Metabolic bone disease (Osteopenia of prematurity) is a common problem in premature very low birth weight babies. Preterm neonates are at risk of decreased bone strength and mineralization due to limited accretion of bone mass in utero^1,2 and the severity is inversely proportional to birth weight and gestational age. Significant bone demineralization is seen at term in more than 50% of infants with birth weight of less than 1500 gm and close to 100% of those with birth weight of less than 1000 gm ^3,4.

            From birth premature babies begin the process of physiologic post natal adaptation, which is characterized by an increase in bone remodeling with a progressive increase in marrow cavity size and a concomitant decrease in physical density. This is reflected in lower speed of sound  values on quantitative ultrasound of bone in preterm infants as compared to term infants during early post natal life and decreasing measurements when measured longitudinally over next several weeks. Osteopenia is exacerbated by prolonged parenteral nutrition, feeding with unsupplemented human milk, postnatal morbidity like bronchopulmonary dysplasia and necrotizing enterocolitis and drugs like diuretics, steroids and caffeine⁵.  Preterm infants because of inherent weakness, poor tone, or confinement (nesting) have limited  physical activity which increases bone resorption and decreases bone mineral density.  Though weight bearing physical activity and mechanical strain are considered the most powerful stimulators of bone formation and growth in children, adolescents and adults⁶, the effects of physical activity (spontaneous or passive) on bone strength and mineralization in newborns, in particular premature babies is largely unknown.

            Mechanical strain on bones and joints stimulates bone formation and growth.  Osteoblasts, the cells responsible for bone formation, increase activity in response to mechanical strain in vitro . Given the evidence from studies in older children and adults, regular physical activity programs (range-of-motion exercises) may provide a simple intervention for improving bone mineral content and skeletal growth in preterm infants.  Studies in preterms^11,12,14-18 have compared in the exercise group, range-of-motion exercises with gentle compression, extension and flexion of both upper and lower extremities with each movement done five times at each joint (wrist, elbow, shoulder, ankle, knee, and hip) for five times a week. For the control group, tactile stimulation was provided, i.e., a daily interactive period of holding and stroking but no range-of-motion activity.

 These  protocols were administered for 4 weeks in most of the studies and in one study for 8 weeks. Outcomes included were bone mineralization as measured by absorptiometric x-ray techniques, short-term growth, and biochemical markers of bone metabolism.  The studies by Laurie Moyer- Mileur et al ^{11, 12}  and CM Vignochi et al ¹⁸ were based on short term effects of physical exercise on bone mineral content and density as measured by  absorptiometric  x ray techniques. Where as D. Nemet et al¹⁵  studied the effect of physical exercise on biochemical markers of bone metabolism. Ita Litmanovitz  et al ^16,17 evaluated  short term changes in bone speed of sound (SOS) after a period of physical activity for 4 weeks and 8 weeks respectively . All these studies reported moderate short term benefits on bone metabolism, more importantly outcomes were measured soon after intervention. There was only one follow up study assessing bone mineralization and post discharge growth at 12 months corrected age in infants who had been enrolled in an identical physical activity program during initial hospitalization  which showed no difference in bone mineral content or in body weight though the follow up rate was only 55% in the study¹³. 

The measurement of bone mineralization in the newborn has represented a methodical challenge.  Biochemical parameters like levels of calcium, phosphate and alkaline phosphatase are relatively nonspecific and following sequential levels of alkaline phosphatase rather than a single level is more useful which requires repeated  venipunctures. Standard radiographs can detect bone demineralization when bone mineral density decreases by more than 30% and there is considerable inter observer variability. Dual energy x Ray absorptiometry (DEXA) which is the current standard in whole body mineral measurement, in which other than the risk of ionizing radiation, the equipment is expensive, time consuming, not easily available and is not portable and hence performing a scan involves transportation of infant which is not always feasible and requirement of sedation. DEXA is also limited by the fact that mineral accretion and bone growth are not parallel. This is evident in preterm babies because the mineralized to total bone volume ratio increases continuously during the third trimester of gestation leading to a progressive change in volumetric bone mineral density (BMD)⁷. The variables provided by DEXA (bone mineral content and bone mineral density) are also substantially confounded by the changes in size and shape of the skeleton as well as in the amount of soft tissue occurring during the rapid growth of neonates.

Quantitative ultrasound ( QUS) on the other hand has been proven to be a reliable method to determine bone health⁸.  In this method propagation of ultrasound signal through a medium and  its speed, dispersion and attenuation of signal strength are strongly influenced by the physical properties of the medium. QUS measures the time taken by the ultrasound signal to travel between two transmitters and two receivers contained within the probe. These propagation times are used by a proprietary algorithm to determine the bone speed of sound (SOS) which is expressed as meters per second (m/sec). In contrast to DEXA which measures the bone size and mineral content, QUS is thought to measure parameters of bone structure and strength and is dependent on bone density, cortical thickness, elasticity and microarchitecture. QUS which  is a relatively inexpensive, portable, noninvasive, and radiation free method  has been increasingly used during the last decade.

Studies have shown modest but significant correlations between bone QUS and both total body (r=0.48) and regional (r=0.45) DEXA derived bone mineral density in preterm and term newborns⁹ . The database of normative data for bone status measurement by QUS in preterm and term infants is available¹⁰. Published studies have reported lower SOS values in preterm infants than in term infants during early post natal life and decreasing measurements in preterm infants when measured longitudinally³¹.

             Considering this background a randomized controlled trial comparing physical exercise  and no exercise in preterm babies born at less than 35 weeks gestation and assessing the strength of bone as assessed by quantitative ultrasound  at term age would be relevant . In all the previous studies mentioned earlier, physical exercise was executed by a trained health worker. In the study by Sari Goldstein Ferber mothers were able to achieve same weight gain after executing physical exercise themselves as that of trained professionals, allowing cost-effective application of the treatment within neonatal intensive care unit¹⁹. Similarly study by L J Moyer Mileur demonstrated that physical activity program administered by infants own mother was equally effective as therapist administered physical activity in promoting greater bone growth  and mineral  acquisition in preterm VLBW infants ³².  In our study mothers will be trained to do range of motion exercises till corrected term age which indirectly might add to early stimulation leading to better neurodevelopmental outcome in addition to better bone strength and anthropometric parameters.