INTRODUCTION
Osteoporosis, a skeletal disease having characteristic bone mass reduction and bone micro architecture deterioration including bone fragility and high risk of fractures. Fractures are more prone due to decrease in bone mineral density and has some importance in both men and women [1]. Osteoporosis has become major health problem with the advancement in socioeconomical conditions and delay of humanoid life span. Bone mass maintained by bone resorption and dynamic balance of bone formation, when lost results in osteoporosis[2].
Fastest growing population in the world are elderly age, bone mass decline and risk of fractures increases as age increases. As population longevity in developing countries continues to increase likelihood of osteoporosis will increase in these countries [3].The prevalence of osteoporosis that is reported in women in United Kingdom, France and Germany, United States of America, and Japan, as 9%, 15%, 16% and 38% respectively; whereas in men, United Kingdom, Japan, Canada and France as 1%, 4%, 3%, 8% respectively. In 2000, around 9.0 million osteoporotic fractures were stated, 1.6, 1.7 and 1.4 million of which found at the hips, forearm and vertebral fractures[4]. It was concluded that in Pakistan there are 9.90 million osteoporotic patients (7.19 million are women and 2.7 million are male) and these numbers will increase to 11.3 million in 2020 and 12.9 million in 2050; after conducting the large countrywide study using the quantitative ultrasound in Pakistan[5].
In osteoporosis patients, care of patients and underlying drug development continues to improve with increased understanding of bone loss. In a co-ordinated and continuous fashion old bones are removed by osteoclast and new bones are formed by osteoblast and process is called bone remodeling. With certain diseases and aging among old and new bone incomplete replacement occurs [6]. A new mechanism for osteoporosis recently suggested is imbalance between osteoblastogensis and adipogenesis of mesenchymal stem cells of bone marrow. The comprehensiveness and exhaustiveness of this mechanism is still uncertain [7].
Osteoporosis can be classified in two main categories; primary osteoporosis and secondary osteoporosis. Primary osteoporosis can occur both in males and females but occur oftenly in postmenopausal women, also happens in men’s life later. Use of medications (glucocorticoid, immunosuppressant’s), disease (Cushing’s syndrome, hyperthyroidism), other conditions (vitamin D deficiency and hypogonadism) results in secondary osteoporosis[8]. Primary osteoporosis is the most commonly found type of disease and it has sub types as: post-menopausal osteoporosis or type-I and senile osteoporosis or type-II [9]. At menopause ovarian function reduces that give consequences as limited estrogen production and parallel increasing follicle stimulating hormone. A significant bone resorption and quick bone loss is result of combined effect of estrogen decrease and increase in FSH; this is the basic for onset of post-menopausal osteoporosis [10] .Senile osteoporosis is also called Involutional osteoporosis (type-II) and is related to bone mass loss due to cortical and trabicular bones aging[11]. Secondary osteoporosis is characterized by micro architectural bone changes causes fragility fractures accompanied by underlying disease or medication associated with low bone mass[12] .Medical conditions or treatments that interfere with the attachment of peak bone mass and/or may predispose to accelerated bone loss results in secondary osteoporosis. Secondary osteoporosis is becoming more frequently diagnosed despite of being less common. It shows similar prevalence among men and women[13].
In osteoporosis major component of fragile bone is low bone mass resulting from: (1) A small peak bone mass at young adult hood. (2) At menopause or later ages as increased bone loss. (3) Combination of both.
Peak bone mass and subsequent bone loss is influenced by many factors that are physical in activity, genetic factors, nutritional factors and hormonal factors [14] .Development or appearance of osteoporosis is due to many causes. When cause is natural it is known as primary osteoporosis. Idiopathic osteoporosis develops when cause is unknown [15] .Low estrogen level, genetic predispositions, low body weight, smoking, excessive consumption of coffee and long periods of immobilization are contributing factors towards osteoporosis. Deficiency of calcium, 1.25 dihydroxy vitamin D and proteins are dietary factors which increase the risk of osteoporosis[16]. Many of the nutrients and food components we consume influence bones by various mechanisms that include bone structure alterations, bone metabolism rate, the endocrine system, homeostasis of calcium and other bone active mineral elements. These dietary factors include inorganic minerals (e.g. calcium, magnesium, phosphorus, sodium, potassium and various trace elements), vitamins (vitamin A, D, E, K, C and certain B vitamins) and macronutrients such as proteins and fatty acids increase risk of osteoporosis[17]. Osteoporosis is diagnosed clinically or radio graphically. Low impact fractures or fragility fractures may present with osteoporosis. T-score of -1.25 or below as determined by DEXA scan of the total hip, femoral, neck or lumbar spine is most common method for diagnosis of osteoporosis. BMD can be assessed by quantitative computed tomography by radiation exposure and cost has been limited [18].
The whole population must focus on nutritional and life style changes for prevention of osteoporosis. Increase awareness through patient education about the modifiable risks of osteoporosis is an important primary care role [19] .As described women (especially post-menopausal) are osteoporotic in high ratio, so preventive measures are taken in women to avoid osteoporosis. Ensuring that women reach their peak bone mass (PBM) and minimize bone loss through their early adult years is primary prevention goal in osteoporosis. In women who have osteoporosis or osteopenia by bone density measurement, fracture prevention is basic focus of secondary prevention. In women who have already sustained fractures in osteoporosis, preventing future fractures is tertiary prevention strategy [20].
By assessment of bone mineral density by DEXA scan in vast majority of cases; those at high risks of osteoporotic fractures should be targeted for treatment. The treatment can be started without measuring BMD in people with two or more vertebral fractures and having high risks of future fractures. Goals of treatment are fracture prevention, stabilization and achievement of an increase bone mass, relieving fractures and skeletal deformity and physical function minimization[21] .Bracing, exercise programs, calcium and vitamin D supplementation, fall prevention and kyphoplasty are non-pharmacological therapies for managing osteoporosis and have significant role in fractures minimization [22].Various pharmacological treatments are also available for treatment of osteoporosis. In alphabetic order, bisphosphonates (alendronate, alendronate plus D, risedronate and zoledronic acid) calcitonin, estrogen (estrogen and/or hormone therapy), estrogen agonists, tissue selective estrogen complex, parathyroid hormone (PTH, teriperatide) and receptor activator of nuclear factor kappa-B, ligand inhibitor denosumab; are current FDA approved pharmacological treatment of osteoporosis [23]
Osteoporosis pharmacological treatment comprises of two main classes; antiresorptive agents and anabolic agents. Bone resorption is limited through inhibition of osteoclasts activity by use of anti resorptive agents such as bisphosphonates. Active building of bone mass is promoted using anabolic agents such as parathyroid hormone[24].
Various physiochemical effects on bone salt crystals and biological effects on mineralization and resorption of bones are biological actions of bisphosphonates [25] .Bisphosphonates are reported as most potent and effective inhibitors of bone resorption. Extended use of bisphosphonates in all conditions such as excessive osteoclast-mediated bone resorption such as steroid induced osteoporosis has been reported in clinical use [26].Bisphosphonates discovery and development for the treatment of bone diseases is fascinating story extended over three decades. The bone resorption inhibitors bisphosphonates are “P-C-P” structures i.e. two phosphonates groups attached to single carbon atom. Bisphosphonates are therefore stable analogs of naturally occurring pyrophosphonate compounds helpful in intracellular and extra cellular mode of action[27].
Bisphosphonates as anti resorptive agents are most broadly consumed drugs group for osteoporosis. By inhibiting recruitment of osteoclasts bisphosphonates straightaway diminish the count of osteoclasts and also inhibit osteoclast stimulating activity of osteoblasts. In patients with osteoporosis, bisphosphonates normalize bone turn over, reduce number of bone remodeling unit, restore the balance of bone remodeling, prevent bone loss and deterioration of bone structure and reduce fracture risks.[1] In many clinical trials of postmenopausal women suffering osteoporosis, efficacy of bisphosphonates is thoroughly researched and reported. Large number of meta-analysis of bisphosphonates have been performed but recently adverse effects related reviews are found and few reviews on clinical impact in population for future prevention [28]. Adverse effect such as gastro esophageal irritation was recognized early on with bisphosphonates therapy. Short term adverse effects include: upper GI adverse effects, acute phase reaction, severe musculoskeletal pain, hypocalcaemia, esophageal cancer with oral use and ocular inflammation. Long term adverse effects include: osteonecrosis of jaw, atrial fibrillation, severe suppression of bone turn over and subtrochanteric femoral fractures [29].
In mammals maintenance of calcium homeostasis is central role played by human parathyroid hormone that is an 84-amino acid peptide. The primary mechanism through which this class of drug operates is inhibition of bone remodeling. Decline in remodeling rate have several beneficial effects such as bone density improvement through decrease in remodeling space size, cancellous bone architecture prevention, decrease in resorption cavities number and cortical porosity decrease[30]. Teriperatide is amino-terminal fragment of parathyroid hormone and is a potent bone formation agent. Teriperatide increases the number of osteoblasts and rate of new bone formation by increasing osteoblasts birth rate and preventing osteoblasts apoptosis. Teriperatide is administered parenterally; subcutaneously[31].
Injection site pain and swelling (<3.3% of patients), nausea (8.5%), headache (7.5%), leg cramps (2.6%) and dizziness (8%) are most common adverse effects of parathyroid hormone; Teriperatide. Hypocalcaemia associated with Teriperatide is an uncommon side effect. In less than 1 in 1000 teriperatide recipients allergic reactions including dyspnea, urticaria and chest pain have occurred. In patients with risk of osteocarcoma such as Paget’s disease, teriperatide use should be avoided. Drug should not be use more than two years[32].
Another major cause of osteoporosis is malnutrition. Calcium intake less than 500mg/day contributes to low bone mass, like wise osteoporosis may also be caused by high intake of caffeine, tea, soft drink, sodium chloride, cigarette smoking, protein and alcohol[33].
Large intake of salt is another major risk factor for development of osteoporosis because excretion of sodium and calcium both increased in urine due to excessive salt intake. Salt intake at a level of 9g/day contributes osteoporosis [34].
Like all developed and developing countries, osteoporosis is also very common in Pakistan especially in elderly population. Different treatment options are offered to the patients by their treating physician.