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The American College of Physicians (ACP) has updated their guideline for pharmacotherapy to reduce fracture risk in adults with primary osteoporosis or osteopenia (low bone mass) based on a systematic review of the evidence.

This is the first update for 5 years since the previous guidance was published in 2017.

It strongly recommends initial therapy with bisphosphonates for postmenopausal women with osteoporosis, as well as men with osteoporosis, among other recommendations.

However, the author of an accompanying editorial, ofloxacin kaina Susan M. Ott, MD, says: “The decision to start a bisphosphonate is actually not that easy.”

She also queries some of the other recommendations in the guidance.

Her editorial, along with the guideline by Amir Qaseem, MD, PhD, MPH, and colleagues, and systematic review by Chelsea Ayers, MPH, and colleagues, were published January 2 in the Annals of Internal Medicine.

Ryan D. Mire, MD, MACP, president of the ACP gives a brief overview of the new guidance in a video.

Systematic Review

The ACP commissioned a review of the evidence because it says new data have emerged on the efficacy of newer medications for osteoporosis and low bone mass, as well as treatment comparisons, and treatment in men.

The review authors identified 34 randomized controlled trials (in 100 publications) and 36 observational studies, which evaluated the following pharmacologic interventions:

  • Antiresorptive drugs: four bisphosphonates (alendronate, ibandronate, risedronate, zoledronate) and a RANK ligand inhibitor (denosumab);

  • Anabolic drugs: an analog of human PTH–related protein (abaloparatide), recombinant human PTH (teriparatide), and a sclerostin inhibitor (romosozumab);

  • Estrogen agonists: selective estrogen receptor modulators (SERMs) (bazedoxifene, raloxifene).

The authors focused on effectiveness and harms of active drugs compared with placebo or bisphosphonates.

Major Changes From 2017 Guidelines, Some Questions

“Though there are many nuanced changes in this [2023 guideline] version, perhaps the major change is the explicit hierarchy of pharmacologic recommendations: bisphosphonates first,” then denosumab,” Thomas G. Cooney, MD, senior author of the clinical guideline explained to Medscape Medical News in an email.

“Bisphosphonates had the most favorable balance among benefits, harms, patient values and preferences, and cost among the examined drugs in postmenopausal females with primary osteoporosis,” Cooney, professor of medicine, Oregon Health & Science University, Portland, noted, as is stated in the guideline.

“Denosumab also had a favorable long-term net benefit, but bisphosphonates are much cheaper than other pharmacologic treatments and available in generic formulations,” the document states.

The new guideline suggests use of denosumab as second-line pharmacotherapy in adults who have contraindications to or experience adverse effects with bisphosphonates.

The choice among bisphosphonates (alendronate, risedronate, zoledronic acid) would be based on a patient-centered discussion between physician and patient, addressing costs (often related to insurance), delivery-mode preferences (oral versus intravenous), and “values,” which includes the patient’s priorities, concerns, and expectations regarding their healthcare, Cooney explained.

Another update in the new guideline is, “We also clarify the specific, albeit more limited, role of sclerostin inhibitors and recombinant PTH ‘to reduce the risk of fractures only in females with primary osteoporosis with very high-risk of fracture’,” Cooney noted.  

In addition, the guideline now states, “treatment to reduce the risk of fractures in males’ rather than limiting it to ‘vertebral fracture’ in men,” as in the 2017 guideline.

It also explicitly includes denosumab as second-line therapy for men, Cooney noted, but as in 2017, the strength of evidence in men remains low.

“Finally, we also clarified that in females over the age of 65 with low bone mass or osteopenia that an individualized approach be taken to treatment (similar to last guideline), but if treatment is initiated, that a bisphosphonate be used (new content),” he said.

The use of estrogen, treatment duration, drug discontinuation, and serial bone mineral density monitoring was not addressed in this guideline, but will likely be evaluated within 2 to 3 years.

Osteoporosis Treatment: Not Easy — Editorial

In her editorial, Ott, writes: “The data about bisphosphonates may seem overwhelmingly positive, leading to strong recommendations for their use to treat osteoporosis, but the decision to start a bisphosphonate is actually not that easy.”

“A strong recommendation should be given only when future studies are unlikely to change it,” continues Ott, professor of medicine, University of Washington, Seattle.

“Yet, data already suggest that, in patients with serious osteoporosis, treatment should start with anabolic medications because previous treatment with either bisphosphonates or denosumab will prevent the anabolic response of newer medications.”

“Starting with bisphosphonate will change the bone so it will not respond to the newer medicines, and then a patient will lose the chance for getting the best improvement,” Ott clarified in an email to Medscape Medical News.

But, in fact, the new guidance does suggest that, to reduce the risk of fractures in females with primary osteoporosis at very high risk of fracture, consider use of the sclerostin inhibitor romosozumab (moderate-certainty evidence) or recombinant human parathyroid hormone (PTH) (teriparatide) (low-certainty evidence) followed by a bisphosphonate (conditional recommendation).

Ott said: “If the [fracture] risk is high, then we should start with an anabolic medication for 1-2 years. If the risk is medium, then use a bisphosphonate for up to 5 years, and then stop and monitor the patient for signs that the medicine is wearing off,” based on blood and urine tests. 

We Need Medicines That Will Stop Bone Aging

Osteopenia is defined by an arbitrary bone density measurement, Ott explained. “About half of women over 65 will have osteopenia, and by age 85 there are hardly any “normal” women left.”

“We need medicines that will stop bone aging, which might sound impossible, but we should still try,” she continued.

“In the meantime, while waiting on new discoveries,” Ott said, “I would not use bisphosphonates in patients who did not already have a fracture or whose bone density T-score was better than –2.5 because, in the major study, alendronate did not prevent fractures in this group.”

Many people are worried about bisphosphonates because of problems with the jaw or femur. These are real, but they are very rare during the first 5 years of treatment, Ott noted. Then the risk starts to rise, up to more than 1 in 1000 after 8 years. So people can get the benefits of these drugs with very low risk for 5 years.

“An immediate [guideline] update is necessary to address the severity of bone loss and the high risk for vertebral fractures after discontinuation of denosumab,” Ott urged.

“I don’t agree with using denosumab for osteoporosis as a second-line treatment,” she said. “I would use it only in patients who have cancer or unusually high bone resorption. You have to get a dose strictly every 6 months, and if you need to stop, it is recommended to treat with bisphosphonates. Denosumab is a poor choice for somebody who does not want to take a bisphosphonate. Many patients and even too many doctors do not realize how serious it can be to skip a dose.”

“I also think that men could be treated with anabolic medications,” Ott said. Clinical trials show they respond the same as women. Many men have osteoporosis as a consequence of low testosterone, and then they can usually be treated with testosterone. Osteoporosis in men is a serious problem that is too often ignored — almost reverse discrimination.”

It is also unfortunate that the review and recommendations do not address estrogen, one of the most effective medications to prevent osteoporotic fractures, according to Ott.

Clinical Considerations in Addition to Drug Types

The new guideline also advises:

  • Clinicians treating adults with osteoporosis should encourage adherence to recommended treatments and healthy lifestyle habits, including exercise, and counseling to evaluate and prevent falls.

  • All adults with osteopenia or osteoporosis should have adequate calcium and vitamin D intake, as part of fracture prevention.

  • Clinicians should assess baseline fracture risk based on bone density, fracture history, fracture risk factors, and response to prior osteoporosis treatments.

  • Current evidence suggests that more than 3 to 5 years of bisphosphonate therapy reduces risk for new vertebral but not other fractures; however, it also increases risk for long-term harms. Therefore, clinicians should consider stopping bisphosphonate treatment after 5 years unless the patient has a strong indication for treatment continuation.

  • The decision for a bisphosphonate holiday (temporary discontinuation) and its duration should be based on baseline fracture risk, medication half-life in bone, and benefits and harms. 

  • Women treated with an anabolic agent who discontinue it should be offered an antiresorptive agent to preserve gains and because of serious risk for rebound and multiple vertebral fractures.

  • Adults > 65 years old with osteoporosis may be at increased risk for falls or other adverse events due to drug interactions. 

  • Transgender persons have variable risk for low bone mass.

The review and guideline were funded by the ACP. Ott has reported no relevant disclosures. Relevant financial disclosures for other authors are listed with the guideline and review.

Ann Intern Med. Published online January 2, 2023. Guideline, Review, Editorial

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