Zoledronate, a bisphosphonate infusion approved to treat osteoporosis, has been shown to prevent fractures in women aged 65 and older with osteopenia (T-score -1 to -2.5). To explore its effects in younger women with bone loss in the osteopenia or less range, researchers randomized 1054 postmenopausal women aged 50 to 60 (average age 56) with a T-score between 0 and -2.5 at the lumbar spine, femoral neck, or total hip (average lumbar spine T-score: -0.43; average total hip T-score: -0.51) to one of three treatments: zoledronate 5 mg at baseline and in 5 years, zoledronate 5 mg at baseline and placebo in 5 years, or placebo at baseline and in 5 years. At 10 years, the primary outcome, morphometric vertebral fracture (fractures identified by their shape on X-ray as opposed to symptoms), occurred in 6.3% (Zoledronate-Zoledronate), 6.6% (Zoledronate-Placebo), and 11.1% (Placebo-Placebo) of patients (p<0.05). Incidences of any fracture were 24.7%, 27.4%., and 35.3%, respectively. (p<0.05). No cases of osteonecrosis of the jaw or atypical femoral fracture, two concerning bisphosphonate side effects, were reported during the trial.

Zoledronate reduced the 10-year fracture risk in postmenopausal women aged 50 to 60 with an average T-score of around -0.46. Two infusions were slightly more effective than one, and both were superior to placebo. A secondary analysis stratifying effect size by baseline bone mineral density (BMD) would have been informative but was not performed. With 45% of women aged 50 to 60 having T-scores less than 0, these results apply to a large population. Current USPSTF guidelines recommend BMD screening in women under 65 at increased risk of osteoporosis, which they loosely define as a 10-year fracture risk of 10% or more.

Providers wanting to incorporate this study into their practice could follow these steps:

1. Screen postmenopausal women aged 50 to 60 with the FRAX tool
2. If the 10-year risk of a major osteoporotic fracture is greater than 10%, order a BMD test
3. If the T-score is 0 to -2.5 at the lumbar spine, femoral neck, or total hip, offer a one-time infusion of zoledronate 5 mg, with an anticipated effect of reducing the absolute risk of any fracture over 10 years by 8%

• Zoledronate vs Placebo in Postmenopausal Women Aged 50 to 60, NEJM (2025)
• Osteoporosis review
• Article on webpage

For decades, dopamine antagonists have been the primary treatment for psychotic disorders like schizophrenia. While effective, these drugs can have significant side effects. First-generation drugs like haloperidol can cause extrapyramidal symptoms (EPS), while second-generation agents like risperidone are known to induce weight gain and hyperprolactinemia. These adverse effects often limit patient compliance, underscoring the need for alternative therapies. Cobenfy, a combination of xanomeline and trospium chloride, is the first non-dopamine antagonist antipsychotic approved to treat schizophrenia. Xanomeline is a muscarinic cholinergic receptor agonist that preferentially stimulates cerebral M1 and M4 receptors, which are involved in schizophrenia pathophysiology. Trospium is a peripheral-acting antimuscarinic agent included to mitigate xanomeline's cholinergic effects. Cobenfy's side effects are primarily gastrointestinal and include nausea (19%), dyspepsia (18%), constipation (17%), and vomiting (15%). It is contraindicated in patients with liver disease and conditions that may be exacerbated by trospium's anticholinergic effects (e.g., urinary retention, reduced GI motility). It comes in a capsule taken twice daily, at least one hour before or two hours after a meal, as food reduces its absorption by 90%.

Providers treating schizophrenia now have an alternative to dopamine antagonists, which have been the only option since the approval of chlorpromazine in 1954. In two studies (see links below), Cobenfy reduced the score on the Positive and Negative Syndrome Scale (range 30 - 210, with higher scores indicating worse symptoms) by 11 points more than placebo. Head-to-head studies with dopamine antagonists are needed to truly define Cobenfy's therapeutic value.

• Xanomeline-Trospium vs Placebo for Schizophrenia in Adults, Lancet (2024) [Pubmed abstract]
• Xanomeline-Trospium vs Placebo for Schizophrenia in Adults, NEJM (2021) [Pubmed abstract]
• Cobenfy review
• Article on webpage

With the publication of two recent Zepbound (tirzepatide) studies, GLP weight-loss drugs continue their streak of positive trials in obesity-related conditions. In the first study, Zepbound was compared to placebo in 731 patients with heart failure with preserved ejection fraction (HFpEF). After two years of follow-up, the absolute risk of a composite of death from cardiovascular causes or worsening heart failure was 5.4% lower in the Zepbound group (9.9% vs 15.3%). [Pubmed abstract] The second trial (N=1032), a substudy of the SURMOUNT-1 weight-loss trial, found that over 3.4 years, Zepbound significantly reduced the incidence of diabetes compared to placebo in individuals with prediabetes (1.3% vs 13.3%). [Pubmed abstract] These studies add to a growing list of trials, summarized below, where Zepbound and Wegovy (semaglutide) have been found to improve outcomes in obesity-related conditions.

• Obstructive sleep apnea (OSA): In a 52-week trial enrolling overweight adults with OSA (N=469), Zepbound significantly reduced the apnea-hypopnea index, body weight, hypoxic burden, and systolic blood pressure compared to placebo. [Pubmed abstract] In December 2024, Zepbound received FDA approval for moderate to severe OSA in adults with obesity.
• Nonalcoholic steatohepatitis (NASH): In a 52-week study (N=190) enrolling adults with NASH, more patients treated with Zepbound had NASH resolution compared to placebo (62% [15 mg dose] vs 10%) [Pubmed abstract]
• Heart failure with preserved ejection fraction (HFpEF): Like Zepbound, Wegovy has also been shown to improve HFpEF. In a 52-week study (N=529) enrolling obese adults with HFpEF, Wegovy was superior to placebo for improving heart failure symptoms and physical endurance. [Pubmed abstract]
• Secondary prevention of cardiovascular disease (CVD): In a 40-month study (N=17,604) enrolling overweight adults with a history of CVD, Wegovy was superior to placebo for reducing a composite of CVD events (6.5% vs 8%). [Pubmed abstract] Based on this study, Wegovy received FDA approval for the secondary prevention of CVD events.
• Knee osteoarthritis (OA): In a 68-week study (N=407) enrolling obese adults with moderate knee OA, Wegovy was superior to placebo for improving knee pain. [Pubmed abstract]
• Prediabetes: As discussed above, Zepbound was significantly better than placebo at preventing progression to diabetes over 3.4 years in participants with prediabetes (1.3% vs 13.3%). [Pubmed abstract]

To date, the FDA has granted two non-obesity indications for Zepbound and Wegovy: OSA for Zepbound and secondary prevention of CVD events for Wegovy. However, more are sure to come as these highly effective weight-loss drugs continue to change people's lives.

• Article on a webpage

Nocturnal leg cramps are a common complaint, affecting 50% to 60% of adults at some point during their lifetime. When asked about treatment, providers struggle to provide meaningful advice, as there are no FDA-approved therapies, and traditional remedies like quinine have potentially serious adverse events, including arrhythmias and sensory disturbances (e.g., tinnitus). Given the lack of options, there has been interest in using a form of vitamin K that may have anti-spasmodic properties.

Vitamin K exists in two primary forms:

• Vitamin K1 (phylloquinone): Most common form; found in plants, especially green leafy vegetables; essential for blood clotting
• Vitamin K2 (menaquinone): Present in some animal products and fermented foods; has ten subtypes, designated menaquinone-4 through menaquinone-13, based on the length of the side chain; plays a role in blood clotting and calcium regulation

Menaquinone-7, a subtype of vitamin K2, is believed to inhibit calcium uptake by muscle cells, thereby preventing excessive contraction and potentially alleviating nocturnal leg cramps. To test this theory, researchers randomized 199 adults aged 65 and older with nocturnal leg cramps (baseline average 2.65 cramps/week) to menaquinone-7 180 mcg at bedtime or placebo. At the end of the study, the average number of weekly leg cramps in the menaquinone-7 group decreased to 0.96, while the placebo group saw an increase to 3.6 (p<0.001). No adverse events were reported in either group.

Even though this study was small, it provides useful information, as there is a lack of evidence-based therapies for leg cramps. Menaquinone-7 (also called MK-7 or menaquinone for short) is available on Amazon from numerous manufacturers in doses of 100 and 200 mcg. In the future, I will suggest that patients with bothersome cramps give it a try. The only apparent major precaution is its potential to interfere with vitamin K antagonists, precluding its use in patients on warfarin.

• Vitamin K2 vs Placebo for Nocturnal Leg Cramps, JAMA Intern Med (2024) [PubMed abstract]
• Article on a webpage

Secondary hypertension is high blood pressure with an identifiable and sometimes treatable cause. Studies have suggested that secondary hypertension may be present in 10% of individuals with hypertension and up to 30% of those with resistant hypertension. Despite its significant prevalence, many providers do not consider secondary causes when diagnosing hypertension, as obesity and essential hypertension, which affects up to 50% of U.S. adults, are so common that other etiologies are overlooked. To further explore the issue, researchers performed a cross-sectional study involving 2090 hypertensive adults aged 18 to 40 who underwent comprehensive evaluations for secondary causes. Secondary hypertension was identified in 29.6% of participants (N=619), with the most frequent etiologies being:

• Primary aldosteronism (54.8%)
• Primary kidney disease (12.9%)
• Drugs or substances (6%)
• Pheochromocytoma/functional paraganglioma (5.9%)
• Other (2.7%)

Factors associated with a higher prevalence of secondary causes included female sex, hypokalemia, treatment with at least two medications, no family history of hypertension, BMI less than 25, and diabetes.

This study was eye-opening, as I rarely consider secondary hypertension in adult patients. So many people are overweight and/or out of shape, it is easy to fall into the trap of attributing most conditions to these issues. After seeing these results, I will be more inclined to consider secondary causes, particularly in patients with factors associated with greater risk.

• AHA recommendations on whom to evaluate for secondary hypertension
• Causes of secondary hypertension
• Article on webpage