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Treatment fears, controversies result in largely undertreated osteoporosis population

The field of bone health is filled with excitement and fraught with challenges, according to experts. Forward motion is interspersed with roadblocks. Solid first-line osteoporosis therapies are plagued with concerns about drug holidays following their media spotlight. New treatments show promise but require research on utilization in distinct groups, including premenopausal women.

With a growing aging population, helping men and women maintain strong skeletons is more important than ever. The critical first steps of ensuring patients are properly diagnosed and start the therapy they need, however, may not be happening.

“The problem is we’re not treating people,” Paul D. Miller, MD, FACP, of the Colorado Center for Bone Research in Lakewood, Colo., told Endocrine Today. “The number of people being treated has actually gone down. It’s really kind of discouraging to see, when you work in the field for more than 30 years.”

Fears, first-lines and drug holidays

The estimated use of postfracture osteoporosis medication in the year after discharge for hip fracture dropped from 40.2% in 2002 to 20.5% in 2011 (P for trend <.001), according to research by Daniel H. Solomon, MD, MPH, of Brigham and Women’s Hospital, and colleagues published in the Journal of Bone and Mineral Research.

The retrospective, observational study looked at US administrative insurance claims data for beneficiaries aged at least 50 years at admission with commercial or Medicare supplemental health insurance who were hospitalized for hip fracture; 62,498 patients were included in 12 months of follow-up. The predictor most strongly and positively associated with medication use after fracture was its use before fracture.

Miller said many theories for the steep decrease exist, but one looms a little larger.

“There is a fear about bisphosphonates that’s been driven by a lot of media about atypical subtrochanteric femur fractures,” Miller said. “Patients come in and either don’t want to take them or don’t want to stay on them.”

Paul D. Miller, MD, FACP, of the Colorado Center for Bone Research in Lakewood, Colo., said the number of patients receiving appropriate treatment for osteoporosis has declined over his 30 years of practice.

Photo courtesy of Paul D. Miller, MD, FACP.

 

The most common medications prescribed for osteoporosis for nearly 2 decades, bisphosphonates — alendronate, risedronate, ibandronate and zoledronic acid — have a unique pharmacology at the center of the debate over drug holidays.

“Bisphosphonates are the only drugs in clinical medicine that are not metabolized,” Miller said. “You look at blood pressure medicine, diabetes medicines or statins; any other medicines are usually broken down in the liver. Bisphosphonates get retained in bone, in remodeling cavities, buried there, and then detach from the bone surface, go back in the bloodstream and then reattach back on the bone surface.”

Due to this “recycling” and maintenance of pharmacologic effect, giving patients a break after a loading period of a certain amount could offer continual efficacy when it comes to stable bone densities and stable biochemical markers of bone turnover for a number of years, Miller said. But clinicians will never have the luxury of certainty as it pertains to persistence of fracture risk reduction, he added.

“You’ll never have true, hard scientific evidence,” Miller said. “After 5 years, nobody has any controlled data because they stopped the trials. You can never continue the placebo groups for that long a time. It’s just not ethical.”

In 2011, Miller took his thoughts on drug holidays to the Capitol for an FDA advisory board meeting on bisphosphonate duration of use and a related potential label change. Beneath the surface lingered concern about atypical subtrochanteric femur fractures 5 years or more into treatment with alendronate, Miller said. After a day of deliberation, however, the FDA did not change the label.

Miller said the longest available data come from a subset of patients treated with alendronate in the Fracture Intervention Trial (FIT) trial, published in JAMA, who, after 5 years of alendronate therapy, were randomly reassigned to continued therapy or placebo in the 5-year FIT Long-term Extension (FLEX) trial, published in JAMA Internal Medicine.

“The biochemical marker of bone reabsorption C-telopeptide that we use as a surrogate marker for bone turnover did not really change in the first 2 years of FLEX but by the third year started to go up, suggesting that you were losing some of the biological effect of the bisphosphonate,” Miller said. No between-group differences were observed in hip, nonvertebral or morphometric vertebral fractures, but there was a significant difference in clinical vertebral fractures, with more fractures in the placebo group, he noted.

The fracture risk assessment tool (FRAX) algorithms developed by WHO are helpful in defining 10-year probability of fracture when considering treatment, Miller said.

“It’s a perfectly acceptable standard of care to consider discussing a drug holiday in lower-risk patients,” Miller said. “You can watch periodically to see if they’re going down on their bone density and if other biochemical markers of bone turnover are beginning to go up as evidence of the loss of efficacy. Continuation of bisphosphonates in high-risk patients is appropriate since in these patients the benefits outweigh the risk.”

An evolving armamentarium of therapies

Cathepsin K inhibitors and antisclerostin therapies are two pharmacologic approaches that may be on the horizon for treating osteoporosis based on results from recent trials, according to Matthew T. Drake, MD, PhD, of the Mayo Clinic in Rochester, Minn.

Data from phase 3 of the Long-Term Odanacatib Fracture Trial (LOFT) examining safety and efficacy of the once-weekly oral cathepsin K inhibitor, developed by Merck, was presented at the American Society for Bone and Mineral Research (ASBMR) 2014 Annual Meeting in Houston.

“The study team showed it was effective at limiting fractures,” Drake told Endocrine Today. “They also showed the rates of dermatologic complications were not particularly high, which was an issue of concern raised in the phase 2 portion of the trial.”

The randomized, double blind, placebo-controlled, international trial involved 16,071 postmenopausal women diagnosed with osteoporosis. Odanacatib reduced new and worsening morphometric vertebral fractures by 54%, clinical hip fractures by 47%, clinical nonvertebral fractures by 23% and clinical vertebral fractures by 72% (P<.001 for all), according to a press release from the company.

Further, progressive bone mineral density increases were observed at the lumbar spine (11.2%) and total hip (9.5%) during 5 years compared with placebo (P<.001 for both).

To break down bone, osteoclasts sit on the bone surface and create a sealed area into which they secrete both the protease cathepsin K to break down the bone matrix and acid that dissolves the mineral adherent to the bone matrix, Drake said.

Odanacatib’s novel mechanism inhibits the cathepsin K enzyme and offers some benefits over other therapies.

“We have not had this type of molecule previously,” Drake said. “It has a shorter half-life than bisphosphonates, which remian in bone for a long time. Because it has a much shorter duration of action, patients will need to continue to take it.”

The drug may not serve as a first-line therapy for osteoporosis with so many other solid medications already available, but it provides another option, Drake said, particularly in patients with treatment intolerance to other medications.

“For those patients, odanacatib certainly would be a welcome addition to our armamentarium,” Drake said.

Sclerostin molecules — produced by osteocytes, or bone-forming cells that have become terminally differentiated and entombed within the bone they have made — are the target of new therapies romosozumab (Amgen) and blosozumab (Eli Lilly).

“Sclerostin helps the skeleton respond to mechanical stresses in order to maintain bone strength, so you don’t make either too much bone or too little bone,” Drake said. “It’s a negative regulator of bone formation.”

Antisclerostins bind to these naturally formed target molecules, allowing the formation of bone, according to Drake.

“Sclerostin always has its foot a little on the brake. Antisclerostin therapy takes the foot off,” he said.

Amgen is further along in trials than Eli Lilly, Drake noted. He highlighted phase 2 results from a multicenter, international trial by Michael R. McClung, MD, and colleagues published in The New England Journal of Medicine that included 419 women aged 55 to 85 years with low bone mineral density (BMD; T-score of −2 or less at the lumbar spine, total hip or femoral neck and −3.5 or more at each of the three sites).

Women were randomly assigned to subcutaneous romosozumab once monthly (70 mg, 140 mg or 210 mg) or every 3 months (140 mg or 210 mg); subcutaneous placebo; or open-label oral alendronate (70 mg/week) or subcutaneous teriparatide (20 mcg/day; Forteo, Eli Lilly).

At 12 months, significant BMD increases were seen at the lumbar spine with all romosozumab doses, including an 11.3% increase with 210 mg monthly vs. a decrease of 0.1% with placebo and increases of 4.1% with alendronate and 7.1% with teriparatide.

Phase 3 data from a study of postmenopausal women randomly assigned to subcutaneous romosozumab monthly (210 mg; n=17), subcutaneous teriparatide (20 mcg; n=19) or placebo (n=20) assessing parameters at various locales also were presented at ASBMR 2014. Romosozumab demonstrated greater improvements in cortical thickness (P<.001), cortical BMD (P=.04) and cortical mass (P<.001) vs. teriparatide.

“The therapy works completely differently than the others available,” Drake said. “The antisclerostin molecule is the only one that tries to only affect the bone-building cell activity.”

Teriparatide works to increase bone resorption in addition to bone building, with the latter ideally predominating, according to Drake. Bisphosphonates and denosumab (Prolia and Xgeva; Amgen) inhibit osteoclast activity and prevent bone from being removed, he said.

“The exciting thing about the antisclerostin molecule is that it targets the osteoblasts to actually stimulate bone to be formed,” Drake said. “It’s really a skeletal anabolic therapy that tries to build up bone instead of just prevent it from being removed.”

Assessing bone loss, treatment and costs

Mone Zaidi, MD, PhD, of the Icahn School of Medicine at Mount Sinai Hospital, called it “therapeutically meaningful” to view bone loss as a continuum.

“You don’t suddenly become osteoporotic, without being osteopenic; it’s a continuation of that same process,” Zaidi told Endocrine Today. “It’s important to note that bone loss in a woman starts very early, at the onset of menopause.”

For women, bone is maximized in their 30s and remains stable during the reproductive phase of their life but is reduced dramatically in their early 50s or at the onset of menopause, Zaidi said. To date, this phase of rapid bone loss had not been studied in detail, mainly because the means had not been available, he added.

Mone Zaidi

Early bone loss has become obvious through several recent clinical studies, according to Zaidi. He pointed to research by the late MaryFran Sowers, PhD, part of the ongoing SWAN study, which examined parameters of more than 3,000 women who were entering menopause at enrollment.

“Hormonal changes and bone loss during early menopause are now being looked at very carefully,” Zaidi said. “Researchers have clearly demonstrated that bone loss starts 3 years prior to the last menstrual period, and the correlation is strong with elevated follicle-stimulating hormone levels. These may actually be a contributor to the early loss, and estrogen could be at normal levels.”

Osteopenia is actually an epidemiologic definition, Zaidi said, with the representative T-score between –1 and –2.5 standard deviations below the mean of the reference population, now called low bone mass, and osteoporosis is characterized by a T-score of less than –2.5.

“Essentially, it’s the same thing,” Zaidi said. “Women start losing bone very early in menopause, and the process continues through the phases of osteopenia and osteoporosis to end up, at some point, at a very high fracture risk.”

With the exception of estrogen, drugs have not traditionally been used in the very early phase of bone loss, Zaidi said. Treating this active bone loss has come to the forefront as an area that needs addressing — but also one that is highly debated.

Drake said most insurance companies are relatively hesitant to treat osteopenia, although because many more people have osteopenia than have osteoporosis, there are more fractures that occur in people with osteopenia than with osteoporosis. Treatment becomes a question of what is best to do from both an individual personal management perspective and a population perspective, he added.

“Treating everyone with osteopenia would likely involve a lot of people who don’t really need it because they may never have a fracture,” Drake said. “Certainly medical costs would run up significantly, and patients would be at increased risk for potential side effects.”

According to Drake, the community is working to stratify patients with osteopenia to decide who might benefit most from therapy. “We have to come up with a number to see whether it will be cost-effective or not to treat someone,” he said.

An analysis by Bess Dawson-Hughes, MD, of Tufts University, and colleagues published in Osteoporosis International employed FRAX to evaluate the impact of guidance on treatment eligibility in the United States.

If the risk for any osteoporotic fracture is ≥20% or the risk of a hip fracture is ≥3%, it would be cost-effective to begin a pharmacologic management approach in patients with osteopenia, the researchers found.

Arriving at assessing patients, however, is a hurdle that would need to be overcome first.

“It has been well documented by the International Society for Clinical Densitometry (ISCD) that the number of bone density measurements being done is going down and with that the number of diagnoses,” Miller said.

Miller recalled testifying in front of Medicare to get the Bone Mass Measurement Act passed. Backed by the National Osteoporosis Foundation, the congressional statute broadened the indication and CMS reimbursement for bone densitometry. In time, the recommendations for BMD testing included all women aged at least 65 years with no risk factors or aged at least 60 years with one or more risk factors.

It is one of only two population-based screenings formally recommended by the US Preventive Services Task Force and US Surgeon General, but Miller said enactment of this policy has been hampered by declining reimbursement for DXA.

“The only other disease where population screening is endorsed is breast cancer with a mammography,” Miller said. “We got all the legislation through, we got the political support; but the reimbursements dropped, and the number of people being tested is declining.”

Further, Miller said the demands of an internal medicine practice make implementation of bone health assessments challenging, particularly with patients coming through the doors with diabetes, obesity and high cholesterol.

Zaidi agreed that ascertainment of key populations is being missed. “Only 3% of wrist fractures ever get a diagnosis for osteoporosis and treated,” he said. “That’s probably the harbinger of osteoporosis in early postmenopausal women; it’s the first presenting fracture.”

A recent report by Peter Ebeling, MD, FRACP, of Monash University in Victoria, Australia, and colleagues released by the IOF detailed the grave effects resulting from the lack of detection of osteoporosis in men. Worldwide, approximately one in five men aged at least 50 years will break a bone due to osteoporosis, according to the report. Further, men are twice as likely as women to die in the year after a hip fracture, with a mortality rate as high as 37%.

“An inadequate amount of health care resources are being invested in bone, muscle and joint diseases,” John A. Kanis, MD, professor emeritus at the University of Sheffield, United Kingdom, said in a press release. “People should not have to live with the pain and suffering caused by osteoporosis as we can help prevent and control the disease.”

Investigation into idiopathic osteoporosis

Elizabeth Shane, MD, of Columbia University, and colleagues are figuring out what it takes to forecast and reduce fractures in an entirely different population: premenopausal women.

“We want to understand the general pathogenesis of unexplained osteoporosis in these women, to devise ways to manage these women, particularly those who are having fractures or continuing to lose bone despite conservative therapy, and to investigate potential genetic causes that could possibly be related to this,” Shane told Endocrine Today.

Elizabeth Shane

The researchers’ data suggest a number of potential causes for the condition, some genetic, and treatment results that leave questions, she said.

“It’s challenging enough to manage osteoporosis in older people,” Shane said. “When you’re talking about younger women, and younger men, there is limited evidence about the benefits and the risks of treatment.”

Because these patients often have reduced bone remodeling, therapies that further suppress that activity are unattractive, she said. “You wouldn’t want to reduce remodeling further.”

Teriparatide demonstrated improvements in a pilot study of 21 premenopausal women with idiopathic osteoporosis conducted by Shane, along with Adi Cohen, MD, also of Columbia University, and colleagues, published in The Journal of Clinical Endocrinology & Metabolism. BMD increased at the spine (10.8 ± 8.3%), total hip (6.2 ± 5.6%) and femoral neck (7.6 ± 3.4%; P<.001 for all).

“Because the study is small and because the disorder is rare, we don’t really know that this is going to prevent fractures,” Shane said.

Approximately 20% of patients did not seem to respond to the therapy, which appears to be related to extremely low bone remodeling at the outset, she said. Still another challenge is determining what to do after teriparatide therapy — typically a maximum 2-year course of therapy, and in older people followed with an antiresorptive drug to prevent the effects from dissipating, she added.

The Columbia University researchers are currently recruiting 40 women with the condition to investigate the lack of response; the study is approximately 60% recruited, and the investigators encourage clinicians to reach out to more patients.

“We recruit nationally and internationally, we have some funding to help with travel, and we work very closely with referring physicians to accomplish the goals of the grant, which is to provide patients with treatment shown to be effective — at least in improving bone density,” Shane said. “Hopefully, this new study will give us the evidence we need to see who responds and who doesn’t, so we can predict response very early on in a personalized way.”

Answers not always apparent

Although osteoporosis makes up the brunt of metabolic bone disease, thin bones do not make a diagnosis, said Michael D. Whitaker, MD, FRCPC, of the Mayo Clinic Arizona.

“Bone density tests will tell you a patient has metabolic bone disease, but it won’t tell you the cause,” Whitaker told Endocrine Today. He gave a keynote talk addressing the topic at the American Association of Clinical Endocrinologists 23rd Annual Scientific & Clinical Congress in Las Vegas.

Several conditions exist besides osteoporosis that, although not as frequently occurring, warrant clinicians’ attention, Whitaker said.

In osteomalacia, bones may not mineralize adequately due to vitamin D deficiency, severe calcium malabsorption or other rare conditions, such as tumor-induced osteomalacia.

“Thin bones could be osteoporosis, or they could be an entirely different bone disease that would be treated differently and needs to be looked at differently,” he said.

In hypophosphatasia, an inborn error of metabolism disrupts mineralization and thereby affects the bones and teeth, Whitaker said. Some nonendocrine-related conditions, such as multiple myeloma or mast cell disease, can also result in reduced bone density.

“These are uncommon causes of reduced bone density, but need to be considered in a differential diagnosis every time,” he said.

Replacement therapy is used to treat the vitamin D deficiency and calcium malabsorption in osteomalacia, Whitaker said. Osteoporosis therapies are not effective in this population.

Mesenchymal tumors that produce too much fibroblast growth factor-23 (FGF-23) can result in profound deficiency in the active vitamin D metabolite 1,25-dihydroxyvitamin D over time, leading to failure to mineralize bone, severe osteomalacia and subsequent fractures, he said.

“It’s important to identify because identifying where the tumor is and surgically removing it will cure the problem,” Whitaker said. “It’s very uncommon but can’t be missed.”

Patients with osteomalacia typically present with widespread bone pain, in contrast to patients with osteoporosis.

“Bones tend to bend, and they become painful,” he said. “A patient with bone pain who has a low bone density makes you think more of osteomalacia.”

Bone fractures also are frequent in this population, and extremely low serum phosphorous levels characterize the disease, Whitaker said. All factors combined would trigger testing for FGF-23 and 1,25-dihydroxyvitamin D, and if elevated and low, respectively, would suggest a diagnosis.

Expanding the differential diagnosis of low bone density is critical, Whitaker said.

“It’s just making doctors, particularly endocrinologists, aware that what is seemingly obvious isn’t necessarily so,” he said. “You need a T-score of –2.5 to make a diagnosis for osteoporosis. But a T-score of –2.5 is not necessarily always osteoporosis.” – by Allegra Tiver

For more information:
  • Black DM. JAMA. 2006;296:2927-2938.
  • Cohen A. J Clin Endocrinol Metab. 2013;98:1971-1981.
  • Cummings SR. JAMA. 1998;280:2077-2082.
  • Dawson-Hughes B. Osteoporos Int. 2011;23:811-820.
  • Ebeling P. International Osteoporosis Foundation. Osteoporosis in Men: Why Change Needs to Happen. Available at: www.iofbonehealth.org/data-publications/reports/osteoporosis-men-why-change-needs-happen. Accessed Nov. 19, 2014.
  • McClung MR. Abstract #1147. Presented at: ASBMR 2014 Annual Meeting; Sept. 12-15, 2014; Houston.
  • McClung MR. N Engl J Med. 2014;370:412-420.
  • Solomon DH. J Bone Miner Res. 2014;29:1929-1937.
  • Whitmarsh T. Abstract #1049. Presented at: ASBMR 2014 Annual Meeting; Sept. 12-15, 2014; Houston.
  • Matthew T. Drake, MD, PhD, can be reached at the Endocrine Research Unit, Mayo Clinic, 200 First St. SW, Rochester, MN 55905; email: drake.matthew@mayo.edu.
  • Paul D. Miller, MD, FACP, can be reached at the Colorado Center for Bone Research, 3190 S. Wadsworth Blvd., Lakewood, CO 80227; email: millerccbr@aol.com.
  • Elizabeth Shane, MD, can be reached at Columbia University, College of Physicians and Surgeons, Department of Medicine, 630 W. 168th St., New York, NY 10032; email: es54@columbia.edu.
  • Michael D. Whitaker, MD, can be reached at the Mayo Clinic Hospital, 5777 E. Mayo Blvd., Phoenix, AZ 85054; email: whitaker.michael@mayo.edu.
  • Mone Zaidi, MD, PhD, can be reached at Mount Sinai Hospital, Atran Berg Laboratory Building, 4th Floor, Room AB4-06, 1428 Madison Ave., New York, NY 10029; email: mone.zaidi@mountsinai.org.

Disclosures:
  • Drake, Miller, Shane and Whitaker do not have any relevant financial disclosures. Zaidi reports being a consultant for Merck, Novartis and Roche.


POINT/COUNTER

Should drug holidays be considered for patients at all levels of fracture risk?

POINT

Good evidence supports continuing benefit after bisphosphonates are suspended.

People with relatively low risk for fracture, but high enough to warrant treatment, likely incorporate enough bisphosphonate within 3 to 5 years of regular therapy that they are able to discontinue the medication for at least some time. Duration of the drug holiday should be individualized, with higher-risk patients discontinuing treatment for shorter periods than those at lower risk.

Nelson Watts

In one placebo-controlled trial of risedronate, researchers told patients to discontinue the study drug at the end of 3 years, while continuing to take calcium and vitamin D. After 1 year, bone density had dropped slightly. Markers of bone turnover in the treatment group were similar to those in the placebo group, but the fracture rate was 46% lower.

In the FLEX trial, the rate of clinical vertebral fractures after 5 years in patients who stayed on therapy was reduced by 55% vs. those who stopped. This result is evidence that continuing treatment has benefit. However, during the first years of the study, virtually no difference in fracture rates was observed, which suggests a lingering benefit. Patients who had 5 years of therapy might have been able to stop, at least for a year or two, and still have a benefit. That is the best available evidence that long-term treatment is better for higher-risk patients and that some residual benefit remains even when therapy is stopped early.

Zoledronic acid placebo-controlled trials also support longer treatment (approximately 6 years) for higher-risk patients, but suggest a lingering benefit once treatment has stopped after 6 years.

Finally, a bisphosphonate holiday could potentially reset the clock for the safety concerns patients fear most: osteonecrosis of the jaw and atypical femur fractures, which are extremely rare events.

Nelson Watts, MD, FACP, MACE, CCD, is Director of Mercy Health Osteoporosis and Bone Health Services in Cincinnati. Disclosure: Watts reports financial relationships with AbbVie, Amarin, Amgen, Bristol-Meyers Squibb, Corcept, Corus, Endo, Imagepace, Janssen, Lilly, Merck, Novartis, Noven, NPS, OsteoDynamics, Pfizer/Wyeth, Radius and Sanofi-Aventis.

COUNTER

The morbidity and mortality associated with refracture are serious enough to avoid discontinuing these medications.

The original extension of the FIT trial was widely misinterpreted and led to almost a universal stoppage of the drug in all patients. This did a great disservice to patients and to a class of drugs, which offered a major advance in osteoporosis treatment.

Solomon Epstein

The FIT trial demonstrated that alendronate is extremely effective for fracture reduction over the long term, even beyond 5 years, and the FLEX results extended that finding to 10 years. Data support the efficacy of risedronate beyond 7 years and zoledronic up to 5 years. These studies and their subanalyses showed that the criteria for continuing therapy depend on the patient’s risk. Although the numbers were small, the FLEX subanalysis showed continuing treatment not only increased bone mineral density, but reduced the risk of clinical vertebral fractures. The third subset showed that patients with a T-score of –2.5 at the femoral neck had a subsequent reduction of nonvertebral fractures.

People are frightened of the extremely uncommon occurrences of atypical fractures and osteonecrosis of the jaw, but reducing the risk of future fracture far outweighs the risk of atypical fracture and osteonecrosis of the jaw.

For patients who have a low or moderate risk for fracture, a drug holiday with continued follow-up is a reasonable consideration. However, certain patients, including those with a T-score of –2.5 at the femoral neck, those who had previous fractures, perhaps much older patients, should continue these medications.

Patients often interpret a drug holiday to mean their disease is not serious or has been cured, and they neglect returning for appropriate follow-up.

Solomon Epstein, MD, FRCP, is Professor of Medicine and Associate Director for Clinical Research at Icahn School of Medicine at Mount Sinai. Disclosure: Epstein reports being a consultant and advisory board member for Merck Pharmaceuticals and an invited speaker for Takeda Pharmaceuticals.

The field of bone health is filled with excitement and fraught with challenges, according to experts. Forward motion is interspersed with roadblocks. Solid first-line osteoporosis therapies are plagued with concerns about drug holidays following their media spotlight. New treatments show promise but require research on utilization in distinct groups, including premenopausal women.

With a growing aging population, helping men and women maintain strong skeletons is more important than ever. The critical first steps of ensuring patients are properly diagnosed and start the therapy they need, however, may not be happening.

“The problem is we’re not treating people,” Paul D. Miller, MD, FACP, of the Colorado Center for Bone Research in Lakewood, Colo., told Endocrine Today. “The number of people being treated has actually gone down. It’s really kind of discouraging to see, when you work in the field for more than 30 years.”

Fears, first-lines and drug holidays

The estimated use of postfracture osteoporosis medication in the year after discharge for hip fracture dropped from 40.2% in 2002 to 20.5% in 2011 (P for trend <.001), according to research by Daniel H. Solomon, MD, MPH, of Brigham and Women’s Hospital, and colleagues published in the Journal of Bone and Mineral Research.

The retrospective, observational study looked at US administrative insurance claims data for beneficiaries aged at least 50 years at admission with commercial or Medicare supplemental health insurance who were hospitalized for hip fracture; 62,498 patients were included in 12 months of follow-up. The predictor most strongly and positively associated with medication use after fracture was its use before fracture.

Miller said many theories for the steep decrease exist, but one looms a little larger.

“There is a fear about bisphosphonates that’s been driven by a lot of media about atypical subtrochanteric femur fractures,” Miller said. “Patients come in and either don’t want to take them or don’t want to stay on them.”

Paul D. Miller, MD, FACP, of the Colorado Center for Bone Research in Lakewood, Colo., said the number of patients receiving appropriate treatment for osteoporosis has declined over his 30 years of practice.

Photo courtesy of Paul D. Miller, MD, FACP.

 

The most common medications prescribed for osteoporosis for nearly 2 decades, bisphosphonates — alendronate, risedronate, ibandronate and zoledronic acid — have a unique pharmacology at the center of the debate over drug holidays.

“Bisphosphonates are the only drugs in clinical medicine that are not metabolized,” Miller said. “You look at blood pressure medicine, diabetes medicines or statins; any other medicines are usually broken down in the liver. Bisphosphonates get retained in bone, in remodeling cavities, buried there, and then detach from the bone surface, go back in the bloodstream and then reattach back on the bone surface.”

Due to this “recycling” and maintenance of pharmacologic effect, giving patients a break after a loading period of a certain amount could offer continual efficacy when it comes to stable bone densities and stable biochemical markers of bone turnover for a number of years, Miller said. But clinicians will never have the luxury of certainty as it pertains to persistence of fracture risk reduction, he added.

“You’ll never have true, hard scientific evidence,” Miller said. “After 5 years, nobody has any controlled data because they stopped the trials. You can never continue the placebo groups for that long a time. It’s just not ethical.”

In 2011, Miller took his thoughts on drug holidays to the Capitol for an FDA advisory board meeting on bisphosphonate duration of use and a related potential label change. Beneath the surface lingered concern about atypical subtrochanteric femur fractures 5 years or more into treatment with alendronate, Miller said. After a day of deliberation, however, the FDA did not change the label.

Miller said the longest available data come from a subset of patients treated with alendronate in the Fracture Intervention Trial (FIT) trial, published in JAMA, who, after 5 years of alendronate therapy, were randomly reassigned to continued therapy or placebo in the 5-year FIT Long-term Extension (FLEX) trial, published in JAMA Internal Medicine.

PAGE BREAK

“The biochemical marker of bone reabsorption C-telopeptide that we use as a surrogate marker for bone turnover did not really change in the first 2 years of FLEX but by the third year started to go up, suggesting that you were losing some of the biological effect of the bisphosphonate,” Miller said. No between-group differences were observed in hip, nonvertebral or morphometric vertebral fractures, but there was a significant difference in clinical vertebral fractures, with more fractures in the placebo group, he noted.

The fracture risk assessment tool (FRAX) algorithms developed by WHO are helpful in defining 10-year probability of fracture when considering treatment, Miller said.

“It’s a perfectly acceptable standard of care to consider discussing a drug holiday in lower-risk patients,” Miller said. “You can watch periodically to see if they’re going down on their bone density and if other biochemical markers of bone turnover are beginning to go up as evidence of the loss of efficacy. Continuation of bisphosphonates in high-risk patients is appropriate since in these patients the benefits outweigh the risk.”

An evolving armamentarium of therapies

Cathepsin K inhibitors and antisclerostin therapies are two pharmacologic approaches that may be on the horizon for treating osteoporosis based on results from recent trials, according to Matthew T. Drake, MD, PhD, of the Mayo Clinic in Rochester, Minn.

Data from phase 3 of the Long-Term Odanacatib Fracture Trial (LOFT) examining safety and efficacy of the once-weekly oral cathepsin K inhibitor, developed by Merck, was presented at the American Society for Bone and Mineral Research (ASBMR) 2014 Annual Meeting in Houston.

“The study team showed it was effective at limiting fractures,” Drake told Endocrine Today. “They also showed the rates of dermatologic complications were not particularly high, which was an issue of concern raised in the phase 2 portion of the trial.”

The randomized, double blind, placebo-controlled, international trial involved 16,071 postmenopausal women diagnosed with osteoporosis. Odanacatib reduced new and worsening morphometric vertebral fractures by 54%, clinical hip fractures by 47%, clinical nonvertebral fractures by 23% and clinical vertebral fractures by 72% (P<.001 for all), according to a press release from the company.

Further, progressive bone mineral density increases were observed at the lumbar spine (11.2%) and total hip (9.5%) during 5 years compared with placebo (P<.001 for both).

To break down bone, osteoclasts sit on the bone surface and create a sealed area into which they secrete both the protease cathepsin K to break down the bone matrix and acid that dissolves the mineral adherent to the bone matrix, Drake said.

Odanacatib’s novel mechanism inhibits the cathepsin K enzyme and offers some benefits over other therapies.

“We have not had this type of molecule previously,” Drake said. “It has a shorter half-life than bisphosphonates, which remian in bone for a long time. Because it has a much shorter duration of action, patients will need to continue to take it.”

The drug may not serve as a first-line therapy for osteoporosis with so many other solid medications already available, but it provides another option, Drake said, particularly in patients with treatment intolerance to other medications.

“For those patients, odanacatib certainly would be a welcome addition to our armamentarium,” Drake said.

Sclerostin molecules — produced by osteocytes, or bone-forming cells that have become terminally differentiated and entombed within the bone they have made — are the target of new therapies romosozumab (Amgen) and blosozumab (Eli Lilly).

“Sclerostin helps the skeleton respond to mechanical stresses in order to maintain bone strength, so you don’t make either too much bone or too little bone,” Drake said. “It’s a negative regulator of bone formation.”

Antisclerostins bind to these naturally formed target molecules, allowing the formation of bone, according to Drake.

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“Sclerostin always has its foot a little on the brake. Antisclerostin therapy takes the foot off,” he said.

Amgen is further along in trials than Eli Lilly, Drake noted. He highlighted phase 2 results from a multicenter, international trial by Michael R. McClung, MD, and colleagues published in The New England Journal of Medicine that included 419 women aged 55 to 85 years with low bone mineral density (BMD; T-score of −2 or less at the lumbar spine, total hip or femoral neck and −3.5 or more at each of the three sites).

Women were randomly assigned to subcutaneous romosozumab once monthly (70 mg, 140 mg or 210 mg) or every 3 months (140 mg or 210 mg); subcutaneous placebo; or open-label oral alendronate (70 mg/week) or subcutaneous teriparatide (20 mcg/day; Forteo, Eli Lilly).

At 12 months, significant BMD increases were seen at the lumbar spine with all romosozumab doses, including an 11.3% increase with 210 mg monthly vs. a decrease of 0.1% with placebo and increases of 4.1% with alendronate and 7.1% with teriparatide.

Phase 3 data from a study of postmenopausal women randomly assigned to subcutaneous romosozumab monthly (210 mg; n=17), subcutaneous teriparatide (20 mcg; n=19) or placebo (n=20) assessing parameters at various locales also were presented at ASBMR 2014. Romosozumab demonstrated greater improvements in cortical thickness (P<.001), cortical BMD (P=.04) and cortical mass (P<.001) vs. teriparatide.

“The therapy works completely differently than the others available,” Drake said. “The antisclerostin molecule is the only one that tries to only affect the bone-building cell activity.”

Teriparatide works to increase bone resorption in addition to bone building, with the latter ideally predominating, according to Drake. Bisphosphonates and denosumab (Prolia and Xgeva; Amgen) inhibit osteoclast activity and prevent bone from being removed, he said.

“The exciting thing about the antisclerostin molecule is that it targets the osteoblasts to actually stimulate bone to be formed,” Drake said. “It’s really a skeletal anabolic therapy that tries to build up bone instead of just prevent it from being removed.”

Assessing bone loss, treatment and costs

Mone Zaidi, MD, PhD, of the Icahn School of Medicine at Mount Sinai Hospital, called it “therapeutically meaningful” to view bone loss as a continuum.

“You don’t suddenly become osteoporotic, without being osteopenic; it’s a continuation of that same process,” Zaidi told Endocrine Today. “It’s important to note that bone loss in a woman starts very early, at the onset of menopause.”

For women, bone is maximized in their 30s and remains stable during the reproductive phase of their life but is reduced dramatically in their early 50s or at the onset of menopause, Zaidi said. To date, this phase of rapid bone loss had not been studied in detail, mainly because the means had not been available, he added.

Mone Zaidi

Early bone loss has become obvious through several recent clinical studies, according to Zaidi. He pointed to research by the late MaryFran Sowers, PhD, part of the ongoing SWAN study, which examined parameters of more than 3,000 women who were entering menopause at enrollment.

“Hormonal changes and bone loss during early menopause are now being looked at very carefully,” Zaidi said. “Researchers have clearly demonstrated that bone loss starts 3 years prior to the last menstrual period, and the correlation is strong with elevated follicle-stimulating hormone levels. These may actually be a contributor to the early loss, and estrogen could be at normal levels.”

Osteopenia is actually an epidemiologic definition, Zaidi said, with the representative T-score between –1 and –2.5 standard deviations below the mean of the reference population, now called low bone mass, and osteoporosis is characterized by a T-score of less than –2.5.

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“Essentially, it’s the same thing,” Zaidi said. “Women start losing bone very early in menopause, and the process continues through the phases of osteopenia and osteoporosis to end up, at some point, at a very high fracture risk.”

With the exception of estrogen, drugs have not traditionally been used in the very early phase of bone loss, Zaidi said. Treating this active bone loss has come to the forefront as an area that needs addressing — but also one that is highly debated.

Drake said most insurance companies are relatively hesitant to treat osteopenia, although because many more people have osteopenia than have osteoporosis, there are more fractures that occur in people with osteopenia than with osteoporosis. Treatment becomes a question of what is best to do from both an individual personal management perspective and a population perspective, he added.

“Treating everyone with osteopenia would likely involve a lot of people who don’t really need it because they may never have a fracture,” Drake said. “Certainly medical costs would run up significantly, and patients would be at increased risk for potential side effects.”

According to Drake, the community is working to stratify patients with osteopenia to decide who might benefit most from therapy. “We have to come up with a number to see whether it will be cost-effective or not to treat someone,” he said.

An analysis by Bess Dawson-Hughes, MD, of Tufts University, and colleagues published in Osteoporosis International employed FRAX to evaluate the impact of guidance on treatment eligibility in the United States.

If the risk for any osteoporotic fracture is ≥20% or the risk of a hip fracture is ≥3%, it would be cost-effective to begin a pharmacologic management approach in patients with osteopenia, the researchers found.

Arriving at assessing patients, however, is a hurdle that would need to be overcome first.

“It has been well documented by the International Society for Clinical Densitometry (ISCD) that the number of bone density measurements being done is going down and with that the number of diagnoses,” Miller said.

Miller recalled testifying in front of Medicare to get the Bone Mass Measurement Act passed. Backed by the National Osteoporosis Foundation, the congressional statute broadened the indication and CMS reimbursement for bone densitometry. In time, the recommendations for BMD testing included all women aged at least 65 years with no risk factors or aged at least 60 years with one or more risk factors.

It is one of only two population-based screenings formally recommended by the US Preventive Services Task Force and US Surgeon General, but Miller said enactment of this policy has been hampered by declining reimbursement for DXA.

“The only other disease where population screening is endorsed is breast cancer with a mammography,” Miller said. “We got all the legislation through, we got the political support; but the reimbursements dropped, and the number of people being tested is declining.”

Further, Miller said the demands of an internal medicine practice make implementation of bone health assessments challenging, particularly with patients coming through the doors with diabetes, obesity and high cholesterol.

Zaidi agreed that ascertainment of key populations is being missed. “Only 3% of wrist fractures ever get a diagnosis for osteoporosis and treated,” he said. “That’s probably the harbinger of osteoporosis in early postmenopausal women; it’s the first presenting fracture.”

A recent report by Peter Ebeling, MD, FRACP, of Monash University in Victoria, Australia, and colleagues released by the IOF detailed the grave effects resulting from the lack of detection of osteoporosis in men. Worldwide, approximately one in five men aged at least 50 years will break a bone due to osteoporosis, according to the report. Further, men are twice as likely as women to die in the year after a hip fracture, with a mortality rate as high as 37%.

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“An inadequate amount of health care resources are being invested in bone, muscle and joint diseases,” John A. Kanis, MD, professor emeritus at the University of Sheffield, United Kingdom, said in a press release. “People should not have to live with the pain and suffering caused by osteoporosis as we can help prevent and control the disease.”

Investigation into idiopathic osteoporosis

Elizabeth Shane, MD, of Columbia University, and colleagues are figuring out what it takes to forecast and reduce fractures in an entirely different population: premenopausal women.

“We want to understand the general pathogenesis of unexplained osteoporosis in these women, to devise ways to manage these women, particularly those who are having fractures or continuing to lose bone despite conservative therapy, and to investigate potential genetic causes that could possibly be related to this,” Shane told Endocrine Today.

Elizabeth Shane

The researchers’ data suggest a number of potential causes for the condition, some genetic, and treatment results that leave questions, she said.

“It’s challenging enough to manage osteoporosis in older people,” Shane said. “When you’re talking about younger women, and younger men, there is limited evidence about the benefits and the risks of treatment.”

Because these patients often have reduced bone remodeling, therapies that further suppress that activity are unattractive, she said. “You wouldn’t want to reduce remodeling further.”

Teriparatide demonstrated improvements in a pilot study of 21 premenopausal women with idiopathic osteoporosis conducted by Shane, along with Adi Cohen, MD, also of Columbia University, and colleagues, published in The Journal of Clinical Endocrinology & Metabolism. BMD increased at the spine (10.8 ± 8.3%), total hip (6.2 ± 5.6%) and femoral neck (7.6 ± 3.4%; P<.001 for all).

“Because the study is small and because the disorder is rare, we don’t really know that this is going to prevent fractures,” Shane said.

Approximately 20% of patients did not seem to respond to the therapy, which appears to be related to extremely low bone remodeling at the outset, she said. Still another challenge is determining what to do after teriparatide therapy — typically a maximum 2-year course of therapy, and in older people followed with an antiresorptive drug to prevent the effects from dissipating, she added.

The Columbia University researchers are currently recruiting 40 women with the condition to investigate the lack of response; the study is approximately 60% recruited, and the investigators encourage clinicians to reach out to more patients.

“We recruit nationally and internationally, we have some funding to help with travel, and we work very closely with referring physicians to accomplish the goals of the grant, which is to provide patients with treatment shown to be effective — at least in improving bone density,” Shane said. “Hopefully, this new study will give us the evidence we need to see who responds and who doesn’t, so we can predict response very early on in a personalized way.”

Answers not always apparent

Although osteoporosis makes up the brunt of metabolic bone disease, thin bones do not make a diagnosis, said Michael D. Whitaker, MD, FRCPC, of the Mayo Clinic Arizona.

“Bone density tests will tell you a patient has metabolic bone disease, but it won’t tell you the cause,” Whitaker told Endocrine Today. He gave a keynote talk addressing the topic at the American Association of Clinical Endocrinologists 23rd Annual Scientific & Clinical Congress in Las Vegas.

Several conditions exist besides osteoporosis that, although not as frequently occurring, warrant clinicians’ attention, Whitaker said.

In osteomalacia, bones may not mineralize adequately due to vitamin D deficiency, severe calcium malabsorption or other rare conditions, such as tumor-induced osteomalacia.

“Thin bones could be osteoporosis, or they could be an entirely different bone disease that would be treated differently and needs to be looked at differently,” he said.

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In hypophosphatasia, an inborn error of metabolism disrupts mineralization and thereby affects the bones and teeth, Whitaker said. Some nonendocrine-related conditions, such as multiple myeloma or mast cell disease, can also result in reduced bone density.

“These are uncommon causes of reduced bone density, but need to be considered in a differential diagnosis every time,” he said.

Replacement therapy is used to treat the vitamin D deficiency and calcium malabsorption in osteomalacia, Whitaker said. Osteoporosis therapies are not effective in this population.

Mesenchymal tumors that produce too much fibroblast growth factor-23 (FGF-23) can result in profound deficiency in the active vitamin D metabolite 1,25-dihydroxyvitamin D over time, leading to failure to mineralize bone, severe osteomalacia and subsequent fractures, he said.

“It’s important to identify because identifying where the tumor is and surgically removing it will cure the problem,” Whitaker said. “It’s very uncommon but can’t be missed.”

Patients with osteomalacia typically present with widespread bone pain, in contrast to patients with osteoporosis.

“Bones tend to bend, and they become painful,” he said. “A patient with bone pain who has a low bone density makes you think more of osteomalacia.”

Bone fractures also are frequent in this population, and extremely low serum phosphorous levels characterize the disease, Whitaker said. All factors combined would trigger testing for FGF-23 and 1,25-dihydroxyvitamin D, and if elevated and low, respectively, would suggest a diagnosis.

Expanding the differential diagnosis of low bone density is critical, Whitaker said.

“It’s just making doctors, particularly endocrinologists, aware that what is seemingly obvious isn’t necessarily so,” he said. “You need a T-score of –2.5 to make a diagnosis for osteoporosis. But a T-score of –2.5 is not necessarily always osteoporosis.” – by Allegra Tiver

For more information:
  • Black DM. JAMA. 2006;296:2927-2938.
  • Cohen A. J Clin Endocrinol Metab. 2013;98:1971-1981.
  • Cummings SR. JAMA. 1998;280:2077-2082.
  • Dawson-Hughes B. Osteoporos Int. 2011;23:811-820.
  • Ebeling P. International Osteoporosis Foundation. Osteoporosis in Men: Why Change Needs to Happen. Available at: www.iofbonehealth.org/data-publications/reports/osteoporosis-men-why-change-needs-happen. Accessed Nov. 19, 2014.
  • McClung MR. Abstract #1147. Presented at: ASBMR 2014 Annual Meeting; Sept. 12-15, 2014; Houston.
  • McClung MR. N Engl J Med. 2014;370:412-420.
  • Solomon DH. J Bone Miner Res. 2014;29:1929-1937.
  • Whitmarsh T. Abstract #1049. Presented at: ASBMR 2014 Annual Meeting; Sept. 12-15, 2014; Houston.
  • Matthew T. Drake, MD, PhD, can be reached at the Endocrine Research Unit, Mayo Clinic, 200 First St. SW, Rochester, MN 55905; email: drake.matthew@mayo.edu.
  • Paul D. Miller, MD, FACP, can be reached at the Colorado Center for Bone Research, 3190 S. Wadsworth Blvd., Lakewood, CO 80227; email: millerccbr@aol.com.
  • Elizabeth Shane, MD, can be reached at Columbia University, College of Physicians and Surgeons, Department of Medicine, 630 W. 168th St., New York, NY 10032; email: es54@columbia.edu.
  • Michael D. Whitaker, MD, can be reached at the Mayo Clinic Hospital, 5777 E. Mayo Blvd., Phoenix, AZ 85054; email: whitaker.michael@mayo.edu.
  • Mone Zaidi, MD, PhD, can be reached at Mount Sinai Hospital, Atran Berg Laboratory Building, 4th Floor, Room AB4-06, 1428 Madison Ave., New York, NY 10029; email: mone.zaidi@mountsinai.org.

Disclosures:
  • Drake, Miller, Shane and Whitaker do not have any relevant financial disclosures. Zaidi reports being a consultant for Merck, Novartis and Roche.


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POINT/COUNTER

Should drug holidays be considered for patients at all levels of fracture risk?

POINT

Good evidence supports continuing benefit after bisphosphonates are suspended.

People with relatively low risk for fracture, but high enough to warrant treatment, likely incorporate enough bisphosphonate within 3 to 5 years of regular therapy that they are able to discontinue the medication for at least some time. Duration of the drug holiday should be individualized, with higher-risk patients discontinuing treatment for shorter periods than those at lower risk.

Nelson Watts

In one placebo-controlled trial of risedronate, researchers told patients to discontinue the study drug at the end of 3 years, while continuing to take calcium and vitamin D. After 1 year, bone density had dropped slightly. Markers of bone turnover in the treatment group were similar to those in the placebo group, but the fracture rate was 46% lower.

In the FLEX trial, the rate of clinical vertebral fractures after 5 years in patients who stayed on therapy was reduced by 55% vs. those who stopped. This result is evidence that continuing treatment has benefit. However, during the first years of the study, virtually no difference in fracture rates was observed, which suggests a lingering benefit. Patients who had 5 years of therapy might have been able to stop, at least for a year or two, and still have a benefit. That is the best available evidence that long-term treatment is better for higher-risk patients and that some residual benefit remains even when therapy is stopped early.

Zoledronic acid placebo-controlled trials also support longer treatment (approximately 6 years) for higher-risk patients, but suggest a lingering benefit once treatment has stopped after 6 years.

Finally, a bisphosphonate holiday could potentially reset the clock for the safety concerns patients fear most: osteonecrosis of the jaw and atypical femur fractures, which are extremely rare events.

Nelson Watts, MD, FACP, MACE, CCD, is Director of Mercy Health Osteoporosis and Bone Health Services in Cincinnati. Disclosure: Watts reports financial relationships with AbbVie, Amarin, Amgen, Bristol-Meyers Squibb, Corcept, Corus, Endo, Imagepace, Janssen, Lilly, Merck, Novartis, Noven, NPS, OsteoDynamics, Pfizer/Wyeth, Radius and Sanofi-Aventis.

COUNTER

The morbidity and mortality associated with refracture are serious enough to avoid discontinuing these medications.

The original extension of the FIT trial was widely misinterpreted and led to almost a universal stoppage of the drug in all patients. This did a great disservice to patients and to a class of drugs, which offered a major advance in osteoporosis treatment.

Solomon Epstein

The FIT trial demonstrated that alendronate is extremely effective for fracture reduction over the long term, even beyond 5 years, and the FLEX results extended that finding to 10 years. Data support the efficacy of risedronate beyond 7 years and zoledronic up to 5 years. These studies and their subanalyses showed that the criteria for continuing therapy depend on the patient’s risk. Although the numbers were small, the FLEX subanalysis showed continuing treatment not only increased bone mineral density, but reduced the risk of clinical vertebral fractures. The third subset showed that patients with a T-score of –2.5 at the femoral neck had a subsequent reduction of nonvertebral fractures.

People are frightened of the extremely uncommon occurrences of atypical fractures and osteonecrosis of the jaw, but reducing the risk of future fracture far outweighs the risk of atypical fracture and osteonecrosis of the jaw.

For patients who have a low or moderate risk for fracture, a drug holiday with continued follow-up is a reasonable consideration. However, certain patients, including those with a T-score of –2.5 at the femoral neck, those who had previous fractures, perhaps much older patients, should continue these medications.

Patients often interpret a drug holiday to mean their disease is not serious or has been cured, and they neglect returning for appropriate follow-up.

Solomon Epstein, MD, FRCP, is Professor of Medicine and Associate Director for Clinical Research at Icahn School of Medicine at Mount Sinai. Disclosure: Epstein reports being a consultant and advisory board member for Merck Pharmaceuticals and an invited speaker for Takeda Pharmaceuticals.