Osteoporosis

Osteoporosis

1. OSTEOPOROSIS Dr. Navin Adhikari

2. INTRODUCTION Osteoporosis is a skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture . World Health Organization (WHO) provided a practical definition of osteoporosis as a bone mineral density (BMD) of below 2.5 SD of the young female normal mean . Who has defined osteopenia as a T-score at the femoral neck of between – 1.0 SD and –2.5 SD below the young female adult mean. Although osteoporosis (a term used to define decreased bone mass per unit volume of anatomical bone) has become synonymous with decreased bone mineral density (BMD), this feature is not always present.

3. Factors contributing to decreased strength Low bone mass Small bone size, Unfavorable macroarchitecture ( eg , increased length of the femoral neck), Disrupted microarchitecture cortical porosity, Decreased viability of osteocytes

4. RISK FACTORS Age Low body mass index (BMI) Excessive alcohol intake (daily intake or >10 servings per week) Current smoking Chronic corticosteroid use History of prior fractures History of falls within the past year, History of cerebrovascular accident, and Diabetes Mellitus

5. Ty p es Primary and Secondary types Primary Osteoporosis Type I primary osteoporosis has been called postmenopausal osteoporosis because it affects many more women than men associated with the dramatic loss of estrogen . Active trabecular bone is lost . Vertebral fractures are more common. Type II primary osteoporosis is associated with ages 70 years in both sexes and affects both trabecular and cortical bone . Therefore both vertebral and hip fractures occur in such patients.

6. CAUSES OF SECONDARY OSTEOPOROSIS Endocrine diseases – Hypogonadism , delayed puberty, estrogen deficiency, hypercortisolism hyperthyroidism, hyperparathyroidism, vitamin D deficiency, growth hormone deficiency Diabetes mellitus (type 1 and 2) Gastrointestinal diseases – Malabsorption syndromes ( eg , celiac disease, postoperative states), Inflammatory bowel disease, Cirrhosis of liver. Hematologic disorders – Multiple myeloma, Chronic hemolytic anemia, Systemic mastocytosis

7. Connective tissue diseases – Osteogenesis imperfecta , Ehlers- Danlos syndrome, Marfan syndrome and Homocystinuria Drugs – Alcohol, Heparin, Glucocorticoids Thyroxine , Antiseizure medications, Gonadotropin -releasing hormone analogs, Cyclosporine, Chemotherapy, HIV medications ( eg , tenofovir ) Miscellaneous – Eating disorders ( eg , anorexia nervosa), Hypercalciuria , Immobilization )

8. CLINICAL FEATURES No clinical manifestations until there is a fracture. Vertebral fracture is the most common clinical manifestation of osteoporosis Hip fractures are also common Distal radius fractures ( Colles fractures) The pain from a vertebral compression fracture is variable in quality and may be sharp or dull aggravated by sitting, spine extension, Valsalva maneuver , and movement and mostly assosiated with sleep disturbance.

9. Acute episodes of pain following a vertebral body fracture usually resolve after four to six weeks, but pain may persist for longer periods (many months) On physical examination, tenderness upon palpation and percussion of the corresponding spinous process and paravertebral structures. kyphosis ("dowager hump") may be an indicator of multiple vertebral compression fractures .

10. DIAGNOSIS  Clinical diagnosis in presence fragility fracture , particularly at the spine, hip, wrist, humerus , rib, and pelvis or T-score ≤-2.5 standard deviations (SDs) at any site based upon bone mineral density (BMD) measurement by dual-energy x-ray absorptiometry (DXA). (WHO ) Fragility fractures are those occurring spontaneously or from minor trauma , such as a fall from a standing height or less. F ragility fracture common sites are spine, hip, wrist, humerus , rib, and pelvis.

11. ISCD criteria Postmenopausal women and men ≥50 years – The ISCD advises that the WHO criteria be used in postmenopausal women and in men age 50 years and older. Premenopausal women and men <50 years – The ISCD advises that the WHO criteria not be used in premenopausal women or men under age 50 years, because the relationship between BMD and fracture risk is not the same in younger women and men. Children – The WHO classification should not be used in children (male or female under age 20 years), Z-scores, not T-scores, should be used, since it is not appropriate to compare the BMD of someone who has not yet achieved peak bone mass with that of an adult who has. Osteoporosis can be diagnosed in children based on the presence of a vertebral compression fracture, or a Z-score <-2 in combination with a significant fracture history ( eg , two long bone fractures before age 10 years or three long bone fractures before 19 years)

12. DIFFERENTIAL DIAGNOSIS Osteomalacia Bone malignancy Potts Spine Osteonecrosis Physical abuse

13. FRACTURE RISK ASSESSMENT TOOL (FRAX) Estimates the patient’ s ten-year probability of sustaining a hip or major (i.e., hip, clinical vertebral, proximal humerus or forearm) osteoporotic fracture . permutation is country-specific takes into account the patient’s age, weight, height, and seven risk factors: a history of hip fractures in one of the biologic parents, a personal history of fragility fractures, cigarette smoking, alcohol abuse, rheumatoid arthritis, corticosteroid therapy, and secondary osteoporosis

14. LIMITATION AND ADVANTAGES Limitations are risk factors are dichotomized and have to be answered in a yes/no manner, no assessment of severity of risk factor , cant be used for follow up. One of the advantages of FRAX is that it can be calculated without BMD and therefore can be used to identify patients who would need a DXA scan.

15. BMD  Bone mineral density (BMD) testing is a widely available clinical tool to diagnose osteoporosis predict fracture risk, and monitor response to therapy. conventional radiography, dual-energy x-ray absorptiometry (DEXA), quantitative computed tomography (QCT), and high-resolution imaging techniques DXA is the best method for monitoring changes in BMD over time because of a strong correlation between mechanical strength and BMD measured by DXA. Contraindications of DXA pregnancy.

16. Skeletal site selection  — The World Health Organization (WHO) recommends that the international standard for diagnosis of osteoporosis be made using the T-score measured by DXA at the femoral neck . However the International Society for Clinical Densitometry (ISCD) suggest that the diagnosis of osteoporosis in clinical practice be made by DXA using the lowest T-score of the lumbar spine (L1-L4), total proximal femur, or femoral neck .

17. INDICATIONS Fragility fracture Glucocorticoid therapy (≥5 mg prednisone for ≥ 3 months) Androgen deprivation therapy for prostate cancer Hypogonadism Height loss > 1.5–2 inches from maximum height Current smoking/chronic obstructive pulmonary disease Malabsorption Bariatric or Bilroth surgery Use of medication associated with secondary osteoporosis Hyperparathyroidism Hypercalciuria /recurrent calcium-containing kidney stones All postmenopausal women With a history of fracture without major trauma, osteopenia identified radiographically

18. LABORATORY EVALUATION Biochemistry profile (especially calcium, phosphorous, albumin, total protein, creatinine , liver enzymes including alkaline phosphatase , electrolytes) 25-hydroxyvitamin D (25[OH]D) Complete blood count (CBC) If the diagnosis of osteoporosis is based upon the presence of a fragility fracture , obtain a BMD measurement (dual-energy x-ray absorptiometry [DXA]), performed on a nonurgent basis , for quantitative assessment of bone density and to monitor response to therapy.

19. Unexplained anemia , vitamin D deficiency, and/or low urinary calcium excretion should be tested for celiac disease . Cancer or multiple myeloma should be considered in patients with hypercalcemia , otherwise unexplained anemia , weight loss, or proteinuria . Measurement of serum and urine protein electrophoresis would be indicated. Serum parathyroid hormone (PTH) should be measured in patients with hypercalcemia , hypercalciuria , a history of renal stones, or osteopenia .

20. Urinary cortisol excretion should be measured if Cushing's syndrome is suspected and in patients with unexplained osteoporosis and vertebral fracture since patients with subclinical hypercortisolism (mild hypercortisolism without clinical manifestations of Cushing's syndrome) are also at risk for low BMD and fractures. TSH –measure thyroid-stimulating hormone (TSH) in men who are taking levothyroxine , or if there are clinical findings suspicious for hyperthyroidism.

21. Treatment Hormonal Pharmacological Lifestyle Modifications Lifestyle measures include adequate calcium and vitamin D, exercise, smoking cessation, counseling on fall prevention, and avoidance of heavy alcohol use, Weight-bearing exercise has beneficial effects on BMD but has not been shown to reduce fracture risk

22. Calcium and vitamin D

23. Dietary calcium may be preferred over supplemental calcium and that total calcium intake should not exceed 1,500 mg/day .Increasing calcium intake beyond the recommended levels has lead to increased risk of cardiovascular disease, stroke and nephrolithiasis . Recommended intake of vitamin D is at least 1,000 IU of per day for adults aged 50 years and older. Adults who are vitamin D insufficient or deficient (serum 25[OH]D 20 to 29 or <20 ng / mL , respectively) maybe treated with 5,000 IU vitamin D3 daily for 8 to 12 weeks to achieve a 25(OH)D blood level >30 ng / mL .

24. BISPHOSPHONATE THERAPY Bisphosphonates bind to hydroxyapatite in bone, particularly at sites of active bone remodeling , and reduce activity of bone- resorbing osteoclasts . Four bisphosphonates are available ( alendronate , ibandronate , risedronate , and zoledronate ) . Three of the four ( alendronate , risedronate , and zoledronate ) have evidence for broad-spectrum antifracture efficacy .

25. INDICATIONS Postmenopausal women with a history of fragility fractur e or with osteoporosis based upon bone mineral density (BMD) measurement (T-score ≤-2.5 ) high-risk postmenopausal women with T-scores between -1.0 and -2.5. calculate fracture risk using the Fracture Risk Assessment Tool (FRAX) For men with osteoporosis ( history of fragility fracture , or a T-score below -2.5 in men ≥50 years ) Men ≥50 years with T-scores between -1.0 and -2.5 who are at high risk for fracture.

26. Alendronate or risedronate as the initial choice of oral bisphosphonate Alendronate , in part due to direct evidence showing residual fracture benefit If history of gastrointestinal (GI) side effects to alendronate (but without esophageal disorders), risedronate can be substituted. Contraindications to oral thera p y Esophageal disorders ( eg , achalasia , esophageal stricture, esophageal varices , Barrett's esophagus ) or with an inability to follow the dosing requirements . Bariatric surgery in which surgical anastomoses are present in the gastrointestinal (GI) tract . If contraindications or intolerance to oral bisphosphonates , IV zoledronic acid is used

27. Assessment before starting bisphosphonates 1. Biochemical Calcium 25-hydroxyvitamin D (25[OH]D) Creatinine For both oral and intravenous (IV) bisphosphonates , correction of hypocalcemia and/or vitamin D deficiency (to at least 20 ng / mL [50 nmol /L]) is necessary prior to administration 2. Assess comorbidities history to detect any abnormalities of the esophagus (stricture, achalasia ) and an inability to remain upright for at least 30 to 60 minutes. 3. Plans for invasive dental procedures developing osteonecrosis of the jaw.

28. DURATION OF THERAPY Low risk for fracture – For patients at low risk for fracture in the near future ( eg , stable bone mineral density [BMD], no previous vertebral or hip fractures), discontinuing the drug (after three years for zoledronic acid, five years for alendronate or risedronate ) High risk for fracture – For patients at highest risk for fracture (history of osteoporotic fracture before or during therapy, T-score below -3.0 in the absence of fractures) who are taking alendronate or risedronate , continuing therapy for up to 10 years Drug holiday because bisphosphonates accumulate and may have a prolonged residence time in bone (and residual therapeutic effect after stopping), “ bisphosphonate holidays” may be considered. Drug holiday can be considered after 5 years of stability on oral bisphosphonates or 3 years of IV zoledronate

29. ADVERSE EFFECT Upper gastrointestinal symptoms, oeso p hagitis bowel disturbance, headaches and musculoskeletal pain. Tablets should be swallowed whole with a glass of plain water (∼200 ml) while the patient is sitting or standing in an upright position. Patients should not lie down for 30 min after taking the tablet

30. DENOSUMAB Denosumab , a fully human monoclonal antibody that specifically binds RANKL, blocks the binding of RANKL to RANK and thereby reduces the formation, function, and survival of osteoclasts , which results in decreased bone resorption and increased bone density. Denosumab (60 mg) is administered by subcutaneous injection once every six months. Denosumab is an option for patients who are intolerant of or unresponsive to other therapies .

31. Other Pharmacological Treatment Injectable and nasal spray recombinant salmon calcitonin are forpostmenopausal osteoporosis. The approved dosage of injectable calcitonin for treatment of postmenopausal osteoporosis is 100 IU daily given subcutaneously or intramuscularly. Raloxifene is approved for prevention and treatment of postmenopausal osteoporosis . Estrogen is approved by the for prevention of postmenopausal osteoporosis not for treatment

32. Main factor influencing drug of choice Gastrointestinal intolerance - intravenous ibandronate , rolaxifane and denosumab . Convenience monthly - ibandronate , intravenous zolendonate , denosumab Cost effectiveness - alendronate and risedronate High risk of breast cancer - rolaxifane Severe osteoporosis - teriperatide

33. MONITORING THE RESPONSE TO THERAPY  obtain a follow-up dual-energy x-ray absorptiometry ( DXA) of hip and spine after one or two years and, if bone mineral density (BMD) is stable or improved, less monitoring can de done frequently thereafter .

34. GLUCOCORTICOID-INDUCED OSTEOPOROSIS Glucocorticoids (GCs) play an important role in the treatment of many inflammatory conditions . 10% of patients who receive long-term GC treatment are diagnosed with a fracture, and 30–40% have radiographic evidence of vertebral fractures . The highest rate of bone loss occurs within the first 3–6 months of GC treatment, and a slower decline continues with persistent use . ACR has stratified risk based on clinical settings, adults 40 years of age based on BMD, history of fracture, and10-year risk of major OP fracture and hip fracture calculated using a tool that combines risk factors with GC dose . Risk group are High fracture risk , Moderate fracture risk and Low fracture risk .

35. Initial Treatment For Prevention Of GIOP In Adults Recommendations All adults taking prednisone at a dose of 2.5 mg/day for 3months Optimize calcium intake (1,000–1,200 mg/day) and vitamin D intake (600–800 IU/day) and lifestyle modifications. Adults age 40 years at low risk of fracture and Adults age <40 years at low risk of fracture Optimize calcium and vitamin D intake and lifestyle modifications over treatment with bisphosphonates , teriparatide , denosumab , or raloxifene . Adults age 40 years at moderate risk of major fracture and high risk of fracture.Treat with an oral bisphosphonate over calcium and vitamin D alone.

36. MANAGEMENT OF OSTEOPOROTIC VERTEBRAL COMPRESSION Pain control and activity modification . Oral analgesics are first-line therapy for the relief of acute pain. acetaminophen, ibuprofen, naproxen, mild opioids combined with acetaminophen, or mixed mechanism drugs ( eg , tramadol , tapentadol ). Choice of initial agent depends upon the severity of the pain). For patients incapacitated by pain due to vertebral compression fractures, hospitalization and parenteral analgesia may be necessary. Vertebral augmentation procedures ( vertebroplasty and kyphoplasty

37. References Surgical and Medical Treatment of Osteoporosis_ Principles and Practice 1st Edition Uptodate American College Of Endocrinology Clinical Practice Guidelines For The Diagnosis And Treatment Of Postmenopausal Osteoporosis UK clinical guideline for the prevention and treatment of osteoporosis Osteoporosis Diagnosis and Management by Dale w.