Osteoporosis

Osteoporosis is a systemic skeletal disease characterised by low bone mass and microarchitectural deterioration, leading to increased bone fragility. It is the most common metabolic bone disease, and it is under-diagnosed and under-treated.

Who and how many. About 200 million people are affected globally, and there are 1.5 million fragility fractures a year in the US. Women are affected more than men because of postmenopausal oestrogen loss.

Where it breaks. The vertebra is the most common fracture site and the hip the most morbid. Second-fracture risk is 20% within 1 year, and the healthcare cost is enormous.

Fragility fracture needs context. Hip and vertebral fragility fractures usually identify high treatment risk. Distal radius, proximal humerus and other low-energy fractures trigger bone-health assessment but do not make every patient osteoporotic by definition.

Remodelling. Bone is constantly remodelled by osteoclasts, which resorb it, and osteoblasts, which form it, in a cycle of 3-6 months: resorption, then formation. Osteoporosis results from an imbalance favouring resorption. Peak bone mass is achieved by age 30, and after this net bone loss begins.

Cortical and trabecular bone. Cortical bone is the dense outer layer, 80% of the skeleton, with slow turnover. Trabecular bone is the spongy interior, the remaining 20%, with rapid turnover.

Why the balance tips. Three routes lead to the same imbalance:

• Oestrogen deficiency after the menopause increases osteoclast activity
• Age reduces osteoblast function
• Secondary causes, listed below

Secondary causes. Check for them in all young patients or in severe disease.

• Glucocorticoids
• Hyperthyroidism and hyperparathyroidism
• Alcohol, and aromatase inhibitors
• Low body weight (BMI less than 19)
• Male hypogonadism (testosterone deficiency)
• Early menopause, before 45
• Renal and gastrointestinal disease: CKD, malabsorption
• Rheumatoid and other inflammatory arthritis
• Type 1 diabetes, although BMD may be normal

The T-score compares the patient's BMD with the young adult (20-30 years) mean. The WHO categories built on it apply to postmenopausal women and men aged 50 years or older; younger adults are read by the age-matched Z-score.

WHO DEXAZ-Score

WHO DEXA Classification

Normal

T-Score

At or above -1.0

Interpretation

Normal bone density

Action

Lifestyle measures, rescreen 5-10 years

Osteopenia

T-Score

-1.0 to -2.5

Interpretation

Low bone mass

Action

Calculate FRAX, treat if high risk

Osteoporosis

T-Score

At or below -2.5

Interpretation

Osteoporosis

Action

Pharmacotherapy indicated

Severe Osteoporosis

T-Score

At or below -2.5 + fracture

Interpretation

Established osteoporosis

Action

Consider anabolic therapy first

Category	T-Score	Interpretation	Action
Normal	At or above -1.0	Normal bone density	Lifestyle measures, rescreen 5-10 years
Osteopenia	-1.0 to -2.5	Low bone mass	Calculate FRAX, treat if high risk
Osteoporosis	At or below -2.5	Osteoporosis	Pharmacotherapy indicated
Severe Osteoporosis	At or below -2.5 + fracture	Established osteoporosis	Consider anabolic therapy first

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Z-Score Interpretation

In premenopausal women and men under 50, BMD is compared with an age-matched mean and the Z-score is used instead of the T-score. A Z-score greater than -2.0 is normal; below -2.0 suggests secondary pathology, and the causes should be screened for.

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History. A prior fracture is the strongest risk factor. Ask about hip fracture in a parent, smoking, alcohol and low calcium intake, early menopause, and thyroid, parathyroid or rheumatoid disease. The drug history includes steroids, aromatase inhibitors and PPIs. A comprehensive history is what identifies the high-risk patient.

Examination. Examine for vertebral fractures and for fall risk.

• Measure height, and look for thoracic kyphosis (dowager's hump), quantified by the wall-occiput distance
• A reduced rib-pelvis distance points to vertebral fractures
• Romberg's test assesses balance for fall risk
• The Timed Up and Go test assesses functional mobility

DEXA. DEXA is the gold standard for diagnosis. Measure the femoral neck and the lumbar spine and use the lowest T-score; the femoral neck is preferred for treatment decisions.

Reading the report. A DXA report needs clinical interpretation. Degenerative artefact may elevate lumbar BMD, while the trabecular bone score (TBS) can show degraded texture in the same spine.

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Bloods. The aim is to exclude secondary causes: calcium, phosphate, vitamin D, PTH, renal function, thyroid function, FBC and LFTs. Consider testosterone in men and coeliac serology.

Vertebral imaging. A lateral spine X-ray or VFA identifies prevalent vertebral fractures once height loss or kyphosis has raised the question. On MRI, marrow signal separates an acute fracture from a chronic one.

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FRAX computes the 10-year probability of a major osteoporotic fracture and of a hip fracture from clinical risk factors, with femoral-neck BMD optional, so it works without DEXA. It is one component of decision-making, not a diagnosis or a universal treatment threshold.

Thresholds are national. Intervention thresholds vary by national model, age and guideline, so apply the threshold from the relevant country model and guideline. The 3%/20% thresholds are US thresholds, not universal constants.

Its clinical inputs.

What FRAX cannot see. Almost every input is yes/no, so FRAX is blind to dose and severity and can under-estimate risk. When any of these blind spots applies, clinical judgement must override a reassuring FRAX:

• Glucocorticoid dose: high-dose steroids are under-weighted, so adjust upward
• The number, recency and site of prior fractures: a recent or vertebral fracture confers very high imminent (near-term) risk that FRAX flattens
• Falls, the dominant driver of hip fracture in the very old
• Lumbar-spine BMD: FRAX uses femoral-neck BMD only, and discordant low spine BMD can be added with TBS
• Treatment: FRAX is not validated in patients already on treatment

Low BMD or an apparent fragility fracture is not always primary osteoporosis. The mimics change management entirely, so distinguish them before prescribing.

Vertebral mimics. Myeloma, tuberculous spondylitis and pyogenic spondylitis can each look at first like an osteoporotic compression fracture. What gives them away is the laboratory result, the pathology or a course that does not behave.

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Lifestyle, for every patient. Lifestyle measures are the foundation for all patients.

• Calcium 1000-1200mg/day and vitamin D 800-2000 IU/day, from food where possible and supplemented if intake is inadequate. Correct deficiency without automatic megadosing.
• Regular weight-bearing and resistance exercise (walking, dancing, strength training) improves BMD and reduces falls.
• A fall prevention programme: home hazard assessment, vision check, medication review and balance training.
• Stop smoking, limit alcohol to less than 2 drinks a day and maintain a healthy body weight.

Choosing a drug. There is no one universal first-line drug. Bisphosphonates are common first antiresorptives when risk, renal function, gastrointestinal tolerance, adherence and route make them suitable; very-high-risk patients may benefit from anabolic-first sequencing, set out in the next section.

Denosumab needs an exit plan. Do not delay or stop denosumab without arranging sequential antiresorptive therapy. The FREEDOM extension data in the evidence section are more specific than the word "rebound": turnover markers rise above baseline, BMD falls back to baseline and the vertebral fracture rate returns to the untreated rate. What is peculiar to denosumab is that the fractures which follow tend to be multiple, concentrated in susceptible patients, especially those with a prior vertebral fracture.

Drug holidays. A holiday may be considered after 3-5 years of bisphosphonate if the patient is stable. Denosumab and the anabolics have no holiday concept.

The order in which drugs are given is one of the most important modern concepts, and the basis of the ARCH trial and of the ESCEO/AACE "very high risk" pathway.

Two classes, opposite actions. Anabolics, teriparatide (PTH 1-34) and romosozumab (anti-sclerostin), build new bone. Their effect is front-loaded and wanes over roughly 12-24 months, the so-called anabolic window; romosozumab is dual-action, increasing formation and decreasing resorption at the same time. Antiresorptives, bisphosphonates and denosumab, preserve bone by suppressing osteoclasts.

Why anabolic first, then antiresorptive.

• Building bone first and then giving an antiresorptive consolidates ("locks in") the newly formed bone, producing larger, more durable BMD and strength gains.
• A potent antiresorptive given first blunts the later anabolic response: teriparatide works less well, and more slowly, after a bisphosphonate or denosumab has suppressed the remodelling it acts on.
• Anabolic gains are lost if not followed by an antiresorptive. As with denosumab, an anabolic course must always be consolidated with a bisphosphonate or denosumab.

The trial. ARCH showed exactly this: romosozumab-then-alendronate beat alendronate-throughout for fracture reduction in high-risk women.

Osteoporotic bone requires modified fixation strategies.

Fixation principles.

• Longer plates spread load over more screws
• Locking plates give angular stability and reduce toggle
• Use multiple points of fixation, with more screws if needed
• Consider cement augmentation for poor bone
• Avoid cortical stress risers by keeping transitions smooth
• Protect the fracture: early motion, but protected weight-bearing

Screw augmentation. PMMA cement placed around screws increases pullout strength 2-3x and is useful in spine and periarticular fractures.

Vertebroplasty and kyphoplasty. Both inject cement into the vertebral body of a painful vertebral compression fracture; kyphoplasty restores some height.

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Rare but serious. ONJ and atypical femoral fractures are rare but serious, and for patients with osteoporosis the benefits of treatment far outweigh the risks. Lateral-cortical thickening and a transverse lucent line are the characteristic warning findings of an atypical femoral fracture.

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Fracture Liaison Service. The FLS is the evidence-based model for making sure eligible fragility-fracture patients are investigated and treated. FLS programmes improve case finding, investigation and treatment initiation, but referral does not mean every fracture patient receives the same drug.

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Fracture risk reduction. The reductions quoted for each class:

• Bisphosphonates: 40-50% for hip and vertebral fractures
• Denosumab: 40-70%
• Teriparatide: 65% vertebral, 50% non-vertebral
• Romosozumab: 70%+ vertebral

After hip fracture. These are the commonly quoted rates, though mortality and loss of independence vary by population and care system. Early treatment prevents second fractures and mortality.

Global Epidemiology:

• An estimated 500 million people worldwide have osteoporosis; roughly 1 in 3 women and 1 in 5 men over 50 will sustain a fragility fracture
• Lifetime hip-fracture risk approaches that of breast cancer in women; the global hip-fracture burden is projected to rise sharply with population ageing, with the largest increases in Asia
• Bone mineral density thresholds (T-score) are universal, but fracture incidence varies by region (higher in Northern Europe/Scandinavia, lower in parts of Africa and Asia), reflecting genetics, body habitus, vitamin D status and fall rates

Major Guidelines — Side by Side:

Across all major bodies the core message is consistent: a fragility fracture warrants treatment irrespective of BMD, FRAX (or QFracture) guides therapy in osteopenia, and bisphosphonates remain first-line for most, with anabolic-first sequencing reserved for very high risk.

Related pages: DEXA and Bone Densitometry for how the T-score this page treats as a threshold is actually acquired and where it misleads; Bisphosphonates for the drug class in detail, including the holiday decision this page only summarises; Denosumab for the agent whose discontinuation behaviour is the single most examinable prescribing rule here; Atypical Femoral Fractures and Medication-Related Osteonecrosis of the Jaw for the two rare harms that drive the holiday decision; Osteomalacia for the mineralization defect that must be excluded before starting an antiresorptive, since bisphosphonates given to an osteomalacic patient worsen it; Vitamin D Deficiency for the repletion required before any antiresorptive; Glucocorticoid-Induced Osteoporosis for the commonest secondary cause, which is treated at a higher BMD threshold; Osteoclasts and Bone Resorption and Osteoblasts and Bone Formation for the RANKL and sclerostin biology every drug on this page targets; and Transient Osteoporosis of the Hip for the self-limiting mimic that must not be treated as this disease.

Anabolic-first versus antiresorptive-first. Trials (ARCH, and teriparatide-then-antiresorptive data) and ESCEO/AACE favour an anabolic-first sequence in very-high-risk patients. The threshold defining "very high risk", and cost, remain debated.

The denosumab exit. That protection is lost after stopping denosumab is established, but the best transition (timing of zoledronic acid, single versus repeated dosing, the role of bone-turnover markers) is not fully settled. Most guidance gives a bisphosphonate around 6 months after the last denosumab dose.

Drug holidays. A bisphosphonate holiday balances falling atypical-fracture risk against rising fracture risk. There is no validated tool to time resumption, so the decision rests on BMD, fracture history and clinical judgement.

Calcium and vitamin D supplements. Routine supplementation in community-dwelling, replete adults gives uncertain fracture benefit and a debated cardiovascular and renal-stone signal. Its value is clearest in deficient or institutionalised populations and as an adjunct to active drug therapy.

Osteopenia and the very elderly. FRAX-guided treatment of osteopenia is widely endorsed, yet the cost-effective threshold varies by country. Evidence in the very old and those with limited life expectancy is thinner, favouring agents with rapid benefit such as zoledronic acid.

Romosozumab's cardiovascular signal. The excess cardiovascular events against alendronate in ARCH, not seen against placebo in FRAME, remain incompletely explained, and the underlying mechanism is unresolved.