Drug‐related sarcopenia as a secondary sarcopenia

Abstract

Sarcopenia has a significant impact on falls, physical function, activities of daily living, and quality of life in older adults, and its prevention and treatment are becoming increasingly important as the global population ages. In addition to primary age‐related sarcopenia, activity‐related sarcopenia, disease‐related sarcopenia, and nutrition‐related sarcopenia have been proposed as secondary sarcopenia. Polypharmacy and potentially inappropriate medication based on multiple diseases cause health problems in older patients. In some cases, drugs used for therapeutic or preventive purposes act on skeletal muscle as adverse drug reactions and induce sarcopenia. Although sarcopenia caused by these adverse drug reactions may be more common in older patients, in particular those taking many medications, drug‐related sarcopenia has not yet received much attention. This review summarizes drugs that may induce sarcopenia and emphasizes the importance of drug‐related sarcopenia as a secondary sarcopenia. Geriatr Gerontol Int 2024; 24: 195–203.

Various drugs can act directly or indirectly on skeletal muscle, causing skeletal muscle atrophy, muscle weakness, and muscle wasting. In older patients, polypharmacy is particularly common, and drug‐related sarcopenia, a secondary sarcopenia, requires attention.

Introduction

Sarcopenia is a term proposed by Rosenberg to describe the excessive loss of lean body mass and skeletal muscle atrophy associated with aging. ¹ In recent years, the diagnosis of sarcopenia has been based not only on a decrease in skeletal muscle mass, but also on an assessment of muscle strength and physical function. ² Furthermore, the European Working Group on Sarcopenia in Older People proposed primary sarcopenia as a primary factor of aging, and activity‐related sarcopenia, disease‐related sarcopenia, and nutrition‐related sarcopenia as secondary sarcopenia. ² However, there are many other factors affecting muscle mass loss and strength, not to mention genetic disorders. In particular, there may be several drugs that affect skeletal muscle as adverse drug reactions (ADRs), but they have not received much attention as factors in sarcopenia. Polypharmacy is not uncommon in older patients, and attention should be paid to sarcopenia involving ADRs, drug‐related sarcopenia. This review describes drugs that may have a negative effect on skeletal muscle, which may warrant attention.

Data sources, search methods, and review policy

Using PubMed as the database, a search from 2013 to July 2023 using the following search formula yielded 1657 articles (“muscular atrophy” [MeSH Terms] OR “muscle weakness” [MeSH Terms] OR “muscle wasting” [All Fields]) AND (“drug related side effects and adverse reactions” [MeSH Terms] OR “Pharmacologic Actions” [MeSH Terms]).

In addition, many other articles were cited through hand searches. Although this review emphasized human clinical data, basic studies, such as animal studies examining the mechanisms of drug effects on muscle, were included. Drug‐induced myopathy involves many drugs and has a variety of muscle‐related symptoms. Some drugs cause only muscle pain or weakness without an increase in serum creatinine kinase (CK) levels, while others cause severe muscle damage such as rhabdomyolysis or an increase in serum CK levels more than 10 times the normal level. ³ However, these rare cases of severe drug‐induced myopathy may not be considered a cause of sarcopenia due to prolonged use of these drugs, as they are accompanied by significant subjective symptoms or are usually noted as abnormal by the medical institution. However, drug‐induced CK elevations vary from patient to patient, and drugs that may be associated with elevated CK were also addressed in this review (Table 1).

Table 1.

Serum creatinine kinase levels of various drug‐related sarcopenia

Drugs	CK levels
Statin	➡, ⬆ (~20%)
Sulfonylureas/insulin secretagogue (glinides)	➡
GLP‐1 receptor agonists	➡
SGLT2 inhibitors	➡
Glucocorticoid	➡
Antineoplastic drugs	➡, ⬆
Immune checkpoint inhibitors	⬆ (~70%)
Androgen deprivation therapy	➡
Chloroquine/hydroxychloroquine	⬆ (~20%)
Colchicine	➡, ⬆
Nucleoside analogues	➡, ⬆
Loop diuretics	➡
D‐penicillamine	⬆

Abbreviations: GLP‐1, glucagon like peptide‐1; SGLT2, sodium–glucose cotransporter 2; ⬆, increase; ➡, no change.

It should also be emphasized that the articles used in this review deal not only with sarcopenia diagnosed according to formal criteria, but also with muscle atrophy, muscle weakness and muscle wasting, as the search formula suggests. In addition to the drugs discussed here, there are many other drugs that may induce myopathy as ADRs, but many of them have only been reported in a few case reports and are still not common, so they are not discussed in this review. In addition, many drugs induce anorexia as ADRs and may affect skeletal muscle via malnutrition. ⁴ Drugs that indirectly affect skeletal muscle in this way are not discussed in this review, although there are some exceptions. Importantly, a systematic review has not been conducted, and therefore, some important articles may have been missed in the review.

Drugs that cause a certain frequency of sarcopenia or myopathy

Hydroxymethylglutaryl‐CoA reductase inhibitors (statins)

Statins are widely used as drugs to prevent atherosclerotic diseases such as coronary artery disease by lowering serum low‐density lipoprotein‐cholesterol. It is also known to produce various skeletal muscle symptoms (statin‐associated muscle symptoms [SAMS]), which may interfere with continued use of the drug. SAMS range from myalgia to statin‐induced myopathy with or without elevated CK to, most severely, rhabdomyolysis. The frequency of SAMS varies by report, but in observational studies, 10–30% of patients complain of some muscle symptoms, and about 30% of these patients discontinue their medication. Statin intervention studies show that the risk of SAMS differs between moderate and intense statin therapy, with an approximately 4% increased incidence of muscle problems with intense statin therapy compared with moderate statin therapy. ⁵ In a systematic review of 26 intervention studies, patients treated with statins tended to have more muscle problems than the placebo group (12.7% vs. 12.4%, P = 0.06). ⁶

Possible causes of SAMS include mitochondrial dysfunction and decreased coenzyme Q10 due to antagonism of the chloride (Cl⁻) channel at the muscle membrane level. Furthermore, statins may enhance apoptosis and atrogin‐1 expression via the prenylation of small GTPases of the Rho family, resulting in a decrease in myofiber size, an increase in muscle protein catabolism, and an increase in myostatin expression in muscle (Table 2). ³ , ⁵ , ⁷ However, the clear mechanism of SAMS remains unclear.

Table 2.

Drugs that may cause sarcopenia and their direct effects on muscle

Drugs	Effects on skeletal muscle
Statin	Mitochondrial function ⬇, coenzyme Q10 ⬇, apoptosis ⬆, muscle protein catabolism ⬆
Sulfonylureas/insulin secretagogue (glinides)	Apoptosis ⬆
SGLT2 inhibitors	Muscle protein ⬇ a
Antineoplastic drugs	Various b
Immune checkpoint inhibitors	Cytotoxic T cell ⬆, inflammation in muscle ⬆
Glucocorticoids	Muscle protein ⬇, satellite cell differentiation ⬇, muscle IGF‐I production ⬇
Androgen deprivation therapy	Muscle protein ⬇, inflammation ⬆
Chloroquine/hydroxychloroquine	Autophagy ⬇
Colchicine	Autophagy ⬇
Nucleoside analogues	Mitochondrial function ⬇
Loop diuretics	Myoblast fusion ⬇
D‐penicillamine	Inflammation in muscle ⬆

Abbreviations: SGLT2, sodium–glucose cotransporter 2; ⬆, increase; ⬇, decrease.

^a Indirect action on muscles.

^b Refer to Table 5.

Several observational studies have shown that statins reduce physical activity, ⁸ muscle strength, ⁹ , ¹⁰ and delay muscle recovery after cerebrovascular injury. ¹¹ However, there are several conflicting reports that statins do not affect skeletal muscle mass ¹² and that statins reduce the development of sarcopenia and enhance physical function. ¹³ , ¹⁴ , ¹⁵ In the only intervention study targeting the effects of statins on skeletal muscle (420 healthy subjects followed for 6 months for exercise capacity and muscle strength after 80 mg atorvastatin or placebo), during the observation period, 9.4% in the statin group (4.6% in the placebo group, P = 0.05) developed myalgia and a mild elevation of serum CK was observed in the statin group (mean increase since enrollment 20.8 ± 141.1 U/L). ¹⁶ CK levels exceeded the upper limit of normal in 19.8% and 13.3% of the atorvastatin and placebo groups, respectively, but no participants had serum CK elevations greater than 10 times the upper limit of normal. There were no significant differences in muscle strength or exercise capacity between the two groups in this intervention study, but both groups showed muscle weakness in myalgic subjects. ¹⁶ The results of this intervention study suggest that high‐dose statins have little effect on muscle strength or physical function, at least in the absence of myalgia or other muscle symptoms, but the effects of long‐term administration remain unknown.

Glucose‐lowering drugs

Diabetes (both type 1 and type 2) itself is recognized as a risk for sarcopenia. ¹⁷ , ¹⁸ Various glucose‐lowering drugs have been developed in recent years and are already being used clinically in patients with diabetes. Among those, there are drugs that also affect skeletal muscle metabolism and may be associated with a risk of developing sarcopenia (Table 3). ¹⁹ , ²⁰ Most studies on the effects of diabetes medications on skeletal muscle are based on observational studies, and even in intervention studies, muscle assessment is a secondary endpoint, not a primary endpoint, and studies that comprehensively assess skeletal muscle, including muscle mass, strength, and physical function are very limited. Therefore, the definitive effects of some drugs on skeletal muscle are still unclear. Glucose‐lowering drugs that may induce sarcopenia are described below.

Table 3.

Effects of glucose‐lowering drugs on sarcopenia

Glucose‐lowering drugs	Possible effect		Potential underlying mechanisms
	Muscle mass	Muscle strength/physical function
Biguanides	⬆	⬆	Insulin sensitivity ⬆, reactive oxygen species ⬇, AMPK ⬆, mitochondrial biogenesis ⬆
Thiazolidinediones	⬆	⬆	Insulin sensitivity ⬆, AMPK ⬆, mitochondrial biogenesis ⬆
Alpha‐glucosidase inhibitors	?	?
Sulfonylureas and insulin secretagogue (glinides)	⬇	⬇	Hypoglycemia risk ⬆, apoptosis ⬆, muscle protein ⬇
Dipeptidyl peptidase‐4 inhibitors	⬆	⬆	Skeletal muscle glucose uptake ⬆, mitochondrial biogenesis ⬆
GLP‐1 receptor agonists	⬆ ➡ ⬇	⬆ ➡ ⬇	Insulin sensitivity ⬆, myostatin ⬇, mitochondrial biogenesis ⬆
SGLT2 inhibitors	⬇	?	Insulin level ⬇, glucagon level ⬆
Insulin	⬆	⬆	Muscle protein synthesis ⬆, degradation ⬇

Abbreviations: AMPK, AMP‐activated protein kinase; GLP‐1, glucagon like peptide‐1; SGLT2, sodium–glucose cotransporter 2; ⬆, increase, activation; ⬇, decrease, inactivation; ➡, no effect; ?, not known.

Sulfonylureas and insulin secretagogue (glinides) induce depolarization of the β‐cell membrane by closing the ATP‐sensitive K‐channel in the pancreatic β‐cell membrane, thereby promoting calcium influx into the β‐cell and insulin secretion. Although studies on the effects of these drugs on skeletal muscle in humans are limited, reports in the FDA‐Adverse Effects Reporting System (AERS) database for glibenclamide/glyburide indicate that 8 months of treatment with these drugs has resulted in a significant reduction in skeletal muscle mass. ²¹ One mechanism is that these drugs have a high risk of inducing hypoglycemia, which is a risk factor for skeletal muscle atrophy. In addition, animal studies have reported that the closure of ATP‐sensitive K‐channels in muscle may induce muscle atrophy via apoptosis in muscle and reducing muscle protein (Tables 2 and 3). ²²

Basic studies, including animal studies, have reported that glucagon‐like peptide‐1 (GLP‐1) receptor agonists promote insulin secretion, increase insulin sensitivity, inhibit myostatin expression, suppress muscle protein degradation, and decrease inflammation and reactive oxygen species (ROS) production. ¹⁹ , ²⁰ These pharmacological effects suggest that GLP‐1 receptor agonists may have protective effects on skeletal muscle, i.e., they may have inhibitory effects on sarcopenia. While some clinical studies support these findings, others report that GLP‐1 receptor agonists decrease skeletal muscle mass and impair muscle performance (Table 3). ¹⁹ , ²³ , ²⁴ It is unclear whether the negative effects of these drugs on skeletal muscle are secondary effects mediated by decreased appetite or direct effects on skeletal muscle. Thus, the definitive clinical effects of GLP‐1 receptor agonists on skeletal muscle remain unclear.

Sodium–glucose cotransporter 2 inhibitors that decrease proximal tubular glucose reabsorption, not only reduce body weight and body fat, but meta‐analyses have indicated that they also reduce lean body mass and skeletal muscle mass. ²⁵ , ²⁶ Sodium–glucose cotransporter 2 itself is not present in skeletal muscle, and its effects on skeletal muscle may be mediated by indirect systemic effects. Possible mechanisms include decreased uptake of glucose and amino acids and increased degradation of muscle proteins in skeletal muscle associated with decreased insulin secretion, but the detailed mechanisms remain unclear (Tables 2 and 3). ²²

Other glucose‐lowering drugs such as biguanides, thiazolidinediones, dipeptidyl peptidase‐4 inhibitors, and insulin may be protective with respect to sarcopenia (Table 3). ¹⁹ , ²⁰ , ²² The effects of alpha‐glucosidase inhibitors on sarcopenia are unknown, as there are no reports of their effects on skeletal muscle. However, given their mechanism of action (inhibition of alpha‐glucosidase, a digestive enzyme secreted from the small intestine), a direct effect on skeletal muscle is unlikely.

Antineoplastic (chemotherapy) drugs

Chemotherapy is now frequently used as one of the main treatments for malignant tumors. However, adverse reactions to chemotherapy itself occur frequently, with nausea, loss of appetite, tiredness, fatigue, and weight loss being the major adverse reactions. In some cases, weight loss, a frequently observed side effect of chemotherapy, is mainly related to skeletal muscle loss, which exacerbates the symptoms of cachexia induced by the malignancy itself. ²⁷ According to one review, chemotherapy for various malignancies, with or without radiation therapy, is associated with a loss of skeletal muscle mass ranging from 2.5% to 7.8%/100 days. ²⁸ Furthermore, this reduction in skeletal muscle mass worsens the prognosis for patients with malignant tumors.

There are various factors that may contribute to muscle wasting caused by chemotherapy for malignant tumors. Although muscle wasting may be the result of chemotherapy‐related side effects such as decreased appetite, nausea/vomiting, and diarrhea, postoperative studies comparing chemotherapy with placebo have shown that chemotherapy itself directly affects muscle mass loss ²⁹ and animal studies also support a direct effect of chemotherapy on skeletal muscle. ²⁷ , ³⁰ , ³¹

Table 4 lists antineoplastic drugs that have been shown from basic or clinical studies to act directly on skeletal muscle. ²⁷ , ³² Table 5 shows the mechanisms (various pathways and organelles involved) by which each antineoplastic drug induces muscle atrophy or wasting.

Table 4.

Antineoplastic drugs with possible direct action on skeletal muscle according to ATC level 2, 3, and 4 classification

ATC level 4	ATC level 3	ATC level 2
Nitrogen mustard analogues	ALKYLATING AGENTS	ANTINEOPLASTIC AGENTS
Pyrimidine analogues	ANTIMETABOLITES
Folic acid analogues
Taxanes	PLANT ALKALOIDS AND OTHER NATURAL PRODUCTS
Vinca alkaloids and analogues
Podophyllotoxin derivatives
Topoisomerase 1 inhibitors
Vinca alkaloids and analogues
Podophyllotoxin derivatives
Anthracyclines and related substances	CYTOTOXIC ANTIBIOTICS AND RELATED SUBSTANCES
EGFR tyrosine kinase inhibitors	PROTEIN KINASE INHIBITORS
Other protein kinase inhibitors
Human epidermal growth factor receptor 2 inhibitors	MONOCLONAL ANTIBODIES AND ANTIBODY DRUG CONJUGATES
EGFR inhibitors
VEGF/VEGFR inhibitors
Platinum compounds	OTHER ANTINEOPLASTIC AGENTS

Abbreviations: EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Table 5.

Effect of antineoplastic drugs on various pathways or organelles affecting skeletal muscle atrophy or wasting

Pathways or organelles affected by anticancer drugs		Effects	Outcomes	Examples of potentially relevant anticancer drugs (ATC level 5)
1	IGF‐1/IRS‐1/PI3K/Akt/mTOR pathway	⬇	Protein synthesis ⬇	Cisplatin, 5‐fluorouracil, doxorubicin
2	Satellite‐cell maturation	⬇	Myogenic differentiation ⬇	Doxorubicin
3	Myostatin/ActRIIB/SMAD pathway	⬆	Protein synthesis ⬇, muscle differentiation ⬇	Cisplatin, gemcitabine
4	IL‐6/JAK/STAT pathway	⬆	Protein degradation ⬆	Oxaliplatin
5	NF‐κB pathway	⬆	Protein degradation ⬆ (UPP ⬆, ALP ⬆)	Cisplatin, 5‐fluorouracil, doxorubicin
6	ALP	⬆*	Protein degradation ⬆	Oxaliplatin, cisplatin, doxorubicin
7	UPP	⬆	Protein degradation ⬆	Gemcitabine, cisplatin, oxaliplatin
8	Mitochondria biogenesis	⬇	Oxidative stress ⬆	Doxorubicin, cyclophosphamide
9	Microtubule architecture	⬆⬇**	Mitochondrial biogenesis ⬇	Paclitaxel, vinblastine

Note: Table modified by the author based on 27, 32

Abbreviations: ActRIIB, activin receptor type‐2B; ALP, autophagy–lysosome pathway; IGF‐1, insulin‐like growth factor I; IL‐6, interleukin‐6; IRS‐1, insulin receptor substrate‐1; JAK/STAT, Janus kinase/signal transducers and activators of transcription; mTOR, mammalian target of rapamycin; NF‐κB, nuclear factor‐kappaB; PI3K, phosphatidylinositol‐3 kinase; UPP, ubiquitin–proteasome pathway; ⬆, activation or increase; ⬇, inactivation or decrease; ⬆*, dysregulation of autophagy; ⬆⬇**, stabilizing or destabilizing.

Immune checkpoint inhibitors

Immune checkpoint inhibitors are monoclonal antibodies that target cytotoxic T lymphocyte‐associated protein 4, programmed cell death protein 1 (PD‐1), or its ligand, PD‐ligand 1 (PDL‐1). The common function of these antibodies is to block receptors or ligands that send inhibitory signals to immune cells, thereby preventing the entry of inhibitory signals from antigen‐presenting cells or tumor cells, thereby sustaining T‐cell activation and attacking cancer cells. Typically, adverse reactions associated with the release of immunosuppression by immune checkpoint inhibitors occur when T cells infiltrate various organs throughout the body, triggering an excessive immune response. Such adverse reactions have symptoms similar to those of autoimmune diseases and are referred to as immune‐related adverse events (irAEs). ³³ , ³⁴

Among these irAEs, myalgia and myositis occurred in 4% and <1%, respectively, more frequently with anti‐PD‐1/PD‐L1 antibodies than with anti‐cytotoxic T lymphocyte‐associated protein‐4 antibodies, and more frequently in older patients. ³³ , ³⁴ Myalgia appears on average 4 weeks after the start of treatment, followed by muscle weakness, mainly in the proximal muscles, and ptosis and ocular motility disorders similar to myasthenia gravis. ³⁴ Myocarditis is present in 25–40% of irAEs with skeletal muscle symptoms; CK is elevated in ~70%, but normal in one‐third, and the degree of elevation varies (Table 1). Myositis‐specific antibodies are usually negative, and a muscle biopsy is necessary for diagnosis. In total, 20% of patients present with skin rash such as dermatomyositis. Muscle biopsy reveals myofiber necrosis with infiltration of T cells (CD4⁺, CD8⁺), B cells (CD20⁺), and CD68⁺ macrophages. Treatment is usually with prednisolone. The mechanism is not yet clear, but it is suspected to involve aberrant cytotoxic T‐cell activation and the production of autoantibodies (Table 2). ³³ , ³⁴

Glucocorticoids

Glucocorticoid‐induced myopathy, characterized by muscle weakness and muscle atrophy, has been recognized since the 1950s, when glucocorticoids were first used as therapeutic agents. In fact, in addition to therapeutic glucocorticoids, blood glucocorticoids are elevated in pathological conditions such as sepsis, cachexia, and starvation, and are known to be involved in the muscle atrophy associated with these conditions. ³⁵ , ³⁶ Glucocorticoid‐induced myopathy used for therapeutic purposes has been reported in as many as 60% of cases and is a very frequent adverse reaction. Fluorinated steroids (e.g., dexamethasone, triamcinolone, and betamethasone) are more likely to cause myopathy than non‐fluorinated steroids (e.g., hydrocortisone, prednisolone, prednisone).

Generally, myopathy develops and progresses slowly with chronic glucocorticoid use (depending on the type and dose of glucocorticoids). In total, ≥10 mg of prednisone equivalent per day and 2–3 weeks is usually enough to start some symptoms of myopathy. ³⁶ , ³⁷ These glucocorticoid‐induced myopathies are not accompanied by myalgia or elevated serum CK, and muscle atrophy and weakness begin in the proximal muscles of the lower extremities and extend to the proximal and distal parts of the upper extremities (Table 1). ³⁸ Thus, long‐term use of glucocorticoids has been reported to induce sarcopenia, which is a risk for falls. ³⁹

Glucocorticoid‐induced muscle atrophy is more likely to occur in fast‐twitch muscles (type II fibers), which are rich in glucocorticoid receptors, and muscles with mixed fibers, in which both types of fibers are mixed, are also more likely to atrophy than type I fibers. The mechanism of muscle atrophy is that glucocorticoid inhibits muscle protein anabolism and enhances catabolism via its receptors in muscle, thereby inducing a decrease in muscle protein content. In fact, glucocorticoid inhibits the uptake into myofibers of amino acids necessary for muscle protein synthesis and inhibits the phosphorylation of eukaryotic translation initiation factor 4E‐binding protein 1 and the ribosomal protein S6 kinase 1, which stimulate muscle protein anabolism. It also suppresses local production of insulin‐like growth factor‐1, which stimulates muscle growth and hypertrophy, and increases the production of myostatin, which inhibits differentiation and proliferation of muscle satellite cells. With regard to muscle protein catabolism, glucocorticoid stimulates not only the ubiquitin proteasome system‐dependent proteolysis but also the lysosomal system (autophagy) and the calcium‐dependent system (calpains) (Table 2). ³⁵ , ⁴⁰ Decreased physical activity increases glucocorticoid receptors in skeletal muscle and enhances glucocorticoid‐induced myopathy. In fact, exercise is known to prevent glucocorticoid‐induced myopathy. ⁴¹

Androgen deprivation therapy

Androgens are a class of steroid hormones, also called anabolic steroids, that have muscle‐building effects and include testosterone, dehydroepiandrosterone, and androstenedione. Of these, testosterone is the strongest androgen. The androgen receptor is a type of nuclear receptor that binds to and activates the androgen hormone testosterone or dihydrotestosterone in the cytoplasm and translocates it into the nucleus. Androgen receptor is also present in skeletal muscle and is involved in the growth and maintenance of muscle mass by increasing muscle protein anabolism and decreasing catabolism in muscle cells and activating muscle satellite cells. ⁴² With aging, the level of testosterone in the blood decreases, inducing various symptoms as late‐onset hypogonadism syndrome, among which is sarcopenia. ⁴² , ⁴³

Hormone therapy (androgen deprivation therapy [ADT]), which decreases circulatory androgen and block androgen signaling, is currently the most effective and basic treatment for prostate cancer, along with surgery and radiation therapy. In addition to orchiectomy (surgical castration), ADT includes luteinizing hormone‐releasing hormone agonists and antagonists, gonadotropin‐releasing hormone antagonists, and androgen synthesis inhibitors, that lower testosterone levels in the blood. Androgen receptor inhibitors (antagonists), which block androgen receptor signaling, are also included in ADT. ADT is associated with decreased bone density, changes in body composition (increased body fat and decreased lean body mass), and muscle weakness, increasing the risk of falls and fractures. ⁴⁴ , ⁴⁵ The use of ADT in prostate cancer patients results in an average annual loss of lean body mass of approximately 2.0–3.6%. ⁴⁶ Furthermore, the older the patient, the greater the rate of loss of muscle mass. For example, patients >70 years of age are three times more likely to lose lean body mass than patients <70 years of age. ⁴⁶

As mentioned above, androgens play an important role in the maintenance of skeletal muscle, and the decrease in blood testosterone or suppression of androgen receptor signaling by ADT causes suppression of muscle protein anabolism and increased catabolism in skeletal muscle. Furthermore, the increase in visceral fat associated with ADT induces the expression of proinflammatory cytokines, such as interleukin (IL)‐6 and tumor necrosis factor‐α, which increase muscle protein catabolism in skeletal muscle (Table 2). This ADT‐induced loss of lean body mass is reported preventable by exercise interventions such as resistance exercise. ⁴⁷

Antimalaria drugs: chloroquine and hydroxychloroquine

Chloroquine (CQ) and hydroxychloroquine (HCQ) are used not only as antimalaria drugs but also in inflammatory diseases such as sarcoidosis, systemic lupus erythematosus, rheumatoid arthritis (RA), and COVID‐19. A systematic review of CQ/HCQ‐induced myopathy included five articles with more than 10 case reports. ⁴⁸ The duration of CQ/HCQ administration in these articles ranged from 3 months to 9 years. The longest durations of treatment were in patients with systemic lupus erythematosus and other rheumatology‐related diseases. Of a total of 1367 subjects in the five articles, 37 had symptoms of muscle weakness or symptoms related to CQ/HCQ myotoxicity. The incidence ranged from 1.4% to 26.1% (overall pooled for event rate: 6.5%), with a predilection for women over 50 years of age. They recovered from myopathy after discontinuation of CQ/HCQ. Ultrastructural examination of the muscles revealed typical autophagic vacuolar changes, curvilinear and lamellar bodies in the muscles. Elevated blood muscle enzymes were found in 13.2–27.9% (overall pooled for event rate: 19.5%) (Table 1).

The mechanism of CQ/HCQ‐induced myopathy is that CQ/HCQ has a marked lysosomal affinity, which makes these drugs prone to lysosomal accumulation. CQ/HCQ accumulation in lysosomes increases lysosomal pH and suppresses lysosomal enzyme activity. This inhibits the fusion of autophagosomes and lysosomes, thereby blocking the protein removal system and inducing myopathy (Table 2). ³ Autophagy in muscle fibers plays a variety of muscle maintenance and growth‐related roles (Table 6).

Table 6.

Role of autophagy in skeletal muscle growth and maintenance

Events involved in the growth and maintenance of myofibers		Effect of autophagy
1	Intracellular homeostasis	⬆
2	Oxidative stress	⬇
3	Mitochondrial function	⬆
4	Cellular senescence	⬇
5	Inflammation	⬇
6	Muscular regeneration	⬆
	Satellite cells: maintaining stemness	⬆
	Differentiation to myoblasts, myocytes	⬆
	Fusion to myotubes	⬆

Note: Table modified by the author based on Xie et al. and Chen et al. ⁵⁶ , ⁵⁷

Abbreviations: ⬆, increase; ⬇, decrease.

Anti‐rheumatoid drug

Patients with inflammatory rheumatic diseases such as RA have previously shown decreased skeletal muscle mass, muscle strength, and physical function. In fact, the prevalence of sarcopenia in patients with RA has been reported to range from 17.1% to 60%. ⁴⁹ , ⁵⁰ The cause is not only due to chronic inflammation with elevated inflammatory cytokines such as tumor necrosis factor‐α, IL‐1β, and IL‐6 in patients with inflammatory rheumatic diseases, but also to the possible influence of anti‐RA drugs. ⁴⁹ Glucocorticoids are also widely used in rheumatoid patients, and as described in detail in another section, glucocorticoids are known to have a significant negative effect on skeletal muscle. A meta‐analysis of seven studies reported an association between glucocorticoid use in rheumatic patients and sarcopenia (odds ratio [OR]: 1.46, 95% confidence interval [CI]: 0.94–2.29, I ² = 47.5%). ⁵¹ Prospective studies have also reported that glucocorticoid administration is a risk for the development of sarcopenia. ⁵²

In addition to glucocorticoids, many anti‐rheumatic drugs, particularly disease‐modifying antirheumatic drugs, have recently been introduced into clinical practice. In particular, biologic and targeted synthetic disease‐modifying antirheumatic drugs are expected to act in an inhibitory (protective) manner against sarcopenia by suppressing intracellular signaling of inflammatory cytokines and Janus kinases, thereby reducing inflammation. ⁵¹ , ⁵³ Therefore, details regarding these agents are omitted from this review, which deals with agents that induce sarcopenia.

Colchicine

Colchicine is a fat‐soluble alkaloid that has long been used as a treatment for gout. It is also known to be effective in the treatment or prevention of various other diseases (e.g., pulmonary fibrosis, psoriatic arthritis, Behçet's disease, etc.). There have been several case reports of myopathy possibly caused by this colchicine, but no quantitative epidemiological studies have been conducted, and the frequency of the disease is unknown. According to a report of 75 cases, the time from colchicine administration to the onset of myopathy ranged from 4 days to 2 years, and symptoms were mainly proximal muscle weakness and myalgia, with varying degrees of elevation of serum CK, with some cases showing no elevation (Table 1). ⁵⁴

Impaired hepatic and renal function related to colchicine metabolism may decrease colchicine excretion and increase the risk of colchicine‐induced myopathy. Colchicine inhibits polymerization of microtubules, which play a major role in the transport of intracellular organelles. Therefore, it has been proposed that colchicine induces myopathy by inhibiting the transport of lysosomes and autophagic vacuoles, which are necessary for the removal of damaged proteins and organelles (Table 2). In fact, an accumulation of autophagic lysosomes has been observed in the muscle tissue of patients with colchicine myopathy. ⁵⁵ Autophagy has already been shown to play various roles in the maintenance and regeneration of skeletal muscle (Table 6). ⁵⁶ , ⁵⁷

Nucleoside analogues

Zidovudine is a nucleoside analogue used primarily as an antiretroviral therapy in patients infected with human immunodeficiency virus (HIV). Zidovudine‐induced myopathy is perceived as wasting and weakness of proximal muscles and sometimes myalgia. Elevations in serum CK, if any, are mild and intermittent (Table 1). ⁵⁸ Patients with HIV have long been noted to be more prone to sarcopenia, and one factor may be the long‐term use of antiviral medications. ⁵⁹

Prolonged use of zidovudine increases ROS production and oxidative stress by disrupting the electron transport chain, resulting in mitochondria dysfunction. ³ Recently, tenofovir‐based regimen, a nucleoside analogue other than a zidovudine‐based regimen, has been reported to induce myopathy in patients with HIV as well. ⁶⁰ Furthermore, long‐term administration of clevudine, a nucleoside analogue used in the treatment of chronic hepatitis B, has been reported to cause reversible mitochondrial myopathy with proximal muscle weakness in 3.9–11.4% of patients. ⁶¹ These nucleoside analogues not only inhibit viral DNA synthesis by blocking viral DNA polymerase, but also inhibit mitochondrial DNA synthesis, potentially causing muscle damage via mitochondrial damage and dysfunction (Table 2).

Drugs or drug prescriptions that may lead to sarcopenia or myopathy

Polypharmacy and potentially inappropriate medications

Many older adults have multimorbidity and often take many medications accordingly. Much has already been reported on the adverse effects of polypharmacy on the health of older adults, and several reports on the relationship between polypharmacy and sarcopenia have been published, including a recent meta‐analysis using cross‐sectional data from 29 studies. ⁶² This systematic review showed that sarcopenia was associated with a higher prevalence of polypharmacy (most studies defined polypharmacy as five or more drugs) (OR: 1.65, 95% CI: 1.23–2.20, I ² = 84%), and that older adults with sarcopenia were taking more drugs than control (mean difference: 1.39, 95% CI: 0.59–2.29, I ² = 95%). ⁶² The cross‐sectional relationship between polypharmacy and sarcopenia may be due to a variety of factors. For example, the presence of drugs that induce skeletal muscle atrophy in many medications, the disease background of older patients taking polypharmacy, and the presence of malnutrition that induces sarcopenia due to anorexia caused by polypharmacy. ⁴

Recently, a prospective cohort study of community‐dwelling older adults over a 9‐year period demonstrated that polypharmacy with potentially inappropriate medications (PIMs), rather than just polypharmacy, is a risk for the development of sarcopenia. ⁶³ In addition, a study examining the effects of post‐stroke rehabilitation found that taking PIMs had a negative effect on physical function and sarcopenia recovery. ⁶⁴ These studies suggest that PIMs may be a risk factor for the development of sarcopenia and an inhibitory factor for rehabilitation interventions for sarcopenia. However, the specific drugs or combinations of drugs involved in PIMs that contribute to sarcopenia are still unknown and await further study.

Loop diuretics

Loop diuretics are frequently used for heart failure, renal failure, and other organ failures, and not infrequently these organ failures are accompanied by sarcopenia. Na⁺‐K⁺‐2Cl⁻ cotransporter 1 (NKCC1) is upregulated during myoblast differentiation, and loop diuretics may induce sarcopenia by inhibiting NKCC1 and suppressing myoblast fusion into myotubes. ⁶⁵ In animal studies, exercise in mice enhances NKCC1 expression in skeletal muscle and induces hypertrophy of leg muscle fibers, but administration of loop diuretics inhibits exercise‐induced hypertrophy of leg muscle. ⁶⁵ These results suggest that loop diuretics may inhibit skeletal muscle differentiation and exercise‐induced skeletal muscle hypertrophy by suppressing NKCC1. Indeed, the use of loop diuretics in patients with heart failure, renal failure, and liver failure is associated with or at risk for the development of sarcopenia. ⁶⁶ , ⁶⁷ , ⁶⁸ However, studies showing a causal relationship between loop diuretics and sarcopenia are still limited and the evidence is still weak.

Iron and iron chelators

With aging, iron accumulates in various organs, and this iron overload leads to the production of ROS, which consume the ROS scavenging system, resulting in the collapse of redox homeostasis and the accumulation of lipid peroxide in the cell membrane, which induces cell death (ferroptosis, iron‐dependent non‐apoptotic cell death). ⁶⁹ It is hypothesized that this ferroptosis is also induced in skeletal muscle, resulting in age‐related sarcopenia. ⁷⁰ In animal experiments and in humans, non‐heme iron accumulation in skeletal muscle occurs with aging and is associated with skeletal atrophy, ⁷¹ , ⁷² , ⁷³ , ⁷⁴ and in animal experiments excessive iron administration causes skeletal muscle atrophy. ⁷⁵ Conversely, iron deficiency induced by iron chelators causes myotube atrophy, reduces myoblast proliferation, decreases myoglobin expression and mitochondrial function, and increases myoprotein catabolism and apoptosis cells. ⁷⁶ , ⁷⁷ Thus, not only iron excess but also deficiency in skeletal muscle may induce skeletal muscle atrophy.

There are also conflicting observations on the relationship between iron status and skeletal muscle in humans. Some reports suggest that decreased skeletal muscle mass is associated with iron excess, while others suggest that it is related to iron deficiency. ⁷⁷ , ⁷⁸ Iron deficiency has also been reported to inhibit muscle strength recovery after stroke. ⁷⁹ Thus, the relationship between iron status and sarcopenia in clinical studies does not appear to be simple. However, most studies in humans have not evaluated iron accumulation in skeletal muscle, but rather ferritin levels or transferrin saturation concentrations in blood, which limits the ability to conclude a relationship between iron status in skeletal muscle and sarcopenia. Although there are contradictory results from the various reports above, animal and some human studies suggest that iron status in skeletal muscle may be associated with sarcopenia in both deficiency and excess, but further research needs to be accumulated.

Considering the main topic of this review, drug‐related sarcopenia, excessive iron administration, and the use of iron chelating agents may induce sarcopenia. Unfortunately, however, the current literature review did not find sufficient studies to support these hypotheses. One report was found on the effects of chelating agents on skeletal muscle in humans. According to that report, deferasirox (an iron chelator) used for iron overload resulted in proximal muscle atrophy in 6‐year‐old female monozygotic twins with beta thalassemia major undergoing transfusion therapy. When deferasirox was discontinued, the muscle atrophy improved. ⁸⁰ Thus, long‐term use of iron chelating agents may induce an iron deficiency state in skeletal muscle tissue, leading to muscle atrophy as in the above basic study, but no other similar reports were found in the present literature search, and future clinical studies are needed.

D‐penicillamine has chelating activity against heavy metals, including iron, and was once used as an antirheumatic drug. Apart from its chelating effect, this drug can cause inflammatory myopathy. Symptoms include myalgia and muscle weakness, particularly in the proximal muscles, and dysphagia in about half of the patients. Most patients also have elevated CK levels. Symptoms are not related to the dose or duration of drug administration, but are thought to be triggered by an immune response to the muscle. ³

Interferon

Inflammation is believed to be a major factor in skeletal muscle wasting associated with cachexia. In particular, the response of skeletal muscle itself to various inflammatory cytokines induces muscle atrophy. ⁸¹ Interferon (IFN) is a cytokine released from inflammatory cells, and its effects on skeletal muscle include suppression of myoblast differentiation, increased muscle protein catabolism via increased atrogin mRNA expression in myotubes, and induction of mitochondrial dysfunction in muscle tissue. ⁸² In fact, IFN (types I, II, and III) has been implicated in the pathogenesis of idiopathic inflammatory myopathies, and the effects of IFN on skeletal muscle are noteworthy. IFN is used not only for viral hepatitis, but also for the treatment of several hematologic malignancies, solid tumors, and COVID‐19. However, reports on the effects of these IFNs on skeletal muscle are limited and their effects are not well understood. ⁸³ It is possible that ADRs of IFN therapy to skeletal muscle have not received much attention, but future research in this area is needed.

Neuromuscular blocking agents

Intensive care unit (ICU)‐acquired weakness (ICU‐AW) is a general term for skeletal muscle dysfunction associated with critically ill patients under ICU care, and is assumed to be caused by a variety of factors. In a meta‐analysis of 30 studies (four randomized controlled trials, 21 prospective studies, and five retrospective studies), the use of neuromuscular blocking agents (NMBAs) was not significantly associated with the development of ICU‐AW (OR: 1.44, 95% CI: 0.61–3.40, I ² = 75%) when only four randomized controlled trials were examined. However, when the results of the observational studies were combined, the conclusion was that NMBA use was associated with the development of ICU‐AW (OR: 2.77, 95% CI: 1.98–3.88, I ² = 62%), although there were issues of heterogeneity and bias. ⁸⁴ In this meta‐analysis, NMBAs were divided into benzyl quinolinic NMBAs (atracurium and cisatracurium) and amino‐steroid NMBAs (vecuronium and pancuronium) and their relationship with ICU‐AW was (OR: 14.79, 95% CI: 1.19–183.84, I ² = 82%) and (OR: 3.68, 95% CI: 1.51–9.00, I ² = 37%), respectively. Another meta‐analysis targeting five cohort studies also suggested a possible association between the use of NMBAs and ICU‐AW (OR: 1.43, 95%CI: 0.92–2.22, I ² = 0%). ⁸⁵ Although these observational studies suggest a possible relationship between NMBAs and ICU‐AW, the lack of intervention studies means that a clear causal relationship between NMBAs and ICU‐AW is still unclear, and further research is needed.

Others

Non‐steroidal anti‐inflammatory drugs, antipsychotics, antidepressants, anticholinergics, cardiovascular drugs, histamine antagonists, anticonvulsants, and proton pump inhibitors (with possible indirect effects) were also searched for a relationship with skeletal muscle, including sarcopenia, but this literature search found no evidence of clear direct adverse effects on skeletal muscle.

Conclusion

In this review article, various drugs that act directly (and some indirectly) on skeletal muscle as ADRs and induce sarcopenia, muscle atrophy, muscle weakness, and muscle wasting were presented, as well as their frequency and mechanisms whenever possible (Table 2). We should prescribe with caution drugs that may induce drug‐induced sarcopenia as a secondary sarcopenia in clinical practice. Although the percentage of drug‐induced sarcopenia in total sarcopenia is unknown, drug‐induced sarcopenia may be hidden among those diagnosed with age‐related sarcopenia and among those diagnosed with disease‐related sarcopenia. The combination of these secondary sarcopenias must make sarcopenia more severe. Drug‐induced sarcopenia can be prevented from developing and progressing and should be considered when prescribing drugs.

Disclosure statement

The author declares no conflict of interest.

Kuzuya M. Drug‐related sarcopenia as a secondary sarcopenia. Geriatr. Gerontol. Int. 2024;24:195–203. 10.1111/ggi.14770

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.