initiating treatment to 1 year after the last dose of blosozumab; however, none of the investigators considered this adverse event to be related to blosozumab treatment. McClung and colleagues examined the efficacy and tolerability of different doses and dosing intervals of subcutaneous injections of romosozumab compared with placebo, oral alendronate (70 mg, weekly) or subcutaneous injections of teriparatide (20 μg daily) in 419 postmenopausal women, aged 55–85 years, with BMD T‑scores between –2.0 and –3.5.9 All women received calcium and vitamin D supplements and were randomly assigned to receive subcutaneous injections of placebo or romosozumab either monthly (70 mg, 140 mg or 210 mg) or every 3 months (140 mg or 210 mg). All doses of romosozumab induced notable increases in BMD. The highest dose of romosozumab increased BMD at the spine (by 11.3%), total hip (by 4.1%) and femoral neck (by 3.7%) after 1 year. These increases were considerably higher than those observed in women treated with either alendronate or teriparatide. No statistically significant differences in BMD at the distal radius were observed at 12 months between any of the treatment groups and placebo. The incidence of adverse events was similar among 100
all groups except for mild reactions at the injection sites of romosozumab. Neutralizing antibodies developed in 3% of patients on romosozumab, but had no effect on treatment outcomes. One patient who received romosozumab was diagnosed with breast cancer during the trial, but that was not considered by the investigators to be treatment-related. This study,9 as well as the study of the combination of teriparatide with denosumab,2 was not designed to assess the efficacy of treatments on the incidence of osteoporotic fractures, which is currently being investigated in ongoing phase III clinical trials with monthly injections of romosozumab. Both sclerostin inhibitors rapidly increased levels of markers of bone formation and also decreased levels of markers of bone resorption, possibly via an effect on the production of RANKL and/or osteoprotegerin by osteocytes; these changes were different from those induced by teriparatide (Figure 1). The early increase in levels of markers of bone formation with sclerostin inhibitors was followed by a progressive decline to baseline values over time, which was not due to the development of neutralizing antibodies. Similarly, levels of markers of bone resorption increased towards baseline values but remained lower than baseline after 1 year of treatment, which suggests that, with treatment prolongation, the sclerostin antibodies act as mild inhibitors of bone turnover. Although a study of ovariectomized monkeys treated with romosozumab by Ominsky and colleagues and published in 2014 showed that the majority of bone mass accrual is due to the stimulation of modellingbased bone formation,10 a mechanistic explanation of the change in levels of markers of bone turnover over time in humans is not 250
Romosozumab Bone formation Bone resorption
Teriparatide
200
50 150
100
0
50 –50
0 0 0.25 1
2 3 6 9 Treatment duration (months)
12
0
1 3 6 9 Treatment duration (months)
12
Figure 1 | Bone turnover in response to anabolic bone therapies. Schematic representation Nature Reviews with | Endocrinology of changes in the levels of biochemical markers of bone turnover during treatment subcutaneous injections of either romosozumab (210 mg once monthly) or teriparatide (20 μg daily) for 1 year. Bone formation and bone resorption were assessed by measuring serum levels of procollagen type 1 aminoterminal propeptide (P1NP) and carboxy-terminal collagen crosslinking (CTX), respectively. Figure was compiled, in part, on the basis of data published elsewhere.9
2 | ADVANCE ONLINE PUBLICATION
readily available. In addition, these observations prompt the questions of whether longterm treatment with a sclerostin inhibitor is associated with a sustained anabolic effect on bone or whether initial treatment should be followed by another agent. The findings of the studies with sclerostin inhibitors establish these agents as novel bone-building therapies for postmenopausal osteoporosis; however, the antifracture efficacy and tolerability of these agents await the results of ongoing phase III clinical trials. Center for Bone Quality, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands. [email protected] Acknowledgements The author’s studies on sclerostin are supported by and carried out within the FP7 programme TALOS, which is funded by the European Commission (Grant Number: TALOS:Health‑F2‑2008‑201,099). Competing interests The author has received consulting fees and speaker honoraria from Amgen and UCB. 1.
Tsai, J. N. et al. Teriparatide and denosumab, alone or combined in women with postmenopausal osteoporosis: the DATA study randomized trial. Lancet 382, 50–56 (2013). 2. Leder, B. Z. et al. Two years of denosumab and teriparatide administration in postmenopausal women with osteoporosis (the DATA extension study): a randomized controlled trial. J. Clin. Endocrinol. Metab. 99, 1694–1700 (2014). 3. Ke, H. Z., Richards, W. G., Li, X. & Ominsky, M. S. Sclerostin and Dickkopf‑1 as therapeutic targets in bone diseases. Endocr. Rev. 33, 747–783 (2012). 4. Moester, M. J., Papapoulos, S. E., Lowik, C. W. & van Bezooijen, R. L. Slerostin: current knowledge and future perspectives. Calcif. Tissue Int. 87, 99–107 (2010). 5. Li, X. et al. Sclerostin antibody treatment increases bone formation, bone mass and bone strength in a rat model of postmenopausal osteoporosis. J. Bone Miner. Res. 24, 578–588 (2009). 6. Ominsky, M. S. et al. Two doses of sclerostin antibody in cynomologous monkeys increase bone formation, bone mineral density and bone stength. J. Bone Miner. Res. 25, 948–959 (2010). 7. Padhi, D., Jang, G., Struch, B., Fang, L. & Posrar, E. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J. Bone Miner. Res. 26, 19–26 (2011). 8. Recker, R. et al. A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density. J. Bone Miner. Res. http://dx.doi.org/10.1002/jbmr.2351. 9. McClung, M. R. et al. Romosozumab in postmenopausal women with low bone mineral density. N. Engl. J. Med. 370, 412–420 (2014). 10. Ominsky, M. S., Niu, Q.‑T., Li, C., Li, X. & Ke, H. Z. Tissue-level mechanisms responsible for the increase in bone formation and bone volume by sclerostin antibody. J. Bone Miner. Res. 29, 1424–1430 (2014).
www.nature.com/nrendo © 2014 Macmillan Publishers Limited. All rights reserved
New bone-forming treatments for osteoporosis Socrates E. Papapoulos
In 2014, two phase II clinical studies reported rapid, impressive increases in BMD in women with low bone mass who were treated with sclerostin inhibitors for 1 year. The antifracture efficacy and tolerability of these new, bone-building therapies are currently being investigated in phase III clinical trials. Papapoulos, S. E. Nat. Rev. Endocrinol. advance online publication 9 December 2014; doi:10.1038/nrendo.2014.214
Osteoporosis is characterized by low bone mass and structural decay of bone tissue, which lead to increased bone fragility and fractures. Pharmacological interventions for osteoporosis aim to decrease the risk of fractures and the associated clinical consequences (such as deterioration in quality of life and risk of new fractures and mortality) by correcting the imbalance between bone resorption and bone formation that constitutes the pathophysiological basis of the disease. Most currently available pharmacological agents inhibit bone resorption and bone turnover to varying degrees and decrease the risk of fractures; however, these agents do not stimulate the formation of new bone that is essential for the management of patients with severe disease. For these patients, agents capable of stimulating new bone formation are required. Teriparatide (a recombinant form of parathyroid hormone, PTH1–34, that is the most extensively studied bone-forming treatment) stimulates not only bone formation but also bone resorption, and acts mainly at sites in the bone that are undergoing active remodel ling rather than at quiescent bone surfaces, a property which, in my view, differentiates a bone-forming therapy from an anabolic therapy. A key question is whether concurrent inhibition of bone resorption might improve the effect of teriparatide on bone mass, particularly at cortical sites. Previously, it was reported that postmeno pausal women with osteoporosis who were treated with both teriparatide and denosumab (a bone resorption inhibitor) for 1 year had considerably increased BMD at the spine and at the hip compared with
women who received either monotherapy alone.1 The greater increase in BMD was probably due to inhibition by denosumab of the production of RANKL, which is stimulated by PTH. In 2014, Leder and colleagues reported the results of the second year of this study.2 For 24 months, 94 women with osteo porosis received teriparatide (20 μg per day), denosumab (60 mg every 6 months) or both agents. Although BMD increased further with all treatments, the increase in BMD did not differ between the groups, which led the authors to suggest that the most cost-effective way to achieve greater increases in BMD might be to use the combination therapy for 1 year followed by an antiresorptive agent in the second year. An early rapid increase in bone mass is particularly relevant for patients with severe disease and a recent fracture, as these patients are at the highest risk of a new fracture in the following 1–2 years. In addition to illustrating the feasibility of an efficacious combination therapy for patients with osteoporosis, the results of this study 2 strongly suggest that for an optimal effect on bone mass in cancellous bone and
cortical bone, stimulation of bone formation should be accompanied by a decrease in bone resorption. Treatments to achieve this aim are currently being investigated following the identification of new targets in bone. One such target is sclerostin, a natural inhibitor of the Wnt signalling pathway that is produced in the skeleton exclusively by osteocytes and inhibits bone formation.3 The restricted expression of sclerostin in the skeleton, the markedly increased bone mass and bone strength in patients and mice with sclerostin deficiency, and the lack of extraskeletal complications has made sclerostin an attractive therapeutic target in osteoporosis.4 Inhibitors of sclerostin increase bone formation at all skeletal envelopes and considerably improve bone strength without affecting or even decreasing bone resorption in appropriate animal models.5,6 The latter action of sclero stin inhibitors was confirmed in a phase I clinical study by measuring the levels of biochemical markers of bone turnover.7 In 2014, two phase II studies of different sclerostin inhibitors (the humanized antibodies romosozumab and blosozumab) and with different study designs were reported.8,9 Recker et al. reported the results of a dosefinding study of blosozumab given sub cutaneously for 1 year to 120 postmenopausal women aged 45–85 years with BMD T‑scores between –2.0 and –3.5.8 All women received calcium and vitamin D supplements and were randomly assigned to receive placebo or blosozumab (180 mg every 4 weeks; 180 mg every 2 weeks or 270 mg every 2 weeks). Blosoz umab treatment induced dose- dependent increases in spine BMD of 8.4%, 14.9% and 17.0%, respectively, in total hip BMD of 2.1%, 4.5% and 6.3%, respectively, in femoral neck BMD of 2.7%, 3.9% and 6.3%, respectively, and in total body bone mineral
Key advances ■■ Teriparatide, a bone-forming agent, stimulates not only bone formation but also bone resorption2 ■■ During a 1 year extension of the combination study of teriparatide and denosumab, further increases in BMD were observed at the spine and at the hip for a second year2 ■■ Antibodies to sclerostin rapidly stimulate bone formation, decrease bone resorption and impressively increase BMD at the spine and at the hip after 1 year 8,9 ■■ Treatment with the sclerostin antibody romosozumab resulted in considerably greater increases in BMD than those observed with either teriparatide or alendronate treatment9 ■■ The increase in bone mass with sclerostin antibodies is mainly due to the stimulation of bone formation at quiescent bone surfaces,10 establishing these agents as new bone-building therapies for osteoporosis
NATURE REVIEWS | ENDOCRINOLOGY
ADVANCE ONLINE PUBLICATION | 1 © 2014 Macmillan Publishers Limited. All rights reserved
YEAR IN REVIEW
Changes of markers of bone turnover (%)
content of 1.7%, 4.2% and 7.3%, respectively, after 1 year; blosozumab treatment had no effect on BMD at the distal radius. Mild injection site reactions were more frequently observed with blosozumab than with placebo and neutralizing antibodies developed in one patient, which affected her response to treatment. Although the frequency of adverse events was similar among all groups, four women (all Japanese) were diagnosed with breast cancer in the period between 3 months of initiating treatment to 1 year after the last dose of blosozumab; however, none of the investigators considered this adverse event to be related to blosozumab treatment. McClung and colleagues examined the efficacy and tolerability of different doses and dosing intervals of subcutaneous injections of romosozumab compared with placebo, oral alendronate (70 mg, weekly) or subcutaneous injections of teriparatide (20 μg daily) in 419 postmenopausal women, aged 55–85 years, with BMD T‑scores between –2.0 and –3.5.9 All women received calcium and vitamin D supplements and were randomly assigned to receive subcutaneous injections of placebo or romosozumab either monthly (70 mg, 140 mg or 210 mg) or every 3 months (140 mg or 210 mg). All doses of romosozumab induced notable increases in BMD. The highest dose of romosozumab increased BMD at the spine (by 11.3%), total hip (by 4.1%) and femoral neck (by 3.7%) after 1 year. These increases were considerably higher than those observed in women treated with either alendronate or teriparatide. No statistically significant differences in BMD at the distal radius were observed at 12 months between any of the treatment groups and placebo. The incidence of adverse events was similar among 100
all groups except for mild reactions at the injection sites of romosozumab. Neutralizing antibodies developed in 3% of patients on romosozumab, but had no effect on treatment outcomes. One patient who received romosozumab was diagnosed with breast cancer during the trial, but that was not considered by the investigators to be treatment-related. This study,9 as well as the study of the combination of teriparatide with denosumab,2 was not designed to assess the efficacy of treatments on the incidence of osteoporotic fractures, which is currently being investigated in ongoing phase III clinical trials with monthly injections of romosozumab. Both sclerostin inhibitors rapidly increased levels of markers of bone formation and also decreased levels of markers of bone resorption, possibly via an effect on the production of RANKL and/or osteoprotegerin by osteocytes; these changes were different from those induced by teriparatide (Figure 1). The early increase in levels of markers of bone formation with sclerostin inhibitors was followed by a progressive decline to baseline values over time, which was not due to the development of neutralizing antibodies. Similarly, levels of markers of bone resorption increased towards baseline values but remained lower than baseline after 1 year of treatment, which suggests that, with treatment prolongation, the sclerostin antibodies act as mild inhibitors of bone turnover. Although a study of ovariectomized monkeys treated with romosozumab by Ominsky and colleagues and published in 2014 showed that the majority of bone mass accrual is due to the stimulation of modellingbased bone formation,10 a mechanistic explanation of the change in levels of markers of bone turnover over time in humans is not 250
Romosozumab Bone formation Bone resorption
Teriparatide
200
50 150
100
0
50 –50
0 0 0.25 1
2 3 6 9 Treatment duration (months)
12
0
1 3 6 9 Treatment duration (months)
12
Figure 1 | Bone turnover in response to anabolic bone therapies. Schematic representation Nature Reviews with | Endocrinology of changes in the levels of biochemical markers of bone turnover during treatment subcutaneous injections of either romosozumab (210 mg once monthly) or teriparatide (20 μg daily) for 1 year. Bone formation and bone resorption were assessed by measuring serum levels of procollagen type 1 aminoterminal propeptide (P1NP) and carboxy-terminal collagen crosslinking (CTX), respectively. Figure was compiled, in part, on the basis of data published elsewhere.9
2 | ADVANCE ONLINE PUBLICATION
readily available. In addition, these observations prompt the questions of whether longterm treatment with a sclerostin inhibitor is associated with a sustained anabolic effect on bone or whether initial treatment should be followed by another agent. The findings of the studies with sclerostin inhibitors establish these agents as novel bone-building therapies for postmenopausal osteoporosis; however, the antifracture efficacy and tolerability of these agents await the results of ongoing phase III clinical trials. Center for Bone Quality, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands. [email protected] Acknowledgements The author’s studies on sclerostin are supported by and carried out within the FP7 programme TALOS, which is funded by the European Commission (Grant Number: TALOS:Health‑F2‑2008‑201,099). Competing interests The author has received consulting fees and speaker honoraria from Amgen and UCB. 1.
Tsai, J. N. et al. Teriparatide and denosumab, alone or combined in women with postmenopausal osteoporosis: the DATA study randomized trial. Lancet 382, 50–56 (2013). 2. Leder, B. Z. et al. Two years of denosumab and teriparatide administration in postmenopausal women with osteoporosis (the DATA extension study): a randomized controlled trial. J. Clin. Endocrinol. Metab. 99, 1694–1700 (2014). 3. Ke, H. Z., Richards, W. G., Li, X. & Ominsky, M. S. Sclerostin and Dickkopf‑1 as therapeutic targets in bone diseases. Endocr. Rev. 33, 747–783 (2012). 4. Moester, M. J., Papapoulos, S. E., Lowik, C. W. & van Bezooijen, R. L. Slerostin: current knowledge and future perspectives. Calcif. Tissue Int. 87, 99–107 (2010). 5. Li, X. et al. Sclerostin antibody treatment increases bone formation, bone mass and bone strength in a rat model of postmenopausal osteoporosis. J. Bone Miner. Res. 24, 578–588 (2009). 6. Ominsky, M. S. et al. Two doses of sclerostin antibody in cynomologous monkeys increase bone formation, bone mineral density and bone stength. J. Bone Miner. Res. 25, 948–959 (2010). 7. Padhi, D., Jang, G., Struch, B., Fang, L. & Posrar, E. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J. Bone Miner. Res. 26, 19–26 (2011). 8. Recker, R. et al. A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density. J. Bone Miner. Res. http://dx.doi.org/10.1002/jbmr.2351. 9. McClung, M. R. et al. Romosozumab in postmenopausal women with low bone mineral density. N. Engl. J. Med. 370, 412–420 (2014). 10. Ominsky, M. S., Niu, Q.‑T., Li, C., Li, X. & Ke, H. Z. Tissue-level mechanisms responsible for the increase in bone formation and bone volume by sclerostin antibody. J. Bone Miner. Res. 29, 1424–1430 (2014).
www.nature.com/nrendo © 2014 Macmillan Publishers Limited. All rights reserved
