INTRODUCTION:

Osteoporosis is a metabolic bone disorder distinguished by decreased in the density of bone leading to increased fracture risk¹^,². If left untreated it even leads to the mortality of a person. Osteoporosis is becoming a major public health threat globally. The diseases are often silent and known only when fractures occur to a person. The aging population becomes the target of Osteoporosis very easily³. In a developing country like India Osteoporosis is less known among the population⁴. Only when fractures occur people know that they have Osteoporosis. Studies have been reported that bone loss occurs from the age of 30 – 40 in both men and women⁵. Women are more prone to Osteoporosis due to estrogen deficiency. It is reported that in India the life expectancy was calculated as 67 years and it is expected to escalate to 71 years by the year 2025. It was reported, in 2013 that Indian population or either the osteoporotic are had a low bone density⁶.

The main reason behind the prevalence of osteoporosis in India is lack of awareness about the disease. Urbanization has made a major role in popularity of osteoporosis because of the lifestyle changes, lower physical activity, lower sun exposure, and decreased intake of calcium and vitamin D^7,8 reasons behind the bone mineral density in Indian population are difference in gene, insufficiency in nutrition, and the size of skeletal is small^9,10,11. Bone mass is determined by the imbalance between bone formation and bone resorption. Osteoporosis is induced by the inequality of these two activities which are altered by diet, physical activity, hormonal status, cytokines, clinical status, such as diabetic Mellitus, and high intake of glucocorticoid drugs¹². The major types of osteoporosis Inhuman are classified as type 1, type 2 which are further subdivided as post-menopausal osteoporosis, disuse osteoporosis, and glucocorticoid-induced osteoporosis¹³.The pathogenesis of osteoporosis is understood by establishing the various animal model and the pre-clinical testing of the anti-resorptive drugs¹⁴. The requirement for an animal model to simulate the osteoporotic behavior has been always different from that of the pharmacological testing. This review intends to have an idea on the current animal models and their assessment of bone mass and microarchitecture.

ANIMAL MODELS:

Osteoporosis is a gradually developing disease which requires long term study to allow for the response to therapy. The study is more difficult to maintain and time-consuming by natural attrition on the consequence of death. The factors like smoking, alcoholism, and diet which increases the osteoporosis risk^15,16,17,18. The animal model produces more constant experimental material and potential therapies are tested extensively¹⁹. The limitation in the study of osteoporosis can be minimised by selecting the convenient animal model which is associated with human namely time and behavioural variability the well proved large animal and rat data needed by us food and drug administration (FDA) for preclinical assessment of new experiments drug therapy at clinical dose and 5 time the doses^20,21. The designing of a prosthetic device in research is an additional goal which will be performed in the presence of osteoporotic bone²². It is infeasible to test the biological and biomechanical characteristics of an orthopedic implant, bone graft substitute in human clinical research and it can be done by using a large number of animal. The current osteoporosis research model is essential and valuable at this time²³. There is no refined animal model for the study of osteoporosis. Because osteoporosis is a family of disorders negatively altering the human skeletal system. It mimics the several features of human disease because the animal model fights with certain pro and cons. The in vitro analysis of different bone cell types are supportive in responding to answering important questions at the molecular biological level, in several questions concerning intra- and intercellular signaling. The need for animal experiments is reduced by this in vitro analysis. The interaction of various organs system or biomechanical and structural issues in the complex organism are never studied. The ovariectomized animal model is a preferred model in research of bone loss and it is recommended by American food and drug administration²⁴. In osteoporotic research the small animal models especially rodents are well established^{25, 26,27}. The small animals are inexpensive and time consuming compared to large animal. The necessity for housing and handling are of small extent. The approval for the animal ethical committee is lower in contrast to the large animal²⁸.

RAT:

The rat is a frequently used laboratory animal model in the study of osteoporosis, and its acceptance as an animal model has expanded in current years. Due to its availability, low cost to obtain, maintenance rats are preferred. It grows rapidly, has a short life span, and have a distinguished skeleton. In rat skeleton, after many time of transition remodeling follows modeling in different sites includes cancellous of lumbar vertebrae and proximal tibial metaphysis, endo cortical bone of lumbar vertebrae and proximal tibial metaphysis^17,26. Earlier the rat is considered as an inappropriate model as a human skeletal model due to growth of epiphyseal cartilage in male rats¹⁸. In female rats, by age 6-9 months the termination of bone elongation and closure of epiphyseal arise at essential sampling site^21,29,30. At the age of 10 months, the female rat achieves peak bone mass and the periosteal expansion continues^31,32. The adult female has a life span of 21-24 months. It has a considerable life span before and after the accomplishment of peak bone mass. The interior and exterior determinants of peak bone mass by yielding sample from the accumulation of lengthy bone. The estrus cycle in female rats are regular and attain spike level for 18 hours every 4 days³³. The constant diestrus moderately increased slowly in the portion of rats at the age of 12-24 months³⁴. The reduction in cancellous bone is noticed³¹. The OVX rats display most of the features of human postmenopausal osteoporosis³⁵. The toxicity, efficacy studies of the latest pharmacological agents are done in rodents and it is the initial stage followed by validation in other species before the clinical trials in human³⁶. Natural menopause does not exist in rodents, therefore, the OVX model is preferred to produce artificial menopause^37,38. The Haversian system is present in aged rats which result in notable bone loss^{39,40 41}. The osteopenia induced in rat with a low calcium diet by glucocorticoid treatment³⁸.

RABBIT:

Adult rabbits have an osteon system. The change in bone mass in cortical bone are observed by this osteon system. In the investigation of anabolic agents, the rabbit model is considered as effective for osteoporosis because the rate of turnover is high with the prevailing remodeling of bone over the modeling process⁴². Rabbit is less expensive and easy to feed⁴³. Compare to rat it provides more serum sample and is suitable for the study of osteoporosis due to the presence of large bone size. Though it has the large bone size it has less cancellous bone result in inconvenience for densitometry. Eight-month rabbit is required for the study. In cortical and cancellous bone-implant studies the hindlimbs are commonly used. The femur is preferred for the internal fixation studies due to the presence of adequate medullary space. It attains skeletal maturity at early age therefor it considers as a major advantage over the large animal. In spite of positive features, the rabbit and human bone have a notable difference⁴⁴. There are multiple osteoporotic models in rabbit-like by reducing calcium intake, administration of glucocorticoid, bilateral OVX^{45,46,47,48,49}. The bone mineral density is measured in OVX rabbit by utilizing the trabecular bone⁵⁰. The osteoporosis cannot be induced by OVX alone. By the addition of other therapeutic intervention like glucocorticoid administration which increases the BMD loss in bone⁴².

SHEEP:

Sheep are sizeable and have a greater lifespan. It can produce abundant blood sample and the bone tissue. In the study of osteoporosis, the sheep model is considered as a preferable experimental model due to adequate bone size^51,52. The requirement for suitable sheep is increasing. Sheep are huge animal wit appreciable docility. It has a lengthy lifespan and produces an adequate blood sample and bone tissue. The BMD value is differ based on the season but it attains lower value in the winter season. Sheep are an appropriate model in surgical or medical treatment in the study of osteoporosis. Based on US food and drug administration agency not less than two animals species are tested with new osteoporotic agents²⁴. The OVX sheep model is accepted as a larger animal model in osteoporosis. The major advantage of this model was that there structure and metabolism of bone are alike to humans. This OVX sheep model was used in various studies and it takes six months to induce osteoporosis. The bone loss was increased by combining the OVX with glucocorticoid administration and it also reduces the time to induce osteoporosis. The weekly administration of glucocorticoid for over a long period leads to a severe side effect and bone loss^53,54. The side effect is reduced by administration of glucocorticoid monthly further increases the plasma bone remodeling and there is a decrease in BMD.

ZEBRA FISH:

Zebrafish a well-established animal model in recent times has gained much importance in metabolic disorders like Osteoporosis⁵⁵.The embryonic development is fast which was helpful to understand the disease onset, the composition of skeletal in zebrafish looks similar to the human skeleton. Key genes controlling skeletal development are stable across human and zebrafish. Hence zebrafish are used in the study of human gene and demonstrated using the same biomarker⁵⁶. In both organisms for osteoclast and osteoblast function, the biomarker Sp7 and cathepsin K are used. Due to less cost, easy maintenance and short life cycle span with high efficiency in genetic research, zebra fishes are used. A large number of larvae in zebrafish can provide appreciable sample size^57,58. Zebrafish lays hundreds of eggs in each clasp and prompts every week or in short frequencies (intervals). The larvae of zebrafish are transculent and promote in-vitro⁵⁹. Which is favorable for examine and portraying the development in the skeleton. Generating it a productive tool to study skeletal-related disease during the refining process⁶⁰. The skeletal phenotype of both zebrafish larvae and adult fish are identified by developing the live imaging, staining by using calcein, alcian blue, micro CT⁶¹. Many animals have been tested assuring in mimicking osteoporosis in human. For instance, biphosphate treatment in zebrafish possessing high genetic homology and is similar to human GIOP⁶².

DOGS:

Dogs have been used extensively for the human skeletal model in osteoporosis disease. Due to their basic multicellular unit based remodeling. The bone loss is accessible for estrogen depletion in the dog model. Dogs are inexpensive and similar to human. They are monogastric beagles are used in a longitudinal study by using densitometer as an endpoint⁶³. There is about 8-10 % degradation in the density of vertebral bone 8-10 month post ovariectomy. In OVX ca²⁺ restricted beagles the biphosphate was proved⁶⁴. There is an increase in sensation of bone in guinea big rat but not in OVX beagles⁶⁵. It is focused by evaluating the BMD, strength, structure, and turnover of bone. The dogs are dioestrus and have ovulation in twice a year. This has been suspended due to an ethical issue.

FERRETS:

Ferrets are the new animal model for postmenopausal osteoporosis⁶⁶. OVX ferrets show the bone loss in proximal tibia like in rat⁶⁷. It requires less space for housing because of its small size and is periodically polyoestrous. It has a peculiar drug metabolism because they are carnivores. The parathyroid hormone has been studied in ferrets⁶⁸.

MINIPIGS:

The farm pigs have a limiting factor due to their size in research as an animal model. The minipigs are eliminating this problem. It is more expensive and weighs up to 60 kg while farm pigs can weigh upto 150 kg. Mini pigs required less housing space and it is easy to handle. The duration of a reproductive cycle in minipigs are similar to human and it is continuing same as the human. Some features of minipigs skeletal are identical to human⁶⁹. The major advantages of minipigs are it has similar anatomy of the gastrointestinal tract and omnivore’s diet of swine⁷⁰. The cancellous and metaphysical cortical bone is displayed BMU based remodeling. It attains peak bone mass at the age of 2.5- 3 years. The syndrome of spontaneous vertebral fractures is reported in pigs among few animals. While the pigs are considered as quadrupeds and have an increased bone mass and condensed trabecular network than human. Because of their size it enough to receive a prosthetic implant and large blood sampling. The proportional rate of trabecular and cortical bone with that of human and lamellar bone is possessed in swine⁷¹. These model have some advantages such as bone metabolism, estrous cycle, gastrointestinal tract function. But it also has some disadvantage. It is expensive, rare in some areas the handling, housing of a larger farm pig are difficult. The technician, special equipment are required to overcome the difficulties.

GUINEA PIG:

Guinea pig is a favored mammal in research because of its reproductive cycle. Guinea pig instinctively ovulates and also have an actively secreting corpus luteum because of its long cycle⁷³. Guinea pig is inexpensive and requires less space because of its small body size than other larger model. The size of a chicken and rodent prohibit the blood or bone sampling and prevent their use as a model for a human prosthesis. The guinea pig has no importance on bone mass in estrogen deficiency⁷⁴. Therefore guinea pig is an unconvincing model for human Osteoporosis.

ESTIMATION OF BONE MASS AND MICROARCHITECTURE IN RODENTS

RADIOGRAPHS:

2D radiograph is a convenient tool in assessing gross skeletal morphology both in vivo and ex vivo. In mouse model, it is used to evaluate the limb development and the range of motion⁷⁵. Radiographs are generally used to evaluate fracture healing. It is formed by the attenuation along a single scan direction. It is rapid, low cost in imaging of skeleton morphology. The evaluation of qualitative and semi-quantitative are limited⁷⁶.

DUAL ENERGY X-ray absorptiometry DXA:

DEXA is a widely utilized method in osteoporosis research for the determination of bone-related disease in animal and human. DXA scan has obtained approval as a research tool for the determination of fat mass, lean free tissue mass, mineral content in bone, the density of the bone in body composition by in vivo method⁷⁷. It uses the absorption of the two-photon beam and is determined at two various energy level to measure the mineral density of bone. It is the most commonly used method for measuring the mineral density of the bone in small animals in metabolic bone disease research⁷⁸. It is considered as an uncomplicated and quick method when contrast to micro-computed tomography for the investigation of the bone structure quantitatively. It is cost-effective and requires less radiation exposure. It will measure the bone mineral density in the proximal femur and lumbar vertebral region. The only drawback of this imaging is that it cannot differentiate cortical and trabecular bone. In clinical research of small animals, it is used for monitoring the Bone mineral density changes after the intake of certain drugs or any kind of supplement⁷⁹.

Peripheral quantitative computed tomography – Pqct:

Peripheral quantitative computed tomography is a strong technique for non-invasive observing of definite changes in the bone mineral density and cortical parameters in rodents⁷⁹. It is considered a special method as it can produce a separate estimation of the bone mineral content in trabecular and the cortical bone. It can also quantify the geometric properties of the bones with high efficiency and anticipate the mechanical properties. It is used to monitor the appropriate bone changes in rodents with induced diseases⁸⁰. The true potential of pcqt in genetically modified animal the skeletal phenotype is studied and the determination of therapeutic effectiveness by assessing the bone and muscle development in vivo⁸¹.

MICROCOMPUTED TOMOGRAPHY - µCT:

The micro-computed tomography imaging under high resolution has gained much importance in recent times. It is used for assessing the trabecular and the cortical bone. Some commercially available µCT is made with a different purpose of image acquisition, evaluation of the bone structure and reporting the desired outcomes⁸⁰. Bone microarchitecture evaluations in recent times are assessed by using µCT which has replaced the conventional methodology where only two-dimensional images were used and was a time-consuming procedure. The 3D image of the sample was obtained by taking X-ray images at different rotations. With this latest development µCT is found to be potent to determine the effectiveness of the pharmacological interference on bone using 3D structures which provide the vision of bone microarchitecture. The investigation of osteoporosis risk by expressing the bone mass, the strength of a bone and bone density.

CONCLUSION:

The animal model will sustain to be a major tool helps to understand the contribution of a particular gene to demonstrate the peak bone mass and architecture of bone and also the genetic basis for a tendency towards increased bone loss in the appearance of comorbidity factor such as hormonal deficiency. Existing animal model is helpful for modeling differences in metabolism of bone and bone architecture which was induced by specific systemic and local factors. To investigate prevention, etiology, treatment of a certain form of osteoporosis. The well established and approved animal model was suggested. Also, these animal models are temporarily suggested. These recent model have potency but are partially described and vary naturally from the human response, need the accurate choice of age, strain or are adopted by most investigators practically. The animal as osteoporosis model should not be stresses and its potential can be accomplished if care is taken in the selection of species, design of experiment, age and their measurement. The inferior section will result in the misconception of outcome which finally produces harm to patients who suffer from osteoporosis by delaying the advance of knowledge

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Received on 30.08.2019 Modified on 15.10.2019

Research J. Pharm. and Tech 2020; 13(3):1543-1548.

DOI: 10.5958/0974-360X.2020.00280.2