Defined by the World Health Organization (WHO) in 1994: 

• “A skeletal disease characterised by low bone mass and deterioration of the microarchitecture of bone tissue with a consequent increase in bone fragility and susceptibility to low trauma fractures.”

• Quantitatively, osteoporosis is defined by WHO as a bone mineral density (BMD) that is 2.5 standard deviations or more below the peak bone mass of an average young, healthy adult as measured on dual X-ray absorptiometry (DEXA) scan.
• Normal:bone mineral density above 1 standard deviation below the mean.
• Osteopenia:1–2.5 standard deviations below the mean for a young adult.
• Osteoporosis: >2.5 standard deviations below the mean for a young adult.
• T score is the number of standard deviations away from the mean for a sex and race-matched young healthy population.
• Z score is the number of standard deviations away from the mean for an age, sex and race-matched population.
• Z score should not be used to define osteoporosis. 
• These are general guidelines, not used to dictate whether treatment should be given but to be used in conjunction with the history and examination to determine the best course of action for each individual.
• Primary osteoporosis is idiopathic or age related. 
• Secondary osteoporosis occurs when underlying agents or disease induces the bone loss.

• Incidence is difficult to measure, as most cases are not recorded until a fracture has occurred. The National Osteoporosis Society (UK) state that at least one in three women and one in 12 men will develop osteoporosis.

Primary osteoporosis

Genetic:

• Ethnicity: Caucasian or Asian
• Blond hair, red hair, freckles, hypermobility and adolescent scoliosis reported as having a genetic predisposition
• Family history of fracture
• Low body mass index <19 kg/m

Lifestyle and environment:

• Smoking
• Excess alcohol
• Sedentary, or prolonged immobilisation

Hormonal:

• Loss of oestrogen protection 
• Early menopause <45 years of age 
• Primary hypogonadism 
• Secondary amenorrhoea for more than 1 year 

Diet:

• Deficiency of calcium or vitamin D

Secondary osteoporosis

Medical conditions:

• Anorexia nervosa 
• Rheumatoid arthritis
• Hyperthyroidism 
• Primary hyperparathyroidism
• Multiple myeloma
• Organ transplantation 
• Cushings disease/syndrome 
• Chronic kidney, lung or gastrointestinal diseases 

Drugs:

• Chronic corticosteroid therapy (>7.5 mg per day for >1 year) increases risk of fracture by two to three times
• Excessive thyroid therapy 
• Anticoagulants 
• Anticonvulsants 
• Chemotherapy 
• Gonadotrophin releasing hormone agonist or antagonist 

In addition these factors should increase suspicion:

• Previous history of a fragility fracture wrist, hip or vertebra especially. Previous wrist fracture doubles the risk of future hip fracture and triples the risk of future vertebral fracture
• Loss of height suggesting a kyphosis 
• Osteopenia or loss of vertebral morphology on plain X-ray

Pathophysiology

• There is an uncouplingof bone formation by osteoblasts and bone absorption by osteoclasts. It is a quantitative not qualitative defect in bone. 
• Normally, men and women increase bone mass until age 30 years to a peak bone mass. 
• After this, bone is lost slowly for men. Women have a sudden increase in bone loss at the menopause. After 60 years of age the rate of bone loss for women is the same as that for men. 
• With aging the body expands the cortical bone further away from the epicentre of bone. This can compensate for loss of bone strength in torque and bending, but not for compression. 

Histology

• Histological examination reveals thinning of trabeculae, decreased size of osteons and enlargement of haversian and marrow spaces.

Classification using the Riggs and Melton system

• Type 1:post-menopausal, affects mainly cancellous bone,so vertebral and distal radius fracture is common. Related to loss of oestrogen. F:M = 6:1.
• Type 2: age-related in those over 75 years, affects cancellous and cortical bone, is related to poor calcium absorption. Hip and pelvic fractures common. F:M = 2:1.

Osteoporosis can also be described as:

• High turnover: increased number and depth of osteoclast resorption sites and the normal osteoblast effort cannot repair the defect.
• Low turnover: normal or decreased osteoclastic absorption, but osteoblasts even more inactive.

Osteoporosis is predominantly asymptomatic until fractures occur, commonly with vertebral, distal radius or hip fractures as the presenting complaint.

Osteoporosis and osteomalacia

• It is important to be able to distinguish between these distinctly different diseases.

Osteoporosis

• Bone mass reduced, mineralisation normal
• Generally elderly and postmenopausal
• Causes include endocrine abnormality, inactivity, disuse, alcoholism, calcium deficiency, idiopathic
• Symptoms are pain and tenderness specific to site of fracture only
• Mainly axial skeleton fractures on X-ray
• Lab tests:
• Serum calcium normal
• Serum phosphate normal
• Alkaline phosphotase normal
• Urine calcium high or normal
• Bone biopsy with tetracycline labeling is normal

Osteomalacia

• Bone mass variable, mineralisation decreases
• Can affect any age group
• Causes include vitamin D deficiency, abnormality of vitamin D pathway, hypophosphatasia syndromes, renal tubular acidosis
• Symptoms are tenderness at fracture site and generalised tenderness and bone pain
• X-rays often reveal symmetric pseudofractures or complete fractures in the appendicular skeleton
• Lab tests:
• Serum calcium low or normal (high in hypophosphatasia) 
• Serum phosphate low or normal
• Alkaline phosphotase elevated (unless hypophosphatasia)
• Urine calcium normal or low (high in hypophosphatasia) 
• Bone biopsy with tetracycline labeling is abnormal

Investigation

• The aims are to:
• Confirm the diagnosis of osteoporosis 
• Exclude other causes of fracture 
• Look for correctable causes of osteoporosis 
• Allow prognostication 
• Aid in the selection of treatment 
• Provide a baseline for assessment of response to treatment 

Routine diagnostic tests in all patients with suspected osteoporosis: 

• History of risk factors 
• Physical examination, including ruling out causes of falling, eyesight, etc.
• X-ray of lumbar and thoracic spine. Although >30% of bone loss required to be visible on X-ray, there may be some asymptomatic wedge fractures 
• Bone mineral density measurement 
• Blood tests, full blood count, erythrocyte sedimentation rate, serum biochemistry, bone profile, thyroid function test to rule out other causes of bone weakness 
• Testosterone and gonadotrophin levels in men 
• Laboratory tests are usually unremarkable in osteoporosis

• The gold standard test in clinical practice is measurement of bone mineral density (g/cm³⁾, of the vertebral spine and the hip. This is as recommended by the National Osteoporosis Society. Only vertebral measurements can be used to assess effectiveness of treatment at present.

When to measure bone mineral density:

• When there are risk factors present 
• When it will alter management of a particular patient 

Bone mineral density (BMD) measurement techniques:

DEXA scans

• Dual X-ray absorptiometry. Introduced in 1987. 
• Simultaneous measurement of the passage through the body of X-rays with two different energies. 
• Low radiation, accurate.
• Can be performed on vertebra, hip, whole body, or more peripheral areas.
• The National Osteoporosis Society has guidelines on the use of wrist DEXA scans.
• Wrist scans are less predictive of hip and vertebral fractures than hip and vertebra scans.
• If T score is above –1, reassure patient.
• If T score between –1 and –2, request DEXA of hip/spine.
• If T score is less than –2, treat, if clinically indicated. If monitoring required, refer for DEXA of hip/spine.

Limitations of DEXA:

• DEXA scans only indicate a relative risk and cannot predict those who will actually experience a fracture.
• The presence of vertebral compression fractures or osteoarthritis or previous spinal surgery may produce a false negative result.
• Peripheral scans are useful to quantify fracture risk but only central scans can be used to monitor the effect of treatment.

Radiographic absorptiometry 

• The first quantitative technique. Standard hand X-rays are taken next to an aluminium wedge. Bone mineral density is measured by comparison to the density of the aluminium. Only suitable for phalanges and metacarpals which are surrounded by only small amounts of soft tissue. 

Single photon X-ray absorptiometry

• Still only useful in the peripheral skeleton, e.g. wrist as the body part needs to be placed within water, water bags or a water equivalent material to correct for overlying soft tissue.

Quantitative computer tomography

• An external bone mineral reference phantom is scanned along with the patient to calibrate the computed tomography measurements with bone equivalent values. 
• More sensitive in vertebra than DEXA but less precision. 
• Used for assessment of vertebral fracture risk, and follow up. 
• However, much more expensive than DEXA and radiation dose higher. 

Quantitative ultrasound 

• Inexpensive, small, portable, does not involve radiation. Renewed interest in its use. 
• The exact mechanism of the ultrasound interaction with bone is unclear. 
• Different instruments will give different readings, due to differences in calibration, analysis software used. 
• There is positive correlation with BMD of 0.7–0.9. 
• Can be used to discriminate between normal and osteoporotic groups as effectively as DEXA. 

• Optional tests that may also be useful:
• Serum parathyroid hormone, 25- oral hypoglycaemic drug (OHD) levels, plasma electrophoresis.
• Bone marrow biopsy after tetracyline labelling, can rule out osteomalacia.
• Urinary free cortisol.
• Measurement of serum and urine markers of bone absorption and formation can be used:

Markers for bone formation: bone-specific alkaline phosphatase, osteocalcin.

Markers for bone resorption: collagen breakdown products in urine, e.g. N and C telopeptides.

T score

• The T score is the number of standard deviations (SD) above or below the mean peak bone mass for a sex and race-matched healthy normal young adultpopulation. 
• This is the value the WHO takes its definition of osteoporosis from. 
• The T score is approximately what the patient should have been at their peak bone density at about age 20 years.

Z score

• The Z score is the number of standard deviations below the mean for an age, sex and racematched population.
• As the Z score is measured against an age-matched group it cannot detect age-related osteoporosis.
• Elderly white women have weak bones even if the bone density is average.
• Low Z scores in young patients may suggest anorexia, chronic ill health or vitamin D deficiency.

Bone mineral density (g/cm²)

• This is most useful when values are compared to a previous earlier scan result after starting treatment to quantify any improvement.

• lThis has been developed by the WHO to evaluate fracture risk of patients. 
• Algorithms give the 10-year probability of fracture. 
• The output is a 10-year probability of hip fracture and the 10-year probability of a major osteoporotic fracture (clinical spine, forearm, hip or shoulder fracture).

• The UK national screening committee have concluded it is not appropriate to implement a national screening programme for osteoporosis because:
• There is no randomised controlled trial (RCT) assessing the clinical and cost effectiveness of any current approach to screening for osteoporosis. 
• There is a lack of consensus between the two leading UK sources of guidance, the National Osteoporosis Guideline Group (NOGG) and the National Institute for Health and Care Excellence (NICE), regarding which women should be eligible for treatment.
• The long-term clinical and cost effectiveness of osteoporosis treatment is not known.

• The aims are to achieve an adequate peak bone mass, by: 
• Encourage load bearing exercise in young women 
• Encourage non-smoking 
• Encourage controlled alcohol intake 
• Avoid drug abuse 
• Monitor those on corticosteroid treatment, considering BMD measurement and treatment 
• Adequate dietary intake of calcium 
• Children 700 mg 
• Measures to prevent falls
• Evaluation of women at menopause for hormone replacement therapy (HRT) 

Calcium and vitamin D supplements 

• Currently the use of vitamin D and vitamin D analogues is under scrutiny due to poor evidence supporting use.
• Minimum daily intake of calcium should be achieved. Should only be prescribed if this is not achieved by diet. 
• Vitamin D in all elderly institutionalised people with osteoporosis is recommended. 
• People over 65 years have approximately 700 mg calcium in normal diet and vitamin D blood levels of 200 IU. 
• Recommended diatary allowance (RDA) calcium = 1400 mg. 
• RDA vitamin D = 600–800 IU.
• Adding 500 mg calcium and 700 IU vitamin D reduced fractures by 50% over 3 years of taking supplements in a double blind, placebo study of 176 men and 213 women over 65 years.¹
• However, 36,000 healthy post-menopausal women (not taking corticosteroids) randomly assigned to vitamin D and calcium or placebo showed no difference in number of fractures at 7 years mean follow-up (treatment group had statistically significant increased BMD by 0.9% at hip but not spine).²
• A recent meta-analysis of studies of vitamin D supplementation alone showed slight increased BMD at the femoral neck but no significant benefit at any other body site. The conclusion was that continued use of vitamin D in the community in adults without risk factors for deficiency seems to be inappropriate.³
• The latest Cochrane review, including 53 trials and over 91,000 patients, concluded that vitamin D in current therapeutic preparations alone is unlikely to prevent fractures but vitamin D with calcium may prevent hip and other fractures. Although there were small increases in gastrointestinal symptoms and renal disease, there is no increased risk of death (Cochrane Database Syst Rev, 2014).⁴
• This is a classic article, reporting a randomised, placebo-controlled trial of 36,000 women at 40 different sites, healthy, postmenopausal aged 50–70 years (of note, corticosteriod use was an exclusion criteria). Mean follow-up period was 7 years.
• Intervention: CaCO³1000 mg plus vitamin D 400 IU daily. Personal use of calcium, vitamin D, bisphosphonates and calcitonin was allowed. 52% of women were taking HT at baseline.
• Outcomes: no difference in number of hip, wrist, vertebral, or total fractures. At year 6, calcium plus vitamin D did increase BMD by 0.9% at the hip but not at the spine.
• Conclusions: No significant benefit, slight increase in risk of kidney stones.

Hormone replacement therapy (HRT)

• Helps to prevent osteoporosis and slows or reverses progression of osteoporosis in postmenopausal women. 
• If given at doses equivalent to 0.625 mg of premarin, it will increase bone density by 2% per year. 
• Bone loss may begin again if HRT discontinued at 2% per year. 
• If given for 5–10 years from menopause almost halves the risk of postmenopausal fractures. 
• Also plays a role in corticosteroid induced osteoporosis.
• Contraindications: endometrial carcinoma, breast cancer, undiagnosed vaginal bleeding.
• Other benefits: loss of menopausal symptoms, cardiovascular protection.
• If a patient has doubts about the use of HRT, performing BMD measurement may help make the decision. 

Bisphosphonates 

• Inhibit bone resorption by deactivating or killing osteoclasts. These drugs are synthetic analogues of inorganic pyrophosphate. This similarity to pyrophosphate inhibits activation of enzymes that osteoclasts use during bone resorption. There are two classes: nitrogenous and non-nitrogenous bisphosphonates.
• Non-nitrogenous bisphosphonates (etidronate, clodronate and tiludronate) are metabolised within the osteoclast, forming compounds that produce non-functional ATP, affecting cellular energy metabolism, leading to cell apoptosis.⁵This leads to decreased bone resorption due to fewer cells acting upon the bone.
• Nitrogen-containing bisphosphonates (pamidronate, alendronate, risedronate and zolendronate) bind and block the enzyme farnesyl diphosphate synthase (FPPS), disrupting the HMG-CoA reductase pathway, blocking protein prenylation within the cell membrane of osteoclasts.⁶This adversely affects cytoskeletal dynamics, particularly the function of the “ruffled border” necessary for bone resorption, leading to decreased bone mineral loss.

Alendronate (fosamax)

• There is high quality evidence that alendronate significantly reduces the incidence of hip, wrist and vertebral fractures in postmenopausal women.
• It is only licensed for postmenopausal osteoporosis in the UK. 

Disodium etidronate (didronel) 

• Etidronate has also been proved significantly to reduce vertebral fracture. 
• Has been shown to reduce non-vertebral fractures. Licensed for use in postmenopausal women and in corticosteroid-induced osteoporosis.

• Oral bisphosphonates are associated with gastric and oesophageal irritation. They should be taken after food.
• Intravenous bisphosphonates can cause osteonecrosis of the jaw, atrial fibrillation, ’flu like symptoms.
• Atypical femoral fractures with long-term use (typically sub-trochanteric and diaphyseal fractures). These are rare and the overall reduction in hip fractures outweigh the risks of these unusual fractures.⁷It is suggested that these fractures occur due to the inability of the bone to remodel micro-fractures (secondary to the loss of osteoclastic function). 
• Patients at increased risk of these fractures may be managed with bisphosphonate “holidays” in which the drug is withheld for a period of months or treated with alternative drugs such as teriparetide (due to reduced suppression of bone turnover).
• Alendronate, etidronate, residronate and zoledronic acid have all been shown to improve bone mineral density in patients with osteoporosis and to reduce the risk of vertebral, hip and other non-vertebral fractures.^8,9Risk of vertebral fracture is reportedly reduced by between 40 and 70%^10,11while hip fracture risk is reduced by between 40 and 60%.^12,13

Selective oestrogen receptor modulators (raloxifene)

• Work like oestrogen at bone without other harmful effects. 
• Can reduce risk of vertebral fractures by 40–50%. 
• No reported prediction ion risk of hip fracture. 
• Can increase postmenopausal symptoms so not to be given within 5 years of menopause.

Calcitonin 

• Non-sex, non-steroid hormone.
• Reduces resorption of bone.
• Nasal form at dosages of 200 units per day increases bone mass in the spine and reduces spinal fractures incidence.
• No data on other fracture types.

Calcitriol (1,25 dihydroxycholecalciferol) 

• The active metabolite of vitamin D, 0.25 mg o.d. may reduce risk of vertebral fracture. 
• Needs monitoring of plasma calcium levels.

• Thorough history and examination.
• Modify diet with or without supplements and other clinical risk factors for fracture.
• Estimate 10 year risk of major fracture (using FRAX tool).
• Decision to treat depending on assessments above.

Non-medical therapies

• Modify fall risk factors.
• Consider walking aids and physical therapy.
• Daily weight-bearing activities.

Medical therapies initiated if:

• Patient has sustained a vertebral or hip fracture.
• DEXA hip or spine <–2.5.
• Low BMD and 10 year probability of hip fracture >3% or any major fracture >20%.
• Patients on medical therapy should have laboratory and BMD re-evaluation every 2 years or sooner if indicated.

Jackson et al. Calcium plus Vitamin D supplementation and the risk of fractures. N Engl J Med. 2006 Mar 9; 354(10): 1102.

• This is a classic article, reporting a randomized, placebo-controlled trial of 36,000 women at 40 different sites, healthy, postmenopausal aged 50 – 70 years (of note, corticosteriod use was an exclusion criteria).  Mean follow up period was 7 years.
• Intervention: CaCO3 1000mg plus Vitamin D 400 IU daily.  Personal use of calcium, vitamin D, bisphosphonates, and calcitonin was allowed.  52% of women were taking HT at baseline.
• Outcomes: no difference in number of hip, wrist, vertebral, or total fractures.  At year 6, Calcium plus vitamin D did increase BMD by 0.9% at the hip but not at the spine.
• Conclusions: No significant benefit, slight increase in risk of kidney stones