Osteoporosis — Definition, Pathogenesis, Diagnosis and Management including Newer Interventions; Male and Premenopausal Osteoporosis

Osteoporosis is a systemic skeletal disease in which bone mass is reduced and the microarchitecture of bone tissue deteriorates, so that bone becomes fragile and fractures easily.

The WHO densitometric definition uses the DXA T-score: normal ≥ −1.0, osteopenia −1.0 to −2.5, osteoporosis ≤ −2.5, and severe (established) osteoporosis ≤ −2.5 with a fragility fracture.

One in three women and one in five men over 50 will sustain an osteoporotic fracture. About 15% of women at age 80 have had a hip fracture, and hip fracture incidence rises exponentially with age.

Typical osteoporotic fractures are vertebral, hip, distal radius (Colles) and proximal humerus. Hip fracture carries the greatest burden of mortality and disability-adjusted life years.

Indian context: LASI wave-1 data show a very high burden of low bone mass; osteoporosis presents roughly a decade earlier than in the West, vitamin D deficiency exceeds 70%, and average dietary calcium intake is often under 400 mg/day against an ICMR-NIN requirement of 1000 mg/day.

Bone is continuously remodelled in bone multicellular units (BMUs) — osteoclasts resorb, osteoblasts form, and osteocytes couple the two processes. Osteoporosis results when resorption exceeds formation in each BMU.

Oestrogen normally increases osteoclast apoptosis, suppresses RANKL, and increases osteoprotegerin (OPG), the decoy receptor for RANKL. Menopausal hypo-oestrogenism prolongs the resorption phase and shortens the formation phase, giving rapid postmenopausal bone loss.

The RANK–RANKL–OPG axis is the final common pathway for osteoclast formation and survival — the target of denosumab.

The Wnt/β-catenin pathway drives osteoblastic bone formation. Sclerostin, secreted by osteocytes, blocks it at LRP5/6 — the target of romosozumab.

Age-related contributors: secondary hyperparathyroidism from vitamin D and calcium deficiency, decline of the GH/IGF-1 axis, sarcopenia and immobility (reduced mechanical loading), and inflammaging (IL-1, IL-6, TNF-α).

Trabecular bone (spine, femoral neck, distal radius) is lost earlier and faster; increasing cortical porosity dominates later hip fracture risk.

Non-modifiable: age, female sex, prior fragility fracture (strongest single predictor), parental hip fracture, early or surgical menopause, low BMI, Asian or Caucasian ethnicity.

Modifiable: smoking, alcohol above 3 units/day, immobility, low calcium and vitamin D, low protein intake, falls.

Secondary osteoporosis: glucocorticoids (commonest drug cause), rheumatoid arthritis, hyperthyroidism, primary hyperparathyroidism, hypogonadism, type 1 and type 2 diabetes, coeliac disease and IBD, aromatase inhibitors, androgen deprivation therapy, anorexia nervosa, transplantation, COPD, HIV, CKD-MBD, myeloma, anticonvulsants and long-term PPIs.

DXA of the lumbar spine and hip is the reference standard. Screen women ≥65 and men ≥70, and younger patients with risk factors. USPSTF 2024 reaffirmed screening of women ≥65 and younger postmenopausal women at increased risk.

FRAX integrates clinical risk factors with or without BMD to give the 10-year probability of a major osteoporotic fracture and of hip fracture. It can be modulated by TBS, glucocorticoid dose, falls history, type 2 diabetes and hip axis length. An India-specific FRAX model is available.

Vertebral fracture assessment (VFA) or lateral spine X-ray is indicated for height loss over 4 cm, new kyphosis, or unexplained back pain — two-thirds of vertebral fractures are clinically silent.

Baseline laboratory screen to exclude secondary causes: serum calcium (mg/dL), phosphate, alkaline phosphatase, creatinine (mg/dL), 25(OH)D (ng/mL), PTH, TSH, complete blood count, serum protein electrophoresis, testosterone (ng/dL) in men, coeliac serology and 24-hour urinary calcium.

Bone turnover markers — s-CTX (resorption) and P1NP (formation) — are used at 3–6 months to confirm adherence and response, not to make the diagnosis.

Universal measures for everyone: calcium 800–1000 mg/day (diet preferred), protein ≥1 g/kg/day, vitamin D 800– 1000 IU/day, daily weight-bearing and resistance exercise, balance training, smoking and alcohol reduction, falls prevention, and medication review using Beers/STOPP-START and STOPPFall.

Risk-stratified pathway (Kanis/ESCEO): low risk → reassurance, lifestyle, consider MHT or a SERM; high risk → oral or IV bisphosphonate, or denosumab; very high or imminent risk → anabolic agent first, followed by an antiresorptive.

Bisphosphonates: alendronate 70 mg weekly, risedronate 35 mg weekly (gastro-resistant formulation improves adherence), zoledronic acid 5 mg IV yearly. Zoledronate is first-line after hip fracture, reducing both re-fracture and mortality.

Denosumab 60 mg SC 6-monthly — anti-RANKL, safe in renal impairment, but must never be stopped abruptly: discontinuation causes rebound multiple vertebral fractures, so always follow with a bisphosphonate for 1–2 years.

Anabolic agents: teriparatide 20 mcg SC daily (up to 24 months), abaloparatide 80 mcg SC daily (18 months), romosozumab 210 mg SC monthly (12 months). All are self-limited and must be followed by an antiresorptive or the gains are lost.

Other options: raloxifene (reduces vertebral fracture and breast cancer risk, increases VTE and hot flushes), menopausal hormone therapy in early postmenopause, and local osteo-enhancement procedure (LOEP) in selected patients at high hip fracture risk. Calcitonin is now largely obsolete.

Drug holiday: consider after 5 years of oral or 3 years of IV bisphosphonate in low-risk patients, reviewing yearly; continue treatment in high-risk patients and after any incident fracture. No holiday is permissible with denosumab.

Fracture Liaison Services (FLS) and the IOF “Capture the Fracture” initiative systematically identify and treat every patient after a fragility fracture; orthogeriatric co-management improves hip fracture outcomes. The treatment gap remains large worldwide, especially in the very old.

Men account for about one-third of hip fractures worldwide and have higher post-fracture mortality (approaching 30% at one year) than women, yet are far less often investigated or treated.

Secondary causes are present in 40–60% of men — hypogonadism (including androgen deprivation therapy for prostate cancer), alcohol excess, glucocorticoids, smoking, hypercalciuria, myeloma, COPD, hyperthyroidism and malabsorption. A secondary work-up is mandatory in every man.

Use the same T-score threshold of ≤ −2.5 for diagnosis; ISCD recommends a male reference database for men.

Testosterone replacement (target 300–400 ng/dL in older men, lower than the young adult target) increases BMD in genuinely hypogonadal men but has no fracture-reduction data — it is not a substitute for a bisphosphonate. Prostate carcinoma is an absolute contraindication; monitor PSA and haematocrit.

Alendronate, risedronate, zoledronate, denosumab, teriparatide, abaloparatide and romosozumab are all approved for men.

In premenopausal women, use the Z-score, not the T-score. A Z-score ≤ −2.0 is reported as “below the expected range for age”. Diagnosis requires a fragility fracture or an identified secondary cause together with low bone mass.

Causes: anorexia nervosa and the female athlete triad, glucocorticoids, coeliac disease and IBD, hyperthyroidism, primary hyperparathyroidism, idiopathic hypercalciuria, pregnancy- and lactation-associated osteoporosis, and idiopathic disease.

Treat the underlying cause first — restore nutrition, weight and menses, correct calcium and vitamin D, and reduce glucocorticoid exposure. Reserve drugs for continuing fractures or ongoing bone loss.

Bisphosphonates cross the placenta and have a very long skeletal half-life — counsel about contraception. Teriparatide is preferred when a drug is needed in a woman who may become pregnant.