27th February 2025

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