Sage Journals: Discover world-class research

Abstract

Osteopenia/osteoporosis and sarcopenia are both age-related conditions. Given the well-defined bone and muscle interaction, when osteopenia and sarcopenia occur simultaneously, this geriatric syndrome is defined as ‘osteosarcopenia’. Evidence exists about therapeutic interventions common to both bone and muscle, which could thereby be effective in treating osteosarcopenia. In addition, there are roles for common nonpharmacological strategies such as nutritional intervention and physical exercise prescription in the management of this condition. In this review we summarize the evidence on current and upcoming therapeutic approaches to osteosarcopenia.

Keywords

aging bone elderly falls fractures frailty muscle Osteosarcopenia osteoporosis sarcopenia

Introduction

Bone and muscle function are an integral part of locomotion, both of which are affected by advancing age. Osteopenia/osteoporosis and sarcopenia are age-related musculoskeletal diseases that lead to loss of independence, poor quality of life, and an increased likelihood of transition to residential aged care.¹ The bone and muscle interaction is now being increasingly recognized,^2–4 including direct mechanistic interaction through endocrine pathways and activating receptor signaling.^2–4 The concept of a ‘bone–muscle unit’ encompasses the notion that there exists communication between both tissues; thus, disease affecting one part of the musculoskeletal unit is likely to affect the other, and vice versa. In this context, the term osteosarcopenia has been coined to describe the concomitant occurrence of osteopenia/osteoporosis and sarcopenia,⁵ and thus indicative of a new geriatric syndrome. Based on the concept of a bone-muscle unit, this article summarizes evidence regarding therapeutic approaches to manage osteosarcopenia.

Osteosarcopenia as a new geriatric syndrome

In 2009, Binkley and Buehring coined the term sarco-osteopenia, which referred to adults with an increased risk of falls and fractures secondary to underlying weak muscle (sarcopenia) and weak bones (osteopenia/osteoporosis).⁶ That concept has since evolved, and now is known as ‘osteosarcopenia’, which is a geriatric syndrome characterized by the concomitant presence of osteopenia or osteoporosis and sarcopenia.⁵

Although biological bases of this syndrome are proposed owing to the robust evidence on bone and muscle interaction^2–4 and the common developmental origin from mesenchymal precursors,⁷ it is the clinical phenotype of this syndrome that makes it peculiar owing to its increased vulnerability to adverse events.⁸ Older adults with osteosarcopenia have poorer physical function and are at increased risk of fracture, functional decline, and mortality when compared with those with sarcopenia or osteoporosis alone.^9,10 Yoo et al. reported, in a cohort of older people with hip fracture, that the prevalence of osteosarcopenia was 28.7%, and mortality rate was 1.8 times higher than those without it or its components.⁸

Osteosarcopenia must be discerned from the concept of frailty, a term that has been used to describe age-related decline in physiological reserves with increased vulnerability to minor stressors.¹¹ Frailty encompasses many organ systems whereas osteosarcopenia is confined to musculoskeletal tissue.^5,11 It is possible that osteosarcopenia exacerbates frailty, however temporal association between two needs to be investigated in a longitudinal study.

Osteopenia and osteoporosis are defined as per World Health Organization (WHO) criteria with bone mineral density (BMD) T-scores less than −1 and −2.5 SD below young adult mean, respectively.¹² Sarcopenia represents a progressive and generalized pathological decline in skeletal muscle mass and strength which is more than what could be expected as a part of aging.¹³ It is defined as per European Working Group of Sarcopenia in Older People (EWGSOP) as loss of muscle strength associated with loss of muscle quality¹³ (Table 1). Various tools have been used to measure the muscle parameters, outlined in Table 2.

Table 1.

Operational definition of sarcopenia (adapted from the European Working Group on Sarcopenia in Older People, EWGSOP2).¹³

Probable sarcopenia is identified by Criterion 1.

Diagnosis is confirmed by additional documentation of Criterion 2.

If Criteria 1, 2, and 3 are all met, sarcopenia is considered severe.

1. Low muscle strength assessed by Grip strength (cut point <27 kg for men and <16 kg for women) or Chair stand test (cut point >15 s for 5 rises).

2. Low muscle quantity or quality assessed by measuring appendicular skeletal muscle mass (ASM) by dual-energy X-ray absorptiometry (DXA) with cut point <20 kg for men and <15 kg for women

3. Low physical performance measured by gait speed with cut-point ⩽0.8 m/s, short physical performance battery (SPPB) with cut point ⩽8 point score, timed up and go test (TUG) with cut point ⩾20 s and 400-meter walk (400 m walk) with cut point ⩾6 min for completion or noncompletion

Table 2.

Clinical tools for measurement of muscle strength, muscle mass and physical performance in sarcopenia (adapted from European Working Group on Sarcopenia in Older People, EWGSOP2).¹³

Variable	Clinical tools
Case finding	SARC-F (5 item questionnaire)
	Ishii screening tool
Skeletal muscle Strength	Grip strength
	Chair stand test
Skeletal muscle mass or Skeletal muscle quality	ASM by DXA
	Whole-body ASM predicted by BIA
	Lumbar muscle cross-sectional area by CT or MRI
Physical performance	Gait speed
	SPPB
	TUG
	400 m walk or long-distance corridor walk

ASM, appendicular skeletal muscle mass; BIA, bioelectrical impedance analysis; CT, computed tomography; DXA, dual-energy X-ray absorptiometry; MRI, magnetic resonance imaging; SPPB, Short Physical Performance Battery; TUG, timed up and go.

Overall, when diagnosing osteosarcopenia, the clinician should take into consideration the EWGSOP2 proposed algorithm for early identification and diagnosis of sarcopenia (Table 1 and Figure 1) and osteopenia or osteoporosis should be investigated by BMD score on dual-energy X-ray absorptiometry (DXA) scan.¹²

Figure 1.

Sarcopenia: EWGSOP2 algorithm for case-finding, making a diagnosis and quantifying severity in practice (adapted from Cruz-Jentoff et al.¹³).

Risk factors for osteosarcopenia

Primary osteosarcopenia is a result of age-related declines in bone and muscle function; however, there are many risk factors that affect bone and muscle, thereby aggravating osteosarcopenia.^13,14 While treating osteosarcopenia, these risk factors should be considered by the managing clinicians (Table 3).

Table 3.

Risk factors for osteosarcopenia.^1,15

Osteoporosis	Sarcopenia	Osteoporosis and sarcopenia
Asian or Caucasian race	Low albumin	Age
History of fragility fracture	Use of angiotensin-converting enzyme inhibitors	Female
History of maternal hip fracture	Stroke	Genetic factors
	Dyslipidemia	Low body weight
		Obesity
		Sedentary lifestyle/poor mobility
		Smoking
		High alcohol consumption
		Glucocorticoids
		Low dietary calcium and protein
		Low vitamin D
		Hypogonadism (male)
		Menopause (female)
		Hyperparathyroidism
		Low growth hormone
		Rheumatoid arthritis
		Chronic kidney disease
		Living in residential aged care facility

Potential therapeutic targets in osteosarcopenia

Given the interconnectedness between bone and muscle, treatment targets common to both have been proposed; however, to date, there is a lack of data from randomized controlled trials (RCTs) that have investigated a common pharmacological target for osteosarcopenia. In addition to mechanical interactions between bone and muscle, there are common chemokines that act on these tissues, in addition to the interactions of osteokines and myokines² (Figure 2).

Figure 2.

Interaction between muscle and bone. Bone and muscle are clearly interconnected via a two-way cross talk (adapted from Tagliaferri et al.²).

Commonalities in pathophysiology suggest that potential therapeutic strategies may include focusing on (i) targets that affect bone and muscle, such as insulin-like growth factor-1 (IGF-1), androgens, selective androgen receptor modulators (SARMs), or vitamin D, amongst others,¹⁶ or (ii) targets involved in the cross-talk between muscle and bone, for instance activin signaling inhibitors, myostatin neutralizing antibodies, recombinant follistatin derivatives, and soluble activin receptors or myokines.^2,16,17 Another novel therapeutic target is the prevention of fat infiltration, which is a common feature observed in primary and secondary osteoporosis, and sarcopenia. A decrease in marrow and intrafiber fat in bone and muscle, respectively, would be expected to have a beneficial effect on their mass and function. Although this has been demonstrated in separate studies in muscle and bone,¹⁸ a combined experiment targeting fat in these both tissues is still lacking.

Nonpharmacological management of osteosarcopenia

Role of lifestyle modification in treating osteosarcopenia

Whilst various genetic factors determine peak bone mass and muscle strength,^19,20 environmental factors that exacerbate the loss of bone and muscle are suggested to be imperative in the pathogenesis of osteoporosis and sarcopenia, and thus osteosarcopenia.¹

Among these factors, the roles of smoking and alcohol consumption are well studied. However, despite the well-described association of smoking and alcohol consumption with poor bone and muscle health, the therapeutic benefits of smoking cessation and decreasing alcohol consumption are less clear.

Current smoking status is associated with increased risk of fracture at any site²¹ and hip fracture in females²² and one meta-analysis reported the therapeutic benefit of smoking cessation for more than 10 years in decreasing the risk of hip fractures.²²

Similarly, although the negative effects of alcohol consumption on bone and muscle are documented,²³ the therapeutic benefit of minimizing alcohol consumption is not described so far. However, it is expected that decreasing alcohol consumption may have beneficial effect in improving bone and muscle function, thus decreasing risk of fall and fracture.

Nutritional strategies to treat osteosarcopenia

Role of dietary calcium and calcium supplements

Calcium is well-documented as an important mineral of bone, and its importance in muscle function is suggested by its role in calcium-induced muscle contraction and calcium-induced calcium release from sarcoplasmic reticulum.²⁴ Therefore, it could have a role in treatment of osteosarcopenia. Calcium intake from the diet and supplements has shown to produce marginal increases in BMD, although no convincing influence on the risk of hip fracture has been observed.²⁵ The therapeutic benefit of calcium supplements in sarcopenia is yet to be studied.

Current guidelines recommend an adequate intake of calcium (1000–1300 mg/day) in diet for optimal bone health.²⁶ If dietary intake of calcium is below the recommended level, supplementation of 500–600 mg/day is recommended in older adults.²⁶ However, there is controversy regarding supplementing the diet with higher doses of calcium (>2000 mg/day) as it is associated with increase cardiovascular side-effects in older adults aged ⩾50 years.²⁷

Role of dietary protein and protein supplements

Importance of dietary protein is evident from being not only a source of the bone and muscle matrix but also through its direct effect on regulatory proteins and growth factors involved in bone and muscle function through assisting in calcium absorption, suppression of parathyroid hormone, and release of IGF-1.^28,29

Clinical evidence of the role of dietary protein in bone health stems from the Framingham Osteoporosis Study, which showed that low protein intake was associated with bone loss at proximal femur and spine over 4 years.³⁰ Regarding association of protein with sarcopenia, low dietary protein (⩽0.45 g/kg/day) in older persons aged ⩾65 years was associated with muscle atrophy³¹, and a moderate or high consumption of protein (⩾1.1 g/kg/day) in adults aged 70–79 years was associated with less muscle loss.³² In addition, high intake of protein (>1.0 g/kg/day) has been associated with better lower limb physical performance when compared with protein intake lower than 0.8 g/kg/d in community-dwelling older people.³³

Given this association between protein and bone and muscle strength, the role of protein supplements was proposed. In clinical trials, protein supplements have been demonstrated to improve osteopenia by increasing BMD and decreasing the risk of fracture.^34,35 Similarly, protein supplements (6–30 g/day) over 3–24 months helped to correct sarcopenia by improving muscle strength over 12–24 weeks in healthy older people when combined with resistance exercise³⁶ (Table 4).

Table 4.

Summary of findings from meta-analyses that investigated the role of dietary protein and protein supplements on osteopenia/osteoporosis and sarcopenia related outcomes.

Reference	Description of studies	Results
Osteopenia/osteoporosis
Koutsofta et al.³⁴	Systematic review (best evidence synthesis) of 5 RCTs (n = 677 postmenopausal women; mean age 61.4 years)^*Treatment with protein supplements	Protein supplements alone or in combination with dietary protein improved BMD and reduced risk of fracture.
Shams-White et al.³⁷	Systematic review and meta-analysis of 36 studies16 RCTs (n = 1553 healthy adults; age ⩾18 years)20 prospective cohort studies (n = 452,443 healthy adults; age ⩾18 years)^*Association with high protein intake	(1) Higher protein (>0.8 g/kg/day) intake in diet or supplements have a protective effect on lumbar spine BMD (pooled net percentage change in BMD: 0.52%; 95% CI 0.06–0.97%)(2) There is limited evidence to support role of protein with calcium and vitamin D at lumbar spine BMD, hip BMD, or forearm fracture.
Wallace et al.³⁵	Systematic review and meta-analysis of 29 studies16 RCTs (n = 1375 healthy adults; age 18–80 years)13 Prospective cohort studies (n = 271,963 adults; age 26–96 years)^*Association with high protein intake	High protein intake above 0.8 g/kg/day resulted in 16% decrease in hip fractures (SMD = 0.84; 95% CI 0.73–0.95), compared with low protein intake.
Sarcopenia
Coelho-Junior et al.³³	Meta-analysis of 7 studies;4 prospective and 3 cross-sectional studies (n = 8754, mean age 74.5 years)^*Association with high protein intake	Very high (⩾1.2 g/kg/day) and high (⩾1.0 g/kg/day) intake of protein is associated with better lower limb physical function (ES = 0.18; 95% CI 0.01–0.35) and walking speed (ES = 0.06; 95% CI 0.02–0.11) respectively when compared to low protein (⩽0.8 g/kg/day) intake.
Komar et al.³⁸	Meta-analysis of 16 RCT (n = 999; mean age 69.72 years)^*Treatment with protein supplements	Leucine-containing protein supplements improved lean mass (mean differences 0.99 kg, 95% CI 0.43–1.55, p = 0.0005) but not strength in older people prone to sarcopenia.
Liao et al.³⁶	Meta-analysis of 17 RCTs (n = 892; mean age 73.4 years)^*Treatment with protein supplements	Protein supplements in combination with resistance exercises improved lean mass and strength (SMD = 0.58; 95% CI 0.32–0.84) in older people when compared with resistance exercise alone.
Tieland et al.³⁹	Meta-analysis of 8 RCTs (n = 557, mean age 74.6 years)^*Treatment with protein supplements	Protein or amino acid supplements did not have significant positive effect on muscle mass (mean difference: 0.014 kg: 95% CI 0.152–0.18) and strength (mean difference: 2.26 kg: 95% CI 0.56–5.08) in healthy older people.

BMD, bone mineral density; CI, confidence interval; ES, effect size; RCT, randomized controlled trial; SMD, standardized mean difference.

Whether study described association with osteoporosis or sarcopenia or treatment of osteopenia or sarcopenia.

The recommended dietary intake of protein is 0.8 grams per kg of body weight per day (g/kg/day) for healthy populations, irrespective of age or sex.⁴⁰ However, the sensitivity of musculoskeletal tissue to dietary protein intake is influenced by advancing age, therefore adults aged 65 years and above require higher than recommended protein (up to 1.2 g/kg/day).²⁸ Meta-analysis incorporating trials investigating the different amounts of proteins concluded that high intake of dietary protein (higher than recommended >0.8 g/kg/day) in older adults with osteoporosis was associated with preservation of BMD at lumbar spine³⁷ and reduced risk of hip fracture.³⁵ Older adults in residential aged care facilities are likely to have lower dietary protein intake,⁴¹ therefore dietary protein intake of at least 1–1.2 g/kg/day with 25–30 g of protein with each meal is recommended.⁴²

The distribution of dietary protein across meals is another area that is contested in the literature, whereby some studies suggest beneficial outcomes from pulse feeding concentrated in the lunch or evening meal,⁴³ whilst others show benefits of distributing the dietary protein throughout the daily intake.⁴⁴

Exercise

Bone is a dynamic tissue and responds to multiple physical and dynamic stimuli encompassing movements, traction, and vibration.⁴⁵ These forces come into play constantly during locomotion and have an important role in bone and muscle remodeling, thereby they are important to consider in the management of osteopenia and sarcopenia in older adults.⁴⁵ The most appropriate type, intensity, duration, and frequency of exercise to positively influence osteosarcopenia is not known, however role of different types of exercises has been previously described individually for osteopenia and sarcopenia (Table 5).

Table 5.

Summary of findings from systematic reviews and meta-analyses regarding the effect of different types of exercises on osteopenia/osteoporosis and sarcopenia.

Reference	Brief description of studies	Results
Osteopenia/osteoporosis
Marin-Cascales et al.⁴⁶	10 RCTs (n = 462 postmenopausal females aged ⩾55 years)^*Effect of WBV	WBV for 3–12 months did not improve total or femoral neck BMD, however improved BMD at lumbar spine (MD = 0.02; 95% CI 0.00–0.03; p = 0.03) in postmenopausal women aged ⩾65 years.
Xu et al.⁴⁷	Overview of 12 systematic reviews (best evidence synthesis). (n = 12,219 premenopausal and postmenopausal females)^*Effect of combined impact and resistance exercises	Combined impact and resistance exercises are best choice to preserve and improve BMD in premenopausal and postmenopausal women
Zhao et al.⁴⁸	11 RCTs (n = 1061 postmenopausal females)^*Effect of multiple physical activities	Combined exercise interventions involving multiple physical activities for 8–30 months were effective in preserving BMD at lumbar spine (SMD = 0.170; 95% CI 0.027–0.313; p = 0.019), femoral neck (SMD = 0.177; 95% CI 0.030–0.324; p = 0.018), total hip (SMD = 0.198; 95% CI 0.037–0.359; p = 0.016), and total body (SMD = 0.257; 95% CI 0.053–0.461; p = 0.014).Effect of individual type of physical activity on outcome could not be ascertained.
Sarcopenia
Jepsen et al.⁴⁹	4 RCTs (n = 746 adults aged ⩾50 years)^*Effect of WBV	WBV for 6 months reduced rate of fall with a rate ratio of 0.67 (95% CI 0.50–0.89, p = 0.0006).
Sardeli et al.⁵⁰	6 RCTs (n = not reported; adults aged ⩾50 years)^*Effect of resistant exercises	In obese older people undergoing calorie restriction, resistant exercises 3 times a week over 12–24 weeks can prevent muscle loss related to calorie restriction.
Vlietstra et al.⁵¹	6 RCTs (n = 480 adults aged ⩾60 years)^*Effect of multiple physical activities	Exercise intervention for 3–6 months improved knee-extension strength (MD = 0.14; 95% CI 0.03–0.26; p ⩽ 0.01), timed up and go (MD = 0–1.67; 95% CI −2.43–0.91; p < 0.0001), appendicular muscle mass (MD = 0.45; 95% CI 0.03–0.87; p = 0.04), and leg muscle mass (MD = 0.35; 95% CI 0.02–0.68; p = 0.04).However, heterogeneity of exercise program was noted and effect of individual type of exercises could not be ascertained.

BMD, bone mineral density; CI, confidence interval; MD, mean difference; RCT, randomized controlled trial; SMD, standardized mean difference; TUG, timed up and go; WBV, whole-body vibration.

Type of physical activity in the treatment of osteopenia or sarcopenia.

As different types of exercise have distinct effects on bone and muscle, not all exercises are beneficial. For osteopenia, aerobic and low-impact exercises such as cycling or walking have failed to show beneficial effects on BMD at any site,⁵² however resistance exercises or high-impact exercises such as running have a positive effect on bone by improving BMD.⁴⁷ Similarly resistant exercises play a positive role in sarcopenia by a direct effect on muscles.⁵³ A recent meta-analysis investigated the role of exercise on sarcopenia related outcomes, and reported improvement in some operational measures of muscle mass, strength and physical function.⁵¹ In addition, resistant exercises 3 times a week over 12–24 weeks have shown to prevent loss of muscle mass in obese older people on calorie restricted diet.⁵⁰ In older people, resistant exercises have been described to improve self-reported physical function and activities of daily living (ADLs).⁵⁴

Whole-body vibration (WBV) is a process in which a vibrating force is transmitted to muscle and bone, an intervention that has been proposed to have a positive role in both osteopenia and sarcopenia. Although the effects of WBV on BMD are not consistent,^55–57 these discrepancies may be explained due to the optimum frequency or duration of WBV therapy currently being unclear.⁴⁶

Vitamin D

Vitamin D is well recognized as an integral part of bone and muscle physiology through its role in calcium and phosphate absorption to calcium-mediated muscle functions such as contractility, mitochondrial function, and insulin sensitivity.⁵⁸ Vitamin D acts as a mediator in the cross-talk between muscle and bone by affecting myokines (myostatin, VEGF, IGF-1, osteoglycin) and osteokines (sclerostin, osteocalcin, FGF-23), which have a positive effect on bone and muscle, respectively (Figure 3).⁵⁹ Under effect of sunlight (UV light), vitamin D is synthesized in the skin from 7-dehydrocholestrol:⁶⁰ it is converted into 25-hydroxy vitamin D in the liver and then into 1,25 hydroxy vitamin D (1,25(OH)₂D) in the kidneys.⁶⁰ 1,25(OH)₂D is a biologically active form of vitamin D and exerts its effect on bone and muscle through the vitamin D receptor (VDR), which binds to the vitamin D response element (VDRE) in DNA as well as directly without genomic transcription.⁶⁰

Figure 3.

Vitamin D mediates several mechanisms of the bone–muscle cross-talk (adapted from Gunton et al.⁵⁹).

Association of vitamin D with osteosarcopenia or role of vitamin D supplements in treating osteosarcopenia has not yet been evaluated in a single study; however, its therapeutic benefit can be inferred from studies on osteopenia and sarcopenia (Table 6).

Table 6.

Summary of the effect of vitamin D supplements on osteopenia/osteoporosis and sarcopenia related outcomes.

Study	Description	Results
Osteopenia/osteoporosis
Bolland et al.⁶¹	Pooled analysis of 81 RCTs (n = 53,537 adults aged ⩾18 years)^*Therapeutic effect of vitamin D supplements.	Vitamin D supplements (regardless of dose) did not prevent fall (37 trials; n = 34,144, RR 0.97, 95% CI 0.93–1.02), total fracture (36 trials; n = 44,790, RR 1.00, 95% CI 0.93–1.07) or hip fracture (20 trials; n = 36,655, RR 1.11, 95% CI 0.97–1.26).
Kahwati et al.⁶²	Meta-analysis of 11 RCTs (n = 51,419 community-dwelling older adults aged ⩾50 years)^*Therapeutic effect of vitamin D supplements.	Vitamin D supplements did not decrease risk of fracture in community-dwelling older adults (3 RCTs; n = 5496; pooled ARD = –0.01; 95% CI −0.80 to −0.78) without known Vitamin D deficiency, osteoporosis, or prior fracture.
Zhao et al.⁶³	Meta-analysis of 33 RCTs (n = 51,145 community dwelling older adults aged ⩾50 years)^*Therapeutic effect of calcium supplements and vitamin D supplements.	There was no association of risk of hip fracture with calcium supplements (RR 1.53; 95% CI 0.97–2.42) or vitamin D supplements (RR 1.21; 95% CI 0.99–1.47) compared with placebo in community-dwelling older adults.
Sarcopenia
Beaudart et al.⁶⁴	Meta-analysis of 30 RCTs (n = 5615 adults, mean age 61.1 years)^*Therapeutic effect of vitamin D supplements.	Vitamin D supplements have positive effect on muscle strength (SMD 0.25; 95% CI 0.01–0.98) in older adults aged ⩾65 years but optimal treatment modalities including dose, mode of administration, and duration are unclear.
De Spiegeleer et al.⁶⁵	Review of 7 systematic reviews (best evidence synthesis) (n = not reported; age ⩾65 years)^*Therapeutic effect of vitamin D supplements.	Vitamin D supplements in older women (with low vitamin D levels <25 nmol/l) improved muscle mass (pooled SMD = 0.058; 95% CI 0.118–0.233), strength (pooled SMD = 0.25; 95% CI 0.01–0.48) and physical function (pooled SMD TUG −0.19; 95% CI −0.35 to −0.02).
Rosendahl-Riise et al.⁶⁶	Meta-analysis of 10 RCTs (n = 2866 community-dwelling older adults aged ⩾65 years)^*Therapeutic effect of vitamin D supplements.	Vitamin D supplements did not improve handgrip strength (7 studies; MD 0.2 kg; 95% CI −0.3 to 0.7) but improved physical performance on TUG (5 studies; MD TUG−0.3; 95% CI −0.1 to −0.05).

ARD, absolute risk difference; BMD, bone mineral density; CI, confidence interval; MD, mean difference; RCT, randomized controlled trial; SMD, standardized mean difference; TUG, timed up and go.

Association with osteoporosis or sarcopenia or treatment of osteopenia or sarcopenia.

Many studies have already described association of low vitamin D status with osteoporosis and increase risk of fracture.⁶⁷ For sarcopenia, although there are few studies, evidence exists regarding association of low vitamin D levels with negative muscle-related outcomes.⁶⁸ A recent epidemiological study in Australian population reported that low vitamin D levels (<40 nmol/l) were associated with increased incidence of sarcopenia over 5 years.⁶⁹

The role of vitamin D supplements in treating osteopenia, preventing fall and fracture has been a subject of controversy recently. Many randomized trials have been conducted and although earlier data suggested a reduced risk of nonvertebral fracture with vitamin D supplements,⁷⁰ recent meta-analyses have failed to show its persistent benefits in reducing risk of fall or fracture at any site in community-dwelling older adults.^62,63 Analysis by Bolland et al. reported that vitamin D supplements did not prevent falls or fractures, or improve BMD in adults aged ⩾20 years.⁶¹ This lack of apparent benefit of vitamin D supplementation could be due to the inclusion of a substantial number of younger adults and healthy older adults with minimal or no risk factors for bone disease.⁶² Moreover, the aggregate results could be affected due to the dose of vitamin D used. While frequently used vitamin D supplements (400–2000 IU) have shown beneficial effects, studies with a bolus dose of vitamin D have consistently revealed increased risk of falls.⁷¹ Despite these controversies, it is acknowledged that vitamin D supplements have a role particularly in those with vitamin D deficiency or osteoporosis.⁶⁷ Regarding role of vitamin D supplements in treating sarcopenia, there are only few studies with some showing a positive while others produced nonsignificant results. In older women aged ⩾65 years who had low vitamin D levels (<25 nmol/l), vitamin D supplements (1000 units) improved muscle mass and strength.⁶⁵ In community-dwelling older adults, vitamin D supplement improved physical performance as indicated by timed up and go (TUG) test, however improvement in muscle strength as measured by handgrip strength was not significant.⁶⁶

Despite the long-standing availability of vitamin D supplements, there remains insufficient evidence with regards to the most appropriate dose, mode of administration, and duration of treatment on the functional outcome in older adults.⁶⁴ Current recommendations are for oral vitamin D supplements (800–1000 units/day) and calcium supplements (500 mg/day).⁷² Ideal vitamin D levels should be 50–60 nmol/l with a conservative upper limit of 100 nmol/l, only if dietary intake is inadequate.⁷² Importantly, there is no evidence that loading doses have a positive effect on falls or fracture outcomes.⁷²

Pharmacological management of osteosarcopenia

Treatment of osteosarcopenia with pharmacological agents is a new area of investigation. There is paucity of evidence in this regard. Nevertheless, the therapeutic effects of some compounds on osteoporosis and sarcopenia hint at a possible dual effect on muscle and bone mass and therefore could be useful in treatment of osteosarcopenia (Table 7).

Table 7.

Summary of the evidence regarding the effect of pharmacological agents on osteoporosis and sarcopenia related outcomes.

Pharmacological agent	Osteoporosis	Sarcopenia
Denosumab	Meta-analysis of 4 RCTs, investigating the effect of denosumab on BMD reported significant improvement in BMD at lumbar spine, hip, and radius.⁷³	Reduction in falls in the Denosumab treatment group of the FREEDOM Study. No evidence of effect on muscle function.⁷⁴ Improves muscle strength and insulin sensitivity in osteoporotic humans.⁷⁵
Testosterone	Intramuscular testosterone increased lumbar spine bone density in men.⁷⁶	Testosterone in older men with decreased testosterone levels and muscle weakness can improve muscle mass, strength and physical performance.⁶⁵
Growth hormone	Meta-analysis of 7 RCTs and one extension trial concluded that growth hormone may not improve bone density but decrease fracture risk in women with age related bone loss.⁷⁷	Low growth hormone levels with age contribute to decrease in lean body mass and increase adipose tissue.⁷⁸
Antimyostatin antibodies	Antimyostatin antibody in combination with resistance exercise improved bone health in rats.⁷⁹	(1) Antimyostatin antibodies increased muscle mass and strength in mice.⁸⁰ (2) Antimyostatin antibodies increased lean mass and may improve functional measures of muscle power.⁸¹

BMD, bone mineral density; RCT, randomized controlled trial.

Denosumab

Denosumab in humanized monoclonal antibody to RANKL (receptor activator of nuclear factor-κB ligand). The binding of RANKL to RANK receptor on osteoclast is responsible for its activation, differentiation and osteoclastic action. By blocking RANKL, denosumab blocks the activation of osteoclasts and leads to a subsequent increase in BMD.⁷⁴ Denosumab is proposed to have an action on muscle as well through blockage of RANK/RANKL. In nonclinical studies, RANK/RANKL blockade has shown to improve muscle function.⁸²

Evidence of the efficacy of denosumab emerged from the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6 months) trial. Results of the FREEDOM trial indicated that denosumab treatment reduced the risk of vertebral, nonvertebral, and hip fracture over 36 months.⁷⁴ It was also observed that group treated with denosumab experienced fewer falls (4.5%) compared with the untreated group (5.7%) (p = 0.02).⁷⁴ This led to further investigation of the effect of denosumab on muscle strength. A recent study by Bonnet et al.⁷⁵ tested the effect of denosumab on animals and humans (postmenopausal women); the authors reported that RANKL deteriorates, while its inhibitor improves muscle strength and insulin sensitivity in osteoporotic mice and humans, and concluded that, in addition to its role as a treatment for osteoporosis, denosumab could represent a novel therapeutic approach for sarcopenia and, thus, for osteosarcopenia. Further mechanistic studies are needed to investigate the direct effect of denosumab on muscle mass and function.

Testosterone and SARMs

Testosterone levels decrease with age and are considered an important cause of age-related decline in bone mass⁷⁶ and muscle function.⁸³ Testosterone exerts its effect on bone through estradiol and increased bone mineralization and strength,^76,84 and increases muscle mass and strength by increasing protein synthesis.⁸⁵ Although the dual effect of testosterone on osteosarcopenia has not been tested in a single study, we suggest biological plausibility for positive effects, given results from separate trials of bone- and muscle-related outcomes. For instance, testosterone replacement in hypogonadal men improved bone mass and strength.⁸⁶ Testosterone improved muscle mass and function in older adults (aged 60–65 years), as well as young adults (aged 19–35 years):⁸⁷ results are not suggested as being sex-specific.⁸⁸ Moreover, positive effects of testosterone on muscle strength have been reported in community-dwelling frail older adults (aged ⩾65 years),⁸⁹ as well as healthy community dwelling older adults (aged ⩾60 years).⁹⁰ In addition, testosterone replacement improved muscle strength and gait speed in older adults (aged ⩾65 years)⁹¹ and has shown to be safe in chronic heart failure.⁹²

Owing to the fear of side-effects with testosterone treatment, interest in research into SARMs has advanced. Several of these have been trialed in sarcopenia and include LDG-4033, BMS-564929 in phase I trial, and enobasarm in phase II trials but at present, SARMs do not appear to have an advantage over testosterone.⁹³

Given its role in both osteoporosis and sarcopenia, it would be interesting to see testosterone effect on both in a single study. Two major trials, ’The Testosterone Trial in Older Men‘ (ClinicalTrials.gov identifier: ) and T4DM (www.t4dm.org.au), are underway and should clarify the role of testosterone in the management of osteosarcopenia.

Growth hormone and IGF-1

Normal ageing is associated with decrease in growth hormone (GH) and IGF-1 levels.⁷⁸ GH efficacy in osteoporosis management has been studied in many RCTs.⁷⁷ A recent meta-analysis of seven RCTs and one extension trial suggested that it may have a role in fracture prevention in postmenopausal osteoporosis, however it has failed to show a positive effect on BMD.⁷⁷

It was first described in 1990 that low GH levels contributes to a decrease in lean body mass and increase in adipose tissue.⁷⁸ However, since then, it has failed to show a consistent benefit in improving muscle mass or function.⁹³ Furthermore, there are various side-effects to consider, including carpal tunnel syndrome, gynecomastia, joint and muscle pain, edema, and hyperglycaemia.⁹⁴ Similarly, there is limited data regarding the role of IGF-1 in sarcopenia.⁹³ IGF-1 is also associated with multiple side-effects: myositis, edema, orthostatic hypotension, and gynecomastia.⁹⁵

Anti-myostatin antibodies

Myostatin is produced in skeletal muscle and inhibit muscle growth. Lack of myostatin leads to muscle hypertrophy. In mice, antimyostatin antibodies increased muscle mass and strength.⁸⁰ In phase II trials in older adults (aged ⩾75 years) with a history of fall, antimyostatin antibodies increased the lean body mass and mildly improved functional measures associated with muscle strength.⁸¹ Regarding role of myostatin antibodies in improving bone health, data from animal studies indicate that in combination with resistant exercise, myostatin antibodies improved bone mass,⁷⁹ however, this effect has not been confirmed in clinical trials.

Future directions

In conclusion, the notion of bone muscle interaction through direct and indirect interaction imply the possible presence of the geriatric syndrome ‘osteosarcopenia’. Those with osteosarcopenia have worse prognosis than adults with either osteopenia or sarcopenia alone. Therapeutic strategies that have a dual effect on bone and muscle are critical in the management of osteosarcopenia. Adequate protein and calcium intake, maintaining sufficient vitamin D levels, and undertaking regular muscle and bone strengthening exercises are important nonpharmacological therapies for consideration by the treating clinician. Future research should be directed toward pharmacological agents with therapeutic actions on both bone and muscle and investigating the efficacy of agents that are currently used for osteoporosis and sarcopenia alone, in terms of a dual effect on bone and muscle.

Footnotes

Funding

SB-O is supported by a Career Development Fellowship from the National Health and Medical Research Council (NHMRC) of Australia (1107510).

Conflict of interest statement

GD has served as a member of Advisory Boards at Lilly and Amgen Australia and is a member of the board of speakers for Amgen, Lilly, Sanofi and Novartis Australia.

MF and SBO have no conflict of interest to declare.

ORCID iD

Gustavo Duque

References

Curtis

Litwic

Cooper

et al . Determinants of muscle and bone aging. J Cell Physiol 2015; 230: 2618–2625.

Tagliaferri

Wittrant

Davicco

et al . Muscle and bone, two interconnected tissues. Ageing Res Rev 2015; 21: 55–70.

Kawao

Kaji

Interactions between muscle tissues and bone metabolism. J Cell Biochem 2015; 116: 687–695.

Isaacson

Brotto

Physiology of mechanotransduction: how do muscle and bone “talk” to one another?

Clin Rev Bone Miner Metab 2014; 12: 77–85.

Hirschfeld

Kinsella

Duque

Osteosarcopenia: where bone, muscle, and fat collide. Osteoporos Int 2017; 28: 2781–2790.

Binkley

Buehring

Beyond FRAX: it’s time to consider “sarco-osteopenia”. J Clin Densitom 2009; 12: 413–416.

Ankrum

Ong

Karp

JM.

Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol 2014; 32: 252.

Yoo

Kim

et al . Osteosarcopenia in patients with hip fracture is related with high mortality. J Korean Med Sci 2017; 33: e27.

Drey

Sieber

Bertsch

et al . Osteosarcopenia is more than sarcopenia and osteopenia alone. Aging Clin Exp Res 2016; 28: 895–899.

10.

Huo

Suriyaarachchi

Gomez

et al . Phenotype of osteosarcopenia in older individuals with a history of falling. J Am Med Dir Assoc 2015; 16: 290–295.

11.

Fried

Tangen

Walston

et al . Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001; 56: M146–M156.

12.

Kanis

Melton

III Christiansen

et al . The diagnosis of osteoporosis. J Bone Miner Res 1994; 9: 1137–1141.

13.

Cruz-Jentoft

Bahat

Bauer

et al . Sarcopenia: revised European consensus on definition and diagnosis. Age and Ageing 2019; 48: 16–31.

14.

Fitzpatrick

LA.

Secondary causes of osteoporosis. Mayo Clin Proc 2002; 77: 453–468.

15.

Hassan

Duque

Osteosarcopenia: a new geriatric syndrome. Aust Fam Physician 2017; 46: 849–853.

16.

Reginster

Beaudart

Buckinx

et al . Osteoporosis and sarcopenia: two diseases or one? Curr Opin Clin Nutr Metab Care 2016; 19: 31.

17.

Buehring

Binkley

Myostatin–the holy grail for muscle, bone, and fat?

Curr Osteoporos Rep 2013; 11: 407–414.

18.

Bermeo

Gunaratnam

Duque

Fat and bone interactions. Curr Osteoporos Rep 2014; 12: 235–242.

19.

Silventoinen

Magnusson

Tynelius

et al . Heritability of body size and muscle strength in young adulthood: a study of one million Swedish men. Genetic Epidemiology 2008; 32: 341–349.

20.

Eisman

JA.

Genetics of osteoporosis. Endocr Rev 1999; 20: 788–804.

21.

Kanis

Johnell

Oden

et al . Smoking and fracture risk: a meta-analysis. Osteoporos Int 2005; 16: 155–162.

22.

Shen

Zhao

et al . Cigarette smoking and risk of hip fracture in women: a meta-analysis of prospective cohort studies. Injury 2015; 46: 1333–1340.

23.

Kanis

Johansson

Johnell

et al . Alcohol intake as a risk factor for fracture. Osteoporos Int 2005; 16: 737–742.

24.

Endo

Calcium-induced calcium release in skeletal muscle. Physiol Rev 2009; 89: 1153–1176.

25.

Tai

Leung

Grey

et al . Calcium intake and bone mineral density: systematic review and meta-analysis. BMJ 2015; 351: h4183.

26.

Del Valle

Yaktine

Taylor

et al . Dietary reference intakes for calcium and vitamin D. Washington, DC: National Academies Press, 2011.

27.

Tankeu

Ndip Agbor

Noubiap

JJ.

Calcium supplementation and cardiovascular risk: a rising concern. J Clin Hypertens 2017; 19: 640–646.

28.

Rizzoli

Stevenson

Bauer

et al . The role of dietary protein and vitamin D in maintaining musculoskeletal health in postmenopausal women: a consensus statement from the European society for clinical and economic aspects of osteoporosis and osteoarthritis (ESCEO). Maturitas 2014; 79: 122–132.

29.

Mangano

Sahni

Kerstetter

JE.

Dietary protein is beneficial to bone health under conditions of adequate calcium intake: an update on clinical research. Curr Opin Clin Nutr Metab Care 2014; 17: 69–74.

30.

Hannan

Tucker

Dawson-Hughes

et al . Effect of dietary protein on bone loss in elderly men and women: the Framingham osteoporosis study. J Bone Miner Res 2000; 15: 2504–2512.

31.

Castaneda

Gordon

Fielding

et al . Marginal protein intake results in reduced plasma IGF-I levels and skeletal muscle fiber atrophy in elderly women. J Nutr Health Aging 2000; 4: 85–90.

32.

Houston

Nicklas

Ding

et al . Dietary protein intake is associated with lean mass change in older, community-dwelling adults: the health, aging, and body composition (Health ABC) study. Am J Clin Nutr 2008; 87: 150–155.

33.

Coelho-Junior

Milano-Teixeira

Rodrigues

et al . Relative protein intake and physical function in older adults: a systematic review and meta-analysis of observational studies. Nutrients 2018; 10. pii: E1330.

34.

Koutsofta

Mamais

Chrysostomou

The effect of protein diets in postmenopausal women with osteoporosis: systematic review of randomized controlled trials. J Women Aging 2019; 31: 117–139.

35.

Wallace

Frankenfeld

CL.

Dietary protein intake above the current RDA and bone health: a systematic review and meta-analysis. J Am Coll Nutr 2017; 36: 481–496.

36.

Liao

Tsauo

et al . Effects of protein supplementation combined with resistance exercise on body composition and physical function in older adults: a systematic review and meta-analysis. Am J Clin Nutr 2017; 106: 1078–1091.

37.

Shams-White

Chung

et al . Dietary protein and bone health: a systematic review and meta-analysis from the national osteoporosis foundation. Am J Clin Nutr 2017; 105: 1528–1543.

38.

Komar

Schwingshackl

Hoffmann

Effects of leucine-rich protein supplements on anthropometric parameter and muscle strength in the elderly: a systematic review and meta-analysis. J Nutr Health Aging 2015; 19: 437–446.

39.

Tieland

Franssen

Dullemeijer

et al . The impact of dietary protein or amino acid supplementation on muscle mass and strength in elderly people: individual participant data and meta-analysis of RCT’s. J Nutr Health Aging 2017; 21: 994–1001.

40.

Joint WHO/FAO/UNU Expert Consultation. Protein and amino acid requirements in human nutrition. World Health Organ Tech Rep Ser 2007; (935): 1–265.

41.

Tieland

Borgonjen-Van den Berg

van Loon

et al . Dietary protein intake in community-dwelling, frail, and institutionalized elderly people: scope for improvement. Eur J Nutr 2012; 51: 173–179.

42.

Bauer

Biolo

Cederholm

et al . Evidence-based recommendations for optimal dietary protein intake in older people: a position paper from the PROT-AGE study group. J Am Med Dir Assoc 2013; 14: 542–559.

43.

Bouillanne

Curis

Hamon-Vilcot

et al . Impact of protein pulse feeding on lean mass in malnourished and at-risk hospitalized elderly patients: a randomized controlled trial. Clin Nutr 2013; 32: 186–192.

44.

Mamerow

Mettler

English

et al . Dietary protein distribution positively influences 24-h muscle protein synthesis in healthy adults–3. J Nutr 2014; 144: 876–880.

45.

Moreira

Oliveira

Lirani-Galvão

et al . Physical exercise and osteoporosis: effects of different types of exercises on bone and physical function of postmenopausal women. Arq Bras Endocrinol Metabol 2014; 58: 514–522.

46.

Marin-Cascales

Alcaraz

Ramos-Campo

et al . Whole-body vibration training and bone health in postmenopausal women: a systematic review and meta-analysis. Medicine 2018; 97: e11918.

47.

Lombardi

Jiao

et al . Effects of exercise on bone status in female subjects, from young girls to postmenopausal women: an overview of systematic reviews and meta-analyses. Sports Med 2016; 46: 1165–1182.

48.

Zhao

Zhang

The effectiveness of combined exercise interventions for preventing postmenopausal bone loss: a systematic review and meta-analysis. J Orthop Sports Phys Ther 2017; 47: 241–251.

49.

Jepsen

Thomsen

Hansen

et al . Effect of whole-body vibration exercise in preventing falls and fractures: a systematic review and meta-analysis. BMJ Open 2017; 7: e018342.

50.

Sardeli

Komatsu

Mori

et al . Resistance training prevents muscle loss induced by caloric restriction in obese elderly individuals: a systematic review and meta-analysis. Nutrients 2018; 10: pii: E423.

51.

Vlietstra

Hendrickx

Waters

DL.

Exercise interventions in healthy older adults with sarcopenia: A systematic review and meta-analysis. Australas J Ageing 2018; 37: 169–183.

52.

Effects of walking on the preservation of bone mineral density in perimenopausal and postmenopausal women: a systematic review and meta-analysis. Menopause 2013; 20: 1216–1226.

53.

Liu

Latham

NK.

Progressive resistance strength training for improving physical function in older adults. Cochrane Database Syst Rev 2009; CD002759.

54.

Wilhelm

Roskovensky

Emery

et al . Effect of resistance exercises on function in older adults with osteoporosis or osteopenia: a systematic review. Physiother Can 2012; 64: 386–394.

55.

Stolzenberg

Belavy

Beller

et al . Bone strength and density via pQCT in post-menopausal osteopenic women after 9 months resistive exercise with whole body vibration or proprioceptive exercise. J Musculoskelet Neuronal Interact 2013; 13: 66–76.

56.

Slatkovska

Alibhai

Beyene

et al . Effect of 12 months of whole-body vibration therapy on bone density and structure in postmenopausal women: a randomized trial. Ann Intern Med 2011; 155: 668–679, w205.

57.

Lai

Tseng

Chen

et al . Effect of 6 months of whole body vibration on lumbar spine bone density in postmenopausal women: a randomized controlled trial. Clin Interv Aging 2013; 8: 1603.

58.

Anagnostis

Dimopoulou

Karras

et al . Sarcopenia in post-menopausal women: is there any role for vitamin D? Maturitas 2015; 82: 56–64.

59.

Gunton

Girgis

Baldock

et al . Bone muscle interactions and vitamin D. Bone 2015; 80: 89–94.

60.

Bikle

DD.

Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol 2014; 21: 319–329.

61.

Bolland

Grey

Avenell

Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis. Lancet Diabetes Endocrinol 2018; 6: 847–858.

62.

Kahwati

Weber

Pan

et al . Vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults: evidence report and systematic review for the US preventive services task force. JAMA 2018; 319: 1600–1612.

63.

Zhao

Zeng

Wang

et al . Association between calcium or vitamin d supplementation and fracture incidence in community-dwelling older adults: a systematic review and meta-analysis. JAMA 2017; 318: 2466–2482.

64.

Beaudart

Buckinx

Rabenda

et al . The effects of vitamin D on skeletal muscle strength, muscle mass, and muscle power: a systematic review and meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 2014; 99: 4336–4345.

65.

De Spiegeleer

Beckwee

Bautmans

et al . Pharmacological interventions to improve muscle mass, muscle strength and physical performance in older people: an umbrella review of systematic reviews and meta-analyses. Drugs Aging 2018; 35: 719–734.

66.

Rosendahl-Riise

Spielau

Ranhoff

et al . Vitamin D supplementation and its influence on muscle strength and mobility in community-dwelling older persons: a systematic review and meta-analysis. J Hum Nutr Diet 2017; 30: 3–15.

67.

Gorter

Krijnen

Schipper

IB.

Vitamin D deficiency in adult fracture patients: prevalence and risk factors. Eur J Trauma Emerg Surg 2016; 42: 369–378.

68.

Bruyère

Cavalier

Reginster

JY.

Vitamin D and osteosarcopenia: an update from epidemiological studies. Curr Opin Clin Nutr Metab Care 2017; 20: 498.

69.

Hirani

Cumming

Naganathan

et al . Longitudinal associations between vitamin D metabolites and sarcopenia in older Australian men: the Concord health and aging in men project. J Gerontol A Biol Sci Med Sci 2017; 73: 131–138.

70.

Bischoff-Ferrari

Willett

Wong

et al . Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med (Chic) 2009; 169: 551–561.

71.

Gallagher

JC.

Vitamin D and falls—the dosage conundrum. Nat Rev Endocrinol 2016; 12: 680.

72.

Duque

Daly

Sanders

et al . Vitamin D, bones and muscle: myth versus reality. Australas J Ageing 2017; 36(Suppl. 1): 8–13.

73.

et al . Efficacy and safety of denosumab in postmenopausal women with osteoporosis: a meta-analysis. Medicine 2015; 94: e1674.

74.

Cummings

Martin

McClung

et al . Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009; 361: 756–765.

75.

Bonnet

Bourgoin

Biver

et al . RANKL inhibition improves muscle strength and insulin sensitivity and restores bone mass. J Clin Invest 2019; 130: 1.

76.

Tracz

Sideras

Bolona

et al . Testosterone use in men and its effects on bone health. A systematic review and meta-analysis of randomized placebo-controlled trials. J Clin Endocrinol Metab 2006; 91: 2011–2016.

77.

Barake

Arabi

Nakhoul

et al . Effects of growth hormone therapy on bone density and fracture risk in age-related osteoporosis in the absence of growth hormone deficiency: a systematic review and meta-analysis. Endocrine 2018; 59: 39–49.

78.

Rudman

Feller

Nagraj

et al . Effects of human growth hormone in men over 60 years old. N Engl J Med 1990; 323: 1–6.

79.

Tang

Gao

Yang

et al . Combination of weight-bearing training and anti-MSTN polyclonal antibody improve bone quality in rats. Int J Sport Nutr Exerc Metab 2016; 26: 516–524.

80.

Camporez

JPG

Petersen

Abudukadier

et al . Anti-myostatin antibody increases muscle mass and strength and improves insulin sensitivity in old mice. J Gerontol A Biol Sci Med Sci 2016: 201525795.

81.

Becker

Lord

Studenski

et al . Myostatin antibody (LY2495655) in older weak fallers: a proof-of-concept, randomised, phase 2 trial. Lancet Diabetes Endocrinol 2015; 3: 948–957.

82.

Dufresne

Boulanger-Piette

Bossé

et al . Physiological role of receptor activator nuclear factor-kB (RANK) in denervation-induced muscle atrophy and dysfunction. Receptors Clin Investig 2016; 3: e13231–e13236.

83.

Baumgartner

Waters

Gallagher

et al . Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev 1999; 107: 123–136.

84.

Nieschlag

Current topics in testosterone replacement of hypogonadal men. Best Pract Res Clin Endocrinol Metab 2015; 29: 77–90.

85.

Wolfe

Ferrando

Sheffield-Moore

et al . Testosterone and muscle protein metabolism. Mayo Clin Proc 2000; 75(Suppl): S55–S59; discussion S59–S60.

86.

Irwig

MS.

Bone health in hypogonadal men. Curr Opin Urol 2014; 24: 608–613.

87.

Bhasin

Woodhouse

Casaburi

et al . Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab 2005; 90: 678–688.

88.

Morley

Perry

III . Androgens and women at the menopause and beyond. J Gerontol A Biol Sci Med Sci 2003; 58: M409–M416.

89.

Srinivas-Shankar

Roberts

Connolly

et al . Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 2010; 95: 639–650.

90.

Wittert

Chapman

Haren

et al . Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low–normal gonadal status. J Gerontol A Biol Sci Med Sci 2003; 58: M618–M625.

91.

Travison

Basaria

Storer

et al . Clinical meaningfulness of the changes in muscle performance and physical function associated with testosterone administration in older men with mobility limitation. J Gerontol A Biol Sci Med Sci 2011; 66: 1090–1099.

92.

Stout

Tew

Doll

et al . Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study. American Heart J 2012; 164: 893–901.

93.

Morley

JE.

Pharmacologic options for the treatment of sarcopenia. Calcif Tissue Int 2016; 98: 319–333.

94.

Liu

Bravata

Olkin

et al . Systematic review: the safety and efficacy of growth hormone in the healthy elderly. Ann Intern Med 2007; 146: 104–115.

95.

Sullivan

Carter

Warr

et al . Side effects resulting from the use of growth hormone and insulin-like growth factor-I as combined therapy to frail elderly patients. J Gerontol A Biol Sci Med Sci 1998; 53: M183–M187.

Therapeutic approaches to osteosarcopenia: insights for the clinician

Abstract

Keywords

Introduction

Osteosarcopenia as a new geriatric syndrome

Risk factors for osteosarcopenia

Potential therapeutic targets in osteosarcopenia

Nonpharmacological management of osteosarcopenia

Role of lifestyle modification in treating osteosarcopenia

Nutritional strategies to treat osteosarcopenia

Role of dietary calcium and calcium supplements

Role of dietary protein and protein supplements

Exercise

Vitamin D

Pharmacological management of osteosarcopenia

Denosumab

Testosterone and SARMs

Growth hormone and IGF-1

Anti-myostatin antibodies

Future directions

Footnotes

Funding

Conflict of interest statement

ORCID iD

References