Prof.M.Azizul Kahhar Professor of medicine Dhaka medical college hospital
Deﬁnition :Osteoporosis is deﬁned as ‘a disease characterized by low bone mass and micro- architectural deterioration of bone , leading to enhanced bone fragility and an increase in fracture risk’. The World Health Organization (WHO) deﬁnes osteoporosis as a bone density of 2.5 standard deviations (SDs) below the young healthy adult mean value (T-score ≤ −2.5) or lower. Values between −1 and −2.5 SDs below the young adult mean are termed ‘osteopenia’.
The prevalence of osteoporosis and osteoporosis- related fractures increases markedly with age, reflecting the age-related decline in bone mass and the increased risk of falling in the elderly . One in two women and one in ﬁve men aged 50 years will have an osteoporotic fracture during their remaining lifetime. Caucasian and Asian races are particularly at risk. Osteoporotic bone is more likely to fracture than normal bone at any level of trauma, and a fracture in a person over 50 should trigger evaluation for
Osteoporosis may be either primary or secondary. Primary or physiological osteoporosis has been divided into two main types by some as 1. postmenopausal osteoporosis(Type I) 2.Age-related(senile )osteoporosis(Type II) The most common forms of osteoporosis are senile and post-menopausal osteoporosis Age-related osteoporosis affects men & women of 7o years or older.
Osteoporosis may be localized to a certain bone or region,as in disuse osteoporosis of a limb, or may involved the entire skeleton, as a menifestation of a metabolic bone disease. Bone is constantly undergoing remodeling, with areas of resorption produced by osteoclastic action being replaced by bone laid down by osteoblasts. Osteoporosis results from an imbalance between bone resorption and formation.
Post-menopausal osteoporosis : There is an accelerated phase of bone loss in women after the menopause as a result of oestrogen deficiency which causes uncoupling of bone resorption and bone formation, such that the amount of bone removed during the bone remodelling cycle slightly exceeds that which is replaced . Post-menopausal osteoporosis occurs because of: 1. low peak bone mass 2. accelerated bone loss after the menopause and with ageing 3. a combination of both factor
Secondary osteoporosis :In primary hyperparathyroidism, osteoporosis mainly occurs in post-menopausal women and here it appears that the high levels of PTH increase bone turnover and aggravate the uncoupling of bone resorption and bone formation which already occurs due to oestrogen deficiency. A similar mechanism operates in thyrotoxicosis, driven by raised levels of thyroid hormones. Anorexia nervosa causes osteoporosis through several mechanisms including calcium deficiency, weight loss and hypogonadism, whereas malabsorption predisposes to osteoporosis through calcium deficiency and secondary hyperparathyroidism. Inflammatory diseases cause osteoporosis by increasing bone resorption and suppressing bone formation through release of pro-inflammatory cytokines such as IL-1 and TNF, and similar mechanisms operate in certain types of cancer where a variety of bone-resorbing factors are released by the tumour, including TNF, lymphotoxin and parathyroid hormone- related protein (PTHrP). Release of bone resorbing factors is also thought to underlie the pathogenesis of osteoporosis in Gauchers disease and mastocytosis.
Corticosteroid-induced osteoporosis :It is directly related to dose and duration of therapy. osteoporosis is less likely to occur in patients who are receiving inhaled glucocorticoids, short-term courses of steroids or prednisolone doses of less than 5 mg daily. The risk becomes substantial when the dose of prednisolone exceeds 7.5 mg daily and is continued for more than 3 months. Osteoporosis in men:Osteoporosis is less common in men than in women, and a secondary cause can be identified in about 50% of cases, most notably hypogonadism, corticosteroid use or alcoholism. The pathogenesis is similar to that in post-menopausal osteoporosis, in that testosterone deficiency results in an increase in bone turnover and uncoupling of bone resorption from bone formation. No obvious cause can be identified in 50% of men with osteoporosis and it is likely that genetic factors play an important role in these cases.
Pathophysiology of postmenopausal and senile osteoporosis
The clinical menifestations of structural failure of the skeleton depend on which bones are involved.This include: 1. asymptomatic 2. fragility fracture 3. back pain 4. height loss and 5. kyphosis Osteoporotic fractures can affect virtually any bone, but the most common sites are the forearm (Colles fracture), spine (vertebral fracture) and femur (hip fracture). Sudden onset of severe pain in the spine, often radiating around to the front, suggests vertebral crush fracture. Pain from mechanical derangement, increasing kyphosis, height loss and abdominal protuberance follow crushed vertebrae. Colles’ fractures typically follow a fall on an outstretched arm,causing pain, sympathetic algodystrophy, deformity, and functional impairment.
Fractures of the proximal femur usually occur in older individuals falling on their side or back Multiple vertebral deformities result in spinal deformity (kyphosis), height loss, and corresponding alterations in body shape with protuberance of the abdomen and loss of normal body contours. When taking the medical history, the practitioner should pay careful attention to medication use (especially glucocorticoids), smoking, alcohol intake, dietary calcium intake, and family history of osteoporosis and fractures. The physical examination focuses on height loss, the presence of bone pain or deformity, and signs of anemia, hyperthyroidism, hypercortisolism, malnutrition, and other disorders that cause secondary forms of osteoporosis . Physical examination should include a search for endocrine disease (thyrotoxicosis, Cushings disease, hypogonadism), neoplasia (evidence of weight loss, lymphadenopathy) and inflammatory disease.
Plain radiographs usually show a fracture and may reveal previously asymptomatic vertebral deformities. Bone Densitometry :These include: 1.dual energy X-ray absorptiometry (DXA) : the preferred measurement sites are the lumbar spine and hip. Bone mineral density in typically expressed in gm/cm2of the area scanned . DXA machines give results as T-scores and Z-scores. The T-score measures by how many standard deviations the patients BMD value differs from that of a young healthy control, whereas the Z-score measures by how many standard deviations the BMD deviates from that of an aged-matched control . 2. single-energy x-ray absorptiometry (SXA). 3. quantitative CT, and ultrasound . The World Health Organization has established criteria for defining osteoporosis in postmenopausal white women, based on T score: T score –1.0: Normal. T score –1.0 to –2.5: Osteopenia ("low bone density"). T score < –2.5: Osteoporosis. T score < –2.5 with a fracture: Severe osteoporosis.
INDICATIONS FOR BONE DENSITOMETRY : Low trauma fracture (fall from standing height or less) Clinical features of osteoporosis (height loss, kyphosis) Osteopenia on plain X-ray Corticosteroid therapy (> 7.5 mg prednisolone daily for > 3 months) Family history of osteoporotic fracture Low body weight (body mass index < 19) Early menopause (< 45 years) Diseases associated with osteoporosis Assessing response of osteoporosis to treatment
Routine Laboratory Evaluation: 1. complete blood count, 2. serum and 24-h urine calcium, and 3. renal and hepatic function tests .Biochemical Markers: Bone formation 1. Serum bone-specific alkaline phosphatase 2. Serum osteocalcin 3. Serum propeptide of type I procollagen Bone resorption 1.Urine and serum cross-linked N-telopeptide 2. Urine and serum cross-linked C-telopeptide 3.Urine total free deoxypyridinoline
Additional investigations : 1. serum 25(OH)D and PTH measurement. 2. Levels of sex hormones and gonadotrophins should be measured in men with osteoporosis and in amenorrhoeic women below 50. 3.Transiliac bone biopsy is only required in patients with early-onset osteoporosis of unknown cause or when coexisting osteomalacia is suspected. 4.others: according to clinical suspicion . eg. urinary free cortisol levels or a fasting serum cortisol in Cushings syndrome.
Symptomatic management. New vertebral fractures require bed rest for 1– 2 weeks with strong analgesia and transcutaneous electrical nerve stimulation (TENS) may be helpful. Muscle relaxants (e.g. diazepam 2 mg three times daily), subcutaneous calcitonin (50 IU daily) or a single intravenous infusion of pamidronate (60–90 mg) may be useful for pain relief, and physiotherapy helps restore confident mobilization. Back-strengthening exercises (paraspinal) may be beneficial. Heat treatments help relax muscles and reduce the muscular component of discomfort. Non-spinal fractures should be treated by conventional orthopaedic means. Nutritional interventions. 1. Calcium and vitamin D : Calcium is typically given in doses of 500-1000 mg daily, and vitamin D supplements in doses of 400- 800 U daily. 2. Other Nutrients: such as salt, high animal protein intakes,and caffeine may have modest effects on calcium excretion or absorption.
Lifestyle modifications: 1. Discontinue tobacco & alcohol intake 2. Exercise regularly: a weight-bearing exercise, Thirty minutes of weight-bearing exercise threetimes a week may increase BMD 3. Wear hip protector. Pharmacologic therapies: 1. Bisphosphonates: synthetic analogues of bone pyrophosphate, adhere to hydroxyapatite and inhibit osteoclasts. Alendronate: 70 mg orally once weekly (tablet or solution) Risedronate: 35 mg orally once weekly . Ibandronate sodium:is taken once monthly in a dose of 150 mg orally .
Zoledronic acid: every 12 months in doses of 2–4 mg intravenously over 15–30 minutes. Pamidronate: is an older parenteral bisphosphonate that can be given in doses of 30–60 mg by slow intravenous infusion in normal saline solution every 3–6 months 2. Hormone replacement therapy (HRT) : For oral estrogens, 0.3 mg/d for esterified estrogens, 0.625 mg/d for conjugated equine estrogens, and 5g/d for ethinyl estradiol. For transdermal estrogen, the commonly used dosesupplies 50 g estradiol per day. 3. Selective estrogen receptor modulators(SERMs): Raloxifene, 60mg/d orally. Tamoxifen. 4. Calcitriol (1,25-(OH)2D3): may reduce vertebral fracture rate. 5. Calcitonin: binds to receptors on osteoclasts, and this interaction inhibits osteoclast-mediated bone resorption The usual dose is one puff (0.09 mL, 200 international units) once daily, alternating nostrils.
6. Parathyroid hormone (PTH): works by stimulating bone formation. teriparatide (exogenous PTH analogue ):given by single daily subcutaneous injection of 20 μg over a 12-18-month period. Teriparatide increases BMD by 10% or more.7. Strontium ranelate: it has weak anti-resorptive activity whilst maintaining bone formation. The dose is 2 g daily, given as granules dissolved in water at night. 8. Denosumab: It is a monoclonal antibody that inhibits osteoclast activation by binding to the osteoclasts receptor activator of nuclear factor-kappa B ligand (RANKL). Denosumab is effective at doses of 60 mg subcutaneously every 6 months.Nonpharmacologic Approaches: 1.Kyphoplasty and vertebroplasty are also useful for the treatment of painful vertebral fractures. 2. Measures should be taken to avoid falls at home (eg, adequate lighting, handrails on stairs, handholds in bathrooms). Patients who have weakness or balance problems must use a cane or a walker.
Response to treatment can be monitored either by repeated BMD measurement or by measuring biochemical markers of bone turnover. Changes must exceed ~4% in the spine and 6% in the hip to be considered significant in any individual. The hip is the preferred site due to larger surface area and greater reproducibility. BMD should be repeated at intervals >2 years. If bone turnover markers are used, a determination should be made before starting therapy and repeated 4 months after therapy is initiated. In general, a change in bone turnover markers must be 30–40% lower than the baseline to be significant. If neither BMD nor biochemical markers are available, treatment response can be assessed by monitoring changes in height and the occurrence of clinical fractures.