Hypertrophic Osteoarthropathy Treatment & Management

Updated: Jan 08, 2018
  • Author: Richa Dhawan, MD, CCD; Chief Editor: Herbert S Diamond, MD  more...
  • Print

Medical Care


So far, no medical treatment has been suggested to alleviate pachydermoperiostosis (PDP). Botulinum toxin A (BTX-A) administration is a simple procedure that may be of value in providing temporary cosmetic improvement.

Medical care of PDP is palliative and includes nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, tamoxifen citrate, retinoids, and risedronate sodium to alleviate the painful polyarthritis/osteoarthropathy. [6] Colchicine may be helpful for the pain due to subperiosteal new bone formation. Colchicine inhibits neutrophil chemotaxis and tissue edema; thereby improving joint symptoms, pachyderma, and folliculitis. Steroids and bisphosphonate work by inhibition of osteoclasts and antiresorptive effects have been tried with promising results for rheumatological symptoms of hypertrophic osteoarthropathy. Retinoids, by decreasing procollagen mRNA in fibroblasts, have shown improvements in pachyderma, seborrhea, acne, folliculitis, and cutis vertices gyrate.

Isolated reports suggest that pamidronate (30–60 mg intravenous) and octreotide may help in relieving bone pain in some cases.

For correction of gross disfigurement, plastic and reconstructive surgery may be indicated. Otherwise, reassurance is all that is required. Prognosis for life is excellent but the effect on function depends on the degree of bone and joint involvement. [11]

Secondary hypertrophic osteoarthropathy

Hypertrophic osteoarthropathy represents a dilemma in medicine in which diagnosis is relatively simple whereas management is exceedingly difficult due to obscure pathogenesis mechanism, varied treatment modalities, and individualized treatment responses. The management and prognosis of hypertrophic osteoarthropathy depend on the underlying disease and, past studies have shown that hypertrophic osteoarthropathy most commonly improves with treatment of the primary tumor. To date several treatment modalities have been suggested, with various degrees of success. [6]

Treatments for hypertrophic osteoarthropathy is classified into 2 categories: (1) treatment of primary cause (eg, resection of tumor, surgery for cardiac anomalies, chemotherapy, radiotherapy, treatment of infection) and (2) symptomatic treatments (eg, bisphosphonates, octreotide, NSAIDs, vagotomy).

Primary treatment is the most widely reported modality to be efficacious. Although removal of the primary tumor usually resolves this syndrome, effective treatment in patients with advanced lung cancer has not been established. Treatment of Pneumocystis pneumonia, pulmonary pseudotumor, and pulmonary tuberculosis have been reported to result in resolution of associated hypertrophic osteoarthropathy, as has corticosteroid treatment of inflammatory interstitial lung disease with associated hypertrophic osteoarthropathy. [99] In cases in which primary therapy is not possible, several symptomatic treatment modalities are suggested, with various degree of success. [6]

NSAIDs may be helpful for the painful osteoarthropathy in controlling the symptoms. In 2006, a case study published by Kozak et al raised the possibility that cyclo-oxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) could have a role in hypertrophic osteoarthropathy pathogenesis. COX-2 is an enzyme that is involved in the formation of prostaglandins, which are critical mediators of many physiologic and pathologic processes. He described a case of hypertrophic osteoarthropathy in a 65-year-old woman with recurrent non-small cell lung cancer and adrenal metastasis who had clinical improvement with rofecoxib (a COX-2 inhibitor). Finally, the measured levels of urinary prostaglandin E (PGE) in these patients correlated with their pain level. [6]

Aside from rofecoxib, other NSAIDs including ketorolac and indomethacin have also been reported in various case series to be effective at relieving hypertrophic osteoarthropathy pain symptoms. In humans, PGE has been found to induce periostitis and overt hypertrophic osteoarthropathy symptoms. Letts et al reported 5 cases of infants developing limp pain and swelling in association with periostitis after chronic infusion of PGE for congenital duct-dependent heart disease. In these cases, periostitis gradually improved once PGE was discontinued. Although involvement of PGE in the pathogenesis of hypertrophic osteoarthropathy is still unclear, successful use of NSAIDs to relieve hypertrophic osteoarthropathy pain symptoms warrants further investigation. [6]

In 2016, a systematic review of the effectiveness and safety of anti-inflammatory and analgesic agents for the symptomatic management of cystic fibrosis–related hypertrophic osteoarthritis in adults and children found no randomized controlled trials to evaluate these agents. Thus, no conclusions could be reached and clinicians were advised to balance potential benefit against the possible risk of complications in each case. [100]  However, a 2017 systematic review of NSAIDs for treatment of primary hypertrophic osteoarthropathy concluded that these drugs are effective in improving arthralgia or arthritis symptoms in the majority of these patients, and recommended NSAID use for this indication. [101]

Given the evidence supporting a role of vascular endothelial growth factor (VEGF) in hypertrophic osteoarthropathy and the pathogenesis theory of pulmonary shunting of vascular growth factors, a logical proposed treatment involves the use of VEGF inhibitors. According to Atkinson et al, VEGF may partly mediate clubbing by providing a persistent positive autocrine and paracrine loop to drive cellular and stromal changes including angiogenesis resulting in increased microvessel density, new bone formation, and edema.

Furthermore, both VEGF plasma levels and tissue expression have been reported in almost all of the medical diseases associated with hypertrophic osteoarthritis and has been found to be correlated with disease activity. This discovery supports the use of agents with VEGF inhibition in the treatment of hypertrophic osteoarthritis. Clinical trials have shown that a specific anti-VEGF antibody, bevacizumab, combined with standard first-line chemotherapy provide a statistically and clinically significant survival advantage and anti-tumor efficacy in non–small cell lung cancer (NSCLC).

Thus, bevacizumab may be investigated for use in alleviating pain symptoms in patients with NSCLC and secondary hypertrophic osteoarthropathy. As anti-VEGF monoclonal antibodies (eg, bevacizumab) and VEGF pathway inhibitors (several drugs in are different phases of clinical trials) become more frequently used in the clinical practice of various cancers, more knowledge about the pathogenesis of hypertrophic osteoarthropathy may be revealed in the near future. [102, 103]

Another promising treatment outcome for hypertrophic osteoarthropathy has been reported with octreotide. The first case report was in 1997 when Johnson et al treated a patient with hypertrophic osteoarthropathy secondary to squamous cell carcinoma with 200 μg of subcutaneous octreotide daily resulting in complete relief of pain. Perhaps, the success of this treatment is due to the similarities of hypertrophic osteoarthropathy to acromegaly. Octreotide as a somatostatin analog has a well-established role in controlling the growth and secretions from pituitary adenomas, particularly in acromegaly and neuroendocrine tumors. Of note, octreotide also has a nonopioid analgesic effect by intrathecal infusion, which has been reported in an uncontrolled series of 6 patients and further supported by growing evidence on inhibitory effects of octreotide on nociceptive neurons.

Angel-Moreno Maroto et al also reported complete pain relief with octreotide in a young patient with hypertrophic osteoarthropathy symptoms after having a bypass procedure to treat Fallot tetralogy with pulmonary artery atresia. The pain-relieving efficacy of octreotide for hypertrophic osteoarthropathy may also be due to its inhibitory effect on the production of VEGF and endothelial proliferation. [104, 6]

Bisphosphonates such as zoledronic acid and pamidronate are also effective for pain relief in hypertrophic osteoarthropathy. [105, 106] Generally, these nitrogen-containing bisphosphonates promote osteoclast apoptosis by inhibiting the activity of farnesyl pyrophosphate synthase. Their mechanisms also involve inhibiting osteocyte apoptosis and targeting monocytes/macrophages. In addition, bisphosphonates may also have antitumor, anti-inflammatory, anti-angiogenic effects and reduce VEGF in patients with metastatic solid tumors. [81]

In 1997, Speden et al reported 3 cases of hypertrophic osteoarthropathy in bronchogenic carcinoma that responded to the use of pamidronate with pain reduction in all 3 cases along with reduced radiolabel uptake in 2 of those cases. The beneficial effect of pamidronate in alleviating hypertrophic osteoarthropathy symptoms was replicated in 2 additional case reports of hypertrophic osteoarthropathy in metastatic breast carcinoma and in hypertrophic osteoarthropathy complicating cystic fibrosis. [6] In 2004, Amital et al also described a case of hypertrophic osteoarthropathy in a 50 year-old woman with cyanotic congenital heart disease, who responded to a single intravenous infusion of pamidronate 60 mg, leading to resolution of her limb pain.

Bisphosphonates, notably pamidronate, have been used to treat hypertrophic osteoarthropathy associated pain. However, the data on zoledronic acid (ZA), a more potent bisphosphonate with demonstrated 40-fold to 850-fold greater potency than pamidronate, in managing hypertrophic osteoarthropathy–associated pain is scarce. [81] In 2008, King et al reported a case of hypertrophic osteoarthropathy–related limb pain that resulted from bronchogenic carcinoma and completely resolved following a single intravenous infusion of ZA (4 mg over 15 min). In 2012 Sonthalia et al reported painful hypertrophic osteoarthropathy associated with pulmonary metastasis secondary to nasopharyngeal carcinoma treated with 4 mg of ZA, which resulted in complete resolution of the pain and significant reduction in the swelling. [107]

Thompson and coworkers reported another case of hypertrophic osteoarthropathy associated with metastatic melanoma and the hypertrophic osteoarthropathy–associated pain was largely controlled by ZA and concomitant chemotherapy. Approximately 14 cases of hypertrophic osteoarthropathy were treated with bisphosphonates in the medical literature, with a case series containing 3 cases. Among the 14 patients, 10 were successfully treated with pamidronate, 3 with ZA, and 1 with risedronate. [108, 107]

Based on the above, ZA may be even more efficacious and longer lasting than pamidronate for management of the bone and joint pain associated with hypertrophic osteoarthropathy, irrespective of the underlying disorders. [81] The authors supported the theory that VEGF may play a role in the development of hypertrophic osteoarthropathy and noted that although the inhibitory effects of bisphosphonates on bone metabolism may be responsible for its benefits in hypertrophic osteoarthropathy, both pamidronate and ZAs have been shown to decrease levels of plasma VEGF in patients with cancer. Current use of bisphosphonates to treat hypertrophic osteoarthropathy–associated musculoskeletal pain is off-label rather than approved by the US Food and Drug Administration. [81]

An orally active selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (gefitinib) provided clinical antitumor activity in a case report in Tokyo [109] to induce disappearance of periostitis in a case of hypertrophic osteoarthropathy with advanced lung adenocarcinoma. [6]

Reduction of the serum estrogen level or tissue sensitivity to circulating sex steroids might become a therapeutic strategy for hypertrophic osteoarthropathy. Tamoxifen has been reported to improve arthralgia, sweating of hands, and gynecomastia.

TNF-alpha is an inflammatory cytokine found in high levels in hypertrophic osteoarthropathy and it is involved on the production of other inflammatory mediators, which increases osteoclastogenesis (increasing RANKL expression). Infliximab is a monoclonal antibody that binds to TNF preventing its biologic action. A case report has been defined showing improvement of hypertrophic osteoarthropathy symptoms with infliximab. The good response to the TNF-blocking agent in hypertrophic osteoarthropathy suggests that TNF-alpha can be involved in the pathogenesis of periostitis and arthritis in this condition. [45]

Reports described symptomatic relief following vagotomy, but this is not currently used. Along the same line, another neurogenic therapy for hypertrophic osteoarthropathy was proposed in 1976 by Readon et al. They reported fall in the thermographic index along with subjective improvement on combined adrenergic blockade with propranolol and phenoxybenzamine. [6]


Surgical Care

Hypertrophic osteoarthropathy improves and in many cases resolves with resection and/or treatment of the primary tumor. As early as 1976, Atkinson et al reported that chemotherapy treatment of primary malignancy, Hodgkin lymphoma, also leads to complete resolution of hypertrophic osteoarthropathy symptoms. By 1991 and 1992, 2 reported cases of resolved hypertrophic osteoarthropathy following surgical resection of lung tumor were noted. Similarly in 2009, Poanta et al reported complete resolution of hypertrophic osteoarthropathy symptoms following pneumonectomy for primary spinocellular lung cancer. Other treatment modalities of primary causes leading to alleviation of hypertrophic osteoarthropathy symptoms include cytoreduction of tumor by radiofrequency ablation, antibiotics treating recurrent infections in cystic fibrosis, and lung transplantation for cystic fibrosis. [6]

In most lung cancer patients, digital clubbing resolves after effective surgical treatment of the tumor, as can occur in patients with other conditions. [102] Joint and bone pains also resolve quickly after tumor resection, which confirms its paraneoplastic nature. [110]

Outside of primary pulmonary processes, treatment of primary liver condition, heart disease, and esophageal tumors have also been reported to alleviate symptoms of hypertrophic osteoarthropathy. In 1987, Huaux et al reported the first case of liver graft alleviating symptoms of hypertrophic osteoarthropathy associated with end-stage cholestatic cirrhosis related to non-Wilsonian copper overload. Since then, full liver transplantation has also led to resolution of hepatic hypertrophic osteoarthropathy. [6]

Correction of cyanotic heart malformation has also been found to be effective in relieving hypertrophic osteoarthropathy symptoms. In 1982, Frand et al reported two cases of hypertrophic osteoarthropathy–associated cyanotic heart disease corrected by surgery leading to complete resolution of hypertrophic osteoarthropathy symptoms both clinically and radiologically.

Finally, multiple case reports describe patients with hypertrophic osteoarthropathy secondary to esophageal leiomyoma or esophageal squamous cell carcinoma whose hypertrophic osteoarthropathy symptoms resolved with total esophagectomy. Pallecaros et al also reported that total esophagogastrectomy of a patient with crippling hypertrophic osteoarthropathy secondary to an inflammatory fibroid polyp led to resolution of pain. However, the author noted that vagotomy unavoidable during esophagogastrectomy, may have led to the resolution of the patient's hypertrophic osteoarthropathy.

In patients with secondary hypertrophic osteoarthropathy, tumor resection results in spontaneous improvement within 2-4 weeks. In fact, hypertrophic osteoarthropathy may disappear completely by 3-6 months. [43] Thus, in cases where the primary cause can be treated, symptoms of hypertrophic osteoarthropathy most likely improves or resolves. The challenge lies in symptomatic treatment of hypertrophic osteoarthropathy when the primary cause cannot be eliminated. [6]

In patients with primary hypertrophic osteoarthropathy, plastic surgery may be necessary to remove excess facial skin. The treatment of pachydermia is usually centered on improving the cosmetic appearance through plastic surgery. Surgical management of pachydermia includes bilateral blepharoplasties, tarsal wedge resections, excision of skin furrows, and facial rhytidectomy and scalp-reduction techniques. [60] More recently, forehead lifting and direct excision of the dermal folds have been described. A reported case described an approach using endotines in combination with mask subperiosteal and lateral SMASectomy facelifts.

Patients with the rare condition of PDP with secondary ptosis and floppy eyelid was successfully treated with a combination of levator advancement and an upper eyelid tarsal strip. [70]

In the 1950s, thoracic surgeon Dr. Geoffrey Flavell discovered that unilateral vagotomy on the side of the lung cancer lead to symptomatic relief of hypertrophic osteoarthropathy symptoms in some severe cases. Flavell observed that patients with failed dissection, inoperable tumor, or disseminated disease had complete resolution of pain with dissection of the vagus nerve.

In 1962 and 1964, Dr. Magdi Yacoub further justified Dr. Flavell’s hypothesis by performing vagotomy on 2 patients with severe hypertrophic osteoarthropathy, effectively relieving their pain symptoms. It should be noted that these patients had both physical and radiological regression of symptoms, negating the placebo effect. Despite varying success with vagotomy, the vagal mechanism has largely been deemed implausible given that it does not fit with physiological mechanisms accepted in current practices.

However, Ooi et al revived the old vagus nerve hypothesis in their report of a 50-year-old woman with disabling hypertrophic osteoarthropathy and inoperable lung cancer who experienced effective pain relief after video-assisted thoracoscopic truncal vagotomy. [6] Vagotomy improved the associated articular pain and swelling. Surgical correction of digital clubbing has also been reported.