Osteoporosis

01Definition and overview

Osteoporosis is a systemic skeletal disease with low bone mass and microarchitectural deterioration of bone tissue, leading to fragility and a higher risk of fracture. It is defined in two ways:

• By its consequence: a fragility fracture, one from a fall from standing height or less, or with no injury at all. The typical sites are the vertebrae, the proximal femur (hip), the distal radius (wrist) and the proximal humerus.
• By bone density, measured by dual-energy X-ray absorptiometry (DXA) at the hip and lumbar spine and expressed as a T-score, the number of standard deviations from the mean of young adults:

These categories apply to postmenopausal women and men aged 50 or more. In premenopausal women, younger men and children the Z-score, against people of the same age and sex, is used, and a Z-score of −2.0 or lower is "below the expected range for age".

The one thing to remember: the T-score is a diagnosis, not a decision. Most fragility fractures happen in people whose T-score is above −2.5, and an older woman with osteopenia can be at higher risk than a younger one with osteoporosis. Treatment follows the risk of fracture.

02Etiology and pathophysiology

Remodelling and peak bone mass

Bone is renewed throughout life by osteoclasts that resorb small packets of it and osteoblasts that fill them with new bone. Osteoblasts and their descendants, the osteocytes, steer the process: they make RANKL, which switches osteoclasts on, and its decoy receptor osteoprotegerin, which switches them off; osteocytes also make sclerostin, which blocks bone formation through the Wnt pathway. Parathyroid hormone, oestrogen, vitamin D, mechanical loading and cytokines adjust the balance.

1. 1

   Building

   Bone mass rises through childhood and puberty to a peak in the third decade, consolidated to about 30. Genes set most of the peak; calcium, vitamin D, exercise, body weight and sex hormones the rest.
2. 2

   Balance

   In young adults resorption and formation are matched.
3. 3

   Loss

   From about 40, each remodelling cycle leaves a small deficit. After the menopause, oestrogen deficiency lets RANKL rise, more remodelling units open and resorption outruns formation: trabeculae thin and perforate, and cortical bone becomes porous. Loss is fastest in the 5 to 10 years after the menopause.
4. 4

   Fragility

   Low mass and lost connections between trabeculae weaken bone more than the density alone shows; a fall then breaks it.

This sketch simplifies: fracture risk also depends on bone quality, geometry and, above all, falls.

Types

Secondary causes

Glucocorticoids first speed up resorption and then, above all, shut down osteoblasts and promote their death, so bone is lost fast. Fracture risk rises within three months of starting oral glucocorticoids, at doses as low as 2.5 to 7.5 mg of prednisolone a day, and falls again after stopping.

03Clinical features

Osteoporosis has no symptoms until a fracture.

• Vertebral fractures are the commonest. About two thirds come to no medical attention, found only as height loss or on imaging. Others cause sudden severe back pain after bending or lifting, easing over weeks. Several fractures cause a thoracic kyphosis (the "dowager's hump"), height loss of 4 cm or more, a protuberant abdomen, chronic back pain, reduced lung capacity and early satiety.
• Hip fractures follow a sideways fall in older people. They are the most serious: most need surgery, and many patients never regain their previous independence.
• Distal radius (Colles) fractures follow a fall on the outstretched hand, often in women in their fifties and sixties: the first warning.
• Fractures of the humerus, pelvis, ribs and other sites.

04Diagnosis and management

Who to assess

Fracture risk is assessed in postmenopausal women and men aged 50 or more with a fragility fracture, height loss or kyphosis, a secondary cause, glucocorticoid treatment, or other risk factors, and opportunistically in older people.

FRAX estimates the 10-year probability of a major osteoporotic fracture (clinical vertebral, hip, forearm or humerus) and of a hip fracture, from age, sex, body mass index, previous fragility fracture, a parent's hip fracture, current glucocorticoids, smoking, alcohol of 3 units a day or more, rheumatoid arthritis, secondary osteoporosis and, optionally, the femoral neck bone density. It does not count falls, the number of fractures or the glucocorticoid dose, so clinicians adjust it (for prednisolone above 7.5 mg a day, for example).

NOGG thresholds in the UK

UK guidance runs FRAX first, then DXA where the result lies near a threshold, and sorts patients into low, intermediate, high and very high risk:

• Up to the age of 70 the intervention threshold is the risk of a woman of the same age who has already had a fracture, so it rises with age (a 10-year probability of a major fracture of about 7 per cent at 50 and 12 per cent at 60); from 70 it is fixed (about 20 per cent).
• Very high risk is a probability 60 per cent above the intervention threshold, or a single strong factor: a vertebral fracture in the past 2 years, two or more vertebral fractures, a T-score of −3.5 or lower, glucocorticoids of 7.5 mg of prednisolone a day or more for three months, or several risk factors with a recent fracture. These patients are considered for referral to a specialist and for injected treatment, some for an anabolic drug first, especially with several vertebral fractures.
• Treatment is considered, particularly in older people, for anyone with a previous fragility fracture; DXA is done if it is practical but need not delay it.

Other European countries use FRAX with their own thresholds, and American guidance treats people with low bone mass at a 10-year probability of 20 per cent for a major fracture or 3 per cent for the hip.

Tests

• DXA of the hip and lumbar spine; spine values can be falsely high from osteophytes, aortic calcification and old fractures in older people.
• Vertebral fracture assessment (a lateral spine image on DXA, or X-rays) after 4 cm of height loss, with kyphosis, glucocorticoids, a T-score of −2.5 or lower, or acute back pain; finding a vertebral fracture changes treatment.
• Blood tests for secondary causes: full blood count, ESR or CRP, calcium, phosphate, alkaline phosphatase, albumin, creatinine and eGFR, liver tests, TSH; 25-hydroxyvitamin D; serum protein electrophoresis with free light chains (myeloma); coeliac serology; PTH if the calcium is high; testosterone, SHBG, LH and FSH in men; others as the history suggests.
• Bone turnover markers (CTX for resorption, P1NP for formation), in specialist practice, to check response and adherence.

Lifestyle and falls

• Calcium of at least 700 mg a day, from food where possible (dairy), with supplements if the diet falls short.
• Vitamin D of at least 800 IU a day for people at risk of deficiency (housebound, care homes, dark skin, covered skin); deficiency is corrected before zoledronate or denosumab to avoid hypocalcaemia.
• Weight-bearing and muscle-strengthening exercise; stopping smoking; alcohol within national limits; adequate protein.
• Falls assessment for anyone who has fallen: strength and balance training, a medication review (sedatives, antihypertensives causing postural hypotension), vision, home hazards and footwear; hip protectors in care homes.

Drugs

Bisphosphonates are first-line for most patients because they are effective and cheap. Alendronate, risedronate and zoledronate reduce vertebral, non-vertebral and hip fractures. Oral tablets are taken on an empty stomach with a full glass of plain water, upright, at least 30 minutes before food or other drugs, because they are poorly absorbed and can cause oesophagitis. They are avoided with oesophageal stricture or achalasia, or when the patient cannot stay upright, and with hypocalcaemia; alendronate and zoledronate are avoided when the creatinine clearance is below 35 ml/min, risedronate and ibandronate below 30. Yearly zoledronate suits patients who cannot take tablets and is a first-line option after a hip fracture, where it reduced new fractures and deaths; about a third of patients have a flu-like reaction for a few days after the first infusion.

Denosumab reduced vertebral fractures by about two thirds, and hip fractures by about 40 per cent, in its main trial. It is not cleared by the kidney, so it can be used when bisphosphonates cannot, but it can cause severe hypocalcaemia in advanced kidney disease, and the calcium is checked. Its effect vanishes within months of a missed dose (below). Biosimilars of denosumab have been authorised in the EU since 2024.

Anabolic treatment

• Teriparatide, the active fragment of parathyroid hormone, given intermittently, stimulates osteoblasts more than osteoclasts. It reduced new vertebral fractures by about half compared with risedronate in women with severe osteoporosis. It is avoided with hypercalcaemia, Paget disease, unexplained raised alkaline phosphatase, previous skeletal radiotherapy, bone tumours or metastases, and severe kidney disease. In the UK it is also a first-line option for glucocorticoid-induced osteoporosis at very high risk.
• Abaloparatide, an analogue of PTH-related peptide, was refused in the EU in 2018 and then authorised in December 2022 for postmenopausal women at increased risk of fracture, for up to 18 months.
• Romosozumab, an antibody against sclerostin, both builds bone and reduces resorption. Followed by alendronate, it lowered new vertebral fractures by about half and hip fractures by about 40 per cent against alendronate alone. More serious cardiovascular events (myocardial infarction, stroke) occurred with it in that trial, so romosozumab is contraindicated after a myocardial infarction or stroke. In the EU it is licensed for severe osteoporosis in postmenopausal women at high risk; in the UK it is funded after a major osteoporotic fracture within the past 24 months.

Every anabolic course is followed at once by an antiresorptive drug, alendronate, zoledronate or denosumab, or the bone gained is lost. Giving the anabolic drug first, then the antiresorptive, gives the biggest gain.

Hormone therapy

Hormone replacement therapy prevents bone loss and reduces vertebral and hip fractures. It is a good option for women under 60 or within 10 years of the menopause, especially with menopausal symptoms, and for premature menopause until the usual age of menopause; its risks (breast cancer with combined therapy, venous thrombosis, stroke) weigh against long use in older women. The climacteric and its treatment are in the climacterium. Raloxifene, a selective oestrogen receptor modulator, reduces vertebral fractures only, lowers the risk of oestrogen-receptor-positive breast cancer, and increases venous thromboembolism and hot flushes.

How long, and stopping safely

After a bisphosphonate break, risk is reassessed after 18 months for risedronate and ibandronate, 2 years for alendronate and 3 years for zoledronate, or sooner after a new fracture. A "drug holiday" is a planned, reviewed pause in a patient whose risk has fallen, not an end of care.

Rare harms of antiresorptive drugs

• Atypical femoral fractures: transverse fractures of the femoral shaft after little or no trauma, often bilateral, preceded by weeks of thigh or groin pain. The risk rises with years of bisphosphonate use and is higher in Asian women, and falls quickly on stopping. Thigh pain on treatment calls for X-rays of both femurs.
• Osteonecrosis of the jaw: exposed bone in the mouth for more than 8 weeks, mostly after extractions, much rarer at osteoporosis doses (estimates range from about 1 in 100,000 to 1 in 1,000 patient-years) than at cancer doses. Smoking, poor oral health, extractions, glucocorticoids and cancer raise the risk. Good oral hygiene and routine dental check-ups continue; severe dental disease is treated first where possible, without long delays to treatment after a fracture.

Over years of treatment, the fractures prevented by bisphosphonates far outnumber the atypical fractures caused.

Glucocorticoid-induced osteoporosis

Bone protection starts with the glucocorticoid, without waiting for a DXA scan, in anyone with a previous fragility fracture, women aged 70 or more, postmenopausal women and men aged 50 or more taking 7.5 mg of prednisolone a day or more for three months, and those above the FRAX threshold. An oral bisphosphonate or zoledronate is first-line, denosumab an alternative, and teriparatide for those at very high risk; calcium and vitamin D are made adequate. The lowest effective steroid dose is used, and the bone treatment may be stopped when the steroid stops, after reassessment.

Osteoporosis in men

About one in five men over 50 will have a fragility fracture. A secondary cause is found in up to half of men, most often glucocorticoids, alcohol excess and hypogonadism, including androgen deprivation for prostate cancer. Alendronate, risedronate, zoledronate, denosumab and teriparatide are licensed for men; romosozumab and abaloparatide are not. Testosterone is given for proven hypogonadism, but a bone drug is added when fracture risk is high.

After a vertebral fracture

Pain is treated with simple analgesia, opioids for a short time, and early mobilisation with physiotherapy; in hospital, calcitonin for up to 4 weeks can ease acute pain. Vertebroplasty or kyphoplasty (injecting cement) is reserved for severe pain that persists despite good care. Fragility fractures elsewhere are treated surgically or in a cast as usual, and every one is followed by secondary prevention.

05Epidemiology

In the 27 countries of the EU with the UK and Switzerland, about 32 million people had osteoporosis in 2019, 25.5 million women and 6.5 million men, and there were 4.3 million fragility fractures, a fifth of them hip fractures, costing about 57 billion euros a year. After the age of 50, about one woman in two and one man in five will have an osteoporotic fracture. The incidence rises steeply with age, and is highest in northern Europe, Scandinavia above all, and in white and Asian people. Because populations are ageing, the number of fractures is rising. Yet most patients at high risk, even after a first fracture, receive no treatment: the treatment gap in Europe is about 70 per cent of women at high risk.

06Prognosis

Treatment reduces vertebral fractures by about 40 to 70 per cent and hip fractures by about 20 to 40 per cent, depending on the drug and the patient, if it is taken: a large share of patients stop oral bisphosphonates within the first year, so adherence is checked at each review.

Untreated, each fracture brings the next. A hip fracture is a turning point: about a quarter of patients die within a year, mostly from their other illnesses, and many survivors lose mobility or move into care. Vertebral fractures shorten life and cause chronic pain, kyphosis and loss of function, and their number predicts more fractures. Follow-up reviews adherence, side effects and new fractures, repeats FRAX and DXA about every 3 to 5 years (sooner on steroids or after stopping a drug), and plans what comes after each drug.