Taking the Skeletons Out of the Closet

Three Studies Reveal New Insights into Osteoporosis and Bone Health

A trio of studies from the Endocrine Society’s Journal of Clinical Endocrinology & Metabolism examines several issues relating to bone health complications. These papers looked at treatment options to increase bone density in breast cancer patients; the impact of sleeve gastrectomy procedures on bone mass in postmenopausal women; and the confounding increase in fragility fractures while osteoporosis appears to be underdiagnosed and thus undertreated. 

Since May is National Osteoporosis Awareness Month, Endocrine News is highlighting three articles published in The Journal of Clinical Endocrinology & Metabolism (JCEM) in January focusing on various aspects of osteoporosis research help further this goal. They also make important strides in answering the many clinical questions surrounding this prevalent disease, including some we didn’t know needed asking.

Between 2030 and 2034, the number of osteoporosis cases is projected to reach 263.2 million globally (prevalence varies by country), with women being affected 1.5 times more than men. The increased bone fragility it causes leads to 37 million fragility fractures (hip, spine, and wrist) annually, which can severely impact individual health and well-being in terms of decreasing quality of life, mobility, and functioning and causing chronic pain, hospitalization, long-term disability, need for skilled care, and death. And the associated enormous global economic, social, and health burden keeps growing.

Since osteoporosis can develop without any obvious symptoms, it is often up to endocrinologists (and primary care clinicians) to spot commonly overlooked signs of bone loss before fracture occurs. Endocrinologists are also at the forefront of conducting research that improves our understanding of osteoporosis, like the three studies presented here.

Mind the Gap

In “Trends in Osteoporosis Drug Therapy Receipt Among Commercial and Medicare Advantage Enrollees in the United States, 2011–2022,”  Juan P. Brito, MD, MSc, medical director of the Shared Decision Making National Resource Center; Innovation and Quality chair, Division of Endocrinology; and investigator, Knowledge and Evaluation Research Unit at the Mayo Clinic in Rochester, Minn., and Rozalina G. McCoy, MD, MS, associate division chief for clinical research, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine in Baltimore, Md. and director of Precision Medicine and Population Health, at the University of Maryland Institute for Health Computing in North Bethesda, Md., and team took a deep dive into who is (and is not) taking what osteoporosis medications and why (or why not).

McCoy says that the team undertook this 12-year retrospective cohort study of more than 13 million patients (13,408,733) because treatment rates are low (“far below where we would expect them to be given the prevalence of osteoporosis”), despite the highly effective treatments that are widely available. “However, who is most likely to be undertreated and why is not clearly understood,” she says. “We hypothesized that there are components of both: underdiagnosis — patients are not recognized as having osteoporosis and are therefore not being treated — and undertreatment — patients are recognized as having osteoporosis and are still not being treated.”

“More than 70% of patients who had a recent fragility fracture — meaning that they have osteoporosis and are at highest risk for fracture — did not have an osteoporosis diagnosis. Men were much less likely than women to be diagnosed with osteoporosis even after experiencing a fragility fracture …. What was even more concerning is that rates of underdiagnosis increased during the study period in both women and men.” — Rozalina G. McCoy, MD, MS, associate division chief, clinical research, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Md.; director, Precision Medicine and Population Health, University of Maryland Institute for Health Computing, North Bethesda, Md.

McCoy explains that although prior studies have examined one or the other of these gaps in care, none has looked at both simultaneously and in the same population nor assessed the current state of osteoporosis management across the United States. “Our goal,” she says, “was to perform a broader analysis of osteoporosis drug therapy (ODT) trends in a diverse middle-age and older adult population (all those who may require treatment) to identify osteoporosis care gaps. The ultimate goal is to then explore these care gaps more deeply and develop interventions that can address them.”

Perhaps the most pressing question to tackle first is why, with all of our available tools, is osteoporosis underdiagnosed and undertreated?  McCoy and Brito cite a host of factors, ranging from provider specific (e.g., care fragmentation, guideline complexity, and low screening rates) to patient specific (cost and potential inconvenience) as well as some that bridge both, like side effect concerns and lack of awareness.

To get to the bottom of this seeming contradiction, the team used claims data from the OptumLabs Data Warehouse, which includes enrollees in commercial and Medicare Advantage health plans across the United States. “We identified men and women ages 50 years and older between 2011 and 2022 and grouped them by whether they had a diagnosis of osteoporosis or by history of fragility fracture within the past year, meaning that they have osteoporosis and an indication for treatment for secondary prevention of recurrent fracture,” explains McCoy.

Groups were then subdivided by age (older than 65 years and ages 54 – 64 years) and sex. They excluded patients who had any contraindication to ODT and those who had other health conditions that may cause fractures (e.g., stage 5 chronic kidney disease, end-stage kidney disease, pregnancy, metastatic cancer, disorders of collagen, Paget disease of the bone, rickets, osteomalacia, osteogenesis imperfecta, hypophosphatasia, bone cancers, and plasma cell neoplasms), with the aim of focusing their analysis on the population that would truly benefit from — and should receive — ODT. “We then analyzed ODT use trends, zooming in on whether patients were receiving intravenous zoledronic acid, other bisphosphonates, denosumab, and anabolic agents, and whether therapy was newly started or ongoing/continued. Statistical analyses then identified trends over time,” McCoy says.

Reassuringly, among women ages 65 years and older with documented osteoporosis, ODT fill rates increased from 36.3% to 50.1% for women without fragility fractures and from 30.8% to 43.7% for women with fragility fractures. These rates represent prescribing for primary prevention and signal increasing awareness about the potential for preventing fractures among those at risk.

Other ODT use trends did not surprise the team but were alarming: “The proportion of patients across all ages with documented diagnosis of osteoporosis increased from 3.3% in 2011–2012 to 4.9% in 2021–2022. But concerningly, the proportion of patients experiencing a fragility fracture within the year increased from 1.4% to 2.5% during the same time period,” McCoy says. They also saw that underdiagnosis of osteoporosis is very common: “More than 70% of patients who had a recent fragility fracture — meaning that they have osteoporosis and are at highest risk for fracture — did not have an osteoporosis diagnosis. Men were much less likely than women to be diagnosed with osteoporosis even after experiencing a fragility fracture (30% of women 65+ who had fragility fracture were diagnosed with osteoporosis, compared to just 9% of men 65+),” McCoy says. But here is one surprise: “What was even more concerning,” she adds, “is that rates of underdiagnosis increased during the study period in both women and men.”

The unpleasant surprises revealed by the data continued. Said McCoy: “Only 1 in 10 women 65+ received ODT, and rates of treatment were lower in women who had fragility fractures but were not diagnosed with osteoporosis — and this got worse over time, with ODT use for secondary prevention (highest need group) declining from 9.2% to 7.4% during the study period. Only 1% of men 65+ received ODT.”

Notably, a shift in therapy occurred, with denosumab use rising, while bisphosphonate use declined, despite guidelines favoring bisphosphonates as the preferred treatment for osteoporosis — and that bisphosphonates cost less are and more easily accessible for many patients than denosumab. And the biggest and most concerning surprise of all? “Despite the recent (small) increases in the rate of ODT use, fractures continued to rise, raising concerns about treatment effectiveness,” Brito says. “Our data cannot tell us with certainty the reasons for why fractures are increasing, but results suggest several concerning hypotheses. First, most of the increase in ODT has been driven by denosumab. Importantly, discontinuation of denosumab therapy without immediately transitioning to a bisphosphonate can lead to rapid bone loss and rebound fractures.”

“Our data cannot tell us with certainty the reasons for why fractures are increasing, but results suggest several concerning hypotheses. … most of the increase in ODT has been driven by denosumab. Importantly, discontinuation of denosumab therapy without immediately transitioning to a bisphosphonate can lead to rapid bone loss and rebound fractures.”  — Juan P. Brito, MD, MSc, medical director, Shared Decision Making National Resource Center; Innovation and Quality chair, Division of Endocrinology; investigator, Knowledge and Evaluation Research Unit, Mayo Clinic, Rochester, Minn.

Clinical guidelines state that denosumab use requires close follow up, including monitoring calcium and vitamin D levels, and management, consisting of either lifelong therapy or immediate transition to a bisphosphonate on discontinuation because of the associated increased risk of bone density loss and rebound fracture. “Patients may not be transitioning appropriately, contributing to higher fracture rates,” Brito says.

The team gleaned several key takeaways for clinicians from their analysis. To mitigate the underdiagnosis and undertreatment aspect, clinicians should improve follow-up of fragility fractures and understand that they are diagnostic of osteoporosis, “treat patients to prevent recurrent fracture regardless of or while waiting for bone density scores,” “increase bone density testing in high-risk groups,” “recognize that osteoporosis also affects men and screen for and treat osteoporosis in this population,” and educate patients to mitigate concerns about ODTs. To redress some of the unfortunate trends they identified, they urge clinicians to “prioritize bisphosphonates as first-line therapy unless contraindicated because their discontinuation will not result in rebound bone density loss and heightened risk of fracture” and “monitor denosumab use and ensure proper transition to bisphosphonates if discontinued.”

McCoy and Brito offer an additional important consideration: “systemic interventions, such as Fracture Liaison Services, can enhance care coordination and reduce fracture rates but face implementation challenges. Addressing these barriers is critical for improving osteoporosis management.”

Against this backdrop of current trends, two other studies provide insights into areas for improvement when bone health is impacted secondarily to other conditions.

Sleeve Gastrectomy May Not Bypass the Problem

In “Impact of Sleeve Gastrectomy on Skeletal Health: An Overlooked Concern,” Peter R. Ebeling, AO, FAHMS, MBBS, MD, FRACP, FRCP, FASBMR, head of the School of Clinical Sciences at Monash University in Clayton, Australia, provides a commentary on a study published in JCEM in November 2024, by Wu, K. C. et al. “Skeletal effects of sleeve gastrectomy, by sex and menopausal status and compared to Roux-en-Y gastric bypass surgery” was undertaken by [Anne L.] Schafer’s team at [University of California San Francisco] because little was known about bone health after sleeve gastrectomy as opposed to the previously more favored Roux-en-Y gastric bypass surgery,” Ebeling says.

In short, that study demonstrated that bone mass, microstructure, and strength decrease after sleeve gastrectomy (SG), now the most commonly performed bariatric procedure worldwide, and postmenopausal women may be at the highest risk of these skeletal consequences after SG. These effects seem to be driven by decreased calcium absorption, despite optimal calcium and vitamin D dosing during the study period that reflected current clinical guideline recommendations. Although the decline in calcium absorption was less than that after Roux-en-Y gastric bypass (RYGB) surgery, it was nevertheless significant.

These skeletal health impairments may have been thus far “overlooked,” or perhaps unanticipated, because of the differences in mechanism of action between RYGB and SG. Whereas in RYGB, the intestine — the main site of calcium absorption — is bypassed, in SG, by contrast, most of the stomach is removed without altering the intestinal pathway. To explain the unforeseen consequences, given that the site of calcium absorption is left untouched with SG, Ebeling says, “SG likely reduced calcium absorption by reducing gastric acidification and through alterations in other markers of nutrition, such as insulin-like growth factor (IGF)-1, that can affect calcium absorption.”

As mentioned, SG has overtaken RYGB as the most commonly performed bariatric procedure, due to various patient and surgeon preferences. The slightly lower weight loss achieved with SG is overshadowed by its simpler surgical approach and lower peri- and postoperative complication and mortality rates. SG also seems to be associated with lower fracture risk compared with RYGB in some studies. “Greater decreases in calcium absorption following [RYGB] surgery were associated with greater increases in bone turnover markers and declines in bone density, which could increase fracture risk particularly at cortical bone sites,” Ebeling says. “As the magnitude of these changes were smaller after [SG], this may contribute to their lower fracture risk in other studies.”

“The key takeaway is not to neglect bone health after surgical or medical bariatric treatment. Calcium nutrition and vitamin D levels need optimization, and at least 2,000 IU/d of vitamin D is required. Regular resistance training exercise should also be encouraged before and after commencing bariatric treatment, and there should be consideration of bone density testing, particularly in postmenopausal women.” — Peter R. Ebeling, AO, FAHMS, MBBS, MD, FRACP, FRCP, FASBMR, head, School of Clinical Sciences, Monash University, Clayton, Australia

Again, although these risks may be lower, they should not be underestimated. Moreover, “there are also implications for patients initiating medical bariatric therapy with glucagon-like peptide-1 receptor agonists,” Ebeling says. “Non-surgical weight loss can also be associated with decreases in calcium absorption and increases in bone turnover markers. Recent studies with glucagon-like peptide-1 receptor agonists have shown decreases in spine and total hip bone mineral density over 12 months after commencing treatment.”

These effects can be attenuated with lifestyle approaches that include an exercise intervention. Given that the rates of bariatric surgeries and GLP-1RA prescribing are likely to increase, attention to these adjunct lifestyle approaches is essential. “The key takeaway is not to neglect bone health after surgical or medical bariatric treatment,” Ebeling says. “Calcium nutrition and vitamin D levels need optimization, and at least 2,000 IU/d of vitamin D is required. Regular resistance training exercise should also be encouraged before and after commencing bariatric treatment, and there should be consideration of bone density testing, particularly in postmenopausal women.”

Breakthrough in Bone Health

For at least one subset of patients with risks for osteoporosis, there is good news. In “Eldecalcitol Add-on to Risedronate Reduces Bone Loss From Aromatase Inhibitors in Postmenopausal Breast Cancer Patients,” Yasuo Imanishi, MD, PhD, Department of Metabolism, Endocrinology, and Molecular Medicine at the Osaka Metropolitan University Graduate School of Medicine, in Japan, and team may have demonstrated an effective way to offset the negative effects of aromatase inhibitors (AIs) prescribed for treatment of hormone receptor-positive (HR+) early-stage breast cancer (EBC).

AIs are given as adjuvant therapy in HR+ EBC because of the reductions in recurrence and mortality rates they confer — but these benefits come with the well-known cost of increased osteoporotic fracture risk. AIs are also known to reduce bone mineral density (BMD), trabecular bone score (TBS), and bone microarchitecture. Patients taking AIs are advised to protect their bone health with nutrition, physical activity, and lifestyle modifications in accordance with clinical practice guidelines. Although these patients are advised to take vitamin D and calcium, many remain vitamin D deficient or insufficient.

Therefore, Imanishi and team sought an improved approach to preserve bone health in these patients. Knowing from prior studies that antiresorptive agents (e.g., risedronate) given alongside AIs can prevent bone loss, they conducted CERAMIQUE (Combination therapy of Eldecalcitol with Risedronate on Aromatase inhibitor-treated post-operative Mammary carcinoma In the prevention of bone QUality and quantity Exacerbation), in which 200 postmenopausal women median age 67 years with HR+ EBC were randomized to either an eldecalcitol add-on therapy group (17.5 mg risedronate + 0.75 ug eldecalcitol) or a risedronate monotherapy group (17.5 mg) for 24 months to determine differences primarily in the change of lumbar spine BMD and secondarily in femoral neck BMD, total hip BMD, TBS, and the incidence of vertebral and nonvertebral fractures.

As the researchers expected, the additional bisphosphonate improved primary and some secondary outcomes in the 90 participants who completed the trial (95 in the monotherapy group). Eldecalcitol, an oral, active form of vitamin D with antiresorptive properties, added to risedronate significantly increased BMD at each of the three sites of interest (but did not improve TBS). Regarding the primary outcome, eldecalcitol improved lumbar spine BMD even at a low starting point, “suggesting that eldecalcitol could improve BMD in patients who do not achieve adequate BMD with oral bisphosphonate treatment alone,” they said. The lack of improvement in TBS may possibly be explained by the relatively high TBS at commencement, due to pretreatment with risedronate among the participants (an enrollment prerequisite).

All in all, conclude the researchers, “this study puts forward a third option for patients who respond poorly to oral bisphosphonates.”

Horvath is a freelance writer based in Baltimore, Md. In the April issue, she wrote about the ENDO 2025 session, “Thyroid Disruptors,” that discusses impact of certain endocrine-disrupting chemicals on various aspects of thyroid health.