Publish date:January 4, 2023

ByMarlene Busko


The American College of Physicians has updated their guideline forpharmacotherapy to reduce fracture risk in adults with primary osteoporosis orosteopenia (low bone mass) based on a systematic review of the evidence.This is the fi rst update for 5 years since the previous guidance was published in2017. It strongly recommends initial therapy with bisphosphonates forpostmenopausal women with osteoporosis, as well as men with osteoporosis,among other recommendations.However, the author of an accompanying editorial, 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.

The ACP commissioned a review of the evidence because it says new datahave emerged on the effi cacy of newer medications for osteoporosis and lowbone mass, as well as treatment comparisons, and treatment in men.The review authors identifi ed 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 parathyroid hormone (PTH)–relatedprotein (abaloparatide), recombinant human PTH (teriparatide), and asclerostin inhibitor (romosozumab). 

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

The authors focused on eff ectiveness and harms of active drugs comparedwith 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 in an interview.“Bisphosphonates had the most favorable balance among benefits, harms, patient values and preferences, and cost among the examined drugs inpostmenopausal females with primary osteoporosis,” Dr. Cooney, professor of ObGyn  medicine, Oregon Health & Science University, Portland, noted, as is stated in the guideline. “Denosumab also had a favorable long-term net benefit, but bisphosphonatesare much cheaper than other pharmacologic treatments and available ingeneric formulations,” the document states. The new guideline suggests use of denosumab as second-linepharmacotherapy in adults who have contraindications to or experienceadverse eff ects with bisphosphonates. The choice among bisphosphonates (alendronate, risedronate, zoledronic acid)would be based on a patient-centered discussion between physician andpatient, addressing costs (often related to insurance), delivery-modepreferences (oral versus intravenous), and “values,” which includes the patient’s priorities, concerns, and expectations regarding their health care, Dr. Cooney explained. Another update in the new guideline is, “We also clarify the specifi c, albeitmore limited, role of sclerostin inhibitors and recombinant PTH ‘to reduce therisk of fractures only in females with primary osteoporosis with very high-risk offracture’,” Dr. Cooney noted.In addition, the guideline now states, “treatment to reduce the risk of fracturesin males rather than limiting it to ‘vertebral fracture’ in men,” as in the 2017guideline.It also explicitly includes denosumab as second-line therapy for men, Dr.Cooney noted, but as in 2017, the strength of evidence in men remains low.“Finally, we also clarifi ed 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 (newcontent),” he said. The use of estrogen, treatment duration, drug discontinuation, and serial bonemineral density monitoring were not addressed in this guideline, but will likelybe evaluated within 2 to 3 years.‘Osteoporosis treatment: Not easy’ – editorialIn her editorial, Dr. Ott writes: “The data about bisphosphonates may seemoverwhelmingly positive, leading to strong recommendations for their use totreat osteoporosis, but the decision to start a bisphosphonate is actually notthat easy.” “A strong recommendation should be given only when future studies areunlikely to change it,” continues Dr. Ott, professor of medicine, University ofWashington, Seattle.“Yet, data already suggest that, in patients with serious osteoporosis, treatmentshould start with anabolic medications because previous treatment with eitherbisphosphonates or denosumab will prevent the anabolic response of newermedications.” “Starting with bisphosphonate will change the bone so it will not respond to thenewer medicines, and then a patient will lose the chance for getting the bestimprovement,”  Dr. Ott clarifi ed in an email to this news organization. But, in fact, the new guidance does suggest that, to reduce the risk of fracturesin females with primary osteoporosis at very high risk of fracture, one shouldconsider use of the sclerostin inhibitor romosozumab (moderate-certaintyevidence) or recombinant human parathyroid hormone (teriparatide) (low- certainty evidence) followed by a bisphosphonate (conditionalrecommendation). Dr. Ott said: “If the [fracture] risk is high, then we should start with an anabolicmedication for 1-2 years.  If the risk is medium, then use a bisphosphonate forup to 5 years, and then stop and monitor the patient for signs that the medicineis wearing off ,” based on blood and urine tests.‘We need medicines that will stop bone aging’Osteopenia is defi ned by an arbitrary bone density measurement, Dr. Ottexplained. “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,” Dr. Ott said, “I would notuse bisphosphonates in patients who did not already have a fracture or whosebone 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 thejaw or femur. These are real, but they are very rare during the fi rst 5 years oftreatment, Dr. Ott noted. Then the risk starts to rise, up to more than 1 in 1,000after 8 years. So people can get the benefi ts of these drugs with very low riskfor 5 years.“An immediate [guideline] update is necessary to address the severity of boneloss and the high risk for vertebral fractures after discontinuation ofdenosumab,” Dr. Ott urged  “I don’t agree with using denosumab for osteoporosis as a second-linetreatment,” she said. “I would use it only in patients who have cancer orunusually 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 abisphosphonate. Many patients and even too many doctors do not realize howserious it can be to skip a dose.”“I also think that men could be treated with anabolic medications,” Dr. Ott said.“Clinical trials show they respond the same as women. Many men haveosteoporosis as a consequence of low testosterone, and then they can usuallybe treated with testosterone. Osteoporosis in men is a serious problem that istoo often ignored – almost reverse discrimination.”It is also unfortunate that the review and recommendations do not addressestrogen, one of the most eff ective medications to prevent osteoporoticfractures, according to Dr. Ott.Clinical considerations in addition to drug typesThe new guideline also advises: Clinicians treating adults with osteoporosis should encourage adherenceto recommended treatments and healthy lifestyle habits, includingexercise, and counseling to evaluate and prevent falls.All adults with osteopenia or osteoporosis should have adequate calciumand 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 osteoporosistreatments.Current evidence suggests that more than 3-5 years of bisphosphonatetherapy reduces risk for new vertebral but not other fractures; however, italso increases risk for long-term harms. Therefore, clinicians shouldconsider stopping bisphosphonate treatment after 5 years unless thepatient has a strong indication for treatment continuation.The decision for a bisphosphonate holiday (temporary discontinuation) andits duration should be based on baseline fracture risk, medication half-lifein bone, and benefi ts and harms.Women treated with an anabolic agent who discontinue it should beoff ered an antiresorptive agent to preserve gains and because of seriousrisk for rebound and multiple vertebral fractures.Adults older than 65 years with osteoporosis may be at increased risk forfalls or other adverse events because of drug interactions.Transgender persons have variable risk for low bone mass.The review and guideline were funded by the ACP. Dr. Ott has reported norelevant disclosures. Relevant fi nancial disclosures for other authors are listedwith the guideline and review.