Abstract:
A method and an apparatus for estimating bone age by at least one acoustic signal in an ossification-actuated skeletal structure. The apparatus includes an acoustic transmitter and an acoustic receiver positioned facing each other so that the structure is positioned between them. The structure has at least two bones. The transmitter is adapted for transmitting a signal to cross the structure transversely. An electronic moveable gantry is provided for adjusting the position of the acoustic transmitter and the acoustic receiver in relation to the structure. A computer system is enabled to perform one or more functions to position the moveable gantry; transmit the signal by the transmitter; control the signal transmitted by the transmitter; receive the transmitted signal by the receiver; and estimate bone age responsive to the received signal by at least one bone age calculation formula.

Description:
RELATED APPLICATION 
     This application is a continuation of PCT Application PCT/IL01/00683, filed Jul. 24, 2001, which designates the United States. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to assessing bone age using ultrasound. 
     BACKGROUND OF INVENTION 
     Bone age assessment in growing subjects is a well-known diagnostic tool that is especially useful in predicting stature and/or growth problems in children, teenagers and adults. 
     Many methods of assessing bone age are based upon radiographic analysis, such as the Greulich and Pyle (GP) method (Greulich W W, Pyle S I, Radiographic atlas of skeletal development of the hand and wrist, 2 nd  ed. Stanford Calif., Stanford University Press, 1959.) and the Tanner and Whitehouse (TW2) method [Tanner, J M, Whitehouse, R H, Marshall, W A, et al. “Assessment of skeletal maturity and prediction of adult height” (TW2 method). NY, Academic Press], both of which assess bone age by the radiographic presentation of the bones of the wrist and hand. In the Greulich and Pyle method a comparison is made between the child&#39;s radiograph and the corresponding standard in the Greulich and Pyle atlas. In the TW2 method  20  bones in hand and wrist are scored according to their stage, thus producing a total score for which a skeletal age may be read directly from the tables. 
     These methods present problems of accessibility as X-ray units are often available only in secondary care centers such as hospitals. Additionally, ionizing radiation is undesirable in elective procedures, especially to children. 
     Allessandro Castriota-Scanderbeg et al., in “Skeletal age assessment in children and young adults: Comparison between a newly developed sonographic method and conventional methods,” Skeletal Radiology 1998 27:271-277, propose a method for assessing skeletal age using ultrasound imaging measurements of the thickness of femoral head articular cartilage. In this method, a non-cartilage structure in an ultrasound image, an epiphysis, is linearly measured along a cross sectional plane without regard to structural aspects such as bone density. Further, this method is inaccurate and likely requires an imaging specialist for its administration, detracting from its cost-effectiveness. 
     Chalana et al. U.S. Pat. No. 5,605,155 uses ultrasound images for the measurement of fetal head structure to predict fetal head size. Hechard Patrick, FR 2768322 uses X-rays or ultrasound to measure the thickness of the epiphysis and metaphysis of a bone to establish an index used for assessing a “Ratio of Residual Growth.” Holmberg, U.S. Pat. No. 6,135,960 proposes using ultrasound transducers placed in a Cartesian coordinate system for characterizing objects within the body. The above publications assess object boundaries utilizing dimensional ultrasound imaging techniques without regard to structural aspects such as bone density. 
     Ultrasonic methods of bone density measurement are known. For instance, according to prior art ultrasound measurement systems, (for example, WO 00/28316 and U.S. Pat. No. 5,564,423, the disclosure of which are incorporated herein by reference), ultrasound is used to determine the density of a non-cartilage osseous structure. 
     Thus use of backscatter attenuation to determine bone density is described by Wear, K A and Garra, B S, “Assessment of bone density using ultrasonic backscatter”,  Ultrasound Med Biol,  1998 June; 24(5):689-95. 
     Langton, et al. in “Quantitative Ultrasound” Chapter 17, p. 311-312, measure bone&#39;s speed of sound and broadband ultrasound attenuation in children using the center of the posterior portion of the Calcaneal, specifically so the ultrasound signal does not pass through the Calcaneal growth plate. This measurement area begins ossification prenatally so that this method estimates bone&#39;s speed of sound and broadband ultrasound attenuation based upon non-cartilage properties. 
     SUMMARY OF THE INVENTION 
     An aspect of some embodiments of the invention relates to estimating bone age from acoustic signals of ossifying structures. 
     In an exemplary embodiment of the present invention, bone age is estimated by measuring an acoustic velocity in cartilage structures that are in the process of ossifying wherein the velocity is expected to increase as a function of the ossification during the human maturation process. Such acoustic signal velocity, for example, is measured in primary ossification centers such as the bones of the wrist or secondary ossification centers such as the distal regions of the ulna and radius. 
     Optionally, two or more acoustic signals of one or more ossification centers are measured to determine bone age. Additionally or alternatively, the ratio of acoustic signals between two or more ossification centers is used to measure bone age. Additionally or alternatively, acoustic signals from structures associated with ossifying structures are used to measure bone age, for example, the fibrocartilage of the pubic symphysis, skull suture ligaments and tooth and mandibular changes. 
     Bone age may be used to predict adult stature or other aspects of the maturation process. Such predictions are based on bone age derived by other methods known in the art. Alternatively or additionally, tracking of ossification in bone is used to detect and/or track the progress of various disease states and/or disorders, with, for instance, a more accurate profile than X-ray evaluation due to its non-ionizing nature, allowing frequent monitoring without harm. 
     In an exemplary embodiment, parameters other than acoustic velocity, such as broadband ultrasound attenuation (BUA) and dispersion of ultrasound signal, are used to estimate bone age, for example by correlating these parameters with the known BA assessment of a group of children. Additionally or alternatively, signals reflected from bone are used to measure bone age, for example, by measuring attenuation of backscatter intensity of the ultrasound signal. 
     Optionally, especially for some types of measures and/or where object boundaries are unclear, a scanning or multi-beam measurement system may be used. Optionally, the acoustic signal provides a spatial measure, for example, indicating a profile of velocity along a bone axis or a radial profile of an ossification center. 
     Different bones, different measures and/or different measurement systems may be used for different situations and/or for analyzing different bone ages or disease states. 
     An aspect of some embodiments of the invention relates to using an existing osteoporosis measurement device, possibly with minimal changes, to assess bone age. In one example, a device designed for measuring osteoporosis in a finger is reprogrammed with a table that associates acoustic velocities with bone ages, rather than with states of osteoporosis. 
     Further, the transducers for measuring acoustic signal are modified specifically for application to growth centers. It is noted that velocity limits used in osteoporosis measurement-devices are designed to obtain measurements from non-growth center areas. 
     There is thus provided, in accordance with an exemplary embodiment of the invention a method for measuring bone age comprising: 
     transmitting an acoustic energy into the body of a subject; 
     receiving an acoustic signal from one or more structures including an ossification-actuated skeletal structure or a cranial structure that changes with age, responsive to said transmitted acoustic energy; 
     analyzing the acoustic signal to determine at least one effect of said structure on said signal; and 
     estimating the age of the structure from said determined effect. 
     Optionally, said ossification-actuated skeletal structure comprises one or more areas undergoing ossification. Optionally, said ossification-actuated skeletal structure comprises one or more bones. Optionally, said ossification-actuated skeletal structure comprises one or more regions of cartilage. Optionally, said ossification-actuated skeletal structure comprises one or more regions of non-cartilage soft tissue. Optionally, said ossification-actuated skeletal structure comprises one or more regions of fibrocartilage. 
     In an embodiment of the invention, said ossification-actuated skeletal structure comprises a region with one or more primary ossification centers. Optionally, said ossification-actuated skeletal structure comprises one or more of: the bones of the wrist, the bones of the palm, the bones of the tarsus, the mandible. 
     In an embodiment of the invention, said ossification-actuated skeletal structure comprises a region with one or more secondary ossification centers. Optionally, said ossification-actuated skeletal structure contains an epiphysis. Optionally said ossification-actuated skeletal structure comprises a region of one or more of: an ulna, a radius, a femur, a bone of a ray of an extremity. 
     Optionally, said receiving comprises utilizing two or more different acoustic signals to provide a measure of bone age. Optionally, said two or more acoustic signals are associated with the same bone. Optionally, said two or more acoustic signals are associated with paths in different bones. Optionally, said two or more acoustic signals are received from the same direction. Optionally, said two or more acoustic signals are received from the different directions. 
     In an embodiment of the invention, said signal passes through said one or more structures including an ossification-actuated skeletal structure. 
     In an embodiment of the invention, said signal echoes from said one or more structures including an ossification-actuated skeletal structure. 
     Optionally, said analysis of said signal is responsive to speed of sound from said one or more structures including an ossification-actuated skeletal structure. 
     Optionally, said analysis of said signal is responsive to broadband ultrasound attenuation from said one or more structures including an ossification-actuated skeletal structure. 
     Optionally, said analysis of said signal is responsive to dispersion of ultrasound from said one or more structures including an ossification-actuated skeletal structure. 
     Optionally, said analysis of said signal is performed, at least in part, in the frequency domain. Optionally, said analysis of said signal is performed, at least in part, in the time domain. 
     In an embodiment of the invention, said analysis of said signal is responsive to attenuation of an ultrasound signal in said one or more structures including an ossification-actuated skeletal structure. 
     Optionally, said analysis is used to predict adult stature. 
     In an embodiment of the invention, to provide an estimate of bone age, said analysis is compared to a database having correlation with one or more of: conventional radiographs, CT images, MRI images and Nuclear Medicine scans. 
     In an embodiment of the invention, said transmitting is by a scanning acoustic signal transmitter. 
     In an embodiment of the invention, said transmitting is by a multi-beam acoustic signal transmitter. 
     Optionally, said receiving provides two or more acoustic signal measures along an axis of said one or more structures including an ossification-actuated skeletal structure. 
     Optionally, said receiving provides two or more acoustic signal measures radially around said one or more structures including an ossification-actuated skeletal structure. 
     In an embodiment of the invention, said analysis is correlated with a known bone age measurement system. 
     In an embodiment of the invention, said analysis is responsive to a formula providing a correlation with a known bone age measurement system. Optionally, is responsive to at least one of speed of sound, broadband ultrasound attenuation, scattering and dispersion of acoustic signal through or from an ossification activated skeletal structure. Optionally, an estimate of bone age is responsive to time of flight of an acoustic signal between two transducers, with said ossification activated skeletal structure being situated intermediate to said transducers. 
     Optionally, separate formulas are used to correlate known bone age data with acoustic signals from males and females. 
     In an embodiment of the invention, said acoustic information is constructed into a database of bone age measurements. Optionally, said database is arranged according to one or more of: sex, ethnic group, geographic location, nutrition and general inheritance. Optionally, said database includes two or more measurements of one or more of said one or more structures including an ossification-actuated skeletal structure. Optionally, said database includes one or more measurements of two or more growth stages from said one or more structures including an ossification-actuated skeletal structure Optionally, said database includes one or more measurements of said one or more structures including an ossification-actuated skeletal structure in two or more populations. 
     Optionally, said received signals are compared to similar signals in a database to predict one or more of predict one or more of adult bone length, density, thickness and resilience and adult stature. Optionally, said received signals are compared to similar signals in a database to indicate a bone-growth related disorder. Optionally, said received signals are compared to similar signals in a database to track the progress of a bone-growth related disorder. Optionally, said received signals are compared to similar signals in a database to track hormone therapy in a growth stature disorder. Optionally, said received signals are compared to similar signals in a database to indicate one or more growth-plate related disease states, including osteogenic sarcoma, slipped growth plate, premature arrest of growth plate growth and inflammation of growth plate. 
     Optionally, two or more acoustic measurements are made on a single subject and entered into said database. Optionally, said two or more acoustic measurements are compared to track one or more growth-related disorders, including precocious puberty, delayed puberty, rickets, kwashiorkor, hypoparathyroidism, pituitary dwarfism and diabetes. 
     Optionally, said two or more acoustic measurements are compared to track treatment of one or more growth-related disorders, including precocious puberty, delayed puberty, rickets, kwashiorkor, hypoparathyroidism, pituitary dwarfism and diabetes. 
     There is further provided, in accordance with an exemplary embodiment of the invention, an apparatus for estimating bone age comprising: 
     an acoustic transmitter and an acoustic receiver positioned on either side of one or more structures including an ossification-actuated skeletal structure; 
     an electronic moveable gantry that adjusts the position of said acoustic transmitter and said acoustic receiver in relation to said ossification-actuated structure; 
     a computer system that performs one or more functions of: 
     positioning of said moveable gantry; 
     controlling acoustic signals transmitted by said acoustic transmitter; 
     receiving acoustic signals from said receiver responsive to said transmitted signals; and 
     estimating said bone age responsive to said received signals. 
     In an embodiment of the invention, said apparatus transmits and receives one or more acoustic signals linearly along an axis through said ossification-actuated structure. 
     In an embodiment of the invention, said apparatus transmits and receives one or more acoustic signals radially around an axis through said ossification-actuated structure. 
     Optionally, said computer system controls said acoustic signal transmitter to provide an acoustic signal appropriate for said ossification-actuated structure. 
     Optionally, said computer system estimates said bone age responsive to one of more of broadband ultrasound attenuation, acoustic backscatter, dispersion of acoustic signal and speed of sound in said ossification-actuated structure. 
     Optionally, said computer system uses an imager to control the position of said acoustic signal receiver and said acoustic signal transmitter. 
     Optionally, said computer system contains a visual display to provide information on said bone age. Optionally, said visual display comprises a graph. 
     Optionally, said computer system is comprised in a computer network. 
     Optionally, said computer system comprises a neural network. 
     Optionally, said computer system compares said received acoustic signal to a database containing information of one or more acoustic signals from one or more structures including an ossification-actuated skeletal structure to provide an estimate of bone age. 
     Optionally, said computer system compares said received acoustic signal to a database containing information of one or more acoustic signals from one or more structures, including an ossification-actuated skeletal structure to predict stature. Optionally, said computer system compares said received acoustic signal to a database containing information of one or more acoustic signals from one or more structures including an ossification-actuated skeletal structure to indicate, track or follow treatment of one or more of: a bone-growth related disorder, a growth plate disorder, and a growth related disorder. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       Exemplary non-limiting embodiments of the present invention described in the following description, read with reference to the figures attached hereto. In the figures, identical and similar structures, elements or parts thereof that appear in more than one figure are generally labeled with the same or similar references in the figures in which they appear. Dimensions of components and features shown in the figures are chosen primarily for convenience and clarity of presentation and are not necessarily to scale. The attached figures are: 
         FIG. 1  schematically illustrates ultrasound measurements of ossifying wrist and arm bones of a 6.5-year-old male, in accordance with an embodiment of the present invention; 
         FIG. 2A  schematically illustrates ultrasound measurements of a portion of ossifying arm, wrist and hand bones of an 11 year old female in accordance with an embodiment of the present invention; 
         FIG. 2B  schematically illustrates a typical graph of ultrasound measurements associated with a path along the bones of  FIG. 2A , in accordance with an embodiment of the present invention; 
         FIG. 3A  schematically illustrates ultrasound measurements of ossifying femora and pelvis of a male, age 14, shown in a radiographic representation in accordance with an embodiment of the present invention; and 
         FIG. 3B  schematically illustrates a pubic symphysis, shown in cross-section and a typical graph of its ultrasound measurement in accordance with an embodiment of the present invention. 
         FIG. 4  is a graph of Bone Age of the hand assessed by ultrasonic multi parameter model as compared to standard X-ray. 
     
    
    
     DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS 
       FIG. 1  illustrates ultrasound measurements of a portion of an arm  150  and a wrist  100  of a 6.5-year-old male in accordance with an exemplary embodiment of the present invention. Each bone of wrist  100  exhibits an ossification center, represented by a crosshatched area, that begins from a central portion and progresses toward the periphery and is referred to as a “primary ossification center”. Bones with only primary ossification centers continue to show changes in acoustic velocity due to increased ossification, increased bone size and/or changes in bone shape through the 15th-19th years. Some bones have additional ossification centers that appear as a strip of cartilage between ossified bone sections, referred to as a “secondary ossification center.” 
     A radius  232 , for instance, contains a secondary ossification center consisting of a cartilaginous growth plate  242  that is situated between an epiphysis  232   b  and a metaphysis  232   a , both of which are ossified. Growth plate  242  first appears in the first postnatal year and ossifies in the seventeenth year in females and in the nineteenth year in males. When a secondary ossification center ossifies, at a later age, epiphysis  232   b  and metaphysis  232   a  fuse together with growth plate  242  that ossifies as well. After the stage when fusion occurs, bone  232  is fully ossified lacking the bands of cartilage and hence is radio-opaque throughout. 
     Ulna  244  similarly contains a growth plate  244   a  that appears in the fifth year in females and in the sixth year in males. Ulnar growth plate  244   a  ossifies in the seventeenth year in females and eighteenth year in males. 
     In an exemplary embodiment, two transducers, such as a receiver  122  and a transmitter  120 , are held in a gantry  174  and placed so that they are in contact with the skin over ulna  244  and radius  232 . The thickness of soft tissue covering the bone is measured or the effect of soft tissue is optionally ignored. Transducers  122  and  120  are positioned so that they transmit along a region  276 , to obtain acoustic signals from ulna  244  and radius  232  and their respective ossification centers. This method of ultrasound transmission is referred to herein as a “through” method. In an exemplary embodiment, the frequency of transducers  122  and  120  is between 300 kHz to 2 MHz. The distance between transducers  122  and  120  is measured using a ruler in which the distance is indicated by a digital readout  182 . 
     Generally, the transducers are controlled and the received signals processed by a controller  142  (e.g., a computer), which optionally includes a display  140  and/or a printer  144 . 
     The acoustic signal from a growth plate, such as ulna growth plate  244   a , is markedly different than that of bone, such as bone  244 . One parameter that can be measured from the obtained acoustic signal is the speed of sound. The distance between transducers is evaluated by digital ruler  182  that is connected to transducers  120  and  122  and the average speed of sound is calculated by dividing the distance between the transducers by the transmission time. Alternatively or additionally the distance between the transducers can be measured using optic or acoustic distance measurement devices. The speed of sound in ulnar cartilage  244   a  is about 1700 meters per second (m/s) while speed of sound in bone  244  is about 2000-4500 m/s, depending on probe localization and age. The transmission time of a signal varies based upon the composition of the structures in the path, which changes with age. 
     An ultrasound signal passing along region  276  will pass through ossified ulna  244 , ulnar growth plate cartilage  244   a , and ulnar epiphysis  248  that is also ossified. It continues through ossified radial epiphysis  232   b , radial growth plate cartilage  242  and ossified radius  232 . 
     The acoustic path in the measurement of speed of sound, for example, is based upon the time of flight of the first acoustic signal to arrive at the receiver. As bone provides the fastest acoustic signal transmission time, the first received ultrasound signal indicates the path with the greatest ossification in a given area. The first ultrasound signal passing through region  276 , for example, will be markedly faster than the first ultrasound signal transmitted in an area along axis  152 , due to the greater amount of ossification in area  276 . 
     The acoustic signal from transducers  122  and  120 , taken along region  276  is sent to a controlling unit  142 , and can be analyzed either locally, such as using a PC, or remotely through a computer network. Such analysis can be immediate or the information can be stored and analyzed at a later time. Further, the analysis may be based upon, for instance, spectral analysis (frequency domain) and/or temporal analysis (time domain), which are known to characterize biological tissue. 
     Other parameters that can be obtained from the acoustic signal include, dispersion and Broadband Ultrasound Attenuation. Dispersion is the slope at which the speed of sound changes with frequency. Dispersion is calculated from the dispersion graph, which is the curve of speed of sound versus frequency, calculated using the phase of each Fourier component of the signal and the distance. In a linear graph, the dispersion value is the slope of the graph and is given in units of m·s −1 ·MHz −1 . 
     Broadband ultrasound attenuation is the value of the slope at which attenuation changes with frequency. Broadband ultrasound attenuation is calculated from an attenuation graph, which is the curve of the logarithm of amplitude of the Ultrasound signal versus frequency, calculated using the amplitude of each Fourier component of the signal and the distance. If the attenuation graph is linear, the broadband ultrasound attenuation is the slope of the graph in units of db·cms −1 ·MHz −1 . 
     In an exemplary embodiment of the invention, a database is established of children of different ages that contains the children&#39;s ultrasound parameters and their bone age as assessed by conventional radiograph. Statistical algorithms, for instance, can be used to correlate the ultrasound parameters and the bone age. 
     In an exemplary embodiment, such an algorithm correlates speed of sound measured from the radius-ulna site, including the metaphysis and epiphysis, to radiographic bone age of the wrist and palm as read by the Greulich and Pyle (see Greulich and Pyle reference noted above) whereby acoustic signals provide the Bone Age (BA) utilizing equations such as:
 
 BA =( SOS− 1566)/27.9 for females  [Eq. 1]
 
 BA =( SOS− 1655)/15.6 for males, [Eq. 2]
 
     Where speed of sound (SOS) is in units of m/s and bone age (BA) is given in years. These formulae, for instance, are valid for an age range of 4-18 years. 
     Multi Parameter Bone Age Assessment 
     In an exemplary embodiment of the invention two or more of the following parameters are obtained from the ultrasound signal are used to provide an estimation of bone age: The distance (D), in mm, between the transmitter and receiver probes, the time (T1) of the arrival of the pulse, calculated by extrapolating a linear fit, as explained below, to the zero-signal level and the time (T2) of receipt of the pulse front, calculated by interpolating the same linear fit as in T1 to the signal half-amplitude level. 
     The linear fit is calculated on several data points around the first half-amplitude level of the first half-wave of the ultrasound pulse. This type of processing requires that the first half wave of the ultrasound signal will not be saturated. 
     In an exemplary embodiment, all three parameters are formulated to calculate two new parameters. C1=D/T1 and C2=D/T2, and uses a linear combination of T1, T2, C1 and C2 as an estimator to the bone age:
 
 BA=a 1· C 1+ a 2· C 2+ a 3· T 1+ a 4· T 2+ b,   [Eq. 3]
 
Where a1, a2, a3, a4 and b are constants in the model. Optionally, this model uses different sets of constants for males and females.
 
     For males: a1=0.35; a2=−0.32; a3=22.7; a4=−22.5; b=−56.8; 
     For females: a1=0.14; a2=−0.13; a3=10.1; a4=−9.8; b=−31.0; 
       FIG. 4  is an exemplary embodiment of a graph  410  of bone age of hand  200 , assessed by ultrasonic multiparameter model as compared to standard X-ray for a population of girls represented by square marks and a population of boys, represented by triangular marks. A y axis  420  represents the bone age calculated by a multiparameter model on graph  440  and an x axis  422  represents the bone age calculated using X-ray on graph  440 , with line  424  demonstrating the best linear fit to the results. Graph  410  demonstrates an R 2  obtained for this correlation of 0.92 where R 2  is the square of the Pearson Correlation Coefficient. 
     Bone Age Estimated From Other Sites 
     Wrist bones  100  comprise a Lunate  102 , a Scaphoid  104 , a Capitate  106 , a Trapezium  108 , a Trapezoid  110 , a Hamate  112 , a Triquetral  114  and a Pisiform  116 . 
     Wrist bones  100  are cartilaginous at birth. Ossification, the process by which cartilage is replaced with bone, begins soon after birth in Capitate  106 . Ossification centers appear in bones on a regular pattern and predictably increase in size until skeletal maturation in the late teens. At age 6.5, most of the bones of wrist  100  contain a region of ossification, represented by the shaded areas, while the clear areas represent regions that are still made up of cartilage. Ossified regions contain calcium that is relatively opaque to X-ray, whereas cartilage does not contain calcium and is not well differentiated over other soft tissue in the body on X-ray images. Thus the shaded areas would appear less dense on an X-ray image on a fairly uniform dense background. 
     The ossified areas of wrist  100  of a 6.5-year-old male are: the Lunate  102   a , the Scaphoid  104   a , the Capitate  106   a , the Trapezium  108   a , the Trapezoid  110   a , the Hamate  112   a  and the Triquetral  114   a . Pisiform  116  will not begin to ossify until the 9 th  to 12 th  year. 
     In an exemplary embodiment of the invention, velocity in wrist  100  is measured by transmitting an ultrasonic signal from transducer  120  to transducer  122  with the transducers  120  and  122  moved so that they transmit and receive along axis  152 . In an exemplary embodiment of the invention, the distance between transducers  120  and  122  is fixed or known. For instance, the distance is measured by ruler  182  with a digital readout that is connected to ultrasound transducers  120  and  122  so that the average velocity through wrist  100  can be determined. 
     As indicated, the measured average velocity is assumed to be a function of the ratio between soft tissue (including cartilage) and ossified or partly ossified tissue. Therefore, the velocity of the acoustic signal is an indicator of bone age. By varying the location of measurement, a more exact estimate may be provided, for example, indicating which particular bones have ossified and which have not. 
     Alternatively or additionally, a statistic of the velocity may be used for bone age assessment, for example, maximal, average or minimal velocity or any percentile or the velocity along a certain line in wrist  100 . In an exemplary embodiment these should be compared to the bone age A formula using one or more of these statistics, or a combination of these statistics is correlated with the bone age as assessed by standard age determination methods such as using the Greulich and Pyle method. Ultimately, the best correlative formula is utilized to provide a standard reference upon which bone age assessment is based. 
     The above-defined methods are in distinct contrast to those of Langton, et al. (“Quantitative Ultrasound” Chapter 17, p. 311-312) who use a portion of non-cartilage Calcaneus as a basis for measuring bone&#39;s speed of sound and broadband ultrasound attenuation as noted above. There is no mention of bone age measurement in this reference. 
     Assessing Bone Age Using Ultrasound Along a Defined Path 
     Using various methods, as described below, bone age can be measured in premature babies, from birth through infancy, childhood, puberty, and teenage years and beyond. For instance, in the second month following birth, Capitate  106  ossification center appears within area marked  106   a  and an acoustic signal traveling through Capitate  106  will travel faster than a signal transmitted immediately following birth when Capitate  106  and all wrist  100  bones are cartilaginous. Even prior to the second month when Capitate ossification center  106   a  appears, the density of parts of Capitate  106  may increase, indicating the amount of time that has passed since birth. Such increase may occur in other bones as well. Thus, by determining the acoustic velocity associated with ossification of infant wrist  100 , bone age can be estimated. 
     Capitate ossification center  106   a  continues to increase in size. At the end of the third month, the ossification center of Hamate  112   a  appears and bone age can be measured based upon the amount of ossification in either bone or both bones simultaneously. Hamate  112  and Capitate  106  continue to ossify, so that when transducers  120  and  122  are put in a position so that the acoustic signal travels along dashed line  162 , it has a higher velocity in the ninth month and a still higher velocity in the second year, providing a measure of bone age. 
     Such measurements soon after birth have application, for instance, in judging crucial maturation progress of premature babies who are born with fetal bone structure according to the month of gestation at which they were born. For example, a premature baby born after 4.5 months of gestation will not have bone ossification of Capitate  106   a  until the equivalent of 9 months gestation plus one month. By measuring premature baby bone age, appearance of ossification in Capitate  106   a , signifies a real age of one-month though the baby is 5.5 months postpartum. Ultrasound, being non-ionizing as is a radiograph beam, is much more suited for making these measurements on pediatric subjects, particularly when multiple measurements are made. 
     With time, other bones develop ossification centers. For instance, Triquetral ossification center  114   a  appears in the third year, while Lunate ossification center  102   a  appears during the fourth year, providing increased ossification density and faster speed of sound for measuring bone age along paths that include these structures. 
     The ossification centers in the Scaphoid ( 104   a ), the trapezium ( 108   a ), and the trapezoid ( 110   a ), appear in the fourth year in females and the fifth year in males and continue to increase in size, providing further acceleration of acoustic signals for measuring bone age. Pisiform  116  ossification center  116   a  appears in the ninth or tenth year in females and the twelfth year in males and continues to increase in size, providing further acceleration of acoustic signals for measuring bone age. 
     Shown for reference only, without ossification, are the bases of metacarpals, associated with Thumb,  124 , index finger  126 , middle finger  128 , ring finger  130  and pinkie finger  132 . 
     In one embodiment of the invention, ultrasound transmitter  120  and ultrasound receiver  122  remain stationary during the transmission and reception of ultrasound signals that pass through two or more bones of wrist  100 . Ultrasound transducers  120  and  122  are positioned in a specific relationship to wrist  100 , such as with both transducers in contact with the skin over one of more bones. In the present set-up, for instance, ultrasound transmitter  120  is set in position near base of metacarpal  132 , at Pisiform bone  116  and ultrasound receiver  122  is set in position near metacarpal  124 , over Scaphoid bone  104 . This position allows a signal to travel along axis  152 , through non-ossified Pisiform  116 , ossified  114   a  and non-ossified portions of Triquetral  114 , Capitate non-ossified portion  106 , and ossified portion  104   a  and non-ossified portions of Scaphoid  104 . The amount of skin and muscle tissue over these structures is small, so the acoustic signal transmitted along axis  152  has a velocity that reflects the amount of ossification along its path. 
     Additionally or alternatively, measurement is made of a single wrist bone. For instance, ultrasound transmitter  120  is positioned on the dorsal surface of the hand, directly over Trapezoid  108 . Ultrasound receiver  122  is positioned on the ventral surface of the hand directly below Trapezoid  108 . The amount of ossification in the bone results in a specific acoustic velocity that provides a measure of bone age. 
     Ultrasound transmitter  120  and ultrasound receiver  122  can be positioned over a variety of individual wrist structures to measure age. For instance, in the second month, over the dorsal and ventral surfaces of Capitate  106  and in the third month over the dorsal and ventral surfaces of Hamate  112 . In addition, both individual bones and multi-bone paths can be measured for determining a bone age single estimate using statistical analysis. The statistical analysis can be performed using discriminant analysis, binaric logistic regression, multinomial logistic regression or neural networks methods. 
     Alternatively, a ratio between the acoustic signal velocity of two ossifying bones (or paths) is used to measure bone age. For instance, at the end of the fourth month, one month after Hamate  112  begins ossification; ultrasound transducers  120  and  122  are positioned over the dorsal and ventral surfaces over Hamate  112  to provide one measure of acoustic velocity. Transducers  120  and  122  are then placed over the dorsal and ventral surfaces of Capitate  106  to provide a second measure of acoustic velocity. These two acoustic signal velocities provide a ratio as a measure of bone age. Alternatively, two or more sets of transducers are used. 
     In an exemplary embodiment transducers  120  and  122  are modified specifically for obtaining measurements from the wrist, with the transducer shape being, for instance, of a size and shape that matches the size and shape of wrist bones  100 . Optionally, the gantry is designed to place the transducers against the skin automatically or manually. For instance one transducer remains fixed in position and the other transducer is moved in relation to the hand to place a standard pressure against the skin. Such a transducer may incorporate a calibrated pressure-sensitive sensor within the head to provide optimal accuracy of pressure. Optionally, the hand is held in a bed that can move up or down in relation to the position of transducers  120  and  122 , so that a standard acoustic path is traced through wrist  100 . An imager may be provided to better locate the path  276  of acoustic signal, either signaling the operator to make positional adjustments of wrist  100  in relation to transducers  120  and  122 , or, optionally, making such adjustments automatically. 
     Optionally, measurement using ultrasound transducers  120  and  122  is repeated at a plurality of locations, for example, locations along a reference line  146  or in a radial fashion according to a reference  148 . Such measurement provides spatial acoustic information of one or more of a plurality of ossification centers from one or more of a plurality of reception and transmission points. Such acoustic velocities provide an acoustic map of wrist  100  for measuring bone age. Additionally or alternatively, two or more such acoustic velocities can be used to provide a ratio as a measure of bone age. Additionally or alternatively, two or more such acoustic velocities are averaged to provide a measure of bone age. 
     In an exemplary embodiment of the invention, spatial information is provided as a profile of velocities. Such a profile may be used, for example, to locate an area of minimum or maximum velocity, to locate an ossified or partially ossified area and/or to detect and/or identify abnormal ossification patterns. Such a profile can be generated, for example, using a computer system that maintains a record of the coordinates of the probes along with acoustic signal measurements. This data is displayed by the computer system, for example, as a 3D graph with 2 spatial axes and one speed of sound axis. Additionally or alternatively, the data provides a basis for directives on the further placement, movement or changes in signal frequency or signal analysis from probes  122  and  120 . In an exemplary embodiment, computer system  142  automatically controls gantry  174  and transducers  120  and  122 . 
     Additionally or alternatively, a first acoustic velocity is measured along one axis such as along line  146  and a second acoustic velocity is measured along another axis such as along line  154  and these values are averaged or placed in a ratio to provide a measure of bone age. 
     Additionally or alternatively to moving transducers, transducer  120  and/or transducer  122  (e.g., receiver and/or transmitter) comprises an acoustic transmission grid that transmits multiple signals at specific time/space intervals. The multiple input and output points provide spatial measurements of the bone velocity and hence the extent and location of ossification and ossification centers. Alternatively or additionally, one or both of transducers  120  and  122  is a phased array beam scanning transducer. 
       FIG. 2A  illustrates ultrasound measurements of a portion of an arm  250 , a wrist  252  and digit structures  254  of an 11-year-old female in accordance with an exemplary embodiment of the present invention. The ossified portions of wrist  252 , comprise a Scaphoid  104   a , Capitate  106   a , Trapezium  108   a , Trapezoid  110   a , Hamate  112   a  and Triquetral  114   a , which show greater ossification than in 6.5 year-old male wrist  100  of  FIG. 1 . Additionally, Pisiform  116  has begun to ossify in region  116   a . Corresponding to these changes, the acoustic signal from each of these bones will show increase in velocity over those of 6.5-year-old wrist  100  illustrated in  FIG. 1 . 
     Secondary growth plates are also seen in the bones of the rays of each digit. A ray  270 , for instance, contains a distal phalanx  226  with a secondary growth plate  216  and epiphysis  226   a ; a middle phalanx  224  with a secondary growth plate  214  and an epiphysis  224   a ; a proximal phalanx  222  with a secondary growth plate  212  and epiphysis  222   a ; and a metacarpal  220  with a secondary growth plate  210  and epiphysis  220   a . Shown for reference, without ossification patterns, are metacarpals and associated rays of thumb,  124 , middle finger  128 , ring finger  130  and pinkie finger  132 . 
     In an exemplary embodiment, ultrasound transmitter  256  and ultrasound receiver  258  are moved along an axis  270 . The transducers  256  and  258  are moved in position so that the signal between them passes from the dorsal to ventral surfaces of portions of radius  232 , Scaphoid  104 , Trapezoid  110 , and through a second ray  218  of digit structures  254 .  FIG. 2B  shows an exemplary graph  260  of such ultrasound measurements taken along axis  270 . Where the y axis represents the speed of sound and the x axis represents the distance along ray  218  in centimeters. 
     As ultrasound transducers  256  and  258  pass end of radius  232 , the velocity of the acoustic signal, shown in graph portion  262 , decreases. As transducers  256  and  258  pass epiphysis  232   b , the acoustic velocity increases, as shown in a graph section  264 , reflecting the presence of increased ossification within the cartilage. However, as the ossification is not complete, signal  264  does not reflect as high a velocity as prior to signal area  262 . 
     As transducers  256  and  258  pass Scaphoid  104  and Trapezoid  110  along axis  270 , a graph area  266  demonstrates a decrease in velocity, reflecting a decrease in ossification in base of Scaphoid  104 . Transducers  256  and  258  pass through second ray  218  of digit structures  254 , passing a metacarpal  220 . As they pass a growth plate  210 , there is a corresponding decrease in velocity indicated by a graph region  210   a . Transducers  256  and  258  pass a proximal phalanx  222 , showing an increased velocity. As they pass a growth plate  212 , there is a corresponding decrease in velocity indicated by a graph region  212   a . Transducers  256  and  258  pass a middle phalanx  224  with an increase in velocity due to ossification. As they pass a growth plate  214 , there is a corresponding decrease in velocity indicated by a graph region  214   a . Transducers  256  and  258  pass a distal phalanx  226  with an increase in acoustic velocity. As they pass a growth plate  216 , there is a corresponding slow down in acoustic signal indicated by a graph region  216   a.    
     Reduced velocity corresponding to the growth plate position will change until fusion when the growth plate becomes ossified. Typically, the length and shape of the bones will continue to remodel and grow in size until fusion is completed. 
     In an exemplary embodiment of the invention, the bone age is estimated by comparing the profile of velocity changes along multiple ossifying structures, such as those values contained in graph  260  to a database of standardized profiles. Alternatively or additionally, the bone age is estimated by comparing the velocity at one or more particular anatomical points (e.g., metacarpal  220 ) to a database of standardized velocities. Optionally, final bone age is an average of a plurality of such bone ages. Alternatively, the bone age is based on an averaging of the velocity at the plurality of points. Additionally or alternatively, the bone age is based on a ratio between average acoustic velocity of a bone, such as metacarpal  220 , and a second bone, such as proximal phalanx  222 . 
     In another example, the average acoustic velocity across the width of a bone, such as metacarpal  220 , and the acoustic velocity through the length of the same bone  220 , are divided to provide a measure of bone age. To provide a measure along the bone length, for example, the finger is bent and measurements are taken along the length of the proximal, middle and distal phalanges either separately or through two or more at along the same axis. 
     In an exemplary embodiment a database is constructed of bone measurements. The database is used to analyze acoustic signals. Extraction of information from the database can be, for example, via matching received signals to similar signal and values contained in the database, or by interpolation. 
     In an exemplary embodiment, the information extracted from the database is used as an aid in diagnosis, e.g. estimating a bone age or a disease state. Additionally or alternatively, the extracted information is used for adult height prediction, e.g. final stature. In an exemplary embodiment, height prediction can be made utilizing any of the known formulae and tables stated above. Such a derivation can be arrived at, for instance, by substituting the ultrasound bone age obtained by quantitative ultrasound in place of the bone age obtained by an X-ray film. 
     In an exemplary embodiment, the database associates one of more of the following items of information with acoustic velocity or acoustic signal parameters: sex, ethnic group, geographic location, nutrition, genetic inheritance. In an exemplary embodiment, the database is created by acquiring acoustic signal measurement in a plurality of subjects, in a plurality of bones, at a plurality of growth stages, and in a plurality of populations. Optionally, the bone age is estimated by comparing acoustic signals to known bone age measurement systems such as those based on X-ray, CT, MRI and Nuclear Medicine. Alternatively to creating a database, the measurements may be used to train a neural network. 
     In an exemplary embodiment, the database is used as an aid in medical diagnosis and for monitoring. For instance, in conjunction with repeated bone age measurements the database monitors growth hormone therapy that is often administered to children who have short stature. Alternatively, the database can be used to diagnose such conditions as precocious puberty or delayed puberty so that appropriate hormone therapy can be administered. In an exemplary embodiment, multiple measurements of a single subject are stored in a personal database. Such a personal database may be used, for example, for tracking changes in bone age over time or in diagnosing bone-age related disorders. Such disorders, for instance, can be related to malnutrition syndromes such as rickets and kwashiorkor. Additionally or alternatively, such a personal database may be used in tracking treatment of metabolic disease states such as diabetes. Additionally or alternatively, such a personal database may be used in diagnosis and/or treatment of endocrine-related growth disorders such as primary hyperparathyroidism or pituitary dwarfism. 
     Alternatively or additionally, the measurement or measurements may be compared to data in a data-base that compares such measurements with one or more of adult bone length, density, thickness and resilience to predict one or more of adult bone length, density, thickness and resilience. 
     In an exemplary embodiment, transducer frequency is between 300 kHz to 5 MHz. When the structures being measured are more superficial, as in digit structures  254 , a frequency closer to 5 MHz can be used as there is less attenuation of the ultrasound signal and a higher signal to noise ratio that improves the quality of signal. Along the mid shaft of the femur, for instance, a frequency near  200  kHz is used, as a higher frequency may be attenuated excessively while going through several centimeters of tissue. 
     When greater clarity of microstructure is desired, such as in spatial radial measurement of the bone growth center, a higher ultrasound frequency, such as 10 MHz or even 50 MHz or higher may be used. With alternative transducer design, higher or lower frequencies can be utilized. 
     In an exemplary embodiment, an existing osteoporosis measurement device, such as the DBM Sonic 1200 ultrasound system by IGEA of Carpi (Mo), Italy, is modified to provide a bone age estimate. In an exemplary embodiment, a database is reprogrammed with a table that associates acoustic velocities with bone ages, rather than with states of osteoporosis. Additionally or alternatively, a gantry  274  and ultrasound transducers  256  and  258  are electronically controlled by computer system  142 . In an exemplary embodiment, parameters such as transducer positional changes and acoustic signal, are automatically effected by the computer system&#39;s analysis of the acoustic signal against an ultrasound bone age database for the purpose of obtaining optimal bone age data from ray  218 . 
     Growth plates, such as growth plate  212 , exhibit patterns of interdigitation with adjacent areas of bone  222  and this interdigitation may exhibit changes that can be used to forecast stature, metabolic bone health and age. In an exemplary embodiment, multiple measurements with transducers  256  and  258  are taken radially while rotating the transducers around a growth plate  212  of bone  222  to provide a spatial map of growth plate  222  interdigitation. 
     Additionally or alternatively, acoustic signals of interdigitation can be used for detecting signs of disease associated with growing bones. Osteogenic sarcoma, for example, is a cancer that often begins from a growth plate such as in the knee. Ossification patterns in a growth plate affected by osteogenic sarcoma generally exhibit differences as compared to a normal growth plate, which differences can support early detection using ultrasound. Optionally, ultrasonic measurements are used for screening for various conditions. 
     Acoustic signals from the radial movement—a movement along line  270 —of transducers  256  and  258  are entered into computing means  142  and can be viewed on visual display  140 , for instance as a graph  260 . Additionally or alternatively, display  140  provides an image of the bone and accompanying data, or a database of information based on sex, race and/or other factors. Such information can be printed on printer  144 . 
       FIG. 3A  Illustrates ultrasound measurements of femora  310  and a pelvis  300  of a male age 14 using the echo method of transducer measurement in accordance with an embodiment of the present invention. Shown in  FIG. 3A  are an illium  320 , a sacrum  322  and an ishium  324  that are shaded to demonstrate ossification. An ultrasound transducer  344  contains one or more receivers and transmitters of acoustic signals arranged, for example, in a grid pattern. Probe  344  is shown sending and receiving acoustic signals to femur  310  to scan a femoral head  312  and a femoral trochanter  314 . Femoral head  312  develops a secondary ossification center  312   a  at six months after birth and fuses with femur  310  at age 14 in females and 17 in males. In backscatter attenuation measurements, ultrasound signal reflecting off a bone produces backscatter, picked up by the receiver in the echo method. The backscatter attenuates according to the density of material from which it is received, so that the bone content of a particular tissue is assessed. Hence, transducer  344  may be used to measure backscatter attenuation to determine the ossification level of the location of growth plates in femora  310 . For example, greater trochanter  314  develops a secondary ossification center  314   a  in the fourth year and fuses with femura  310  at age 14 in females and 17 in males. Ultrasound probe  344  measures bone age based on the backscatter attenuation of an acoustic signal in one or more of these structures to determine age. 
     Additionally or alternatively, probe  344  is rotated along an arc  340  to provide an ossification ratio of femur  310  and pelvis  300  using backscatter attenuation, for instance, as a measure of bone age. Optionally such measurement includes acoustic signal information of a pubic symphysis  328 . Additionally or alternatively, probe  344 , containing both a receiver and transmitter, is rotated fully around pelvis  300  using the echo method of measurement, obtaining information from backscatter attenuation of ultrasound signal. 
     Additionally or alternatively, a receiver probe is placed along line III, on one side of pubic symphysis  328  and a transmitter probe is placed at the opposite end of line III so that Broadband ultrasound attenuation can be measured from the pubic symphysis,  328 . As in other measurements, a ratio between broadband ultrasound attenuation velocities of these structures, using two or more broadband ultrasound attenuation measurements and/or averages of broadband ultrasound attenuation within each structure can be used to measure bone age. 
     In an exemplary embodiment, probe  344  indicates and/or tracks a disease state such as slipped capitus femoris, where femoral head  312  is displaced on femur  310 . Additionally or alternatively, ultrasound probe  344  is positioned over pubic symphysis  328  to give acoustic velocity information. To determine SOS, two or more transducers should be contained in the probe or two or more separate transducers should be used. 
       FIG. 3B  illustrates a cross-sectional diagram of a pubic symphysis  328  along line III-III in a mature male and an associated graph  370  of acoustic backscatter attenuation. Pubic symphysis  328  is made up of an interpubic disc  352  that is fibrocartilaginous hyaline cartilage. One either side is hyaline cartilage  350  and  350   a  and a portion of a pubic tubercle  356  and  356   a . Pubic tubercle  356  is ossified at age 14. 
     In graph  370 , as the acoustic signal measures pubic tubercle  356 , the acoustic backscatter is high due to the ossification content of the bone, corresponding to a region  372  of graph  370 . At hyaline cartilage  350 , the acoustic backscatter decreases as seen in a region  374  of graph  370 , due to the lack of ossification of this structure. At interpubic disc  352  the signal backscatter decreases even further, as seen in a region  376  of graph  370 , as this structure is fibrocartilaginous, with less dense fibers interspersed in the cartilage. 
     At hyaline cartilage  350   a  the signal backscatter increases representing the greater density of hyaline cartilage as shown in an area  378  in graph  370 . At pubic tubercle  356   a , the signal backscatter increases even further representing the greater density of bone as represented by an area  380  of graph  370 . 
     According to T. W. Todd, in “Age changes in the pubic bones,”  Am. J. Phys. Anthropology,  3:285-334 and T. W. McKern and T. D. Stewart, “Skeletal age changes in young American males” Tech Rep. EP 45. Environmental Protection Research Div. Natick, Mass., changes within the pubic symphysis, such as changes in the bony surfaces, occur from the late teens to the fifties and beyond. Similarly, skeletal age is measured by the appearance and changes in the cranial sutures above  25  years of age. (T. W. Todd and D. W. Lyon, “Endocranial suture closure, its progress and age relationship.  Am. J. Phys. Anthropol.  7:325-384). Thus, using acoustic signals in one or more structures that exhibit changes after bone growth has ceased in the long bones of the body, bone age can continue to be measured. Such measurements can also be used to indication the presence of a disease such as acromegaly, a diagnosis that can be confirmed by measuring the amount of somatotropin hormone production in the blood. 
     While the invention has been described with respect to limited number of embodiments, it will be appreciated that many variations, modifications and other applications of the invention may be made. Also, combination of elements from variations may be combined and single elements may be used. Any and all such variations and modifications, as well as others that may become apparent to those skilled in the art are intended to be included within the scope of the invention, as defined by the appended claims. 
     The terms “include”, “comprise” and “have” and their conjugates as used herein mean “including but not necessarily limited to.” 
     It will be appreciated by a person skilled in the art that the present invention is not limited by what has thus far been described. Rather, the scope of the present invention is limited only by the following claims.