HealthDay News — In a living clinical guideline issued by the American College of Physicians (ACP) and published online January 3 in the Annals of Internal Medicine, updated recommendations are presented for the pharmacologic treatment of primary osteoporosis or low bone mass to prevent fractures in adults.

Based on a systematic review and grading of the evidence, Amir Qaseem, MD, PhD, from ACP in Philadelphia, and colleagues developed four recommendations. To reduce the risk for fractures in postmenopausal women diagnosed with primary osteoporosis, ACP strongly recommends use of bisphosphonates for initial pharmacologic treatment; for men diagnosed with primary osteoporosis, bisphosphonates are suggested for initial pharmacologic treatment to reduce the risk for fracture. For postmenopausal women and for men diagnosed with primary osteoporosis who have contraindications to or experience adverse effects of bisphosphonates, the receptor activator of nuclear factor κB ligand inhibitor denosumab is suggested as second-line pharmacologic treatment. For women with primary osteoporosis with a very high risk for fracture, the sclerostin inhibitor romosozumab or recombinant human parathyroid hormone teriparatide, followed by a bisphosphonate, is suggested. For women older than the age of 65 years with osteopenia, an individualized approach regarding whether to start pharmacologic treatment with a bisphosphonate is suggested.

“Future studies should aim to identify which patients will benefit from medication, and when to initiate an anabolic medication versus a bisphosphonate,” write the authors of an accompanying editorial.

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Chintan V. Dave, PharmD, PhD, from Rutgers University in New Brunswick, New Jersey, and colleagues conducted a retrospective cohort study using target trial emulation for data obtained from 29,648 older longer-term care nursing home residents in the Veterans Health Administration to examine the association between antihypertensive medication initiation and fracture risk.

The researchers found that the incidence rate of fractures per 100 person-years was 5.4 for residents initiating antihypertensive medication vs 2.2 in the control arm in a propensity score-matched cohort of 64,710 residents (mean age, 77.9 years). The finding corresponded to an adjusted hazard ratio of 2.42 and an adjusted excess risk of 3.12 per 100 person-years. There was also an association seen for antihypertensive medication initiation with a higher risk for severe falls requiring hospitalizations or emergency department visits and syncope (hazard ratio, 1.80 and 1.69, respectively). A numerically higher magnitude of fracture risk was observed for subgroups of residents with dementia, systolic blood pressure of 140 mm Hg or higher, diastolic blood pressure of 80 mm Hg or higher, and no recent antihypertensive medication use (hazard ratios, 3.28, 3.12, 4.41, and 4.77, respectively).

“This study sheds light on the potential impact of fracture risk associated with antihypertensive medication use among long-term nursing home residents, emphasizing the need for caution when initiating therapy, especially in the high-risk period after drug initiation,” the authors write.

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HealthDay News — For patients with orthopedic trauma, thromboprophylaxis with aspirin is noninferior to low-molecular-weight heparin for preventing death, according to a study published in the January 19 issue of the New England Journal of Medicine.

Robert V. O’Toole, MD, from the University of Maryland School of Medicine in Baltimore, and colleagues conducted a randomized, noninferiority trial involving adult patients who had a fracture of an extremity that had been treated operatively or any pelvic or acetabular fracture. Patients were randomly assigned to receive either low-molecular-weight heparin or aspirin while they were in the hospital (6,110 and 6,101 patients, respectively). The patients continued to receive thromboprophylaxis after discharge according to the hospital clinical protocol.

The researchers found that death at 90 days occurred in 0.78 and 0.73% of patients in the aspirin and low-molecular-weight heparin groups, respectively (difference, 0.05 percentage points; 96.2% CI, −0.27 to 0.38; P <.001 for noninferiority). Deep vein thrombosis occurred in 2.51 and 1.71% of patients in the aspirin and low-molecular-weight heparin groups, respectively. The groups had a similar incidence of pulmonary embolism, bleeding complications, and other serious adverse events.

“The findings in this trial clearly indicate that guidelines for the prevention of hospital-acquired venous thromboembolism will need to be rewritten to include the option of aspirin in patients with traumatic injuries,” write the authors of an accompanying editorial.

Several authors disclosed financial ties to the medical device and health care industries.

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HealthDay News — Individuals with statin-associated muscle symptoms do not have worse exercise-induced muscle injury after prolonged moderate-intensity exercise, according to a study published in the April 11 issue of the Journal of the American College of Cardiology.

Neeltje A.E. Allard, MD, from the Radboud University Medical Center in Nijmegen, Netherlands, and colleagues examined the effect of prolonged moderate-intensity exercise on markers of muscle injury in statin users with and without statin-associated muscle symptoms (35 and 34 participants, respectively) and in 31 controls. Participants walked 30, 40, or 50km/day for 4 consecutive days. Markers of muscle injury, muscle performance, and reported muscle symptoms were examined at baseline and after exercise.

The researchers found that at baseline, all muscle injury markers were comparable and they increased following exercise, with no difference between the groups observed in terms of the magnitude of exercise-induced elevations. Symptomatic statin users had higher muscle pain scores at baseline, but scores increased similarly in all groups following exercise. Compared with control participants, symptomatic statin users had a greater increase in muscle relaxation time following exercise. Symptomatic and asymptomatic statin users and control participants had no difference in leukocyte coenzyme Q10 levels, which were measured at baseline; levels were not related to muscle injury markers, fatigue resistance, or reported muscle symptoms.

“This study demonstrated that habitually active statin users can engage in prolonged moderate-intensity exercise without exacerbating skeletal muscle injury and reinforces the recommendation to combine statin therapy with a physically active lifestyle,” the authors write.

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In November 2022, the FDA had issued a safety communication regarding the possibility of severe hypocalcemia with serious outcomes in patients with advanced CKD treated with the osteoporosis drug. The Agency went on to assess this risk in 2 studies using data from the Centers for Medicare & Medicaid Services.

Findings showed treatment with Prolia significantly increased the risk of developing severe hypocalcemia compared with bisphosphonates, especially in patients with advanced CKD. Severe hypocalcemia typically developed 2 to 10 weeks after each injection with Prolia; the greatest risk was observed between week 2 and 5.

The investigation also included 77 cases submitted to the FDA from July 2010 through May 2021. In these reports, patients with CKD (n=25) had experienced complications of severe hypocalcemia (eg, arrhythmias, confusion, seizures, face twitching, muscle spasms or weakness) following treatment with Prolia.

In response to these findings, the FDA has added a Boxed Warning to the prescribing information for Prolia about the increased risk of severe hypocalcemia in patients with advanced CKD, particularly in patients on dialysis or with mineral and bone disorder (MBD). This information has also been added to the patient Medication Guide and to the Prolia Risk Evaluation and Mitigation Strategy (REMS).

The FDA is recommending that health care providers assess their patients’ renal function before prescribing Prolia. The risk of severe hypocalcemia with Prolia treatment should be considered in patients with advanced CKD. If Prolia is still being considered, calcium blood levels should be obtained and these patients should be assessed for CKD-MBD.

To help reduce the risk of severe hypocalcemia, a health care professional with expertise in the diagnosis and management of CKD-MBD should be involved in the decision-making.  Managing CKD-MBD, correcting hypocalcemia and supplementing with calcium and activated vitamin D before and during Prolia treatment may decrease the risk of severe hypocalcemia. Close monitoring of serum calcium and prompt management of severe hypocalcemia is necessary to minimize the risk of complications.

Jubbonti is approved to treat postmenopausal women with osteoporosis at high risk for fracture, to increase bone mass in men with osteoporosis at high risk for fracture, to treat glucocorticoid-induced osteoporosis in men and women at high risk for fracture, to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer, and to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer. The Jubbonti approval also includes a Risk Evaluation and Mitigation Strategy program designed to inform prescribers of the risk of severe hypocalcemia in patients with advanced kidney disease. 

Wyost is indicated to prevent skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors, to treat adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity, and to treat hypercalcemia of malignancy refractory to bisphosphonate therapy.

For this approval, the FDA reviewed a comprehensive clinical data package, which included data from the phase 3 ROSALIA trial (ClinicalTrials.gov Identifier: NCT03974100). The study compared denosumab-bbdz to the reference product (Prolia) in 527 postmenopausal women with osteoporosis. Study participants were randomly assigned to receive the biosimilar or the reference product for up to 78 weeks of treatment. Findings showed the biosimilar denosumab was comparable to the reference product with regard to pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity.

The availability of Jubbonti and Wyost is still unclear as ongoing patent litigation precludes Sandoz from launching the products at this time.

The Food and Drug Administration’s (FDA) Endocrinologic and Metabolic Drugs Advisory Committee voted favorably (10 yes, 4 no) on whether the available evidence supports the effectiveness of palovarotene as a treatment for fibrodysplasia ossificans progressiva (FOP).

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by an abnormal development of bone in areas outside the normal skeleton. The disease causes restricted movement and fused joints, leading to deformities, restricted mobility and premature mortality. Palovarotene reduces new abnormal bone formation by selectively targeting the retinoic-acid receptor gamma (RARγ) within the retinoid signaling pathway.

The panel’s recommendation was based on efficacy and safety data that included results from the phase 3 MOVE trial (ClinicaTrials.gov Identifier: NCT03312634). The open-label study enrolled adult and pediatric patients with FOP. Patients (N=107) received oral palovarotene 5mg once daily, increased at the time of flare-up symptoms to 20mg once daily for 4 weeks, followed by 10mg for 8 weeks.

The primary endpoint was annualized change in new heterotopic ossification (HO) volume measured by low-dose whole-body computed tomography. Efficacy data were compared with data from FOP Natural History Study (NHS) participants (untreated beyond standard of care; ClinicalTrials.gov Identifier: NCT02322255). Results showed a 60% reduction in new abnormal bone formation HO volume in patients treated with palovarotene vs patients on standard of care.

On the question of whether the benefits of palovarotene outweigh the risks in the treatment of FOP, the committee voted 11 yes and 3 no. In the briefing document, the panel reported 3 issues of concern: 1) the appropriateness of relying on post hoc analyses to support efficacy; 2) the use of an external control group (NHS) and 3) an increased incidence of flare-ups symptoms.

“Retinoids have been associated with myositis and other musculoskeletal adverse effects, including back pain, arthralgia, and myalgia,” the panel noted in the briefing document. “There is uncertainty as to whether palovarotene may in some cases trigger flare-ups, or symptoms that could mimic flare-ups, and if so, whether the development of new HO over longer periods of treatment than were assessed in the palovarotene studies, eg, greater than 1 year, could be worse than without palovarotene treatment.”

Although not bound to the committee’s recommendations, the FDA does take them into consideration when making decisions on approval. A regulatory decision is expected by August 16, 2023.

“We are pleased with the outcome today and believe that the vote of the FDA advisory committee conveys the potential of palovarotene in helping manage the severe impacts of FOP,” said Howard Mayer, Executive Vice President and Head of Research and Development for Ipsen.