26th February 2025

Metabolic Bone Disease

Hypercalcaemia

Overview of hypercalcaemia

Calcium levels are predominantly maintained through: (a) parathyroid hormone’s (PTH) direct effect on bone and the kidneys and (b) activated vitamin D’s indirect effect on the gut.

The list of diagnoses underlying hypercalcaemia range from benign disorders that do not require monitoring to life-threatening illnesses that demand immediate treatment. These conditions can be grouped according to the method through which they raise calcium levels. The degree of derangement can be classified as mild (2.6-3.00 mmol/L), moderate (3.01-3.40 mmol/L), or severe (>3.40 mmol/L).

Table 1 Aetiologies of hypercalcaemia classified by cause. *Most common causes of hypercalcaemia

Increased PTH or PTHrP release

Primary hyperparathyroidism

Hypercalcaemia with an ‘inappropriately normal’ or raised PTH in a patient with normal renal function (i.e., tertiary hyperparathyroidism has been excluded) who does not take lithium points to a probable diagnosis of primary hyperparathyroidism (PHPT). Over 80% of cases are due to a solitary adenoma, with nodular hyperplasia and multiple adenomas forming most of the remainder. Parathyroid malignancy accounts for ≤1% of PHPT, usually with calcium and PTH levels far higher than typical PHPT. Gathering a family history is important as inherited conditions are implicated up to 10% with PHPT, with familial isolated hyperparathyroidism, multiple endocrine neoplasia (MEN), and hyperparathyroidism-jaw tumour syndrome (HPT-JT) the three most notable (all inherited in an autosomal dominant pattern).

Familial hypocalciuric hypercalcaemia

For a diagnosis of PHPT to be confirmed, familial hypocalciuric hypercalcaemia (FHH) must be excluded via urinary tests to rule out hypocalciuria (24-hour urinary calcium excretion, random renal calcium:creatinine excretion ratio, or random calcium:creatinine clearance ratio). In contrast to PHPT, however, FHH is almost always asymptomatic with little clinical significance and so is unlikely in symptomatic hypercalcaemia. This autosomal dominant condition occurs via an inactivating mutation in the calcium-sensing receptor (CaSR) gene, reducing receptor sensitivity to calcium. Higher than normal calcium levels are therefore required to suppress PTH secretion, and defective CaSR in renal tubules leads to increased reabsorption of calcium with subsequent hypocalciuria.

Hypercalcaemia of malignancy

Hypercalcaemia is seen in around 20% of cancer patients, with humoral hypercalcaemia of malignancy accounting for 80% of these. A history highly suspicious of cancer is often the primary concern when hypercalcaemia is incidentally noted. Given the limited physiological role of PTH-related protein (PTHrP), elevated PTHrP warrants urgent investigation for a causative malignancy. These are most often solid tumours, with lung primaries accounting for nearly 30% of cases. Negative feedback on PTH release results in a biochemical picture resembling PHPT except for a normal or low PTH rather than normal or raised.

Management of primary hyperparathyroidism

Referral to an endocrinologist is warranted in patients with PHPT if symptomatic, their serum calcium is ≥2.85 mmol/L, there is concurrent CKD stage ≥III, or they have developed renal stones or are at an increased risk of renal stones (e.g. obesity, gout, diabetes mellitus, Crohn’s disease, structural ureteric abnormalities).

Total or subtotal resection of the parathyroid glands is first-line in primary and tertiary hyperparathyroidism. If surgery is unsuccessful or not possible, calcimimetics such as cinacalcet can be used if serum calcium is >2.85 mmol/L with symptoms or >3.0 mmol/L regardless of symptoms, where it acts to increase CaSR sensitivity and, therefore, decrease PTH levels. Bisphosphonates are considered in moderate or severe hypercalcaemia refractory to IV fluids and in those with an increased risk of fractures.

Increased vitamin D

Vitamin D2 (ergocalciferol; mainly found in plants) or vitamin D3 (cholecalciferol; mainly found in fish & meat) are activated in a two-step process: hepatic hydroxylation creates 25(OH)D (calcifediol), with subsequent renal hydroxylation producing the active metabolite 1,25(OH)2D (calcitriol). Calcitriol increases serum calcium levels through actions on the small intestine and bones. Hypercalcaemia may, therefore, occur with prolonged and excessive ingestion of vitamin D supplements (hypervitaminosis D), granulomatous diseases, e.g. sarcoidosis, TB (as epithelioid histiocytes in granulomas display 1α-hydroxylase activity), or ectopic production of calcitriol in lymphoma. Steroids may be trialled where granulomas or malignancies producing 1α-hydroxylase are implicated.

Increased bone turnover

Osteoclastic bone resorption may be directly promoted by hyperthyroidism, malignancies, e.g. multiple myeloma or metastases to bone, and prolonged immobilisation (e.g. after spinal cord injuries). Osteoblastic bone formation is depressed with prolonged immobilisation, and accounts for the hypercalcaemia seen in immobilised patients with Paget’s disease of bone (whose high bone turnover state otherwise does not cause hypercalcaemia).

Image source: Wikimedia Commons (2020). Emmentalersign, Licensed under a Creative Commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Emmentalersign_.jpg (Accessed: 24 January 2024). 

Image source: BioMed Central Ltd (2009). Abdominal radiograph showing osteoblastic changes of spine, pelvic and femoral bones (arrows)., Licensed under a Creative Commons licence. Available for free at: https://casesjournal.biomedcentral.com/articles/10.1186/1757-1626-2-54/figures/2 (Accessed: 24 January 2024).

Decreased renal excretion of calcium

Thiazide diuretics enhance proximal tubular reabsorption of calcium, while glucocorticoid deficiency (as in adrenal insufficiency) also reduces renal excretion of calcium through an unclear mechanism.

Rare causes

Hypervitaminosis A (promotes osteoclastic bone resorption), aluminium intoxication (impairs osteoblastic bone formation), and milk-alkali syndrome (excessive ingestion of calcium-containing antacids or calcium supplements) are rarely seen in clinical practice, particularly as PPIs have replaced aluminium and calcium-containing antacids.

References

• National Institute for Health and Care Excellence. CKS: Hypercalcaemia [Internet]. NICE. 2019 [cited 2023 Feb 20. Available from: https://cks.nice.org.uk/topics/hypercalcaemia/
• Ayuk J, Gittoes N. Primary hyperparathyroidism [Internet]. BMJ Best Practice. 2021 [cited 2023 Feb 20. Available from: https://bestpractice.bmj.com/topics/en-gb/133
• National Institute for Health and Care Excellence. Hyperparathyroidism (primary): diagnosis, assessment and initial management [Internet]. NICE. 2019 [cited 2023 Feb 20. Available from: https://www.nice.org.uk/guidance/ng132
• Donovan PJ, Achong N, Griffin K, Galligan J, Pretorius CJ, McLeod DS. PTHRP-mediated hypercalcemia: causes and survival in 138 patients. J Clin Endocrinol Metab. 2015;100(5):2024–9
• Guise TA, Wysolmerski JJ. Cancer-associated hypercalcemia. N Engl J Med. 2022;386(15):1443–51

Osteoporosis

Defining osteoporosis

Osteoporosis is characterised by decreased bone mineral density (BMD) and micro-architectural tissue changes that increase bone fragility and, therefore, risk of fractures (particularly affecting the hip, spine and wrists). The WHO defines osteoporosis as a BMD (assessed via DXA, dual-energy x-ray absorptiometry, scan) ≥2.5 standard deviations below the mean for young, healthy adults of the same sex and ethnicity (i.e., a T-score of -2.5), with the pre-disease state of osteopenia defined as a T-score between 1 and 2.5 standard deviations below normal.

Where there is no clear cause, patients are diagnosed with idiopathic osteoporosis. Though the term idiopathic suggests an unidentified aetiology, the underlying pathogenesis relates to age-related changes ± polygenic variants. Where suspected, fracture risk should be assessed in anyone over 50 with a known risk factor, all women over 65 and men over 75. Risk factors include but are not limited to previous fragility fracture, advanced age, female sex, early menopause, low body weight (BMI <18.5 kg/m2), family history of osteoporosis, frequent or current use of systemic glucocorticoids, smoking, and excessive alcohol intake (≥14 units/week).

Secondary osteoporosis

Disease causes of secondary osteoporosis may be divided into those which impair bone formation and those which enhance bone resorption:

• Impaired formation: 
  • Reduced intake or malabsorption of micronutrients essential for bone development (e.g. anorexia nervosa, chronic malnutrition, gastric bypass surgery, coeliac disease, IBD, pancreatic insufficiency, chronic liver disease)
  • Deficiency of normal endocrine-mediated promotion of osteoblast activity (hypothyroidism, growth hormone deficiency, hypogonadism)
• Enhanced resorption:
  • Abnormal endocrine-mediated promotion of osteoclast activity (hyperthyroidism, primary hyperparathyroidism, diabetes mellitus, acromegaly)
  • Cytokine-mediated enhanced osteoclastogenesis in inflammatory disease states (IBD, MGUS, multiple myeloma, RA, SLE, ankylosing spondylitis, MS)
  • Renal osteodystrophy (see ‘CKD-MBD and other bone diseases’) and acid-mediated calcium removal from bone (end-stage renal disease, renal tubular acidosis)

Osteoporosis secondary to medication

For many of these diseases, the association with osteoporosis is partially explained by the frequent use of glucocorticoids, which constitute the most common cause of secondary osteoporosis through downregulation of both osteoblast numbers and activity. National guidelines, therefore, advise prescribing bone protection without assessing bone density in patients on long-term glucocorticoids if they have ever had a fragility fracture if they are female and over 70 years of age, or if they are a postmenopausal woman or man over 50 years who either has a FRAX score exceeding the intervention threshold or their glucocorticoid prescription is high-dose (the equivalent of ≥7.5mg prednisolone over 3 months).

Similarly, many instances of hypogonadism may be drug-induced, as seen in patients taking aromatase inhibitors (e.g. anastrozole, letrozole) for oestrogen-receptor positive breast cancer, GnRH agonists (e.g. goserelin, leuprorelin acetate) for prostate cancer or endometriosis, and medroxyprogesterone acetate (Depo-ProveraⓇ) as a contraceptive or as a treatment in certain cancers and gynaecological conditions.

Guidelines, therefore, suggest that men starting androgen-depriving therapies and women starting aromatase inhibitors receive a FRAX assessment. They additionally recommend that patients with a score near the intervention threshold or with additional risk factors (e.g. requiring glucocorticoids) undergo reassessment of their FRAX with BMD measurement 12-18 months (if male) or 12-24 months (if female) after initiation of treatment.

Other drug causes include PPIs, loop diuretics, SSRIs, antiepileptics (particularly enzyme-inducing drugs), heparin, thiazolidinediones, calcineurin inhibitors, and antiretrovirals.

Management of osteoporosis

National guidance suggests that treatment can be given without BMD measurement in:

• Those with a history of a fragility fracture
• Patients with a high risk of fragility fracture, as suggested by a 10-year probability of a major osteoporotic fracture above the upper assessment threshold (estimated via FRAX score)

However, baseline BMD measurements are useful for comparison against future measurements. Those with an intermediate FRAX score should undergo BMD measurement via DXA scanning, with treatment offered if their updated FRAX score is greater than an age-specific intervention threshold.

Bisphosphonates

In most cases, first-line treatment involves oral bisphosphonates alongside lifestyle measures such as a healthy diet with sufficient calcium and vitamin D intake (or supplementation as necessary), smoking cessation, moderation of alcohol use, and regular weight-bearing exercises. While oral alendronate and risedronate are generally preferred, IV zoledronate is first-line following a hip fracture or in patients with pre-existing oesophageal disorders. Patients who suffer upper gastrointestinal side effects should be first trialled on an alternative oral bisphosphonate.

Patients receiving intravenous bisphosphonates should be notified of the risk of a transient flu-like illness, which infrequently recurs after the first injection and requires symptom management only. Other notable side effects for all bisphosphonates, though rare, include osteonecrosis of the jaw and atypical femoral fractures. The latter are often bilateral and associated with prodromal pain up to a few months before the fracture(s). Management involves cessation of bisphosphonate therapy, restriction of weight-bearing movements and orthopaedic review.

Patients on oral bisphosphonates whose FRAX ± BMD at 5-year reassessment does not warrant intervention may be considered for a 1.5-3 year pause (‘bisphosphonate holiday’) in an effort to maintain the balance between potential side effects and treatment benefit (as bisphosphonates are retained in bone for a prolonged period following cessation). However, patients who are currently on high-dose glucocorticoids, have a previous hip fracture or ≥2 vertebral fractures, or are over 70 years of age should be counselled for 10 years of treatment; although reassessment at 5 years is advised, most should continue for a further 5 years. Specialist opinion may need to be sought when considering whether to continue treatment beyond 10 years. Similar guidance applies to those on intravenous bisphosphonates, though reassessment is advised at 3 years rather than 5, with a full treatment course consisting of 6 years rather than 10.

Reassessment before 5 or 3 years is advised if risk factors change or a fracture occurs. Consideration of alternative treatments (i.e. treatment failure) is required if fracture occurs and there is a fall in BMD, or if there are two or more fractures while on treatment.

Other antiresorptive agents

The RANK ligand inhibitor denosumab is one alternative, but cessation is associated with an increased likelihood of vertebral fractures. To minimise this risk, IV zoledronate is recommended 6 months after the last dose, with further treatment guided by monitoring of the bone biomarker CTX-1 (C-terminal telopeptide of type I collagen, cleaved by osteoclasts during bone resorption).

Calcitriol (activated vitamin D) reduces vertebral fracture risk in postmenopausal women with osteoporosis, but requires baseline, 1 month, 3 month and then 6 monthly measurement of renal function and serum calcium levels.

The last antiresorptive agents include HRT and the selective oestrogen receptor modulator raloxifene (which has partial anabolic properties too). One mechanism through which oestrogens prevent bone demineralisation is stimulation of calcitonin, which inhibits osteoclastic activity. HRT specifically should be considered in women aged ≤60 years with a low background risk for the most serious of HRT’s side effects (increased cancer and thromboembolic risk). It should be noted that raloxifene has not been shown to reduce non-vertebral fractures.

Anabolic agents

Though persistent hyperparathyroidism is associated with osteoporosis, intermittent exposure to PTH results in greater stimulation of osteoblasts than it does osteoclasts; this is in part mediated by PTH’s downregulation of sclerostin, which inhibits osteoblasts. Teriparatide (a form of PTH) and romosozumab (a sclerostin inhibitor), therefore, act as anabolic agents. They are first-line in postmenopausal women at very high fracture risk, with teriparatide first-line in men ≥50 years at very high fracture risk and are particularly beneficial in patients with vertebral fractures. Once the treatment course for teriparatide or romosozumab expires (24 or 12 months respectively), an antiresorptive agent should be initiated.

Strontium ranelate

In severe osteoporosis, where neither antiresorptive nor anabolic drugs are appropriate in a postmenopausal woman or a man, the dual-acting drug strontium ranelate can be considered if the risk of fracture outweighs the increased risk of cardiovascular and thromboembolic events associated with the drug.

References

• Christodoulou C, Cooper C. What is osteoporosis? Postgrad Med J. 2003;79(929):133–8
• Mirza F, Ernesto C. Secondary osteoporosis: pathophysiology and management. Eur J Endocrinol. 2015;173(3):R131-151
• National Osteoporosis Guideline Group. Clinical guideline for prevention and treatment of osteoporosis [Internet]. NOGG. 2021 [cited 2023 Feb 20. Available from: https://www.nogg.org.uk/sites/nogg/download/NOGG-Guideline-2021-g.pdf 
• National Institute for Health and Care Excellence. Osteoporosis [Internet]. NICE. 2017 [cited 2023 Feb 20. Available from: https://www.nice.org.uk/guidance/qs149
• Cremers S, Garnero P, Seibel MJ. Chapter 87 – biochemical markers of bone metabolism. In: Bilezikian JP, Raisz LG, Martin TJ, editors. Principles of bone biology (third edition). Academic Press; 2008. P. 1857-1881

Vitamin D deficiency, rickets and osteomalacia

Vitamin D deficiency

In UK populations, >80% of vitamin D is derived from exposure to sunlight, with the remainder acquired through dietary sources. Except in uncomplicated deficiency of doubtful clinical significance, measurement of renal function, calcium, phosphate, PTH, and ALP should be considered, particularly if complications of deficiency are suspected.

Risk factors for deficiency include poor sun exposure, darker complexion, pregnancy/breastfeeding, obesity, age over 65, malabsorption disorders, and severe hepatic or renal disease. Vitamin D deficiency is also associated with a range of other conditions, including diabetes, most cancers, and auto-inflammatory diseases, though this is unlikely causative in any significant way.

Those with risk factors are advised to take a 400 IU supplement of vitamin D2 or D3 daily, with all other adults advised to take supplements only in the autumn and winter. If found to be deficient, non-urgent cases (i.e. asymptomatic, no relevant comorbidities, no drug indications) can be treated with a maintenance regimen of 800-2,000 IU daily, whereas those requiring faster correction require a loading dose of 280,000-300,000 IU over 6-10 weeks before reducing to maintenance levels.

Caution is advised when prescribing in pregnant or breastfeeding patients, while patients with a high risk of hypercalcaemia or renal stones, gastrointestinal disorders resulting in vitamin D malabsorption, or end-stage liver or kidney disease (i.e. have impaired hydroxylation of vitamin D to its active metabolite) should not receive standard supplementation.

Rickets and osteomalacia

Severe vitamin D deficiency (through decreased sun exposure, poor diet or malabsorption) is the most common cause of rickets, seen in children before growth plate closure, and osteomalacia.

Rickets

Rickets is characterised by inappropriate expansion of the growth plate, preventing its replacement by osteoblasts.

Clinical features include developmental delay, hypotonia, bowing of the legs, end thickening of long bones, ‘rickety rosary’ (costochondral nodularity), craniotabes, and frontal/parietal bossing.

Osteomalacia

Osteomalacia is characterised by impaired mineralisation of bone matrix proteins, with hypocalcaemia and hypophosphataemia directly involved in the pathophysiology. Prolonged deficiencies in these minerals for any reason may, therefore, result in osteomalacia.

Clinical manifestations include fatigue, generalised aches and pains, bone pain and tenderness, proximal myopathy with waddling gait, and an increased risk of fractures. If not already present, significant hypocalcaemia can eventually develop, as osteoclasts are unable to further mobilise calcium from unmineralised bone. High bone turnover often results in a raised ALP.

Though definitive, bone biopsy is rarely performed, and instead, diagnosis most often relies on history, examination and biochemistry. Imaging may also be of use as plain film radiographs might show transverse lines of increased lucency (pseudofractures or Looser’s zones), and DXA may demonstrate low BMD. Alongside the increased risk of fracture, low BMD often means osteomalacia is mistaken for osteoporosis. However, in contrast to osteomalacia, the ratio of mineralised to unmineralised bone remains constant in osteoporosis.

Treatment consists of loading doses of vitamin D followed by daily maintenance therapy, with calcium supplementation as required.

Congenital causes of rickets/osteomalacia and similar conditions

If low sun exposure, poor diet or malabsorption are excluded, congenital causes of rickets and osteomalacia should be sought.

Vitamin D-resistant rickets

In addition to chronic renal failure, impaired 1α-hydroxylation of calcifediol occurs in vitamin D-resistant rickets type I, caused by an autosomal recessive loss-of-function mutation in the renal 25(OH)D 1α-hydroxylase. Calcifediol levels may be normal, while calcitriol (1,25(OH)2D) is low, so supplementation is with calcitriol instead of ergocalciferol/cholecalciferol. Inactivating mutations in the vitamin D receptor results in vitamin D-resistant rickets type II, another autosomal recessive disorder, though calcitriol levels may instead be raised alongside PTH. Very high doses of calcitriol are given alongside calcium and phosphate supplements (though not together to avoid GI calcium phosphate mineral precipitation).

Hypophosphataemic rickets and osteomalaica

The protein FGF23 acts similarly to PTH in down-regulating sodium/phosphate co-transporters in the proximal tubule to increase phosphate excretion in urine and can additionally reduce synthesis of calcitriol. Hypophosphataemic rickets increases FGF23 levels (through increased production or resistance to degradation) via autosomal dominant, autosomal recessive, and X-linked dominant mutations. Tumour-induced hypophosphataemic osteomalacia is seen in mesenchymal tumours with ectopic production of FGF23. In addition to vitamin D ± calcium, phosphate supplementation is required in these conditions.

Hypophosphatasia

Hypophosphatasia sees autosomal dominant or autosomal recessive mutations in the gene for ALP, resulting in reduced bone mineralisation and phosphate accumulation in bone. ALP levels are low or undetectable, while other biochemistry is normal. Though once fatal, asfotase alfa (a recombinant form of ALP) has transformed outcomes.

Other causes of osteomalacia

Other potential causes of osteomalacia include chronic acidosis (prevents calcium phosphate mineral formation), aluminium ingestion (e.g., through certain antacids, phosphate binders and dialysate fluids), and Fanconi syndrome.

References

• National Institute for Health and Care Excellence. CKS: Vitamin D deficiency in adults [Internet]. NICE. 2022 [cited 2023 Feb 20]. Available from: https://cks.nice.org.uk/topics/vitamin-d-deficiency-in-adults/
• Palacio C, Warda F. Rickets [Internet]. BMJ Best Practice. 2021 [cited 2023 Feb 20]. Available from: https://bestpractice.bmj.com/topics/en-gb/635
• Sabbagh Y, Carpenter TO, Demay MB. Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes. Proc Natl Acad Sci USA. 2005;102(27):9637–42
• Sinnott B. Osteomalacia [Internet]. BMJ Best Practice. 2021 [cited 2023 Feb 20]. Available from: https://bestpractice.bmj.com/topics/en-gb/517
• Merck, Sharp & Dohme. Differentiating osteoporosis and osteomalacia [Internet]. MSD Manual Professional Version. 2023 [cited 2023 Feb 20]. Available from: https://www.msdmanuals.com/en-gb/professional/multimedia/table/differentiating-osteoporosis-and-osteomalacia

Paget’s disease of bone and sclerotic bone diseases

Paget’s disease of bone

Paget’s disease of bone is characterised by disordered localised bone remodelling leading to osteosclerotic bone. The aetiology is unclear, though some predisposing genetic factors are known. Pagetic lesions are commonly seen in the skull, spine, pelvis, femurs and tibia, though any area can be affected.

Although most are asymptomatic, some may experience pain at disease foci (often sites of muscle insertion or previous fracture). Secondary osteoarthritis due to disrupted load distribution, hearing loss, bone deformity (e.g. frontal bossing, kyphosis, bowing of the legs), and pathological fractures are all common presentations in symptomatic patients. Rarer presentations include bone overgrowth leading to nerve impingement and increased bone vascularity leading to high-output heart failure. Of note, hearing loss is less commonly sensorineural secondary to CN VIII impingement, but rather, most cases are conductive due to temporal bone osteosclerosis. Osteosarcoma is one complication that should be suspected in any patient reporting an increase in pain or new swelling, though it occurs in fewer than 1% of patients.

As most patients are asymptomatic, diagnosis is most often incidental via an isolated raised ALP or an X-ray or CT requested for another purpose. Such imaging directly visualises pagetic lesions, characterised by a mix of osteosclerosis and radiolucency ± pathological fractures. ALP may be normal if disease is minimal, restricted to a single site, or inactive (particularly post-treatment). In these circumstances, or in concurrent hepatobiliary disease, bone-specific ALP may be useful. As with osteomalacia, bone biopsy is rarely required.

Unless due to a complication of the disease (e.g. osteoarthritis or pathological fracture), pain due to a pagetic lesion, nerve impingement and hearing loss following temporal bone involvement can be treated with limited courses of bisphosphonates. Bisphosphonates may also be used before orthopaedic surgery as lesions are highly vascular and may lead to excessive blood loss. Caution is required, however, as concurrent vitamin D deficiency is common in the elderly (i.e. those susceptible to Paget’s disease), in which case bisphosphonates may result in symptomatic hypocalcaemia. Where bisphosphonates are contraindicated, calcitonin may be considered.

Sclerosing bone dysplasia

Sclerosing bone dysplasia is a term used to refer to a variety of congenital disorders that range in severity from mild to fatal and in age of onset from childhood to late life, depending on the nature of the genetic abnormality. Cranial nerve palsies can occur in many of these conditions as bone overgrowth narrows cranial foramina, which may cause vision and hearing loss.

In osteopetrosis, general loss of osteoclast function results in a diffuse increase in bone mass, as demonstrated by a ‘marble bone’ appearance on X-ray. Poor remodelling in childhood forms of osteopetrosis result in bone marrow failure due to narrowed marrow cavity. If completed in early life, bone marrow transplantation can provide a cure as osteoclast progenitors are replaced.

Other sclerosing bone dysplasias may affect different parts of the skeleton in unequal ways. These include melorheostosis, which usually affects one limb only, and pyknodysostosis, a lysosomal storage disease affecting osteoclasts, which presents with blue sclera, rhizomelic dwarfism, and osteosclerosis.

Other causes of osteosclerosis

Sclerotic metastases may arise from a number of primaries, particularly of the prostate and breast. Myeloma, too, has an uncommon osteosclerosing subtype affecting bones in a focal or diffuse manner, while osteosclerosis in myelofibrosis, where present, sees changes restricted to medullary cavities. Though predominantly associated with diffuse osteopenia, cases of osteosclerosis in hyperparathyroid patients have been recorded. Sickle cell crises affecting bone also result in osteosclerosis. Hepatitis C-associated osteosclerosis has been reported in patients with prior infection, severe diffuse bone pain and high levels of ALP. Where exposure via poisoned water wells or industrial sources is a possibility, fluorosis should be considered in patients with soft tissue calcification, osteosclerosis and skeletal abnormalities, such as ankylosis, kyphosis and osteosclerosis.

References

• Shaker JL. Paget’s disease of Bone: A review of epidemiology, pathophysiology and management. Ther Adv Musculoskelet Dis. 2009;1(2):107–25
• Monsell EM. The mechanism of hearing loss in Paget’s disease of bone. Laryngoscope. 2004;114(4):598–606
• Civitelli R, Mohseni M. Paget’s disease of bone [Internet]. BMJ Best Practice. 2022 [cited 2023 Feb 20]. Available from: https://bestpractice.bmj.com/topics/en-gb/525
• Ihde LL, Forrester DM, Gottsegen CJ, Masih S, Patel DB, Vachon LA, et al. Sclerosing bone dysplasias: Review and differentiation from other causes of osteosclerosis. Radiographics. 2011;31(7):1865–82 
• Wu CC, Econs MJ, DiMeglio LA, Insogna KL, Levine MA, Orchard PJ, et al. Diagnosis and management of osteopetrosis: Consensus guidelines from the Osteopetrosis Working Group. J Clin Endocrinol Metab. 2017;102(9):3111–23
• Boulet C, Madani H, Lenchik L, Vanhoenacker F, Amalnath DS, de Mey J, et al. Sclerosing bone dysplasias: Genetic, clinical and radiology update of hereditary and non-hereditary disorders. Br J Radiol. 2016;89(1062):20150349
• Guañabens N, Mumm S, Gifre L, Ruiz‐Gaspà S, Demertzis JL, Stolina M, et al. Idiopathic acquired osteosclerosis in a middle‐aged woman with systemic lupus erythematosus. J Bone Miner Res. 2016;31(9):1774–82
• Kurdi MS. Chronic fluorosis: The disease and its anaesthetic implications. Indian J Anaesth. 2016;60(3):157

CKD-MBD and other bone diseases

Chronic kidney disease-mineral and bone disorder (CKD-MBD)

Impaired phosphate excretion and 1-hydroxylation of 25(OH)D (calcifediol) are the primary drivers of mineral bone disease in renal failure. Secondary hyperparathyroidism follows, with subsequent osteopenia, pseudogout, osteitis fibrosa cystica (high-turnover bone disease causing pain and deformity; also called a brown tumour), and calcinosis (soft tissue calcification). Plain film radiographs may demonstrate subperiosteal resorption of the terminal phalanges and soft tissue calcifications, while blood tests show hyperphosphataemia, hypocalcaemia and raised PTH. In addition, calcium phosphate deposition in blood vessels is in part responsible for the increased risk of cardiovascular disease seen in advanced CKD.

Hyperphosphataemia is treated by limiting foods high in phosphate, such as dairy products, egg and protein-rich foods, and prescribing phosphate binders such as sevelamer. Active vitamin D metabolites such as calcitriol are used to treat hypocalcaemia and hyperparathyroidism. Tertiary hyperparathyroidism may develop with subsequent hypercalcaemia, in which case parathyroidectomy or calcimimetics such as cinacalcet are used to reduce PTH.

Fibrous dysplasia

Fibrous dysplasia is characterised by cystic (radiolucent) bone lesions which expand to cause pain, deformity and fractures.

McCune-Albright syndrome refers to a polyostotic (involving multiple bones) form of the disease with significant female preponderance that is associated with certain extraskeletal features. These consist of café-au-lait macules and hyperfunctioning endocrinopathies, such as growth hormone excess, thyroid lesions/hyperthyroidism and gonadotropin-independent precocious puberty. Diagnosis is often obvious from the clinical history, examination, and imaging, which demonstrate characteristic lesions with increased radionuclide uptake on scintigraphy. However, those presenting with monostotic disease without extraskeletal manifestations (more common presenting form in adults) may require histological examination, as conditions causing similar lesions on imaging, including primary or secondary bone malignancies, must be excluded. Any patient complaining of a rapid increase in pain and swelling of an affected site should be investigated for potential malignant transformation, which is known to rarely occur.

Osteogenesis imperfecta

Genetic abnormalities affecting (mostly type I) collagen production result in this connective tissue disorder, characterised clinically by blue-grey sclera, restricted growth, and osteopenic/osteoporotic brittle bones, with subsequent deformity and fragility fractures. The heterogeneity of possible genetic defects allows for a spectrum of severities and, therefore, presentations. The most severe forms include multiple fractures in childhood, dental disease, valvular regurgitation, hearing loss, and lung disease secondary to kyphoscoliosis and chest wall deformities with recurrent pneumonias (the leading cause of death in osteogenesis imperfecta).

Hypertrophic osteoarthropathy

Thickened skin, excess periosteal bone formation in the extremities and digital clubbing may present in this syndrome that most often occurs secondary to certain lung diseases or as a paraneoplastic phenomenon. The possibility of malignancy as the underlying cause highlights the importance of not mistaking the condition for acromegaly or thyroid acropachy, which present similarly. Treatment of the underlying condition stabilises secondary forms of the disease, with partial or complete resolution sometimes seen.

The rare primary form is inherited in an autosomal dominant fashion and is termed pachydermoperiostosis. This is self-limiting, frequently stabilising approximately a decade after symptom onset.

Osteonecrosis

Osteonecrosis, also known as aseptic or avascular necrosis, is an important differential to consider in any patient presenting with chronic and progressive musculoskeletal pain. Commonly affected areas include the humeral head, femoral head, patella and talus, with approximately half of atraumatic cases bilateral. While the aetiology of atraumatic osteonecrosis is unclear, risk factors include high-dose glucocorticoid therapy, alcohol excess, coagulopathies, sickle cell anaemia, SLE and radiotherapy. Only in advanced disease does physical examination reveal restriction of movement due to pain. Similarly, radiographs are normal in early disease, making MRI the investigation of choice.

SAPHO syndrome

This rare, relapsing-remitting inflammatory disorder classically consists of synovitis, acne, pustulosis, hyperostosis and osteitis. However, presentation is variable, with non-infective osteitis or osteomyelitis as the only core feature. Over half of patients see characteristic anterior chest wall involvement (particularly affecting the sternoclavicular, sternocostal and costoclavicular areas), often seen on radionuclide imaging as ‘bull’s head sign’. The third of patients suffering axial skeletal disease are at risk of critical complications and thus require more aggressive treatment. While plain film or CT imaging will identify the affected areas, radionuclide bone scanning is helpful in differentiating SAPHO syndrome from similar conditions.

References

• Nikodimopoulou M, Liakos S. Secondary hyperparathyroidism and target organs in chronic kidney disease. Hippokratia. 2011;15(Suppl 1):33-38
• Martin KJ, González EA. Metabolic bone disease in chronic kidney disease. J Am Soc Nephrol. 2007;18(3):875–85
• Javaid MK, Boyce A, Appelman-Dijkstra N, Ong J, Defabianis P, Offiah A, et al. Best practice management guidelines for fibrous dysplasia/McCune-Albright Syndrome: A consensus statement from the FD/MAS International Consortium. Orphanet J Rare Dis. 2019;14(1)
• Marini JC, Forlino A, Bächinger HP, Bishop NJ, Byers PH, Paepe AD, et al. Osteogenesis imperfecta. Nat Rev Dis Primers. 2017;3(1)
• Yap FY, Skalski MR, Patel DB, Schein AJ, White EA, Tomasian A, et al. Hypertrophic osteoarthropathy: Clinical and imaging features. Radiographics. 2017;37(1):157–95
• Liu S, Tang M, Cao Y, Li C. Synovitis, acne, pustulosis, hyperostosis, and Osteitis Syndrome: Review and Update. Ther Adv Musculoskelet Dis. 2020;12