The therapeutic arsenal for osteoporosis has expanded dramatically since the early 1980s, when the only options were estrogen for women and calcium and vitamin D for men. Today, the picture is much different. Available therapies include estrogen, raloxifene, four different bisphosphonates, the anabolics teriparatide and abaloparatide, and the monoclonal antibody denosumab.

A new option has just joined that list. The FDA in April approved a biologics license application for romosozumab (Evenity, Amgen), a humanized monoclonal antibody that targets sclerostin. The indication is for the treatment of osteoporosis in postmenopausal women at high risk for fracture, which includes those with multiple risk factors for fracture or a history of osteoporotic fracture, those who cannot tolerate other agents or those for whom other agents have failed.

“Our therapeutic options have increased in terms of the availability of more potent drugs and also our ability to increase bone formation,” Meryl Susan LeBoff, MD, chief of the calcium and bone section in the endocrinology, diabetes and hypertension division at Brigham and Women’s Hospital and a professor of medicine at Harvard Medical School, told Endocrine Today. “It is critically important to have ways to treat patients who have more severe disease. Romosozumab is unique — it is a monoclonal antibody against sclerostin, but it stimulates bone formation and inhibits bone breakdown.”

For all the progress made in osteoporosis research, there are still major challenges to confront, LeBoff said. Most patients with fragility fractures are not evaluated and treated for their osteoporosis and most high-risk patients are not starting or continuing treatments that reduce risk for fractures. All the while, the prevalence of osteoporosis in the United States continues to rise with increasing life expectancy.

“The risk for a new osteoporotic fracture is greater than the combined risk of a new diagnosis of breast cancer, a new diagnosis of prostate cancer or a new myocardial infarction,” LeBoff said. “This is a very prevalent disease. It’s incumbent on us as clinicians to look at osteoporosis as not just a women’s disease, and not a normal occurrence for all aging individuals. We must identify people who are at risk for fracture. We need effective therapies, and we have some for osteoporosis, but new approaches can advance patient care.”

‘A new point of entry’

The effect of romosozumab is unique among antiosteoporosis agents — it has the dual effect of preventing bone resorption and stimulating bone formation. By binding to sclerostin, it prevents the glycoprotein from inhibiting the canonical Wnt signaling pathway, which plays a substantial role in skeletal development, adult skeletal homeostasis and bone remodeling. In the presence of romosozumab, the Wnt signaling pathway is activated, leading to bone formation and gains in bone mineral density. The drug’s effect on BMD wanes by 12 months of therapy; therefore, treatment duration is limited to 1 year, to be followed by an antiresorptive agent. The dose is given once monthly.

“If you look at the field conceptually, romosozumab is truly pathbreaking because it is a new point of entry into this system,” Robert Blank, MD, PhD, professor of medicine in the division of endocrinology, metabolism and clinical nutrition at the Medical College of Wisconsin, told Endocrine Today. “It is not as though people didn’t know about the Wnt pathway before, but it is an exciting drug because it was built on discoveries made in the lab and brought forward in a science-driven manner, from understanding the mechanism to having the drug.”

The dual action of romosozumab, which Blank called a surprise, points to where the osteoporosis field needs to go next, he said.

“What that says to me is that there is a checkpoint on the Wnt pathway that we don’t yet fully understand,” Blank said. “I don’t believe that the other inhibitors of signaling are sufficient to account for it. There is another pathway communicating with the Wnt pathway, and the next big advance will be figuring out exactly what that is.”

CV concerns

Romosozumab was approved with a boxed warning alerting users that it may increase risks for heart attack, stroke and cardiovascular death and that patients should not use the drug if they have had a heart attack or stroke within the previous year.

In January, the Bone, Reproductive and Urologic Drugs Advisory Committee of the FDA voted 18-1 in favor of recommending approval of romosozumab, but the panel members unanimously called for additional data regarding the CV safety of drug, with most members supporting conduct of a randomized controlled trial or an observational study upon approval.

In July 2017, the FDA issued a complete response letter for romosozumab, asking Amgen to add safety and efficacy data from the ARCH and BRIDGE trials into the drug application. In ARCH, postmenopausal women with osteoporosis assigned to romosozumab saw a 50% reduction in the RR for spinal fracture, a 19% reduced risk for nonvertebral fracture and a 72% reduced risk for clinical fracture; however, a 2.5% incidence of CV events after 12 months was reported. In BRIDGE, the incidence of positively adjudicated serious adverse CV events in men was 4.9% in the romosozumab group and 2.5% in the placebo group, according to Amgen. The incidence of positively adjudicated CV death was 0.6% in the romosozumab group and 1.2% in the placebo group.

The original application, submitted to the FDA in September 2016, was based on efficacy and safety data from the FRAME study, which did not show an increase in CV risk. Amgen and UCB resubmitted their application to the FDA in July, this time proposing to narrow the drug’s indication to treatment of osteoporosis in postmenopausal women at high risk for fracture. Amgen is also proposing a boxed warning as well as a warning and precaution for CV risk.

“The cardiovascular ‘signal’ with romosozumab was similar in magnitude to what was seen with odanacatib, an oral weekly cathepsin K inhibitor,” Nelson B. Watts, MD, director of Mercy Health Osteoporosis and Bone Health Services in Cincinnati, told Endocrine Today. “I don’t know for sure why Merck decided not to proceed with further FDA consideration of odanacatib, but the difference may be that odanacatib was intended for long-term use and romosozumab is not — and the signal with romosozumab was early and not sustained, whereas the signal with odanacatib was significant over the 5-year study period.” Merck announced in a September 2016 press release that is was discontinuing the odanacatnib development program after an independent adjudication and analysis of major adverse cardiovascular events confirmed an increased risk of stroke.

Mone Zaidi, MD, PhD, professor of endocrinology, diabetes and bone disease at the Icahn School of Medicine at Mount Sinai and director of the Mount Sinai Bone Program, said the threshold for hospitalization can vary internationally, potentially leading to an imbalance of events in a multicenter, worldwide trial that may not be attributable to the drug.

“A cancer signal would have concerned me most, which was not seen,” Zaidi told Endocrine Today. “As a scientist, I look for a mechanism. Is there a potential mechanism by which you could explain a serious adverse event? I can’t think of a mechanism through which the Wnt signaling pathway could cause a CV event — I just can’t — and we work on the Wnt signaling pathway.”

Thomas J. Weber, MD, associate professor of medicine in the division of endocrinology, metabolism and nutrition at Duke University Medical Center and a member of the FDA advisory committee, said the panel struggled to parse through why one study showed possible CV risk and the other did not.

“The appropriate approach that the committee took was, in the absence of definitive data, gather more data to understand it better,” Weber told Endocrine Today. “In the meantime, restrict the use of it. Do not give it to patients within 1 year of an MI or cardiovascular event, who have the highest risk for another CV event. I think that is a reasonable approach.”

Treatment sequence matters

In treating osteoporosis, recommendations regarding which agent to use first-line, which to use next, and for how long have all evolved as new analyses suggested that substantial differences in BMD outcomes may depend on those choices.

“We learned in the last several years that the sequence of administration of the newer medications is extremely important,” LeBoff said. “After an anabolic like teriparatide or abaloparatide, we must follow with an inhibitor of bone resorption, such as a bisphosphonate or denosumab. Denosumab, unlike bisphosphates, however, does not stay in the bone very long after 6 months. When this treatment is stopped, the bone turnover markers increase above baseline, and it is important that patients be treated with another antiresorptive agent.”

In a February 2017 analysis published in the Journal of Bone and Mineral Research,Felicia Cosman, MD, an endocrinologist at Helen Hayes Hospital Regional Bone Center in West Haverstraw, New York, and professor of medicine at Columbia University, and colleagues noted that both anabolic and potent antiresorptive agents improve BMD and reduce risk for fracture in treatment-naive patients; however, the effects of most medications differ in patients already pretreated with other potent osteoporosis therapies.

BMD responses to initial teriparatide (Forteo, Lilly) or parathyroid hormone therapy followed by potent antiresorptive therapy are substantial in both spine and hip sites as a result of the effects of both components of the treatment sequence, the researchers wrote. However, several studies have indicated that hip BMD responses to teriparatide are lower in patients already pretreated with potent antiresorptive therapies and consistently decline transiently for the first year or even longer.

“Our observations clearly highlight that the common practice of providing patients with first-line antiresorptive therapy and then only after patients have an inadequate BMD response and/or an intercurrent fracture to switch to [teriparatide] is not the optimal utilization of anabolic treatment,” Cosman and colleagues wrote, adding that the approach is particularly critical for a patient currently treated with a bisphosphonate or denosumab (Prolia, Amgen) who experiences a hip fracture.

“In cases such as these, we suggest consideration of combination treatment with utilization of potent antiresorptive therapy and addition of [teriparatide], for up to 2 years, to improve skeletal strength during this critical period,” the researchers wrote.

Deciding which therapy works best for which patient requires taking multiple factors into consideration, Weber said.

“That’s the $64,000 question,” Weber said. “Patients are different and have a spectrum of needs and requirements. My approach is pragmatic — I look at the patient’s age, the level of bone density and the risk for fracture, including whether they’ve had a fracture before. I put all of those into the equation, as well as other concomitant clinical factors, to determine the best therapy for that individual patient.”

Most patients, Weber noted, will obtain adequate fracture risk reduction from oral bisphosphonates.

“If you take them long enough, there is evidence of persistent benefit,” Weber said. “When patients have a higher fracture burden, particularly patients who take steroids, then that should guide you toward other options. For instance, in women with a history of multiple or severe vertebral fractures, teriparatide is superior to risedronate.”

Romosozumab might serve as a new option for patients for whom other osteoporosis medications failed or were not tolerated; however, questions still remain about its use, according to Sharon Chou, MD, instructor in medicine at Brigham and Women’s Hospital.

“We know the anabolic properties of romosozumab last for about 6 to 9 months, and then in trials it was followed with denosumab or alendronate,” Chou told Endocrine Today. “If my patients did not tolerate those therapies in the first place, we’re going to need to figure out how to best utilize this.

“I’m excited for romosozumab, but there are still a lot of questions,” Chou said. “In the trial, they used it for only 1 year. Can you use it again? Will you have the same effect if you use it again? It would be nice if it could be used repeatedly and still have that initial anabolic effect.”

Weber said more research is needed to help better answer those and other treatment sequence questions.

“We have a good armamentarium now of existing antiresorptive and anabolic therapies, and we’re learning more and more about how to refine them,” Weber said. “Questions remain in terms of which therapies do we give first, which do you follow up with, and when do you give a drug holiday? We’re not quite there yet. If we can give sequential therapies with potential drug holidays where indicated and apply a pragmatic approach, we can do well by our patients.”

A trickling pipeline

Apart from romosozumab, there are no other antiosteoporosis therapies in the late-stage pipeline, according to experts. The FDA approved abaloparatide (Tymlos, Radius Health) in 2017; before that, the last approved treatment was denosumab in 2010. Development of odanacatib was halted in 2016 due to CV safety concerns.

“Part of the concern is there are not a lot of new biological agents or therapies in the pipeline,” Weber said. “Certainly, there are some early-phase studies looking at ways to address bone fragility, there is work on concepts like cellular senescence, and there are different approaches for some of our therapies with drug delivery issues. That’s a huge issue.”

Other research is still in early stages. In February, Zaidi and colleagues at the Icahn School of Medicine at Mount Sinai were awarded a $12.5 million grant from the National Institute on Aging for a 5-year program called U19, consisting of four multidisciplinary projects in aging biology. One of the program’s goals is establishing follicle-stimulating hormone (FSH) as a potential therapeutic target for the treatment of osteoporosis, Zaidi said.

“We looked at FSH and found that FSH directly caused bone loss,” Zaidi said. “There was a huge pushback from the scientific community — this is a fertility hormone — but time has told us that not only FSH, but other pituitary hormones also directly affect bone.”

The first project, to be carried out at Mount Sinai, will analyze the role of FSH in regulating bone mass and body composition across the life span of mice, Zaidi said. The second study, to be performed collaboratively between investigators at Mount Sinai and UT Southwestern Medical School, will determine whether monoclonal FSH-blocking antibodies will prevent fat accrual and bone loss, and whether they will also treat established obesity and osteoporosis. The third project at Maine Medical Center Research Institute will study the effects of FSH on bone marrow fat deposits during aging and menopause. The fourth study at University of California, San Francisco, will use population-based data sets from the AGES-Reykjavik cohort of older men and women to study the relationships between FSH, body fat, bone mass and incident fracture, Zaidi said.

Zaidi said he hopes that the program will move toward a phase 1 clinical trial within 2 years.

“Now, we have an antibody against FSH that not only increased bone mass, but reduces body fat and increases energy expenditure,” Zaidi said. “It is important because during [menopause] in women, there is also a gain of visceral fat and a loss in energy metabolism.”

However, for more osteoporosis developments to reach the later clinical trial phases, Blank said several factors must be addressed.

“That depends on whether or not we, as a research community, do our job and find something conceptually new and potentially druggable,” Blank said. “It also depends on whether we continue to have a reasonably favorable environment at the NIH, and it remains to be seen how the policy conversations that are taking place right now in terms of access to care and potential limits on drug pricing are going to play into the evolving development of new pharmaceuticals. I don’t think it is unreasonable for the government to say that there is going to be a cap on the potential price of new drugs, but in order to accomplish that, there is going to have to be some give on the other side to make it easier and less expensive for someone to bring out a new drug. All of those pieces cannot be separated from each other.”

A ‘crisis’ in osteoporosis care

At the 2018 annual meeting of the American Society for Bone and Mineral Research, E. Michael Lewiecki, MD, director of the New Mexico Clinical Research & Osteoporosis Center and director of Bone Health TeleECHO Clinic at the University of New Mexico Health Sciences Center in Albuquerque, noted that fracture rates generally increased from 2013 to 2017, in part because of a decline in DXA screening, despite a drop in fracture rates among U.S. adults aged at least 50 years from 2007 to 2013.

“The osteoporosis treatment gap has gotten so severe that it’s been called a crisis in the care of osteoporosis,” Lewiecki told Endocrine Today. “Most people who have had fractures, for example, are not being treated to reduce the risk of the next fracture. Most people who need a bone density test to evaluate fracture risk are not getting it, and even when people are started on treatment, many of them don’t take treatment long enough to benefit from a reduction in fracture risk.”

LeBoff said it is critical for clinicians to establish better communication with patients and to listen to their concerns about issues like adverse effects, to avoid situations where a patient will stop the medication and then experience another fracture.

“In the next decade, it will be important for us to identify and treat the high-risk patients at risk for fractures and try to maximize bone health across the life span, from young adulthood to extreme old age, so we can optimize peak bone mass in young adults and identify those with risk factors for bone loss under the age of 50 years,” LeBoff said. “We need to advance the diagnosis and treatment of this disease and expand the next generation of therapeutic agents so we can seek to find a cure.” – by Regina Schaffer

• References:
• Cosman F, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1607948.
• Kendler DL, et al. Lancet. 2017;doi:10.1016/S0140-6736(17)32137-2.
• Lewiecki EM, et al. J Clin Endocrinol Metab. 2018;doi:10.1210/jc.2017-02163.
• McClung MR. Curr Osteoporos Rep. 2017;doi:10.1007/s11914-017-0376-x.
• Saag KG, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1708322.

• For more information:
• Robert Blank, MD, PhD, can be reached at the Medical College of Wisconsin, Division of Endocrinology, Metabolism and Clinical Nutrition, 8701 W. Watertown Plank Road, Wauwatosa, WI 53226; email: roblank@mcw.edu.
• Sharon Chou, MD, can be reached at Brigham and Women’s Hospital, Department of Medicine, Endocrinology, 221 Longwood Ave., Boston MA 02115; email: shchou@bwh.harvard.edu.
• Meryl Susan LeBoff, MD, can be reached at Brigham and Women’s Hospital, Department of Medicine, Endocrinology, 75 Francis St., Boston, MA 02115; email: mleboff@bwh.harvard.edu.
• E. Michael Lewiecki, MD, FACP, FACE, can be reached at the New Mexico Clinical Research & Osteoporosis Center, 300 Oat St. NE, Albuquerque, NM 87106; email: mlewiecki@gmail.com.
• Nelson B. Watts, MD, can be reached at Mercy Health Osteoporosis and Bone Health Services, 4760 E. Galbraith Road, Suite 212, Cincinnati, OH 45236; email: nwatts@mercy.com.
• Thomas J. Weber, MD, can be reached at Duke University Medical Center, Division of Endocrinology, Metabolism and Nutrition, 303 Baker House, DUMC 3470, Durham, NC 27710; email: thomas.weber2@duke.edu.
• Mone Zaidi, MD, PhD, can be reached at the Icahn School of Medicine at Mount Sinai, 5 E. 98th St., Third Floor, New York, NY 10029; email: mone.zaidi@mountsinai.org.