Muscle atrophy and bone loss after 90 days' bed rest and the effects of flywheel resistive exercise and pamidronate: Results from the LTBR study

Abstract

Muscle atrophy and bone loss pose substantial problems for long-term space flight and in clinical immobilization. We therefore tested the efficacy of flywheel resistive exercise and pamidronate to counteract such losses.

Twenty five young healthy males underwent strict bed rest with −6° head-down tilt for 90 days. Subjects were randomized into an exercise group that practiced resistive exercise with a ‘flywheel’ (FW) device every 2–3 days, a pamidronate group (Pam) that received 60 mg pamidronate i.v. 14 days prior to bed rest and a control group (Ctrl) that received none of these countermeasures.

During the study, Ca⁺⁺ and protein intake were controlled. Peripheral quantitative computed tomography (pQCT) was used to assess bone mineral content (BMC) and muscle cross sectional area (mCSA) of calf and forearm. Measurements were taken twice during baseline data collection, after 28 and after 89 days bed rest, and after 14 days recovery. On the same days, urinary Pyridinoline excretion and serum levels of alkaline phosphatase, Ca⁺⁺ and PTH were measured. Pre-study exercise habits were assessed through the Freiburg questionnaire.

Losses in calf mCSA were significantly reduced in FW (Ctrl: −25.6% ± 2.5% Pam: −25.6% ± 3.7%, FW: −17.3% ± 2.7%), but not in the forearm mCSA (Ctrl: −6.4% ± 4.33%, Pam: −7.7% ± 4.1%, FW: −7.6% ± 3.3%). Both diaphyseal and epiphyseal BMC losses of the tibia were mitigated in Pam and FW as compared to Ctrl, although this was significant only at the diaphysis.

Inter-individual variability was significantly greater for changes in BMC than in mCSA, and correlation of BMC losses was poor among different locations of the tibia. A significant positive correlation was found between change in tibia epiphyseal BMC and serum cortisol levels.

These findings suggest that both countermeasures are only partly effective to preserve BMC (FW and Pam) and mCSA (FW) of the lower leg during bed rest. The partial efficacy of flywheel exercise as well as the bones' response to unloading per se underlines the importance of mechanical stimuli. The huge variability of BMC changes, however, suggests that other factors affect changes in whole-bone strength following acute mechanical disuse.

Introduction

Bone loss is well known to occur as a response to immobilization, for example in the paralyzed limbs in poliomyelitis and after stroke [1] or spinal cord injury [2], and in the bones next to the knee after ligament reconstruction of the patella [3]. In all these conditions, bone loss ensues a number of secondary problems, such as fragility of bones, hypercalcaemia [4] and heterotopic ossification [5].

Bone loss from the lower limbs is also known to occur during space flight [6], [7]. At present, that constitutes one of the major obstacles to human long-term space missions [8]. Very similar to real space flight, bone loss of the lower limbs occurs during bed rest [9], [10]. Therefore, bed rest is recognized as a human ground based model to simulate microgravity induced bone loss, and physical de-conditioning in general.

Besides the bone loss, muscle atrophy is well established to occur during unloading, be it in bed rest [9] or partial unloading models [11], in spinal cord injury [12], [13], after stroke or after tendon reconstruction [14]. Muscle atrophy, obviously, leads to reduced levels of force and power development.

We argue that the reduced levels of muscle force development play a causative role for bone loss in the examples given above. The updated physiology in the still-evolving Utah paradigm of skeletal physiology [15], [16], [17], [18] suggests that the most important mechanical feature of load-bearing bones lies in providing and retaining a normal strength relative to the typical peak voluntary loads on a bone. It is now accepted that mechanical stimuli per se evoke an osteogenic response [19]. The largest forces, however, are caused by muscle pull and not by body weight per se. This is because our muscles act with short levers, ranging between 1:10 and 1:2 [20].

Thinking of countermeasures which could prevent bone loss under space flight, but also under clinical conditions, muscle exercise appears to be an intriguing option since it could potentially prevent bone loss and muscle atrophy at the same time. Alternatively, immobilization induced bone loss might be counteracted through the pharmacological inhibition of bone resorption by bisphosphonates. Applying these two to bedridden subjects–provided they are effective–should offer the unique opportunity to discern secondary effects of muscle atrophy from secondary effects of bone loss. We therefore decided to help to design and participate in the Long Term Bed Rest (LTBR) study.