Trajectories in muscular strength and physical function among men with and without prostate cancer in the health aging and body composition study.

OBJECTIVES: To examine and compare changes in strength and physical function from pre- to post-diagnosis among men with prostate cancer (PC, [cases]) and matched non-cancer controls identified from the Health, Aging and Body Composition (Health ABC) study.
MATERIALS AND METHODS: We conducted a longitudinal analysis of 2 strength and 3 physical function-based measures among both cases and controls, identified from a large cohort of community living older adults enrolled in the Health ABC study. We plotted trajectories for each measure and compared cases vs. controls from the point of diagnosis onwards using mixed-effects regression models. For cases only, we examined predictors of poor strength or physical function.
RESULTS: We identified 117 PC cases and 453 matched non-cancer controls (50% African Americans). At baseline, there were no differences between cases and controls in demographic factors, comorbidities or self-reported physical function; however, cases had slightly better grip strength (44.6 kg vs. 41.0 kg, p<0.01), quadriceps strength (360.5 Nm vs. 338.7 Nm, p = 0.02) and Health ABC physical performance battery scores (2.4 vs. 2.3, p = 0.01). All men experienced similar declines in strength and physical function over an equivalent amount of time. The loss of quad strength was most notable, with losses of nearly two-thirds of baseline strength over approximately 7 years of follow up.
CONCLUSIONS: Among both cases and controls, strength and physical function decline with increasing age. The largest declines were seen in lower body strength. Regular assessments should guide lifestyle interventions that can offset age- and treatment-related declines among men with PC.

Introduction

Prostate cancer (PC) is the most prevalent form of male cancer worldwide, with an estimated 174, 650 new cases being diagnosed in US men in 2018 [1]. Effective treatment and disease management strategies now result in long-term survival [2]. The majority of men remain clinically asymptomatic and if diagnosed with low-risk disease may opt for active surveillance or treatment with surgery and/or radiation. Active surveillance is a promising approach for low-risk PC, yet a significant number of men still opt for more aggressive treatments such as surgery and radiation that often result in sexual, bowel and urinary dysfunction [3]. These significant ongoing health-related quality of life (HRQL) challenges may cause men to become depressed, less-active and dis-engaged from activities of daily living (ADL’s)[4-6], which could further influence their physical HRQL. Furthermore, disease progression and treatment-related factors can exacerbate already compromised functioning. For example, approximately 50% of men with low-risk disease may eventually receive androgen deprivation therapy (ADT) [7] for recurrent or metastatic disease. ADT leads to well-documented adverse effects, including large declines in strength and physical function [8-11]. What is not well appreciated is how a PC diagnosis in combination with aging-related factors, from pre- to post-diagnosis, can impact physical aspects of HRQL such as strength and physical function. Factors of interest include, comorbidity, body composition, lifestyle behaviors, and psycho-social well-being.

Strength physical function are prognostically important for cancer survivors [12, 13]. In the Health Aging and Body Composition (Health ABC) study, physical function among a mixed group of cancer patients predicted both disability and survival [14]. Several studies have examined physical function cross-sectionally [15] and prospectively [11, 16] following a PC diagnosis, yet few studies have assessed changes from pre- to post-diagnosis or in comparison with that of age-matched non-cancer controls [17]. Alibhai et al., [11] and Pardo et al., [18] examined changes in physical function among patients with PC on different treatments, and Reeve and colleagues compared cases to non-cancer controls [17], however, these studies either examined post-diagnosis changes, which limits our understanding of how pre-diagnosis physical function impacts change post-diagnosis and treatment, or used self-report rather than objective metrics of function [17]. Due to the advanced age of many men diagnosed with PC, it is important to understand how pre-diagnosis levels of strength and physical function influences future risk for decline.

The Health ABC study is a large and well-characterized prospective cohort study of older adults who were healthy at entry into the study, with incident cases of PC and sufficient follow-up data to fully characterize pre- to post-diagnosis changes. A significant strength of the Health ABC study is the racially and ethnically diverse cohort with data on numerous age-related covariates such as comorbidity, body composition, physical activity, and the inclusion of objective muscular strength and physical performance measures. The aims of our study were to: 1) to examine trajectories of objectively measured strength and physical function in PC patients from pre- to post-diagnosis compared to matched non-cancer controls; and 2) to determine whether demographic, treatment or psychosocial factors were associated with clinically meaningful changes in strength and/or physical function among patients with PC. We hypothesized that patients with PC would have similar trajectories of strength and physical function to non-cancer controls pre-diagnosis, but that following diagnosis, men with PC would experience greater declines than non-cancer controls. Further we hypothesized that among cases, treatment with ADT, more comorbidities, lower levels of physical activity and a greater severity of depressive symptoms would be associated with worse trajectories in strength and physical function than non-cancer controls.

Materials and methods

The Health ABC Study enrolled 3075 black and white community dwelling older adults. Participants were recruited from a random sample of white Medicare beneficiaries and all age-eligible black residents in designated ZIP code areas in and around Pittsburgh, Pennsylvania, and Memphis, Tennessee, between March 1997 and July 1998. Eligibility criteria for the Health ABC Study were: aged 70 to 79; no difficulty performing activities of daily living, walking one-quarter or a mile, or climbing 10 steps without resting; no reported need of assistive devices for ambulation; no active treatment for cancer in the prior 3 years; no life-threatening illness; and no plans to leave the area for 3 years. All participants provided written informed consent. The Institutional Review Boards at the University of Pittsburgh, the University of Tennessee and the University of California, San Francisco approved the Health ABC protocol. Study participants were contacted every 6 months by telephone or in person and interviewed about health status, hospitalizations, outpatient procedures, and new cancer diagnoses. Information regarding incident cancer diagnoses was also obtained from hospital or clinic records.

Study sample

For the current analyses, we identified 117 adjudicated PC diagnoses that were confirmed by pathology reports or other medical record information over 10 years of follow-up (study visits 1, 2, 4, 6, 8, 10). An analytic dataset was created to include socio-demographics, strength and physical function outcomes data for all 117 PC cases and 468 matched non-cancer controls (Fig 1). Each participant was assigned an index visit with the participant having had to attempt the 400m walk during the visit and have attempted a 400m walk at a later visit. The Health ABC study collected data on the 400m walk at years 1 (baseline), 2, 4, 6, 8, and 10. For each PC case with an incident diagnosis since Health ABC baseline, we used the last pre-diagnosis visit as an index visit. Frequency matching, weighted by race, was used to randomly assign an index visit for the non-cancer controls at a ratio of 4:1 for a total analytic sample of 585 men.

Fig 1

Participant flow chart.

CONSORT diagram depicting selection of analytic sample.

Measures

Muscular strength

Muscular strength was assessed with 2 objective measures to capture upper and lower body strength: 1) Isometric grip strength (kg) using a hand-held dynamometer (JAMAR Technologies, Inc., Hatfield, PA); and 2) Quadriceps (quad) strength (Nm) using an isokinetic dynamometer.

Physical function

Physical function was assessed with a further 3 objective measures: 1) a 400m walk test recorded as the proportion of men completing the test at each visit (failure to complete 400m in 15 minutes is indicative of major mobility disability (MMD)[19, 20]); 2) Health ABC physical performance battery (HABCPPB), a combination test (5x timed chair stands, double and single-leg balance tests held for 30 seconds, and narrow walk test for balance and 6m gait speed) designed to measure a wide range of function in the Health ABC cohort of well-functioning older adults. Scores for the HABCPPB are on a scale of 0–4 with a scoring system designed to limit floor and ceiling effects [21]; and 3) 20m gait speed at usual pace over a 20m course assessed on a continuous scale in meters per second (m/s). The correlations between all measures of muscular strength and physical function ranged from 0.24 and 0.37.

Covariates

We examined several covariates (as potential confounders of the relationship between PC status and our primary outcomes) and their relationship with muscular strength and physical function among both cases and controls at baseline, index visit and a follow-up visit 2–3 years post-diagnosis. Demographic variables included age at index visit, race, education and marital status. We also considered the presence of multiple comorbidities including diabetes, previous heart attack, hypertension, previous stroke, chronic heart failure (CHF), arthritis, other cancers and total number of comorbidities. Depressive symptoms were measured with the Center for Epidemiologic Studies Depression Scale (CESD) [22]. Body mass index (BMI; kg/m2) was used as an index of obesity status. Self-reported functional status was further assessed by the number of falls in the previous 12 months, perceived capacity to easily walk a quarter mile, lift or carry 10lbs, and having engaged in high intensity exercise over the past 12 months, or past 7 days.

Statistical analysis

Summary statistics were calculated for both the PC cases and controls at the Health ABC baseline (Table 1), index visit, and at a short-term follow-up visit (2 or 3 years depending on the index year). T-tests were used to compare continuous measures and Chi-square tests were used for categorical measures. To visualize longitudinal data, we plotted the means of each outcome by visit year, centered at the index visit. Nonparametric loess regression was used to plot a smooth curve enabling a better visualization of the effect of time (actual time from diagnosis/index visit) on outcomes. Repeated measures mixed-effects regression analyses were used to test for differences in the effect of time between the two groups and to test whether the slope of the function among cases was different pre- to post-diagnosis. Cubic, quadratic, and linear terms for time were investigated to see which provided the best fit to the data and to verify what was seen in the loess plots. Residual plots were created to verify the assumptions of the model (not shown). To assess the association of relevant covariates with trajectories of upper body strength (grip strength), lower body strength (quad strength) and gait (20m usual pace gait speed), we placed PC cases into 1 of 4 groups for each outcome as follows: group 1—decreasing; group 2 –consistently low; group 3 –consistently high; group 4—increasing. Cut offs for determining a meaningful change (±) and the groups men were placed into (decreasing, consistently low, consistently high or increasing) are shown in Table 3 and were based on published literature, except in the case of quad strength (where a 1.0 standard deviation (SD) was used). Bivariate association of all covariates was by group (1–4). Loess plots were produced with the ggplot2 package in R 3.4.1 and all other analyses were done using SAS version 9.4 (SAS institute Inc. Cary, NC).

Table 1

Characteristics of the study sample at Health ABC study baseline.

	PC Cases (N = 117) Mean (SD) or n (%)	Controls (n = 468) Mean (SD) or n (%)	p-value
Age at Health ABC baseline	74.0 (2.7)	74.1 (2.8)	0.61
Race			0.97
White	58 (49.6%)	231 (49.4%)
Black	59 (50.4%)	237 (50.6%)
Education			0.08
Less than HS	32 (27.4%)	157 (33.5%)
HS grad	26 (22.2%)	129 (27.6%)
Postsecondary	59 (50.4%)	182 (38.9%)
Married			0.10
No	39 (33.6%)	116 (25.9%)
Yes	77 (66.4%)	332 (74.1%)
Diabetes			0.96
No	94 (80.3%)	377 (80.6%)
Yes	23 (19.7%)	91 (19.4%)
Heart Attack			0.10
No	103 (89.6%)	386 (83.4%)
Yes	12 (10.4%)	77 (16.6%)
Hypertension/High BP			0.87
No	57 (49.6%)	234 (50.4%)
Yes	58 (50.4%)	230 (49.6%)
Stroke			0.36
No	115 (99.1%)	453 (97.8%)
Yes	1 (0.9%)	10 (2.2%)
CHF			0.29
No	113 (98.3%)	440 (96.3%)
Yes	2 (1.7%)	17 (3.7%)
Arthritis			0.41
No	65 (55.6%)	234 (51.3%)
Yes	52 (44.4%)	222 (48.7%)
Other Cancers B			<0.01
No	111 (94.9%)	468 (100.0%)
Yes	6 (5.1%)	0 (0.0%)
Number of comorbidities A	0.8 (0.8)	0.9 (0.8)	0.31
BMI	26.8 (3.6)	27.0 (4.0)	0.72
% Body Fat	29.0 (4.3)	28.9 (5.0)	0.81
Lean Body Mass (Kg)	54.5 (64.8)	54.6 (71.9)	0.87
CESD	3.8 (4.5)	4.0 (4.5)	0.69
Falls in last 12 months			0.32
No	99 (85.3%)	381 (81.4%)
Yes	17 (14.7%)	87 (18.6%)
Easy walking a quarter mile			0.56
No (Unable to do–Not that easy)	3 (2.6%)	17 (3.7%)
Yes (Easy or Somewhat easy)	112 (97.4%)	439 (96.3%)
Easy walking up 10 steps			0.86
No (Unable to do–Not that easy)	5 (4.3%)	18 (3.9%)
Yes (Easy or Somewhat easy)	111 (95.7%)	438 (96.1%)
Easy lifting/carrying 10 pounds			0.12
No (Unable to do–Not that easy)	1 (0.9%)	17 (3.6%)
Yes (Easy or Somewhat easy)	116 (99.1%)	451 (96.4%)
Past 12 months high intensity exercise			0.82
No	86 (73.5%)	348 (74.5%)
Yes	31 (26.5%)	119 (25.5%)
Past 7 days high intensity exercise			0.35
No	100 (85.5%)	382 (81.8%)
Yes	17 (14.5%)	85 (18.2%)
Hours per week watching TV			0.19
0—<7	17 (14.5%)	84 (18.1%)
7—<14	36 (30.8%)	100 (21.5%)
14—<21	26 (22.2%)	120 (25.8%)
21 +	38 (32.5%)	161 (34.6%)
Completed 400m walk			0.33
No	20 (17.1%)	99 (21.2%)
Yes	97 (82.9%)	369 (78.8%)
20m gait speed (m/sec)	1.3 (0.2)	1.3 (0.2)	0.08
HABCPPB	2.4 (0.4)	2.3 (0.5)	0.01
Grip Strength C	44.6 (8.6)	41.0 (8.7)	<0.01
Isokinetic Quad Strength	360.5 (81.5)	338.7 (88.5)	0.02

PC, Prostate Cancer; CHF, Chronic Heart Failure; BMI, Body Mass Index; CESD, Center for Epidemiologic Studies Depression Scale; HABCPPB, Health Aging and Body Composition Physical Performance Battery;

A diabetes, heart attack, hypertension/high blood pressure, stroke, CHF;

B by design of our sample there are no cancer in control group,

C max of two hands.

Bold figures indicate statistical significance.

Table 3

Change in physical function among PC cases at 3–4 years post-diagnosis.

	Median baseline value (to determine high/low)	Criteria for Change	Follow-up Status
			Decreasing	Consistently Low	Consistently High	Increasing
Grip strength (Kg)	42	±6.5A	18 (24%)	29 (39%)	26 (35%)	2 (3%)
Quad strength (Nm)	322	±100B	33 (46%)	16 (23%)	22 (31%)	0
20m gait speed (m/s)	1.2	±0.05A	50 (65%)	10 (13%)	10 (13%)	7 (9%)

A = reported in the literature,

B = ~1 baseline SD

Results

Sample characteristics

Briefly, we identified 117 men who reported a diagnosis of PC at a Health ABC follow-up visit and 468 men without cancer, who were randomly chosen from remaining HABC cohort, weighted by race (Fig 1). S1 Table shows sample characteristics at index visit (last visit before diagnosis, including a breakdown of the proportion of patients and matched controls who had their index visit in years 1 (baseline), 2, 4, 6 and 8, which ranged from 9% in year 8 to 33.35% in year 2.The mean age of the PC cases and controls at baseline was similar (74.0 vs. 74.1 years, respectively). Approximately half of cases and controls were black (50.6% vs. 50.4%) with the majority of men having a post-secondary education and being married or partnered. There were no statistically significant differences (all p’s >0.05) between cases and controls for demographic factors, comorbidities, self-reported functional capacity or levels of physical activity. There were, however, significant differences in grip strength (mean ± SD: 44.6 ± 8.6kg vs. 41.0 ± 8.7kg; p <.001), quad strength (mean ± SD: 360.5 ± 81.5Nm vs. 338.7 ± 88.5Nm; p <.001), and in HABCPPB scores (mean ± SD: 2.4 ± 0.4 vs. 2.3 ± 0.5 p = 0.01), at baseline. There were no statistically significant differences between the proportion of cases vs. controls completing 400m walk or for 20m gait speed. Four people included in our dataset (all cases) were taking ADT drugs identified in the study medications list (Leuprolide, Goserelin, Buserelin, Nafarelin). Due the small numbers we did not conduct any further analyses using ADT as a sub-population. At index visit, a significantly higher number of controls had a previous heart attack than cases (23.3% vs. 13.7% respectively) while quad strength and HABCPPB scores were no longer significantly different between cases and controls.

Trajectories in strength and physical function

Fig 2 (panel A-E) shows the group-based trajectories of change in strength and physical function, from pre- to post-diagnosis. Plot A shows a different pattern in the trajectory of grip strength for cases compared with controls. In controls, grip strength declines by approximately 16% in a steady linear fashion. Among cases, grip strength increases slightly in the years pre-diagnosis but then declines from 2 years prior to diagnosis to 9 years post-diagnosis. Plot B shows that quad strength follows a different pattern to grip strength scores. Cases and controls show similar trends, declining in quad strength at a slower rate initially, but then a much faster rate from about 3 years post-diagnosis, losing approximately two-thirds of their strength over the last 6–7 years of follow-up. Plot C shows the percentage of Health ABC participants completing the 400m walk test. Among both cases and controls, there was a decrease in the proportion of men completing the 400m at follow-up visits, however, the rate of decline in cases and controls appeared to differ depending on the timeframe (pre- or post-diagnosis). Plot D indicates a similar decline in HABCPPB performance scores among both cases and controls over approximately 16 years of total follow-up. Plot E, in a similar fashion to plot D, shows gait speed over 20m follows a pattern of steady, but gentle decline in both cases and controls. Across measures, there are no discernable changes in pattern associated with the point of diagnosis.

Fig 2

Strength and physical function trajectories.

Loess regression models depicting trajectories of strength and physical function among cancer cases and controls.

Table 2 shows the results of repeated measures models for each outcome. All models include a linear effect for time. For quad strength, HABCPPB, and gait speed there was a significant quadratic effect for time, a comparison of functional trajectory in cases vs controls, and effect of time since diagnosis in PC cases. Grip strength declined significantly over time in both groups (p<0.01), though less quickly in cancer cases compared to controls (p = 0.02). Among cases, from the point of diagnosis onwards grip strength declined more rapidly than before diagnosis (p = 0.02). Quad strength declined significantly over time among both cases and controls (p<0.01) and at the same rate (p = 0.52). For the proportion of cases and controls completing the 400m walk test, the effects of both time (p<0.01) and time since diagnosis (p<0.04) were significant, though in opposite directions. In general, fewer cases and controls completed the 400m walk test over time but from the point of diagnosis onwards, an increasing proportion of cases remaining in the study completed the test. In terms of the HABCPPB scores, performance declined significantly over time (p<0.01), though this was equivalent in cases and in controls and the rate of decline did not change after diagnosis. For 20m gait speed, both cases and controls experienced declines, with no differences in trajectory (p = 0.89), though cases declined at a slightly slower rate from the point of diagnosis onwards (p<0.02).

Table 2

Repeated measures mixed-effects regression models of change in physical function by prostate cancer status.

Model		beta	se	p-value
Grip strength
	Time (years pre/post diagnosis)	-0.70	0.03	<0.01
	Prostate cancer status (cases vs control)	1.90	0.81	0.02
	Time since diagnosis (cancer only)	-0.24	0.10	0.02
Quad strength
	Time (years pre/post diagnosis)	-29.18	0.51	<0.01
	Time2 (years pre/post diagnosis)	-0.92	0.09	<0.01
	Prostate cancer status (cases vs controls)	-6.39	10.01	0.52
	Time since diagnosis (cases only)	-3.13	1.65	0.06
Completed 400m walk
	Time (years pre/post diagnosis)	-0.17	0.01	<0.01
	Prostate cancer status (cases vs controls)	-0.10	0.17	0.56
	Time since diagnosis (cases only)	0.09	0.05	0.04
HABCPPB
	Time (years pre/post diagnosis)	-0.08	0.004	<0.01
	Time2 (years pre/post diagnosis)	-0.002	0.0006	0.01
	Prostate cancer status (cases vs controls)	0.06	0.06	0.29
	Time since diagnosis (cases only)	0.02	0.01	0.16
20m gait speed
	Time (years pre/post diagnosis)	-0.04	0.001	<0.01
	Time2 (years pre/post diagnosis)	0.0005	0.0002	0.01
	Prostate cancer status (cases vs controls)	-0.003	0.02	0.89
	Time since diagnosis (cases only)	0.008	0.004	0.02

HABCPPB, Health Aging and Body Composition Physical Performance Battery. Bold figures indicate statistical significance

Factors associated with clinically meaningful change strength and physical function

Table 3 indicates the categorization of PC cases into 4 groups (decreasing, consistently low, consistently high, increasing) representing change in upper body strength (grip strength), lower body strength (quad strength) and 20m gait speed, separately. S2–S4 Tables show the results of bivariate associations between change score groups for grip strength, quad strength, and 20m gait speed and all covariates 3–4 years post diagnosis. Men with PC who were younger at their index visit (p = 0.03), who had greater lean body mass (p = 0.03) and who had fewer depressive symptoms (p = 0.01) were significantly more likely to maintain a high level of grip strength. Men with PC who were older at index visit (p <.01), who had more follow up years in the study (p≤.01), and who were taking PC drugs (p<0.01) were significantly more likely to have decreased quad strength. PC cases who had arthritis (p = 0.02) and who had more years of follow up in the study (p = 0.01) were significantly more likely to have experienced a decrease in their 20m gait speed.

Discussion

In the current study, the trajectories of strength and physical function among both older men diagnosed with PC and among race-matched men without cancer declined at similar rates over an equivalent amount of time, with the greatest declines seen in lower leg strength as indexed by quad strength testing. Starting from approximately 80 years of age, both cases and controls lost around 70% of their quad strength over the following 6 years compared with having lost only 7% over the previous decade. Given the low rates of ADT use among this sample of men diagnosed with prostate cancer, it appears the majority of the decline in lower body strength was due to aging related changes. Unexpectedly, the overall rate of decline for grip strength was slower in men with PC compared to men without cancer, which may be a result of the fact that PC cases had significantly greater grip strength than controls at study baseline and at index visit unlike for other measures of strength and function. Previous studies examining upper and lower body strength changes among PC patients (both receiving and not receiving ADT) have found mixed results. This may relate to the specific tests being used or the time frame across which patients were tested. For example, studies using maximal leg press have found no differences in strength while those examining leg extension have found differences (Cheung). Among men with PC, mobility (proportion completing 400m walk and 20m gait speed) remained relatively intact; however, changes in muscle strength were apparent. The majority of men with PC either had significant declines in physical performance or maintained a low level of physical performance on upper and lower body strength tests (63% and 69% respectively) and gait (78%).

Our study differed from previously reported data in noteworthy ways. Alibhai and colleagues [11], examined differences in physical function between men with PC (some receiving ADT) and non-cancer controls over time and found that grip strength declined only among PC patients receiving ADT. In our study, grip strength decreased in both cases and controls, but was the most dissimilar outcome between the two groups. These estimates may have also been affected by a smaller number of participants at the beginning and end of the follow-up periods. The Alibhai study found no changes over time among any group for the timed up and go test (TUG), used as a measure of lower body strength, in contrast to our finding of a large decline in quad strength over time. The discrepancy may be due to their shorter follow up (12 months) and the slightly different testing components [23]. The most significant difference in our study was that physical function was examined before men were diagnosed with PC, illustrating the acute effects of diagnosis and first line treatments on physical function over time. To our knowledge, no other studies have used objective measures of functioning to evaluate change across this period. Moreover, we did not discriminate between men who were on/off ADT. A relatively small proportion of men in this study had ADT exposure, highlighting the significance of the change in quad strength with advancing age.

Our sample contained 50% African Americans, vs only 6% African Americans in the SEER cohort [17], a critical contribution considering that the majority of PC literature underrepresents African Americans. Reeve et al reported significant differences in physical health-related quality of life (HRQL) between cases and controls over 6 months following diagnosis, including worse depressive symptoms. Except for grip strength, we did not find significant differences between cases and controls in objective measures of physical performance over time. Furthermore, Chambers and colleagues [24] examined trajectories of self-reported HRQL in 2250 men recently diagnosed with PC over a 6-year period, reporting poorer physical HRQL was predicted by older age, lower education, lower income, comorbidities and receiving hormonal therapy. We found no associations between level of education, number of comorbidities and any physical performance measure. Overall, among men with PC, increasing age was the factor most consistently associated with meaningful declines in function over time.

Previous studies have reported that up to 50% of men diagnosed with PC will at some point receive ADT [7]. Though use may be declining for men with low-risk early stage disease, due to its adverse effects [25], ADT remains the cornerstone of treatment for advanced PC. Preparing for possible disease progression in conjunction with inevitable aging-related functional declines may promote maintenance of physical health-related QOL among men diagnosed with early-stage disease. Largely in contrast to our hypothesis, we found men diagnosed with PC who were healthy at baseline (eligibility criteria for Health ABC study) did not experience accelerated declines in long-term physical function when compared to men without cancer. Similar self-reported changes in long-term physical function have been described among women with breast cancer [26] but other findings suggest a cancer history is associated with marked declines in short-term function [27]. In our study, all older men experienced decreases in their function over time, with the largest declines seen in lower body strength. Helping all older men, particularly those diagnosed with PC, to maintain function as they age is an important clinical goal. Previous studies show that physical function declines less rapidly during exercise intervention [28]. Therefore, it is critical to identify strategies for maintaining effective and sustainable lifestyle behaviors that support optimal physical function [29]. In addition, aerobic training to support cardiovascular health is also critical among men who are at risk of developing CVD [30, 31]. Our finding that older men are, in general, not engaging in regular exercise provides an opportunity for such interventions.

Maintaining muscle strength and quality [32] through the adoption of exercise training may be particularly important for promoting healthy survivorship among patients with PC. In the RENEW study [28], cancer survivors (breast, prostate and colorectal), in a wait-listed control group experienced significant declines in self-reported physical function over 12 months when compared with those receiving a home-based exercise intervention. In a separate study, Klepin et al. [14] found that lower extremity physical performance predicted both 2-year progression to disability and overall survival among cancer survivors from the Health ABC cohort. Therefore, early intervention to offset functional declines in aging patients with PC may be critical, with diagnosis providing an important opportunity (teachable moment) [33] to engage with these men.

We believe this study had a number of important strengths including: 1) the diverse sample (50% African Americans); with 2) multiple years of follow-up; which allowed us to 3) characterize change in physical function from pre-diagnosis; using 4) objective measures of function on multiple domains; and 5) a matched non-cancer cohort. We also recognize the following limitations: We did not have reliable information on the disease stage at diagnosis, making comparison by stage within and across other studies impossible. Relatively few men were on ADT, suggesting the majority had early stage disease at diagnosis [34] and making it unlikely that we could detect significant differences between groups. A further limitation of the study is the lack of other treatment information such as surgery or radiation as these may also have impacted aspects of strength or physical function, especially in the early post diagnosis period. Men with high risk disease or more advanced cancer at diagnosis would also likely have different treatments and/or psychosocial reactions to diagnosis. Additionally, while we did not find specific associations between BMI and trajectories of physical function over time, the use of more precise measures of body composition may have provided better information. Finally, we did not evaluate diet or nutrition, a critical factor contributing to changes in body composition in men who begin hormone therapy [35].

In conclusion, our findings reinforce the importance of health status at diagnosis. Furthermore, as part of multidisciplinary care, all aging men should undergo assessments of strength and physical function to identify those with deficits. Routine assessments will provide a basis for the prescription of exercise programs and for assessing the risk of disablement and mortality as these men age. Older patients with PC should be prescribed resistance exercise training to promote the maintenance of muscular strength [36, 37].

Characteristics of the study sample at last pre-diagnosis (index) visit.

(DOCX)

Click here for additional data file.

Change in grip strength at 3–4 year follow-up visit.

(DOCX)

Click here for additional data file.

Change in quad strength at 3–4 year follow-up visit.

(DOCX)

Click here for additional data file.

Change in 20 m walking speed at 3–4 year follow-up visit.

(DOCX)

Click here for additional data file.

7 Nov 2019

PONE-D-19-28019

Trajectories in Muscular Strength and Physical Function Among Men with and without Prostate Cancer in the Health Aging and Body Composition Study

PLOS ONE

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We look forward to receiving your revised manuscript.

Kind regards,

Justin C. Brown

Academic Editor

PLOS ONE

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"The institutional review boards of the study sites approved the protocol."

a) Please amend your current ethics statement to include the full name of the ethics committee/institutional review board(s) that approved your specific study.

b) Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”).

For additional information about PLOS ONE ethical requirements for human subjects research, please refer to http://journals.plos.org/plosone/s/submission-guidelines#loc-human-subjects-research.

3.  Thank you for stating in your Funding Statement:

"Dr. Lucas’s work on this project was partly supported by a National Cancer Institute training grant (R25 CA122061). Dr. Klepin receives support from Wake Forest University Claude D. Pepper Older Americans Independence Center (P30-AG21332). Dr. Isom is supported by National Cancer Institute’s Cancer Center Support Grant award number P30CA012197 issued to the Wake Forest Baptist Comprehensive Cancer Center. This research was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, and NINR grant R01-NR012459. This research was funded in part by the Intramural Research Program of the NIH, National Institute on Aging.The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.".

i) Please provide an amended statement that declares *all* the funding or sources of support (whether external or internal to your organization) received during this study, as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now.  Please also include the statement “There was no additional external funding received for this study.” in your updated Funding Statement.

ii) Please include your amended Funding Statement within your cover letter. We will change the online submission form on your behalf.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for the opportunity to review this manuscript. The purpose of this research was to compare longitudinal changes in strength and physical function between prostate cancer survivors and matched controls in a cohort of community living older adults. A large body of literature supports muscle mass and muscle strength loss after treatment for prostate cancer; however, very few studies have captured objective assessments of strength and function prior to diagnosis. This research provides valuable insight into trajectories of change in these facets of aging both prior to and after a prostate cancer diagnosis among older men. Comments and suggestions are detailed below.

Introduction:

•The introduction of this study does a sufficient job introducing the rationale behind the strength and physical function concerns with prostate cancer; however, it focuses on the specific effects of ADT. This does not seem to carry through the rest of the paper in terms of analyses. It would be beneficial for this section to expand to include the effects of prostate cancer more broadly, rather than those of ADT.

•It’s unclear how depressive symptoms are associated with strength and physical function for inclusion as a covariate. Please elaborate on the effects of depressive symptoms on strength and physical function in this population.

Methods:

•The authors may consider separately defining muscle strength and physical function. The methods section would be strengthened by specifically describing how each construct was operationalized.

•The authors may consider defining self-reported physical function in the previous section “muscular strength and physical function” with the other measures of physical function rather than with the covariates.

•It is surprising that a cohort study focused on body composition would only include body mass index in an analysis of muscle strength and physical function. It seems that muscle mass would be an important factor in this relationship, and it is unclear why this would be omitted.

•The author may consider including details on which measures were continuous or categorical for analysis.

•Please include methodology for “placement” into decreasing, consistently low, consistently high, and increasing group.

•Please clarify the use of baseline versus index visit results. The authors may consider including more detail on the index visit (e.g. time since baseline visit).

Results:

•Please provide data on the number of participants at each visit included in this analysis.

•Please include the HABCPPB acronym definition in the notes for Table 1.

•If available, please provide descriptive data on prostate cancer diagnoses (Gleason score, treatment type).

Discussion:

•Please provide further rationale for cases’ preservation of upper body strength as compared to controls. (paragraph 1, page 13)

•Please consider discussing the sensitivity of measurement techniques used to assess lower body strength. Many studies have found differences in upper body strength, but not lower body. The authors may consider referencing Cheung, 2014. (paragraph 2, page 13)

•It is unclear if the observed declines in function have more to do with age-related decline than with cancer diagnosis. Please elaborate. (paragraph 1, page 14)

•The authors state that resistance exercise should be utilized to maintain muscular strength in those treated with ADT. Given that the authors stated the proportion of patients treated with ADT appeared lower than previously reported prevalence rates, this conclusion extends beyond this scope of these results. Please consider revising this statement. (paragraph 3, page 15)

•The authors include body mass index as a limitation of this study; however, other publications from this cohort include DXA. It is unclear why the authors chose to not include these measurements and instead used an assessment that is known to be a limitation to this study. (paragraph 2, page 15)

•The statement regarding older prostate cancer patients contradicts the previous statement that older patients did not fare worse than younger patients provided they were healthy at baseline. Please revise. (paragraph 2, page 14; paragraph 3, page 15)

Reviewer #2: The present study by Lucas et al describes the trajectories in muscular strength and physical function in older men with prostate cancer compared to a matched sample of non-cancer controls from within the Health ABC dataset. The study utilizes a unique data source (the HABC cohort study) to examine differences in strength and function both before and after a cancer diagnosis, and utilizes several objective measures. The study ultimately finds significant age-related declines in measures of strength and function across both groups, but no difference in the prostate cancer cases compared to non-cancer controls. The manuscript is well written and the study is well designed. Overall, this is an interesting study and presents novel data on these measures in older adults with prostate cancer. Only a few comments for the authors.

- How exactly were the non-cancer cases chosen? The methods suggest the frequency matching was weighted by race. Also the discussion says it was age- and race-matched, but I find this is not well explained within the methods and is critically important to the study.

- The lack of cancer stage is a significant limitation. I believe within the HABC dataset there is some information regarding limited vs. metastatic disease, and may want to include this information at least in the patient characteristics table.

- I would also add the androgen deprivation information into table 1 as part of the description of the cohort. How was the use of ADT attained? May be helpful to look at the overall % receiving ADT as part of prostate cancer therapy, rather than just having the range in proportions for any given year. I realize this sub-population may have been too small to examine, but any analyses focused on this group would be of great interest (which I believe the authors well-recognize).

- Why do the authors think there were baseline differences in HABCPPB, grip strength, and quad strength between cases and controls? May be worth further elaborating in the discussion.

- As there are several other therapies utilized in prostate cancer treatment other than androgen deprivation, I would be sure to explain the lack of treatment information as a limitation within the discussion.

Minor comments

- Typically manuscripts are written in the past tense “i.e. ‘The aims of our study were…’ etc.”, but I leave that to the discretion of the authors/journal staff as otherwise the manuscript is well written.

- On page 15, line 74, there is a stray 2 after the word found

**********

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Reviewer #1: No

Reviewer #2: No

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20 Jan 2020

January 20th, 2020

Justin C. Brown, PhD

Academic Editor, PLOS ONE

Dear Dr. Brown and Reviewers:

We thank you for the positive feedback on our manuscript and we appreciate the opportunity to respond to and address the areas of concern. Our point-by-point responses and details of changes are below. We have highlighted the changes in the revised manuscript.

Journal Requirements:

1. When submitting your revision, we need you to address these additional requirements.

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Response: Thank you for the guidance, we believe our manuscript complies with your style requirements.

2. Thank you for including your ethics statement:

"The institutional review boards of the study sites approved the protocol."

a) Please amend your current ethics statement to include the full name of the ethics committee/institutional review board(s) that approved your specific study.

Response: We have now added the more detailed statement to include the full name of the IRB’s that approved our study. This is in line with how the HABC Study ethics statements have been described in other recently published PLOS ONE manuscripts.

Text in the methods now reads: “The Institutional Review Boards at the University of Pittsburgh, the University of Tennessee and the University of California, San Francisco approved the Health ABC protocol.”

b) Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”).

For additional information about PLOS ONE ethical requirements for human subjects research, please refer to http://journals.plos.org/plosone/s/submission-guidelines#loc-human-subjects-research.

Response: Done

3. Thank you for stating in your Funding Statement:

"Dr. Lucas’s work on this project was partly supported by a National Cancer Institute training grant (R25 CA122061). Dr. Klepin receives support from Wake Forest University Claude D. Pepper Older Americans Independence Center (P30-AG21332). Dr. Isom is supported by National Cancer Institute’s Cancer Center Support Grant award number P30CA012197 issued to the Wake Forest Baptist Comprehensive Cancer Center. This research was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, and NINR grant R01-NR012459. This research was funded in part by the Intramural Research Program of the NIH, National Institute on Aging. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.".

i) Please provide an amended statement that declares *all* the funding or sources of support (whether external or internal to your organization) received during this study, as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now. Please also include the statement “There was no additional external funding received for this study.” in your updated Funding Statement.

ii) Please include your amended Funding Statement within your cover letter. We will change the online submission form on your behalf.

[Note: HTML markup is below. Please do not edit.]

Response: We have updated the funding statement to include all funding sources of support during the study.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for the opportunity to review this manuscript. The purpose of this research was to compare longitudinal changes in strength and physical function between prostate cancer survivors and matched controls in a cohort of community living older adults. A large body of literature supports muscle mass and muscle strength loss after treatment for prostate cancer; however, very few studies have captured objective assessments of strength and function prior to diagnosis. This research provides valuable insight into trajectories of change in these facets of aging both prior to and after a prostate cancer diagnosis among older men. Comments and suggestions are detailed below.

Introduction:

•The introduction of this study does a sufficient job introducing the rationale behind the strength and physical function concerns with prostate cancer; however, it focuses on the specific effects of ADT. This does not seem to carry through the rest of the paper in terms of analyses. It would be beneficial for this section to expand to include the effects of prostate cancer more broadly, rather than those of ADT.

Response: We agree with the reviewer and have now expanded the introduction and rationale for the study, to include more than just a description of the specific effects of ADT. As part of this expansion we have included information relative to the point made below regarding the effects of depressive symptoms on strength and physical function.

•It’s unclear how depressive symptoms are associated with strength and physical function for inclusion as a covariate. Please elaborate on the effects of depressive symptoms on strength and physical function in this population.

Response: A recent study has examined the relationship between depressive symptoms and grip strength in the NHANES data for adults over 60 years of age (Brooks, et al. 2018). Findings showed that increasing levels of depressive symptoms were associated with diminished grip strength. Other recent studies have found relationships between depression and physical functioning among older adults in nursing homes (Kvael, et al. 2017) and in men and women with and without Alzheimer’s disease (Watts, et al. 2018). The rationale for these linkages is that older adults who are depressed may tend to limit their engagement in previously important activities that may further result in declining functional status. We have added this to the introduction (page 1, paragraph 1).

Methods:

•The authors may consider separately defining muscle strength and physical function. The methods section would be strengthened by specifically describing how each construct was operationalized.

Response: We have separately operationalized muscle strength and physical function constructs.

•The authors may consider defining self-reported physical function in the previous section “muscular strength and physical function” with the other measures of physical function rather than with the covariates.

Response: We have decided to keep the self-reported measures of functional status under the section on covariates. This decision is based on the rationale that we are separating the influence of perceived capacity to engage in these tasks from the actual measures of strength and physical function.

•It is surprising that a cohort study focused on body composition would only include body mass index in an analysis of muscle strength and physical function. It seems that muscle mass would be an important factor in this relationship, and it is unclear why this would be omitted.

Response: The reviewer is correct. The Health ABC study did include more precise measures of body composition. CT scans were only performed at years 1, 6 and 10 and 11; however, DXA scans for assessing body fat % and lean body mass did occur at years 1-6, 8 and 10, therefore we have now included body fat % and lean body mass from those scans where data were not missing. These data are now included in Table 1, and S1-S4 Tables.

•The author may consider including details on which measures were continuous or categorical for analysis.

Response: The requested information on variables is included in all tables. Variables shown as Yes or No are categorical while those with a mean (SD) after the variable name are continuous variables.

•Please include methodology for “placement” into decreasing, consistently low, consistently high, and increasing group.

Response: On page 7, paragraph 1, we have expanded upon the description of how cases were placed into groups.

The relevant text now reads:

“To assess the association of relevant covariates with trajectories of upper body strength (grip strength), lower body strength (quad strength) and gait (20m usual pace gait speed), we placed PC cases into 1 of 4 groups for each outcome as follows: group 1 - decreasing; group 2 – consistently low; group 3 – consistently high; group 4 - increasing. Cut offs for determining a meaningful change (±) and the groups men were placed into (decreasing, consistently low, consistently high or increasing) are shown in Table 3 and were based on currently published literature, except in the case of quad strength (a 1.0 standard deviation (SD) was used).”

•Please clarify the use of baseline versus index visit results. The authors may consider including more detail on the index visit (e.g. time since baseline visit).

Response: First, we presented baseline characteristics to examine the difference or similarity of cases to control prior to prostate diagnosis. Second, under Results in paragraph 1, page 10 we have added text to describe the Table S1 showing patient characteristics at the index visit. We have also added the following text.

“S1 Table shows sample characteristics at index visit (last visit before diagnosis, including a breakdown of the proportion of patients and matched controls who had their index visit in years 1 (baseline), 2, 4, 6 and 8, which ranged from 9% in year 8 to 33.35% in year 2.”

Results:

•Please provide data on the number of participants at each visit included in this analysis.

Response: As mentioned under the previous point. S1 Table shows the breakdown of identified cases and matched controls by study visit/year.

•Please include the HABCPPB acronym definition in the notes for Table 1.

Response: Done

•If available, please provide descriptive data on prostate cancer diagnoses (Gleason score, treatment type).

Response: Unfortunately the HABC study was not focused on cancer outcomes, therefore limited clinical data for the purposes of describing prostate cancer diagnoses exist. Exceptions were adjudication of cancer diagnoses and the medications list, which we used to identify ADT.

Discussion:

•Please provide further rationale for cases’ preservation of upper body strength as compared to controls. (paragraph 1, page 13)

Response: We have provided further rationale for the preservation of upper body strength. The text in paragraph 1, page 14 now reads:

“Unexpectedly, the overall rate of decline for grip strength was slower in men with PC compared to men without cancer, which may be a result of the fact that PC cases had significantly greater grip strength than controls at study baseline and at index visit unlike for other measures of strength and function.”

•Please consider discussing the sensitivity of measurement techniques used to assess lower body strength. Many studies have found differences in upper body strength, but not lower body. The authors may consider referencing Cheung, 2014. (paragraph 2, page 13)

Response: We have now added a brief discussion regarding sensitivity of measurement. The text reads:

“Previous studies examining upper and lower body strength changes among PC patients (both receiving and not receiving ADT) have found mixed results. This may relate to the specific tests being used or the time frame across which patients were tested. For example, studies using maximal leg press have found no differences in strength while those examining leg extension have found differences (Cheung, 2014).”

•It is unclear if the observed declines in function have more to do with age-related decline than with cancer diagnosis. Please elaborate. (paragraph 1, page 14)

Response: We believe in this cohort of well-functioning older men, that the observed declines are predominantly due to age-related changes and not to cancer diagnosis per se. This has been added on page 14 paragraph 1.

•The authors state that resistance exercise should be utilized to maintain muscular strength in those treated with ADT. Given that the authors stated the proportion of patients treated with ADT appeared lower than previously reported prevalence rates, this conclusion extends beyond this scope of these results. Please consider revising this statement. (paragraph 3, page 15)

Response: We have removed the above statement from our conclusions based on the limited data we have presented.

•The authors include body mass index as a limitation of this study; however, other publications from this cohort include DXA. It is unclear why the authors chose to not include these measurements and instead used an assessment that is known to be a limitation to this study. (paragraph 2, page 15)

Response: We have now included all DXA measures of body fat % and lean body mass where possible and removed the statement of BMI as a limitation.

•The statement regarding older prostate cancer patients contradicts the previous statement that older patients did not fare worse than younger patients provided they were healthy at baseline. Please revise. (paragraph 2, page 14; paragraph 3, page 15)

Response: we have revised the above referenced statements to reflect that: first, among men with PC, increasing age was the factor most associated with declines in function; second, we clarified that in contrast to our hypotheses, men with PC did not experience accelerated declines in physical function compared to men without cancer.

Reviewer #2: The present study by Lucas et al describes the trajectories in muscular strength and physical function in older men with prostate cancer compared to a matched sample of non-cancer controls from within the Health ABC dataset. The study utilizes a unique data source (the HABC cohort study) to examine differences in strength and function both before and after a cancer diagnosis, and utilizes several objective measures. The study ultimately finds significant age-related declines in measures of strength and function across both groups, but no difference in the prostate cancer cases compared to non-cancer controls. The manuscript is well written and the study is well designed. Overall, this is an interesting study and presents novel data on these measures in older adults with prostate cancer. Only a few comments for the authors.

- How exactly were the non-cancer cases chosen? The methods suggest the frequency matching was weighted by race. Also the discussion says it was age- and race-matched, but I find this is not well explained within the methods and is critically important to the study.

Response: Thank you for catching this discrepancy. The description in the methods is accurate and the cases and controls were identified by frequency matching, weighted by race, to randomly assign an index visit for the non-cancer controls at a ratio of 4:1 for a total analytic sample of 585 men. We have removed the text in the discussion referring to age-matched.

- The lack of cancer stage is a significant limitation. I believe within the HABC dataset there is some information regarding limited vs. metastatic disease, and may want to include this information at least in the patient characteristics table.

Response: We were unable to identify any information regarding cancer stage, including the limited vs metastatic disease. Given the low number of patients in our cohort with ADT (4 patients) we believe most were likely early stage disease, but we cannot verify that.

- I would also add the androgen deprivation information into table 1 as part of the description of the cohort. How was the use of ADT attained? May be helpful to look at the overall % receiving ADT as part of prostate cancer therapy, rather than just having the range in proportions for any given year. I realize this sub-population may have been too small to examine, but any analyses focused on this group would be of great interest (which I believe the authors well-recognize).

Response:

Over the course of all the visits there were 17 instances of subjects using 4 ADT drugs (based on the codes for the medications list of the study: Leuprolide, Goserelin, Buserelin, Nafarelin). These instances were for 12 unique people and only 4 of these people are included in our dataset (all 4 are in the cancer group). These 4 had an index year prior to the drug appearing in their records (i.e. index year = 2 and medication found in year 3). Each only has one visit (1 year post index visit for 3 participants and 2 years post for the other) with the drug in their record with all having at least 1 visit after the drug was recorded where it was no longer one of their listed medications. Due the small numbers we are unfortunately unable to conduct any further analyses using ADT as a sub-population. This has been added to page 10, paragraph 1.

- Why do the authors think there were baseline differences in HABCPPB, grip strength, and quad strength between cases and controls? May be worth further elaborating in the discussion.

Response: One possibility as to why the cases and controls may have differed in baseline measures of grip strength, quad strength and HABCPPB may be the relatively smaller number of PC cases compared with controls, reflected by less variability in the control group. While these differences were significant, they no longer existed by the index visit and the difference was still within the cut off for meaningful change, as used to place men into groups (decreasing, consistently low, consistently high or increasing).

- As there are several other therapies utilized in prostate cancer treatment other than androgen deprivation, I would be sure to explain the lack of treatment information as a limitation within the discussion.

Response: We have added the lack of treatment information as a limitation. (page 16, paragraph 3)

Minor comments

- Typically manuscripts are written in the past tense “i.e. ‘The aims of our study were…’ etc.”, but I leave that to the discretion of the authors/journal staff as otherwise the manuscript is well written.

Response: We have corrected instances of incorrect tense.

- On page 15, line 74, there is a stray 2 after the word found

Response: removed

Submitted filename: Response to Reviewers_1.20.20.docx

Click here for additional data file.

24 Jan 2020

Trajectories in Muscular Strength and Physical Function Among Men with and without Prostate Cancer in the Health Aging and Body Composition Study

PONE-D-19-28019R1

Dear Dr. Lucas,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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With kind regards,

Justin C. Brown

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

31 Jan 2020

PONE-D-19-28019R1

Trajectories in Muscular Strength and Physical Function Among Men with and without Prostate Cancer in the Health Aging and Body Composition Study

Dear Dr. Lucas:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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on behalf of

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